Sexual Health

Vaginal estradiol tablets promoted significant changes in the vaginal microbiota in postmenopausal women compared with vaginal moisturizer or placebo, but reduction in bothersome symptoms were similar, based on data from 144 individuals.

“In the Menopause Strategies–Finding Lasting Answers and Health (MsFLASH) trial network’s Vaginal Health Trial of treatment for moderate to severe vaginal symptoms of menopause, there were no significant differences in reduction of vaginal symptoms among women using the estradiol vaginal tablet or vaginal moisturizer compared to women using the placebo regimen; all three groups had a reduction in vaginal symptoms,” lead author Sujatha Srinivasan, PhD, of the Fred Hutchinson Cancer Center, Seattle, said in an interview.

“However, the impact of these treatments on the vaginal microenvironment are poorly understood,” she said.

In a study published in JAMA Network Open, Dr. Srinivasan and colleagues conducted a secondary analysis to examine the effects of estradiol or a low-pH vaginal moisturizer on the vaginal microbiota, metabolome, and pH after 12 weeks of treatment vs. a low-pH placebo.

“Changes, or lack thereof, in the vaginal microenvironment might have implications beyond symptoms, and might be linked to risk for cervical cancer, genital infections, or other outcomes, though our study did not evaluate those associations,” Dr. Srinivasan said in an interview. Dr. Srinivasan’s comments were corroborated by coauthor Caroline M. Mitchell, MD, of Massachusetts General Hospital, Boston.

The study population included postmenopausal women with moderate to severe genitourinary symptoms who were enrolled in a randomized, controlled trial between April 2016 and February 2017. The average age of the women was 61 years, and 90% were White. The women were randomized to 10 mcg vaginal estradiol plus placebo gel, placebo tablet plus vaginal moisturizer, or a dual placebo.

The primary outcome in the original study was a change in the reported most bothersome symptoms (MBS) selected by the participants at the time of study enrollment; these included pain with penetration, vaginal dryness, and vulvovaginal irritation, itching, and pain. The main outcomes in the secondary analysis were changes in the diversity and composition of the vaginal microbiota, changes in the metabolome, and pH. Microbiota diversity was calculated via the Shannon Diversity Index (SDI).

After 12 weeks, the bacterial microbiota were dominated by Lactobacillus and Bifidobacterium in 80% of the estradiol group, 36% of the moisturizer group, and 26% of the placebo group (P < .001).

In addition, diversity analysis showed significant changes in bacterial composition in women in the estradiol group compared with the placebo group, but no significant differences between the moisturizer and placebo groups.

The composition of vaginal fluid small molecule metabolites changed significantly in 90 of 171 metabolites measured in the estradiol group from baseline to 12 weeks. Changes in the moisturizer and placebo groups were not significant.

Vaginal pH among women in the estradiol group was significantly lower than placebo at 12 weeks, with a median of 5 vs. 6 (P = .005). No significant difference in pH occurred for women in the moisturizer group. “However, pH significantly decreased over 12 weeks within each treatment group, reflecting the low-pH formulations of both the moisturizer and the placebo,” the researchers wrote.

Overall, women with high-diversity bacterial communities at baseline showed a greater median change in pH compared with women with low-diversity communities (median change of −1 vs. −0.3, P = .007).

Improvement in MBS symptoms by at least 2 points occurred in 53% of the estradiol group, 44% of the moisturizer group, and 49% of the placebo group. The similarity in severe symptom improvement among the groups confirms the lack of a causal association between microbiota and postmenopausal vaginal symptom severity, the researchers wrote.

“This study demonstrated that a decrease in vaginal pH alone was insufficient to change the vaginal microbiota,” Dr. Srinivasan said. “While the changes with estrogen were somewhat expected, the observation that low-pH vaginal products don’t change the vaginal microbiota is contrary to some expectations, and suggests that “low-pH” products may not be as helpful as their marketing claims,” she added. “A vaginal microbiota with an abundance of lactobacilli, a vaginal microenvironment with high concentrations of lactate, and a low vaginal pH is associated with health in premenopausal women. We also know that such a microenvironment is typically associated with low inflammation,” said Dr. Srinivasan. “At this time, we don’t have specific information as to how this is beneficial to postmenopausal women,” she noted. However, “If we extrapolate from the data on premenopausal women, the data from this secondary analysis suggests that vaginal estradiol may have positive impacts on the vaginal microenvironment regardless of impact on symptoms,” she said.

“Future areas of investigation should focus on understanding potential benefits of a Lactobacillus-dominant microbiota in postmenopausal women,” Dr. Srinivasan said.

The study findings were limited by several factors including the relatively small number of participants, and collection of data samples at only three time periods, as well as the lack of data on whether the observed changes are durable over longer treatment times, the researchers noted.

“The need to increase participant diversity in studies of postmenopausal women is highlighted by our finding that the 6 Black women in our analysis were all categorized in the low-diversity subgroup; data from premenopausal women suggest that Black women have diverse bacterial communities,” they added.

However, the results suggest that “a significant decrease in pH over the course of a trial may not reflect the same underlying biological processes among different interventions, and thus, lowering pH should not be a primary goal,” they concluded.
 

Estradiol may have limited clinical impact

“For postmenopausal women with dyspareunia, vaginal dryness, and/or burning/itching/irritation, the question of appropriate treatment is common,” Constance Bohon, MD, a gynecologist in private practice in Washington, said in an interview. “It is helpful to have a study that focuses on the benefit of a moisturizer as compared with vaginal estrogen for these women,” she said.

Dr. Bohon said she was not surprised with the benefits of the moisturizer for dyspareunia and vaginal dryness. “What did surprise me was that the complaint of vaginal itch, burn, or irritation was not significantly improved in the vaginal estrogen group compared with the moisturizer group. I assumed that estrogen would have been more beneficial in this group because these symptoms are more likely to be caused by a vaginal infection that would not be improved with moisturizer alone,” she said. “I expected that the change in the vaginal flora to increase Lactobacillus would have had a greater impact on an infection than the moisturizer, which did not significantly change the flora.”

For clinicians, the take-home message is that, for these patients, use of a moisturizer may be sufficient, Dr. Bohon said.

“Additional research should be done to assess each issue,” she noted. “For example, in the women who have pain with sex, what is the frequency of intercourse?” she asked. Other research should address the questions of whether women who have intercourse at least once a week have less dyspareunia than those who have less frequent sex, and whether a lubricant decreases dyspareunia as well as a moisturizer or vaginal estrogen, she added.

The study was supported by the National Institutes of Health. Dr. Srinivasan disclosed personal fees from Lupin unrelated to the current study. Dr. Bohon had no financial conflicts to disclose and serves on the editorial advisory board of Ob.Gyn. News.

Vaginal estradiol tablets promoted significant changes in the vaginal microbiota in postmenopausal women compared with vaginal moisturizer or placebo, but reduction in bothersome symptoms were similar, based on data from 144 individuals.

“In the Menopause Strategies–Finding Lasting Answers and Health (MsFLASH) trial network’s Vaginal Health Trial of treatment for moderate to severe vaginal symptoms of menopause, there were no significant differences in reduction of vaginal symptoms among women using the estradiol vaginal tablet or vaginal moisturizer compared to women using the placebo regimen; all three groups had a reduction in vaginal symptoms,” lead author Sujatha Srinivasan, PhD, of the Fred Hutchinson Cancer Center, Seattle, said in an interview.

“However, the impact of these treatments on the vaginal microenvironment are poorly understood,” she said.

In a study published in JAMA Network Open, Dr. Srinivasan and colleagues conducted a secondary analysis to examine the effects of estradiol or a low-pH vaginal moisturizer on the vaginal microbiota, metabolome, and pH after 12 weeks of treatment vs. a low-pH placebo.

“Changes, or lack thereof, in the vaginal microenvironment might have implications beyond symptoms, and might be linked to risk for cervical cancer, genital infections, or other outcomes, though our study did not evaluate those associations,” Dr. Srinivasan said in an interview. Dr. Srinivasan’s comments were corroborated by coauthor Caroline M. Mitchell, MD, of Massachusetts General Hospital, Boston.

The study population included postmenopausal women with moderate to severe genitourinary symptoms who were enrolled in a randomized, controlled trial between April 2016 and February 2017. The average age of the women was 61 years, and 90% were White. The women were randomized to 10 mcg vaginal estradiol plus placebo gel, placebo tablet plus vaginal moisturizer, or a dual placebo.

The primary outcome in the original study was a change in the reported most bothersome symptoms (MBS) selected by the participants at the time of study enrollment; these included pain with penetration, vaginal dryness, and vulvovaginal irritation, itching, and pain. The main outcomes in the secondary analysis were changes in the diversity and composition of the vaginal microbiota, changes in the metabolome, and pH. Microbiota diversity was calculated via the Shannon Diversity Index (SDI).

After 12 weeks, the bacterial microbiota were dominated by Lactobacillus and Bifidobacterium in 80% of the estradiol group, 36% of the moisturizer group, and 26% of the placebo group (P < .001).

In addition, diversity analysis showed significant changes in bacterial composition in women in the estradiol group compared with the placebo group, but no significant differences between the moisturizer and placebo groups.

The composition of vaginal fluid small molecule metabolites changed significantly in 90 of 171 metabolites measured in the estradiol group from baseline to 12 weeks. Changes in the moisturizer and placebo groups were not significant.

Vaginal pH among women in the estradiol group was significantly lower than placebo at 12 weeks, with a median of 5 vs. 6 (P = .005). No significant difference in pH occurred for women in the moisturizer group. “However, pH significantly decreased over 12 weeks within each treatment group, reflecting the low-pH formulations of both the moisturizer and the placebo,” the researchers wrote.

Overall, women with high-diversity bacterial communities at baseline showed a greater median change in pH compared with women with low-diversity communities (median change of −1 vs. −0.3, P = .007).

Improvement in MBS symptoms by at least 2 points occurred in 53% of the estradiol group, 44% of the moisturizer group, and 49% of the placebo group. The similarity in severe symptom improvement among the groups confirms the lack of a causal association between microbiota and postmenopausal vaginal symptom severity, the researchers wrote.

“This study demonstrated that a decrease in vaginal pH alone was insufficient to change the vaginal microbiota,” Dr. Srinivasan said. “While the changes with estrogen were somewhat expected, the observation that low-pH vaginal products don’t change the vaginal microbiota is contrary to some expectations, and suggests that “low-pH” products may not be as helpful as their marketing claims,” she added. “A vaginal microbiota with an abundance of lactobacilli, a vaginal microenvironment with high concentrations of lactate, and a low vaginal pH is associated with health in premenopausal women. We also know that such a microenvironment is typically associated with low inflammation,” said Dr. Srinivasan. “At this time, we don’t have specific information as to how this is beneficial to postmenopausal women,” she noted. However, “If we extrapolate from the data on premenopausal women, the data from this secondary analysis suggests that vaginal estradiol may have positive impacts on the vaginal microenvironment regardless of impact on symptoms,” she said.

“Future areas of investigation should focus on understanding potential benefits of a Lactobacillus-dominant microbiota in postmenopausal women,” Dr. Srinivasan said.

The study findings were limited by several factors including the relatively small number of participants, and collection of data samples at only three time periods, as well as the lack of data on whether the observed changes are durable over longer treatment times, the researchers noted.

“The need to increase participant diversity in studies of postmenopausal women is highlighted by our finding that the 6 Black women in our analysis were all categorized in the low-diversity subgroup; data from premenopausal women suggest that Black women have diverse bacterial communities,” they added.

However, the results suggest that “a significant decrease in pH over the course of a trial may not reflect the same underlying biological processes among different interventions, and thus, lowering pH should not be a primary goal,” they concluded.
 

Estradiol may have limited clinical impact

“For postmenopausal women with dyspareunia, vaginal dryness, and/or burning/itching/irritation, the question of appropriate treatment is common,” Constance Bohon, MD, a gynecologist in private practice in Washington, said in an interview. “It is helpful to have a study that focuses on the benefit of a moisturizer as compared with vaginal estrogen for these women,” she said.

Dr. Bohon said she was not surprised with the benefits of the moisturizer for dyspareunia and vaginal dryness. “What did surprise me was that the complaint of vaginal itch, burn, or irritation was not significantly improved in the vaginal estrogen group compared with the moisturizer group. I assumed that estrogen would have been more beneficial in this group because these symptoms are more likely to be caused by a vaginal infection that would not be improved with moisturizer alone,” she said. “I expected that the change in the vaginal flora to increase Lactobacillus would have had a greater impact on an infection than the moisturizer, which did not significantly change the flora.”

For clinicians, the take-home message is that, for these patients, use of a moisturizer may be sufficient, Dr. Bohon said.

“Additional research should be done to assess each issue,” she noted. “For example, in the women who have pain with sex, what is the frequency of intercourse?” she asked. Other research should address the questions of whether women who have intercourse at least once a week have less dyspareunia than those who have less frequent sex, and whether a lubricant decreases dyspareunia as well as a moisturizer or vaginal estrogen, she added.

The study was supported by the National Institutes of Health. Dr. Srinivasan disclosed personal fees from Lupin unrelated to the current study. Dr. Bohon had no financial conflicts to disclose and serves on the editorial advisory board of Ob.Gyn. News.

Vaginal estradiol tablets promoted significant changes in the vaginal microbiota in postmenopausal women compared with vaginal moisturizer or placebo, but reduction in bothersome symptoms were similar, based on data from 144 individuals.

“In the Menopause Strategies–Finding Lasting Answers and Health (MsFLASH) trial network’s Vaginal Health Trial of treatment for moderate to severe vaginal symptoms of menopause, there were no significant differences in reduction of vaginal symptoms among women using the estradiol vaginal tablet or vaginal moisturizer compared to women using the placebo regimen; all three groups had a reduction in vaginal symptoms,” lead author Sujatha Srinivasan, PhD, of the Fred Hutchinson Cancer Center, Seattle, said in an interview.

“However, the impact of these treatments on the vaginal microenvironment are poorly understood,” she said.

In a study published in JAMA Network Open, Dr. Srinivasan and colleagues conducted a secondary analysis to examine the effects of estradiol or a low-pH vaginal moisturizer on the vaginal microbiota, metabolome, and pH after 12 weeks of treatment vs. a low-pH placebo.

“Changes, or lack thereof, in the vaginal microenvironment might have implications beyond symptoms, and might be linked to risk for cervical cancer, genital infections, or other outcomes, though our study did not evaluate those associations,” Dr. Srinivasan said in an interview. Dr. Srinivasan’s comments were corroborated by coauthor Caroline M. Mitchell, MD, of Massachusetts General Hospital, Boston.

The study population included postmenopausal women with moderate to severe genitourinary symptoms who were enrolled in a randomized, controlled trial between April 2016 and February 2017. The average age of the women was 61 years, and 90% were White. The women were randomized to 10 mcg vaginal estradiol plus placebo gel, placebo tablet plus vaginal moisturizer, or a dual placebo.

The primary outcome in the original study was a change in the reported most bothersome symptoms (MBS) selected by the participants at the time of study enrollment; these included pain with penetration, vaginal dryness, and vulvovaginal irritation, itching, and pain. The main outcomes in the secondary analysis were changes in the diversity and composition of the vaginal microbiota, changes in the metabolome, and pH. Microbiota diversity was calculated via the Shannon Diversity Index (SDI).

After 12 weeks, the bacterial microbiota were dominated by Lactobacillus and Bifidobacterium in 80% of the estradiol group, 36% of the moisturizer group, and 26% of the placebo group (P < .001).

In addition, diversity analysis showed significant changes in bacterial composition in women in the estradiol group compared with the placebo group, but no significant differences between the moisturizer and placebo groups.

The composition of vaginal fluid small molecule metabolites changed significantly in 90 of 171 metabolites measured in the estradiol group from baseline to 12 weeks. Changes in the moisturizer and placebo groups were not significant.

Vaginal pH among women in the estradiol group was significantly lower than placebo at 12 weeks, with a median of 5 vs. 6 (P = .005). No significant difference in pH occurred for women in the moisturizer group. “However, pH significantly decreased over 12 weeks within each treatment group, reflecting the low-pH formulations of both the moisturizer and the placebo,” the researchers wrote.

Overall, women with high-diversity bacterial communities at baseline showed a greater median change in pH compared with women with low-diversity communities (median change of −1 vs. −0.3, P = .007).

Improvement in MBS symptoms by at least 2 points occurred in 53% of the estradiol group, 44% of the moisturizer group, and 49% of the placebo group. The similarity in severe symptom improvement among the groups confirms the lack of a causal association between microbiota and postmenopausal vaginal symptom severity, the researchers wrote.

“This study demonstrated that a decrease in vaginal pH alone was insufficient to change the vaginal microbiota,” Dr. Srinivasan said. “While the changes with estrogen were somewhat expected, the observation that low-pH vaginal products don’t change the vaginal microbiota is contrary to some expectations, and suggests that “low-pH” products may not be as helpful as their marketing claims,” she added. “A vaginal microbiota with an abundance of lactobacilli, a vaginal microenvironment with high concentrations of lactate, and a low vaginal pH is associated with health in premenopausal women. We also know that such a microenvironment is typically associated with low inflammation,” said Dr. Srinivasan. “At this time, we don’t have specific information as to how this is beneficial to postmenopausal women,” she noted. However, “If we extrapolate from the data on premenopausal women, the data from this secondary analysis suggests that vaginal estradiol may have positive impacts on the vaginal microenvironment regardless of impact on symptoms,” she said.

“Future areas of investigation should focus on understanding potential benefits of a Lactobacillus-dominant microbiota in postmenopausal women,” Dr. Srinivasan said.

The study findings were limited by several factors including the relatively small number of participants, and collection of data samples at only three time periods, as well as the lack of data on whether the observed changes are durable over longer treatment times, the researchers noted.

“The need to increase participant diversity in studies of postmenopausal women is highlighted by our finding that the 6 Black women in our analysis were all categorized in the low-diversity subgroup; data from premenopausal women suggest that Black women have diverse bacterial communities,” they added.

However, the results suggest that “a significant decrease in pH over the course of a trial may not reflect the same underlying biological processes among different interventions, and thus, lowering pH should not be a primary goal,” they concluded.
 

Estradiol may have limited clinical impact

“For postmenopausal women with dyspareunia, vaginal dryness, and/or burning/itching/irritation, the question of appropriate treatment is common,” Constance Bohon, MD, a gynecologist in private practice in Washington, said in an interview. “It is helpful to have a study that focuses on the benefit of a moisturizer as compared with vaginal estrogen for these women,” she said.

Dr. Bohon said she was not surprised with the benefits of the moisturizer for dyspareunia and vaginal dryness. “What did surprise me was that the complaint of vaginal itch, burn, or irritation was not significantly improved in the vaginal estrogen group compared with the moisturizer group. I assumed that estrogen would have been more beneficial in this group because these symptoms are more likely to be caused by a vaginal infection that would not be improved with moisturizer alone,” she said. “I expected that the change in the vaginal flora to increase Lactobacillus would have had a greater impact on an infection than the moisturizer, which did not significantly change the flora.”

For clinicians, the take-home message is that, for these patients, use of a moisturizer may be sufficient, Dr. Bohon said.

“Additional research should be done to assess each issue,” she noted. “For example, in the women who have pain with sex, what is the frequency of intercourse?” she asked. Other research should address the questions of whether women who have intercourse at least once a week have less dyspareunia than those who have less frequent sex, and whether a lubricant decreases dyspareunia as well as a moisturizer or vaginal estrogen, she added.

The study was supported by the National Institutes of Health. Dr. Srinivasan disclosed personal fees from Lupin unrelated to the current study. Dr. Bohon had no financial conflicts to disclose and serves on the editorial advisory board of Ob.Gyn. News.

As family medicine physicians it is our duty to help facilitate patients’ health care based on what is in patients’ best interests and aligns with the goals they have for their lives.

I am aware of how intersecting social, economic, familial, and environmental factors influence what is best for patient’s lives, and I consider having this awareness to be part of being a family medicine physician.

People being able to make choices about their reproductive health and their reproductive futures without unnecessary and harmful barriers is a part of a person’s overall health that family medicine physicians should recognize and prioritize. Helping people achieve their reproductive health care goals includes helping patients access abortion care if that is the care that they decide that they need.

According to the Guttmacher Institute, 2021 was “the worst year for abortion rights in almost half a century” as 108 abortion restrictions were enacted throughout the country. The most damaging restriction was introduced in Texas in the fall of 2021 called SB8, which has virtually stopped all abortion care in person for any person with a pregnancy greater than 6 weeks’ gestation. Now, in 2022 we are seeing several other states, including Idaho and Oklahoma, set to pass similar laws that will essentially halt most abortion care in the clinical setting in those states.

Abortion access had already been a problem in much of the country prior to 2021 because of burdensome and not medically necessary restrictions. Based on current political trends we are getting to a place where it is not hard to imagine that up to half of the states in this country will not allow their communities to access abortion care in the clinical setting at all in the very near future. This is not reproductive freedom, and I am outraged that people are being forced to travel hundreds of miles for their abortion care, forced to continue pregnancies that they don’t want, or forced to find other ways to obtain medication abortion pills.

While obtaining medication abortion pills online and managing the abortion process at home is safe and recognized as safe by the World Health Organization, no one should be forced to utilize a certain type of care based on their state of residence, in my opinion.

Providing evidence-based medicine to patients is ‘my duty’

Abortion care is health care and is primary care. One in four women will have an abortion by the age of 45, and we know that transgender, nonbinary, and gender-expansive people also have abortions. That means on any given day as family medicine physicians we are likely taking care of more than one person who has had an abortion, will have an abortion, and/or is considering an abortion. Therefore, all family medicine physicians need to be prepared to counsel patients about all of their pregnancy options, answer questions about pregnancy and abortion, and help people get the compassionate care that they deserve.

Our patients turn to us as trusted sources of information. When they reach out to us, I consider providing evidence-based medicine to patients – that includes factual information about abortion care if and when our patients need it – to be my duty as a family medicine physician.
 

Resources on abortion care for family medicine physicians

For family medicine physicians who did not have adequate exposure to abortion care during residency, there are many evidence-based resources to review in order to become more knowledgeable in abortion care.

In many areas of medicine, we have to continue to learn and seek out references, and abortion care is no different. One could argue that understanding abortion care and providing patients with factual information about their options and abortion care is even more important because of stigma surrounding abortion care and the rampant lies about abortion care that are easily accessible and that even other medical professionals and politicians spread. There are even fake clinics, often called “crisis pregnancy centers”, that intimidate, lie about abortion, and coerce patients to make decisions that are against their desires. Thus, being that trusted source of factual information about abortion care is even more important in the face of so many lies.

There are several organizations that are dedicated to education surrounding abortion care, in particular within the primary care setting. The Reproductive Health Access Project (RHAP), Reproductive Health Education in Family Medicine (RHEDI), and Training in Early Abortion for Comprehensive Healthcare (TEACH) all provide free resources on abortion care, how to incorporate abortion care into primary care, and how to teach medical students and residents about abortion care.

In addition, the National Network of Abortion Funds connects people to community-led organizations that provide assistance related to direct financial and logistical support for obtaining abortion care. I believe it is critical that we familiarize ourselves with our local abortion funds and share what we learn about these resources with our patients.

As abortion access continues to be further stripped away from many people that we take care of, I think standing up for what is right and what is our duty as physicians becomes more important. That duty is to provide our patients with evidence-based medicine and compassionate care so that our communities can obtain reproductive health outcomes and freedom that are best for their lives.
 

Dr. Lockley is a family physician currently living in Harlem, N.Y., and a member of the editorial advisory board of Family Practice News. She currently works for Public Health Solutions’ Sexual and Reproductive Health Centers in Brooklyn, providing primary care and reproductive health care services there, and as an abortion provider throughout the New York region. She completed both medical school and residency in Philadelphia and then did a fellowship in reproductive health care and advocacy through the Family Health Center of Harlem and the Reproductive Health Access Project. She can be reached at fpnews@mdedge.com.

As family medicine physicians it is our duty to help facilitate patients’ health care based on what is in patients’ best interests and aligns with the goals they have for their lives.

I am aware of how intersecting social, economic, familial, and environmental factors influence what is best for patient’s lives, and I consider having this awareness to be part of being a family medicine physician.

People being able to make choices about their reproductive health and their reproductive futures without unnecessary and harmful barriers is a part of a person’s overall health that family medicine physicians should recognize and prioritize. Helping people achieve their reproductive health care goals includes helping patients access abortion care if that is the care that they decide that they need.

According to the Guttmacher Institute, 2021 was “the worst year for abortion rights in almost half a century” as 108 abortion restrictions were enacted throughout the country. The most damaging restriction was introduced in Texas in the fall of 2021 called SB8, which has virtually stopped all abortion care in person for any person with a pregnancy greater than 6 weeks’ gestation. Now, in 2022 we are seeing several other states, including Idaho and Oklahoma, set to pass similar laws that will essentially halt most abortion care in the clinical setting in those states.

Abortion access had already been a problem in much of the country prior to 2021 because of burdensome and not medically necessary restrictions. Based on current political trends we are getting to a place where it is not hard to imagine that up to half of the states in this country will not allow their communities to access abortion care in the clinical setting at all in the very near future. This is not reproductive freedom, and I am outraged that people are being forced to travel hundreds of miles for their abortion care, forced to continue pregnancies that they don’t want, or forced to find other ways to obtain medication abortion pills.

While obtaining medication abortion pills online and managing the abortion process at home is safe and recognized as safe by the World Health Organization, no one should be forced to utilize a certain type of care based on their state of residence, in my opinion.

Providing evidence-based medicine to patients is ‘my duty’

Abortion care is health care and is primary care. One in four women will have an abortion by the age of 45, and we know that transgender, nonbinary, and gender-expansive people also have abortions. That means on any given day as family medicine physicians we are likely taking care of more than one person who has had an abortion, will have an abortion, and/or is considering an abortion. Therefore, all family medicine physicians need to be prepared to counsel patients about all of their pregnancy options, answer questions about pregnancy and abortion, and help people get the compassionate care that they deserve.

Our patients turn to us as trusted sources of information. When they reach out to us, I consider providing evidence-based medicine to patients – that includes factual information about abortion care if and when our patients need it – to be my duty as a family medicine physician.
 

Resources on abortion care for family medicine physicians

For family medicine physicians who did not have adequate exposure to abortion care during residency, there are many evidence-based resources to review in order to become more knowledgeable in abortion care.

In many areas of medicine, we have to continue to learn and seek out references, and abortion care is no different. One could argue that understanding abortion care and providing patients with factual information about their options and abortion care is even more important because of stigma surrounding abortion care and the rampant lies about abortion care that are easily accessible and that even other medical professionals and politicians spread. There are even fake clinics, often called “crisis pregnancy centers”, that intimidate, lie about abortion, and coerce patients to make decisions that are against their desires. Thus, being that trusted source of factual information about abortion care is even more important in the face of so many lies.

There are several organizations that are dedicated to education surrounding abortion care, in particular within the primary care setting. The Reproductive Health Access Project (RHAP), Reproductive Health Education in Family Medicine (RHEDI), and Training in Early Abortion for Comprehensive Healthcare (TEACH) all provide free resources on abortion care, how to incorporate abortion care into primary care, and how to teach medical students and residents about abortion care.

In addition, the National Network of Abortion Funds connects people to community-led organizations that provide assistance related to direct financial and logistical support for obtaining abortion care. I believe it is critical that we familiarize ourselves with our local abortion funds and share what we learn about these resources with our patients.

As abortion access continues to be further stripped away from many people that we take care of, I think standing up for what is right and what is our duty as physicians becomes more important. That duty is to provide our patients with evidence-based medicine and compassionate care so that our communities can obtain reproductive health outcomes and freedom that are best for their lives.
 

Dr. Lockley is a family physician currently living in Harlem, N.Y., and a member of the editorial advisory board of Family Practice News. She currently works for Public Health Solutions’ Sexual and Reproductive Health Centers in Brooklyn, providing primary care and reproductive health care services there, and as an abortion provider throughout the New York region. She completed both medical school and residency in Philadelphia and then did a fellowship in reproductive health care and advocacy through the Family Health Center of Harlem and the Reproductive Health Access Project. She can be reached at fpnews@mdedge.com.

As family medicine physicians it is our duty to help facilitate patients’ health care based on what is in patients’ best interests and aligns with the goals they have for their lives.

I am aware of how intersecting social, economic, familial, and environmental factors influence what is best for patient’s lives, and I consider having this awareness to be part of being a family medicine physician.

People being able to make choices about their reproductive health and their reproductive futures without unnecessary and harmful barriers is a part of a person’s overall health that family medicine physicians should recognize and prioritize. Helping people achieve their reproductive health care goals includes helping patients access abortion care if that is the care that they decide that they need.

According to the Guttmacher Institute, 2021 was “the worst year for abortion rights in almost half a century” as 108 abortion restrictions were enacted throughout the country. The most damaging restriction was introduced in Texas in the fall of 2021 called SB8, which has virtually stopped all abortion care in person for any person with a pregnancy greater than 6 weeks’ gestation. Now, in 2022 we are seeing several other states, including Idaho and Oklahoma, set to pass similar laws that will essentially halt most abortion care in the clinical setting in those states.

Abortion access had already been a problem in much of the country prior to 2021 because of burdensome and not medically necessary restrictions. Based on current political trends we are getting to a place where it is not hard to imagine that up to half of the states in this country will not allow their communities to access abortion care in the clinical setting at all in the very near future. This is not reproductive freedom, and I am outraged that people are being forced to travel hundreds of miles for their abortion care, forced to continue pregnancies that they don’t want, or forced to find other ways to obtain medication abortion pills.

While obtaining medication abortion pills online and managing the abortion process at home is safe and recognized as safe by the World Health Organization, no one should be forced to utilize a certain type of care based on their state of residence, in my opinion.

Providing evidence-based medicine to patients is ‘my duty’

Abortion care is health care and is primary care. One in four women will have an abortion by the age of 45, and we know that transgender, nonbinary, and gender-expansive people also have abortions. That means on any given day as family medicine physicians we are likely taking care of more than one person who has had an abortion, will have an abortion, and/or is considering an abortion. Therefore, all family medicine physicians need to be prepared to counsel patients about all of their pregnancy options, answer questions about pregnancy and abortion, and help people get the compassionate care that they deserve.

Our patients turn to us as trusted sources of information. When they reach out to us, I consider providing evidence-based medicine to patients – that includes factual information about abortion care if and when our patients need it – to be my duty as a family medicine physician.
 

Resources on abortion care for family medicine physicians

For family medicine physicians who did not have adequate exposure to abortion care during residency, there are many evidence-based resources to review in order to become more knowledgeable in abortion care.

In many areas of medicine, we have to continue to learn and seek out references, and abortion care is no different. One could argue that understanding abortion care and providing patients with factual information about their options and abortion care is even more important because of stigma surrounding abortion care and the rampant lies about abortion care that are easily accessible and that even other medical professionals and politicians spread. There are even fake clinics, often called “crisis pregnancy centers”, that intimidate, lie about abortion, and coerce patients to make decisions that are against their desires. Thus, being that trusted source of factual information about abortion care is even more important in the face of so many lies.

There are several organizations that are dedicated to education surrounding abortion care, in particular within the primary care setting. The Reproductive Health Access Project (RHAP), Reproductive Health Education in Family Medicine (RHEDI), and Training in Early Abortion for Comprehensive Healthcare (TEACH) all provide free resources on abortion care, how to incorporate abortion care into primary care, and how to teach medical students and residents about abortion care.

In addition, the National Network of Abortion Funds connects people to community-led organizations that provide assistance related to direct financial and logistical support for obtaining abortion care. I believe it is critical that we familiarize ourselves with our local abortion funds and share what we learn about these resources with our patients.

As abortion access continues to be further stripped away from many people that we take care of, I think standing up for what is right and what is our duty as physicians becomes more important. That duty is to provide our patients with evidence-based medicine and compassionate care so that our communities can obtain reproductive health outcomes and freedom that are best for their lives.
 

Dr. Lockley is a family physician currently living in Harlem, N.Y., and a member of the editorial advisory board of Family Practice News. She currently works for Public Health Solutions’ Sexual and Reproductive Health Centers in Brooklyn, providing primary care and reproductive health care services there, and as an abortion provider throughout the New York region. She completed both medical school and residency in Philadelphia and then did a fellowship in reproductive health care and advocacy through the Family Health Center of Harlem and the Reproductive Health Access Project. She can be reached at fpnews@mdedge.com.

Over the past 200 years, identification of the specific organism causing an infection has evolved from a reliance on patient history and physical examination to the use of microscopic examination of relevant biological samples to the rise of microbial culture and immunological testing as the gold standards for diagnosis. More recently, advances in nucleic acid testing have made nucleic acid amplification testing (NAAT) a primary method for identifying the specific organism causing an infection.

The evolution of the diagnosis of gonorrhea in clinical practice is a good example of the inexorable evolution of diagnostic techniques from physical examination to microscopic analysis to culture and finally to NAAT. Neiseer discovered Neisseria gonorrhea in 1879.¹ In 19th century general medical practice gonorrhea was often diagnosed based on history and physical examination and sometimes microscopy was also utilized.² In the mid-20th century, it was realized that culture was a superior approach to diagnosis of gonorrhea, and it became the gold standard for diagnosis in general practice.³ NAAT has now replaced culture as the gold standard for the diagnosis of gonorrhea because of its superior performance in clinical practice.⁴ It may now be time to consider using NAAT rather than microscopy and culture in general practice for the identification of specific microorganisms causing vaginitis.

Trichomoniasis

Vaginitis caused by Trichomonas vaginalis is characterized by a discharge that is foamy and green-yellow in color, with a vaginal pH that is >4.5. Microscopy of a vaginal specimen has low sensitivity, in the range of 50%, for detecting T vaginalis.^5-7 There are many factors that make microscopy a poor approach to the diagnosis of T vaginalis, including the rapid decrease in protozoan motility once a vaginal specimen is placed on a glass slide and the similar size of non-motile T vaginalis and other cells in the vagina.

Given the low sensitivity of microscopy for the diagnosis of trichomoniasis, the American College of Obstetricians and Gynecologists (ACOG) recommends NAAT as a primary approach to test for T vaginalis, with culture or NAAT testing as alternative approaches.⁸ The Centers for Disease Control and Prevention (CDC) recommends that if a wet mount is negative for T vaginalis that NAAT should be utilized.⁹

In this 2-step testing process, the first step is to test the vaginal pH and perform a microscopic examination of a vaginal specimen for T vaginalis. If T vaginalis organisms are detected, the diagnosis of trichomoniasis is confirmed. If organisms are not detected the second step would be to send a vaginal or urine specimen for NAAT for T vaginalis or for culture. An advantage of NAAT over culture is that urine specimens can be used for diagnosis of T vaginalis while urine specimens are not suitable for culture because of low sensitivity. For patients diagnosed with trichomoniasis, the CDC recommends that testing be repeated in 3 months because of high rates of reinfection. NAAT would be an optimal test to use in this situation.

Continue to: Bacterial vaginosis and candidiasis...

Bacterial vaginosis and candidiasis

ACOG recommends using Amsel criteria or Nugent scoring of a specimen colorized with a Gram stain for the diagnosis of bacterial vaginosis and microscopy or culture for the diagnosis of candidiasis.⁸ Recent research reports that NAAT testing for bacterial vaginosis and candidiasis may be more sensitive than standard office-based approaches for detecting these two causes of vaginitis. In a study of approximately 1,740 patients with symptoms of vaginitis, vaginal specimens were analyzed using NAAT or standard office approaches to diagnosis.¹⁰ In this study the diagnostic gold standards were Nugent scoring with Amsel criteria to resolve intermediate Nugent scores for bacterial vaginosis and culture for Candida. The study demonstrated the superiority of NAAT testing over standard office approaches for the identification of the cause of the vaginitis. NAAT testing was reported to have superior sensitivity for diagnosing bacterial vaginosis compared with the original Amsel criteria (93% vs 76%, respectively (P <.0001), with similar respective specificities of 92% and 94% .¹⁰ NAAT testing also had superior sensitivity for diagnosing Candidiasis compared with microscopy after potassium hydroxide treatment of a vaginal specimen (91% vs 58%, respectively (P <.0001).¹⁰ NAAT testing also had superior specificity compared with microscopy after potassium hydroxide treatment of a vaginal specimen (94% vs 89%, respectively (P < .0005).¹⁰

In another study comparing NAAT with clinical diagnosis for 466 patients with symptoms of vaginitis, standard office approaches to the diagnosis of vaginitis resulted in the failure to identify the correct infection in a large number of cases. For the diagnosis of bacterial vaginosis, clinicians missed 42% of the cases identified by NAAT. For the diagnosis of Candida, clinicians missed 46% of the cases identified by NAAT. For T vaginalis diagnosis, clinicians missed 72% of the cases identified by NAAT. Clearly, this resulted in clinicians not treating many infections detected by NAAT.¹¹

Continue to: One in 5 patients with symptoms of vaginitis have 2 causes of vaginitis...

In a recent study, 1,471 patients with a symptom of vaginitis (abnormal vaginal discharge, itching or irritation, or odor) self-collected a vaginal swab and had a vaginal swab collected by a clinician.¹² The swabs were placed in buffer and the samples were tested by NAAT using the BD Max system (Franklin Lakes, New Jersey) for the presence of nucleic acid sequences of the microorganisms responsible for the most common causes of vaginitis. In this cohort, using the clinician collected vaginal swabs for NAAT, the investigators reported the following pattern of detection of nucleic acid sequences: 36.1%, bacterial vaginosis pattern; 16.2%, Candida spp.; 1.6%, T vaginalis; 0.7%, Candida glabrata; and 0.1%, Candida krusei. Nucleic acid sequences of multiple organisms were detected in 21.7% of patients, including 13.9% with bacterial vaginosis pattern plus Candida spp., 4.9% with bacterial vaginosis pattern plus T vaginalis, 0.3% with Candida spp. plus T vaginalis, 0.2% with Candida spp. plus Candida glabrata, 0.2% with bacterial vaginosis pattern plus Candida glabrata, and 2.2% with all 3 organisms. A total of 23.8% of the women had no detectable nucleic acid sequences associated with organisms known to cause vaginitis.

In another study of 1,491 patients with a symptom of vaginitis, clinician-collected vaginal swabs were tested by NAAT using the Aptima BV and Aptima Candida/Trichomonas systems (Hologic, Marlborough, Massachusetts) for the presence of nucleic acid sequences of microorganisms responsible for most cases of vaginitis.¹³ The investigators reported the following pattern of detection of nucleic acid sequences: 28.6%, bacterial vaginosis pattern; 14.2%, Candida spp.; 3%, T vaginalis; 1.9%, Candida glabrata.¹³ Nucleic acid sequences from multiple organisms were detected in 23.3% of patients. Nucleic acid sequences suggesting the presence of two different causes of vaginitis were detected among 20.8% of patients, including bacterial vaginosis plus Candida spp., 11.1%; bacterial vaginosis plus T vaginalis, 7.2%; Candida spp. plus T vaginalis, 1.0%; Candida spp. plus Candida glabrata, 0.9%; bacterial vaginosis plus Candida spp., 0.5%; Candida glabrata plus T vaginalis, 0.1%. Nucleic acid sequences suggesting the presence of 3 different causes of vaginitis were detected in 2.4% of patients, the most common being the combination of bacterial vaginosis plus Candida spp. plus T vaginalis, 1.7% and bacterial vaginosis plus Candida spp. plus Candida glabrata, 0.5%. Nucleic acid sequences suggesting the presence of 4 different causes of vaginitis were detected in 0.1% of patients. A total of 28.8% of the women had no detectable nucleic acid sequences associated with organisms known to cause vaginitis.¹³

In clinical practice it is uncommon to see the diagnosis of multiple causes of vaginitis recorded in the medical record of a patient. This suggests that we are not effectively identifying the 20% of patients with multiple causes of vaginitis.

When multiple organisms that cause vaginitis are present, NAAT is superior to clinical evaluation for diagnosis

In a study of 1,264 patients with symptoms of vaginitis who had an identified microbial cause, more than 20% had multiple organisms detected by NAAT.¹⁰ The reference methods for diagnosis in this study were Nugent scoring with Amsel criteria to resolve intermediate Nugent scores for bacterial vaginosis, culture for Candida, and culture for T vaginalis. Compared with the reference method for diagnosis, the sensitivities for NAAT and clinician detection of cases of bacterial vaginosis plus Candida were 74% and 18%, respectively (P <.0001). Compared with the reference method for diagnosis, the sensitivities for NAAT and clinician detection of cases of bacterial vaginosis plus T vaginalis were 72% and 21%, respectively (P <.0001). Compared with the reference method for diagnosis, the sensitivities for NAAT and clinician detection of cases of bacterial vaginosis plus Candida plus T vaginalis were 80% and 10%, respectively (P <.0005).¹⁰ Based on this one study, it appears that clinicians are not very effective at diagnosing a case of vaginitis caused by multiple different microorganisms.

Patient collection of a vaginal swab for NAAT

Multiple studies have reported that collection of a vaginal swab for NAAT by the patient or a clinician results in similar excellent test performance.^4,12,13 This observation might catalyze the development of clinical protocols where patients with vaginitis could collect the swab for NAAT analysis, without needing to have a speculum examination by a clinician.

When collecting a vaginal specimen for NAAT it is important that no vaginal lubricants or creams contaminate the collection swab. Vaginal lubricants and creams may inhibit the polymerase chain reaction enzymes resulting in a false negative. The swab may be directly inserted into the vagina to collect the specimen or a speculum without a lubricant, except water can be used to facilitate specimen collection. To collect a specimen without a speculum the swab is inserted 2 inches into the vagina and rotated for 10 to 15 seconds.

What should clinicians do while waiting for a NAAT result?

A major problem with NAAT testing for vaginitis is that the results are not available at the initial patient visit, impacting the ability to make an immediate diagnosis and provide targeted antibiotic treatment. Given that bacterial vaginosis and Candida species are the most common causes of infectious vaginitis in many populations of gynecology patients, one approach is to initiate treatment with one dose of an oral antifungal agent and a multiday course of vaginal metronidazole. Once the NAAT test results are available, the treatment can be refined to specific infectious agents identified by the test, or the antibiotics can be discontinued if no relevant microorganisms are detected. Another approach would be to wait until the NAAT test is completed and then prescribe the appropriate antibiotic. My sense is that most patients would not favor this wait and see approach.

Barriers to the use of NAAT for vaginitis

A barrier to the use of NAAT for the diagnosis of vaginitis is that leading organizations do not currently recommend NAAT as a primary approach to diagnosis, favoring microscopy and measurement of vaginal pH.⁹ In addition, clinicians and patients may be rightfully concerned about the cost of NAAT, which can be substantial.

Vaginitis, especially when it is recurrent, can be stressful¹⁴ and have an impact on a patient’s quality of life^15,16 and sexual health.¹⁷ Arguably, our current practice algorithms for diagnosing the cause of vaginitis are not optimized.¹⁸ Our failure to accurately diagnose the cause of vaginitis contributes to inappropriate antibiotic treatment and return visits because of inadequate initial treatment.¹⁸ We can improve and simplify our approach to the diagnosis of vaginitis by prioritizing the use of NAAT.¹⁹ In turn, reliably making the right diagnosis will result in the optimization of treatment. ●

Over the past 200 years, identification of the specific organism causing an infection has evolved from a reliance on patient history and physical examination to the use of microscopic examination of relevant biological samples to the rise of microbial culture and immunological testing as the gold standards for diagnosis. More recently, advances in nucleic acid testing have made nucleic acid amplification testing (NAAT) a primary method for identifying the specific organism causing an infection.

The evolution of the diagnosis of gonorrhea in clinical practice is a good example of the inexorable evolution of diagnostic techniques from physical examination to microscopic analysis to culture and finally to NAAT. Neiseer discovered Neisseria gonorrhea in 1879.¹ In 19th century general medical practice gonorrhea was often diagnosed based on history and physical examination and sometimes microscopy was also utilized.² In the mid-20th century, it was realized that culture was a superior approach to diagnosis of gonorrhea, and it became the gold standard for diagnosis in general practice.³ NAAT has now replaced culture as the gold standard for the diagnosis of gonorrhea because of its superior performance in clinical practice.⁴ It may now be time to consider using NAAT rather than microscopy and culture in general practice for the identification of specific microorganisms causing vaginitis.

Trichomoniasis

Vaginitis caused by Trichomonas vaginalis is characterized by a discharge that is foamy and green-yellow in color, with a vaginal pH that is >4.5. Microscopy of a vaginal specimen has low sensitivity, in the range of 50%, for detecting T vaginalis.^5-7 There are many factors that make microscopy a poor approach to the diagnosis of T vaginalis, including the rapid decrease in protozoan motility once a vaginal specimen is placed on a glass slide and the similar size of non-motile T vaginalis and other cells in the vagina.

Given the low sensitivity of microscopy for the diagnosis of trichomoniasis, the American College of Obstetricians and Gynecologists (ACOG) recommends NAAT as a primary approach to test for T vaginalis, with culture or NAAT testing as alternative approaches.⁸ The Centers for Disease Control and Prevention (CDC) recommends that if a wet mount is negative for T vaginalis that NAAT should be utilized.⁹

In this 2-step testing process, the first step is to test the vaginal pH and perform a microscopic examination of a vaginal specimen for T vaginalis. If T vaginalis organisms are detected, the diagnosis of trichomoniasis is confirmed. If organisms are not detected the second step would be to send a vaginal or urine specimen for NAAT for T vaginalis or for culture. An advantage of NAAT over culture is that urine specimens can be used for diagnosis of T vaginalis while urine specimens are not suitable for culture because of low sensitivity. For patients diagnosed with trichomoniasis, the CDC recommends that testing be repeated in 3 months because of high rates of reinfection. NAAT would be an optimal test to use in this situation.

Continue to: Bacterial vaginosis and candidiasis...

Bacterial vaginosis and candidiasis

ACOG recommends using Amsel criteria or Nugent scoring of a specimen colorized with a Gram stain for the diagnosis of bacterial vaginosis and microscopy or culture for the diagnosis of candidiasis.⁸ Recent research reports that NAAT testing for bacterial vaginosis and candidiasis may be more sensitive than standard office-based approaches for detecting these two causes of vaginitis. In a study of approximately 1,740 patients with symptoms of vaginitis, vaginal specimens were analyzed using NAAT or standard office approaches to diagnosis.¹⁰ In this study the diagnostic gold standards were Nugent scoring with Amsel criteria to resolve intermediate Nugent scores for bacterial vaginosis and culture for Candida. The study demonstrated the superiority of NAAT testing over standard office approaches for the identification of the cause of the vaginitis. NAAT testing was reported to have superior sensitivity for diagnosing bacterial vaginosis compared with the original Amsel criteria (93% vs 76%, respectively (P <.0001), with similar respective specificities of 92% and 94% .¹⁰ NAAT testing also had superior sensitivity for diagnosing Candidiasis compared with microscopy after potassium hydroxide treatment of a vaginal specimen (91% vs 58%, respectively (P <.0001).¹⁰ NAAT testing also had superior specificity compared with microscopy after potassium hydroxide treatment of a vaginal specimen (94% vs 89%, respectively (P < .0005).¹⁰

In another study comparing NAAT with clinical diagnosis for 466 patients with symptoms of vaginitis, standard office approaches to the diagnosis of vaginitis resulted in the failure to identify the correct infection in a large number of cases. For the diagnosis of bacterial vaginosis, clinicians missed 42% of the cases identified by NAAT. For the diagnosis of Candida, clinicians missed 46% of the cases identified by NAAT. For T vaginalis diagnosis, clinicians missed 72% of the cases identified by NAAT. Clearly, this resulted in clinicians not treating many infections detected by NAAT.¹¹

Continue to: One in 5 patients with symptoms of vaginitis have 2 causes of vaginitis...

In a recent study, 1,471 patients with a symptom of vaginitis (abnormal vaginal discharge, itching or irritation, or odor) self-collected a vaginal swab and had a vaginal swab collected by a clinician.¹² The swabs were placed in buffer and the samples were tested by NAAT using the BD Max system (Franklin Lakes, New Jersey) for the presence of nucleic acid sequences of the microorganisms responsible for the most common causes of vaginitis. In this cohort, using the clinician collected vaginal swabs for NAAT, the investigators reported the following pattern of detection of nucleic acid sequences: 36.1%, bacterial vaginosis pattern; 16.2%, Candida spp.; 1.6%, T vaginalis; 0.7%, Candida glabrata; and 0.1%, Candida krusei. Nucleic acid sequences of multiple organisms were detected in 21.7% of patients, including 13.9% with bacterial vaginosis pattern plus Candida spp., 4.9% with bacterial vaginosis pattern plus T vaginalis, 0.3% with Candida spp. plus T vaginalis, 0.2% with Candida spp. plus Candida glabrata, 0.2% with bacterial vaginosis pattern plus Candida glabrata, and 2.2% with all 3 organisms. A total of 23.8% of the women had no detectable nucleic acid sequences associated with organisms known to cause vaginitis.

In another study of 1,491 patients with a symptom of vaginitis, clinician-collected vaginal swabs were tested by NAAT using the Aptima BV and Aptima Candida/Trichomonas systems (Hologic, Marlborough, Massachusetts) for the presence of nucleic acid sequences of microorganisms responsible for most cases of vaginitis.¹³ The investigators reported the following pattern of detection of nucleic acid sequences: 28.6%, bacterial vaginosis pattern; 14.2%, Candida spp.; 3%, T vaginalis; 1.9%, Candida glabrata.¹³ Nucleic acid sequences from multiple organisms were detected in 23.3% of patients. Nucleic acid sequences suggesting the presence of two different causes of vaginitis were detected among 20.8% of patients, including bacterial vaginosis plus Candida spp., 11.1%; bacterial vaginosis plus T vaginalis, 7.2%; Candida spp. plus T vaginalis, 1.0%; Candida spp. plus Candida glabrata, 0.9%; bacterial vaginosis plus Candida spp., 0.5%; Candida glabrata plus T vaginalis, 0.1%. Nucleic acid sequences suggesting the presence of 3 different causes of vaginitis were detected in 2.4% of patients, the most common being the combination of bacterial vaginosis plus Candida spp. plus T vaginalis, 1.7% and bacterial vaginosis plus Candida spp. plus Candida glabrata, 0.5%. Nucleic acid sequences suggesting the presence of 4 different causes of vaginitis were detected in 0.1% of patients. A total of 28.8% of the women had no detectable nucleic acid sequences associated with organisms known to cause vaginitis.¹³

In clinical practice it is uncommon to see the diagnosis of multiple causes of vaginitis recorded in the medical record of a patient. This suggests that we are not effectively identifying the 20% of patients with multiple causes of vaginitis.

When multiple organisms that cause vaginitis are present, NAAT is superior to clinical evaluation for diagnosis

In a study of 1,264 patients with symptoms of vaginitis who had an identified microbial cause, more than 20% had multiple organisms detected by NAAT.¹⁰ The reference methods for diagnosis in this study were Nugent scoring with Amsel criteria to resolve intermediate Nugent scores for bacterial vaginosis, culture for Candida, and culture for T vaginalis. Compared with the reference method for diagnosis, the sensitivities for NAAT and clinician detection of cases of bacterial vaginosis plus Candida were 74% and 18%, respectively (P <.0001). Compared with the reference method for diagnosis, the sensitivities for NAAT and clinician detection of cases of bacterial vaginosis plus T vaginalis were 72% and 21%, respectively (P <.0001). Compared with the reference method for diagnosis, the sensitivities for NAAT and clinician detection of cases of bacterial vaginosis plus Candida plus T vaginalis were 80% and 10%, respectively (P <.0005).¹⁰ Based on this one study, it appears that clinicians are not very effective at diagnosing a case of vaginitis caused by multiple different microorganisms.

Patient collection of a vaginal swab for NAAT

Multiple studies have reported that collection of a vaginal swab for NAAT by the patient or a clinician results in similar excellent test performance.^4,12,13 This observation might catalyze the development of clinical protocols where patients with vaginitis could collect the swab for NAAT analysis, without needing to have a speculum examination by a clinician.

When collecting a vaginal specimen for NAAT it is important that no vaginal lubricants or creams contaminate the collection swab. Vaginal lubricants and creams may inhibit the polymerase chain reaction enzymes resulting in a false negative. The swab may be directly inserted into the vagina to collect the specimen or a speculum without a lubricant, except water can be used to facilitate specimen collection. To collect a specimen without a speculum the swab is inserted 2 inches into the vagina and rotated for 10 to 15 seconds.

What should clinicians do while waiting for a NAAT result?

A major problem with NAAT testing for vaginitis is that the results are not available at the initial patient visit, impacting the ability to make an immediate diagnosis and provide targeted antibiotic treatment. Given that bacterial vaginosis and Candida species are the most common causes of infectious vaginitis in many populations of gynecology patients, one approach is to initiate treatment with one dose of an oral antifungal agent and a multiday course of vaginal metronidazole. Once the NAAT test results are available, the treatment can be refined to specific infectious agents identified by the test, or the antibiotics can be discontinued if no relevant microorganisms are detected. Another approach would be to wait until the NAAT test is completed and then prescribe the appropriate antibiotic. My sense is that most patients would not favor this wait and see approach.

Barriers to the use of NAAT for vaginitis

A barrier to the use of NAAT for the diagnosis of vaginitis is that leading organizations do not currently recommend NAAT as a primary approach to diagnosis, favoring microscopy and measurement of vaginal pH.⁹ In addition, clinicians and patients may be rightfully concerned about the cost of NAAT, which can be substantial.

Vaginitis, especially when it is recurrent, can be stressful¹⁴ and have an impact on a patient’s quality of life^15,16 and sexual health.¹⁷ Arguably, our current practice algorithms for diagnosing the cause of vaginitis are not optimized.¹⁸ Our failure to accurately diagnose the cause of vaginitis contributes to inappropriate antibiotic treatment and return visits because of inadequate initial treatment.¹⁸ We can improve and simplify our approach to the diagnosis of vaginitis by prioritizing the use of NAAT.¹⁹ In turn, reliably making the right diagnosis will result in the optimization of treatment. ●

Over the past 200 years, identification of the specific organism causing an infection has evolved from a reliance on patient history and physical examination to the use of microscopic examination of relevant biological samples to the rise of microbial culture and immunological testing as the gold standards for diagnosis. More recently, advances in nucleic acid testing have made nucleic acid amplification testing (NAAT) a primary method for identifying the specific organism causing an infection.

The evolution of the diagnosis of gonorrhea in clinical practice is a good example of the inexorable evolution of diagnostic techniques from physical examination to microscopic analysis to culture and finally to NAAT. Neiseer discovered Neisseria gonorrhea in 1879.¹ In 19th century general medical practice gonorrhea was often diagnosed based on history and physical examination and sometimes microscopy was also utilized.² In the mid-20th century, it was realized that culture was a superior approach to diagnosis of gonorrhea, and it became the gold standard for diagnosis in general practice.³ NAAT has now replaced culture as the gold standard for the diagnosis of gonorrhea because of its superior performance in clinical practice.⁴ It may now be time to consider using NAAT rather than microscopy and culture in general practice for the identification of specific microorganisms causing vaginitis.

Trichomoniasis

Vaginitis caused by Trichomonas vaginalis is characterized by a discharge that is foamy and green-yellow in color, with a vaginal pH that is >4.5. Microscopy of a vaginal specimen has low sensitivity, in the range of 50%, for detecting T vaginalis.^5-7 There are many factors that make microscopy a poor approach to the diagnosis of T vaginalis, including the rapid decrease in protozoan motility once a vaginal specimen is placed on a glass slide and the similar size of non-motile T vaginalis and other cells in the vagina.

Given the low sensitivity of microscopy for the diagnosis of trichomoniasis, the American College of Obstetricians and Gynecologists (ACOG) recommends NAAT as a primary approach to test for T vaginalis, with culture or NAAT testing as alternative approaches.⁸ The Centers for Disease Control and Prevention (CDC) recommends that if a wet mount is negative for T vaginalis that NAAT should be utilized.⁹

In this 2-step testing process, the first step is to test the vaginal pH and perform a microscopic examination of a vaginal specimen for T vaginalis. If T vaginalis organisms are detected, the diagnosis of trichomoniasis is confirmed. If organisms are not detected the second step would be to send a vaginal or urine specimen for NAAT for T vaginalis or for culture. An advantage of NAAT over culture is that urine specimens can be used for diagnosis of T vaginalis while urine specimens are not suitable for culture because of low sensitivity. For patients diagnosed with trichomoniasis, the CDC recommends that testing be repeated in 3 months because of high rates of reinfection. NAAT would be an optimal test to use in this situation.

Continue to: Bacterial vaginosis and candidiasis...

Bacterial vaginosis and candidiasis

ACOG recommends using Amsel criteria or Nugent scoring of a specimen colorized with a Gram stain for the diagnosis of bacterial vaginosis and microscopy or culture for the diagnosis of candidiasis.⁸ Recent research reports that NAAT testing for bacterial vaginosis and candidiasis may be more sensitive than standard office-based approaches for detecting these two causes of vaginitis. In a study of approximately 1,740 patients with symptoms of vaginitis, vaginal specimens were analyzed using NAAT or standard office approaches to diagnosis.¹⁰ In this study the diagnostic gold standards were Nugent scoring with Amsel criteria to resolve intermediate Nugent scores for bacterial vaginosis and culture for Candida. The study demonstrated the superiority of NAAT testing over standard office approaches for the identification of the cause of the vaginitis. NAAT testing was reported to have superior sensitivity for diagnosing bacterial vaginosis compared with the original Amsel criteria (93% vs 76%, respectively (P <.0001), with similar respective specificities of 92% and 94% .¹⁰ NAAT testing also had superior sensitivity for diagnosing Candidiasis compared with microscopy after potassium hydroxide treatment of a vaginal specimen (91% vs 58%, respectively (P <.0001).¹⁰ NAAT testing also had superior specificity compared with microscopy after potassium hydroxide treatment of a vaginal specimen (94% vs 89%, respectively (P < .0005).¹⁰

In another study comparing NAAT with clinical diagnosis for 466 patients with symptoms of vaginitis, standard office approaches to the diagnosis of vaginitis resulted in the failure to identify the correct infection in a large number of cases. For the diagnosis of bacterial vaginosis, clinicians missed 42% of the cases identified by NAAT. For the diagnosis of Candida, clinicians missed 46% of the cases identified by NAAT. For T vaginalis diagnosis, clinicians missed 72% of the cases identified by NAAT. Clearly, this resulted in clinicians not treating many infections detected by NAAT.¹¹

Continue to: One in 5 patients with symptoms of vaginitis have 2 causes of vaginitis...

In a recent study, 1,471 patients with a symptom of vaginitis (abnormal vaginal discharge, itching or irritation, or odor) self-collected a vaginal swab and had a vaginal swab collected by a clinician.¹² The swabs were placed in buffer and the samples were tested by NAAT using the BD Max system (Franklin Lakes, New Jersey) for the presence of nucleic acid sequences of the microorganisms responsible for the most common causes of vaginitis. In this cohort, using the clinician collected vaginal swabs for NAAT, the investigators reported the following pattern of detection of nucleic acid sequences: 36.1%, bacterial vaginosis pattern; 16.2%, Candida spp.; 1.6%, T vaginalis; 0.7%, Candida glabrata; and 0.1%, Candida krusei. Nucleic acid sequences of multiple organisms were detected in 21.7% of patients, including 13.9% with bacterial vaginosis pattern plus Candida spp., 4.9% with bacterial vaginosis pattern plus T vaginalis, 0.3% with Candida spp. plus T vaginalis, 0.2% with Candida spp. plus Candida glabrata, 0.2% with bacterial vaginosis pattern plus Candida glabrata, and 2.2% with all 3 organisms. A total of 23.8% of the women had no detectable nucleic acid sequences associated with organisms known to cause vaginitis.

In another study of 1,491 patients with a symptom of vaginitis, clinician-collected vaginal swabs were tested by NAAT using the Aptima BV and Aptima Candida/Trichomonas systems (Hologic, Marlborough, Massachusetts) for the presence of nucleic acid sequences of microorganisms responsible for most cases of vaginitis.¹³ The investigators reported the following pattern of detection of nucleic acid sequences: 28.6%, bacterial vaginosis pattern; 14.2%, Candida spp.; 3%, T vaginalis; 1.9%, Candida glabrata.¹³ Nucleic acid sequences from multiple organisms were detected in 23.3% of patients. Nucleic acid sequences suggesting the presence of two different causes of vaginitis were detected among 20.8% of patients, including bacterial vaginosis plus Candida spp., 11.1%; bacterial vaginosis plus T vaginalis, 7.2%; Candida spp. plus T vaginalis, 1.0%; Candida spp. plus Candida glabrata, 0.9%; bacterial vaginosis plus Candida spp., 0.5%; Candida glabrata plus T vaginalis, 0.1%. Nucleic acid sequences suggesting the presence of 3 different causes of vaginitis were detected in 2.4% of patients, the most common being the combination of bacterial vaginosis plus Candida spp. plus T vaginalis, 1.7% and bacterial vaginosis plus Candida spp. plus Candida glabrata, 0.5%. Nucleic acid sequences suggesting the presence of 4 different causes of vaginitis were detected in 0.1% of patients. A total of 28.8% of the women had no detectable nucleic acid sequences associated with organisms known to cause vaginitis.¹³

In clinical practice it is uncommon to see the diagnosis of multiple causes of vaginitis recorded in the medical record of a patient. This suggests that we are not effectively identifying the 20% of patients with multiple causes of vaginitis.

When multiple organisms that cause vaginitis are present, NAAT is superior to clinical evaluation for diagnosis

In a study of 1,264 patients with symptoms of vaginitis who had an identified microbial cause, more than 20% had multiple organisms detected by NAAT.¹⁰ The reference methods for diagnosis in this study were Nugent scoring with Amsel criteria to resolve intermediate Nugent scores for bacterial vaginosis, culture for Candida, and culture for T vaginalis. Compared with the reference method for diagnosis, the sensitivities for NAAT and clinician detection of cases of bacterial vaginosis plus Candida were 74% and 18%, respectively (P <.0001). Compared with the reference method for diagnosis, the sensitivities for NAAT and clinician detection of cases of bacterial vaginosis plus T vaginalis were 72% and 21%, respectively (P <.0001). Compared with the reference method for diagnosis, the sensitivities for NAAT and clinician detection of cases of bacterial vaginosis plus Candida plus T vaginalis were 80% and 10%, respectively (P <.0005).¹⁰ Based on this one study, it appears that clinicians are not very effective at diagnosing a case of vaginitis caused by multiple different microorganisms.

Patient collection of a vaginal swab for NAAT

Multiple studies have reported that collection of a vaginal swab for NAAT by the patient or a clinician results in similar excellent test performance.^4,12,13 This observation might catalyze the development of clinical protocols where patients with vaginitis could collect the swab for NAAT analysis, without needing to have a speculum examination by a clinician.

When collecting a vaginal specimen for NAAT it is important that no vaginal lubricants or creams contaminate the collection swab. Vaginal lubricants and creams may inhibit the polymerase chain reaction enzymes resulting in a false negative. The swab may be directly inserted into the vagina to collect the specimen or a speculum without a lubricant, except water can be used to facilitate specimen collection. To collect a specimen without a speculum the swab is inserted 2 inches into the vagina and rotated for 10 to 15 seconds.

What should clinicians do while waiting for a NAAT result?

A major problem with NAAT testing for vaginitis is that the results are not available at the initial patient visit, impacting the ability to make an immediate diagnosis and provide targeted antibiotic treatment. Given that bacterial vaginosis and Candida species are the most common causes of infectious vaginitis in many populations of gynecology patients, one approach is to initiate treatment with one dose of an oral antifungal agent and a multiday course of vaginal metronidazole. Once the NAAT test results are available, the treatment can be refined to specific infectious agents identified by the test, or the antibiotics can be discontinued if no relevant microorganisms are detected. Another approach would be to wait until the NAAT test is completed and then prescribe the appropriate antibiotic. My sense is that most patients would not favor this wait and see approach.

Barriers to the use of NAAT for vaginitis

A barrier to the use of NAAT for the diagnosis of vaginitis is that leading organizations do not currently recommend NAAT as a primary approach to diagnosis, favoring microscopy and measurement of vaginal pH.⁹ In addition, clinicians and patients may be rightfully concerned about the cost of NAAT, which can be substantial.

Vaginitis, especially when it is recurrent, can be stressful¹⁴ and have an impact on a patient’s quality of life^15,16 and sexual health.¹⁷ Arguably, our current practice algorithms for diagnosing the cause of vaginitis are not optimized.¹⁸ Our failure to accurately diagnose the cause of vaginitis contributes to inappropriate antibiotic treatment and return visits because of inadequate initial treatment.¹⁸ We can improve and simplify our approach to the diagnosis of vaginitis by prioritizing the use of NAAT.¹⁹ In turn, reliably making the right diagnosis will result in the optimization of treatment. ●

The first condom specifically designed for use during anal sex has gained Food and Drug Administration approval.

Anal intercourse is considered to be much riskier than vaginal sex for the transmission of infections such as HIV and HPV, a risk factor for anal cancer, agency officials said in a statement Feb. 23 announcing the decision. And though the Centers for Disease Control and Prevention has long encouraged the use of a condom during anal intercourse, the FDA had not until now deemed this practice safe.

The latex ONE Male Condom, from prophylactic maker Global Protection Corp. of Boston, has already been available for vaginal sex. The FDA action now allows the company to market the product for anal intercourse.

“This authorization helps us accomplish our priority to advance health equity through the development of safe and effective products that meet the needs of diverse populations,” Courtney Lias, PhD, the director of the FDA’s Office of GastroRenal, ObGyn, General Hospital, and Urology Devices, said in a statement.

The FDA said it relied on an Emory University clinical study of condom safety of more than 500 men. Those who took part in the study were evenly divided between men who have sex with men and men who have sex with women. The condom failure rate, meaning that a condom either broke or slipped, was less than 1% during anal sex. The failure rate was 3 times higher during vaginal intercourse.

The Emory researchers also found that roughly 70% of men who have sex with men would be more likely to use condoms marked as safe for anal sex, according to a survey of 10,000 people.

ONE Male Condoms sell for between $3.48 for a three-pack and $14.48 for a 24-pack, according to Milla Impola, Global Protection’s director of marketing and communications. The FDA said the condom should be used with a condom-compatible lubricant when used during anal sex.

A version of this article first appeared on WebMD.com.

The first condom specifically designed for use during anal sex has gained Food and Drug Administration approval.

Anal intercourse is considered to be much riskier than vaginal sex for the transmission of infections such as HIV and HPV, a risk factor for anal cancer, agency officials said in a statement Feb. 23 announcing the decision. And though the Centers for Disease Control and Prevention has long encouraged the use of a condom during anal intercourse, the FDA had not until now deemed this practice safe.

The latex ONE Male Condom, from prophylactic maker Global Protection Corp. of Boston, has already been available for vaginal sex. The FDA action now allows the company to market the product for anal intercourse.

“This authorization helps us accomplish our priority to advance health equity through the development of safe and effective products that meet the needs of diverse populations,” Courtney Lias, PhD, the director of the FDA’s Office of GastroRenal, ObGyn, General Hospital, and Urology Devices, said in a statement.

The FDA said it relied on an Emory University clinical study of condom safety of more than 500 men. Those who took part in the study were evenly divided between men who have sex with men and men who have sex with women. The condom failure rate, meaning that a condom either broke or slipped, was less than 1% during anal sex. The failure rate was 3 times higher during vaginal intercourse.

The Emory researchers also found that roughly 70% of men who have sex with men would be more likely to use condoms marked as safe for anal sex, according to a survey of 10,000 people.

ONE Male Condoms sell for between $3.48 for a three-pack and $14.48 for a 24-pack, according to Milla Impola, Global Protection’s director of marketing and communications. The FDA said the condom should be used with a condom-compatible lubricant when used during anal sex.

A version of this article first appeared on WebMD.com.

The first condom specifically designed for use during anal sex has gained Food and Drug Administration approval.

Anal intercourse is considered to be much riskier than vaginal sex for the transmission of infections such as HIV and HPV, a risk factor for anal cancer, agency officials said in a statement Feb. 23 announcing the decision. And though the Centers for Disease Control and Prevention has long encouraged the use of a condom during anal intercourse, the FDA had not until now deemed this practice safe.

The latex ONE Male Condom, from prophylactic maker Global Protection Corp. of Boston, has already been available for vaginal sex. The FDA action now allows the company to market the product for anal intercourse.

“This authorization helps us accomplish our priority to advance health equity through the development of safe and effective products that meet the needs of diverse populations,” Courtney Lias, PhD, the director of the FDA’s Office of GastroRenal, ObGyn, General Hospital, and Urology Devices, said in a statement.

The FDA said it relied on an Emory University clinical study of condom safety of more than 500 men. Those who took part in the study were evenly divided between men who have sex with men and men who have sex with women. The condom failure rate, meaning that a condom either broke or slipped, was less than 1% during anal sex. The failure rate was 3 times higher during vaginal intercourse.

The Emory researchers also found that roughly 70% of men who have sex with men would be more likely to use condoms marked as safe for anal sex, according to a survey of 10,000 people.

ONE Male Condoms sell for between $3.48 for a three-pack and $14.48 for a 24-pack, according to Milla Impola, Global Protection’s director of marketing and communications. The FDA said the condom should be used with a condom-compatible lubricant when used during anal sex.

A version of this article first appeared on WebMD.com.

The Food and Drug Administration has approved secnidazole for the treatment of bacterial vaginosis (BV) and trichomoniasis in patients aged 12 years and older.

The antimicrobial agent, marketed as Solosec, was first approved in 2017 as a treatment for BV in adult women. In 2021, it was approved for the treatment of trichomoniasis in adult men and women.

Lupin Pharmaceuticals, which manufactures the drug, announced the expanded approval for adolescents in a news release.

The medication is meant to be taken as a single dose. It comes in a packet that should be sprinkled onto applesauce, yogurt, or pudding and consumed without chewing or crunching.

The treatment option may help “address gaps in care related to adherence,” said Tom Merriam, an executive director with Lupin.

Bacterial vaginosis is a common vaginal infection. Trichomoniasis is the most common nonviral, curable STI in the United States. Sexual partners of patients with trichomoniasis can be treated at the same time.

Vulvovaginal candidiasis is one of the possible side effects of secnidazole treatment, the drug’s label notes.

The Food and Drug Administration has approved secnidazole for the treatment of bacterial vaginosis (BV) and trichomoniasis in patients aged 12 years and older.

The antimicrobial agent, marketed as Solosec, was first approved in 2017 as a treatment for BV in adult women. In 2021, it was approved for the treatment of trichomoniasis in adult men and women.

Lupin Pharmaceuticals, which manufactures the drug, announced the expanded approval for adolescents in a news release.

The medication is meant to be taken as a single dose. It comes in a packet that should be sprinkled onto applesauce, yogurt, or pudding and consumed without chewing or crunching.

The treatment option may help “address gaps in care related to adherence,” said Tom Merriam, an executive director with Lupin.

Bacterial vaginosis is a common vaginal infection. Trichomoniasis is the most common nonviral, curable STI in the United States. Sexual partners of patients with trichomoniasis can be treated at the same time.

Vulvovaginal candidiasis is one of the possible side effects of secnidazole treatment, the drug’s label notes.

The Food and Drug Administration has approved secnidazole for the treatment of bacterial vaginosis (BV) and trichomoniasis in patients aged 12 years and older.

The antimicrobial agent, marketed as Solosec, was first approved in 2017 as a treatment for BV in adult women. In 2021, it was approved for the treatment of trichomoniasis in adult men and women.

Lupin Pharmaceuticals, which manufactures the drug, announced the expanded approval for adolescents in a news release.

The medication is meant to be taken as a single dose. It comes in a packet that should be sprinkled onto applesauce, yogurt, or pudding and consumed without chewing or crunching.

The treatment option may help “address gaps in care related to adherence,” said Tom Merriam, an executive director with Lupin.

Bacterial vaginosis is a common vaginal infection. Trichomoniasis is the most common nonviral, curable STI in the United States. Sexual partners of patients with trichomoniasis can be treated at the same time.

Vulvovaginal candidiasis is one of the possible side effects of secnidazole treatment, the drug’s label notes.

Tosha Rogers, MD, is a one-woman HIV prevention evangelist. For nearly a decade now, the Atlanta-based ob/gyn has been on a mission to increase her gynecological colleagues’ awareness and prescribing of the oral HIV prevention pill. At the same time, she’s been tracking the development of a flexible vaginal ring loaded with a month’s worth of the HIV prevention medication dapivirine. That, she thought, would fit easily into women’s lives and into the toolbox of methods women already use to prevent pregnancy.

But now she’s not sure when – or if – the ring will find its way to her patients. In December, the ring’s maker, the International Partnership for Microbicides (IPM), pulled its application for FDA approval for the pre-exposure prophylaxis (PrEP) ring. Now, one year after the World Health Organization recommended the ring for member nations, there appears to be no path forward in the United States for either the dapivirine-only ring or an approach Dr. Rogers said would change the game: a vaginal ring that supplies both contraception and HIV prevention.

“It would take things to a whole other level,” she said. “It sucks that this happened, and I do think it was not anything medical. I think it was everything political.”

That leaves cisgender women – especially the Black and Latinx women who make up the vast majority of women who acquire HIV every year – with two HIV prevention options. One is the daily pill, first approved in 2012. It’s now generic but previously sold as Truvada by Gilead Sciences. The other is monthly injectable cabotegravir long-acting (Apretude). Another HIV prevention pill, tenofovir alafenamide/emtricitabine (Descovy), is approved for gay men and transgender women but not cisgender women.
 

Vagina-specific protection from HIV

The WHO recommendation for the vaginal ring was followed last July by a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) for women in low- and middle-income countries outside the European Union.

The flexible silicone ring, similar to the hormonal NuvaRing contraceptive, works by slowly releasing the antiretroviral dapivirine directly into the vaginal canal, thereby protecting women who might be exposed to the virus through vaginal sex only. Because the medicine stays where it’s delivered and doesn’t circulate through the body, it has been found to be extremely safe with few adverse events.

However, in initial studies, the ring was found to be just 27% effective overall. Later studies, where scientists divided women by how much drug was missing from the ring – a proxy for use – found that higher use was associated with higher protection (as much as 54%). By comparison, Truvada has been found to be up to 99% effective when used daily, though it can take up to 21 days to be available in the vagina in high enough concentrations to protect women from vaginal exposure. And the HIV prevention shot was found to be 90% more effective than that in a recent trial of the two methods conducted by the HIV Prevention Trials Network.

This, and an orientation away from topical HIV prevention drugs and toward systemic options, led the National Institute of Allergy and Infectious Diseases (NIAID) to discontinue funding for such projects under its Microbicide Trials Network.

“Clearly you want to counsel women to use the highest efficacy method, and that is part of our label,” Zeda Rosenberg, ScD, IPM’s founder and chief executive officer, told this news organization. “Women should not choose the ring if they can and will use oral PrEP, and I would argue it should be the same thing for [cabotegravir shots]. But if they can’t or don’t want to – and we know that especially many young women don’t want to use systemic methods – then the dapivirine ring is a great option.”

Still, Dr. Rosenberg said that the gap in efficacy, the relatively small number of women affected by HIV in the U.S. compared with gay and bisexual men, and the emergence of products like the HIV prevention shot cabotegravir, made it “very unlikely” that FDA regulators would approve the ring. And rather than be “distracted” by the FDA process, Dr. Rosenberg said IPM chose to concentrate on the countries where the ring has already been approved or where women make up the vast majority of people affected by HIV.

Zimbabwe publicly announced it has approved the ring, and three other countries may have approved it, according to Dr. Rosenberg. She declined to name them, saying they had requested silence while they formulate their new HIV prevention guidelines. Aside from Zimbabwe, the other countries where women participated in the ring clinical trials were South Africa, Malawi, and Uganda.

“The U.S. population ... has widespread access to oral PrEP, which is unlike countries in Africa, and which would have widespread access to injectable cabotegravir,” she said. “The U.S. FDA may not see choice in the same way that African women and African activists and advocates see the need for choice.”

But women’s rates of accessing HIV prevention medications in the U.S. continues to be frustratingly low. At the end of 2018, just 7% of women who could benefit from HIV prevention drugs were taking them, according to Centers for Disease Control and Prevention data.

New CDC guidelines recommend clinicians talk to every sexually active adult and adolescent about HIV prevention medications at least once and prescribe it to anyone who asks for it, whether or not they understand their patients’ HIV risks. However, research continues to show that clinicians struggle with willingness to prescribe PrEP to Black women, and the American College of Obstetrics and Gynecology’s committee opinion on managing women using HIV prevention drugs has not been updated to reflect the new guidelines. And while the HIV prevention shot is approved for women and its maker ViiV Healthcare is already initiating postmarket studies of the ring in key populations including women, there are lots of things that need to line up in order for clinicians to be willing to stock it and prescribe it to women.

From where Dázon Dixon Diallo, executive director of the nonprofit SisterLove, sits, the decision to withdraw the ring from FDA consideration and the FDA’s seeming argument that the epidemiology in the U.S. doesn’t warrant the ring’s approval is a slap in the face to the Black women who have led the movement to end HIV in the U.S. for decades.

“No matter how you slice it, we’re talking about Black women, and then we’re talking about brown women,” said Ms. Diallo. “The value [they place on us] from a government standpoint, from a political standpoint, from a public health standpoint is just woeful. It’s woeful and it’s disrespectful and it’s insulting and I’m sick of it.”
 

‘America sneezes and Africa catches a cold’

When she first heard the decision to pull the ring from FDA consideration, Yvette Raphael, the South Africa-based executive director of Advocates for the Prevention of HIV in Africa, started asking, “What can we do to help our sisters in America get this ring?” And then she started worrying about other women in her own country and those nearby.

“The FDA plays a big role,” she said. “You know, America sneezes and Africa catches a cold.”

She worries that IPM’s decision to withdraw the ring from FDA consideration will signal to regulators in other countries either (a) that they should not approve it or (b) in countries where it’s already been approved but guidelines have not been issued, that they won’t invest money in rolling it out to women in those countries – especially now with the U.S. approval of the prevention shot. In much of Africa, ministries of health prefer to provide injectable contraception, often giving women few or no other options. But women, she said, think about more than administration of the drug. They look at if it’s an easier option for them to manage.

“This is a long journey, an emotional one too, for women in South Africa, because the idea of a microbicide is one of the ideas that came directly from women in South Africa,” she said. “[The jab] can be seen as a solution to all. We can just give jabs to all the women. And after all, we know that women don’t adhere, so we can just grab them.”

Dr. Rosenberg pointed to the positive opinion from the EMA as another “rigorous review” process that she said ought to equally influence ministries of health in countries where women tested the ring. And she pointed to the WHO statement released last month, the same day as IPM’s announcement that it was withdrawing the ring from FDA considerations, recommitting the ring as a good option in sub-Saharan Africa: “The U.S. FDA decision is not based on any new or additional data on efficacy and safety,” it stated. “WHO will continue to support countries as they consider whether to include the [dapivirine vaginal ring]. WHO recognizes that country decisionmaking will vary based on their context and that women’s voices remain central to discussions about their prevention choices.”
 

Dual action ring on the horizon, but not in U.S.

What this means, though, is that the next step in the ring’s development – the combination dapivirine ring with contraceptive levonorgestrel (used in the Mirena intrauterine device) – may not come to the U.S., at least for a long while.

“It’s not out of the question,” Dr. Rosenberg said of conducting HIV/pregnancy prevention ring trials in the U.S. “But without the approval of the dapivirine-only ring by FDA, I imagine they would want to see new efficacy data on dapivirine. That is a very difficult hill to climb. There would have to be an active control group [using oral PrEP or injectable cabotegravir], and it would be very difficult for the dapivirine ring to be able to go head-to-head for either noninferiority and certainly for superiority.”

The study would need to be quite large to get enough results to prove anything, and IPM is a research organization, not a large pharmaceutical company with deep enough pockets to fund that, she said. Raising those funds “would be difficult.”

In addition to NIAID discontinuing its funding for the Microbicides Trials Network, a new 5-year, $85 million research collaboration through USAID hasn’t slated any money to fund trials of the combination HIV prevention and contraceptive ring, according to Dr. Rosenberg.

But that doesn’t mean avenues for its development are closed. NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is currently funding a phase 1/2 trial of the combination ring, and IPM continues to receive funding from research agencies in Germany, the Netherlands, Denmark, and Ireland. And this means, she said, that the E.U. – not the U.S. – is where they would seek approval for a combination ring first.

That leaves Ms. Rafael and Ms. Diallo debating how to work together to push the FDA – and maybe IPM – to reconsider the ring. For instance, Ms. Diallo suggested that instead of seeking an indication for all women, the FDA might consider the ring for women with very high risk of HIV, such as sex workers or women with HIV positive partners not on treatment. And she said that this has to be bigger than HIV prevention. It has to be about the ways in which women’s health issues in general lag at the FDA. For instance, she pointed to the movement to get contraceptive pills available over the counter, fights against FDA rulings on hormone replacement therapy, and fights for emergency contraception.

In the meantime, ob/gyn Dr. Rogers is expecting access to the ring to follow a similar path as the copper IUD, which migrated to the U.S. from Europe, where it has been among the most popular contraceptive methods for women.

“Contrary to what we may think, we are not innovators, especially for something like this,” she said. “Once we see it is working and doing a good job – that women in Europe love it – then someone here is going to pick it up and make it as if it’s the greatest thing. But for now, I think we’re going to have to take a back seat to Europe.”

Ms. Diallo reports receiving fees from Johnson & Johnson, ViiV Healthcare, and Gilead Sciences. Dr. Rosenberg and Dr. Rogers have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Tosha Rogers, MD, is a one-woman HIV prevention evangelist. For nearly a decade now, the Atlanta-based ob/gyn has been on a mission to increase her gynecological colleagues’ awareness and prescribing of the oral HIV prevention pill. At the same time, she’s been tracking the development of a flexible vaginal ring loaded with a month’s worth of the HIV prevention medication dapivirine. That, she thought, would fit easily into women’s lives and into the toolbox of methods women already use to prevent pregnancy.

But now she’s not sure when – or if – the ring will find its way to her patients. In December, the ring’s maker, the International Partnership for Microbicides (IPM), pulled its application for FDA approval for the pre-exposure prophylaxis (PrEP) ring. Now, one year after the World Health Organization recommended the ring for member nations, there appears to be no path forward in the United States for either the dapivirine-only ring or an approach Dr. Rogers said would change the game: a vaginal ring that supplies both contraception and HIV prevention.

“It would take things to a whole other level,” she said. “It sucks that this happened, and I do think it was not anything medical. I think it was everything political.”

That leaves cisgender women – especially the Black and Latinx women who make up the vast majority of women who acquire HIV every year – with two HIV prevention options. One is the daily pill, first approved in 2012. It’s now generic but previously sold as Truvada by Gilead Sciences. The other is monthly injectable cabotegravir long-acting (Apretude). Another HIV prevention pill, tenofovir alafenamide/emtricitabine (Descovy), is approved for gay men and transgender women but not cisgender women.
 

Vagina-specific protection from HIV

The WHO recommendation for the vaginal ring was followed last July by a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) for women in low- and middle-income countries outside the European Union.

The flexible silicone ring, similar to the hormonal NuvaRing contraceptive, works by slowly releasing the antiretroviral dapivirine directly into the vaginal canal, thereby protecting women who might be exposed to the virus through vaginal sex only. Because the medicine stays where it’s delivered and doesn’t circulate through the body, it has been found to be extremely safe with few adverse events.

However, in initial studies, the ring was found to be just 27% effective overall. Later studies, where scientists divided women by how much drug was missing from the ring – a proxy for use – found that higher use was associated with higher protection (as much as 54%). By comparison, Truvada has been found to be up to 99% effective when used daily, though it can take up to 21 days to be available in the vagina in high enough concentrations to protect women from vaginal exposure. And the HIV prevention shot was found to be 90% more effective than that in a recent trial of the two methods conducted by the HIV Prevention Trials Network.

This, and an orientation away from topical HIV prevention drugs and toward systemic options, led the National Institute of Allergy and Infectious Diseases (NIAID) to discontinue funding for such projects under its Microbicide Trials Network.

“Clearly you want to counsel women to use the highest efficacy method, and that is part of our label,” Zeda Rosenberg, ScD, IPM’s founder and chief executive officer, told this news organization. “Women should not choose the ring if they can and will use oral PrEP, and I would argue it should be the same thing for [cabotegravir shots]. But if they can’t or don’t want to – and we know that especially many young women don’t want to use systemic methods – then the dapivirine ring is a great option.”

Still, Dr. Rosenberg said that the gap in efficacy, the relatively small number of women affected by HIV in the U.S. compared with gay and bisexual men, and the emergence of products like the HIV prevention shot cabotegravir, made it “very unlikely” that FDA regulators would approve the ring. And rather than be “distracted” by the FDA process, Dr. Rosenberg said IPM chose to concentrate on the countries where the ring has already been approved or where women make up the vast majority of people affected by HIV.

Zimbabwe publicly announced it has approved the ring, and three other countries may have approved it, according to Dr. Rosenberg. She declined to name them, saying they had requested silence while they formulate their new HIV prevention guidelines. Aside from Zimbabwe, the other countries where women participated in the ring clinical trials were South Africa, Malawi, and Uganda.

“The U.S. population ... has widespread access to oral PrEP, which is unlike countries in Africa, and which would have widespread access to injectable cabotegravir,” she said. “The U.S. FDA may not see choice in the same way that African women and African activists and advocates see the need for choice.”

But women’s rates of accessing HIV prevention medications in the U.S. continues to be frustratingly low. At the end of 2018, just 7% of women who could benefit from HIV prevention drugs were taking them, according to Centers for Disease Control and Prevention data.

New CDC guidelines recommend clinicians talk to every sexually active adult and adolescent about HIV prevention medications at least once and prescribe it to anyone who asks for it, whether or not they understand their patients’ HIV risks. However, research continues to show that clinicians struggle with willingness to prescribe PrEP to Black women, and the American College of Obstetrics and Gynecology’s committee opinion on managing women using HIV prevention drugs has not been updated to reflect the new guidelines. And while the HIV prevention shot is approved for women and its maker ViiV Healthcare is already initiating postmarket studies of the ring in key populations including women, there are lots of things that need to line up in order for clinicians to be willing to stock it and prescribe it to women.

From where Dázon Dixon Diallo, executive director of the nonprofit SisterLove, sits, the decision to withdraw the ring from FDA consideration and the FDA’s seeming argument that the epidemiology in the U.S. doesn’t warrant the ring’s approval is a slap in the face to the Black women who have led the movement to end HIV in the U.S. for decades.

“No matter how you slice it, we’re talking about Black women, and then we’re talking about brown women,” said Ms. Diallo. “The value [they place on us] from a government standpoint, from a political standpoint, from a public health standpoint is just woeful. It’s woeful and it’s disrespectful and it’s insulting and I’m sick of it.”
 

‘America sneezes and Africa catches a cold’

When she first heard the decision to pull the ring from FDA consideration, Yvette Raphael, the South Africa-based executive director of Advocates for the Prevention of HIV in Africa, started asking, “What can we do to help our sisters in America get this ring?” And then she started worrying about other women in her own country and those nearby.

“The FDA plays a big role,” she said. “You know, America sneezes and Africa catches a cold.”

She worries that IPM’s decision to withdraw the ring from FDA consideration will signal to regulators in other countries either (a) that they should not approve it or (b) in countries where it’s already been approved but guidelines have not been issued, that they won’t invest money in rolling it out to women in those countries – especially now with the U.S. approval of the prevention shot. In much of Africa, ministries of health prefer to provide injectable contraception, often giving women few or no other options. But women, she said, think about more than administration of the drug. They look at if it’s an easier option for them to manage.

“This is a long journey, an emotional one too, for women in South Africa, because the idea of a microbicide is one of the ideas that came directly from women in South Africa,” she said. “[The jab] can be seen as a solution to all. We can just give jabs to all the women. And after all, we know that women don’t adhere, so we can just grab them.”

Dr. Rosenberg pointed to the positive opinion from the EMA as another “rigorous review” process that she said ought to equally influence ministries of health in countries where women tested the ring. And she pointed to the WHO statement released last month, the same day as IPM’s announcement that it was withdrawing the ring from FDA considerations, recommitting the ring as a good option in sub-Saharan Africa: “The U.S. FDA decision is not based on any new or additional data on efficacy and safety,” it stated. “WHO will continue to support countries as they consider whether to include the [dapivirine vaginal ring]. WHO recognizes that country decisionmaking will vary based on their context and that women’s voices remain central to discussions about their prevention choices.”
 

Dual action ring on the horizon, but not in U.S.

What this means, though, is that the next step in the ring’s development – the combination dapivirine ring with contraceptive levonorgestrel (used in the Mirena intrauterine device) – may not come to the U.S., at least for a long while.

“It’s not out of the question,” Dr. Rosenberg said of conducting HIV/pregnancy prevention ring trials in the U.S. “But without the approval of the dapivirine-only ring by FDA, I imagine they would want to see new efficacy data on dapivirine. That is a very difficult hill to climb. There would have to be an active control group [using oral PrEP or injectable cabotegravir], and it would be very difficult for the dapivirine ring to be able to go head-to-head for either noninferiority and certainly for superiority.”

The study would need to be quite large to get enough results to prove anything, and IPM is a research organization, not a large pharmaceutical company with deep enough pockets to fund that, she said. Raising those funds “would be difficult.”

In addition to NIAID discontinuing its funding for the Microbicides Trials Network, a new 5-year, $85 million research collaboration through USAID hasn’t slated any money to fund trials of the combination HIV prevention and contraceptive ring, according to Dr. Rosenberg.

But that doesn’t mean avenues for its development are closed. NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is currently funding a phase 1/2 trial of the combination ring, and IPM continues to receive funding from research agencies in Germany, the Netherlands, Denmark, and Ireland. And this means, she said, that the E.U. – not the U.S. – is where they would seek approval for a combination ring first.

That leaves Ms. Rafael and Ms. Diallo debating how to work together to push the FDA – and maybe IPM – to reconsider the ring. For instance, Ms. Diallo suggested that instead of seeking an indication for all women, the FDA might consider the ring for women with very high risk of HIV, such as sex workers or women with HIV positive partners not on treatment. And she said that this has to be bigger than HIV prevention. It has to be about the ways in which women’s health issues in general lag at the FDA. For instance, she pointed to the movement to get contraceptive pills available over the counter, fights against FDA rulings on hormone replacement therapy, and fights for emergency contraception.

In the meantime, ob/gyn Dr. Rogers is expecting access to the ring to follow a similar path as the copper IUD, which migrated to the U.S. from Europe, where it has been among the most popular contraceptive methods for women.

“Contrary to what we may think, we are not innovators, especially for something like this,” she said. “Once we see it is working and doing a good job – that women in Europe love it – then someone here is going to pick it up and make it as if it’s the greatest thing. But for now, I think we’re going to have to take a back seat to Europe.”

Ms. Diallo reports receiving fees from Johnson & Johnson, ViiV Healthcare, and Gilead Sciences. Dr. Rosenberg and Dr. Rogers have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Tosha Rogers, MD, is a one-woman HIV prevention evangelist. For nearly a decade now, the Atlanta-based ob/gyn has been on a mission to increase her gynecological colleagues’ awareness and prescribing of the oral HIV prevention pill. At the same time, she’s been tracking the development of a flexible vaginal ring loaded with a month’s worth of the HIV prevention medication dapivirine. That, she thought, would fit easily into women’s lives and into the toolbox of methods women already use to prevent pregnancy.

But now she’s not sure when – or if – the ring will find its way to her patients. In December, the ring’s maker, the International Partnership for Microbicides (IPM), pulled its application for FDA approval for the pre-exposure prophylaxis (PrEP) ring. Now, one year after the World Health Organization recommended the ring for member nations, there appears to be no path forward in the United States for either the dapivirine-only ring or an approach Dr. Rogers said would change the game: a vaginal ring that supplies both contraception and HIV prevention.

“It would take things to a whole other level,” she said. “It sucks that this happened, and I do think it was not anything medical. I think it was everything political.”

That leaves cisgender women – especially the Black and Latinx women who make up the vast majority of women who acquire HIV every year – with two HIV prevention options. One is the daily pill, first approved in 2012. It’s now generic but previously sold as Truvada by Gilead Sciences. The other is monthly injectable cabotegravir long-acting (Apretude). Another HIV prevention pill, tenofovir alafenamide/emtricitabine (Descovy), is approved for gay men and transgender women but not cisgender women.
 

Vagina-specific protection from HIV

The WHO recommendation for the vaginal ring was followed last July by a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) for women in low- and middle-income countries outside the European Union.

The flexible silicone ring, similar to the hormonal NuvaRing contraceptive, works by slowly releasing the antiretroviral dapivirine directly into the vaginal canal, thereby protecting women who might be exposed to the virus through vaginal sex only. Because the medicine stays where it’s delivered and doesn’t circulate through the body, it has been found to be extremely safe with few adverse events.

However, in initial studies, the ring was found to be just 27% effective overall. Later studies, where scientists divided women by how much drug was missing from the ring – a proxy for use – found that higher use was associated with higher protection (as much as 54%). By comparison, Truvada has been found to be up to 99% effective when used daily, though it can take up to 21 days to be available in the vagina in high enough concentrations to protect women from vaginal exposure. And the HIV prevention shot was found to be 90% more effective than that in a recent trial of the two methods conducted by the HIV Prevention Trials Network.

This, and an orientation away from topical HIV prevention drugs and toward systemic options, led the National Institute of Allergy and Infectious Diseases (NIAID) to discontinue funding for such projects under its Microbicide Trials Network.

“Clearly you want to counsel women to use the highest efficacy method, and that is part of our label,” Zeda Rosenberg, ScD, IPM’s founder and chief executive officer, told this news organization. “Women should not choose the ring if they can and will use oral PrEP, and I would argue it should be the same thing for [cabotegravir shots]. But if they can’t or don’t want to – and we know that especially many young women don’t want to use systemic methods – then the dapivirine ring is a great option.”

Still, Dr. Rosenberg said that the gap in efficacy, the relatively small number of women affected by HIV in the U.S. compared with gay and bisexual men, and the emergence of products like the HIV prevention shot cabotegravir, made it “very unlikely” that FDA regulators would approve the ring. And rather than be “distracted” by the FDA process, Dr. Rosenberg said IPM chose to concentrate on the countries where the ring has already been approved or where women make up the vast majority of people affected by HIV.

Zimbabwe publicly announced it has approved the ring, and three other countries may have approved it, according to Dr. Rosenberg. She declined to name them, saying they had requested silence while they formulate their new HIV prevention guidelines. Aside from Zimbabwe, the other countries where women participated in the ring clinical trials were South Africa, Malawi, and Uganda.

“The U.S. population ... has widespread access to oral PrEP, which is unlike countries in Africa, and which would have widespread access to injectable cabotegravir,” she said. “The U.S. FDA may not see choice in the same way that African women and African activists and advocates see the need for choice.”

But women’s rates of accessing HIV prevention medications in the U.S. continues to be frustratingly low. At the end of 2018, just 7% of women who could benefit from HIV prevention drugs were taking them, according to Centers for Disease Control and Prevention data.

New CDC guidelines recommend clinicians talk to every sexually active adult and adolescent about HIV prevention medications at least once and prescribe it to anyone who asks for it, whether or not they understand their patients’ HIV risks. However, research continues to show that clinicians struggle with willingness to prescribe PrEP to Black women, and the American College of Obstetrics and Gynecology’s committee opinion on managing women using HIV prevention drugs has not been updated to reflect the new guidelines. And while the HIV prevention shot is approved for women and its maker ViiV Healthcare is already initiating postmarket studies of the ring in key populations including women, there are lots of things that need to line up in order for clinicians to be willing to stock it and prescribe it to women.

From where Dázon Dixon Diallo, executive director of the nonprofit SisterLove, sits, the decision to withdraw the ring from FDA consideration and the FDA’s seeming argument that the epidemiology in the U.S. doesn’t warrant the ring’s approval is a slap in the face to the Black women who have led the movement to end HIV in the U.S. for decades.

“No matter how you slice it, we’re talking about Black women, and then we’re talking about brown women,” said Ms. Diallo. “The value [they place on us] from a government standpoint, from a political standpoint, from a public health standpoint is just woeful. It’s woeful and it’s disrespectful and it’s insulting and I’m sick of it.”
 

‘America sneezes and Africa catches a cold’

When she first heard the decision to pull the ring from FDA consideration, Yvette Raphael, the South Africa-based executive director of Advocates for the Prevention of HIV in Africa, started asking, “What can we do to help our sisters in America get this ring?” And then she started worrying about other women in her own country and those nearby.

“The FDA plays a big role,” she said. “You know, America sneezes and Africa catches a cold.”

She worries that IPM’s decision to withdraw the ring from FDA consideration will signal to regulators in other countries either (a) that they should not approve it or (b) in countries where it’s already been approved but guidelines have not been issued, that they won’t invest money in rolling it out to women in those countries – especially now with the U.S. approval of the prevention shot. In much of Africa, ministries of health prefer to provide injectable contraception, often giving women few or no other options. But women, she said, think about more than administration of the drug. They look at if it’s an easier option for them to manage.

“This is a long journey, an emotional one too, for women in South Africa, because the idea of a microbicide is one of the ideas that came directly from women in South Africa,” she said. “[The jab] can be seen as a solution to all. We can just give jabs to all the women. And after all, we know that women don’t adhere, so we can just grab them.”

Dr. Rosenberg pointed to the positive opinion from the EMA as another “rigorous review” process that she said ought to equally influence ministries of health in countries where women tested the ring. And she pointed to the WHO statement released last month, the same day as IPM’s announcement that it was withdrawing the ring from FDA considerations, recommitting the ring as a good option in sub-Saharan Africa: “The U.S. FDA decision is not based on any new or additional data on efficacy and safety,” it stated. “WHO will continue to support countries as they consider whether to include the [dapivirine vaginal ring]. WHO recognizes that country decisionmaking will vary based on their context and that women’s voices remain central to discussions about their prevention choices.”
 

Dual action ring on the horizon, but not in U.S.

What this means, though, is that the next step in the ring’s development – the combination dapivirine ring with contraceptive levonorgestrel (used in the Mirena intrauterine device) – may not come to the U.S., at least for a long while.

“It’s not out of the question,” Dr. Rosenberg said of conducting HIV/pregnancy prevention ring trials in the U.S. “But without the approval of the dapivirine-only ring by FDA, I imagine they would want to see new efficacy data on dapivirine. That is a very difficult hill to climb. There would have to be an active control group [using oral PrEP or injectable cabotegravir], and it would be very difficult for the dapivirine ring to be able to go head-to-head for either noninferiority and certainly for superiority.”

The study would need to be quite large to get enough results to prove anything, and IPM is a research organization, not a large pharmaceutical company with deep enough pockets to fund that, she said. Raising those funds “would be difficult.”

In addition to NIAID discontinuing its funding for the Microbicides Trials Network, a new 5-year, $85 million research collaboration through USAID hasn’t slated any money to fund trials of the combination HIV prevention and contraceptive ring, according to Dr. Rosenberg.

But that doesn’t mean avenues for its development are closed. NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is currently funding a phase 1/2 trial of the combination ring, and IPM continues to receive funding from research agencies in Germany, the Netherlands, Denmark, and Ireland. And this means, she said, that the E.U. – not the U.S. – is where they would seek approval for a combination ring first.

That leaves Ms. Rafael and Ms. Diallo debating how to work together to push the FDA – and maybe IPM – to reconsider the ring. For instance, Ms. Diallo suggested that instead of seeking an indication for all women, the FDA might consider the ring for women with very high risk of HIV, such as sex workers or women with HIV positive partners not on treatment. And she said that this has to be bigger than HIV prevention. It has to be about the ways in which women’s health issues in general lag at the FDA. For instance, she pointed to the movement to get contraceptive pills available over the counter, fights against FDA rulings on hormone replacement therapy, and fights for emergency contraception.

In the meantime, ob/gyn Dr. Rogers is expecting access to the ring to follow a similar path as the copper IUD, which migrated to the U.S. from Europe, where it has been among the most popular contraceptive methods for women.

“Contrary to what we may think, we are not innovators, especially for something like this,” she said. “Once we see it is working and doing a good job – that women in Europe love it – then someone here is going to pick it up and make it as if it’s the greatest thing. But for now, I think we’re going to have to take a back seat to Europe.”

Ms. Diallo reports receiving fees from Johnson & Johnson, ViiV Healthcare, and Gilead Sciences. Dr. Rosenberg and Dr. Rogers have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A novel twist on the concept of “meeting people where they are” may hold the key to retaining new HIV patients, and even bringing the elusive goal of ending the AIDS epidemic a bit closer. While the concept commonly refers to community outreach and engagement, understanding patient experiences and expectations and personal life stressors in the actual clinic setting may improve overall outcomes, according to new research.

In fact, accounting for both expectations and life stressors may help physicians predict which patients will be lost to follow-up (LTFU) in the first year of HIV care.

“Medical science is not necessarily [at the forefront] of where we want to focus our efforts right now,” Emmanuel Guajardo, MD, lead study author and instructor of infectious diseases at Baylor College of Medicine, Houston, told this news organization. 

Rather, “we need to focus on retention in care and adherence to medications. Doubling down on these efforts could really go a long way toward ending the HIV epidemic,” he said. 

Study findings were published online Jan. 5, 2022, in AIDS and Behavior.
 

First time’s a charm

A total of 450 patients attending an HIV clinic in Houston were asked to complete a postvisit survey detailing their experience with the HIV clinician, as well as personal life stressors in the preceding 6 months. Study participants were predominantly non-Hispanic Black (54.2%) or Hispanic (30.7%) and mostly men who have sex with men (MSM), populations that mimic the patients seen at Dr. Guajardo’s clinic. Patients were given the option of survey completion while awaiting discharge, within 2 weeks at the clinic, or (as a last resort) by phone.

Overall scores were based on a composite of validated scales: patient experience scores were defined dichotomously (best experience, most positive experience vs. not the best experience), and life stressor events (death, relationship, economic) were assigned weighted scores based on life change impact (for example, death of a spouse received a score of 100 while moved/changed living location was assigned a score of 25).

“We found that patients who reported better initial experiences with their provider at the first visit were less likely to be lost to follow-up at 6 and 12 months,” explained Dr. Guajardo. “Having fewer life stressors at the first visit [was] also [protective].”

At 6 months, mean overall patient experience scores were 8.60 for those LTFU versus and 8.98 for those not LTFU (P = .011); corresponding mean scores at 12 months were 8.43 and 8.98 respectively (P = .001).

For the dichotomized scoring, patients reporting the best experience with the health care professional were significantly less likely to be LTFU at 6 months (adjusted odd ratio, 0.866; P = .038) and 12 months (aOR, 1.263; P = .029) versus those not reporting the best experience.

Mean life change scores appeared to portend patient drop-off; patients reporting more stressful life events were likelier to be LTFU at 6 months (mean life change score, 129 vs. 100 for those retained in care) and at 12 months (126 vs. 101). 

Corresponding multivariate logistic regression models controlling for age, baseline CD4 cell count less than 200, and diagnosis of at least 3 months showed that patients with higher life stressor burdens were significantly more likely to be LTFU at both 6 months (aOR, 1.232, P = .037) and 12 months (aOR, 1.263, P = .029).
 

Approach matters

“The [study] really hits the nail on the head in terms of identifying a couple of these very salient issues that affect people’s care, especially concerning HIV,” Philip A. Chan, MD, infectious disease specialist and associate professor of medicine at Brown University, Providence, R.I, told this news organization.

“It highlights things that we see on the ground that can interfere with HIV care or [pre-exposure prophylaxis] care, just health care in general, certainly one’s relationship with the physician or provider, and also, you know, real-life stressors,” said Dr. Chan, who was not involved with the study.

Relationship building is especially important for historically underserved populations, a point that’s hardly lost on either Dr. Chan or Dr. Guajardo, who both pointed to higher levels of mistrust among certain patient populations because of their mistreatment by the health care system. The answer? Let the patient lead the initial discussion, allow them to feel comfortable and participate in their care in ways that are most beneficial to them. 

“There’s so much miscommunication, misunderstanding, and stigma related to HIV out in the community. So, it’s important to really open the floor for whatever they want to talk about first, before I push any agenda on a new patient.” Dr. Guajardo said. Thereafter, he relies on open-ended questions such as ‘tell me about your sexual partners?’ or ‘what sort of sexual practices do you engage in?’ 

“At the end of the day, you just need someone dedicated, who can be respectful and listening and caring, and dedicate time to patients to help keep them in care, to listen, and to navigate our incredibly, incredibly complex health care system,” Dr. Chan added.

This study was partly supported by use of the facilities and resources of the Houston Veterans Affairs Center for Innovations in Quality, Effectiveness, and Safety and Harris Health System. Support for the study was also provided by the National Institute of Mental Health and the University of Texas MD Anderson Foundation Chair at Baylor College of Medicine. Dr. Guajardo and Dr. Chan disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A novel twist on the concept of “meeting people where they are” may hold the key to retaining new HIV patients, and even bringing the elusive goal of ending the AIDS epidemic a bit closer. While the concept commonly refers to community outreach and engagement, understanding patient experiences and expectations and personal life stressors in the actual clinic setting may improve overall outcomes, according to new research.

In fact, accounting for both expectations and life stressors may help physicians predict which patients will be lost to follow-up (LTFU) in the first year of HIV care.

“Medical science is not necessarily [at the forefront] of where we want to focus our efforts right now,” Emmanuel Guajardo, MD, lead study author and instructor of infectious diseases at Baylor College of Medicine, Houston, told this news organization. 

Rather, “we need to focus on retention in care and adherence to medications. Doubling down on these efforts could really go a long way toward ending the HIV epidemic,” he said. 

Study findings were published online Jan. 5, 2022, in AIDS and Behavior.
 

First time’s a charm

A total of 450 patients attending an HIV clinic in Houston were asked to complete a postvisit survey detailing their experience with the HIV clinician, as well as personal life stressors in the preceding 6 months. Study participants were predominantly non-Hispanic Black (54.2%) or Hispanic (30.7%) and mostly men who have sex with men (MSM), populations that mimic the patients seen at Dr. Guajardo’s clinic. Patients were given the option of survey completion while awaiting discharge, within 2 weeks at the clinic, or (as a last resort) by phone.

Overall scores were based on a composite of validated scales: patient experience scores were defined dichotomously (best experience, most positive experience vs. not the best experience), and life stressor events (death, relationship, economic) were assigned weighted scores based on life change impact (for example, death of a spouse received a score of 100 while moved/changed living location was assigned a score of 25).

“We found that patients who reported better initial experiences with their provider at the first visit were less likely to be lost to follow-up at 6 and 12 months,” explained Dr. Guajardo. “Having fewer life stressors at the first visit [was] also [protective].”

At 6 months, mean overall patient experience scores were 8.60 for those LTFU versus and 8.98 for those not LTFU (P = .011); corresponding mean scores at 12 months were 8.43 and 8.98 respectively (P = .001).

For the dichotomized scoring, patients reporting the best experience with the health care professional were significantly less likely to be LTFU at 6 months (adjusted odd ratio, 0.866; P = .038) and 12 months (aOR, 1.263; P = .029) versus those not reporting the best experience.

Mean life change scores appeared to portend patient drop-off; patients reporting more stressful life events were likelier to be LTFU at 6 months (mean life change score, 129 vs. 100 for those retained in care) and at 12 months (126 vs. 101). 

Corresponding multivariate logistic regression models controlling for age, baseline CD4 cell count less than 200, and diagnosis of at least 3 months showed that patients with higher life stressor burdens were significantly more likely to be LTFU at both 6 months (aOR, 1.232, P = .037) and 12 months (aOR, 1.263, P = .029).
 

Approach matters

“The [study] really hits the nail on the head in terms of identifying a couple of these very salient issues that affect people’s care, especially concerning HIV,” Philip A. Chan, MD, infectious disease specialist and associate professor of medicine at Brown University, Providence, R.I, told this news organization.

“It highlights things that we see on the ground that can interfere with HIV care or [pre-exposure prophylaxis] care, just health care in general, certainly one’s relationship with the physician or provider, and also, you know, real-life stressors,” said Dr. Chan, who was not involved with the study.

Relationship building is especially important for historically underserved populations, a point that’s hardly lost on either Dr. Chan or Dr. Guajardo, who both pointed to higher levels of mistrust among certain patient populations because of their mistreatment by the health care system. The answer? Let the patient lead the initial discussion, allow them to feel comfortable and participate in their care in ways that are most beneficial to them. 

“There’s so much miscommunication, misunderstanding, and stigma related to HIV out in the community. So, it’s important to really open the floor for whatever they want to talk about first, before I push any agenda on a new patient.” Dr. Guajardo said. Thereafter, he relies on open-ended questions such as ‘tell me about your sexual partners?’ or ‘what sort of sexual practices do you engage in?’ 

“At the end of the day, you just need someone dedicated, who can be respectful and listening and caring, and dedicate time to patients to help keep them in care, to listen, and to navigate our incredibly, incredibly complex health care system,” Dr. Chan added.

This study was partly supported by use of the facilities and resources of the Houston Veterans Affairs Center for Innovations in Quality, Effectiveness, and Safety and Harris Health System. Support for the study was also provided by the National Institute of Mental Health and the University of Texas MD Anderson Foundation Chair at Baylor College of Medicine. Dr. Guajardo and Dr. Chan disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A novel twist on the concept of “meeting people where they are” may hold the key to retaining new HIV patients, and even bringing the elusive goal of ending the AIDS epidemic a bit closer. While the concept commonly refers to community outreach and engagement, understanding patient experiences and expectations and personal life stressors in the actual clinic setting may improve overall outcomes, according to new research.

In fact, accounting for both expectations and life stressors may help physicians predict which patients will be lost to follow-up (LTFU) in the first year of HIV care.

“Medical science is not necessarily [at the forefront] of where we want to focus our efforts right now,” Emmanuel Guajardo, MD, lead study author and instructor of infectious diseases at Baylor College of Medicine, Houston, told this news organization. 

Rather, “we need to focus on retention in care and adherence to medications. Doubling down on these efforts could really go a long way toward ending the HIV epidemic,” he said. 

Study findings were published online Jan. 5, 2022, in AIDS and Behavior.
 

First time’s a charm

A total of 450 patients attending an HIV clinic in Houston were asked to complete a postvisit survey detailing their experience with the HIV clinician, as well as personal life stressors in the preceding 6 months. Study participants were predominantly non-Hispanic Black (54.2%) or Hispanic (30.7%) and mostly men who have sex with men (MSM), populations that mimic the patients seen at Dr. Guajardo’s clinic. Patients were given the option of survey completion while awaiting discharge, within 2 weeks at the clinic, or (as a last resort) by phone.

Overall scores were based on a composite of validated scales: patient experience scores were defined dichotomously (best experience, most positive experience vs. not the best experience), and life stressor events (death, relationship, economic) were assigned weighted scores based on life change impact (for example, death of a spouse received a score of 100 while moved/changed living location was assigned a score of 25).

“We found that patients who reported better initial experiences with their provider at the first visit were less likely to be lost to follow-up at 6 and 12 months,” explained Dr. Guajardo. “Having fewer life stressors at the first visit [was] also [protective].”

At 6 months, mean overall patient experience scores were 8.60 for those LTFU versus and 8.98 for those not LTFU (P = .011); corresponding mean scores at 12 months were 8.43 and 8.98 respectively (P = .001).

For the dichotomized scoring, patients reporting the best experience with the health care professional were significantly less likely to be LTFU at 6 months (adjusted odd ratio, 0.866; P = .038) and 12 months (aOR, 1.263; P = .029) versus those not reporting the best experience.

Mean life change scores appeared to portend patient drop-off; patients reporting more stressful life events were likelier to be LTFU at 6 months (mean life change score, 129 vs. 100 for those retained in care) and at 12 months (126 vs. 101). 

Corresponding multivariate logistic regression models controlling for age, baseline CD4 cell count less than 200, and diagnosis of at least 3 months showed that patients with higher life stressor burdens were significantly more likely to be LTFU at both 6 months (aOR, 1.232, P = .037) and 12 months (aOR, 1.263, P = .029).
 

Approach matters

“The [study] really hits the nail on the head in terms of identifying a couple of these very salient issues that affect people’s care, especially concerning HIV,” Philip A. Chan, MD, infectious disease specialist and associate professor of medicine at Brown University, Providence, R.I, told this news organization.

“It highlights things that we see on the ground that can interfere with HIV care or [pre-exposure prophylaxis] care, just health care in general, certainly one’s relationship with the physician or provider, and also, you know, real-life stressors,” said Dr. Chan, who was not involved with the study.

Relationship building is especially important for historically underserved populations, a point that’s hardly lost on either Dr. Chan or Dr. Guajardo, who both pointed to higher levels of mistrust among certain patient populations because of their mistreatment by the health care system. The answer? Let the patient lead the initial discussion, allow them to feel comfortable and participate in their care in ways that are most beneficial to them. 

“There’s so much miscommunication, misunderstanding, and stigma related to HIV out in the community. So, it’s important to really open the floor for whatever they want to talk about first, before I push any agenda on a new patient.” Dr. Guajardo said. Thereafter, he relies on open-ended questions such as ‘tell me about your sexual partners?’ or ‘what sort of sexual practices do you engage in?’ 

“At the end of the day, you just need someone dedicated, who can be respectful and listening and caring, and dedicate time to patients to help keep them in care, to listen, and to navigate our incredibly, incredibly complex health care system,” Dr. Chan added.

This study was partly supported by use of the facilities and resources of the Houston Veterans Affairs Center for Innovations in Quality, Effectiveness, and Safety and Harris Health System. Support for the study was also provided by the National Institute of Mental Health and the University of Texas MD Anderson Foundation Chair at Baylor College of Medicine. Dr. Guajardo and Dr. Chan disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Combining high-risk human papillomavirus (hrHPV)–based screening with cytologic triage detected two times more cases of grade 2+ cervical intraepithelial neoplasia (CIN2+) than cytology alone, according to a new study.

The study, which analyzed data from Mexico’s population-based hrHPV screening program over 6 years, confirms the importance of HPV screening for catching high-grade cervical lesions early.

“Our results provide evidence that hrHPV testing is the best strategy for a timely diagnosis of CIN2+ lesions while avoiding overtreatment of young women,” the study authors write. “Many countries now use hrHPV testing as the primary screening method, given it has higher sensitivity and detects more cervical cancer precursor lesions, such as CIN2+.”

According to Erik Jansen, MSc, the analysis supports recent updates to U.S. screening standards and confirms findings from previous trials, which show that HPV testing significantly improves prevention of cervical cancer.

“The significance of this paper is that the data reported is from a long follow-up in a country that implemented HPV screening on a large scale,” Mr. Jansen, PhD candidate in the Department of Public Health, Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization.

The study, conducted by Mexico’s National Institute of Public Health, analyzed screening data from the country’s public cervical cancer prevention program from 2010 to 2015. More than 2 million women aged 34 to 65 who had hrHPV-based screening tests followed by cytologic triage if they were HPV positive were included, as were 2.8 million women of the same age who received cytologic testing alone.

In the hrHPV group, 1.2% of women (n = 24,276) received referrals to colposcopy versus 3.1% of women (n = 90,980) in the cytology group. And among all women, only 0.8% who had abnormal results (n = 16,459) in the HPV went for a colposcopy versus 1.5% (n = 43,638) in the cytology group.

Overall, the authors found that 13.3 colposcopies were required to detect a single CIN2+ case in the cytology group compared to 5.7 colposcopies in the hrHPV with cytologic triage group.

The authors also note that the cost of colposcopies was three times lower in the HPV testing group and that the positive predictive value of hrHPV testing with cytologic triage was 17.5% versus 7.5% for cytology alone.

“The positive predictive value did not change for either screening strategy whether or not women lost to follow-up were taken into account,” the authors write.

Although Mr. Jansen noted that the findings are important, he also pointed to several limitations – namely, the significant loss to follow-up in the HPV group.

The HPV testing and cytologic triage happened in separate visits, and under the two-visit protocol, more than 50% of women who tested positive for HPV didn’t return for cytology. Such a significant loss to follow-up may call some of the findings into question, Mr. Jansen noted.

For instance, the rate of colposcopy referrals does not account for HPV-positive women who skipped their cytology screening. Assuming the same HPV risk for women who received cytology and those who did not, Mr. Jansen calculated that without any loss to follow-up, the colposcopy referral rate would have increased from the reported 1.2% to 2.6%, which is much closer to the 3.1% of the women referred in the cytology arm.

The lower colposcopy costs in the HPV group were also likely due, in part, to the loss to follow-up, which is not necessarily a good thing, Mr. Jansen said.

Still, “this study does confirm the finding that a primary HPV screening program is more effective than cytology [alone],” Mr. Jansen said.

Co-author Eduardo Franco reported receiving grants and personal fees from MSD and has a pending patent, “Methylation Markers in Cervical Cancer.” All other authors reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

Combining high-risk human papillomavirus (hrHPV)–based screening with cytologic triage detected two times more cases of grade 2+ cervical intraepithelial neoplasia (CIN2+) than cytology alone, according to a new study.

The study, which analyzed data from Mexico’s population-based hrHPV screening program over 6 years, confirms the importance of HPV screening for catching high-grade cervical lesions early.

“Our results provide evidence that hrHPV testing is the best strategy for a timely diagnosis of CIN2+ lesions while avoiding overtreatment of young women,” the study authors write. “Many countries now use hrHPV testing as the primary screening method, given it has higher sensitivity and detects more cervical cancer precursor lesions, such as CIN2+.”

According to Erik Jansen, MSc, the analysis supports recent updates to U.S. screening standards and confirms findings from previous trials, which show that HPV testing significantly improves prevention of cervical cancer.

“The significance of this paper is that the data reported is from a long follow-up in a country that implemented HPV screening on a large scale,” Mr. Jansen, PhD candidate in the Department of Public Health, Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization.

The study, conducted by Mexico’s National Institute of Public Health, analyzed screening data from the country’s public cervical cancer prevention program from 2010 to 2015. More than 2 million women aged 34 to 65 who had hrHPV-based screening tests followed by cytologic triage if they were HPV positive were included, as were 2.8 million women of the same age who received cytologic testing alone.

In the hrHPV group, 1.2% of women (n = 24,276) received referrals to colposcopy versus 3.1% of women (n = 90,980) in the cytology group. And among all women, only 0.8% who had abnormal results (n = 16,459) in the HPV went for a colposcopy versus 1.5% (n = 43,638) in the cytology group.

Overall, the authors found that 13.3 colposcopies were required to detect a single CIN2+ case in the cytology group compared to 5.7 colposcopies in the hrHPV with cytologic triage group.

The authors also note that the cost of colposcopies was three times lower in the HPV testing group and that the positive predictive value of hrHPV testing with cytologic triage was 17.5% versus 7.5% for cytology alone.

“The positive predictive value did not change for either screening strategy whether or not women lost to follow-up were taken into account,” the authors write.

Although Mr. Jansen noted that the findings are important, he also pointed to several limitations – namely, the significant loss to follow-up in the HPV group.

The HPV testing and cytologic triage happened in separate visits, and under the two-visit protocol, more than 50% of women who tested positive for HPV didn’t return for cytology. Such a significant loss to follow-up may call some of the findings into question, Mr. Jansen noted.

For instance, the rate of colposcopy referrals does not account for HPV-positive women who skipped their cytology screening. Assuming the same HPV risk for women who received cytology and those who did not, Mr. Jansen calculated that without any loss to follow-up, the colposcopy referral rate would have increased from the reported 1.2% to 2.6%, which is much closer to the 3.1% of the women referred in the cytology arm.

The lower colposcopy costs in the HPV group were also likely due, in part, to the loss to follow-up, which is not necessarily a good thing, Mr. Jansen said.

Still, “this study does confirm the finding that a primary HPV screening program is more effective than cytology [alone],” Mr. Jansen said.

Co-author Eduardo Franco reported receiving grants and personal fees from MSD and has a pending patent, “Methylation Markers in Cervical Cancer.” All other authors reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

Combining high-risk human papillomavirus (hrHPV)–based screening with cytologic triage detected two times more cases of grade 2+ cervical intraepithelial neoplasia (CIN2+) than cytology alone, according to a new study.

The study, which analyzed data from Mexico’s population-based hrHPV screening program over 6 years, confirms the importance of HPV screening for catching high-grade cervical lesions early.

“Our results provide evidence that hrHPV testing is the best strategy for a timely diagnosis of CIN2+ lesions while avoiding overtreatment of young women,” the study authors write. “Many countries now use hrHPV testing as the primary screening method, given it has higher sensitivity and detects more cervical cancer precursor lesions, such as CIN2+.”

According to Erik Jansen, MSc, the analysis supports recent updates to U.S. screening standards and confirms findings from previous trials, which show that HPV testing significantly improves prevention of cervical cancer.

“The significance of this paper is that the data reported is from a long follow-up in a country that implemented HPV screening on a large scale,” Mr. Jansen, PhD candidate in the Department of Public Health, Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization.

The study, conducted by Mexico’s National Institute of Public Health, analyzed screening data from the country’s public cervical cancer prevention program from 2010 to 2015. More than 2 million women aged 34 to 65 who had hrHPV-based screening tests followed by cytologic triage if they were HPV positive were included, as were 2.8 million women of the same age who received cytologic testing alone.

In the hrHPV group, 1.2% of women (n = 24,276) received referrals to colposcopy versus 3.1% of women (n = 90,980) in the cytology group. And among all women, only 0.8% who had abnormal results (n = 16,459) in the HPV went for a colposcopy versus 1.5% (n = 43,638) in the cytology group.

Overall, the authors found that 13.3 colposcopies were required to detect a single CIN2+ case in the cytology group compared to 5.7 colposcopies in the hrHPV with cytologic triage group.

The authors also note that the cost of colposcopies was three times lower in the HPV testing group and that the positive predictive value of hrHPV testing with cytologic triage was 17.5% versus 7.5% for cytology alone.

“The positive predictive value did not change for either screening strategy whether or not women lost to follow-up were taken into account,” the authors write.

Although Mr. Jansen noted that the findings are important, he also pointed to several limitations – namely, the significant loss to follow-up in the HPV group.

The HPV testing and cytologic triage happened in separate visits, and under the two-visit protocol, more than 50% of women who tested positive for HPV didn’t return for cytology. Such a significant loss to follow-up may call some of the findings into question, Mr. Jansen noted.

For instance, the rate of colposcopy referrals does not account for HPV-positive women who skipped their cytology screening. Assuming the same HPV risk for women who received cytology and those who did not, Mr. Jansen calculated that without any loss to follow-up, the colposcopy referral rate would have increased from the reported 1.2% to 2.6%, which is much closer to the 3.1% of the women referred in the cytology arm.

The lower colposcopy costs in the HPV group were also likely due, in part, to the loss to follow-up, which is not necessarily a good thing, Mr. Jansen said.

Still, “this study does confirm the finding that a primary HPV screening program is more effective than cytology [alone],” Mr. Jansen said.

Co-author Eduardo Franco reported receiving grants and personal fees from MSD and has a pending patent, “Methylation Markers in Cervical Cancer.” All other authors reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has stopped trials of oral and implant formulations of islatravir for HIV, the investigational drug’s developer, Merck, announced in a press release.

Investigational new drug applications were halted for the oral and implant formulations of islatravir, a nucleoside reverse transcriptase translocation inhibitor, for pre-exposure prophylaxis (PrEP); the injectable formulation of islatravir for treatment and prophylaxis; and the oral doravirine/islatravir (DOR/ISL) once-daily treatment, the company announced.

The FDA’s hold followed observations that total lymphocyte and T-cell counts had dropped in some participants receiving islatravir in clinical studies.

The trials have dealt a major setback to Merck’s HIV program momentum: Thirteen trials are now on hold (six on partial hold and seven on full hold). Seven of the trials were in phase 3. But primarily the news is disappointing for patients looking for options with the confounding disease.

Tristan Barber, MD, an HIV consultant with Royal Free London National Health Service Foundation Trust, told this news organization that “the hold on these studies is a blow for those hoping for longer-acting therapies for HIV treatment and prevention. Islatravir and [investigational drug] MK-8507 were being explored in oral and other formulations and potentially would offer a non-integrase, two-drug option, increasing options for people with HIV. Whilst we don’t know the clinical significance of these CD4 drops, [Merck] made the correct decision in pausing these studies until the data is clearer.”

Merck announced in November that it had stopped dosing in the phase 2 IMAGINE-DR clinical trial of islatravir in combination with MK-8507. MK-8507 and islatravir, alone and combined, are investigational and not approved for use.

In that trial as well, decreases were observed in total lymphocyte and T-cell counts in study participants randomly assigned to receive the combination. A review by the external Data Monitoring Committee determined that the drop was related to treatment with the combination.

“We are grateful to the participants and the study investigators for their ongoing contributions to this research,” Joan Butterton, MD, vice president of infectious diseases in Global Clinical Development at Merck Research Laboratories, said in a statement. “Merck continues to investigate the potential of islatravir and nucleoside reverse transcriptase translocation inhibitors and remains committed to helping to address unmet needs in HIV treatment and prevention.”

In light of the hold, no new studies using islatravir may be initiated. People currently receiving islatravir as part of the studies for PrEP, as well as injectable islatravir for treatment and prophylaxis, will no longer receive the study drug, and T-cell and lymphocyte counts will be monitored for recovery.

Those participating in the PrEP studies will be offered approved, once-daily, oral PrEP and those in studies of DOR/ISL who already started treatment will continue to receive study medication under a partial clinical hold.

A full list of the trials that have been placed on full or partial clinical holds can be found in the press release.

In an interview with this news organization, Monica Gandhi, MD, MPH, director of University of California, San Francisco’s Gladstone Center for AIDS Research, described the news of the islatravir trial holds as “very disappointing.”

“There were high hopes for this drug,” she said, adding that the hope was it would be paired with Gilead’s lenacapavir (another long-acting agent) for treatment and be able to give a once-weekly option for HIV treatment.

Lenacapavir is Gilead’s potential first-in-class, long-acting HIV-1 capsid inhibitor in development for treatment and prevention of HIV.

“Moreover,” she said, “additional hope was that, because of [islatravir’s] long half-life, it could be used as a monthly medication for pre-exposure prophylaxis.”

Gilead and Merck have decided to stop all dosing of participants in the phase 2 clinical trial evaluating an oral, weekly combination treatment of islatravir and lenacapavir in people living with HIV who are virologically suppressed on antiretroviral therapy, according to Merck’s press release.

Participants in that trial will stop taking the study drug and restart their previous antiretroviral regimen. According to the press release, both companies are considering whether a different dosing of islatravir combined with lenacapavir may become a once-weekly oral therapy option for people living with HIV.

Neither Merck nor Gilead representatives responded to request for comment by publication time.

Dr. Barber reported conference support, speaker fees, and advisory board honoraria from Gilead, Janssen, Merck, Roche, Thera, and ViiV and research/educational grants from Gilead, Roche, and ViiV. Dr. Gandhi has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has stopped trials of oral and implant formulations of islatravir for HIV, the investigational drug’s developer, Merck, announced in a press release.

Investigational new drug applications were halted for the oral and implant formulations of islatravir, a nucleoside reverse transcriptase translocation inhibitor, for pre-exposure prophylaxis (PrEP); the injectable formulation of islatravir for treatment and prophylaxis; and the oral doravirine/islatravir (DOR/ISL) once-daily treatment, the company announced.

The FDA’s hold followed observations that total lymphocyte and T-cell counts had dropped in some participants receiving islatravir in clinical studies.

The trials have dealt a major setback to Merck’s HIV program momentum: Thirteen trials are now on hold (six on partial hold and seven on full hold). Seven of the trials were in phase 3. But primarily the news is disappointing for patients looking for options with the confounding disease.

Tristan Barber, MD, an HIV consultant with Royal Free London National Health Service Foundation Trust, told this news organization that “the hold on these studies is a blow for those hoping for longer-acting therapies for HIV treatment and prevention. Islatravir and [investigational drug] MK-8507 were being explored in oral and other formulations and potentially would offer a non-integrase, two-drug option, increasing options for people with HIV. Whilst we don’t know the clinical significance of these CD4 drops, [Merck] made the correct decision in pausing these studies until the data is clearer.”

Merck announced in November that it had stopped dosing in the phase 2 IMAGINE-DR clinical trial of islatravir in combination with MK-8507. MK-8507 and islatravir, alone and combined, are investigational and not approved for use.

In that trial as well, decreases were observed in total lymphocyte and T-cell counts in study participants randomly assigned to receive the combination. A review by the external Data Monitoring Committee determined that the drop was related to treatment with the combination.

“We are grateful to the participants and the study investigators for their ongoing contributions to this research,” Joan Butterton, MD, vice president of infectious diseases in Global Clinical Development at Merck Research Laboratories, said in a statement. “Merck continues to investigate the potential of islatravir and nucleoside reverse transcriptase translocation inhibitors and remains committed to helping to address unmet needs in HIV treatment and prevention.”

In light of the hold, no new studies using islatravir may be initiated. People currently receiving islatravir as part of the studies for PrEP, as well as injectable islatravir for treatment and prophylaxis, will no longer receive the study drug, and T-cell and lymphocyte counts will be monitored for recovery.

Those participating in the PrEP studies will be offered approved, once-daily, oral PrEP and those in studies of DOR/ISL who already started treatment will continue to receive study medication under a partial clinical hold.

A full list of the trials that have been placed on full or partial clinical holds can be found in the press release.

In an interview with this news organization, Monica Gandhi, MD, MPH, director of University of California, San Francisco’s Gladstone Center for AIDS Research, described the news of the islatravir trial holds as “very disappointing.”

“There were high hopes for this drug,” she said, adding that the hope was it would be paired with Gilead’s lenacapavir (another long-acting agent) for treatment and be able to give a once-weekly option for HIV treatment.

Lenacapavir is Gilead’s potential first-in-class, long-acting HIV-1 capsid inhibitor in development for treatment and prevention of HIV.

“Moreover,” she said, “additional hope was that, because of [islatravir’s] long half-life, it could be used as a monthly medication for pre-exposure prophylaxis.”

Gilead and Merck have decided to stop all dosing of participants in the phase 2 clinical trial evaluating an oral, weekly combination treatment of islatravir and lenacapavir in people living with HIV who are virologically suppressed on antiretroviral therapy, according to Merck’s press release.

Participants in that trial will stop taking the study drug and restart their previous antiretroviral regimen. According to the press release, both companies are considering whether a different dosing of islatravir combined with lenacapavir may become a once-weekly oral therapy option for people living with HIV.

Neither Merck nor Gilead representatives responded to request for comment by publication time.

Dr. Barber reported conference support, speaker fees, and advisory board honoraria from Gilead, Janssen, Merck, Roche, Thera, and ViiV and research/educational grants from Gilead, Roche, and ViiV. Dr. Gandhi has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has stopped trials of oral and implant formulations of islatravir for HIV, the investigational drug’s developer, Merck, announced in a press release.

Investigational new drug applications were halted for the oral and implant formulations of islatravir, a nucleoside reverse transcriptase translocation inhibitor, for pre-exposure prophylaxis (PrEP); the injectable formulation of islatravir for treatment and prophylaxis; and the oral doravirine/islatravir (DOR/ISL) once-daily treatment, the company announced.

The FDA’s hold followed observations that total lymphocyte and T-cell counts had dropped in some participants receiving islatravir in clinical studies.

The trials have dealt a major setback to Merck’s HIV program momentum: Thirteen trials are now on hold (six on partial hold and seven on full hold). Seven of the trials were in phase 3. But primarily the news is disappointing for patients looking for options with the confounding disease.

Tristan Barber, MD, an HIV consultant with Royal Free London National Health Service Foundation Trust, told this news organization that “the hold on these studies is a blow for those hoping for longer-acting therapies for HIV treatment and prevention. Islatravir and [investigational drug] MK-8507 were being explored in oral and other formulations and potentially would offer a non-integrase, two-drug option, increasing options for people with HIV. Whilst we don’t know the clinical significance of these CD4 drops, [Merck] made the correct decision in pausing these studies until the data is clearer.”

Merck announced in November that it had stopped dosing in the phase 2 IMAGINE-DR clinical trial of islatravir in combination with MK-8507. MK-8507 and islatravir, alone and combined, are investigational and not approved for use.

In that trial as well, decreases were observed in total lymphocyte and T-cell counts in study participants randomly assigned to receive the combination. A review by the external Data Monitoring Committee determined that the drop was related to treatment with the combination.

“We are grateful to the participants and the study investigators for their ongoing contributions to this research,” Joan Butterton, MD, vice president of infectious diseases in Global Clinical Development at Merck Research Laboratories, said in a statement. “Merck continues to investigate the potential of islatravir and nucleoside reverse transcriptase translocation inhibitors and remains committed to helping to address unmet needs in HIV treatment and prevention.”

In light of the hold, no new studies using islatravir may be initiated. People currently receiving islatravir as part of the studies for PrEP, as well as injectable islatravir for treatment and prophylaxis, will no longer receive the study drug, and T-cell and lymphocyte counts will be monitored for recovery.

Those participating in the PrEP studies will be offered approved, once-daily, oral PrEP and those in studies of DOR/ISL who already started treatment will continue to receive study medication under a partial clinical hold.

A full list of the trials that have been placed on full or partial clinical holds can be found in the press release.

In an interview with this news organization, Monica Gandhi, MD, MPH, director of University of California, San Francisco’s Gladstone Center for AIDS Research, described the news of the islatravir trial holds as “very disappointing.”

“There were high hopes for this drug,” she said, adding that the hope was it would be paired with Gilead’s lenacapavir (another long-acting agent) for treatment and be able to give a once-weekly option for HIV treatment.

Lenacapavir is Gilead’s potential first-in-class, long-acting HIV-1 capsid inhibitor in development for treatment and prevention of HIV.

“Moreover,” she said, “additional hope was that, because of [islatravir’s] long half-life, it could be used as a monthly medication for pre-exposure prophylaxis.”

Gilead and Merck have decided to stop all dosing of participants in the phase 2 clinical trial evaluating an oral, weekly combination treatment of islatravir and lenacapavir in people living with HIV who are virologically suppressed on antiretroviral therapy, according to Merck’s press release.

Participants in that trial will stop taking the study drug and restart their previous antiretroviral regimen. According to the press release, both companies are considering whether a different dosing of islatravir combined with lenacapavir may become a once-weekly oral therapy option for people living with HIV.

Neither Merck nor Gilead representatives responded to request for comment by publication time.

Dr. Barber reported conference support, speaker fees, and advisory board honoraria from Gilead, Janssen, Merck, Roche, Thera, and ViiV and research/educational grants from Gilead, Roche, and ViiV. Dr. Gandhi has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Lower urinary tract symptoms (LUTS)are common and tend to increase in frequency with age. Managing LUTS can be complicated, requires an informed discussion between the primary care practitioner (PCP) and patient, and is best achieved by a thorough understanding of the many medical and surgical options available. Over the past 3 decades, medications have become the most common therapy; but recently, newer minimally invasive surgeries have challenged this paradigm. This article provides a comprehensive review for PCPs regarding the evaluation and management of LUTS in men and when to consider a urology referral.

Benign prostatic hyperplasia (BPH) and LUTS are common clinical encounters for most PCPs. About 50% of men will develop LUTS associated with BPH, and symptoms associated with these conditions increase as men age.^1,2 Studies have estimated that 90% of men aged 45 to 80 years demonstrate some symptoms of LUTS.³ Strong genetic influence seems to suggest heritability, but BPH also occurs in sporadic forms and is heavily influenced by androgens.⁴

BPH is a histologic diagnosis, whereas LUTS consists of complex symptomatology related to both static or dynamic components.¹ The enlarged prostate gland obstructs the urethra, simultaneously causing an increase in muscle tone and resistance at the bladder neck and prostatic urethra, leading to increased resistance to urine flow. As a result, there is a thickening of the detrusor muscles in the bladder wall and an overall decreased compliance. Urine becomes stored under increased pressure. These changes result in a weak or intermittent urine stream, incomplete emptying of the bladder, postvoid dribble, hesitancy, and irritative symptoms, such as urgency, frequency, and nocturia.

For many patients, BPH associated with LUTS is a quality of life (QOL) issue. The stigma associated with these symptoms often leads to delays in patients seeking care. Many patients do not seek treatment until symptoms have become so severe that changes in bladder health are often irreversible. Early intervention can dramatically improve a patient’s QOL. Also, early intervention has the potential to reduce overall health care expenditures. BPH-related spending exceeds $1 billion each year in the Medicare program alone.⁵

PCPs are in a unique position to help many patients who present with early-stage LUTS. Given the substantial impact this disease has on QOL, early recognition of symptoms and prompt treatment play a major role. Paramount to this effort is awareness and understanding of various treatments, their advantages, and adverse effects (AEs). This article highlights evidence-based evaluation and treatment of BPH/LUTS for PCPs who treat veterans and recommendations as to when to refer a patient to a urologist.

Evaluation of LUTS and BPH

Evaluation begins with a thorough medical history and physical examination. Particular attention should focus on ruling out other causes of LUTS, such as a urinary tract infection (UTI), acute prostatitis, malignancy, bladder dysfunction, neurogenic bladder, and other obstructive pathology, such as urethral stricture disease. The differential diagnosis of LUTS includes BPH, UTI, bladder neck obstruction, urethral stricture, bladder stones, polydipsia, overactive bladder (OAB), nocturnal polyuria, neurologic disease, genitourinary malignancy, renal failure, and acute/chronic urinary retention.⁶

Relevant medical history influencing urinary symptoms includes diabetes mellitus, underlying neurologic diseases, previous trauma, sexually transmitted infections, and certain medications. Symptom severity may be obtained using a validated questionnaire, such as the International Prostate Symptom Score (IPSS), which also aids clinicians in assessing the impact of LUTS on QOL. Additionally, urinary frequency or volume records (voiding diary) may help establish the severity of the patient’s symptoms and provide insight into other potential causes for LUTS. Patients with BPH often have concurrent erectile dysfunction (ED) or other sexual dysfunction symptoms. Patients should be evaluated for baseline sexual dysfunction before the initiation of treatment as many therapies worsen symptoms of ED or ejaculatory dysfunction.

A comprehensive physical examination with a focus on the genitourinary system should, at minimum, assess for abnormalities of the urethral meatus, prepuce, penis, groin nodes, and prior surgical scars. A digital rectal examination also should be performed. Although controversial, a digital rectal examination for prostate cancer screening may provide a rough estimate of prostate size, help rule out prostatitis, and detect incident prostate nodules. Prostate size does not necessarily correlate well with the degree of urinary obstruction or LUTS but is an important consideration when deciding among different therapies.¹

Laboratory and Adjunctive Tests

A urinalysis with microscopy helps identify other potential causes for urinary symptoms, including infection, proteinuria, or glucosuria. In patients who present with gross or microscopic hematuria, additional consideration should be given to bladder calculi and genitourinary cancer.² When a reversible source for the hematuria is not identified, these patients require referral to a urologist for a hematuria evaluation.

There is some controversy regarding prostate specific antigen (PSA) testing. Most professional organizations advocate for a shared decision-making approach before testing. The American Cancer Society recommends this informed discussion occur between the patient and the PCP for men aged > 50 years at average risk, men aged > 45 years at high risk of developing prostate cancer (African Americans or first-degree relative with early prostate cancer diagnosis), and aged 40 years for men with more than one first-degree relative with an early prostate cancer diagnosis.⁷

Adjunctive tests include postvoid residual (PVR), cystoscopy, uroflowmetry, urodynamics, and transrectal ultrasound. However, these are mostly performed by urologists. In some patients with bladder decompensation after prolonged partial bladder outlet obstruction, urodynamics may be used by urologists to determine whether a patient may benefit from an outlet obstruction procedure. Ordering additional imaging or serum studies for the assessment of LUTS is rarely helpful.

Treatment

Treatment includes management with or without lifestyle modification, medication administration, and surgical therapy. New to this paradigm are in-office minimally invasive surgical options. The goal of treatment is not only to reduce patient symptoms and improve QOL, but also to prevent the secondary sequala of urinary retention, bladder failure, and eventual renal impairment.⁷A basic understanding of these treatments can aid PCPs with appropriate patient counseling and urologic referral.⁸

Lifestyle and Behavior Modification

Behavior modification is the starting point for all patients with LUTS. Lifestyle modifications for LUTS include avoiding substances that exacerbate symptoms, such as α-agonists (decongestants), caffeine, alcohol, spicy/acidic foods, chocolate, and soda. These substances are known to be bladder irritants. Common medications contributing to LUTS include antidepressants, decongestants, antihistamines, bronchodilators, anticholinergics, and sympathomimetics. To decrease nocturia, behavioral modifications include limiting evening fluid intake, timed diuretic administration for patients already on a diuretic, and elevating legs 1 hour before bedtime. Counseling obese patients to lose weight and increasing physical activity have been linked to reduced LUTS.⁹ Other behavioral techniques include double voiding: a technique where patients void normally then change positions and return to void to empty the bladder. Another technique is timed voiding: Many patients have impaired sensation when the bladder is full. These patients are encouraged to void at regular intervals.

Complementary and Alternative Medicine

Multiple nutraceutical compounds claim improved urinary health and symptom reduction. These compounds are marketed to patients with little regulation and oversight since supplements are not regulated or held to the same standard as prescription medications. The most popular nutraceutical for prostate health and LUTS is saw palmetto. Despite its common usage for the treatment of LUTS, little data support saw palmetto health claims. In 2012, a systematic review of 32 randomized trials including 5666 patients compared saw palmetto with a placebo. The study found no difference in urinary symptom scores, urinary flow, or prostate size.^10,11 Other phytotherapy compounds often considered for urinary symptoms include stinging nettle extract and β-sitosterol compounds. The mechanism of action of these agents is unknown and efficacy data are lacking.

Historically, acupuncture and pelvic floor physical therapy have been used successfully for OAB symptoms. A meta-analysis found positive beneficial effects of acupuncture compared with a sham control for short- and medium-term follow-up in both IPSS and urine flow rates in some studies; however, when combining the studies for more statistical power, the benefits were less clear.¹² Physical therapists with specialized training and certification in pelvic health can incorporate certain bladder training techniques. These include voiding positional changes (double voiding and postvoid urethral milking) and timed voiding.^13,14 These interventions often address etiologies of LUTS for which medical therapies are not effective as the sole treatment option.

Medication Management

Medical management includes α-blockers, 5-α-reductase inhibitors (5-α-RIs), antimuscarinic or anticholinergic medicines, β-3 agonists, and phosphodiesterase inhibitors (Table). These medications work independently as well as synergistically. The use of medications to improve symptoms must be balanced against potential AEs and the consequences of a lifetime of drug usage, which can be additive.^15,16

First-line pharmacological therapy for BPH is α-blockers, which work by blocking α1A receptors in the prostate and bladder neck, leading to smooth muscle relaxation, increased diameter of the channel, and improved urinary flow. α-receptors in the bladder neck and prostate are expressed with increased frequency with age and are a potential cause for worsening symptoms as men age. Studies demonstrate that these medications reduce symptoms by 30 to 40% and increase flow rates by 16 to 25%.¹⁷ Commonly prescribed α-blockers include tamsulosin, alfuzosin, silodosin, doxazosin, and terazosin. Doxazosin and terazosin require dose titrations because they may cause significant hypotension. Orthostatic hypotension typically improves with time and is avoided if the patient takes the medication at bedtime. Both doxazosin and terazosin are on the American Geriatric Society’s Beers Criteria list and should be avoided in older patients.¹⁸ Tamsulosin, alfuzosin, and silodosin have a standardized dosing regimen and lower rates of hypotension. Significant AEs include ejaculation dysfunction, nasal congestion, and orthostatic hypotension. Duan and colleagues have linked tamsulosin with dementia. However, this association is not causal and further studies are necessary.^19,20 Patients who have taken these agents also are at risk for intraoperative floppy iris syndrome (IFIS). Permanent visual problems can arise if the intraoperative management is not managed to account for IFIS. These medications have a rapid onset of action and work immediately. However, to reach maximum benefit, patients must take the medication for several weeks. Unfortunately, up to one-third of patients will have no improvement with α-blocker therapy, and many patients will discontinue these medications because of significant AEs.^6,21

5-α-RIs (finasteride and dutasteride) inhibit the conversion of testosterone to more potent dihydrotestosterone. They effectively reduce prostate volume by 25 to 30%.²² The results occur slowly and can take 6 to 12 months to reach the desired outcome. These medications are effective in men with larger prostates and not as effective in men with smaller prostates.²³ These medications can improve urinary flow rates by about 10%, reduce IPSS scores by 20 to 30%, reduce the risk of urinary retention by 50%, and reduce the progression of BPH to the point where surgery is required by 50%.²⁴ Furthermore, 5-α-RIs lower PSA by > 50% after 12 months of treatment.²⁵

A baseline PSA should be established before administration and after 6 months of treatment. Any increase in the PSA even if the level is within normal limits should be evaluated for prostate cancer. Sarkar and colleagues recently published a study evaluating prostate cancer diagnosis in patients treated with 5-α-RI and found there was a delay in diagnosing prostate cancer in this population. Controversy also exists as to the potential of these medications increasing the risk for high-grade prostate cancer, which has led to a US Food and Drug Administration (FDA) warning. AEs include decreased libido (1.5%), ejaculatory dysfunction (3.4%), gynecomastia (1.3%), and/or ED (1.6%).^26-28 A recent study evaluating 5-α-RIs demonstrated about a 2-fold increased risk of depression.²⁹

There are well-established studies that note increased effectiveness when using combined α-blocker therapy with 5-α-RI medications. The Medical Therapy of Prostate Symptoms (MTOPS) and Combination Avodart and Tamsulosin (CombAT) trials showed that the combination of both medications was more effective in improving voiding symptoms and flow rates than either agent alone.^15,16 Combination therapy resulted in a 66% reduction in disease progression, 81% reduction in urinary retention, and a 67% reduction in the need for surgery compared with placebo.

Anticholinergic medication use in BPH with LUTS is well established, and their use is often combined with other therapies. Anticholinergics work by inhibiting muscarinic M3 receptors to reduce detrusor muscle contraction. This effectively decreases bladder contractions and delays the desire to void. Kaplan and colleagues showed that tolterodine significantly improved a patient’s QOL when added to α-blocker therapy.³⁰ Patients reported a positive outcome at 12 weeks, which resulted in a reduction in urgency incontinence, urgency, nocturia, and the overall number of voiding episodes within 24 hours.

β-3 agonists are a class of medications for OAB; mirabegron and vibegron have proven effective in reducing similar symptoms. In phase 3 clinical trials, mirabegron improved urinary incontinence episodes by 50% and reduced the number of voids in 24 hours.³¹ Mirabegron is well tolerated and avoids many common anticholinergic effects.³² Vibegron is the newest medication in the class and could soon become the preferred agent given it does not have cytochrome P450 interactions and does not cause hypertension like mirabegron.³³

Anticholinergics should be used with caution in patients with a history of urinary retention, elevated after-void residual, or other medications with known anticholinergic effects. AEs include sedation, confusion, dry mouth, constipation, and potential falls in older patients.¹⁸ Recent studies have noted an association with dementia in the prolonged use of these medications in older patients and should be used cautiously.²⁰

Phosphodiesterase-5 enzyme inhibitors (PDE-5) are adjunctive medications shown to improve LUTS. This class of medication is prescribed mostly for ED. However, tadalafil 5 mg taken daily also is FDA approved for the treatment of LUTS secondary to BPH given its prolonged half-life. The exact mechanism for improved BPH symptoms is unknown. Possibly the effects are due to an increase mediated by PDE-5 in cyclic guanosine monophosphate (cGMP), which increases smooth muscle relaxation and tissue perfusion of the prostate and bladder.³⁴ There have been limited studies on objective improvement in uroflowmetry parameters compared with other treatments. The daily dosing of tadalafil should not be prescribed in men with a creatinine clearance < 30 mL/min.²⁹ Tadalafil is not considered a first-line agent and is usually reserved for patients who experience ED in addition to BPH. When initiating BPH pharmacologic therapy, the PCP should be aware of adherence and high discontinuation rates.³⁵

Surgical Treatments

Surgical treatments are often delayed out of fear of potential AEs or considered a last resort when symptoms are too severe.³⁶ Early intervention is required to prevent irreversible deleterious changes to detrusor muscle structure and function (Figure). Patients fear urinary incontinence, ED or ejaculatory dysfunction, and anesthesia complications associated with surgical interventions.^6,37 Multiple studies show that patients fare better with early surgical intervention, experiencing improved IPSS scores, urinary flow, and QOL. The following is an overview of the most popular procedures.

Prostatic urethral lift (PUL) using the UroLift System is an FDA-approved, minimally-invasive treatment of LUTS secondary to BPH. This procedure treats prostates < 80 g with an absent median lobe.^6,21,38 Permanent implants are placed per the prostatic urethra to displace obstructing prostate tissue laterally. This opens the urethra directly without cutting, heating, or removing any prostate tissue. This procedure is minimally invasive, often done in the office as an outpatient procedure, and offers better symptom relief than medication with a lower risk profile than transurethral resection of the prostate (TURP).^39,40 The LIFT study was a multicenter, randomized, blinded trial; patients were randomized 2:1 to undergo UroLift or a sham operation. At 3 years, average improvements were statistically significant for total IPSS reduction (41%), QOL improvement (49%), and improved maximum flow rates by (51%).⁴¹ Risk for urinary incontinence is low, and the procedure has been shown to preserve erectile and ejaculatory function. Furthermore, patients report significant improvement in their QOL without the need for medications. Surgical retreatment rates at 5 years are 13.6%, with an additional 10.7% of subjects back on medication therapy with α-blockers or 5-α-RIs.⁴²

Water vapor thermal therapy or Rez¯um uses steam as thermal energy to destroy obstructing prostate tissue and relieve the obstruction.⁴³ The procedure differs from older conductive heat thermotherapies because the steam penetrates prostate zonal anatomy without affecting areas outside the targeted treatment zone. The procedure is done in the office with local anesthesia and provides long-lasting relief of LUTS with minimal risks. Following the procedure, patients require an indwelling urethral catheter for 3 to 7 days, and most patients begin to experience symptom improvement 2 to 4 weeks following the procedure.⁴⁴ The procedure received FDA approval in 2015. Four-year data show significant improvement in maximal flow rate (50%), IPSS (47%), and QOL (43%).⁴⁵ Surgical retreatment rates were 4.4%. Criticisms of this treatment include patient discomfort with the office procedure, the requirement for an indwelling catheter for a short period, and lack of long-term outcomes data. Guidelines support use in prostate volumes > 80 g with or without median lobe anatomy.

TURP is the gold standard to which other treatments are compared.⁴⁶ The surgery is performed in the operating room where urologists use a rigid cystoscope and resection element to effectively carve out and cauterize obstructing prostate tissue. Patients typically recover for a short period with an indwelling urethral catheter that is often removed 12 to 24 hours after surgery. New research points out that despite increasing mean age (55% of patients are aged > 70 years with associated comorbidities), the morbidity of TURP was < 1% and mortality rate of 0 to 0.3%.⁴⁷ Postoperative complications include bleeding that requires a transfusion (3%), retrograde ejaculation (65%), and rare urinary incontinence (2%).⁴⁷ Surgical retreatment rates for patients following a TURP are approximately 13 to 15% at 8 years.³⁴

Laser surgery for BPH includes multiple techniques: photovaporization of the prostate using a Greenlight XPS laser, holmium laser ablation, and holmium laser enucleation (HoLEP). Proponents of these treatments cite lower bleeding risks compared with TURP, but the operation is largely surgeon dependent on the technology chosen. Most studies comparing these technologies with TURP show similar outcomes of IPSS reports, quality of life improvements, and complications.

Patients with extremely large prostates, > 100 g or 4 times the normal size, pose a unique challenge to surgical treatment. Historically, patients were treated with an open simple prostatectomy operation or staged TURP procedures. Today, urologists use newer, safer ways to treat these patients. Both HoLEP and robot-assisted simple prostatectomy work well in relieving urinary symptoms with lower complications compared with older open surgery. Other minimally invasive procedures, such as prostatic artery embolism, have been described for the treatment of BPH specifically in men who may be unfit for surgery.⁴⁸Future treatments are constantly evolving. Many unanswered questions remain about BPH and the role of inflammation, metabolic dysfunction, obesity, and other genetic factors driving BPH and prostate growth. Pharmaceutical opportunities exist in mechanisms aimed to reduce prostate growth, induce cellular apoptosis, as well as other drugs to reduce bladder symptoms. Newer, minimally invasive therapies also will become more readily available, such as Aquablation, which is the first FDA-granted surgical robot for the autonomous removal of prostatic tissue due to BPH.⁴⁹ However, the goal of all future therapies should include the balance of alleviating disruptive symptoms while demonstrating a favorable risk profile. Many men discontinue taking medications, yet few present for surgery. Most concerning is the significant population of men who will develop irreversible bladder dysfunction while waiting for the perfect treatment. There are many opportunities for an effective treatment that is less invasive than surgery, provides durable relief, has minimal AEs, and is affordable.

Conclusions

There is no perfect treatment for patients with LUTS. All interventions have potential AEs and associated complications. Medications are often started as first-line therapy but are often discontinued at the onset of significant AEs. This process is often repeated. Many patients will try different medications without any significant improvement in their symptoms or short-term relief, which results in the gradual progression of the disease.

The PCP plays a significant role in the initial evaluation and management of BPH. These frontline clinicians can recognize patients who may already be experiencing sequela of prolonged bladder outlet obstruction and refer these men to urologists promptly. Counseling patients about their treatment options is an important duty for all PCPs.

A clear understanding of the available treatment options will help PCPs counsel patients appropriately about lifestyle modification, medications, and surgical treatment options for their symptoms. The treatment of this disorder is a rapidly evolving topic with the constant introduction of new technologies and medications, which are certain to continue to play an important role for PCPs and urologists.

Lower urinary tract symptoms (LUTS)are common and tend to increase in frequency with age. Managing LUTS can be complicated, requires an informed discussion between the primary care practitioner (PCP) and patient, and is best achieved by a thorough understanding of the many medical and surgical options available. Over the past 3 decades, medications have become the most common therapy; but recently, newer minimally invasive surgeries have challenged this paradigm. This article provides a comprehensive review for PCPs regarding the evaluation and management of LUTS in men and when to consider a urology referral.

Benign prostatic hyperplasia (BPH) and LUTS are common clinical encounters for most PCPs. About 50% of men will develop LUTS associated with BPH, and symptoms associated with these conditions increase as men age.^1,2 Studies have estimated that 90% of men aged 45 to 80 years demonstrate some symptoms of LUTS.³ Strong genetic influence seems to suggest heritability, but BPH also occurs in sporadic forms and is heavily influenced by androgens.⁴

BPH is a histologic diagnosis, whereas LUTS consists of complex symptomatology related to both static or dynamic components.¹ The enlarged prostate gland obstructs the urethra, simultaneously causing an increase in muscle tone and resistance at the bladder neck and prostatic urethra, leading to increased resistance to urine flow. As a result, there is a thickening of the detrusor muscles in the bladder wall and an overall decreased compliance. Urine becomes stored under increased pressure. These changes result in a weak or intermittent urine stream, incomplete emptying of the bladder, postvoid dribble, hesitancy, and irritative symptoms, such as urgency, frequency, and nocturia.

For many patients, BPH associated with LUTS is a quality of life (QOL) issue. The stigma associated with these symptoms often leads to delays in patients seeking care. Many patients do not seek treatment until symptoms have become so severe that changes in bladder health are often irreversible. Early intervention can dramatically improve a patient’s QOL. Also, early intervention has the potential to reduce overall health care expenditures. BPH-related spending exceeds $1 billion each year in the Medicare program alone.⁵

PCPs are in a unique position to help many patients who present with early-stage LUTS. Given the substantial impact this disease has on QOL, early recognition of symptoms and prompt treatment play a major role. Paramount to this effort is awareness and understanding of various treatments, their advantages, and adverse effects (AEs). This article highlights evidence-based evaluation and treatment of BPH/LUTS for PCPs who treat veterans and recommendations as to when to refer a patient to a urologist.

Evaluation of LUTS and BPH

Evaluation begins with a thorough medical history and physical examination. Particular attention should focus on ruling out other causes of LUTS, such as a urinary tract infection (UTI), acute prostatitis, malignancy, bladder dysfunction, neurogenic bladder, and other obstructive pathology, such as urethral stricture disease. The differential diagnosis of LUTS includes BPH, UTI, bladder neck obstruction, urethral stricture, bladder stones, polydipsia, overactive bladder (OAB), nocturnal polyuria, neurologic disease, genitourinary malignancy, renal failure, and acute/chronic urinary retention.⁶

Relevant medical history influencing urinary symptoms includes diabetes mellitus, underlying neurologic diseases, previous trauma, sexually transmitted infections, and certain medications. Symptom severity may be obtained using a validated questionnaire, such as the International Prostate Symptom Score (IPSS), which also aids clinicians in assessing the impact of LUTS on QOL. Additionally, urinary frequency or volume records (voiding diary) may help establish the severity of the patient’s symptoms and provide insight into other potential causes for LUTS. Patients with BPH often have concurrent erectile dysfunction (ED) or other sexual dysfunction symptoms. Patients should be evaluated for baseline sexual dysfunction before the initiation of treatment as many therapies worsen symptoms of ED or ejaculatory dysfunction.

A comprehensive physical examination with a focus on the genitourinary system should, at minimum, assess for abnormalities of the urethral meatus, prepuce, penis, groin nodes, and prior surgical scars. A digital rectal examination also should be performed. Although controversial, a digital rectal examination for prostate cancer screening may provide a rough estimate of prostate size, help rule out prostatitis, and detect incident prostate nodules. Prostate size does not necessarily correlate well with the degree of urinary obstruction or LUTS but is an important consideration when deciding among different therapies.¹

Laboratory and Adjunctive Tests

A urinalysis with microscopy helps identify other potential causes for urinary symptoms, including infection, proteinuria, or glucosuria. In patients who present with gross or microscopic hematuria, additional consideration should be given to bladder calculi and genitourinary cancer.² When a reversible source for the hematuria is not identified, these patients require referral to a urologist for a hematuria evaluation.

There is some controversy regarding prostate specific antigen (PSA) testing. Most professional organizations advocate for a shared decision-making approach before testing. The American Cancer Society recommends this informed discussion occur between the patient and the PCP for men aged > 50 years at average risk, men aged > 45 years at high risk of developing prostate cancer (African Americans or first-degree relative with early prostate cancer diagnosis), and aged 40 years for men with more than one first-degree relative with an early prostate cancer diagnosis.⁷

Adjunctive tests include postvoid residual (PVR), cystoscopy, uroflowmetry, urodynamics, and transrectal ultrasound. However, these are mostly performed by urologists. In some patients with bladder decompensation after prolonged partial bladder outlet obstruction, urodynamics may be used by urologists to determine whether a patient may benefit from an outlet obstruction procedure. Ordering additional imaging or serum studies for the assessment of LUTS is rarely helpful.

Treatment

Treatment includes management with or without lifestyle modification, medication administration, and surgical therapy. New to this paradigm are in-office minimally invasive surgical options. The goal of treatment is not only to reduce patient symptoms and improve QOL, but also to prevent the secondary sequala of urinary retention, bladder failure, and eventual renal impairment.⁷A basic understanding of these treatments can aid PCPs with appropriate patient counseling and urologic referral.⁸

Lifestyle and Behavior Modification

Behavior modification is the starting point for all patients with LUTS. Lifestyle modifications for LUTS include avoiding substances that exacerbate symptoms, such as α-agonists (decongestants), caffeine, alcohol, spicy/acidic foods, chocolate, and soda. These substances are known to be bladder irritants. Common medications contributing to LUTS include antidepressants, decongestants, antihistamines, bronchodilators, anticholinergics, and sympathomimetics. To decrease nocturia, behavioral modifications include limiting evening fluid intake, timed diuretic administration for patients already on a diuretic, and elevating legs 1 hour before bedtime. Counseling obese patients to lose weight and increasing physical activity have been linked to reduced LUTS.⁹ Other behavioral techniques include double voiding: a technique where patients void normally then change positions and return to void to empty the bladder. Another technique is timed voiding: Many patients have impaired sensation when the bladder is full. These patients are encouraged to void at regular intervals.

Complementary and Alternative Medicine

Multiple nutraceutical compounds claim improved urinary health and symptom reduction. These compounds are marketed to patients with little regulation and oversight since supplements are not regulated or held to the same standard as prescription medications. The most popular nutraceutical for prostate health and LUTS is saw palmetto. Despite its common usage for the treatment of LUTS, little data support saw palmetto health claims. In 2012, a systematic review of 32 randomized trials including 5666 patients compared saw palmetto with a placebo. The study found no difference in urinary symptom scores, urinary flow, or prostate size.^10,11 Other phytotherapy compounds often considered for urinary symptoms include stinging nettle extract and β-sitosterol compounds. The mechanism of action of these agents is unknown and efficacy data are lacking.

Historically, acupuncture and pelvic floor physical therapy have been used successfully for OAB symptoms. A meta-analysis found positive beneficial effects of acupuncture compared with a sham control for short- and medium-term follow-up in both IPSS and urine flow rates in some studies; however, when combining the studies for more statistical power, the benefits were less clear.¹² Physical therapists with specialized training and certification in pelvic health can incorporate certain bladder training techniques. These include voiding positional changes (double voiding and postvoid urethral milking) and timed voiding.^13,14 These interventions often address etiologies of LUTS for which medical therapies are not effective as the sole treatment option.

Medication Management

Medical management includes α-blockers, 5-α-reductase inhibitors (5-α-RIs), antimuscarinic or anticholinergic medicines, β-3 agonists, and phosphodiesterase inhibitors (Table). These medications work independently as well as synergistically. The use of medications to improve symptoms must be balanced against potential AEs and the consequences of a lifetime of drug usage, which can be additive.^15,16

First-line pharmacological therapy for BPH is α-blockers, which work by blocking α1A receptors in the prostate and bladder neck, leading to smooth muscle relaxation, increased diameter of the channel, and improved urinary flow. α-receptors in the bladder neck and prostate are expressed with increased frequency with age and are a potential cause for worsening symptoms as men age. Studies demonstrate that these medications reduce symptoms by 30 to 40% and increase flow rates by 16 to 25%.¹⁷ Commonly prescribed α-blockers include tamsulosin, alfuzosin, silodosin, doxazosin, and terazosin. Doxazosin and terazosin require dose titrations because they may cause significant hypotension. Orthostatic hypotension typically improves with time and is avoided if the patient takes the medication at bedtime. Both doxazosin and terazosin are on the American Geriatric Society’s Beers Criteria list and should be avoided in older patients.¹⁸ Tamsulosin, alfuzosin, and silodosin have a standardized dosing regimen and lower rates of hypotension. Significant AEs include ejaculation dysfunction, nasal congestion, and orthostatic hypotension. Duan and colleagues have linked tamsulosin with dementia. However, this association is not causal and further studies are necessary.^19,20 Patients who have taken these agents also are at risk for intraoperative floppy iris syndrome (IFIS). Permanent visual problems can arise if the intraoperative management is not managed to account for IFIS. These medications have a rapid onset of action and work immediately. However, to reach maximum benefit, patients must take the medication for several weeks. Unfortunately, up to one-third of patients will have no improvement with α-blocker therapy, and many patients will discontinue these medications because of significant AEs.^6,21

5-α-RIs (finasteride and dutasteride) inhibit the conversion of testosterone to more potent dihydrotestosterone. They effectively reduce prostate volume by 25 to 30%.²² The results occur slowly and can take 6 to 12 months to reach the desired outcome. These medications are effective in men with larger prostates and not as effective in men with smaller prostates.²³ These medications can improve urinary flow rates by about 10%, reduce IPSS scores by 20 to 30%, reduce the risk of urinary retention by 50%, and reduce the progression of BPH to the point where surgery is required by 50%.²⁴ Furthermore, 5-α-RIs lower PSA by > 50% after 12 months of treatment.²⁵

A baseline PSA should be established before administration and after 6 months of treatment. Any increase in the PSA even if the level is within normal limits should be evaluated for prostate cancer. Sarkar and colleagues recently published a study evaluating prostate cancer diagnosis in patients treated with 5-α-RI and found there was a delay in diagnosing prostate cancer in this population. Controversy also exists as to the potential of these medications increasing the risk for high-grade prostate cancer, which has led to a US Food and Drug Administration (FDA) warning. AEs include decreased libido (1.5%), ejaculatory dysfunction (3.4%), gynecomastia (1.3%), and/or ED (1.6%).^26-28 A recent study evaluating 5-α-RIs demonstrated about a 2-fold increased risk of depression.²⁹

There are well-established studies that note increased effectiveness when using combined α-blocker therapy with 5-α-RI medications. The Medical Therapy of Prostate Symptoms (MTOPS) and Combination Avodart and Tamsulosin (CombAT) trials showed that the combination of both medications was more effective in improving voiding symptoms and flow rates than either agent alone.^15,16 Combination therapy resulted in a 66% reduction in disease progression, 81% reduction in urinary retention, and a 67% reduction in the need for surgery compared with placebo.

Anticholinergic medication use in BPH with LUTS is well established, and their use is often combined with other therapies. Anticholinergics work by inhibiting muscarinic M3 receptors to reduce detrusor muscle contraction. This effectively decreases bladder contractions and delays the desire to void. Kaplan and colleagues showed that tolterodine significantly improved a patient’s QOL when added to α-blocker therapy.³⁰ Patients reported a positive outcome at 12 weeks, which resulted in a reduction in urgency incontinence, urgency, nocturia, and the overall number of voiding episodes within 24 hours.

β-3 agonists are a class of medications for OAB; mirabegron and vibegron have proven effective in reducing similar symptoms. In phase 3 clinical trials, mirabegron improved urinary incontinence episodes by 50% and reduced the number of voids in 24 hours.³¹ Mirabegron is well tolerated and avoids many common anticholinergic effects.³² Vibegron is the newest medication in the class and could soon become the preferred agent given it does not have cytochrome P450 interactions and does not cause hypertension like mirabegron.³³

Anticholinergics should be used with caution in patients with a history of urinary retention, elevated after-void residual, or other medications with known anticholinergic effects. AEs include sedation, confusion, dry mouth, constipation, and potential falls in older patients.¹⁸ Recent studies have noted an association with dementia in the prolonged use of these medications in older patients and should be used cautiously.²⁰

Phosphodiesterase-5 enzyme inhibitors (PDE-5) are adjunctive medications shown to improve LUTS. This class of medication is prescribed mostly for ED. However, tadalafil 5 mg taken daily also is FDA approved for the treatment of LUTS secondary to BPH given its prolonged half-life. The exact mechanism for improved BPH symptoms is unknown. Possibly the effects are due to an increase mediated by PDE-5 in cyclic guanosine monophosphate (cGMP), which increases smooth muscle relaxation and tissue perfusion of the prostate and bladder.³⁴ There have been limited studies on objective improvement in uroflowmetry parameters compared with other treatments. The daily dosing of tadalafil should not be prescribed in men with a creatinine clearance < 30 mL/min.²⁹ Tadalafil is not considered a first-line agent and is usually reserved for patients who experience ED in addition to BPH. When initiating BPH pharmacologic therapy, the PCP should be aware of adherence and high discontinuation rates.³⁵

Surgical Treatments

Surgical treatments are often delayed out of fear of potential AEs or considered a last resort when symptoms are too severe.³⁶ Early intervention is required to prevent irreversible deleterious changes to detrusor muscle structure and function (Figure). Patients fear urinary incontinence, ED or ejaculatory dysfunction, and anesthesia complications associated with surgical interventions.^6,37 Multiple studies show that patients fare better with early surgical intervention, experiencing improved IPSS scores, urinary flow, and QOL. The following is an overview of the most popular procedures.

Prostatic urethral lift (PUL) using the UroLift System is an FDA-approved, minimally-invasive treatment of LUTS secondary to BPH. This procedure treats prostates < 80 g with an absent median lobe.^6,21,38 Permanent implants are placed per the prostatic urethra to displace obstructing prostate tissue laterally. This opens the urethra directly without cutting, heating, or removing any prostate tissue. This procedure is minimally invasive, often done in the office as an outpatient procedure, and offers better symptom relief than medication with a lower risk profile than transurethral resection of the prostate (TURP).^39,40 The LIFT study was a multicenter, randomized, blinded trial; patients were randomized 2:1 to undergo UroLift or a sham operation. At 3 years, average improvements were statistically significant for total IPSS reduction (41%), QOL improvement (49%), and improved maximum flow rates by (51%).⁴¹ Risk for urinary incontinence is low, and the procedure has been shown to preserve erectile and ejaculatory function. Furthermore, patients report significant improvement in their QOL without the need for medications. Surgical retreatment rates at 5 years are 13.6%, with an additional 10.7% of subjects back on medication therapy with α-blockers or 5-α-RIs.⁴²

Water vapor thermal therapy or Rez¯um uses steam as thermal energy to destroy obstructing prostate tissue and relieve the obstruction.⁴³ The procedure differs from older conductive heat thermotherapies because the steam penetrates prostate zonal anatomy without affecting areas outside the targeted treatment zone. The procedure is done in the office with local anesthesia and provides long-lasting relief of LUTS with minimal risks. Following the procedure, patients require an indwelling urethral catheter for 3 to 7 days, and most patients begin to experience symptom improvement 2 to 4 weeks following the procedure.⁴⁴ The procedure received FDA approval in 2015. Four-year data show significant improvement in maximal flow rate (50%), IPSS (47%), and QOL (43%).⁴⁵ Surgical retreatment rates were 4.4%. Criticisms of this treatment include patient discomfort with the office procedure, the requirement for an indwelling catheter for a short period, and lack of long-term outcomes data. Guidelines support use in prostate volumes > 80 g with or without median lobe anatomy.

TURP is the gold standard to which other treatments are compared.⁴⁶ The surgery is performed in the operating room where urologists use a rigid cystoscope and resection element to effectively carve out and cauterize obstructing prostate tissue. Patients typically recover for a short period with an indwelling urethral catheter that is often removed 12 to 24 hours after surgery. New research points out that despite increasing mean age (55% of patients are aged > 70 years with associated comorbidities), the morbidity of TURP was < 1% and mortality rate of 0 to 0.3%.⁴⁷ Postoperative complications include bleeding that requires a transfusion (3%), retrograde ejaculation (65%), and rare urinary incontinence (2%).⁴⁷ Surgical retreatment rates for patients following a TURP are approximately 13 to 15% at 8 years.³⁴

Laser surgery for BPH includes multiple techniques: photovaporization of the prostate using a Greenlight XPS laser, holmium laser ablation, and holmium laser enucleation (HoLEP). Proponents of these treatments cite lower bleeding risks compared with TURP, but the operation is largely surgeon dependent on the technology chosen. Most studies comparing these technologies with TURP show similar outcomes of IPSS reports, quality of life improvements, and complications.

Patients with extremely large prostates, > 100 g or 4 times the normal size, pose a unique challenge to surgical treatment. Historically, patients were treated with an open simple prostatectomy operation or staged TURP procedures. Today, urologists use newer, safer ways to treat these patients. Both HoLEP and robot-assisted simple prostatectomy work well in relieving urinary symptoms with lower complications compared with older open surgery. Other minimally invasive procedures, such as prostatic artery embolism, have been described for the treatment of BPH specifically in men who may be unfit for surgery.⁴⁸Future treatments are constantly evolving. Many unanswered questions remain about BPH and the role of inflammation, metabolic dysfunction, obesity, and other genetic factors driving BPH and prostate growth. Pharmaceutical opportunities exist in mechanisms aimed to reduce prostate growth, induce cellular apoptosis, as well as other drugs to reduce bladder symptoms. Newer, minimally invasive therapies also will become more readily available, such as Aquablation, which is the first FDA-granted surgical robot for the autonomous removal of prostatic tissue due to BPH.⁴⁹ However, the goal of all future therapies should include the balance of alleviating disruptive symptoms while demonstrating a favorable risk profile. Many men discontinue taking medications, yet few present for surgery. Most concerning is the significant population of men who will develop irreversible bladder dysfunction while waiting for the perfect treatment. There are many opportunities for an effective treatment that is less invasive than surgery, provides durable relief, has minimal AEs, and is affordable.

Conclusions

There is no perfect treatment for patients with LUTS. All interventions have potential AEs and associated complications. Medications are often started as first-line therapy but are often discontinued at the onset of significant AEs. This process is often repeated. Many patients will try different medications without any significant improvement in their symptoms or short-term relief, which results in the gradual progression of the disease.

The PCP plays a significant role in the initial evaluation and management of BPH. These frontline clinicians can recognize patients who may already be experiencing sequela of prolonged bladder outlet obstruction and refer these men to urologists promptly. Counseling patients about their treatment options is an important duty for all PCPs.

A clear understanding of the available treatment options will help PCPs counsel patients appropriately about lifestyle modification, medications, and surgical treatment options for their symptoms. The treatment of this disorder is a rapidly evolving topic with the constant introduction of new technologies and medications, which are certain to continue to play an important role for PCPs and urologists.

Lower urinary tract symptoms (LUTS)are common and tend to increase in frequency with age. Managing LUTS can be complicated, requires an informed discussion between the primary care practitioner (PCP) and patient, and is best achieved by a thorough understanding of the many medical and surgical options available. Over the past 3 decades, medications have become the most common therapy; but recently, newer minimally invasive surgeries have challenged this paradigm. This article provides a comprehensive review for PCPs regarding the evaluation and management of LUTS in men and when to consider a urology referral.

Benign prostatic hyperplasia (BPH) and LUTS are common clinical encounters for most PCPs. About 50% of men will develop LUTS associated with BPH, and symptoms associated with these conditions increase as men age.^1,2 Studies have estimated that 90% of men aged 45 to 80 years demonstrate some symptoms of LUTS.³ Strong genetic influence seems to suggest heritability, but BPH also occurs in sporadic forms and is heavily influenced by androgens.⁴

BPH is a histologic diagnosis, whereas LUTS consists of complex symptomatology related to both static or dynamic components.¹ The enlarged prostate gland obstructs the urethra, simultaneously causing an increase in muscle tone and resistance at the bladder neck and prostatic urethra, leading to increased resistance to urine flow. As a result, there is a thickening of the detrusor muscles in the bladder wall and an overall decreased compliance. Urine becomes stored under increased pressure. These changes result in a weak or intermittent urine stream, incomplete emptying of the bladder, postvoid dribble, hesitancy, and irritative symptoms, such as urgency, frequency, and nocturia.

For many patients, BPH associated with LUTS is a quality of life (QOL) issue. The stigma associated with these symptoms often leads to delays in patients seeking care. Many patients do not seek treatment until symptoms have become so severe that changes in bladder health are often irreversible. Early intervention can dramatically improve a patient’s QOL. Also, early intervention has the potential to reduce overall health care expenditures. BPH-related spending exceeds $1 billion each year in the Medicare program alone.⁵

PCPs are in a unique position to help many patients who present with early-stage LUTS. Given the substantial impact this disease has on QOL, early recognition of symptoms and prompt treatment play a major role. Paramount to this effort is awareness and understanding of various treatments, their advantages, and adverse effects (AEs). This article highlights evidence-based evaluation and treatment of BPH/LUTS for PCPs who treat veterans and recommendations as to when to refer a patient to a urologist.

Evaluation of LUTS and BPH

Evaluation begins with a thorough medical history and physical examination. Particular attention should focus on ruling out other causes of LUTS, such as a urinary tract infection (UTI), acute prostatitis, malignancy, bladder dysfunction, neurogenic bladder, and other obstructive pathology, such as urethral stricture disease. The differential diagnosis of LUTS includes BPH, UTI, bladder neck obstruction, urethral stricture, bladder stones, polydipsia, overactive bladder (OAB), nocturnal polyuria, neurologic disease, genitourinary malignancy, renal failure, and acute/chronic urinary retention.⁶

Relevant medical history influencing urinary symptoms includes diabetes mellitus, underlying neurologic diseases, previous trauma, sexually transmitted infections, and certain medications. Symptom severity may be obtained using a validated questionnaire, such as the International Prostate Symptom Score (IPSS), which also aids clinicians in assessing the impact of LUTS on QOL. Additionally, urinary frequency or volume records (voiding diary) may help establish the severity of the patient’s symptoms and provide insight into other potential causes for LUTS. Patients with BPH often have concurrent erectile dysfunction (ED) or other sexual dysfunction symptoms. Patients should be evaluated for baseline sexual dysfunction before the initiation of treatment as many therapies worsen symptoms of ED or ejaculatory dysfunction.

A comprehensive physical examination with a focus on the genitourinary system should, at minimum, assess for abnormalities of the urethral meatus, prepuce, penis, groin nodes, and prior surgical scars. A digital rectal examination also should be performed. Although controversial, a digital rectal examination for prostate cancer screening may provide a rough estimate of prostate size, help rule out prostatitis, and detect incident prostate nodules. Prostate size does not necessarily correlate well with the degree of urinary obstruction or LUTS but is an important consideration when deciding among different therapies.¹

Laboratory and Adjunctive Tests

A urinalysis with microscopy helps identify other potential causes for urinary symptoms, including infection, proteinuria, or glucosuria. In patients who present with gross or microscopic hematuria, additional consideration should be given to bladder calculi and genitourinary cancer.² When a reversible source for the hematuria is not identified, these patients require referral to a urologist for a hematuria evaluation.

There is some controversy regarding prostate specific antigen (PSA) testing. Most professional organizations advocate for a shared decision-making approach before testing. The American Cancer Society recommends this informed discussion occur between the patient and the PCP for men aged > 50 years at average risk, men aged > 45 years at high risk of developing prostate cancer (African Americans or first-degree relative with early prostate cancer diagnosis), and aged 40 years for men with more than one first-degree relative with an early prostate cancer diagnosis.⁷

Adjunctive tests include postvoid residual (PVR), cystoscopy, uroflowmetry, urodynamics, and transrectal ultrasound. However, these are mostly performed by urologists. In some patients with bladder decompensation after prolonged partial bladder outlet obstruction, urodynamics may be used by urologists to determine whether a patient may benefit from an outlet obstruction procedure. Ordering additional imaging or serum studies for the assessment of LUTS is rarely helpful.

Treatment

Treatment includes management with or without lifestyle modification, medication administration, and surgical therapy. New to this paradigm are in-office minimally invasive surgical options. The goal of treatment is not only to reduce patient symptoms and improve QOL, but also to prevent the secondary sequala of urinary retention, bladder failure, and eventual renal impairment.⁷A basic understanding of these treatments can aid PCPs with appropriate patient counseling and urologic referral.⁸

Lifestyle and Behavior Modification

Behavior modification is the starting point for all patients with LUTS. Lifestyle modifications for LUTS include avoiding substances that exacerbate symptoms, such as α-agonists (decongestants), caffeine, alcohol, spicy/acidic foods, chocolate, and soda. These substances are known to be bladder irritants. Common medications contributing to LUTS include antidepressants, decongestants, antihistamines, bronchodilators, anticholinergics, and sympathomimetics. To decrease nocturia, behavioral modifications include limiting evening fluid intake, timed diuretic administration for patients already on a diuretic, and elevating legs 1 hour before bedtime. Counseling obese patients to lose weight and increasing physical activity have been linked to reduced LUTS.⁹ Other behavioral techniques include double voiding: a technique where patients void normally then change positions and return to void to empty the bladder. Another technique is timed voiding: Many patients have impaired sensation when the bladder is full. These patients are encouraged to void at regular intervals.

Complementary and Alternative Medicine

Multiple nutraceutical compounds claim improved urinary health and symptom reduction. These compounds are marketed to patients with little regulation and oversight since supplements are not regulated or held to the same standard as prescription medications. The most popular nutraceutical for prostate health and LUTS is saw palmetto. Despite its common usage for the treatment of LUTS, little data support saw palmetto health claims. In 2012, a systematic review of 32 randomized trials including 5666 patients compared saw palmetto with a placebo. The study found no difference in urinary symptom scores, urinary flow, or prostate size.^10,11 Other phytotherapy compounds often considered for urinary symptoms include stinging nettle extract and β-sitosterol compounds. The mechanism of action of these agents is unknown and efficacy data are lacking.

Historically, acupuncture and pelvic floor physical therapy have been used successfully for OAB symptoms. A meta-analysis found positive beneficial effects of acupuncture compared with a sham control for short- and medium-term follow-up in both IPSS and urine flow rates in some studies; however, when combining the studies for more statistical power, the benefits were less clear.¹² Physical therapists with specialized training and certification in pelvic health can incorporate certain bladder training techniques. These include voiding positional changes (double voiding and postvoid urethral milking) and timed voiding.^13,14 These interventions often address etiologies of LUTS for which medical therapies are not effective as the sole treatment option.

Medication Management

Medical management includes α-blockers, 5-α-reductase inhibitors (5-α-RIs), antimuscarinic or anticholinergic medicines, β-3 agonists, and phosphodiesterase inhibitors (Table). These medications work independently as well as synergistically. The use of medications to improve symptoms must be balanced against potential AEs and the consequences of a lifetime of drug usage, which can be additive.^15,16

First-line pharmacological therapy for BPH is α-blockers, which work by blocking α1A receptors in the prostate and bladder neck, leading to smooth muscle relaxation, increased diameter of the channel, and improved urinary flow. α-receptors in the bladder neck and prostate are expressed with increased frequency with age and are a potential cause for worsening symptoms as men age. Studies demonstrate that these medications reduce symptoms by 30 to 40% and increase flow rates by 16 to 25%.¹⁷ Commonly prescribed α-blockers include tamsulosin, alfuzosin, silodosin, doxazosin, and terazosin. Doxazosin and terazosin require dose titrations because they may cause significant hypotension. Orthostatic hypotension typically improves with time and is avoided if the patient takes the medication at bedtime. Both doxazosin and terazosin are on the American Geriatric Society’s Beers Criteria list and should be avoided in older patients.¹⁸ Tamsulosin, alfuzosin, and silodosin have a standardized dosing regimen and lower rates of hypotension. Significant AEs include ejaculation dysfunction, nasal congestion, and orthostatic hypotension. Duan and colleagues have linked tamsulosin with dementia. However, this association is not causal and further studies are necessary.^19,20 Patients who have taken these agents also are at risk for intraoperative floppy iris syndrome (IFIS). Permanent visual problems can arise if the intraoperative management is not managed to account for IFIS. These medications have a rapid onset of action and work immediately. However, to reach maximum benefit, patients must take the medication for several weeks. Unfortunately, up to one-third of patients will have no improvement with α-blocker therapy, and many patients will discontinue these medications because of significant AEs.^6,21

5-α-RIs (finasteride and dutasteride) inhibit the conversion of testosterone to more potent dihydrotestosterone. They effectively reduce prostate volume by 25 to 30%.²² The results occur slowly and can take 6 to 12 months to reach the desired outcome. These medications are effective in men with larger prostates and not as effective in men with smaller prostates.²³ These medications can improve urinary flow rates by about 10%, reduce IPSS scores by 20 to 30%, reduce the risk of urinary retention by 50%, and reduce the progression of BPH to the point where surgery is required by 50%.²⁴ Furthermore, 5-α-RIs lower PSA by > 50% after 12 months of treatment.²⁵

A baseline PSA should be established before administration and after 6 months of treatment. Any increase in the PSA even if the level is within normal limits should be evaluated for prostate cancer. Sarkar and colleagues recently published a study evaluating prostate cancer diagnosis in patients treated with 5-α-RI and found there was a delay in diagnosing prostate cancer in this population. Controversy also exists as to the potential of these medications increasing the risk for high-grade prostate cancer, which has led to a US Food and Drug Administration (FDA) warning. AEs include decreased libido (1.5%), ejaculatory dysfunction (3.4%), gynecomastia (1.3%), and/or ED (1.6%).^26-28 A recent study evaluating 5-α-RIs demonstrated about a 2-fold increased risk of depression.²⁹

There are well-established studies that note increased effectiveness when using combined α-blocker therapy with 5-α-RI medications. The Medical Therapy of Prostate Symptoms (MTOPS) and Combination Avodart and Tamsulosin (CombAT) trials showed that the combination of both medications was more effective in improving voiding symptoms and flow rates than either agent alone.^15,16 Combination therapy resulted in a 66% reduction in disease progression, 81% reduction in urinary retention, and a 67% reduction in the need for surgery compared with placebo.

Anticholinergic medication use in BPH with LUTS is well established, and their use is often combined with other therapies. Anticholinergics work by inhibiting muscarinic M3 receptors to reduce detrusor muscle contraction. This effectively decreases bladder contractions and delays the desire to void. Kaplan and colleagues showed that tolterodine significantly improved a patient’s QOL when added to α-blocker therapy.³⁰ Patients reported a positive outcome at 12 weeks, which resulted in a reduction in urgency incontinence, urgency, nocturia, and the overall number of voiding episodes within 24 hours.

β-3 agonists are a class of medications for OAB; mirabegron and vibegron have proven effective in reducing similar symptoms. In phase 3 clinical trials, mirabegron improved urinary incontinence episodes by 50% and reduced the number of voids in 24 hours.³¹ Mirabegron is well tolerated and avoids many common anticholinergic effects.³² Vibegron is the newest medication in the class and could soon become the preferred agent given it does not have cytochrome P450 interactions and does not cause hypertension like mirabegron.³³

Anticholinergics should be used with caution in patients with a history of urinary retention, elevated after-void residual, or other medications with known anticholinergic effects. AEs include sedation, confusion, dry mouth, constipation, and potential falls in older patients.¹⁸ Recent studies have noted an association with dementia in the prolonged use of these medications in older patients and should be used cautiously.²⁰

Phosphodiesterase-5 enzyme inhibitors (PDE-5) are adjunctive medications shown to improve LUTS. This class of medication is prescribed mostly for ED. However, tadalafil 5 mg taken daily also is FDA approved for the treatment of LUTS secondary to BPH given its prolonged half-life. The exact mechanism for improved BPH symptoms is unknown. Possibly the effects are due to an increase mediated by PDE-5 in cyclic guanosine monophosphate (cGMP), which increases smooth muscle relaxation and tissue perfusion of the prostate and bladder.³⁴ There have been limited studies on objective improvement in uroflowmetry parameters compared with other treatments. The daily dosing of tadalafil should not be prescribed in men with a creatinine clearance < 30 mL/min.²⁹ Tadalafil is not considered a first-line agent and is usually reserved for patients who experience ED in addition to BPH. When initiating BPH pharmacologic therapy, the PCP should be aware of adherence and high discontinuation rates.³⁵

Surgical Treatments

Surgical treatments are often delayed out of fear of potential AEs or considered a last resort when symptoms are too severe.³⁶ Early intervention is required to prevent irreversible deleterious changes to detrusor muscle structure and function (Figure). Patients fear urinary incontinence, ED or ejaculatory dysfunction, and anesthesia complications associated with surgical interventions.^6,37 Multiple studies show that patients fare better with early surgical intervention, experiencing improved IPSS scores, urinary flow, and QOL. The following is an overview of the most popular procedures.

Prostatic urethral lift (PUL) using the UroLift System is an FDA-approved, minimally-invasive treatment of LUTS secondary to BPH. This procedure treats prostates < 80 g with an absent median lobe.^6,21,38 Permanent implants are placed per the prostatic urethra to displace obstructing prostate tissue laterally. This opens the urethra directly without cutting, heating, or removing any prostate tissue. This procedure is minimally invasive, often done in the office as an outpatient procedure, and offers better symptom relief than medication with a lower risk profile than transurethral resection of the prostate (TURP).^39,40 The LIFT study was a multicenter, randomized, blinded trial; patients were randomized 2:1 to undergo UroLift or a sham operation. At 3 years, average improvements were statistically significant for total IPSS reduction (41%), QOL improvement (49%), and improved maximum flow rates by (51%).⁴¹ Risk for urinary incontinence is low, and the procedure has been shown to preserve erectile and ejaculatory function. Furthermore, patients report significant improvement in their QOL without the need for medications. Surgical retreatment rates at 5 years are 13.6%, with an additional 10.7% of subjects back on medication therapy with α-blockers or 5-α-RIs.⁴²

Water vapor thermal therapy or Rez¯um uses steam as thermal energy to destroy obstructing prostate tissue and relieve the obstruction.⁴³ The procedure differs from older conductive heat thermotherapies because the steam penetrates prostate zonal anatomy without affecting areas outside the targeted treatment zone. The procedure is done in the office with local anesthesia and provides long-lasting relief of LUTS with minimal risks. Following the procedure, patients require an indwelling urethral catheter for 3 to 7 days, and most patients begin to experience symptom improvement 2 to 4 weeks following the procedure.⁴⁴ The procedure received FDA approval in 2015. Four-year data show significant improvement in maximal flow rate (50%), IPSS (47%), and QOL (43%).⁴⁵ Surgical retreatment rates were 4.4%. Criticisms of this treatment include patient discomfort with the office procedure, the requirement for an indwelling catheter for a short period, and lack of long-term outcomes data. Guidelines support use in prostate volumes > 80 g with or without median lobe anatomy.

TURP is the gold standard to which other treatments are compared.⁴⁶ The surgery is performed in the operating room where urologists use a rigid cystoscope and resection element to effectively carve out and cauterize obstructing prostate tissue. Patients typically recover for a short period with an indwelling urethral catheter that is often removed 12 to 24 hours after surgery. New research points out that despite increasing mean age (55% of patients are aged > 70 years with associated comorbidities), the morbidity of TURP was < 1% and mortality rate of 0 to 0.3%.⁴⁷ Postoperative complications include bleeding that requires a transfusion (3%), retrograde ejaculation (65%), and rare urinary incontinence (2%).⁴⁷ Surgical retreatment rates for patients following a TURP are approximately 13 to 15% at 8 years.³⁴

Laser surgery for BPH includes multiple techniques: photovaporization of the prostate using a Greenlight XPS laser, holmium laser ablation, and holmium laser enucleation (HoLEP). Proponents of these treatments cite lower bleeding risks compared with TURP, but the operation is largely surgeon dependent on the technology chosen. Most studies comparing these technologies with TURP show similar outcomes of IPSS reports, quality of life improvements, and complications.

Patients with extremely large prostates, > 100 g or 4 times the normal size, pose a unique challenge to surgical treatment. Historically, patients were treated with an open simple prostatectomy operation or staged TURP procedures. Today, urologists use newer, safer ways to treat these patients. Both HoLEP and robot-assisted simple prostatectomy work well in relieving urinary symptoms with lower complications compared with older open surgery. Other minimally invasive procedures, such as prostatic artery embolism, have been described for the treatment of BPH specifically in men who may be unfit for surgery.⁴⁸Future treatments are constantly evolving. Many unanswered questions remain about BPH and the role of inflammation, metabolic dysfunction, obesity, and other genetic factors driving BPH and prostate growth. Pharmaceutical opportunities exist in mechanisms aimed to reduce prostate growth, induce cellular apoptosis, as well as other drugs to reduce bladder symptoms. Newer, minimally invasive therapies also will become more readily available, such as Aquablation, which is the first FDA-granted surgical robot for the autonomous removal of prostatic tissue due to BPH.⁴⁹ However, the goal of all future therapies should include the balance of alleviating disruptive symptoms while demonstrating a favorable risk profile. Many men discontinue taking medications, yet few present for surgery. Most concerning is the significant population of men who will develop irreversible bladder dysfunction while waiting for the perfect treatment. There are many opportunities for an effective treatment that is less invasive than surgery, provides durable relief, has minimal AEs, and is affordable.

Conclusions

There is no perfect treatment for patients with LUTS. All interventions have potential AEs and associated complications. Medications are often started as first-line therapy but are often discontinued at the onset of significant AEs. This process is often repeated. Many patients will try different medications without any significant improvement in their symptoms or short-term relief, which results in the gradual progression of the disease.

The PCP plays a significant role in the initial evaluation and management of BPH. These frontline clinicians can recognize patients who may already be experiencing sequela of prolonged bladder outlet obstruction and refer these men to urologists promptly. Counseling patients about their treatment options is an important duty for all PCPs.

A clear understanding of the available treatment options will help PCPs counsel patients appropriately about lifestyle modification, medications, and surgical treatment options for their symptoms. The treatment of this disorder is a rapidly evolving topic with the constant introduction of new technologies and medications, which are certain to continue to play an important role for PCPs and urologists.