Elizabeth Mechcatie

BETHESDA, MD. — Extramammary Paget's disease is most often found in the vulvar area and usually has an excellent prognosis, Peter J. Lynch, M.D., said at a conference on vulvovaginal diseases.

The vulva is the site of about 65% of extramammary Paget's disease (EMPD), which accounts for about 1% of all vulvar malignancies, said Dr. Lynch, emeritus professor and training program director, department of dermatology, University of California, Davis. EMPD is a disease of the elderly, affecting women 55–90 years old, with a mean age of 65. It occurs primarily among whites, although it has been reported increasingly among Asians over the past 4–5 years.

The lesions are primarily found along the “milk line,” where the sites of involvement are anywhere apocrine glands are found, including the axillae, breast, and perianal area.

Typically, extramammary Paget's lesions are similar in appearance, with an erythematous plaque that is sharply marginated. The surface of these lesions is often moist and/or crusted, but patients also may have frank erosions, he said. Whiteness in the vulvar area can be due to the absence of melanocytes, or caused by what happens when keratin gets waterlogged, since keratin is highly hydrophilic. Any disease with a buildup of keratin occurring in a wet area will have whitening in some areas, he explained.

While it may be suspected, the correct diagnosis is rarely made clinically, and generally requires a biopsy. Failure to respond to treatments, such as topical steroids and “anticandidals,” should prompt a biopsy. Diseases that may look like this condition but are less common include lichen planus and lichen sclerosis, Dr. Lynch said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

Histology, which is distinctive, but not pathognomonic, is characterized by clusters of pale staining cells in the epidermis, with variable extension into the hair follicles and sweat glands. However, the degree of cellular atypia can be “quite variable,” he added.

In the vulvar area, 90% of EPMD cases are primary, presenting with only intraepithelial neoplasia, and have an “excellent” prognosis, he said. Primary EPMD arises in the epidermis and does not extend into the surrounding dermis; biopsies show little (1 mm or less) or no invasion, and positive nodes or metastases are rare. (About 15% of patients with primary disease have microscopic invasion, measuring 1 mm or less).

But the prognosis is poor for those with primary disease with a deeper invasion and patients with secondary EPMD. Secondary EPMD arises from within the apocrine gland and grows for a long time, or occurs when the same or similar cells from underlying adenocarcinoma in the genitourinary or GI tract migrate upward.

Historically, the treatment of choice for EPMD has been local excision, but recurrence rates are high: For a patient with primary EPMD, with little (1 mm or less) or no invasion, the recurrence rate after a wide local excision is 35%, Dr. Lynch said.

With invasion or secondary disease, the recurrence rate is 65%, he added, noting that even after a radical vulvectomy, the recurrence rate is about 20%.

Clinical margins are not that helpful because the lesions extend beyond the visible surface. The literature currently calls for 5-cm margins, but even with Mohs micrographic surgery, recurrence rates range from 20% to 30%.

Because patients with primary in situ disease appear to have an extremely low risk of developing an associated underlying malignancy, nonexcisional treatments, such as lasers, radiotherapy, electrosurgery, photodynamic therapy or 5-fluorouracil, can be used when there is no invasion. These approaches can also be used to treat local recurrences, which usually are due to in situ disease, he said.

BETHESDA, MD. — Extramammary Paget's disease is most often found in the vulvar area and usually has an excellent prognosis, Peter J. Lynch, M.D., said at a conference on vulvovaginal diseases.

The vulva is the site of about 65% of extramammary Paget's disease (EMPD), which accounts for about 1% of all vulvar malignancies, said Dr. Lynch, emeritus professor and training program director, department of dermatology, University of California, Davis. EMPD is a disease of the elderly, affecting women 55–90 years old, with a mean age of 65. It occurs primarily among whites, although it has been reported increasingly among Asians over the past 4–5 years.

The lesions are primarily found along the “milk line,” where the sites of involvement are anywhere apocrine glands are found, including the axillae, breast, and perianal area.

Typically, extramammary Paget's lesions are similar in appearance, with an erythematous plaque that is sharply marginated. The surface of these lesions is often moist and/or crusted, but patients also may have frank erosions, he said. Whiteness in the vulvar area can be due to the absence of melanocytes, or caused by what happens when keratin gets waterlogged, since keratin is highly hydrophilic. Any disease with a buildup of keratin occurring in a wet area will have whitening in some areas, he explained.

While it may be suspected, the correct diagnosis is rarely made clinically, and generally requires a biopsy. Failure to respond to treatments, such as topical steroids and “anticandidals,” should prompt a biopsy. Diseases that may look like this condition but are less common include lichen planus and lichen sclerosis, Dr. Lynch said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

Histology, which is distinctive, but not pathognomonic, is characterized by clusters of pale staining cells in the epidermis, with variable extension into the hair follicles and sweat glands. However, the degree of cellular atypia can be “quite variable,” he added.

In the vulvar area, 90% of EPMD cases are primary, presenting with only intraepithelial neoplasia, and have an “excellent” prognosis, he said. Primary EPMD arises in the epidermis and does not extend into the surrounding dermis; biopsies show little (1 mm or less) or no invasion, and positive nodes or metastases are rare. (About 15% of patients with primary disease have microscopic invasion, measuring 1 mm or less).

But the prognosis is poor for those with primary disease with a deeper invasion and patients with secondary EPMD. Secondary EPMD arises from within the apocrine gland and grows for a long time, or occurs when the same or similar cells from underlying adenocarcinoma in the genitourinary or GI tract migrate upward.

Historically, the treatment of choice for EPMD has been local excision, but recurrence rates are high: For a patient with primary EPMD, with little (1 mm or less) or no invasion, the recurrence rate after a wide local excision is 35%, Dr. Lynch said.

With invasion or secondary disease, the recurrence rate is 65%, he added, noting that even after a radical vulvectomy, the recurrence rate is about 20%.

Clinical margins are not that helpful because the lesions extend beyond the visible surface. The literature currently calls for 5-cm margins, but even with Mohs micrographic surgery, recurrence rates range from 20% to 30%.

Because patients with primary in situ disease appear to have an extremely low risk of developing an associated underlying malignancy, nonexcisional treatments, such as lasers, radiotherapy, electrosurgery, photodynamic therapy or 5-fluorouracil, can be used when there is no invasion. These approaches can also be used to treat local recurrences, which usually are due to in situ disease, he said.

BETHESDA, MD. — Extramammary Paget's disease is most often found in the vulvar area and usually has an excellent prognosis, Peter J. Lynch, M.D., said at a conference on vulvovaginal diseases.

The vulva is the site of about 65% of extramammary Paget's disease (EMPD), which accounts for about 1% of all vulvar malignancies, said Dr. Lynch, emeritus professor and training program director, department of dermatology, University of California, Davis. EMPD is a disease of the elderly, affecting women 55–90 years old, with a mean age of 65. It occurs primarily among whites, although it has been reported increasingly among Asians over the past 4–5 years.

The lesions are primarily found along the “milk line,” where the sites of involvement are anywhere apocrine glands are found, including the axillae, breast, and perianal area.

Typically, extramammary Paget's lesions are similar in appearance, with an erythematous plaque that is sharply marginated. The surface of these lesions is often moist and/or crusted, but patients also may have frank erosions, he said. Whiteness in the vulvar area can be due to the absence of melanocytes, or caused by what happens when keratin gets waterlogged, since keratin is highly hydrophilic. Any disease with a buildup of keratin occurring in a wet area will have whitening in some areas, he explained.

While it may be suspected, the correct diagnosis is rarely made clinically, and generally requires a biopsy. Failure to respond to treatments, such as topical steroids and “anticandidals,” should prompt a biopsy. Diseases that may look like this condition but are less common include lichen planus and lichen sclerosis, Dr. Lynch said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

Histology, which is distinctive, but not pathognomonic, is characterized by clusters of pale staining cells in the epidermis, with variable extension into the hair follicles and sweat glands. However, the degree of cellular atypia can be “quite variable,” he added.

In the vulvar area, 90% of EPMD cases are primary, presenting with only intraepithelial neoplasia, and have an “excellent” prognosis, he said. Primary EPMD arises in the epidermis and does not extend into the surrounding dermis; biopsies show little (1 mm or less) or no invasion, and positive nodes or metastases are rare. (About 15% of patients with primary disease have microscopic invasion, measuring 1 mm or less).

But the prognosis is poor for those with primary disease with a deeper invasion and patients with secondary EPMD. Secondary EPMD arises from within the apocrine gland and grows for a long time, or occurs when the same or similar cells from underlying adenocarcinoma in the genitourinary or GI tract migrate upward.

Historically, the treatment of choice for EPMD has been local excision, but recurrence rates are high: For a patient with primary EPMD, with little (1 mm or less) or no invasion, the recurrence rate after a wide local excision is 35%, Dr. Lynch said.

With invasion or secondary disease, the recurrence rate is 65%, he added, noting that even after a radical vulvectomy, the recurrence rate is about 20%.

Clinical margins are not that helpful because the lesions extend beyond the visible surface. The literature currently calls for 5-cm margins, but even with Mohs micrographic surgery, recurrence rates range from 20% to 30%.

Because patients with primary in situ disease appear to have an extremely low risk of developing an associated underlying malignancy, nonexcisional treatments, such as lasers, radiotherapy, electrosurgery, photodynamic therapy or 5-fluorouracil, can be used when there is no invasion. These approaches can also be used to treat local recurrences, which usually are due to in situ disease, he said.

BETHESDA, MD. — HIV-infected women have higher rates of human papilloma virus shedding and higher rates of high grade cervical intraepithelial neoplasia, and are diagnosed more frequently with vulvar intraepithelial neoplasia (VIN) than are women who are not infected, Thomas C. Wright Jr., M.D., said at a conference on vulvovaginal diseases.

Women infected with HIV have an increased rate of human papilloma virus (HPV) shedding that is generally estimated at about four times that of HIV-negative women, said Dr. Wright, director of obstetrics, gynecology, and pathology at Columbia University College of Physicians and Surgeons, New York.

Among HPV-infected women, those who are also infected with HIV have more HPV types than do women without HIV. In one study conducted in New York City, 31% of HIV-positive women had more than one HPV type, vs. 9% of HIV-negative women. A total of 16% and 14% had HPV 16 and HPV 18, respectively, in the HIV-positive group vs. 6% and 3%, respectively, in HIV-negative women.

Studies conducted in the 1990s determined that the distribution of HPV types in women without cervical intraepithelial neoplasia (CIN) tend to be the same in those who are HIV positive and those who are HIV negative. But women with biopsy-confirmed CIN 2,3 who are HIV positive “tend to be more heterogenous for high risk [HPV] types” he said.

Types 16 and 18, which tend to be the most common high-risk HPV types in the general population and appear to be more aggressive than other high-risk HPV types, are found in considerable numbers of CIN 2,3 cases in both HIV-infected and uninfected women. However, in HIV-infected women, the other HPV types that can cause cancer “may become a little more pathogenic” as the immune system deteriorates, Dr. Wright noted.

Viral load and CD4 counts have both been found to be markers for patients who shed HPV: The Women's Interagency HIV Study (WIHS) published in 1999 found that HPV was detected more frequently in women with low (under 200) CD4 counts, regardless of their HIV viral load. Similarly, women with a high HIV viral load, even with a higher CD4 count, will have high rates of HPV shedding, Dr. Wright said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

For more than a decade, it has been clear that the prevalence of CIN among HIV-positive women is high, estimated at two to four times higher than among noninfected women. Dr. Wright referred to four large prospective follow-up studies, including one that he and his associates conducted in New York City, which found that the rates of abnormal cytology in HIV-positive women ranged from 30% to 40%, vs. 8% to 20% among HIV-negative women.

In his study, 7% of the HIV-positive women had high-grade CIN (CIN 2,3), vs. 1% of the HIV-negative women. Over a 3-year follow-up, 20% of the HIV-positive women developed biopsy-confirmed CIN, increasing to 30% over 6 years. Predictably, a woman with low CD4 counts is more likely to develop CIN, Dr. Wright said, adding that a woman with low CD4 counts who is followed for 48 months has a 40% chance of developing biopsy-confirmed CIN.

In HIV-infected women, condylomas are very common. Vulvar condylomas in this population are numerous and multifocal, and tend to respond poorly to standard treatments, he said. Although VIN is less common than is CIN, VIN is much more common in HIV-infected women compared with uninfected women.

In a study published this year of 1,778 HIV-infected women and 500 HIV-negative women followed for 8 years, incident condylomas were detected in 23% of HIV-positive women vs. 7% of HIV-negative women.

In the WIHS study published this year, risk factors for condylomas identified among HIV-positive women were cytologic abnormalities, HPV, smoking, no HAART (highly active antiretroviral therapy), and a low CD4 count, Dr. Wright said.

Now that HAART is used so widely, there is much less cervical and vulvar disease in HIV-infected patients, Dr. Wright observed. At one point, a large proportion of the patients he saw at the Columbia colposcopy clinic were HIV positive, but those numbers have markedly dropped now that most are on HAART, which has been shown to reduce the incidence of condylomas.

VIN, however, is clearly an increasing problem in this population, he said. Because women in the HIV clinic are well screened and treated with loop electrosurgical excision procedure when CIN is detected, cervical cancer is less common. In contrast, “we continue to identify vulvar cancers,” since screening and treating for VIN lesions is not as thorough.

In a study that followed cervical disease in HIV-positive and HIV-negative women, he and his coinvestigators have found that about 4% of HIV-positive women developed biopsy-confirmed VIN over 60 months vs. less than 1% of HIV-negative women. And, as with cervical disease, the risk was higher with lower CD4 counts, where almost 20% of those with CD4 counts under 200 developed biopsy-confirmed VIN.

In the WIHS study, incident VIN 2,3 was detected in 8% of HIV-positive women during follow-up and 2% of HIV-negative women, “a relatively high attack rate” of 1.52 per 100 person years among HIV-positive women, vs. 0.36 per 100 person years for HIV-negative women. This indicates that about 1% of HIV-positive women will develop biopsy-confirmed VIN every year, Dr. Wright pointed out.

In the WIHS study, the risk of VIN 2,3 was increased in women with cytologic abnormalities and high-risk HPV types. However, HAART use and CD4 counts did not have a significant impact on incidence, so while HAART is effective in reducing condylomas and CIN, “we're not seeing the same dramatic impact of HAART on VIN incidence, in the studies that have been reported.”

Based on these findings, Dr. Wright recommended a high level of awareness of vulvar disease in HIV-infected patients, and when an HIV-positive patient is referred with an ASCUS (atypical squamous cells of undetermined significance) and LSIL (low-grade squamous intraepithelial lesions) Pap, “be absolutely certain that you do a very careful inspection of the vulva, and do liberal biopsies” of anything that looks abnormal.

BETHESDA, MD. — HIV-infected women have higher rates of human papilloma virus shedding and higher rates of high grade cervical intraepithelial neoplasia, and are diagnosed more frequently with vulvar intraepithelial neoplasia (VIN) than are women who are not infected, Thomas C. Wright Jr., M.D., said at a conference on vulvovaginal diseases.

Women infected with HIV have an increased rate of human papilloma virus (HPV) shedding that is generally estimated at about four times that of HIV-negative women, said Dr. Wright, director of obstetrics, gynecology, and pathology at Columbia University College of Physicians and Surgeons, New York.

Among HPV-infected women, those who are also infected with HIV have more HPV types than do women without HIV. In one study conducted in New York City, 31% of HIV-positive women had more than one HPV type, vs. 9% of HIV-negative women. A total of 16% and 14% had HPV 16 and HPV 18, respectively, in the HIV-positive group vs. 6% and 3%, respectively, in HIV-negative women.

Studies conducted in the 1990s determined that the distribution of HPV types in women without cervical intraepithelial neoplasia (CIN) tend to be the same in those who are HIV positive and those who are HIV negative. But women with biopsy-confirmed CIN 2,3 who are HIV positive “tend to be more heterogenous for high risk [HPV] types” he said.

Types 16 and 18, which tend to be the most common high-risk HPV types in the general population and appear to be more aggressive than other high-risk HPV types, are found in considerable numbers of CIN 2,3 cases in both HIV-infected and uninfected women. However, in HIV-infected women, the other HPV types that can cause cancer “may become a little more pathogenic” as the immune system deteriorates, Dr. Wright noted.

Viral load and CD4 counts have both been found to be markers for patients who shed HPV: The Women's Interagency HIV Study (WIHS) published in 1999 found that HPV was detected more frequently in women with low (under 200) CD4 counts, regardless of their HIV viral load. Similarly, women with a high HIV viral load, even with a higher CD4 count, will have high rates of HPV shedding, Dr. Wright said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

For more than a decade, it has been clear that the prevalence of CIN among HIV-positive women is high, estimated at two to four times higher than among noninfected women. Dr. Wright referred to four large prospective follow-up studies, including one that he and his associates conducted in New York City, which found that the rates of abnormal cytology in HIV-positive women ranged from 30% to 40%, vs. 8% to 20% among HIV-negative women.

In his study, 7% of the HIV-positive women had high-grade CIN (CIN 2,3), vs. 1% of the HIV-negative women. Over a 3-year follow-up, 20% of the HIV-positive women developed biopsy-confirmed CIN, increasing to 30% over 6 years. Predictably, a woman with low CD4 counts is more likely to develop CIN, Dr. Wright said, adding that a woman with low CD4 counts who is followed for 48 months has a 40% chance of developing biopsy-confirmed CIN.

In HIV-infected women, condylomas are very common. Vulvar condylomas in this population are numerous and multifocal, and tend to respond poorly to standard treatments, he said. Although VIN is less common than is CIN, VIN is much more common in HIV-infected women compared with uninfected women.

In a study published this year of 1,778 HIV-infected women and 500 HIV-negative women followed for 8 years, incident condylomas were detected in 23% of HIV-positive women vs. 7% of HIV-negative women.

In the WIHS study published this year, risk factors for condylomas identified among HIV-positive women were cytologic abnormalities, HPV, smoking, no HAART (highly active antiretroviral therapy), and a low CD4 count, Dr. Wright said.

Now that HAART is used so widely, there is much less cervical and vulvar disease in HIV-infected patients, Dr. Wright observed. At one point, a large proportion of the patients he saw at the Columbia colposcopy clinic were HIV positive, but those numbers have markedly dropped now that most are on HAART, which has been shown to reduce the incidence of condylomas.

VIN, however, is clearly an increasing problem in this population, he said. Because women in the HIV clinic are well screened and treated with loop electrosurgical excision procedure when CIN is detected, cervical cancer is less common. In contrast, “we continue to identify vulvar cancers,” since screening and treating for VIN lesions is not as thorough.

In a study that followed cervical disease in HIV-positive and HIV-negative women, he and his coinvestigators have found that about 4% of HIV-positive women developed biopsy-confirmed VIN over 60 months vs. less than 1% of HIV-negative women. And, as with cervical disease, the risk was higher with lower CD4 counts, where almost 20% of those with CD4 counts under 200 developed biopsy-confirmed VIN.

In the WIHS study, incident VIN 2,3 was detected in 8% of HIV-positive women during follow-up and 2% of HIV-negative women, “a relatively high attack rate” of 1.52 per 100 person years among HIV-positive women, vs. 0.36 per 100 person years for HIV-negative women. This indicates that about 1% of HIV-positive women will develop biopsy-confirmed VIN every year, Dr. Wright pointed out.

In the WIHS study, the risk of VIN 2,3 was increased in women with cytologic abnormalities and high-risk HPV types. However, HAART use and CD4 counts did not have a significant impact on incidence, so while HAART is effective in reducing condylomas and CIN, “we're not seeing the same dramatic impact of HAART on VIN incidence, in the studies that have been reported.”

Based on these findings, Dr. Wright recommended a high level of awareness of vulvar disease in HIV-infected patients, and when an HIV-positive patient is referred with an ASCUS (atypical squamous cells of undetermined significance) and LSIL (low-grade squamous intraepithelial lesions) Pap, “be absolutely certain that you do a very careful inspection of the vulva, and do liberal biopsies” of anything that looks abnormal.

BETHESDA, MD. — HIV-infected women have higher rates of human papilloma virus shedding and higher rates of high grade cervical intraepithelial neoplasia, and are diagnosed more frequently with vulvar intraepithelial neoplasia (VIN) than are women who are not infected, Thomas C. Wright Jr., M.D., said at a conference on vulvovaginal diseases.

Women infected with HIV have an increased rate of human papilloma virus (HPV) shedding that is generally estimated at about four times that of HIV-negative women, said Dr. Wright, director of obstetrics, gynecology, and pathology at Columbia University College of Physicians and Surgeons, New York.

Among HPV-infected women, those who are also infected with HIV have more HPV types than do women without HIV. In one study conducted in New York City, 31% of HIV-positive women had more than one HPV type, vs. 9% of HIV-negative women. A total of 16% and 14% had HPV 16 and HPV 18, respectively, in the HIV-positive group vs. 6% and 3%, respectively, in HIV-negative women.

Studies conducted in the 1990s determined that the distribution of HPV types in women without cervical intraepithelial neoplasia (CIN) tend to be the same in those who are HIV positive and those who are HIV negative. But women with biopsy-confirmed CIN 2,3 who are HIV positive “tend to be more heterogenous for high risk [HPV] types” he said.

Types 16 and 18, which tend to be the most common high-risk HPV types in the general population and appear to be more aggressive than other high-risk HPV types, are found in considerable numbers of CIN 2,3 cases in both HIV-infected and uninfected women. However, in HIV-infected women, the other HPV types that can cause cancer “may become a little more pathogenic” as the immune system deteriorates, Dr. Wright noted.

Viral load and CD4 counts have both been found to be markers for patients who shed HPV: The Women's Interagency HIV Study (WIHS) published in 1999 found that HPV was detected more frequently in women with low (under 200) CD4 counts, regardless of their HIV viral load. Similarly, women with a high HIV viral load, even with a higher CD4 count, will have high rates of HPV shedding, Dr. Wright said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

For more than a decade, it has been clear that the prevalence of CIN among HIV-positive women is high, estimated at two to four times higher than among noninfected women. Dr. Wright referred to four large prospective follow-up studies, including one that he and his associates conducted in New York City, which found that the rates of abnormal cytology in HIV-positive women ranged from 30% to 40%, vs. 8% to 20% among HIV-negative women.

In his study, 7% of the HIV-positive women had high-grade CIN (CIN 2,3), vs. 1% of the HIV-negative women. Over a 3-year follow-up, 20% of the HIV-positive women developed biopsy-confirmed CIN, increasing to 30% over 6 years. Predictably, a woman with low CD4 counts is more likely to develop CIN, Dr. Wright said, adding that a woman with low CD4 counts who is followed for 48 months has a 40% chance of developing biopsy-confirmed CIN.

In HIV-infected women, condylomas are very common. Vulvar condylomas in this population are numerous and multifocal, and tend to respond poorly to standard treatments, he said. Although VIN is less common than is CIN, VIN is much more common in HIV-infected women compared with uninfected women.

In a study published this year of 1,778 HIV-infected women and 500 HIV-negative women followed for 8 years, incident condylomas were detected in 23% of HIV-positive women vs. 7% of HIV-negative women.

In the WIHS study published this year, risk factors for condylomas identified among HIV-positive women were cytologic abnormalities, HPV, smoking, no HAART (highly active antiretroviral therapy), and a low CD4 count, Dr. Wright said.

Now that HAART is used so widely, there is much less cervical and vulvar disease in HIV-infected patients, Dr. Wright observed. At one point, a large proportion of the patients he saw at the Columbia colposcopy clinic were HIV positive, but those numbers have markedly dropped now that most are on HAART, which has been shown to reduce the incidence of condylomas.

VIN, however, is clearly an increasing problem in this population, he said. Because women in the HIV clinic are well screened and treated with loop electrosurgical excision procedure when CIN is detected, cervical cancer is less common. In contrast, “we continue to identify vulvar cancers,” since screening and treating for VIN lesions is not as thorough.

In a study that followed cervical disease in HIV-positive and HIV-negative women, he and his coinvestigators have found that about 4% of HIV-positive women developed biopsy-confirmed VIN over 60 months vs. less than 1% of HIV-negative women. And, as with cervical disease, the risk was higher with lower CD4 counts, where almost 20% of those with CD4 counts under 200 developed biopsy-confirmed VIN.

In the WIHS study, incident VIN 2,3 was detected in 8% of HIV-positive women during follow-up and 2% of HIV-negative women, “a relatively high attack rate” of 1.52 per 100 person years among HIV-positive women, vs. 0.36 per 100 person years for HIV-negative women. This indicates that about 1% of HIV-positive women will develop biopsy-confirmed VIN every year, Dr. Wright pointed out.

In the WIHS study, the risk of VIN 2,3 was increased in women with cytologic abnormalities and high-risk HPV types. However, HAART use and CD4 counts did not have a significant impact on incidence, so while HAART is effective in reducing condylomas and CIN, “we're not seeing the same dramatic impact of HAART on VIN incidence, in the studies that have been reported.”

Based on these findings, Dr. Wright recommended a high level of awareness of vulvar disease in HIV-infected patients, and when an HIV-positive patient is referred with an ASCUS (atypical squamous cells of undetermined significance) and LSIL (low-grade squamous intraepithelial lesions) Pap, “be absolutely certain that you do a very careful inspection of the vulva, and do liberal biopsies” of anything that looks abnormal.

The Food and Drug Administration has approved an insomnia drug with a unique mechanism of action and several features unique among hypnotics approved for insomnia: It is not a controlled substance and does not produce some CNS side effects associated with other hypnotics approved for insomnia, according to one of the drug's investigators.

The drug, ramelteon, a melatonin receptor agonist, was approved last month for treating insomnia characterized by difficulty with sleep onset. Ramelteon binds to melatonin MT₁ and MT₂ receptors, two of the three known melatonin receptors. This action may potentiate sleep, since the receptors “acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle,” according to the drug's label.

Ramelteon, which will be marketed as Rozerem by Takeda Pharmaceuticals Inc., will not be available until late September, the company said in a statement. In two studies of patients with chronic insomnia—one in people aged 18–64 and another in those aged 65 and older—those taking ramelteon fell asleep faster and slept longer than those on placebo. The recommended dosage is 8 mg taken within 30 minutes of going to bed; it should not be taken with or immediately after a high-fat meal, which delays absorption.

In an interview with CLINICAL NEUROLOGY NEWS, Gary Richardson, M.D., senior research scientist at the Sleep Research Center at Henry Ford Hospital, Detroit, said ramelteon does not produce the CNS sedation, memory impairment, or imbalance that are side effects of the other hypnotic drugs approved for insomnia, the benzodiazepines and the newer non-benzodiazepines—a particular advantage in elderly patients. Because the action of the drugs is specific to the MT₁ and MT₂ receptors, which are located only in the suprachiasmatic nuclei (SCN), the activity of the drug is specific.

There are precautions and potential drug interactions to consider, however: Ramelteon should not be used in people with severe hepatic impairment and should be used cautiously in those with moderate hepatic impairment. CYP1A2 is the major isoenzyme involved in metabolizing ramelteon, so it cannot be taken with fluvoxamine, a strong CYP1A2 inhibitor, and should be administered with caution with drugs that are weaker CYP1A2 inhibitors, according to the drug's label. Other drugs on a list of drugs that may have effects on ramelteon metabolism include rifampin, a strong CYP enzyme inducer. Cautious use with strong CYP3A4 inhibitors, such as ketoconazole, and strong CYP2C9 inhibitors, such as fluconazole, are among the other recommendations.

Increases in serum prolactin have been documented in some women and men on ramelteon, with no clinical effects. But the label advises that prolactin and testosterone levels should be considered in patients with unexplained amenorrhea, galactorrhea, reduced libido, or problems with fertility. Dr. Richardson, an investigator in trials and a consultant to Takeda, said that although the increases in prolactin levels in women were self-limited and below what an endocrinologist would consider pathological, this finding should be kept in mind, particularly because some women may have unrecognized mild to moderate hyperprolactinemia at baseline and may be more susceptible to this potential effect.

As a supplement, melatonin has never been shown to be an effective hypnotic when taken to promote sleep. This may be related to a metabolite of melatonin, which increases with increasing doses and prevents it from being effective, he said.

Ramelteon is not scheduled as a controlled substance. In a study evaluating its abuse potential in 14 people with a history of sedative/hypnotic abuse or anxiolytic abuse, there were no differences between a placebo and increasing doses of ramelteon.

The Food and Drug Administration has approved an insomnia drug with a unique mechanism of action and several features unique among hypnotics approved for insomnia: It is not a controlled substance and does not produce some CNS side effects associated with other hypnotics approved for insomnia, according to one of the drug's investigators.

The drug, ramelteon, a melatonin receptor agonist, was approved last month for treating insomnia characterized by difficulty with sleep onset. Ramelteon binds to melatonin MT₁ and MT₂ receptors, two of the three known melatonin receptors. This action may potentiate sleep, since the receptors “acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle,” according to the drug's label.

Ramelteon, which will be marketed as Rozerem by Takeda Pharmaceuticals Inc., will not be available until late September, the company said in a statement. In two studies of patients with chronic insomnia—one in people aged 18–64 and another in those aged 65 and older—those taking ramelteon fell asleep faster and slept longer than those on placebo. The recommended dosage is 8 mg taken within 30 minutes of going to bed; it should not be taken with or immediately after a high-fat meal, which delays absorption.

In an interview with CLINICAL NEUROLOGY NEWS, Gary Richardson, M.D., senior research scientist at the Sleep Research Center at Henry Ford Hospital, Detroit, said ramelteon does not produce the CNS sedation, memory impairment, or imbalance that are side effects of the other hypnotic drugs approved for insomnia, the benzodiazepines and the newer non-benzodiazepines—a particular advantage in elderly patients. Because the action of the drugs is specific to the MT₁ and MT₂ receptors, which are located only in the suprachiasmatic nuclei (SCN), the activity of the drug is specific.

There are precautions and potential drug interactions to consider, however: Ramelteon should not be used in people with severe hepatic impairment and should be used cautiously in those with moderate hepatic impairment. CYP1A2 is the major isoenzyme involved in metabolizing ramelteon, so it cannot be taken with fluvoxamine, a strong CYP1A2 inhibitor, and should be administered with caution with drugs that are weaker CYP1A2 inhibitors, according to the drug's label. Other drugs on a list of drugs that may have effects on ramelteon metabolism include rifampin, a strong CYP enzyme inducer. Cautious use with strong CYP3A4 inhibitors, such as ketoconazole, and strong CYP2C9 inhibitors, such as fluconazole, are among the other recommendations.

Increases in serum prolactin have been documented in some women and men on ramelteon, with no clinical effects. But the label advises that prolactin and testosterone levels should be considered in patients with unexplained amenorrhea, galactorrhea, reduced libido, or problems with fertility. Dr. Richardson, an investigator in trials and a consultant to Takeda, said that although the increases in prolactin levels in women were self-limited and below what an endocrinologist would consider pathological, this finding should be kept in mind, particularly because some women may have unrecognized mild to moderate hyperprolactinemia at baseline and may be more susceptible to this potential effect.

As a supplement, melatonin has never been shown to be an effective hypnotic when taken to promote sleep. This may be related to a metabolite of melatonin, which increases with increasing doses and prevents it from being effective, he said.

Ramelteon is not scheduled as a controlled substance. In a study evaluating its abuse potential in 14 people with a history of sedative/hypnotic abuse or anxiolytic abuse, there were no differences between a placebo and increasing doses of ramelteon.

The Food and Drug Administration has approved an insomnia drug with a unique mechanism of action and several features unique among hypnotics approved for insomnia: It is not a controlled substance and does not produce some CNS side effects associated with other hypnotics approved for insomnia, according to one of the drug's investigators.

The drug, ramelteon, a melatonin receptor agonist, was approved last month for treating insomnia characterized by difficulty with sleep onset. Ramelteon binds to melatonin MT₁ and MT₂ receptors, two of the three known melatonin receptors. This action may potentiate sleep, since the receptors “acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle,” according to the drug's label.

Ramelteon, which will be marketed as Rozerem by Takeda Pharmaceuticals Inc., will not be available until late September, the company said in a statement. In two studies of patients with chronic insomnia—one in people aged 18–64 and another in those aged 65 and older—those taking ramelteon fell asleep faster and slept longer than those on placebo. The recommended dosage is 8 mg taken within 30 minutes of going to bed; it should not be taken with or immediately after a high-fat meal, which delays absorption.

In an interview with CLINICAL NEUROLOGY NEWS, Gary Richardson, M.D., senior research scientist at the Sleep Research Center at Henry Ford Hospital, Detroit, said ramelteon does not produce the CNS sedation, memory impairment, or imbalance that are side effects of the other hypnotic drugs approved for insomnia, the benzodiazepines and the newer non-benzodiazepines—a particular advantage in elderly patients. Because the action of the drugs is specific to the MT₁ and MT₂ receptors, which are located only in the suprachiasmatic nuclei (SCN), the activity of the drug is specific.

There are precautions and potential drug interactions to consider, however: Ramelteon should not be used in people with severe hepatic impairment and should be used cautiously in those with moderate hepatic impairment. CYP1A2 is the major isoenzyme involved in metabolizing ramelteon, so it cannot be taken with fluvoxamine, a strong CYP1A2 inhibitor, and should be administered with caution with drugs that are weaker CYP1A2 inhibitors, according to the drug's label. Other drugs on a list of drugs that may have effects on ramelteon metabolism include rifampin, a strong CYP enzyme inducer. Cautious use with strong CYP3A4 inhibitors, such as ketoconazole, and strong CYP2C9 inhibitors, such as fluconazole, are among the other recommendations.

Increases in serum prolactin have been documented in some women and men on ramelteon, with no clinical effects. But the label advises that prolactin and testosterone levels should be considered in patients with unexplained amenorrhea, galactorrhea, reduced libido, or problems with fertility. Dr. Richardson, an investigator in trials and a consultant to Takeda, said that although the increases in prolactin levels in women were self-limited and below what an endocrinologist would consider pathological, this finding should be kept in mind, particularly because some women may have unrecognized mild to moderate hyperprolactinemia at baseline and may be more susceptible to this potential effect.

As a supplement, melatonin has never been shown to be an effective hypnotic when taken to promote sleep. This may be related to a metabolite of melatonin, which increases with increasing doses and prevents it from being effective, he said.

Ramelteon is not scheduled as a controlled substance. In a study evaluating its abuse potential in 14 people with a history of sedative/hypnotic abuse or anxiolytic abuse, there were no differences between a placebo and increasing doses of ramelteon.

A precaution has been added to the clopidogrel label regarding the increased risk of major bleeding when this platelet aggregation inhibitor is used with aspirin in a certain high-risk patients.

Clopidogrel, an antiplatelet drug marketed as Plavix by Sanofi-Synthelabo Inc., is approved by the Food and Drug Administration for reduction of atherothrombotic events in patients with a recent myocardial infarction, recent stroke, or peripheral arterial disease; and in patients with acute coronary syndrome.

Specifically, the addition to the clopidogrel label reads, “In patients with recent TIA [transient ischemic attack] or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and Plavix has not been shown to be more effective than Plavix alone, but the combination has been shown to increase major bleeding.”

In the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) study and in the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study, there was an increased risk of bleeding and a decreased benefit with concomitant use of clopidogrel with aspirin compared with aspirin alone in patients aged 75 years and older, according to an FDA spokesperson.

The results of another study support these findings regarding the risk of bleeding with aspirin and clopidogrel, the spokesperson said. That study, the Management of Atherothrombosis With Clopidogrel in High-Risk Patients With Recent Transient Ischemic Attack or Ischemic Stroke (MATCH) trial, compared clopidogrel plus aspirin with clopidogrel alone in patients with recent ischemic stroke or TIA. Clopidogrel was approved in 1997.

A precaution has been added to the clopidogrel label regarding the increased risk of major bleeding when this platelet aggregation inhibitor is used with aspirin in a certain high-risk patients.

Clopidogrel, an antiplatelet drug marketed as Plavix by Sanofi-Synthelabo Inc., is approved by the Food and Drug Administration for reduction of atherothrombotic events in patients with a recent myocardial infarction, recent stroke, or peripheral arterial disease; and in patients with acute coronary syndrome.

Specifically, the addition to the clopidogrel label reads, “In patients with recent TIA [transient ischemic attack] or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and Plavix has not been shown to be more effective than Plavix alone, but the combination has been shown to increase major bleeding.”

In the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) study and in the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study, there was an increased risk of bleeding and a decreased benefit with concomitant use of clopidogrel with aspirin compared with aspirin alone in patients aged 75 years and older, according to an FDA spokesperson.

The results of another study support these findings regarding the risk of bleeding with aspirin and clopidogrel, the spokesperson said. That study, the Management of Atherothrombosis With Clopidogrel in High-Risk Patients With Recent Transient Ischemic Attack or Ischemic Stroke (MATCH) trial, compared clopidogrel plus aspirin with clopidogrel alone in patients with recent ischemic stroke or TIA. Clopidogrel was approved in 1997.

A precaution has been added to the clopidogrel label regarding the increased risk of major bleeding when this platelet aggregation inhibitor is used with aspirin in a certain high-risk patients.

Clopidogrel, an antiplatelet drug marketed as Plavix by Sanofi-Synthelabo Inc., is approved by the Food and Drug Administration for reduction of atherothrombotic events in patients with a recent myocardial infarction, recent stroke, or peripheral arterial disease; and in patients with acute coronary syndrome.

Specifically, the addition to the clopidogrel label reads, “In patients with recent TIA [transient ischemic attack] or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and Plavix has not been shown to be more effective than Plavix alone, but the combination has been shown to increase major bleeding.”

In the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) study and in the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study, there was an increased risk of bleeding and a decreased benefit with concomitant use of clopidogrel with aspirin compared with aspirin alone in patients aged 75 years and older, according to an FDA spokesperson.

The results of another study support these findings regarding the risk of bleeding with aspirin and clopidogrel, the spokesperson said. That study, the Management of Atherothrombosis With Clopidogrel in High-Risk Patients With Recent Transient Ischemic Attack or Ischemic Stroke (MATCH) trial, compared clopidogrel plus aspirin with clopidogrel alone in patients with recent ischemic stroke or TIA. Clopidogrel was approved in 1997.

BETHESDA, MD. — HIV-infected women shed more human papilloma virus, have higher rates of high grade cervical intraepithelial neoplasia, and are diagnosed more frequently with vulvar intraepithelial neoplasia (VIN) than are women who are not infected, Thomas C. Wright Jr., M.D., said at a conference on vulvovaginal diseases.

Women infected with HIV have an increased rate of human papilloma virus (HPV) shedding that is generally estimated at about four times that of HIV-negative women, said Dr. Wright, director of obstetrics, gynecology, and pathology at Columbia University College of Physicians and Surgeons, New York.

Among HPV-infected women, those who are also infected with HIV have more HPV types than do women without HIV. In one study conducted in New York City, 31% of HIV-positive women had more than one HPV type, vs. 9% of HIV-negative women. A total of 16% and 14% had HPV 16 and HPV 18, respectively, in the HIV-positive group vs. 6% and 3%, respectively, in HIV-negative women.

Studies conducted in the 1990s determined that the distribution of HPV types in women without cervical intraepithelial neoplasia (CIN) tend to be the same in those who are HIV positive and those who are HIV negative. But women with biopsy-confirmed CIN 2,3 who are HIV positive “tend to be more heterogenous for high risk [HPV] types” he said.

Types 16 and 18, which tend to be the most common high-risk HPV types in the general population and appear to be more aggressive than other high-risk HPV types, are found in considerable numbers of CIN 2,3 cases in both HIV-infected and uninfected women. However, in HIV-infected women, the other HPV types that can cause cancer “may become a little more pathogenic” as the immune system deteriorates, Dr. Wright noted.

Viral load and CD4 counts have both been found to be markers for patients who shed HPV: The Women's Interagency HIV Study (WIHS) published in 1999 found that HPV was detected more frequently in women with low (under 200) CD4 counts, regardless of their HIV viral load. Similarly, women with a high HIV viral load, even with a higher CD4 count, will have high rates of HPV shedding, Dr. Wright said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

For more than a decade, it has been clear that the prevalence of CIN among HIV-positive women is high, estimated at two to four times higher than among noninfected women. He referred to four large prospective follow-up studies, including one he and his associates conducted in New York City, which found that the rates of abnormal cytology in HIV-positive women ranged from 30% to 40%, vs. 8% to 20% among HIV-negative women.

In his study, 7% of the HIV-positive women had high-grade CIN (CIN 2,3), vs. 1% of the HIV-negative women. Over a 3-year follow-up, 20% of the HIV-positive women developed biopsy-confirmed CIN, increasing to 30% over 6 years. Predictably, a woman with low CD4 counts is more likely to develop CIN, Dr. Wright said, adding that a woman with low CD4 counts who is followed for 48 months has a 40% chance of developing biopsy-confirmed CIN.

In HIV-infected women, condylomas are very common. Vulvar condylomas in this population are numerous and multifocal, and tend to respond poorly to standard treatments, he said. Although VIN is less common than is CIN, VIN is much more common in HIV-infected women compared with uninfected women.

In a study published this year of 1,778 HIV-infected women and 500 HIV-negative women followed for 8 years, incident condylomas were detected in 23% of HIV-positive women vs. 7% of HIV-negative women. In the WIHS study published this year, risk factors for condylomas identified among HIV-positive women were cytologic abnormalities, HPV, smoking, no HAART (highly active antiretroviral therapy), and a low CD4 count, he said.

Now that HAART is used so widely, there is much less cervical and vulvar disease in HIV-infected patients, Dr. Wright observed. At one point, a large proportion of the patients he saw at the Columbia colposcopy clinic were HIV positive, but those numbers have markedly dropped now that most are on HAART, which has been shown to reduce the incidence of condylomas.

VIN, however, is clearly an increasing problem in this population, he said. Because women in the HIV clinic are well screened and treated with loop electrosurgical excision procedure when CIN is detected, cervical cancer is less common. In contrast, “we continue to identify vulvar cancers,” since screening and treating for VIN lesions is not as thorough.

In a study that followed cervical disease in HIV-positive and -negative women, he and his coinvestigators have found that about 4% of HIV-positive women developed biopsy-confirmed VIN over 60 months vs. less than 1% of HIV-negative women. And, as with cervical disease, the risk was higher with lower CD4 counts, where almost 20% of those with CD4 counts under 200 developed biopsy-confirmed VIN.

In the WIHS study, incident VIN 2,3 was detected in 8% of HIV-positive women during follow-up and 2% of HIV-negative women, “a relatively high attack rate” of 1.52 per 100 person years among HIV-positive women, vs. 0.36 per 100 person years for HIV-negative women. This indicates that about 1% of HIV-positive women will develop biopsy-confirmed VIN every year, Dr. Wright pointed out.

In the WIHS study, the risk of VIN 2,3 was increased in women with cytologic abnormalities and high-risk HPV types. However, HAART use and CD4 counts did not have a significant impact on incidence, so while HAART is effective in reducing condylomas and CIN, “we're not seeing the same dramatic impact of HAART on VIN incidence, in the studies that have been reported.”

Based on these findings, he recommended a high level of awareness of vulvar disease in HIV-infected patients.

BETHESDA, MD. — HIV-infected women shed more human papilloma virus, have higher rates of high grade cervical intraepithelial neoplasia, and are diagnosed more frequently with vulvar intraepithelial neoplasia (VIN) than are women who are not infected, Thomas C. Wright Jr., M.D., said at a conference on vulvovaginal diseases.

Women infected with HIV have an increased rate of human papilloma virus (HPV) shedding that is generally estimated at about four times that of HIV-negative women, said Dr. Wright, director of obstetrics, gynecology, and pathology at Columbia University College of Physicians and Surgeons, New York.

Among HPV-infected women, those who are also infected with HIV have more HPV types than do women without HIV. In one study conducted in New York City, 31% of HIV-positive women had more than one HPV type, vs. 9% of HIV-negative women. A total of 16% and 14% had HPV 16 and HPV 18, respectively, in the HIV-positive group vs. 6% and 3%, respectively, in HIV-negative women.

Studies conducted in the 1990s determined that the distribution of HPV types in women without cervical intraepithelial neoplasia (CIN) tend to be the same in those who are HIV positive and those who are HIV negative. But women with biopsy-confirmed CIN 2,3 who are HIV positive “tend to be more heterogenous for high risk [HPV] types” he said.

Types 16 and 18, which tend to be the most common high-risk HPV types in the general population and appear to be more aggressive than other high-risk HPV types, are found in considerable numbers of CIN 2,3 cases in both HIV-infected and uninfected women. However, in HIV-infected women, the other HPV types that can cause cancer “may become a little more pathogenic” as the immune system deteriorates, Dr. Wright noted.

Viral load and CD4 counts have both been found to be markers for patients who shed HPV: The Women's Interagency HIV Study (WIHS) published in 1999 found that HPV was detected more frequently in women with low (under 200) CD4 counts, regardless of their HIV viral load. Similarly, women with a high HIV viral load, even with a higher CD4 count, will have high rates of HPV shedding, Dr. Wright said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

For more than a decade, it has been clear that the prevalence of CIN among HIV-positive women is high, estimated at two to four times higher than among noninfected women. He referred to four large prospective follow-up studies, including one he and his associates conducted in New York City, which found that the rates of abnormal cytology in HIV-positive women ranged from 30% to 40%, vs. 8% to 20% among HIV-negative women.

In his study, 7% of the HIV-positive women had high-grade CIN (CIN 2,3), vs. 1% of the HIV-negative women. Over a 3-year follow-up, 20% of the HIV-positive women developed biopsy-confirmed CIN, increasing to 30% over 6 years. Predictably, a woman with low CD4 counts is more likely to develop CIN, Dr. Wright said, adding that a woman with low CD4 counts who is followed for 48 months has a 40% chance of developing biopsy-confirmed CIN.

In HIV-infected women, condylomas are very common. Vulvar condylomas in this population are numerous and multifocal, and tend to respond poorly to standard treatments, he said. Although VIN is less common than is CIN, VIN is much more common in HIV-infected women compared with uninfected women.

In a study published this year of 1,778 HIV-infected women and 500 HIV-negative women followed for 8 years, incident condylomas were detected in 23% of HIV-positive women vs. 7% of HIV-negative women. In the WIHS study published this year, risk factors for condylomas identified among HIV-positive women were cytologic abnormalities, HPV, smoking, no HAART (highly active antiretroviral therapy), and a low CD4 count, he said.

Now that HAART is used so widely, there is much less cervical and vulvar disease in HIV-infected patients, Dr. Wright observed. At one point, a large proportion of the patients he saw at the Columbia colposcopy clinic were HIV positive, but those numbers have markedly dropped now that most are on HAART, which has been shown to reduce the incidence of condylomas.

VIN, however, is clearly an increasing problem in this population, he said. Because women in the HIV clinic are well screened and treated with loop electrosurgical excision procedure when CIN is detected, cervical cancer is less common. In contrast, “we continue to identify vulvar cancers,” since screening and treating for VIN lesions is not as thorough.

In a study that followed cervical disease in HIV-positive and -negative women, he and his coinvestigators have found that about 4% of HIV-positive women developed biopsy-confirmed VIN over 60 months vs. less than 1% of HIV-negative women. And, as with cervical disease, the risk was higher with lower CD4 counts, where almost 20% of those with CD4 counts under 200 developed biopsy-confirmed VIN.

In the WIHS study, incident VIN 2,3 was detected in 8% of HIV-positive women during follow-up and 2% of HIV-negative women, “a relatively high attack rate” of 1.52 per 100 person years among HIV-positive women, vs. 0.36 per 100 person years for HIV-negative women. This indicates that about 1% of HIV-positive women will develop biopsy-confirmed VIN every year, Dr. Wright pointed out.

In the WIHS study, the risk of VIN 2,3 was increased in women with cytologic abnormalities and high-risk HPV types. However, HAART use and CD4 counts did not have a significant impact on incidence, so while HAART is effective in reducing condylomas and CIN, “we're not seeing the same dramatic impact of HAART on VIN incidence, in the studies that have been reported.”

Based on these findings, he recommended a high level of awareness of vulvar disease in HIV-infected patients.

BETHESDA, MD. — HIV-infected women shed more human papilloma virus, have higher rates of high grade cervical intraepithelial neoplasia, and are diagnosed more frequently with vulvar intraepithelial neoplasia (VIN) than are women who are not infected, Thomas C. Wright Jr., M.D., said at a conference on vulvovaginal diseases.

Women infected with HIV have an increased rate of human papilloma virus (HPV) shedding that is generally estimated at about four times that of HIV-negative women, said Dr. Wright, director of obstetrics, gynecology, and pathology at Columbia University College of Physicians and Surgeons, New York.

Among HPV-infected women, those who are also infected with HIV have more HPV types than do women without HIV. In one study conducted in New York City, 31% of HIV-positive women had more than one HPV type, vs. 9% of HIV-negative women. A total of 16% and 14% had HPV 16 and HPV 18, respectively, in the HIV-positive group vs. 6% and 3%, respectively, in HIV-negative women.

Studies conducted in the 1990s determined that the distribution of HPV types in women without cervical intraepithelial neoplasia (CIN) tend to be the same in those who are HIV positive and those who are HIV negative. But women with biopsy-confirmed CIN 2,3 who are HIV positive “tend to be more heterogenous for high risk [HPV] types” he said.

Types 16 and 18, which tend to be the most common high-risk HPV types in the general population and appear to be more aggressive than other high-risk HPV types, are found in considerable numbers of CIN 2,3 cases in both HIV-infected and uninfected women. However, in HIV-infected women, the other HPV types that can cause cancer “may become a little more pathogenic” as the immune system deteriorates, Dr. Wright noted.

Viral load and CD4 counts have both been found to be markers for patients who shed HPV: The Women's Interagency HIV Study (WIHS) published in 1999 found that HPV was detected more frequently in women with low (under 200) CD4 counts, regardless of their HIV viral load. Similarly, women with a high HIV viral load, even with a higher CD4 count, will have high rates of HPV shedding, Dr. Wright said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

For more than a decade, it has been clear that the prevalence of CIN among HIV-positive women is high, estimated at two to four times higher than among noninfected women. He referred to four large prospective follow-up studies, including one he and his associates conducted in New York City, which found that the rates of abnormal cytology in HIV-positive women ranged from 30% to 40%, vs. 8% to 20% among HIV-negative women.

In his study, 7% of the HIV-positive women had high-grade CIN (CIN 2,3), vs. 1% of the HIV-negative women. Over a 3-year follow-up, 20% of the HIV-positive women developed biopsy-confirmed CIN, increasing to 30% over 6 years. Predictably, a woman with low CD4 counts is more likely to develop CIN, Dr. Wright said, adding that a woman with low CD4 counts who is followed for 48 months has a 40% chance of developing biopsy-confirmed CIN.

In HIV-infected women, condylomas are very common. Vulvar condylomas in this population are numerous and multifocal, and tend to respond poorly to standard treatments, he said. Although VIN is less common than is CIN, VIN is much more common in HIV-infected women compared with uninfected women.

In a study published this year of 1,778 HIV-infected women and 500 HIV-negative women followed for 8 years, incident condylomas were detected in 23% of HIV-positive women vs. 7% of HIV-negative women. In the WIHS study published this year, risk factors for condylomas identified among HIV-positive women were cytologic abnormalities, HPV, smoking, no HAART (highly active antiretroviral therapy), and a low CD4 count, he said.

Now that HAART is used so widely, there is much less cervical and vulvar disease in HIV-infected patients, Dr. Wright observed. At one point, a large proportion of the patients he saw at the Columbia colposcopy clinic were HIV positive, but those numbers have markedly dropped now that most are on HAART, which has been shown to reduce the incidence of condylomas.

VIN, however, is clearly an increasing problem in this population, he said. Because women in the HIV clinic are well screened and treated with loop electrosurgical excision procedure when CIN is detected, cervical cancer is less common. In contrast, “we continue to identify vulvar cancers,” since screening and treating for VIN lesions is not as thorough.

In a study that followed cervical disease in HIV-positive and -negative women, he and his coinvestigators have found that about 4% of HIV-positive women developed biopsy-confirmed VIN over 60 months vs. less than 1% of HIV-negative women. And, as with cervical disease, the risk was higher with lower CD4 counts, where almost 20% of those with CD4 counts under 200 developed biopsy-confirmed VIN.

In the WIHS study, incident VIN 2,3 was detected in 8% of HIV-positive women during follow-up and 2% of HIV-negative women, “a relatively high attack rate” of 1.52 per 100 person years among HIV-positive women, vs. 0.36 per 100 person years for HIV-negative women. This indicates that about 1% of HIV-positive women will develop biopsy-confirmed VIN every year, Dr. Wright pointed out.

In the WIHS study, the risk of VIN 2,3 was increased in women with cytologic abnormalities and high-risk HPV types. However, HAART use and CD4 counts did not have a significant impact on incidence, so while HAART is effective in reducing condylomas and CIN, “we're not seeing the same dramatic impact of HAART on VIN incidence, in the studies that have been reported.”

Based on these findings, he recommended a high level of awareness of vulvar disease in HIV-infected patients.

BETHESDA, MD. — Most experts now believe that desquamative inflammatory vaginitis is not a diagnosis of one condition, but may represent a range of blistering disorders, such as lichen planus, mucous membrane pemphigoid, and pemphigus vulgaris, Hope K. Haefner, M.D., said at a conference on vulvovaginal diseases.

With descriptions in the medical literature dating to the 1950s, the signs and symptoms of desquamative inflammatory vaginitis (DIV) include dyspareunia and exudative, chronic vaginitis, with yellow-watery, purulent discharge that is occasionally blood-tinged, said Dr. Haefner, director of the University of Michigan Center for Vulvar Diseases, Ann Arbor.

Patients with DIV also may have a spotted rash on the vagina and cervix, massive vaginal cell exfoliation, and an increased vaginal pH, she said.

Previous terms used to describe this condition include exudative or membranous vaginitis, and hydrorrhea vaginalis.

DIV can occur at any age, and although it has been considered rare, it is being seen more frequently than in the past.

“Although we don't know what it is … we don't think it is an infectious process,” Dr. Haefner said, noting that in studies describing DIV in the 1950s and 1960s infectious organisms were detected in association with DIV but have since been ruled out as a cause.

Other forms of vulvovaginitis caused by trichomonas and other infections can be confused with DIV, as can noninfectious causes of erosive vulvovaginitis, such as lichen planus and graft-versus-host disease, she said. Other noninfectious causes of erosive vulvovaginitis include collagen vascular diseases and a local toxic effect of a drug. The cause also may be idiopathic.

Distinguishing DIV from atrophy can be difficult, since lab findings are similar to those found with atrophic vaginitis, with a nonspecific histology and parabasal cells and many polymorphonuclear leukocytes (PMNs) on cytology. Atrophic vaginitis has serosanguineous or watery discharge similar to that seen with DIV, as well as an elevated vaginal pH, with a thin vagina and red petechiae, Dr. Haefner said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

Atrophic vaginitis and erosive lichen planus are among the noninfectious conditions that are high on Dr. Haefner's list of differential diagnoses in a patient she suspects may have DIV. Lower on the list are other noninfectious causes of these symptoms, including lichen sclerosus, lupus erythematosus, cicatricial pemphigoid, Stevens-Johnson syndrome, graft-versus-host disease, pemphigus of the mouth and skin, and a local drug reaction such as contact dermatitis.

Like other experts in this area, Dr. Haefner believes that DIV can be an expression of erosive lichen planus, which can have the same wet smear, pH, cytology, and biopsy results. However, not all DIV is lichen planus, she pointed out.

Vulvovaginal symptoms of erosive lichen planus include burning; pruritus; dyspareunia that can be mild to severe, preventing coitus at times; bleeding spontaneously after coitus; and vaginal discharge, she said, noting that erosions are very painful. The difference with lichen planus is that it often is associated with erosive changes in the mouth, with a white reticulated border, adhesions, and atrophy, probably related to T-cell autoimmunity.

“When you see patients with DIV, think about looking in the mouth,” she advised.

In lichen planus, erosions may be found in the conjunctivae, external ear canal, esophagus, and anus.

In some cases, histology can help in diagnosing lichen planus, but in Dr. Haef-ner's experience, this has not been very helpful because lab and cytologic changes are nonspecific and may be similar to those found with atrophic vaginitis.

In diagnosing patients with DIV, she recommended considering what is happening with the whole patient, and whether the condition is acute or chronic and focal or diffuse. Also consider whether it involves the vestibule and/or the vagina and whether the patient has a local estradiol deficiency, oral mucosal or ocular disease, or any iatrogenic topical etiology.

For patients with chronic lichen planus, prophylactic dilation is important, because those patients often present with “shut” vaginas. However, prophylactic dilation is not necessary and would be considered overtreatment if used for all patients. To distinguish DIV from lichen planus, consider a biopsy and immunofluorescent studies to rule in or out some of the conditions in the differential diagnosis.

Because DIV is not a single disease, no one treatment will be effective in all cases. Treatment with 2% clindamycin cream for 2 weeks is a first-line therapy for most patients. Although DIV is not considered an infection, clindamycin is still useful because it has an antiinflammatory effect.

Those who need a second course of treatment may respond to hydrocortisone at a dose of 100 mg/g in a clindamycin 2% emollient cream base. A 5-g applicator should be inserted every other day for a total of 14 doses. This regimen is expensive and is not recommended for a first episode, said Dr. Haefner, who stated that she has no relevant financial relationships with any commercial interest relative to the subject of this presentation.

BETHESDA, MD. — Most experts now believe that desquamative inflammatory vaginitis is not a diagnosis of one condition, but may represent a range of blistering disorders, such as lichen planus, mucous membrane pemphigoid, and pemphigus vulgaris, Hope K. Haefner, M.D., said at a conference on vulvovaginal diseases.

With descriptions in the medical literature dating to the 1950s, the signs and symptoms of desquamative inflammatory vaginitis (DIV) include dyspareunia and exudative, chronic vaginitis, with yellow-watery, purulent discharge that is occasionally blood-tinged, said Dr. Haefner, director of the University of Michigan Center for Vulvar Diseases, Ann Arbor.

Patients with DIV also may have a spotted rash on the vagina and cervix, massive vaginal cell exfoliation, and an increased vaginal pH, she said.

Previous terms used to describe this condition include exudative or membranous vaginitis, and hydrorrhea vaginalis.

DIV can occur at any age, and although it has been considered rare, it is being seen more frequently than in the past.

“Although we don't know what it is … we don't think it is an infectious process,” Dr. Haefner said, noting that in studies describing DIV in the 1950s and 1960s infectious organisms were detected in association with DIV but have since been ruled out as a cause.

Other forms of vulvovaginitis caused by trichomonas and other infections can be confused with DIV, as can noninfectious causes of erosive vulvovaginitis, such as lichen planus and graft-versus-host disease, she said. Other noninfectious causes of erosive vulvovaginitis include collagen vascular diseases and a local toxic effect of a drug. The cause also may be idiopathic.

Distinguishing DIV from atrophy can be difficult, since lab findings are similar to those found with atrophic vaginitis, with a nonspecific histology and parabasal cells and many polymorphonuclear leukocytes (PMNs) on cytology. Atrophic vaginitis has serosanguineous or watery discharge similar to that seen with DIV, as well as an elevated vaginal pH, with a thin vagina and red petechiae, Dr. Haefner said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

Atrophic vaginitis and erosive lichen planus are among the noninfectious conditions that are high on Dr. Haefner's list of differential diagnoses in a patient she suspects may have DIV. Lower on the list are other noninfectious causes of these symptoms, including lichen sclerosus, lupus erythematosus, cicatricial pemphigoid, Stevens-Johnson syndrome, graft-versus-host disease, pemphigus of the mouth and skin, and a local drug reaction such as contact dermatitis.

Like other experts in this area, Dr. Haefner believes that DIV can be an expression of erosive lichen planus, which can have the same wet smear, pH, cytology, and biopsy results. However, not all DIV is lichen planus, she pointed out.

Vulvovaginal symptoms of erosive lichen planus include burning; pruritus; dyspareunia that can be mild to severe, preventing coitus at times; bleeding spontaneously after coitus; and vaginal discharge, she said, noting that erosions are very painful. The difference with lichen planus is that it often is associated with erosive changes in the mouth, with a white reticulated border, adhesions, and atrophy, probably related to T-cell autoimmunity.

“When you see patients with DIV, think about looking in the mouth,” she advised.

In lichen planus, erosions may be found in the conjunctivae, external ear canal, esophagus, and anus.

In some cases, histology can help in diagnosing lichen planus, but in Dr. Haef-ner's experience, this has not been very helpful because lab and cytologic changes are nonspecific and may be similar to those found with atrophic vaginitis.

In diagnosing patients with DIV, she recommended considering what is happening with the whole patient, and whether the condition is acute or chronic and focal or diffuse. Also consider whether it involves the vestibule and/or the vagina and whether the patient has a local estradiol deficiency, oral mucosal or ocular disease, or any iatrogenic topical etiology.

For patients with chronic lichen planus, prophylactic dilation is important, because those patients often present with “shut” vaginas. However, prophylactic dilation is not necessary and would be considered overtreatment if used for all patients. To distinguish DIV from lichen planus, consider a biopsy and immunofluorescent studies to rule in or out some of the conditions in the differential diagnosis.

Because DIV is not a single disease, no one treatment will be effective in all cases. Treatment with 2% clindamycin cream for 2 weeks is a first-line therapy for most patients. Although DIV is not considered an infection, clindamycin is still useful because it has an antiinflammatory effect.

Those who need a second course of treatment may respond to hydrocortisone at a dose of 100 mg/g in a clindamycin 2% emollient cream base. A 5-g applicator should be inserted every other day for a total of 14 doses. This regimen is expensive and is not recommended for a first episode, said Dr. Haefner, who stated that she has no relevant financial relationships with any commercial interest relative to the subject of this presentation.

BETHESDA, MD. — Most experts now believe that desquamative inflammatory vaginitis is not a diagnosis of one condition, but may represent a range of blistering disorders, such as lichen planus, mucous membrane pemphigoid, and pemphigus vulgaris, Hope K. Haefner, M.D., said at a conference on vulvovaginal diseases.

With descriptions in the medical literature dating to the 1950s, the signs and symptoms of desquamative inflammatory vaginitis (DIV) include dyspareunia and exudative, chronic vaginitis, with yellow-watery, purulent discharge that is occasionally blood-tinged, said Dr. Haefner, director of the University of Michigan Center for Vulvar Diseases, Ann Arbor.

Patients with DIV also may have a spotted rash on the vagina and cervix, massive vaginal cell exfoliation, and an increased vaginal pH, she said.

Previous terms used to describe this condition include exudative or membranous vaginitis, and hydrorrhea vaginalis.

DIV can occur at any age, and although it has been considered rare, it is being seen more frequently than in the past.

“Although we don't know what it is … we don't think it is an infectious process,” Dr. Haefner said, noting that in studies describing DIV in the 1950s and 1960s infectious organisms were detected in association with DIV but have since been ruled out as a cause.

Other forms of vulvovaginitis caused by trichomonas and other infections can be confused with DIV, as can noninfectious causes of erosive vulvovaginitis, such as lichen planus and graft-versus-host disease, she said. Other noninfectious causes of erosive vulvovaginitis include collagen vascular diseases and a local toxic effect of a drug. The cause also may be idiopathic.

Distinguishing DIV from atrophy can be difficult, since lab findings are similar to those found with atrophic vaginitis, with a nonspecific histology and parabasal cells and many polymorphonuclear leukocytes (PMNs) on cytology. Atrophic vaginitis has serosanguineous or watery discharge similar to that seen with DIV, as well as an elevated vaginal pH, with a thin vagina and red petechiae, Dr. Haefner said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

Atrophic vaginitis and erosive lichen planus are among the noninfectious conditions that are high on Dr. Haefner's list of differential diagnoses in a patient she suspects may have DIV. Lower on the list are other noninfectious causes of these symptoms, including lichen sclerosus, lupus erythematosus, cicatricial pemphigoid, Stevens-Johnson syndrome, graft-versus-host disease, pemphigus of the mouth and skin, and a local drug reaction such as contact dermatitis.

Like other experts in this area, Dr. Haefner believes that DIV can be an expression of erosive lichen planus, which can have the same wet smear, pH, cytology, and biopsy results. However, not all DIV is lichen planus, she pointed out.

Vulvovaginal symptoms of erosive lichen planus include burning; pruritus; dyspareunia that can be mild to severe, preventing coitus at times; bleeding spontaneously after coitus; and vaginal discharge, she said, noting that erosions are very painful. The difference with lichen planus is that it often is associated with erosive changes in the mouth, with a white reticulated border, adhesions, and atrophy, probably related to T-cell autoimmunity.

“When you see patients with DIV, think about looking in the mouth,” she advised.

In lichen planus, erosions may be found in the conjunctivae, external ear canal, esophagus, and anus.

In some cases, histology can help in diagnosing lichen planus, but in Dr. Haef-ner's experience, this has not been very helpful because lab and cytologic changes are nonspecific and may be similar to those found with atrophic vaginitis.

In diagnosing patients with DIV, she recommended considering what is happening with the whole patient, and whether the condition is acute or chronic and focal or diffuse. Also consider whether it involves the vestibule and/or the vagina and whether the patient has a local estradiol deficiency, oral mucosal or ocular disease, or any iatrogenic topical etiology.

For patients with chronic lichen planus, prophylactic dilation is important, because those patients often present with “shut” vaginas. However, prophylactic dilation is not necessary and would be considered overtreatment if used for all patients. To distinguish DIV from lichen planus, consider a biopsy and immunofluorescent studies to rule in or out some of the conditions in the differential diagnosis.

Because DIV is not a single disease, no one treatment will be effective in all cases. Treatment with 2% clindamycin cream for 2 weeks is a first-line therapy for most patients. Although DIV is not considered an infection, clindamycin is still useful because it has an antiinflammatory effect.

Those who need a second course of treatment may respond to hydrocortisone at a dose of 100 mg/g in a clindamycin 2% emollient cream base. A 5-g applicator should be inserted every other day for a total of 14 doses. This regimen is expensive and is not recommended for a first episode, said Dr. Haefner, who stated that she has no relevant financial relationships with any commercial interest relative to the subject of this presentation.

BETHESDA, MD. — An older age, a history of cervical intraepithelial neoplasia, and the presence of multifocal lesions in the upper third of the vagina are among the features associated with vaginal intraepithelial neoplasia, Thomas C. Wright Jr. said at a conference on vulvovaginal diseases.

Vaginal intraepithelial neoplasia (VAIN) is not common, accounting for only 0.4% of intraepithelial lesions of the lower genital tract, according to Dr. Wright, director of obstetrics, gynecology, and pathology at Columbia University College of Physicians and Surgeons, New York.

Women at higher risk include those with vulvar intraepithelial neoplasia (VIN), cigarette smokers, and those who have had radiation therapy. A woman who has had radiation therapy for endometrial cancer and presents with an abnormal Pap smear exemplifies one clinical scenario in which the index of suspicion for VAIN should be high, he noted.

Another typical VAIN case is a postmenopausal patient who has been treated for cervical intraepithelial neoplasia (CIN), even 10 years earlier, often with a hysterectomy, and has been considered cured. She then unexpectedly has a high-grade squamous lesion on cytology, with no lesion on the vagina that is visible to the naked eye.

Some of these risk factors were associated with VAIN in a 2001 study of 121 women with biopsy-confirmed VAIN, which found that 41% smoked, 39% had a history of human papilloma virus (HPV), 22% had undergone surgery for CIN, and 23% had undergone a total abdominal hysterectomy. The mean age of the patients was 35 years, and the majority had VAIN-1, a diagnosis Dr. Wright said he is “very leery” about classifying “as true VAIN lesions.”

Most of the patients he sees with VAIN are in their 40s to late 60s. VAIN is rare among women in their 20s and 30s, but when it does occur among younger women, there usually is a history of immunosuppression or CIN, Dr. Wright said.

The sensitivity of cytology in diagnosing VAIN remains uncertain. Most VAIN patients are postmenopausal, raising the question of whether a patient has high-grade VAIN or “severe atrophy, which is causing the cytology to mimic high-grade VAIN,” he said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

On cytology, squamous intraepithelial neoplasia and VAIN “look exactly the same,” he added. And on histopathology, VAIN looks “exactly the same” as CIN, VIN, or anal intraepithelial neoplasia.

He advised caution about the diagnosis of VAIN-1. “A lot of us are trying not to make low-grade diagnoses of VIN or VAIN,” and instead, “classify the majority of these lesions as flat condylomas, because the natural history of these low-grade lesions is not really well characterized,” he explained.

It is unclear whether a flat, low-grade appearing lesion in a 60-year-old has any premalignant potential, he added. Low-grade VAIN has many features of a flat condyloma, compared with VAIN-3, which is more clearly a high-grade lesion, he said.

As for the location of VAIN lesions, most are found in the upper third of the vagina, usually contiguous with CIN, if a cervix is present. Most cases are multifocal, often with lesions found in the “dog-ears of the vault after hysterectomy,” which makes colposcopy very difficult. Colposcopy is required to diagnose VAIN, but is quite difficult, especially in postmenopausal women who have had a hysterectomy, because it is necessary to look inside the folds and “dog-ears,” he said.

VIN may be present as well, so the vulva needs to be carefully examined, said Dr. Wright, adding that “a fair number of patients” will have VIN, CIN, and VAIN at the same time.

On colposcopy, VAIN “frequently appears as slightly raised, acetowhite lesions,” which can be subtle, especially in postmenopausal patients who have low estrogen levels, he said.

In the vagina, with high-grade lesions, vascular patterns such as mosaicism in the vagina usually are not present as they are with cervical lesions. These lesions usually are not acetowhite and are identified only after the application of Lugol's solution, he said.

On colposcopy, conditions that can mimic VAIN are congenital transformation zones that extend into the vagina and leukoplakia, which can appear on the vagina, not just the cervix, Dr. Wright said.

Vaginal ulcers or trauma and granulation tissue also can look like VAIN lesions on colposcopy. Inflammation caused by trichomonas, candida, atrophic vaginitis, or radiation atrophy can obscure VAIN lesions, Dr. Wright added.

Treatments for VAIN include excisional biopsy in the office, intravaginal 5-fluoracil, laser ablation or electrofulguration, and partial vaginectomy. Cryosurgery is not used very much now, he added. VAIN-1 usually is not treated aggressively, but followed, except in women suspected of having a higher-grade lesion, such as those who have had a hysterectomy for CIN 2 or 3 or cancer, or a conization for CIN 2 or 3, he said.

BETHESDA, MD. — An older age, a history of cervical intraepithelial neoplasia, and the presence of multifocal lesions in the upper third of the vagina are among the features associated with vaginal intraepithelial neoplasia, Thomas C. Wright Jr. said at a conference on vulvovaginal diseases.

Vaginal intraepithelial neoplasia (VAIN) is not common, accounting for only 0.4% of intraepithelial lesions of the lower genital tract, according to Dr. Wright, director of obstetrics, gynecology, and pathology at Columbia University College of Physicians and Surgeons, New York.

Women at higher risk include those with vulvar intraepithelial neoplasia (VIN), cigarette smokers, and those who have had radiation therapy. A woman who has had radiation therapy for endometrial cancer and presents with an abnormal Pap smear exemplifies one clinical scenario in which the index of suspicion for VAIN should be high, he noted.

Another typical VAIN case is a postmenopausal patient who has been treated for cervical intraepithelial neoplasia (CIN), even 10 years earlier, often with a hysterectomy, and has been considered cured. She then unexpectedly has a high-grade squamous lesion on cytology, with no lesion on the vagina that is visible to the naked eye.

Some of these risk factors were associated with VAIN in a 2001 study of 121 women with biopsy-confirmed VAIN, which found that 41% smoked, 39% had a history of human papilloma virus (HPV), 22% had undergone surgery for CIN, and 23% had undergone a total abdominal hysterectomy. The mean age of the patients was 35 years, and the majority had VAIN-1, a diagnosis Dr. Wright said he is “very leery” about classifying “as true VAIN lesions.”

Most of the patients he sees with VAIN are in their 40s to late 60s. VAIN is rare among women in their 20s and 30s, but when it does occur among younger women, there usually is a history of immunosuppression or CIN, Dr. Wright said.

The sensitivity of cytology in diagnosing VAIN remains uncertain. Most VAIN patients are postmenopausal, raising the question of whether a patient has high-grade VAIN or “severe atrophy, which is causing the cytology to mimic high-grade VAIN,” he said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

On cytology, squamous intraepithelial neoplasia and VAIN “look exactly the same,” he added. And on histopathology, VAIN looks “exactly the same” as CIN, VIN, or anal intraepithelial neoplasia.

He advised caution about the diagnosis of VAIN-1. “A lot of us are trying not to make low-grade diagnoses of VIN or VAIN,” and instead, “classify the majority of these lesions as flat condylomas, because the natural history of these low-grade lesions is not really well characterized,” he explained.

It is unclear whether a flat, low-grade appearing lesion in a 60-year-old has any premalignant potential, he added. Low-grade VAIN has many features of a flat condyloma, compared with VAIN-3, which is more clearly a high-grade lesion, he said.

As for the location of VAIN lesions, most are found in the upper third of the vagina, usually contiguous with CIN, if a cervix is present. Most cases are multifocal, often with lesions found in the “dog-ears of the vault after hysterectomy,” which makes colposcopy very difficult. Colposcopy is required to diagnose VAIN, but is quite difficult, especially in postmenopausal women who have had a hysterectomy, because it is necessary to look inside the folds and “dog-ears,” he said.

VIN may be present as well, so the vulva needs to be carefully examined, said Dr. Wright, adding that “a fair number of patients” will have VIN, CIN, and VAIN at the same time.

On colposcopy, VAIN “frequently appears as slightly raised, acetowhite lesions,” which can be subtle, especially in postmenopausal patients who have low estrogen levels, he said.

In the vagina, with high-grade lesions, vascular patterns such as mosaicism in the vagina usually are not present as they are with cervical lesions. These lesions usually are not acetowhite and are identified only after the application of Lugol's solution, he said.

On colposcopy, conditions that can mimic VAIN are congenital transformation zones that extend into the vagina and leukoplakia, which can appear on the vagina, not just the cervix, Dr. Wright said.

Vaginal ulcers or trauma and granulation tissue also can look like VAIN lesions on colposcopy. Inflammation caused by trichomonas, candida, atrophic vaginitis, or radiation atrophy can obscure VAIN lesions, Dr. Wright added.

Treatments for VAIN include excisional biopsy in the office, intravaginal 5-fluoracil, laser ablation or electrofulguration, and partial vaginectomy. Cryosurgery is not used very much now, he added. VAIN-1 usually is not treated aggressively, but followed, except in women suspected of having a higher-grade lesion, such as those who have had a hysterectomy for CIN 2 or 3 or cancer, or a conization for CIN 2 or 3, he said.

BETHESDA, MD. — An older age, a history of cervical intraepithelial neoplasia, and the presence of multifocal lesions in the upper third of the vagina are among the features associated with vaginal intraepithelial neoplasia, Thomas C. Wright Jr. said at a conference on vulvovaginal diseases.

Vaginal intraepithelial neoplasia (VAIN) is not common, accounting for only 0.4% of intraepithelial lesions of the lower genital tract, according to Dr. Wright, director of obstetrics, gynecology, and pathology at Columbia University College of Physicians and Surgeons, New York.

Women at higher risk include those with vulvar intraepithelial neoplasia (VIN), cigarette smokers, and those who have had radiation therapy. A woman who has had radiation therapy for endometrial cancer and presents with an abnormal Pap smear exemplifies one clinical scenario in which the index of suspicion for VAIN should be high, he noted.

Another typical VAIN case is a postmenopausal patient who has been treated for cervical intraepithelial neoplasia (CIN), even 10 years earlier, often with a hysterectomy, and has been considered cured. She then unexpectedly has a high-grade squamous lesion on cytology, with no lesion on the vagina that is visible to the naked eye.

Some of these risk factors were associated with VAIN in a 2001 study of 121 women with biopsy-confirmed VAIN, which found that 41% smoked, 39% had a history of human papilloma virus (HPV), 22% had undergone surgery for CIN, and 23% had undergone a total abdominal hysterectomy. The mean age of the patients was 35 years, and the majority had VAIN-1, a diagnosis Dr. Wright said he is “very leery” about classifying “as true VAIN lesions.”

Most of the patients he sees with VAIN are in their 40s to late 60s. VAIN is rare among women in their 20s and 30s, but when it does occur among younger women, there usually is a history of immunosuppression or CIN, Dr. Wright said.

The sensitivity of cytology in diagnosing VAIN remains uncertain. Most VAIN patients are postmenopausal, raising the question of whether a patient has high-grade VAIN or “severe atrophy, which is causing the cytology to mimic high-grade VAIN,” he said at the conference, sponsored by the American Society for Colposcopy and Cervical Pathology.

On cytology, squamous intraepithelial neoplasia and VAIN “look exactly the same,” he added. And on histopathology, VAIN looks “exactly the same” as CIN, VIN, or anal intraepithelial neoplasia.

He advised caution about the diagnosis of VAIN-1. “A lot of us are trying not to make low-grade diagnoses of VIN or VAIN,” and instead, “classify the majority of these lesions as flat condylomas, because the natural history of these low-grade lesions is not really well characterized,” he explained.

It is unclear whether a flat, low-grade appearing lesion in a 60-year-old has any premalignant potential, he added. Low-grade VAIN has many features of a flat condyloma, compared with VAIN-3, which is more clearly a high-grade lesion, he said.

As for the location of VAIN lesions, most are found in the upper third of the vagina, usually contiguous with CIN, if a cervix is present. Most cases are multifocal, often with lesions found in the “dog-ears of the vault after hysterectomy,” which makes colposcopy very difficult. Colposcopy is required to diagnose VAIN, but is quite difficult, especially in postmenopausal women who have had a hysterectomy, because it is necessary to look inside the folds and “dog-ears,” he said.

VIN may be present as well, so the vulva needs to be carefully examined, said Dr. Wright, adding that “a fair number of patients” will have VIN, CIN, and VAIN at the same time.

On colposcopy, VAIN “frequently appears as slightly raised, acetowhite lesions,” which can be subtle, especially in postmenopausal patients who have low estrogen levels, he said.

In the vagina, with high-grade lesions, vascular patterns such as mosaicism in the vagina usually are not present as they are with cervical lesions. These lesions usually are not acetowhite and are identified only after the application of Lugol's solution, he said.

On colposcopy, conditions that can mimic VAIN are congenital transformation zones that extend into the vagina and leukoplakia, which can appear on the vagina, not just the cervix, Dr. Wright said.

Vaginal ulcers or trauma and granulation tissue also can look like VAIN lesions on colposcopy. Inflammation caused by trichomonas, candida, atrophic vaginitis, or radiation atrophy can obscure VAIN lesions, Dr. Wright added.

Treatments for VAIN include excisional biopsy in the office, intravaginal 5-fluoracil, laser ablation or electrofulguration, and partial vaginectomy. Cryosurgery is not used very much now, he added. VAIN-1 usually is not treated aggressively, but followed, except in women suspected of having a higher-grade lesion, such as those who have had a hysterectomy for CIN 2 or 3 or cancer, or a conization for CIN 2 or 3, he said.

WASHINGTON — The prevalence of urinary tract infections in women resistant to standard treatment has been increasing, but there are indications that the increase has begun to level off, Patricia D. Brown, M.D., said at an update on sexually transmitted infections.

Emerging uropathogenic Escherichia coli antimicrobial resistance—particularly to the front-line, first-choice treatment of urinary tract infections (UTIs), trimethoprim-sulfamethoxazole (TMP-SMX)—has been documented worldwide. However, much of the data are based on passive surveillance, which can overestimate prevalence, because women with acute, uncomplicated UTIs often do not have cultures performed, so these cases are not reported, said Dr. Brown of Wayne State University, Detroit.

Women who do have a culture have complicated disease and fail treatment, leading to overestimates of true prevalence, she added. Still, passive surveillance can provide information on trends.

In the United States, active surveillance has been conducted in specific geographic areas, where the true prevalence may not reflect that of other geographic areas, Dr. Brown said at the meeting, sponsored by OB.GYN. NEWS, FAMILY PRACTICE NEWS, and Boston University.

Recent studies indicate that TMP-SMX resistance “may be leveling off” after peaking at about 25%, which is probably because of the reduced use of this treatment, she said. But as the use of TMP-SMX for UTIs has decreased, resistance to other antimicrobial agents has been increasing.

In 890 isolates from women with UTIs in the United States who were a part of the North American Urinary Tract Infection Collaborative Alliance (NAUTICA) study, the prevalence of TMP-SMX resistance was about 23%. Resistance to ampicillin was 38%, and resistance to levofloxacin was nearly 7%.

As the use of TMP-SMX has dropped, the use of fluoroquinolones has increased, Dr. Brown said, noting that rates of resistance to β-lactams such as ampicillin have been high for some time. In the NAUTICA study, resistance to nitrofurantoin was only 1.8%, which she said was “remarkable,” considering that it has been available for about 50 years. But that rate has probably remained so low because the agent has several mechanisms of action and is indicated only for cystitis, she noted.

There are several clinical implications of these resistance trends: In treatment studies of pyelonephritis, antimicrobial resistance has clearly been shown to increase the risks of both clinical and microbiologic failure, she said. She cited a retrospective cohort study of women with acute uncomplicated cystitis, in which the risk of clinical failure was 45.4%, and a prospective study in Israel of empiric TMP-SMX in an area where the prevalence of resistance was high, in which the risk of clinical failure was 46%.

Identifying risk factors for resistance can help guide antibiotic choice, she said, referring to the difficulty facing clinicians, who usually do not have access to resistance trends and who likely will be given an overestimate of resistance if they call their local microbiology lab.

Results of retrospective case-control studies have identified potential risk factors for infection with a uropathogen resistant to TMP-SMX. Two risk factors found in every such study include recent antibiotic use and recent hospitalization, she said. Recent travel to underdeveloped countries has been identified as an independent risk factor in several studies.

The standard treatment for uncomplicated cystitis is 3 days of double-strength formulations of TMP-SMX twice a day. Avoid empiric treatment with TMP-SMX in patients who have recently been hospitalized or have taken antibiotics in the previous 3 months, she said.

Alternative treatments for those with risk factors for resistance are a 7-day course of nitrofurantoin or a 3-day course of a fluoroquinolone. The major drawback of the former is that a full-week course is necessary. As for the fluoroquinolones, ciprofloxacin is available in generic formulations, so it is less expensive. The Food and Drug Administration has approved gatifloxacin as a single-dose treatment for uncomplicated cystitis. One fluoroquinolone that should not be used for UTI is moxifloxacin, which is indicated for respiratory infections, because treatment results in low levels of the drug in the urinary tract.

A single dose of fosfomycin is another alternative, but this is considered a second-line treatment because the efficacy is not that high and it is expensive. One benefit, however, is that resistance to this agent appears to be low, Dr. Brown said.

Short-course treatment is not appropriate for complicated cystitis, which should be treated with a 7-day course of therapy, she said. Avoid empiric TMP-SMX treatment in patients who have recently been treated with antibiotics or have recently been hospitalized, as you would for uncomplicated cystitis. Culture all patients, and adjust treatment based on susceptibility data, she said.

As many as 25% of women with acute cystitis can develop frequent, recurrent UTIs, which are reinfections, not relapses. (Fewer than 5% of these women have a correctable structural or functional abnormality of the urinary tract.) Management strategies include daily or postcoital prophylaxis and self-start therapy for women concerned about developing a UTI when they are away from home, she added.

Contraceptive methods should be evaluated, Dr. Brown said. She also considers prescribing topical estrogen for postmenopausal women who have recurrent UTIs.

WASHINGTON — The prevalence of urinary tract infections in women resistant to standard treatment has been increasing, but there are indications that the increase has begun to level off, Patricia D. Brown, M.D., said at an update on sexually transmitted infections.

Emerging uropathogenic Escherichia coli antimicrobial resistance—particularly to the front-line, first-choice treatment of urinary tract infections (UTIs), trimethoprim-sulfamethoxazole (TMP-SMX)—has been documented worldwide. However, much of the data are based on passive surveillance, which can overestimate prevalence, because women with acute, uncomplicated UTIs often do not have cultures performed, so these cases are not reported, said Dr. Brown of Wayne State University, Detroit.

Women who do have a culture have complicated disease and fail treatment, leading to overestimates of true prevalence, she added. Still, passive surveillance can provide information on trends.

In the United States, active surveillance has been conducted in specific geographic areas, where the true prevalence may not reflect that of other geographic areas, Dr. Brown said at the meeting, sponsored by OB.GYN. NEWS, FAMILY PRACTICE NEWS, and Boston University.

Recent studies indicate that TMP-SMX resistance “may be leveling off” after peaking at about 25%, which is probably because of the reduced use of this treatment, she said. But as the use of TMP-SMX for UTIs has decreased, resistance to other antimicrobial agents has been increasing.

In 890 isolates from women with UTIs in the United States who were a part of the North American Urinary Tract Infection Collaborative Alliance (NAUTICA) study, the prevalence of TMP-SMX resistance was about 23%. Resistance to ampicillin was 38%, and resistance to levofloxacin was nearly 7%.

As the use of TMP-SMX has dropped, the use of fluoroquinolones has increased, Dr. Brown said, noting that rates of resistance to β-lactams such as ampicillin have been high for some time. In the NAUTICA study, resistance to nitrofurantoin was only 1.8%, which she said was “remarkable,” considering that it has been available for about 50 years. But that rate has probably remained so low because the agent has several mechanisms of action and is indicated only for cystitis, she noted.

There are several clinical implications of these resistance trends: In treatment studies of pyelonephritis, antimicrobial resistance has clearly been shown to increase the risks of both clinical and microbiologic failure, she said. She cited a retrospective cohort study of women with acute uncomplicated cystitis, in which the risk of clinical failure was 45.4%, and a prospective study in Israel of empiric TMP-SMX in an area where the prevalence of resistance was high, in which the risk of clinical failure was 46%.

Identifying risk factors for resistance can help guide antibiotic choice, she said, referring to the difficulty facing clinicians, who usually do not have access to resistance trends and who likely will be given an overestimate of resistance if they call their local microbiology lab.

Results of retrospective case-control studies have identified potential risk factors for infection with a uropathogen resistant to TMP-SMX. Two risk factors found in every such study include recent antibiotic use and recent hospitalization, she said. Recent travel to underdeveloped countries has been identified as an independent risk factor in several studies.

The standard treatment for uncomplicated cystitis is 3 days of double-strength formulations of TMP-SMX twice a day. Avoid empiric treatment with TMP-SMX in patients who have recently been hospitalized or have taken antibiotics in the previous 3 months, she said.

Alternative treatments for those with risk factors for resistance are a 7-day course of nitrofurantoin or a 3-day course of a fluoroquinolone. The major drawback of the former is that a full-week course is necessary. As for the fluoroquinolones, ciprofloxacin is available in generic formulations, so it is less expensive. The Food and Drug Administration has approved gatifloxacin as a single-dose treatment for uncomplicated cystitis. One fluoroquinolone that should not be used for UTI is moxifloxacin, which is indicated for respiratory infections, because treatment results in low levels of the drug in the urinary tract.

A single dose of fosfomycin is another alternative, but this is considered a second-line treatment because the efficacy is not that high and it is expensive. One benefit, however, is that resistance to this agent appears to be low, Dr. Brown said.

Short-course treatment is not appropriate for complicated cystitis, which should be treated with a 7-day course of therapy, she said. Avoid empiric TMP-SMX treatment in patients who have recently been treated with antibiotics or have recently been hospitalized, as you would for uncomplicated cystitis. Culture all patients, and adjust treatment based on susceptibility data, she said.

As many as 25% of women with acute cystitis can develop frequent, recurrent UTIs, which are reinfections, not relapses. (Fewer than 5% of these women have a correctable structural or functional abnormality of the urinary tract.) Management strategies include daily or postcoital prophylaxis and self-start therapy for women concerned about developing a UTI when they are away from home, she added.

Contraceptive methods should be evaluated, Dr. Brown said. She also considers prescribing topical estrogen for postmenopausal women who have recurrent UTIs.

WASHINGTON — The prevalence of urinary tract infections in women resistant to standard treatment has been increasing, but there are indications that the increase has begun to level off, Patricia D. Brown, M.D., said at an update on sexually transmitted infections.

Emerging uropathogenic Escherichia coli antimicrobial resistance—particularly to the front-line, first-choice treatment of urinary tract infections (UTIs), trimethoprim-sulfamethoxazole (TMP-SMX)—has been documented worldwide. However, much of the data are based on passive surveillance, which can overestimate prevalence, because women with acute, uncomplicated UTIs often do not have cultures performed, so these cases are not reported, said Dr. Brown of Wayne State University, Detroit.

Women who do have a culture have complicated disease and fail treatment, leading to overestimates of true prevalence, she added. Still, passive surveillance can provide information on trends.

In the United States, active surveillance has been conducted in specific geographic areas, where the true prevalence may not reflect that of other geographic areas, Dr. Brown said at the meeting, sponsored by OB.GYN. NEWS, FAMILY PRACTICE NEWS, and Boston University.

Recent studies indicate that TMP-SMX resistance “may be leveling off” after peaking at about 25%, which is probably because of the reduced use of this treatment, she said. But as the use of TMP-SMX for UTIs has decreased, resistance to other antimicrobial agents has been increasing.

In 890 isolates from women with UTIs in the United States who were a part of the North American Urinary Tract Infection Collaborative Alliance (NAUTICA) study, the prevalence of TMP-SMX resistance was about 23%. Resistance to ampicillin was 38%, and resistance to levofloxacin was nearly 7%.

As the use of TMP-SMX has dropped, the use of fluoroquinolones has increased, Dr. Brown said, noting that rates of resistance to β-lactams such as ampicillin have been high for some time. In the NAUTICA study, resistance to nitrofurantoin was only 1.8%, which she said was “remarkable,” considering that it has been available for about 50 years. But that rate has probably remained so low because the agent has several mechanisms of action and is indicated only for cystitis, she noted.

There are several clinical implications of these resistance trends: In treatment studies of pyelonephritis, antimicrobial resistance has clearly been shown to increase the risks of both clinical and microbiologic failure, she said. She cited a retrospective cohort study of women with acute uncomplicated cystitis, in which the risk of clinical failure was 45.4%, and a prospective study in Israel of empiric TMP-SMX in an area where the prevalence of resistance was high, in which the risk of clinical failure was 46%.

Identifying risk factors for resistance can help guide antibiotic choice, she said, referring to the difficulty facing clinicians, who usually do not have access to resistance trends and who likely will be given an overestimate of resistance if they call their local microbiology lab.

Results of retrospective case-control studies have identified potential risk factors for infection with a uropathogen resistant to TMP-SMX. Two risk factors found in every such study include recent antibiotic use and recent hospitalization, she said. Recent travel to underdeveloped countries has been identified as an independent risk factor in several studies.

The standard treatment for uncomplicated cystitis is 3 days of double-strength formulations of TMP-SMX twice a day. Avoid empiric treatment with TMP-SMX in patients who have recently been hospitalized or have taken antibiotics in the previous 3 months, she said.

Alternative treatments for those with risk factors for resistance are a 7-day course of nitrofurantoin or a 3-day course of a fluoroquinolone. The major drawback of the former is that a full-week course is necessary. As for the fluoroquinolones, ciprofloxacin is available in generic formulations, so it is less expensive. The Food and Drug Administration has approved gatifloxacin as a single-dose treatment for uncomplicated cystitis. One fluoroquinolone that should not be used for UTI is moxifloxacin, which is indicated for respiratory infections, because treatment results in low levels of the drug in the urinary tract.

A single dose of fosfomycin is another alternative, but this is considered a second-line treatment because the efficacy is not that high and it is expensive. One benefit, however, is that resistance to this agent appears to be low, Dr. Brown said.

Short-course treatment is not appropriate for complicated cystitis, which should be treated with a 7-day course of therapy, she said. Avoid empiric TMP-SMX treatment in patients who have recently been treated with antibiotics or have recently been hospitalized, as you would for uncomplicated cystitis. Culture all patients, and adjust treatment based on susceptibility data, she said.

As many as 25% of women with acute cystitis can develop frequent, recurrent UTIs, which are reinfections, not relapses. (Fewer than 5% of these women have a correctable structural or functional abnormality of the urinary tract.) Management strategies include daily or postcoital prophylaxis and self-start therapy for women concerned about developing a UTI when they are away from home, she added.

Contraceptive methods should be evaluated, Dr. Brown said. She also considers prescribing topical estrogen for postmenopausal women who have recurrent UTIs.

GAITHERSBURG, MD. — The fixed-dose combination of isosorbide dinitrate and hydralazine is the first product approved specifically for treating patients in a specific racial group—a development that has been lauded as a significant advance that could help save the lives of many African Americans and criticized as scientifically unjustified and generating a racial stigma.

The Food and Drug Administration's approval is “for the treatment of heart failure as an adjunct to standard therapy in self-identified black patients to improve survival, to prolong time to hospitalization for heart failure, and to improve patient-reported functional status.”

Those outcomes were evaluated in the African American Heart Failure Trial (A-HeFT), which compared the combination with placebo in self-identified African American patients with moderate to severe heart failure (HF) who were on standard HF treatments, and which was the basis for the approval. The label notes that most patients were on a loop diuretic, an ACE inhibitor or an angiotensin receptor blocker, and a β-blocker; many were also on a cardiac glycoside or an aldosterone antagonist.

The “approval of a drug to treat severe heart failure in a self-identified black population is a striking example of how a treatment can benefit some patients even if it does not help all patients,” Robert Temple, M.D., director of the office of drug evaluation at FDA, Rockville, Md., said in a statement.

One week prior to the June 23 approval, the nine panel members of the FDA's Cardiovascular and Renal Drugs Advisory Committee unanimously agreed that the combination product should be approved. Only two panelists recommended that the approval not specify black patients.

The manufacturer, Massachusetts-based NitroMed Inc., will market the combination as BiDil. Each tablet contains 37.5 mg hydralazine hydrochloride and 20 mg isosorbide dinitrate, which have been approved separately for treating hypertension (hydralazine) and angina (isosorbide dinitrate) for more than 40 years.

If the approval had been for all patients, NitroMed's exclusive rights would expire in 2007. But because BiDil's approval is specifically for self-identified African Americans, the company will retain the rights until 2020 according to a published assessment (N. Engl. J. Med. 2004;351:2035–7).

The treatment's theoretical basis is isosorbide's activity as a nitric oxide donor, and hydralazine's activity as an antioxidant that prevents nitric oxide degradation. Nitric oxide insufficiency in the black population is thought to partially explain why hypertensive black patients tend to respond better to diuretics than to ACE inhibitors or β-blockers, and why black patients with HF apparently do not respond as well to these medications either, according to the FDA briefing document.

A-HeFT compared BiDil with placebo in black men and women with moderate to severe HF who were on standard HF therapies, including ACE inhibitors, angiotensin receptor blockers, aldosterone antagonists, as well as digitalis and diuretics. Patients were titrated up to a target dose of 120 mg isosorbide and 225 mg of hydralazine, 1 tablet three times a day.

A-HeFT's primary end point, a composite score of all-cause mortality, HF hospitalization, and the change in a quality of life score at 6 months, compared with baseline, was significantly lower among those on BiDil. The relative risk of mortality was reduced by 43%, and hospitalization for HF was reduced by 39%, with an improvement in quality of life scores at 6 months.

The study was prematurely terminated in July 2004, when the reduction in mortality was seen. At that time, 1,050 of the targeted sample size of 1,100 patients had been randomized: 40% were women, and 91% of those on BiDil and 86% on placebo completed the study.

The robust effect of the drug on mortality, on top of optimum treatment, is evidence that is “more than adequate” for recommending approval and is “a compelling argument for this population, but only for this population,” said the panel chair, Steven E. Nissen, M.D., medical director of the cardiovascular coordinating center at the Cleveland Clinic at the advisory committee meeting. “We're using self-identified race as a surrogate for genomic-based medicine, and I don't think that's unreasonable.” In the absence of genetic markers to “decide who's going to respond to what drug … we have to use the best evidence available to us today” from the A-HeFT trial.

But Vivian Ota Wang, Ph.D., the director of the ethical, legal, and social implications program at the National Human Genome Research Institute at the National Institutes of Health, Bethesda, Md., said that although she supported approval, she was not satisfied using self-identification as being African American as a surrogate for a biologic process, and did not support the label targeting this group because the underlying rationale of A-HeFT was a biologic reason. Skin tone is “not a great proxy” for biologic traits, she said.

The controversy over the impact of a race-based HF indication were expressed by speakers during the open public hearing. None opposed the drug's approval, but several argued against approving it specifically for black patients.

Charles Rotini, Ph.D., of the National Human Genome Center at Howard University, Washington, said that group identity is confused with ancestry, and that African Americans have a diverse ancestry. He said it would be tragic not to approve the drug, but “just as tragic” to approve it for the black population only.

Charles Curry, M.D., president of the International Society on Hypertension in Blacks and former chief of cardiology at Howard University, said he “vigorously” supported approval and called BiDil “the most important advance in the care of black people we have seen in my lifetime.” But he also expressed concern about limiting a life-saving treatment to one group of patients, noting that early trials were conducted almost exclusively in white men, but have benefited all populations.

“Would anyone restrict the results of 4S [Scandinavian Simvastatin Survival Study] to Scandinavians?” asked Dr. Curry who, as an A-HeFT investigator and member of the trial's cosponsor, the Association of Black Cardiologists, received funds from NitroMed.

Those expressing unconditional support for the approval included the chair of the Congressional Black Caucus and representatives of the National Minority Health Month Foundation and the NAACP.

In A-HeFT, headache, dizziness, and hypotension were higher in the BiDil patients, and worsening of HF was more common in the placebo patients. Arthralgias were reported in 1.5% of those on BiDil, vs. 0.4% of those on placebo, about a fourfold greater rate that falls “into a category of some concern” about the potential for a drug-induced lupus-like syndrome that has been associated with hydralazine, said Jonathan Sackner-Bernstein, M.D., director of the HF program at St. Luke's-Roosevelt Hospital Center, New York, noting that such events could be monitored after approval.

Jay N. Cohn, M.D., was principal investigator of V-HeFT I, which compared the drug combination with placebo added to standard therapy in the early 1980s in male patients with mild HF, and a few years later, V-HeFT II, which compared the combination with enalapril, added to standard therapy. The results suggested benefits, but were not adequate for FDA approval.

In a retrospective analysis, Dr. Cohn found that benefit seemed more favorable in black patients, which, after discussions with the FDA, led to the A-HeFT trial. The FDA said a single positive study in an HF population could be the basis for approval as a treatment for HF in black patients, and the trial began in May 2001. Dr. Cohn, the inventor of BiDil, holds equity in and stands to receive royalties from the sale of BiDil.

The findings confirmed the hypotheses generated from V-HeFT I and II, said Clyde Yancy, M.D., medical director of the Heart Failure/Transplantation Program at the University of Texas Southwestern Medical School, Dallas, speaking for NitroMed. The black population has a high rate of HF, which appears at a younger age, often with greater left ventricular dysfunction and a less favorable prognosis, he noted.

The BiDil application may not be so precedent setting as has been portrayed, Dr. Nissen said, citing the recent approval of the fixed-dose combination of losartan and hydrochlorothiazide for reducing the stroke risk in patients with hypertension and left ventricular hypertrophy, with a label that says evidence suggests this benefit does not apply to black patients.

Dr. Charles Curry lauded BiDil as an unparalleled advance for black people. James Reinaker

GAITHERSBURG, MD. — The fixed-dose combination of isosorbide dinitrate and hydralazine is the first product approved specifically for treating patients in a specific racial group—a development that has been lauded as a significant advance that could help save the lives of many African Americans and criticized as scientifically unjustified and generating a racial stigma.

The Food and Drug Administration's approval is “for the treatment of heart failure as an adjunct to standard therapy in self-identified black patients to improve survival, to prolong time to hospitalization for heart failure, and to improve patient-reported functional status.”

Those outcomes were evaluated in the African American Heart Failure Trial (A-HeFT), which compared the combination with placebo in self-identified African American patients with moderate to severe heart failure (HF) who were on standard HF treatments, and which was the basis for the approval. The label notes that most patients were on a loop diuretic, an ACE inhibitor or an angiotensin receptor blocker, and a β-blocker; many were also on a cardiac glycoside or an aldosterone antagonist.

The “approval of a drug to treat severe heart failure in a self-identified black population is a striking example of how a treatment can benefit some patients even if it does not help all patients,” Robert Temple, M.D., director of the office of drug evaluation at FDA, Rockville, Md., said in a statement.

One week prior to the June 23 approval, the nine panel members of the FDA's Cardiovascular and Renal Drugs Advisory Committee unanimously agreed that the combination product should be approved. Only two panelists recommended that the approval not specify black patients.

The manufacturer, Massachusetts-based NitroMed Inc., will market the combination as BiDil. Each tablet contains 37.5 mg hydralazine hydrochloride and 20 mg isosorbide dinitrate, which have been approved separately for treating hypertension (hydralazine) and angina (isosorbide dinitrate) for more than 40 years.

If the approval had been for all patients, NitroMed's exclusive rights would expire in 2007. But because BiDil's approval is specifically for self-identified African Americans, the company will retain the rights until 2020 according to a published assessment (N. Engl. J. Med. 2004;351:2035–7).

The treatment's theoretical basis is isosorbide's activity as a nitric oxide donor, and hydralazine's activity as an antioxidant that prevents nitric oxide degradation. Nitric oxide insufficiency in the black population is thought to partially explain why hypertensive black patients tend to respond better to diuretics than to ACE inhibitors or β-blockers, and why black patients with HF apparently do not respond as well to these medications either, according to the FDA briefing document.

A-HeFT compared BiDil with placebo in black men and women with moderate to severe HF who were on standard HF therapies, including ACE inhibitors, angiotensin receptor blockers, aldosterone antagonists, as well as digitalis and diuretics. Patients were titrated up to a target dose of 120 mg isosorbide and 225 mg of hydralazine, 1 tablet three times a day.

A-HeFT's primary end point, a composite score of all-cause mortality, HF hospitalization, and the change in a quality of life score at 6 months, compared with baseline, was significantly lower among those on BiDil. The relative risk of mortality was reduced by 43%, and hospitalization for HF was reduced by 39%, with an improvement in quality of life scores at 6 months.

The study was prematurely terminated in July 2004, when the reduction in mortality was seen. At that time, 1,050 of the targeted sample size of 1,100 patients had been randomized: 40% were women, and 91% of those on BiDil and 86% on placebo completed the study.

The robust effect of the drug on mortality, on top of optimum treatment, is evidence that is “more than adequate” for recommending approval and is “a compelling argument for this population, but only for this population,” said the panel chair, Steven E. Nissen, M.D., medical director of the cardiovascular coordinating center at the Cleveland Clinic at the advisory committee meeting. “We're using self-identified race as a surrogate for genomic-based medicine, and I don't think that's unreasonable.” In the absence of genetic markers to “decide who's going to respond to what drug … we have to use the best evidence available to us today” from the A-HeFT trial.

But Vivian Ota Wang, Ph.D., the director of the ethical, legal, and social implications program at the National Human Genome Research Institute at the National Institutes of Health, Bethesda, Md., said that although she supported approval, she was not satisfied using self-identification as being African American as a surrogate for a biologic process, and did not support the label targeting this group because the underlying rationale of A-HeFT was a biologic reason. Skin tone is “not a great proxy” for biologic traits, she said.

The controversy over the impact of a race-based HF indication were expressed by speakers during the open public hearing. None opposed the drug's approval, but several argued against approving it specifically for black patients.

Charles Rotini, Ph.D., of the National Human Genome Center at Howard University, Washington, said that group identity is confused with ancestry, and that African Americans have a diverse ancestry. He said it would be tragic not to approve the drug, but “just as tragic” to approve it for the black population only.

Charles Curry, M.D., president of the International Society on Hypertension in Blacks and former chief of cardiology at Howard University, said he “vigorously” supported approval and called BiDil “the most important advance in the care of black people we have seen in my lifetime.” But he also expressed concern about limiting a life-saving treatment to one group of patients, noting that early trials were conducted almost exclusively in white men, but have benefited all populations.

“Would anyone restrict the results of 4S [Scandinavian Simvastatin Survival Study] to Scandinavians?” asked Dr. Curry who, as an A-HeFT investigator and member of the trial's cosponsor, the Association of Black Cardiologists, received funds from NitroMed.

Those expressing unconditional support for the approval included the chair of the Congressional Black Caucus and representatives of the National Minority Health Month Foundation and the NAACP.

In A-HeFT, headache, dizziness, and hypotension were higher in the BiDil patients, and worsening of HF was more common in the placebo patients. Arthralgias were reported in 1.5% of those on BiDil, vs. 0.4% of those on placebo, about a fourfold greater rate that falls “into a category of some concern” about the potential for a drug-induced lupus-like syndrome that has been associated with hydralazine, said Jonathan Sackner-Bernstein, M.D., director of the HF program at St. Luke's-Roosevelt Hospital Center, New York, noting that such events could be monitored after approval.

Jay N. Cohn, M.D., was principal investigator of V-HeFT I, which compared the drug combination with placebo added to standard therapy in the early 1980s in male patients with mild HF, and a few years later, V-HeFT II, which compared the combination with enalapril, added to standard therapy. The results suggested benefits, but were not adequate for FDA approval.

In a retrospective analysis, Dr. Cohn found that benefit seemed more favorable in black patients, which, after discussions with the FDA, led to the A-HeFT trial. The FDA said a single positive study in an HF population could be the basis for approval as a treatment for HF in black patients, and the trial began in May 2001. Dr. Cohn, the inventor of BiDil, holds equity in and stands to receive royalties from the sale of BiDil.

The findings confirmed the hypotheses generated from V-HeFT I and II, said Clyde Yancy, M.D., medical director of the Heart Failure/Transplantation Program at the University of Texas Southwestern Medical School, Dallas, speaking for NitroMed. The black population has a high rate of HF, which appears at a younger age, often with greater left ventricular dysfunction and a less favorable prognosis, he noted.

The BiDil application may not be so precedent setting as has been portrayed, Dr. Nissen said, citing the recent approval of the fixed-dose combination of losartan and hydrochlorothiazide for reducing the stroke risk in patients with hypertension and left ventricular hypertrophy, with a label that says evidence suggests this benefit does not apply to black patients.

Dr. Charles Curry lauded BiDil as an unparalleled advance for black people. James Reinaker

GAITHERSBURG, MD. — The fixed-dose combination of isosorbide dinitrate and hydralazine is the first product approved specifically for treating patients in a specific racial group—a development that has been lauded as a significant advance that could help save the lives of many African Americans and criticized as scientifically unjustified and generating a racial stigma.

The Food and Drug Administration's approval is “for the treatment of heart failure as an adjunct to standard therapy in self-identified black patients to improve survival, to prolong time to hospitalization for heart failure, and to improve patient-reported functional status.”

Those outcomes were evaluated in the African American Heart Failure Trial (A-HeFT), which compared the combination with placebo in self-identified African American patients with moderate to severe heart failure (HF) who were on standard HF treatments, and which was the basis for the approval. The label notes that most patients were on a loop diuretic, an ACE inhibitor or an angiotensin receptor blocker, and a β-blocker; many were also on a cardiac glycoside or an aldosterone antagonist.

The “approval of a drug to treat severe heart failure in a self-identified black population is a striking example of how a treatment can benefit some patients even if it does not help all patients,” Robert Temple, M.D., director of the office of drug evaluation at FDA, Rockville, Md., said in a statement.

One week prior to the June 23 approval, the nine panel members of the FDA's Cardiovascular and Renal Drugs Advisory Committee unanimously agreed that the combination product should be approved. Only two panelists recommended that the approval not specify black patients.

The manufacturer, Massachusetts-based NitroMed Inc., will market the combination as BiDil. Each tablet contains 37.5 mg hydralazine hydrochloride and 20 mg isosorbide dinitrate, which have been approved separately for treating hypertension (hydralazine) and angina (isosorbide dinitrate) for more than 40 years.

If the approval had been for all patients, NitroMed's exclusive rights would expire in 2007. But because BiDil's approval is specifically for self-identified African Americans, the company will retain the rights until 2020 according to a published assessment (N. Engl. J. Med. 2004;351:2035–7).

The treatment's theoretical basis is isosorbide's activity as a nitric oxide donor, and hydralazine's activity as an antioxidant that prevents nitric oxide degradation. Nitric oxide insufficiency in the black population is thought to partially explain why hypertensive black patients tend to respond better to diuretics than to ACE inhibitors or β-blockers, and why black patients with HF apparently do not respond as well to these medications either, according to the FDA briefing document.

A-HeFT compared BiDil with placebo in black men and women with moderate to severe HF who were on standard HF therapies, including ACE inhibitors, angiotensin receptor blockers, aldosterone antagonists, as well as digitalis and diuretics. Patients were titrated up to a target dose of 120 mg isosorbide and 225 mg of hydralazine, 1 tablet three times a day.

A-HeFT's primary end point, a composite score of all-cause mortality, HF hospitalization, and the change in a quality of life score at 6 months, compared with baseline, was significantly lower among those on BiDil. The relative risk of mortality was reduced by 43%, and hospitalization for HF was reduced by 39%, with an improvement in quality of life scores at 6 months.

The study was prematurely terminated in July 2004, when the reduction in mortality was seen. At that time, 1,050 of the targeted sample size of 1,100 patients had been randomized: 40% were women, and 91% of those on BiDil and 86% on placebo completed the study.

The robust effect of the drug on mortality, on top of optimum treatment, is evidence that is “more than adequate” for recommending approval and is “a compelling argument for this population, but only for this population,” said the panel chair, Steven E. Nissen, M.D., medical director of the cardiovascular coordinating center at the Cleveland Clinic at the advisory committee meeting. “We're using self-identified race as a surrogate for genomic-based medicine, and I don't think that's unreasonable.” In the absence of genetic markers to “decide who's going to respond to what drug … we have to use the best evidence available to us today” from the A-HeFT trial.

But Vivian Ota Wang, Ph.D., the director of the ethical, legal, and social implications program at the National Human Genome Research Institute at the National Institutes of Health, Bethesda, Md., said that although she supported approval, she was not satisfied using self-identification as being African American as a surrogate for a biologic process, and did not support the label targeting this group because the underlying rationale of A-HeFT was a biologic reason. Skin tone is “not a great proxy” for biologic traits, she said.

The controversy over the impact of a race-based HF indication were expressed by speakers during the open public hearing. None opposed the drug's approval, but several argued against approving it specifically for black patients.

Charles Rotini, Ph.D., of the National Human Genome Center at Howard University, Washington, said that group identity is confused with ancestry, and that African Americans have a diverse ancestry. He said it would be tragic not to approve the drug, but “just as tragic” to approve it for the black population only.

Charles Curry, M.D., president of the International Society on Hypertension in Blacks and former chief of cardiology at Howard University, said he “vigorously” supported approval and called BiDil “the most important advance in the care of black people we have seen in my lifetime.” But he also expressed concern about limiting a life-saving treatment to one group of patients, noting that early trials were conducted almost exclusively in white men, but have benefited all populations.

“Would anyone restrict the results of 4S [Scandinavian Simvastatin Survival Study] to Scandinavians?” asked Dr. Curry who, as an A-HeFT investigator and member of the trial's cosponsor, the Association of Black Cardiologists, received funds from NitroMed.

Those expressing unconditional support for the approval included the chair of the Congressional Black Caucus and representatives of the National Minority Health Month Foundation and the NAACP.

In A-HeFT, headache, dizziness, and hypotension were higher in the BiDil patients, and worsening of HF was more common in the placebo patients. Arthralgias were reported in 1.5% of those on BiDil, vs. 0.4% of those on placebo, about a fourfold greater rate that falls “into a category of some concern” about the potential for a drug-induced lupus-like syndrome that has been associated with hydralazine, said Jonathan Sackner-Bernstein, M.D., director of the HF program at St. Luke's-Roosevelt Hospital Center, New York, noting that such events could be monitored after approval.

Jay N. Cohn, M.D., was principal investigator of V-HeFT I, which compared the drug combination with placebo added to standard therapy in the early 1980s in male patients with mild HF, and a few years later, V-HeFT II, which compared the combination with enalapril, added to standard therapy. The results suggested benefits, but were not adequate for FDA approval.

In a retrospective analysis, Dr. Cohn found that benefit seemed more favorable in black patients, which, after discussions with the FDA, led to the A-HeFT trial. The FDA said a single positive study in an HF population could be the basis for approval as a treatment for HF in black patients, and the trial began in May 2001. Dr. Cohn, the inventor of BiDil, holds equity in and stands to receive royalties from the sale of BiDil.

The findings confirmed the hypotheses generated from V-HeFT I and II, said Clyde Yancy, M.D., medical director of the Heart Failure/Transplantation Program at the University of Texas Southwestern Medical School, Dallas, speaking for NitroMed. The black population has a high rate of HF, which appears at a younger age, often with greater left ventricular dysfunction and a less favorable prognosis, he noted.

The BiDil application may not be so precedent setting as has been portrayed, Dr. Nissen said, citing the recent approval of the fixed-dose combination of losartan and hydrochlorothiazide for reducing the stroke risk in patients with hypertension and left ventricular hypertrophy, with a label that says evidence suggests this benefit does not apply to black patients.

Dr. Charles Curry lauded BiDil as an unparalleled advance for black people. James Reinaker

BETHESDA, MD. — Herpes simplex virus 1 has emerged as an important genital pathogen and is more likely than herpes simplex virus 2 to be the cause of primary genital herpes infections in young women, Sharon L. Hillier, Ph.D., said at a conference on vulvovaginal diseases.

Young, sexually active women are more susceptible to HSV-1 because most do not have protective antibodies to HSV-1 due to the dramatic drop in childhood HSV-1 infections, said Dr. Hillier, director, reproductive infectious disease research, Magee-Womens Hospital, Pittsburgh.

Among the major implications of this trend is the potential utility of the genital herpes vaccine that is being developed, since it targets only HSV-2, and HSV-2 antibodies do not confer protection against HSV-1, she pointed out.

Since estimates of genital herpes from national seroprevalence studies include only HSV-2 infections, they “probably greatly underestimate” the amount of U.S. cases, Dr. Hillier said at the conference, held by the American Society for Colposcopy and Cervical Pathology.

Studies documenting the emergence of HSV-1 as a cause of primary genital herpes infections date to 1990, when HSV-1 was found to have replaced HSV-2 as the most common cause of genital herpes in Scotland. Studies published in 2000 reported that HSV-1 was the cause of 85% of all primary genital HSV infections in Sweden and 70%–90% of all first episodes of genital herpes in women younger than 21 in Norway. In the United States, a 2003 study found that the proportion of newly diagnosed genital herpes infections due to HSV-1 in a university student health service increased from 31% in 1993 to 78% in 2001.

In a recent study, Dr. Hillier and her associates found only 29% of a sample of college students at a University of Pittsburgh student health clinic had antibodies to HSV-1, making the majority susceptible to infection. The study enrolled 1,207 women aged 18–30 years at three different health clinics and found that the HSV-1 seroprevalence was 46.6% overall, but 60% at the primary care clinic and 51% at an STD clinic (Sex. Transm. Dis. 2005;32:84–9).

Their results indicated that age and number of sex partners was associated with HSV-1 seroprevalence: 38% of the women aged 18–20 years were positive for HSV-1 antibodies, increasing to 49% among those aged 21–25 years, and 64% among those aged 26–30 years. HSV-1 seroprevalence was 26% among those who previously had no sex partners, 41% among those who had one to four sex partners in their lifetime, and 53% among those who had five or more lifetime sex partners.

Follow-up of these women determined that cunnilingus and vaginal intercourse were risk factors for the acquisition of HSV-1 infections: Of the 516 HSV-1 seronegative women who returned for 1,833 visits, 29 acquired antibodies to HSV-1. That means that 6% of the women per year were acquiring herpes infections due to HSV-1 infection, said Dr. Hillier, also, professor of obstetrics, gynecology, and reproductive sciences, and of molecular genetics and biochemistry at the University of Pittsburgh.

In terms of sex practices, the acquisition rate for HSV-1 was highest among those who had receptive oral sex only, at 9.8 per 100 woman-years, compared with 1.2 cases per 100 woman-years among those who were not sexually active.

Among women having vaginal intercourse, the rate for HSV-1 was 6.8 cases per 100 woman-years, or 6.8% per year, she said. The HSV-2 rate was 5.7 cases per 100 woman-years among those reporting vaginal intercourse, but zero among those reporting receptive oral sex only.

Therefore, “women who report only oral sex are just as likely to acquire HSV-1 as women reporting vaginal sex,” she said. These data are similar to findings from Scotland and Finland, indicating oral sex raises the risk of HSV-1 “and has really changed the way we have begun to think about a lot of the women saying they have herpes,” she added.

BETHESDA, MD. — Herpes simplex virus 1 has emerged as an important genital pathogen and is more likely than herpes simplex virus 2 to be the cause of primary genital herpes infections in young women, Sharon L. Hillier, Ph.D., said at a conference on vulvovaginal diseases.

Young, sexually active women are more susceptible to HSV-1 because most do not have protective antibodies to HSV-1 due to the dramatic drop in childhood HSV-1 infections, said Dr. Hillier, director, reproductive infectious disease research, Magee-Womens Hospital, Pittsburgh.

Among the major implications of this trend is the potential utility of the genital herpes vaccine that is being developed, since it targets only HSV-2, and HSV-2 antibodies do not confer protection against HSV-1, she pointed out.

Since estimates of genital herpes from national seroprevalence studies include only HSV-2 infections, they “probably greatly underestimate” the amount of U.S. cases, Dr. Hillier said at the conference, held by the American Society for Colposcopy and Cervical Pathology.

Studies documenting the emergence of HSV-1 as a cause of primary genital herpes infections date to 1990, when HSV-1 was found to have replaced HSV-2 as the most common cause of genital herpes in Scotland. Studies published in 2000 reported that HSV-1 was the cause of 85% of all primary genital HSV infections in Sweden and 70%–90% of all first episodes of genital herpes in women younger than 21 in Norway. In the United States, a 2003 study found that the proportion of newly diagnosed genital herpes infections due to HSV-1 in a university student health service increased from 31% in 1993 to 78% in 2001.

In a recent study, Dr. Hillier and her associates found only 29% of a sample of college students at a University of Pittsburgh student health clinic had antibodies to HSV-1, making the majority susceptible to infection. The study enrolled 1,207 women aged 18–30 years at three different health clinics and found that the HSV-1 seroprevalence was 46.6% overall, but 60% at the primary care clinic and 51% at an STD clinic (Sex. Transm. Dis. 2005;32:84–9).

Their results indicated that age and number of sex partners was associated with HSV-1 seroprevalence: 38% of the women aged 18–20 years were positive for HSV-1 antibodies, increasing to 49% among those aged 21–25 years, and 64% among those aged 26–30 years. HSV-1 seroprevalence was 26% among those who previously had no sex partners, 41% among those who had one to four sex partners in their lifetime, and 53% among those who had five or more lifetime sex partners.

Follow-up of these women determined that cunnilingus and vaginal intercourse were risk factors for the acquisition of HSV-1 infections: Of the 516 HSV-1 seronegative women who returned for 1,833 visits, 29 acquired antibodies to HSV-1. That means that 6% of the women per year were acquiring herpes infections due to HSV-1 infection, said Dr. Hillier, also, professor of obstetrics, gynecology, and reproductive sciences, and of molecular genetics and biochemistry at the University of Pittsburgh.

In terms of sex practices, the acquisition rate for HSV-1 was highest among those who had receptive oral sex only, at 9.8 per 100 woman-years, compared with 1.2 cases per 100 woman-years among those who were not sexually active.

Among women having vaginal intercourse, the rate for HSV-1 was 6.8 cases per 100 woman-years, or 6.8% per year, she said. The HSV-2 rate was 5.7 cases per 100 woman-years among those reporting vaginal intercourse, but zero among those reporting receptive oral sex only.

Therefore, “women who report only oral sex are just as likely to acquire HSV-1 as women reporting vaginal sex,” she said. These data are similar to findings from Scotland and Finland, indicating oral sex raises the risk of HSV-1 “and has really changed the way we have begun to think about a lot of the women saying they have herpes,” she added.

BETHESDA, MD. — Herpes simplex virus 1 has emerged as an important genital pathogen and is more likely than herpes simplex virus 2 to be the cause of primary genital herpes infections in young women, Sharon L. Hillier, Ph.D., said at a conference on vulvovaginal diseases.

Young, sexually active women are more susceptible to HSV-1 because most do not have protective antibodies to HSV-1 due to the dramatic drop in childhood HSV-1 infections, said Dr. Hillier, director, reproductive infectious disease research, Magee-Womens Hospital, Pittsburgh.

Among the major implications of this trend is the potential utility of the genital herpes vaccine that is being developed, since it targets only HSV-2, and HSV-2 antibodies do not confer protection against HSV-1, she pointed out.

Since estimates of genital herpes from national seroprevalence studies include only HSV-2 infections, they “probably greatly underestimate” the amount of U.S. cases, Dr. Hillier said at the conference, held by the American Society for Colposcopy and Cervical Pathology.

Studies documenting the emergence of HSV-1 as a cause of primary genital herpes infections date to 1990, when HSV-1 was found to have replaced HSV-2 as the most common cause of genital herpes in Scotland. Studies published in 2000 reported that HSV-1 was the cause of 85% of all primary genital HSV infections in Sweden and 70%–90% of all first episodes of genital herpes in women younger than 21 in Norway. In the United States, a 2003 study found that the proportion of newly diagnosed genital herpes infections due to HSV-1 in a university student health service increased from 31% in 1993 to 78% in 2001.

In a recent study, Dr. Hillier and her associates found only 29% of a sample of college students at a University of Pittsburgh student health clinic had antibodies to HSV-1, making the majority susceptible to infection. The study enrolled 1,207 women aged 18–30 years at three different health clinics and found that the HSV-1 seroprevalence was 46.6% overall, but 60% at the primary care clinic and 51% at an STD clinic (Sex. Transm. Dis. 2005;32:84–9).

Their results indicated that age and number of sex partners was associated with HSV-1 seroprevalence: 38% of the women aged 18–20 years were positive for HSV-1 antibodies, increasing to 49% among those aged 21–25 years, and 64% among those aged 26–30 years. HSV-1 seroprevalence was 26% among those who previously had no sex partners, 41% among those who had one to four sex partners in their lifetime, and 53% among those who had five or more lifetime sex partners.

Follow-up of these women determined that cunnilingus and vaginal intercourse were risk factors for the acquisition of HSV-1 infections: Of the 516 HSV-1 seronegative women who returned for 1,833 visits, 29 acquired antibodies to HSV-1. That means that 6% of the women per year were acquiring herpes infections due to HSV-1 infection, said Dr. Hillier, also, professor of obstetrics, gynecology, and reproductive sciences, and of molecular genetics and biochemistry at the University of Pittsburgh.

In terms of sex practices, the acquisition rate for HSV-1 was highest among those who had receptive oral sex only, at 9.8 per 100 woman-years, compared with 1.2 cases per 100 woman-years among those who were not sexually active.

Among women having vaginal intercourse, the rate for HSV-1 was 6.8 cases per 100 woman-years, or 6.8% per year, she said. The HSV-2 rate was 5.7 cases per 100 woman-years among those reporting vaginal intercourse, but zero among those reporting receptive oral sex only.

Therefore, “women who report only oral sex are just as likely to acquire HSV-1 as women reporting vaginal sex,” she said. These data are similar to findings from Scotland and Finland, indicating oral sex raises the risk of HSV-1 “and has really changed the way we have begun to think about a lot of the women saying they have herpes,” she added.