Sharon Worcester

Newly developed polio vaccine strains could replace currently used risky inactivated vaccines, thereby allowing for safer vaccine production in a post-polio eradication environment, according to researchers at the National Institute for Biological Standards and Control (NIBSC).

Polio eradication is in sight, and these new strains are safer than the attenuated Sabin strain currently used for developing inactivated vaccine. The Sabin strain is unstable and thus could repopulate the environment, Sarah Knowlson and her colleagues from the NIBSC, Potters Bar, Hertfordshire, England, argue in an article published Dec. 31 in PLOS Pathogens.

courtesy www.vaccines.mil

“The Global Polio Eradication Initiative is ... very close to eliminating naturally occurring wild poliovirus from the planet. It has involved the extensive use of both the live attenuated vaccines that can revert to a wild type phenotype, and inactivated polio vaccines (IPV) whose production in the main currently requires the growth of very large amounts of virulent wild type poliovirus, ” they explain, noting that the vaccines are therefore a possible source for re-emergence of poliomyelitis following eradication. (PLoS Pathog. 2015 Dec 31;11. doi: 10.1371/journal.ppat.1005316).

To develop the new strains, the researchers started with the well-understood Sabin strain and modified a region of its viral RNA to promote greater genetic stability. The new strains were then compared with the original Sabin vaccine strain and the wild-type strain currently used to produce inactivated vaccine.

The new strains were “extremely attenuated and genetically stable in cell culture by rational design based on understanding of the attenuation of the Sabin vaccine strains of poliovirus. The viruses grow to titers acceptable for IPV production under appropriate conditions of temperature and cell substrate and have the same antigenic properties based on reactions with panels of monoclonal antibodies in ELISA as well as in regulatory assays for antigen and immunogen content as the strains from which their capsids were derived,” the investigators wrote.

The strains were tested in mice and primates and behaved as predicted in that they were “effective, suitable to mass production, and safer than the alternatives,” according to a press statement.

This work was supported by NIBSC. The investigators reported having no disclosures.

sworcester@frontlinemedcom.com

Newly developed polio vaccine strains could replace currently used risky inactivated vaccines, thereby allowing for safer vaccine production in a post-polio eradication environment, according to researchers at the National Institute for Biological Standards and Control (NIBSC).

Polio eradication is in sight, and these new strains are safer than the attenuated Sabin strain currently used for developing inactivated vaccine. The Sabin strain is unstable and thus could repopulate the environment, Sarah Knowlson and her colleagues from the NIBSC, Potters Bar, Hertfordshire, England, argue in an article published Dec. 31 in PLOS Pathogens.

courtesy www.vaccines.mil

“The Global Polio Eradication Initiative is ... very close to eliminating naturally occurring wild poliovirus from the planet. It has involved the extensive use of both the live attenuated vaccines that can revert to a wild type phenotype, and inactivated polio vaccines (IPV) whose production in the main currently requires the growth of very large amounts of virulent wild type poliovirus, ” they explain, noting that the vaccines are therefore a possible source for re-emergence of poliomyelitis following eradication. (PLoS Pathog. 2015 Dec 31;11. doi: 10.1371/journal.ppat.1005316).

To develop the new strains, the researchers started with the well-understood Sabin strain and modified a region of its viral RNA to promote greater genetic stability. The new strains were then compared with the original Sabin vaccine strain and the wild-type strain currently used to produce inactivated vaccine.

The new strains were “extremely attenuated and genetically stable in cell culture by rational design based on understanding of the attenuation of the Sabin vaccine strains of poliovirus. The viruses grow to titers acceptable for IPV production under appropriate conditions of temperature and cell substrate and have the same antigenic properties based on reactions with panels of monoclonal antibodies in ELISA as well as in regulatory assays for antigen and immunogen content as the strains from which their capsids were derived,” the investigators wrote.

The strains were tested in mice and primates and behaved as predicted in that they were “effective, suitable to mass production, and safer than the alternatives,” according to a press statement.

This work was supported by NIBSC. The investigators reported having no disclosures.

sworcester@frontlinemedcom.com

Newly developed polio vaccine strains could replace currently used risky inactivated vaccines, thereby allowing for safer vaccine production in a post-polio eradication environment, according to researchers at the National Institute for Biological Standards and Control (NIBSC).

Polio eradication is in sight, and these new strains are safer than the attenuated Sabin strain currently used for developing inactivated vaccine. The Sabin strain is unstable and thus could repopulate the environment, Sarah Knowlson and her colleagues from the NIBSC, Potters Bar, Hertfordshire, England, argue in an article published Dec. 31 in PLOS Pathogens.

courtesy www.vaccines.mil

“The Global Polio Eradication Initiative is ... very close to eliminating naturally occurring wild poliovirus from the planet. It has involved the extensive use of both the live attenuated vaccines that can revert to a wild type phenotype, and inactivated polio vaccines (IPV) whose production in the main currently requires the growth of very large amounts of virulent wild type poliovirus, ” they explain, noting that the vaccines are therefore a possible source for re-emergence of poliomyelitis following eradication. (PLoS Pathog. 2015 Dec 31;11. doi: 10.1371/journal.ppat.1005316).

To develop the new strains, the researchers started with the well-understood Sabin strain and modified a region of its viral RNA to promote greater genetic stability. The new strains were then compared with the original Sabin vaccine strain and the wild-type strain currently used to produce inactivated vaccine.

The new strains were “extremely attenuated and genetically stable in cell culture by rational design based on understanding of the attenuation of the Sabin vaccine strains of poliovirus. The viruses grow to titers acceptable for IPV production under appropriate conditions of temperature and cell substrate and have the same antigenic properties based on reactions with panels of monoclonal antibodies in ELISA as well as in regulatory assays for antigen and immunogen content as the strains from which their capsids were derived,” the investigators wrote.

The strains were tested in mice and primates and behaved as predicted in that they were “effective, suitable to mass production, and safer than the alternatives,” according to a press statement.

This work was supported by NIBSC. The investigators reported having no disclosures.

sworcester@frontlinemedcom.com

A November 2014 Food and Drug Administration warning against the use of laparoscopic power morcellators in most women undergoing minimally invasive treatment for uterine leiomyomas was based on a “misleading analysis,” according to a published commentary and a related open letter sent to the FDA.

The authors – the 46 members of the Leiomyoma Morcellation Review Group – are requesting that the FDA modify the current guidance to “empower each woman to consider the pertinent issues and have the freedom to undertake shared decision-making with her surgeon to select the procedure which is most appropriate for her.”

The FDA guidance “was prompted by concern that if a patient had an undiagnosed leiomyosarcoma the morcellator might inadvertently spread tumor cells within the peritoneal cavity. We disagree with the methodology the FDA used to determine the prevalence of leiomyosarcoma among women presumed to have benign leiomyomas and the subsequent restrictions placed on the use of the morcellator, which currently deny many women the benefits of minimally invasive surgery,” Dr. William H. Parker of the University of California, Los Angeles, and his colleagues wrote on behalf of the Review Group (Obstet Gynecol. 2016;127:18-22. doi: 10.1097/AOG.0000000000001157).

Based on a literature review, the FDA estimated that 1 of every 458 women having surgery for presumed leiomyomas would be found to have an occult leiomyosarcoma.

“We challenge the calculation,” the authors wrote, explaining that the FDA searched medical databases using the terms “uterine cancer” and “hysterectomy or myomectomy,” and that because the term “uterine cancer” was required, studies in which cancer was not found or discussed were not identified. The Review Group also noted that all but one of nine studies reviewed by the FDA were retrospective, one was a non–peer-reviewed letter to the editor, and one was an abstract from an unpublished study. In addition, three leiomyosarcoma cases identified by the FDA do not meet current pathologic criteria for cancer and would now be classified as benign atypical leiomyomas.

When the non–peer-reviewed data are excluded, the prevalence of leiomyosarcoma among 12,402 women having surgery for presumed leiomyomas is 1 in 1,550 (0.064%); other recently published data found prevalence rates of 0 to 0.051%, according to the review group’s analysis.

Further, a severe restriction of morcellation based on the FDA communication warning against the use of laparoscopic morcellators in most women undergoing myomectomy or hysterectomy for treatment of fibroids would limit women with symptomatic leiomyomas to one option: total abdominal hysterectomy, the group wrote.

A number of procedures, such as vaginal hysterectomy, mini-laparotomy, and laparoscopic myomectomy, to name just a few, would be eliminated for women with leiomyomas larger than a 10-week pregnancy size.

The concerns expressed in the commentary and the open letter have been brewing since before the FDA warning was issued, and it was felt that the voices of those opposed to the restrictions were not fully heard, Dr. Daniel Clarke-Pearson, one of the authors of the commentary, explained in an interview.

Leiomyosarcoma is bad no matter how it is treated; even when removed intact, survival is poor, he said, explaining that a decision analysis using hypothetical assumptions suggested that outcomes are worse when the complications of abdominal surgery for leiomyomas are considered.

“We’re asking for a balanced presentation and that the pros and cons and risks and benefits be considered by the FDA and explained to the public,” said Dr. Clarke-Pearson, professor and chair of clinical research for the Gynecologic Oncology Program at the University of North Carolina, Chapel Hill.

The review group does not contend that the prognosis is not worse in cases when a leiomyosarcoma is morcellated, he said, noting that the findings of decreased early survival in a study published in the same issue of Obstetrics and Gynecology are not surprising. That population-based cohort study of all uterine sarcomas from 2006 to 2013 in an integrated health care system showed a decrease in survival at 1 year among women who underwent morcellation compared with those who did not (adjusted risk ratio, 5.12), according to Dr. Tina Raine-Bennett of Kaiser Permanente Northern California, Oakland, and her colleagues (Obstet Gynecol. 2016;127:29-39. doi: 10.1097/AOG.0000000000001187).

Rather, the overall risks and benefits should be considered to allow for informed consent among women in the context of good clinical judgment on the part of the surgeon, based, for example, on the patient’s age and risk of leiomyosarcoma, Dr. Clarke-Pearson said.

Also, research should continue in an effort to improve the identification of sarcomas prior to surgery, and to better assess techniques, such as the use of containment bags during morcellation, to determine if they can reduce risk and improve outcomes, he said.

The review group asks that a number of clinical recommendations be considered. For example, the group suggests that caution be exercised prior to recommending morcellation procedures for postmenopausal women because of a higher risk of leiomyosarcoma in that population, and that careful inspection for tissue fragments be undertaken following morcellation, with “copious irrigation of the pelvic and abdominal cavities to minimize the risk of retained tissue.

“Respecting women who have leiomyosarcoma, we conclude that the FDA directive was based on a misleading analysis. Consequently, more accurate estimates regarding the prevalence of leiomyosarcoma among women having surgery for leiomyomas should be issued. Women have a right to self-determination,” they wrote in the commentary.

Dr. Charles E. Miller, a clinical associate professor at the University of Illinois, Chicago, and a past president of the AAGL, applauded the work by Dr. Parker and his colleagues in putting together the analysis, but noted that there have been some positive effects of the FDA warning, namely that it challenged physicians and industry to “think outside the box” in creating methods to reduce potential leiomyosarcoma spread.

“I strongly believe that risk can be further decreased at time of morcellation – electronic versus cold knife, via laparoscopy, minilaparotomy, or vaginal if the morcellation is performed in a contained system (i.e. bag),” Dr. Miller said in an interview.

The FDA will likely approve a containment system designed by Dr. Tony Shibley in cooperation with Olympus, according to Dr. Miller. Also, Dr. Miller recently received approval from the FDA to perform an Investigational Device Exemption study on a multiport containment system that his minimally invasive gynecologic surgery team developed in conjunction with Espiner Medical, Ltd.

“It is my opinion, along with many others, that not only can the risk of inadvertent spread of leiomyosarcoma be minimized with contained morcellation, but risk of leiomyomatosis and bowel injury be significantly reduced as well,” he said.

Dr. Hal C. Lawrence, executive vice president and chief executive officer of the American College of Obstetricians and Gynecologists, also weighed in on the morcellation controversy.

“The conclusions of the paper’s authors largely reflect positions that ACOG has reiterated during the ongoing discussion about potential safety concerns with morcellation as well as its value in facilitating minimally invasive gynecologic surgery,” he said in a statement. “Without question, morcellation of an undiagnosed sarcoma can disseminate malignant tissue. However, by allowing some women to avoid the higher morbidity and mortality associated with open abdominal surgery, morcellation can also save lives.”

As a result of the continuing conversation about morcellation, ob.gyns. are “better able to evaluate each individual woman’s risk of an undiagnosed sarcoma, and to counsel her to receive the right approach for her own unique medical needs,” he added.

In a statement, an FDA spokesperson said that the agency’s recommendations have not changed. “We continue to believe that inclusion of a boxed warning and contraindications to the use of power morcellation for uterine fibroid removal in the majority of women is both appropriate and necessary. We welcome the continued scientific dialogue concerning the available evidence about benefits and risks associated with power morcellation and will notify the public if our recommendations change.” 

The authors of the commentary and open letter to the FDA, and Dr. Raine-Bennett and her colleagues, all reported having no conflicts of interest.

*This story was updated 12/9/2015

sworcester@frontlinemedcom.com

A November 2014 Food and Drug Administration warning against the use of laparoscopic power morcellators in most women undergoing minimally invasive treatment for uterine leiomyomas was based on a “misleading analysis,” according to a published commentary and a related open letter sent to the FDA.

The authors – the 46 members of the Leiomyoma Morcellation Review Group – are requesting that the FDA modify the current guidance to “empower each woman to consider the pertinent issues and have the freedom to undertake shared decision-making with her surgeon to select the procedure which is most appropriate for her.”

The FDA guidance “was prompted by concern that if a patient had an undiagnosed leiomyosarcoma the morcellator might inadvertently spread tumor cells within the peritoneal cavity. We disagree with the methodology the FDA used to determine the prevalence of leiomyosarcoma among women presumed to have benign leiomyomas and the subsequent restrictions placed on the use of the morcellator, which currently deny many women the benefits of minimally invasive surgery,” Dr. William H. Parker of the University of California, Los Angeles, and his colleagues wrote on behalf of the Review Group (Obstet Gynecol. 2016;127:18-22. doi: 10.1097/AOG.0000000000001157).

Based on a literature review, the FDA estimated that 1 of every 458 women having surgery for presumed leiomyomas would be found to have an occult leiomyosarcoma.

“We challenge the calculation,” the authors wrote, explaining that the FDA searched medical databases using the terms “uterine cancer” and “hysterectomy or myomectomy,” and that because the term “uterine cancer” was required, studies in which cancer was not found or discussed were not identified. The Review Group also noted that all but one of nine studies reviewed by the FDA were retrospective, one was a non–peer-reviewed letter to the editor, and one was an abstract from an unpublished study. In addition, three leiomyosarcoma cases identified by the FDA do not meet current pathologic criteria for cancer and would now be classified as benign atypical leiomyomas.

When the non–peer-reviewed data are excluded, the prevalence of leiomyosarcoma among 12,402 women having surgery for presumed leiomyomas is 1 in 1,550 (0.064%); other recently published data found prevalence rates of 0 to 0.051%, according to the review group’s analysis.

Further, a severe restriction of morcellation based on the FDA communication warning against the use of laparoscopic morcellators in most women undergoing myomectomy or hysterectomy for treatment of fibroids would limit women with symptomatic leiomyomas to one option: total abdominal hysterectomy, the group wrote.

A number of procedures, such as vaginal hysterectomy, mini-laparotomy, and laparoscopic myomectomy, to name just a few, would be eliminated for women with leiomyomas larger than a 10-week pregnancy size.

The concerns expressed in the commentary and the open letter have been brewing since before the FDA warning was issued, and it was felt that the voices of those opposed to the restrictions were not fully heard, Dr. Daniel Clarke-Pearson, one of the authors of the commentary, explained in an interview.

Leiomyosarcoma is bad no matter how it is treated; even when removed intact, survival is poor, he said, explaining that a decision analysis using hypothetical assumptions suggested that outcomes are worse when the complications of abdominal surgery for leiomyomas are considered.

“We’re asking for a balanced presentation and that the pros and cons and risks and benefits be considered by the FDA and explained to the public,” said Dr. Clarke-Pearson, professor and chair of clinical research for the Gynecologic Oncology Program at the University of North Carolina, Chapel Hill.

The review group does not contend that the prognosis is not worse in cases when a leiomyosarcoma is morcellated, he said, noting that the findings of decreased early survival in a study published in the same issue of Obstetrics and Gynecology are not surprising. That population-based cohort study of all uterine sarcomas from 2006 to 2013 in an integrated health care system showed a decrease in survival at 1 year among women who underwent morcellation compared with those who did not (adjusted risk ratio, 5.12), according to Dr. Tina Raine-Bennett of Kaiser Permanente Northern California, Oakland, and her colleagues (Obstet Gynecol. 2016;127:29-39. doi: 10.1097/AOG.0000000000001187).

Rather, the overall risks and benefits should be considered to allow for informed consent among women in the context of good clinical judgment on the part of the surgeon, based, for example, on the patient’s age and risk of leiomyosarcoma, Dr. Clarke-Pearson said.

Also, research should continue in an effort to improve the identification of sarcomas prior to surgery, and to better assess techniques, such as the use of containment bags during morcellation, to determine if they can reduce risk and improve outcomes, he said.

The review group asks that a number of clinical recommendations be considered. For example, the group suggests that caution be exercised prior to recommending morcellation procedures for postmenopausal women because of a higher risk of leiomyosarcoma in that population, and that careful inspection for tissue fragments be undertaken following morcellation, with “copious irrigation of the pelvic and abdominal cavities to minimize the risk of retained tissue.

“Respecting women who have leiomyosarcoma, we conclude that the FDA directive was based on a misleading analysis. Consequently, more accurate estimates regarding the prevalence of leiomyosarcoma among women having surgery for leiomyomas should be issued. Women have a right to self-determination,” they wrote in the commentary.

Dr. Charles E. Miller, a clinical associate professor at the University of Illinois, Chicago, and a past president of the AAGL, applauded the work by Dr. Parker and his colleagues in putting together the analysis, but noted that there have been some positive effects of the FDA warning, namely that it challenged physicians and industry to “think outside the box” in creating methods to reduce potential leiomyosarcoma spread.

“I strongly believe that risk can be further decreased at time of morcellation – electronic versus cold knife, via laparoscopy, minilaparotomy, or vaginal if the morcellation is performed in a contained system (i.e. bag),” Dr. Miller said in an interview.

The FDA will likely approve a containment system designed by Dr. Tony Shibley in cooperation with Olympus, according to Dr. Miller. Also, Dr. Miller recently received approval from the FDA to perform an Investigational Device Exemption study on a multiport containment system that his minimally invasive gynecologic surgery team developed in conjunction with Espiner Medical, Ltd.

“It is my opinion, along with many others, that not only can the risk of inadvertent spread of leiomyosarcoma be minimized with contained morcellation, but risk of leiomyomatosis and bowel injury be significantly reduced as well,” he said.

Dr. Hal C. Lawrence, executive vice president and chief executive officer of the American College of Obstetricians and Gynecologists, also weighed in on the morcellation controversy.

“The conclusions of the paper’s authors largely reflect positions that ACOG has reiterated during the ongoing discussion about potential safety concerns with morcellation as well as its value in facilitating minimally invasive gynecologic surgery,” he said in a statement. “Without question, morcellation of an undiagnosed sarcoma can disseminate malignant tissue. However, by allowing some women to avoid the higher morbidity and mortality associated with open abdominal surgery, morcellation can also save lives.”

As a result of the continuing conversation about morcellation, ob.gyns. are “better able to evaluate each individual woman’s risk of an undiagnosed sarcoma, and to counsel her to receive the right approach for her own unique medical needs,” he added.

In a statement, an FDA spokesperson said that the agency’s recommendations have not changed. “We continue to believe that inclusion of a boxed warning and contraindications to the use of power morcellation for uterine fibroid removal in the majority of women is both appropriate and necessary. We welcome the continued scientific dialogue concerning the available evidence about benefits and risks associated with power morcellation and will notify the public if our recommendations change.” 

The authors of the commentary and open letter to the FDA, and Dr. Raine-Bennett and her colleagues, all reported having no conflicts of interest.

*This story was updated 12/9/2015

sworcester@frontlinemedcom.com

A November 2014 Food and Drug Administration warning against the use of laparoscopic power morcellators in most women undergoing minimally invasive treatment for uterine leiomyomas was based on a “misleading analysis,” according to a published commentary and a related open letter sent to the FDA.

The authors – the 46 members of the Leiomyoma Morcellation Review Group – are requesting that the FDA modify the current guidance to “empower each woman to consider the pertinent issues and have the freedom to undertake shared decision-making with her surgeon to select the procedure which is most appropriate for her.”

The FDA guidance “was prompted by concern that if a patient had an undiagnosed leiomyosarcoma the morcellator might inadvertently spread tumor cells within the peritoneal cavity. We disagree with the methodology the FDA used to determine the prevalence of leiomyosarcoma among women presumed to have benign leiomyomas and the subsequent restrictions placed on the use of the morcellator, which currently deny many women the benefits of minimally invasive surgery,” Dr. William H. Parker of the University of California, Los Angeles, and his colleagues wrote on behalf of the Review Group (Obstet Gynecol. 2016;127:18-22. doi: 10.1097/AOG.0000000000001157).

Based on a literature review, the FDA estimated that 1 of every 458 women having surgery for presumed leiomyomas would be found to have an occult leiomyosarcoma.

“We challenge the calculation,” the authors wrote, explaining that the FDA searched medical databases using the terms “uterine cancer” and “hysterectomy or myomectomy,” and that because the term “uterine cancer” was required, studies in which cancer was not found or discussed were not identified. The Review Group also noted that all but one of nine studies reviewed by the FDA were retrospective, one was a non–peer-reviewed letter to the editor, and one was an abstract from an unpublished study. In addition, three leiomyosarcoma cases identified by the FDA do not meet current pathologic criteria for cancer and would now be classified as benign atypical leiomyomas.

When the non–peer-reviewed data are excluded, the prevalence of leiomyosarcoma among 12,402 women having surgery for presumed leiomyomas is 1 in 1,550 (0.064%); other recently published data found prevalence rates of 0 to 0.051%, according to the review group’s analysis.

Further, a severe restriction of morcellation based on the FDA communication warning against the use of laparoscopic morcellators in most women undergoing myomectomy or hysterectomy for treatment of fibroids would limit women with symptomatic leiomyomas to one option: total abdominal hysterectomy, the group wrote.

A number of procedures, such as vaginal hysterectomy, mini-laparotomy, and laparoscopic myomectomy, to name just a few, would be eliminated for women with leiomyomas larger than a 10-week pregnancy size.

The concerns expressed in the commentary and the open letter have been brewing since before the FDA warning was issued, and it was felt that the voices of those opposed to the restrictions were not fully heard, Dr. Daniel Clarke-Pearson, one of the authors of the commentary, explained in an interview.

Leiomyosarcoma is bad no matter how it is treated; even when removed intact, survival is poor, he said, explaining that a decision analysis using hypothetical assumptions suggested that outcomes are worse when the complications of abdominal surgery for leiomyomas are considered.

“We’re asking for a balanced presentation and that the pros and cons and risks and benefits be considered by the FDA and explained to the public,” said Dr. Clarke-Pearson, professor and chair of clinical research for the Gynecologic Oncology Program at the University of North Carolina, Chapel Hill.

The review group does not contend that the prognosis is not worse in cases when a leiomyosarcoma is morcellated, he said, noting that the findings of decreased early survival in a study published in the same issue of Obstetrics and Gynecology are not surprising. That population-based cohort study of all uterine sarcomas from 2006 to 2013 in an integrated health care system showed a decrease in survival at 1 year among women who underwent morcellation compared with those who did not (adjusted risk ratio, 5.12), according to Dr. Tina Raine-Bennett of Kaiser Permanente Northern California, Oakland, and her colleagues (Obstet Gynecol. 2016;127:29-39. doi: 10.1097/AOG.0000000000001187).

Rather, the overall risks and benefits should be considered to allow for informed consent among women in the context of good clinical judgment on the part of the surgeon, based, for example, on the patient’s age and risk of leiomyosarcoma, Dr. Clarke-Pearson said.

Also, research should continue in an effort to improve the identification of sarcomas prior to surgery, and to better assess techniques, such as the use of containment bags during morcellation, to determine if they can reduce risk and improve outcomes, he said.

The review group asks that a number of clinical recommendations be considered. For example, the group suggests that caution be exercised prior to recommending morcellation procedures for postmenopausal women because of a higher risk of leiomyosarcoma in that population, and that careful inspection for tissue fragments be undertaken following morcellation, with “copious irrigation of the pelvic and abdominal cavities to minimize the risk of retained tissue.

“Respecting women who have leiomyosarcoma, we conclude that the FDA directive was based on a misleading analysis. Consequently, more accurate estimates regarding the prevalence of leiomyosarcoma among women having surgery for leiomyomas should be issued. Women have a right to self-determination,” they wrote in the commentary.

Dr. Charles E. Miller, a clinical associate professor at the University of Illinois, Chicago, and a past president of the AAGL, applauded the work by Dr. Parker and his colleagues in putting together the analysis, but noted that there have been some positive effects of the FDA warning, namely that it challenged physicians and industry to “think outside the box” in creating methods to reduce potential leiomyosarcoma spread.

“I strongly believe that risk can be further decreased at time of morcellation – electronic versus cold knife, via laparoscopy, minilaparotomy, or vaginal if the morcellation is performed in a contained system (i.e. bag),” Dr. Miller said in an interview.

The FDA will likely approve a containment system designed by Dr. Tony Shibley in cooperation with Olympus, according to Dr. Miller. Also, Dr. Miller recently received approval from the FDA to perform an Investigational Device Exemption study on a multiport containment system that his minimally invasive gynecologic surgery team developed in conjunction with Espiner Medical, Ltd.

“It is my opinion, along with many others, that not only can the risk of inadvertent spread of leiomyosarcoma be minimized with contained morcellation, but risk of leiomyomatosis and bowel injury be significantly reduced as well,” he said.

Dr. Hal C. Lawrence, executive vice president and chief executive officer of the American College of Obstetricians and Gynecologists, also weighed in on the morcellation controversy.

“The conclusions of the paper’s authors largely reflect positions that ACOG has reiterated during the ongoing discussion about potential safety concerns with morcellation as well as its value in facilitating minimally invasive gynecologic surgery,” he said in a statement. “Without question, morcellation of an undiagnosed sarcoma can disseminate malignant tissue. However, by allowing some women to avoid the higher morbidity and mortality associated with open abdominal surgery, morcellation can also save lives.”

As a result of the continuing conversation about morcellation, ob.gyns. are “better able to evaluate each individual woman’s risk of an undiagnosed sarcoma, and to counsel her to receive the right approach for her own unique medical needs,” he added.

In a statement, an FDA spokesperson said that the agency’s recommendations have not changed. “We continue to believe that inclusion of a boxed warning and contraindications to the use of power morcellation for uterine fibroid removal in the majority of women is both appropriate and necessary. We welcome the continued scientific dialogue concerning the available evidence about benefits and risks associated with power morcellation and will notify the public if our recommendations change.” 

The authors of the commentary and open letter to the FDA, and Dr. Raine-Bennett and her colleagues, all reported having no conflicts of interest.

*This story was updated 12/9/2015

sworcester@frontlinemedcom.com

Human gene editing is no longer the stuff of science fiction, and the powerful new technologies that make it possible raise important scientific, ethical, and societal questions.

The organizing committee for a 3-day International Summit On Gene Editing that convened experts from around the world to discuss the issues associated with human gene-editing research, has called upon the international community to work together to establish norms for acceptable uses of human gene editing.

©ktsimage/Thinkstock.com

In a statement issued Dec. 3 at the close of the summit, the committee asked the summit cohosts – the U.S. National Academy of Sciences and U.S. National Academy of Medicine, the Royal Society (United Kingdom), and the Chinese Academy of Sciences – to take the lead in creating an ongoing international forum on gene editing and to work on formulating recommendations and guidelines.

“While each nation ultimately has the authority to regulate activities under its jurisdiction, the human genome is shared among all nations,” the committee wrote. “The international community should strive to establish norms concerning acceptable uses of human germline editing and to harmonize regulations, in order to discourage unacceptable activities while advancing human health and welfare.”

The committee also concluded that:

• Intensive basic and preclinical research is needed, with a specific research focus on technologies for editing genetic sequences in human cells, potential benefits and risks of proposed clinical uses for gene editing, and understanding of the biology of human embryos and germline cells. Any early human embryo or germline cells that undergo gene editing should not be used to establish a pregnancy, the committee wrote.

• Improved understanding of the risks of somatic cell editing – such as inaccurate editing – is needed, as is understanding of the potential benefits of each proposed genetic modification. Such uses of gene editing, which are intended to affect only the individual who receives them, can be “appropriately and rigorously evaluated within existing and evolving regulatory frameworks for gene therapy,” they noted.

• Germline editing poses particularly important issues, such as the challenges with predicting harmful effects of genetic changes, including interactions with other genetic variants and with the environment. Moral and ethical considerations, such as the possibility of permanent genetic enhancements that could exacerbate social inequalities or be used coercively, must also be considered. The committee said that “it would be irresponsible to proceed with any clinical use of germline editing” unless and until the safety and efficacy issues have been resolved, and there is broad consensus about the appropriateness of a proposed application.

“At present these criteria have not been met for any proposed clinical use,” the committee wrote, adding that safety issues have not been adequately explored, and the cases of most compelling benefit are limited.

As the science advances and social views evolve, the clinical use of germline editing should be regularly revisited, they wrote.

The presidents of each of the organizations that hosted the summit welcomed the call for ongoing global discussion on issues related to human gene editing.

In a written response they said that they “stand ready to establish a continuing forum for assessment of the many scientific, medical, and ethical questions surrounding the pursuit of human gene-editing applications,” and will coordinate with other academies around the world and other international scientific and medical institutions in that endeavor.

“This is an important moment in human history and we have a responsibility to provide all sections of society with an informed basis for making decisions about this technology, especially for uses that would affect generations to come,” they wrote.

sworcester@frontlinemedcom.com

Human gene editing is no longer the stuff of science fiction, and the powerful new technologies that make it possible raise important scientific, ethical, and societal questions.

The organizing committee for a 3-day International Summit On Gene Editing that convened experts from around the world to discuss the issues associated with human gene-editing research, has called upon the international community to work together to establish norms for acceptable uses of human gene editing.

©ktsimage/Thinkstock.com

In a statement issued Dec. 3 at the close of the summit, the committee asked the summit cohosts – the U.S. National Academy of Sciences and U.S. National Academy of Medicine, the Royal Society (United Kingdom), and the Chinese Academy of Sciences – to take the lead in creating an ongoing international forum on gene editing and to work on formulating recommendations and guidelines.

“While each nation ultimately has the authority to regulate activities under its jurisdiction, the human genome is shared among all nations,” the committee wrote. “The international community should strive to establish norms concerning acceptable uses of human germline editing and to harmonize regulations, in order to discourage unacceptable activities while advancing human health and welfare.”

The committee also concluded that:

• Intensive basic and preclinical research is needed, with a specific research focus on technologies for editing genetic sequences in human cells, potential benefits and risks of proposed clinical uses for gene editing, and understanding of the biology of human embryos and germline cells. Any early human embryo or germline cells that undergo gene editing should not be used to establish a pregnancy, the committee wrote.

• Improved understanding of the risks of somatic cell editing – such as inaccurate editing – is needed, as is understanding of the potential benefits of each proposed genetic modification. Such uses of gene editing, which are intended to affect only the individual who receives them, can be “appropriately and rigorously evaluated within existing and evolving regulatory frameworks for gene therapy,” they noted.

• Germline editing poses particularly important issues, such as the challenges with predicting harmful effects of genetic changes, including interactions with other genetic variants and with the environment. Moral and ethical considerations, such as the possibility of permanent genetic enhancements that could exacerbate social inequalities or be used coercively, must also be considered. The committee said that “it would be irresponsible to proceed with any clinical use of germline editing” unless and until the safety and efficacy issues have been resolved, and there is broad consensus about the appropriateness of a proposed application.

“At present these criteria have not been met for any proposed clinical use,” the committee wrote, adding that safety issues have not been adequately explored, and the cases of most compelling benefit are limited.

As the science advances and social views evolve, the clinical use of germline editing should be regularly revisited, they wrote.

The presidents of each of the organizations that hosted the summit welcomed the call for ongoing global discussion on issues related to human gene editing.

In a written response they said that they “stand ready to establish a continuing forum for assessment of the many scientific, medical, and ethical questions surrounding the pursuit of human gene-editing applications,” and will coordinate with other academies around the world and other international scientific and medical institutions in that endeavor.

“This is an important moment in human history and we have a responsibility to provide all sections of society with an informed basis for making decisions about this technology, especially for uses that would affect generations to come,” they wrote.

sworcester@frontlinemedcom.com

Human gene editing is no longer the stuff of science fiction, and the powerful new technologies that make it possible raise important scientific, ethical, and societal questions.

The organizing committee for a 3-day International Summit On Gene Editing that convened experts from around the world to discuss the issues associated with human gene-editing research, has called upon the international community to work together to establish norms for acceptable uses of human gene editing.

©ktsimage/Thinkstock.com

In a statement issued Dec. 3 at the close of the summit, the committee asked the summit cohosts – the U.S. National Academy of Sciences and U.S. National Academy of Medicine, the Royal Society (United Kingdom), and the Chinese Academy of Sciences – to take the lead in creating an ongoing international forum on gene editing and to work on formulating recommendations and guidelines.

“While each nation ultimately has the authority to regulate activities under its jurisdiction, the human genome is shared among all nations,” the committee wrote. “The international community should strive to establish norms concerning acceptable uses of human germline editing and to harmonize regulations, in order to discourage unacceptable activities while advancing human health and welfare.”

The committee also concluded that:

• Intensive basic and preclinical research is needed, with a specific research focus on technologies for editing genetic sequences in human cells, potential benefits and risks of proposed clinical uses for gene editing, and understanding of the biology of human embryos and germline cells. Any early human embryo or germline cells that undergo gene editing should not be used to establish a pregnancy, the committee wrote.

• Improved understanding of the risks of somatic cell editing – such as inaccurate editing – is needed, as is understanding of the potential benefits of each proposed genetic modification. Such uses of gene editing, which are intended to affect only the individual who receives them, can be “appropriately and rigorously evaluated within existing and evolving regulatory frameworks for gene therapy,” they noted.

• Germline editing poses particularly important issues, such as the challenges with predicting harmful effects of genetic changes, including interactions with other genetic variants and with the environment. Moral and ethical considerations, such as the possibility of permanent genetic enhancements that could exacerbate social inequalities or be used coercively, must also be considered. The committee said that “it would be irresponsible to proceed with any clinical use of germline editing” unless and until the safety and efficacy issues have been resolved, and there is broad consensus about the appropriateness of a proposed application.

“At present these criteria have not been met for any proposed clinical use,” the committee wrote, adding that safety issues have not been adequately explored, and the cases of most compelling benefit are limited.

As the science advances and social views evolve, the clinical use of germline editing should be regularly revisited, they wrote.

The presidents of each of the organizations that hosted the summit welcomed the call for ongoing global discussion on issues related to human gene editing.

In a written response they said that they “stand ready to establish a continuing forum for assessment of the many scientific, medical, and ethical questions surrounding the pursuit of human gene-editing applications,” and will coordinate with other academies around the world and other international scientific and medical institutions in that endeavor.

“This is an important moment in human history and we have a responsibility to provide all sections of society with an informed basis for making decisions about this technology, especially for uses that would affect generations to come,” they wrote.

sworcester@frontlinemedcom.com

SAN FRANCISCO – Bariatric surgery is an effective treatment for nonalcoholic steatohepatitis (NASH) in obese patients, a Markov model suggests.

Patients with all classes of obesity, including, mild, moderate, and severe, with all stages of fibrosis, experienced gains in life years following laparoscopic Roux-en-Y gastric bypass, compared with standard management and intensive lifestyle changes, based on the model, Dr. Kathleen Corey reported at the annual meeting of the American Association for the Study of Liver Diseases.

©thinkstockphotos.com

Surgery also increased quality-adjusted life years (QALY) in those with moderate and severe obesity with all fibrosis stages, those with mild obesity and F2-F3 fibrosis, and in overweight patients with F3 fibrosis, said Dr Corey of Massachusetts General Hospital, Boston.

The number of F3 patients needed to treat to prevent one liver-related death was favorable across all body mass indexes for those with stage F3 fibrosis. The number needed to treat to prevent one case of cirrhosis in these patients was six to seven, and to prevent one liver-related death was eight to 11, she said.

A cost-effectiveness analysis, with a willingness-to-pay threshold of less than $100,000, also showed that surgery was cost effective for all fibrosis stages for those with severe and moderate obesity.

“The [incremental cost-effectiveness ratio] for BMI of 35-39.9 [kg/m²] was $34,000, for those with a BMI of 40 or greater it was $26,000, and we found that with overweight patients with F3 fibrosis, the ratio was also favorable at $59,000,” she said.

More than 78 million American adults suffer from obesity, and the prevalence of obesity is rising nationwide, she said, adding that obesity results in annual medical costs exceeding $147 billion. Treatment options for obesity are limited, and weight regain after weight loss is frequent, Dr. Corey noted.

“However, bariatric surgery has been shown to be a very effective treatment for obesity. Surgery has been shown to significantly reduce mortality in patients, and reduces progression of many comorbidities, including diabetes,” she said.

Guidelines suggest that bariatric surgery is appropriate for patients with a body mass index of 40 or greater and for those with a BMI of 35 or greater if obesity-related comorbidities such as diabetes or obstructive sleep apnea are present, and data suggest that surgery is also of benefit in those with BMI below 35 with diabetes.

The question remains, though, whether nonalcoholic fatty liver disease (NAFLD) – the most common cause of liver disease in the United States – is an indication in itself for bariatric surgery.

NAFLD is strongly associated with obesity, and its progressive form – NASH – can lead to cirrhosis, hepatocellular carcinoma, and the need for liver transplantation.

“However, there are no FDA-approved therapies for NASH and no randomized controlled trials have been conducted to evaluate the role of bariatric surgery in NASH ... and appropriate BMI cutoffs in those with NASH have not been established,” Dr. Corey said.

Several nonrandomized prospective trials have, however, evaluated bariatric surgery in NASH patients with BMIs of 35 or greater with comorbidities, and in patients with BMIs of 40 or greater, and these have shown that NASH resolution can occur in up to 85% of patients at 1-5 years with fibrosis reduction seen in nearly a third, she said, adding that the risk-benefit ratio for surgery is unknown, as is the value of surgery in NASH patients with BMIs less than 35.

The current study looked at three treatment strategies, including standard management with lifestyle counseling; intensive lifestyle intervention based on a diabetes prevention program with lifestyle, nutrition, and exercise counseling; and bariatric Roux-en-Y gastric bypass in a hypothetical simulated cohort of 45-year-olds with NASH, F0-F3 fibrosis, and varying BMI values.

The findings, though limited by a lack of data on the impact of surgery on patients with a BMI of less than 35, and by evaluation of only one type of surgery, showed that bariatric surgery increased incremental life years at all weight and fibrosis stages vs. standard management and intensive lifestyle intervention, and that surgery increased QALY in those with moderate and severe obesity with all fibrosis stages, those with mild obesity and F2-F3 fibrosis, and in overweight patients with F3 fibrosis.

“We found that surgery was cost effective for F3 fibrosis in those with moderate and severe obesity and those with overweight. Randomized trials, though, are needed to assess the management of weight loss surgery for NASH before this can be recommended, certainly in patients with a BMI of less than 35,” she concluded.

Dr. Corey reported serving on an advisory committee or review panel for Gilead, and serving in a speaking or teaching role for Synageva.

sworcester@frontlinemedcom.com

SAN FRANCISCO – Bariatric surgery is an effective treatment for nonalcoholic steatohepatitis (NASH) in obese patients, a Markov model suggests.

Patients with all classes of obesity, including, mild, moderate, and severe, with all stages of fibrosis, experienced gains in life years following laparoscopic Roux-en-Y gastric bypass, compared with standard management and intensive lifestyle changes, based on the model, Dr. Kathleen Corey reported at the annual meeting of the American Association for the Study of Liver Diseases.

©thinkstockphotos.com

Surgery also increased quality-adjusted life years (QALY) in those with moderate and severe obesity with all fibrosis stages, those with mild obesity and F2-F3 fibrosis, and in overweight patients with F3 fibrosis, said Dr Corey of Massachusetts General Hospital, Boston.

The number of F3 patients needed to treat to prevent one liver-related death was favorable across all body mass indexes for those with stage F3 fibrosis. The number needed to treat to prevent one case of cirrhosis in these patients was six to seven, and to prevent one liver-related death was eight to 11, she said.

A cost-effectiveness analysis, with a willingness-to-pay threshold of less than $100,000, also showed that surgery was cost effective for all fibrosis stages for those with severe and moderate obesity.

“The [incremental cost-effectiveness ratio] for BMI of 35-39.9 [kg/m²] was $34,000, for those with a BMI of 40 or greater it was $26,000, and we found that with overweight patients with F3 fibrosis, the ratio was also favorable at $59,000,” she said.

More than 78 million American adults suffer from obesity, and the prevalence of obesity is rising nationwide, she said, adding that obesity results in annual medical costs exceeding $147 billion. Treatment options for obesity are limited, and weight regain after weight loss is frequent, Dr. Corey noted.

“However, bariatric surgery has been shown to be a very effective treatment for obesity. Surgery has been shown to significantly reduce mortality in patients, and reduces progression of many comorbidities, including diabetes,” she said.

Guidelines suggest that bariatric surgery is appropriate for patients with a body mass index of 40 or greater and for those with a BMI of 35 or greater if obesity-related comorbidities such as diabetes or obstructive sleep apnea are present, and data suggest that surgery is also of benefit in those with BMI below 35 with diabetes.

The question remains, though, whether nonalcoholic fatty liver disease (NAFLD) – the most common cause of liver disease in the United States – is an indication in itself for bariatric surgery.

NAFLD is strongly associated with obesity, and its progressive form – NASH – can lead to cirrhosis, hepatocellular carcinoma, and the need for liver transplantation.

“However, there are no FDA-approved therapies for NASH and no randomized controlled trials have been conducted to evaluate the role of bariatric surgery in NASH ... and appropriate BMI cutoffs in those with NASH have not been established,” Dr. Corey said.

Several nonrandomized prospective trials have, however, evaluated bariatric surgery in NASH patients with BMIs of 35 or greater with comorbidities, and in patients with BMIs of 40 or greater, and these have shown that NASH resolution can occur in up to 85% of patients at 1-5 years with fibrosis reduction seen in nearly a third, she said, adding that the risk-benefit ratio for surgery is unknown, as is the value of surgery in NASH patients with BMIs less than 35.

The current study looked at three treatment strategies, including standard management with lifestyle counseling; intensive lifestyle intervention based on a diabetes prevention program with lifestyle, nutrition, and exercise counseling; and bariatric Roux-en-Y gastric bypass in a hypothetical simulated cohort of 45-year-olds with NASH, F0-F3 fibrosis, and varying BMI values.

The findings, though limited by a lack of data on the impact of surgery on patients with a BMI of less than 35, and by evaluation of only one type of surgery, showed that bariatric surgery increased incremental life years at all weight and fibrosis stages vs. standard management and intensive lifestyle intervention, and that surgery increased QALY in those with moderate and severe obesity with all fibrosis stages, those with mild obesity and F2-F3 fibrosis, and in overweight patients with F3 fibrosis.

“We found that surgery was cost effective for F3 fibrosis in those with moderate and severe obesity and those with overweight. Randomized trials, though, are needed to assess the management of weight loss surgery for NASH before this can be recommended, certainly in patients with a BMI of less than 35,” she concluded.

Dr. Corey reported serving on an advisory committee or review panel for Gilead, and serving in a speaking or teaching role for Synageva.

sworcester@frontlinemedcom.com

SAN FRANCISCO – Bariatric surgery is an effective treatment for nonalcoholic steatohepatitis (NASH) in obese patients, a Markov model suggests.

Patients with all classes of obesity, including, mild, moderate, and severe, with all stages of fibrosis, experienced gains in life years following laparoscopic Roux-en-Y gastric bypass, compared with standard management and intensive lifestyle changes, based on the model, Dr. Kathleen Corey reported at the annual meeting of the American Association for the Study of Liver Diseases.

©thinkstockphotos.com

Surgery also increased quality-adjusted life years (QALY) in those with moderate and severe obesity with all fibrosis stages, those with mild obesity and F2-F3 fibrosis, and in overweight patients with F3 fibrosis, said Dr Corey of Massachusetts General Hospital, Boston.

The number of F3 patients needed to treat to prevent one liver-related death was favorable across all body mass indexes for those with stage F3 fibrosis. The number needed to treat to prevent one case of cirrhosis in these patients was six to seven, and to prevent one liver-related death was eight to 11, she said.

A cost-effectiveness analysis, with a willingness-to-pay threshold of less than $100,000, also showed that surgery was cost effective for all fibrosis stages for those with severe and moderate obesity.

“The [incremental cost-effectiveness ratio] for BMI of 35-39.9 [kg/m²] was $34,000, for those with a BMI of 40 or greater it was $26,000, and we found that with overweight patients with F3 fibrosis, the ratio was also favorable at $59,000,” she said.

More than 78 million American adults suffer from obesity, and the prevalence of obesity is rising nationwide, she said, adding that obesity results in annual medical costs exceeding $147 billion. Treatment options for obesity are limited, and weight regain after weight loss is frequent, Dr. Corey noted.

“However, bariatric surgery has been shown to be a very effective treatment for obesity. Surgery has been shown to significantly reduce mortality in patients, and reduces progression of many comorbidities, including diabetes,” she said.

Guidelines suggest that bariatric surgery is appropriate for patients with a body mass index of 40 or greater and for those with a BMI of 35 or greater if obesity-related comorbidities such as diabetes or obstructive sleep apnea are present, and data suggest that surgery is also of benefit in those with BMI below 35 with diabetes.

The question remains, though, whether nonalcoholic fatty liver disease (NAFLD) – the most common cause of liver disease in the United States – is an indication in itself for bariatric surgery.

NAFLD is strongly associated with obesity, and its progressive form – NASH – can lead to cirrhosis, hepatocellular carcinoma, and the need for liver transplantation.

“However, there are no FDA-approved therapies for NASH and no randomized controlled trials have been conducted to evaluate the role of bariatric surgery in NASH ... and appropriate BMI cutoffs in those with NASH have not been established,” Dr. Corey said.

Several nonrandomized prospective trials have, however, evaluated bariatric surgery in NASH patients with BMIs of 35 or greater with comorbidities, and in patients with BMIs of 40 or greater, and these have shown that NASH resolution can occur in up to 85% of patients at 1-5 years with fibrosis reduction seen in nearly a third, she said, adding that the risk-benefit ratio for surgery is unknown, as is the value of surgery in NASH patients with BMIs less than 35.

The current study looked at three treatment strategies, including standard management with lifestyle counseling; intensive lifestyle intervention based on a diabetes prevention program with lifestyle, nutrition, and exercise counseling; and bariatric Roux-en-Y gastric bypass in a hypothetical simulated cohort of 45-year-olds with NASH, F0-F3 fibrosis, and varying BMI values.

The findings, though limited by a lack of data on the impact of surgery on patients with a BMI of less than 35, and by evaluation of only one type of surgery, showed that bariatric surgery increased incremental life years at all weight and fibrosis stages vs. standard management and intensive lifestyle intervention, and that surgery increased QALY in those with moderate and severe obesity with all fibrosis stages, those with mild obesity and F2-F3 fibrosis, and in overweight patients with F3 fibrosis.

“We found that surgery was cost effective for F3 fibrosis in those with moderate and severe obesity and those with overweight. Randomized trials, though, are needed to assess the management of weight loss surgery for NASH before this can be recommended, certainly in patients with a BMI of less than 35,” she concluded.

Dr. Corey reported serving on an advisory committee or review panel for Gilead, and serving in a speaking or teaching role for Synageva.

sworcester@frontlinemedcom.com

A landmark study in France has demonstrated that preexposure prophylaxis (PrEP) antiretroviral therapy offers protection against HIV-1 infection among HIV-negative men at high risk of infection.

Researchers in the IPERGAY trial, a double-blind, randomized, placebo-controlled study of 400 men who have sex with men (MSM), provided PrEP combination therapy to the study participants using tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) before and after unprotected anal sex. Two of 199 men without HIV infection who received the active prophylaxis contracted HIV during a median of 9.3 months follow-up (incidence, 0.91/100 person-years), compared with 14 of 201 who received placebo (incidence, 6.60/100 person-years; relative reduction, 86%), Dr. Jean-Michel Molina of Saint-Louis Hospital and the University of Paris, and his colleagues reported online Dec. 1 in the New England Journal of Medicine.

©xrender/thinkstockphotos.com

Trial subjects were men at high risk for HIV-infection because of self-reported, unprotected anal sex. They were randomized to receive active TDF-FTC treatment or placebo taken both before and after sexual activity. All study participants also received risk-reduction counseling and condoms (N Engl J Med. 2015 Dec. 1;373:2237-46. doi: 10.1056/NEJMoa1506723).

Subjects in both groups took a median of 15 pills per month. Active treatment was prescribed at a fixed dose of 300 mg TDF and 200 mg FTC per pill, given as a loading dose of two pills or placebo with food 2-24 hours before sex, followed by a third pill 24 hours later, and a fourth pill another 24 hours later. In the case of multiple consecutive episodes of sexual intercourse, one pill daily was prescribed until the last encounter, followed by two postexposure pills. Postexposure prophylaxis in the latter incidence was provided as a loading dose of two pills unless the last drug intake was less than a week prior, in which case only one pill was taken. Adherence was measured by pill count and plasma drug levels.

The rates of grades 3 and 4 serious adverse events were similar in the groups, although those in the TDF-FTC group experienced higher rates of gastrointestinal events (14% vs. 5%) and renal adverse events (18% vs. 10%).

Testing the value of PrEP

Preexposure prophylaxis has been considered a promising intervention for preventing HIV-1 infection, but findings from recent studies have been conflicting, possibly because of low adherence, the IPERGAY investigators said.

Another trial, the Preexposure Prophylaxis Initiative (iPrex) trial, showed a moderate relative reduction of 42% in HIV-1 incidence when TDF-FTC was used daily, they noted. (N Engl J Med. 2010 Dec. 30;363:2587-99. doi: 10.1056/NEJMoa1011205).

alexskopje/ThinkStock

The IPERGAY trial (the Intervention Préventive de l’Exposition aux Risques avec et pour les Gays), assessed the efficacy and safety of sexual activity–dependent PrEP with TDF-FTC, based on a hypothesis that adherence – and thus efficacy – might be higher than with a daily regimen.

“The two participants in the TDF-FTC group in whom HIV-1 infection was diagnosed at scheduled visits returned 60 and 58 pills out of 60, respectively ... and were therefore deemed to be nonadherent to preexposure prophylaxis. Study drugs were not detected in plasma samples obtained from these two participants at the time of HIV-1 diagnosis,” the investigators wrote.

The findings of this study are among the highest-risk reductions that have been reported to date, but short follow-up “may have increased the likelihood of an exaggerated estimate of efficacy,” they noted.

Also, the results cannot be extrapolated to those who have less-frequent sexual intercourse, who would thus be taking TDF-FTC on a more intermittent regimen than was seen in this trial, they said.

The findings nonetheless suggest there is value in PrEP with TDF-FTC.

“While we wait for an effective vaccine against HIV, the use of such preexposure prophylaxis with TDF-FTC among high-risk men could contribute to a reduced incidence of HIV infection,” they concluded.

Time for action

In an accompanying editorial, Dr. Anthony S. Fauci and Dr. Hilary D. Marston of the National Institute of Allergy and Infectious Diseases, said the results of the IPERGAY trial, taken together with those of prior studies, “have shown definitively that the benefits of prompt initiation of [antiretroviral therapy] – regardless of the CD4+ T-cell count – outweigh the risks, for both the infected person and uninfected sexual partners and that PrEP can be implemented in a way that is both acceptable to patients and safe and effective in blocking HIV transmission” (N Engl J Med. 2015 Dec. 1;373:2197-99. doi: 10.1056/NEJMp1502020).

IPERGAY provides important new data that support the use of PrEP for preventing HIV infection in high-risk populations, and the existing data provide an “evidence-based blueprint for effective treatment and prevention of HIV infection and will serve as critical tools in the fight to end the HIV-AIDS pandemic,” Dr. Fauci and Dr. Marston wrote, adding that “the political will must be mobilized to match the scientific evidence and provide the financial and human resources necessary to dramatically scale up HIV testing and treatment around the world.”

“The science has spoken. There can now be no excuse for inaction,” they said.

This study was funded in part by the French National Agency of Research on AIDS and Viral Hepatitis (ANRS). Dr. Molina reports grant support from the ANRS during the conduct of the study, grant support and personal fees from Merck and Gilead, and personal fees from Bristol-Myers Squibb, ViiV, and Janssen outside the submitted work. Dr. Fauci and Dr. Marston reported having no disclosures. Detailed disclosure statements for all authors are available with the full text of the article at NEJM.com.

sworcester@frontlinemedcom.com

A landmark study in France has demonstrated that preexposure prophylaxis (PrEP) antiretroviral therapy offers protection against HIV-1 infection among HIV-negative men at high risk of infection.

Researchers in the IPERGAY trial, a double-blind, randomized, placebo-controlled study of 400 men who have sex with men (MSM), provided PrEP combination therapy to the study participants using tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) before and after unprotected anal sex. Two of 199 men without HIV infection who received the active prophylaxis contracted HIV during a median of 9.3 months follow-up (incidence, 0.91/100 person-years), compared with 14 of 201 who received placebo (incidence, 6.60/100 person-years; relative reduction, 86%), Dr. Jean-Michel Molina of Saint-Louis Hospital and the University of Paris, and his colleagues reported online Dec. 1 in the New England Journal of Medicine.

©xrender/thinkstockphotos.com

Trial subjects were men at high risk for HIV-infection because of self-reported, unprotected anal sex. They were randomized to receive active TDF-FTC treatment or placebo taken both before and after sexual activity. All study participants also received risk-reduction counseling and condoms (N Engl J Med. 2015 Dec. 1;373:2237-46. doi: 10.1056/NEJMoa1506723).

Subjects in both groups took a median of 15 pills per month. Active treatment was prescribed at a fixed dose of 300 mg TDF and 200 mg FTC per pill, given as a loading dose of two pills or placebo with food 2-24 hours before sex, followed by a third pill 24 hours later, and a fourth pill another 24 hours later. In the case of multiple consecutive episodes of sexual intercourse, one pill daily was prescribed until the last encounter, followed by two postexposure pills. Postexposure prophylaxis in the latter incidence was provided as a loading dose of two pills unless the last drug intake was less than a week prior, in which case only one pill was taken. Adherence was measured by pill count and plasma drug levels.

The rates of grades 3 and 4 serious adverse events were similar in the groups, although those in the TDF-FTC group experienced higher rates of gastrointestinal events (14% vs. 5%) and renal adverse events (18% vs. 10%).

Testing the value of PrEP

Preexposure prophylaxis has been considered a promising intervention for preventing HIV-1 infection, but findings from recent studies have been conflicting, possibly because of low adherence, the IPERGAY investigators said.

Another trial, the Preexposure Prophylaxis Initiative (iPrex) trial, showed a moderate relative reduction of 42% in HIV-1 incidence when TDF-FTC was used daily, they noted. (N Engl J Med. 2010 Dec. 30;363:2587-99. doi: 10.1056/NEJMoa1011205).

alexskopje/ThinkStock

The IPERGAY trial (the Intervention Préventive de l’Exposition aux Risques avec et pour les Gays), assessed the efficacy and safety of sexual activity–dependent PrEP with TDF-FTC, based on a hypothesis that adherence – and thus efficacy – might be higher than with a daily regimen.

“The two participants in the TDF-FTC group in whom HIV-1 infection was diagnosed at scheduled visits returned 60 and 58 pills out of 60, respectively ... and were therefore deemed to be nonadherent to preexposure prophylaxis. Study drugs were not detected in plasma samples obtained from these two participants at the time of HIV-1 diagnosis,” the investigators wrote.

The findings of this study are among the highest-risk reductions that have been reported to date, but short follow-up “may have increased the likelihood of an exaggerated estimate of efficacy,” they noted.

Also, the results cannot be extrapolated to those who have less-frequent sexual intercourse, who would thus be taking TDF-FTC on a more intermittent regimen than was seen in this trial, they said.

The findings nonetheless suggest there is value in PrEP with TDF-FTC.

“While we wait for an effective vaccine against HIV, the use of such preexposure prophylaxis with TDF-FTC among high-risk men could contribute to a reduced incidence of HIV infection,” they concluded.

Time for action

In an accompanying editorial, Dr. Anthony S. Fauci and Dr. Hilary D. Marston of the National Institute of Allergy and Infectious Diseases, said the results of the IPERGAY trial, taken together with those of prior studies, “have shown definitively that the benefits of prompt initiation of [antiretroviral therapy] – regardless of the CD4+ T-cell count – outweigh the risks, for both the infected person and uninfected sexual partners and that PrEP can be implemented in a way that is both acceptable to patients and safe and effective in blocking HIV transmission” (N Engl J Med. 2015 Dec. 1;373:2197-99. doi: 10.1056/NEJMp1502020).

IPERGAY provides important new data that support the use of PrEP for preventing HIV infection in high-risk populations, and the existing data provide an “evidence-based blueprint for effective treatment and prevention of HIV infection and will serve as critical tools in the fight to end the HIV-AIDS pandemic,” Dr. Fauci and Dr. Marston wrote, adding that “the political will must be mobilized to match the scientific evidence and provide the financial and human resources necessary to dramatically scale up HIV testing and treatment around the world.”

“The science has spoken. There can now be no excuse for inaction,” they said.

This study was funded in part by the French National Agency of Research on AIDS and Viral Hepatitis (ANRS). Dr. Molina reports grant support from the ANRS during the conduct of the study, grant support and personal fees from Merck and Gilead, and personal fees from Bristol-Myers Squibb, ViiV, and Janssen outside the submitted work. Dr. Fauci and Dr. Marston reported having no disclosures. Detailed disclosure statements for all authors are available with the full text of the article at NEJM.com.

sworcester@frontlinemedcom.com

A landmark study in France has demonstrated that preexposure prophylaxis (PrEP) antiretroviral therapy offers protection against HIV-1 infection among HIV-negative men at high risk of infection.

Researchers in the IPERGAY trial, a double-blind, randomized, placebo-controlled study of 400 men who have sex with men (MSM), provided PrEP combination therapy to the study participants using tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) before and after unprotected anal sex. Two of 199 men without HIV infection who received the active prophylaxis contracted HIV during a median of 9.3 months follow-up (incidence, 0.91/100 person-years), compared with 14 of 201 who received placebo (incidence, 6.60/100 person-years; relative reduction, 86%), Dr. Jean-Michel Molina of Saint-Louis Hospital and the University of Paris, and his colleagues reported online Dec. 1 in the New England Journal of Medicine.

©xrender/thinkstockphotos.com

Trial subjects were men at high risk for HIV-infection because of self-reported, unprotected anal sex. They were randomized to receive active TDF-FTC treatment or placebo taken both before and after sexual activity. All study participants also received risk-reduction counseling and condoms (N Engl J Med. 2015 Dec. 1;373:2237-46. doi: 10.1056/NEJMoa1506723).

Subjects in both groups took a median of 15 pills per month. Active treatment was prescribed at a fixed dose of 300 mg TDF and 200 mg FTC per pill, given as a loading dose of two pills or placebo with food 2-24 hours before sex, followed by a third pill 24 hours later, and a fourth pill another 24 hours later. In the case of multiple consecutive episodes of sexual intercourse, one pill daily was prescribed until the last encounter, followed by two postexposure pills. Postexposure prophylaxis in the latter incidence was provided as a loading dose of two pills unless the last drug intake was less than a week prior, in which case only one pill was taken. Adherence was measured by pill count and plasma drug levels.

The rates of grades 3 and 4 serious adverse events were similar in the groups, although those in the TDF-FTC group experienced higher rates of gastrointestinal events (14% vs. 5%) and renal adverse events (18% vs. 10%).

Testing the value of PrEP

Preexposure prophylaxis has been considered a promising intervention for preventing HIV-1 infection, but findings from recent studies have been conflicting, possibly because of low adherence, the IPERGAY investigators said.

Another trial, the Preexposure Prophylaxis Initiative (iPrex) trial, showed a moderate relative reduction of 42% in HIV-1 incidence when TDF-FTC was used daily, they noted. (N Engl J Med. 2010 Dec. 30;363:2587-99. doi: 10.1056/NEJMoa1011205).

alexskopje/ThinkStock

The IPERGAY trial (the Intervention Préventive de l’Exposition aux Risques avec et pour les Gays), assessed the efficacy and safety of sexual activity–dependent PrEP with TDF-FTC, based on a hypothesis that adherence – and thus efficacy – might be higher than with a daily regimen.

“The two participants in the TDF-FTC group in whom HIV-1 infection was diagnosed at scheduled visits returned 60 and 58 pills out of 60, respectively ... and were therefore deemed to be nonadherent to preexposure prophylaxis. Study drugs were not detected in plasma samples obtained from these two participants at the time of HIV-1 diagnosis,” the investigators wrote.

The findings of this study are among the highest-risk reductions that have been reported to date, but short follow-up “may have increased the likelihood of an exaggerated estimate of efficacy,” they noted.

Also, the results cannot be extrapolated to those who have less-frequent sexual intercourse, who would thus be taking TDF-FTC on a more intermittent regimen than was seen in this trial, they said.

The findings nonetheless suggest there is value in PrEP with TDF-FTC.

“While we wait for an effective vaccine against HIV, the use of such preexposure prophylaxis with TDF-FTC among high-risk men could contribute to a reduced incidence of HIV infection,” they concluded.

Time for action

In an accompanying editorial, Dr. Anthony S. Fauci and Dr. Hilary D. Marston of the National Institute of Allergy and Infectious Diseases, said the results of the IPERGAY trial, taken together with those of prior studies, “have shown definitively that the benefits of prompt initiation of [antiretroviral therapy] – regardless of the CD4+ T-cell count – outweigh the risks, for both the infected person and uninfected sexual partners and that PrEP can be implemented in a way that is both acceptable to patients and safe and effective in blocking HIV transmission” (N Engl J Med. 2015 Dec. 1;373:2197-99. doi: 10.1056/NEJMp1502020).

IPERGAY provides important new data that support the use of PrEP for preventing HIV infection in high-risk populations, and the existing data provide an “evidence-based blueprint for effective treatment and prevention of HIV infection and will serve as critical tools in the fight to end the HIV-AIDS pandemic,” Dr. Fauci and Dr. Marston wrote, adding that “the political will must be mobilized to match the scientific evidence and provide the financial and human resources necessary to dramatically scale up HIV testing and treatment around the world.”

“The science has spoken. There can now be no excuse for inaction,” they said.

This study was funded in part by the French National Agency of Research on AIDS and Viral Hepatitis (ANRS). Dr. Molina reports grant support from the ANRS during the conduct of the study, grant support and personal fees from Merck and Gilead, and personal fees from Bristol-Myers Squibb, ViiV, and Janssen outside the submitted work. Dr. Fauci and Dr. Marston reported having no disclosures. Detailed disclosure statements for all authors are available with the full text of the article at NEJM.com.

sworcester@frontlinemedcom.com

Shorter-course treatment with combinations of three or four different direct-acting antiviral agents achieved sustain viral response in 12 weeks (SVR12) in less than a third of patients with hepatitis C virus infection in an open-label, non-randomized, phase 2a proof-of-concept study.

SVR12 was achieved in 10 of 25 (40%) treatment-naive patients without cirrhosis who were treated with a 3-drug regimen consisting of ledipasvir and sofosbuvir plus GS-9451 (an NS3/4A protease inhibitor) for 4 weeks, and in 5 of 25 (20%) of 25 treatment-naive patients without cirrhosis treated with ledipasvir and sofosbuvir plus GS9451 and GS-9669 (a nonnucleoside NS5B polymerase inhibitor) for 4 weeks, Dr. Anita Kohli of the National Institutes of Health Clinical Center, Bethesda, Md. and her colleagues reported Nov. 23 in Annals of Internal Medicine.

“Given the high cost of DAAs, the medical care required, and the improvements in patient adherence with reductions in treatment duration, attempts to evaluate shorter courses of therapy could have important clinical and public health implications,” Dr. Kohli noted.

Courtesy NIH

Lower baseline HCV viral load, younger age, and HCV genotype 1b were associated with SVR12 with this shortened (vs. the usual 6 weeks) course of direct-acting antiviral (DAA) therapy. Adverse events were mainly mild fatigue, diarrhea, and headaches occurring in 48% and 72% of patients in the 3- and 4-drug regimen groups, respectively, Dr. Kohli said (Ann Intern Med. 2015 Nov. 23[doi:10.7326/M15-0642).

“Sixty-eight percent (34 of 50) of patients had viral relapse, the majority (68%) by posttreatment week 4. Thus, a treatment duration of 4 weeks with 3 or 4 potent DAAs is not sufficient to cure HCV infection in most patients,” she wrote, noting, however, that “some patients are capable of achieving SVR with 4 weeks of therapy, which could be attributable to the presence of several favorable factors, such as early fibrosis, low viral burden, and absence of [resistance-associated variants].

This study was funded in part by the NIH and the German Research Foundation. Study medications were provided by Gilead Sciences. Dr. Kohli reported having no other disclosures. Multiple authors reported other disclosures, including employment and/or stock ownership with Gilead Sciences, research and other funding from Gilead Sciences, and/or stock ownership in Merck, Pfizer, and Johnson & Johnson.

sworcester@frontlinemedcom.com

Shorter-course treatment with combinations of three or four different direct-acting antiviral agents achieved sustain viral response in 12 weeks (SVR12) in less than a third of patients with hepatitis C virus infection in an open-label, non-randomized, phase 2a proof-of-concept study.

SVR12 was achieved in 10 of 25 (40%) treatment-naive patients without cirrhosis who were treated with a 3-drug regimen consisting of ledipasvir and sofosbuvir plus GS-9451 (an NS3/4A protease inhibitor) for 4 weeks, and in 5 of 25 (20%) of 25 treatment-naive patients without cirrhosis treated with ledipasvir and sofosbuvir plus GS9451 and GS-9669 (a nonnucleoside NS5B polymerase inhibitor) for 4 weeks, Dr. Anita Kohli of the National Institutes of Health Clinical Center, Bethesda, Md. and her colleagues reported Nov. 23 in Annals of Internal Medicine.

“Given the high cost of DAAs, the medical care required, and the improvements in patient adherence with reductions in treatment duration, attempts to evaluate shorter courses of therapy could have important clinical and public health implications,” Dr. Kohli noted.

Courtesy NIH

Lower baseline HCV viral load, younger age, and HCV genotype 1b were associated with SVR12 with this shortened (vs. the usual 6 weeks) course of direct-acting antiviral (DAA) therapy. Adverse events were mainly mild fatigue, diarrhea, and headaches occurring in 48% and 72% of patients in the 3- and 4-drug regimen groups, respectively, Dr. Kohli said (Ann Intern Med. 2015 Nov. 23[doi:10.7326/M15-0642).

“Sixty-eight percent (34 of 50) of patients had viral relapse, the majority (68%) by posttreatment week 4. Thus, a treatment duration of 4 weeks with 3 or 4 potent DAAs is not sufficient to cure HCV infection in most patients,” she wrote, noting, however, that “some patients are capable of achieving SVR with 4 weeks of therapy, which could be attributable to the presence of several favorable factors, such as early fibrosis, low viral burden, and absence of [resistance-associated variants].

This study was funded in part by the NIH and the German Research Foundation. Study medications were provided by Gilead Sciences. Dr. Kohli reported having no other disclosures. Multiple authors reported other disclosures, including employment and/or stock ownership with Gilead Sciences, research and other funding from Gilead Sciences, and/or stock ownership in Merck, Pfizer, and Johnson & Johnson.

sworcester@frontlinemedcom.com

Shorter-course treatment with combinations of three or four different direct-acting antiviral agents achieved sustain viral response in 12 weeks (SVR12) in less than a third of patients with hepatitis C virus infection in an open-label, non-randomized, phase 2a proof-of-concept study.

SVR12 was achieved in 10 of 25 (40%) treatment-naive patients without cirrhosis who were treated with a 3-drug regimen consisting of ledipasvir and sofosbuvir plus GS-9451 (an NS3/4A protease inhibitor) for 4 weeks, and in 5 of 25 (20%) of 25 treatment-naive patients without cirrhosis treated with ledipasvir and sofosbuvir plus GS9451 and GS-9669 (a nonnucleoside NS5B polymerase inhibitor) for 4 weeks, Dr. Anita Kohli of the National Institutes of Health Clinical Center, Bethesda, Md. and her colleagues reported Nov. 23 in Annals of Internal Medicine.

“Given the high cost of DAAs, the medical care required, and the improvements in patient adherence with reductions in treatment duration, attempts to evaluate shorter courses of therapy could have important clinical and public health implications,” Dr. Kohli noted.

Courtesy NIH

Lower baseline HCV viral load, younger age, and HCV genotype 1b were associated with SVR12 with this shortened (vs. the usual 6 weeks) course of direct-acting antiviral (DAA) therapy. Adverse events were mainly mild fatigue, diarrhea, and headaches occurring in 48% and 72% of patients in the 3- and 4-drug regimen groups, respectively, Dr. Kohli said (Ann Intern Med. 2015 Nov. 23[doi:10.7326/M15-0642).

“Sixty-eight percent (34 of 50) of patients had viral relapse, the majority (68%) by posttreatment week 4. Thus, a treatment duration of 4 weeks with 3 or 4 potent DAAs is not sufficient to cure HCV infection in most patients,” she wrote, noting, however, that “some patients are capable of achieving SVR with 4 weeks of therapy, which could be attributable to the presence of several favorable factors, such as early fibrosis, low viral burden, and absence of [resistance-associated variants].

This study was funded in part by the NIH and the German Research Foundation. Study medications were provided by Gilead Sciences. Dr. Kohli reported having no other disclosures. Multiple authors reported other disclosures, including employment and/or stock ownership with Gilead Sciences, research and other funding from Gilead Sciences, and/or stock ownership in Merck, Pfizer, and Johnson & Johnson.

sworcester@frontlinemedcom.com

SAN FRANCISCO – ARC-520, the first RNA interference–based drug to reach patients, produced deep and durable knockdown of viral antigens and DNA in chronic hepatitis B patients in a phase II study.

Of 58 patients with chronic hepatitis B (CHB) who were included in the study, 38 were hepatitis B e antigen negative (HBeAg-neg), and 20 were hepatitis B e antigen positive (HBeAg-pos). At enrollment, 32 of the 38 HBeAG-neg, and 14 of the 20 HBeAG-pos patients were treated with entecavir (mean duration, 5 years) and remained on that treatment throughout the study, and the remaining 6 patients in each group initiated entecavir treatment during the study, Dr. Man-Fung Yuen of the University of Hong Kong, China reported at the annual meeting of the American Association for the Study of Liver Diseases.

CDC/Dr. Erskine Palmer

All subjects received either an intravenous dose of ARC (Arrowhead Research Corporation)-520 (48 patients) or placebo (10 patients). The dose was 1-4 mg/kg, divided and given 2 weeks apart in the HBeAg-neg patients, and was 4 mg/kg in the HBeAg-pos patients.

Knockdown of viral parameters was measured over 85 days.

Viral DNA measures showed levels below the threshold for quantification in all patients on entecavir at study entry. Those who were entecavir naive at entry had reduced viral DNA up to 4.3 log (mean, 2.2 log) after treatment with ARC and entecavir, he noted.

ARC reduced viral antigens with quantitative HBeAg (qHBeAg) with best knockdown of 1.7 log after a single 4 mg/kg dose. In treatment-naive patients, the best observed quantitative hepatitis B surface antigen (qHBsAg) knockdown was 1.9 log (99%) in HBeAg-pos patients, and 0.7 log in HBeAg-neg patients (mean max, 1.2 log and 1.1 log, respectively).

A dose-response was seen for quantitative hepatitis B core-related antigen (qHBcrAg) in HBeAg-neg patients, with best knockdown of 0.18 log at a dose of 1 mg/kg (mean max, 0.15 log), and best knockdown of 1.1 log at 4 mg/kg (mean max, 0.9 log). HbeAg-pos showed best knockdown of 1.1 log (mean max, 0.92 log).

The qHBsAg dose response was less deep in patients treated chronically with entecavir (best observed reduction of 0.3 log at 1 mg/kg (mean max, 0.2 log) vs. 0.5 log at 4 mg/kg (mean max, 0.4 log) in HBeAg-neg, and 0.7 log in HBeAg-pos patients (mean max, 0.3).

Divided doses at 4 mg/kg did not increase antigen knockdown, Dr. Yuen noted.

The duration of qHBsAG knockdown was typically 8 weeks, and two distinct knockdown patterns were noted, including an immediate, direct ARC antiviral effect in about 70% of patients, and a delayed response of several weeks after treatment in about 30% of patients, he said.

Chronic hepatitis B has become an important target for drug development, and ARC-520, which targets covalently close circular DNA (ccc-DNA)-derived messenger RNA, is of particular interest. The findings of the current study, which suggest more ccc-DNA–driven antigen production in HBeAg-pos disease, are consistent with those from studies in chimpanzees, as well as with previously reported chronic entecavir reductions in patients for ccc-DNA, Dr. Yuen said.

Studies are currently underway to evaluate the ability of chronic ARC therapy to produce HBsAG seroclearance, he noted.

Dr. Yuen reported advisory committee or review panel participation with GlaxoSmithKline, Bristol-Myers Squibb, and Pfizer, and grant or research support from Roche, Bristol-Myers Squibb, Pfizer, and Gilead Science.

sworcester@frontlinemedcom.com

SAN FRANCISCO – ARC-520, the first RNA interference–based drug to reach patients, produced deep and durable knockdown of viral antigens and DNA in chronic hepatitis B patients in a phase II study.

Of 58 patients with chronic hepatitis B (CHB) who were included in the study, 38 were hepatitis B e antigen negative (HBeAg-neg), and 20 were hepatitis B e antigen positive (HBeAg-pos). At enrollment, 32 of the 38 HBeAG-neg, and 14 of the 20 HBeAG-pos patients were treated with entecavir (mean duration, 5 years) and remained on that treatment throughout the study, and the remaining 6 patients in each group initiated entecavir treatment during the study, Dr. Man-Fung Yuen of the University of Hong Kong, China reported at the annual meeting of the American Association for the Study of Liver Diseases.

CDC/Dr. Erskine Palmer

All subjects received either an intravenous dose of ARC (Arrowhead Research Corporation)-520 (48 patients) or placebo (10 patients). The dose was 1-4 mg/kg, divided and given 2 weeks apart in the HBeAg-neg patients, and was 4 mg/kg in the HBeAg-pos patients.

Knockdown of viral parameters was measured over 85 days.

Viral DNA measures showed levels below the threshold for quantification in all patients on entecavir at study entry. Those who were entecavir naive at entry had reduced viral DNA up to 4.3 log (mean, 2.2 log) after treatment with ARC and entecavir, he noted.

ARC reduced viral antigens with quantitative HBeAg (qHBeAg) with best knockdown of 1.7 log after a single 4 mg/kg dose. In treatment-naive patients, the best observed quantitative hepatitis B surface antigen (qHBsAg) knockdown was 1.9 log (99%) in HBeAg-pos patients, and 0.7 log in HBeAg-neg patients (mean max, 1.2 log and 1.1 log, respectively).

A dose-response was seen for quantitative hepatitis B core-related antigen (qHBcrAg) in HBeAg-neg patients, with best knockdown of 0.18 log at a dose of 1 mg/kg (mean max, 0.15 log), and best knockdown of 1.1 log at 4 mg/kg (mean max, 0.9 log). HbeAg-pos showed best knockdown of 1.1 log (mean max, 0.92 log).

The qHBsAg dose response was less deep in patients treated chronically with entecavir (best observed reduction of 0.3 log at 1 mg/kg (mean max, 0.2 log) vs. 0.5 log at 4 mg/kg (mean max, 0.4 log) in HBeAg-neg, and 0.7 log in HBeAg-pos patients (mean max, 0.3).

Divided doses at 4 mg/kg did not increase antigen knockdown, Dr. Yuen noted.

The duration of qHBsAG knockdown was typically 8 weeks, and two distinct knockdown patterns were noted, including an immediate, direct ARC antiviral effect in about 70% of patients, and a delayed response of several weeks after treatment in about 30% of patients, he said.

Chronic hepatitis B has become an important target for drug development, and ARC-520, which targets covalently close circular DNA (ccc-DNA)-derived messenger RNA, is of particular interest. The findings of the current study, which suggest more ccc-DNA–driven antigen production in HBeAg-pos disease, are consistent with those from studies in chimpanzees, as well as with previously reported chronic entecavir reductions in patients for ccc-DNA, Dr. Yuen said.

Studies are currently underway to evaluate the ability of chronic ARC therapy to produce HBsAG seroclearance, he noted.

Dr. Yuen reported advisory committee or review panel participation with GlaxoSmithKline, Bristol-Myers Squibb, and Pfizer, and grant or research support from Roche, Bristol-Myers Squibb, Pfizer, and Gilead Science.

sworcester@frontlinemedcom.com

SAN FRANCISCO – ARC-520, the first RNA interference–based drug to reach patients, produced deep and durable knockdown of viral antigens and DNA in chronic hepatitis B patients in a phase II study.

Of 58 patients with chronic hepatitis B (CHB) who were included in the study, 38 were hepatitis B e antigen negative (HBeAg-neg), and 20 were hepatitis B e antigen positive (HBeAg-pos). At enrollment, 32 of the 38 HBeAG-neg, and 14 of the 20 HBeAG-pos patients were treated with entecavir (mean duration, 5 years) and remained on that treatment throughout the study, and the remaining 6 patients in each group initiated entecavir treatment during the study, Dr. Man-Fung Yuen of the University of Hong Kong, China reported at the annual meeting of the American Association for the Study of Liver Diseases.

CDC/Dr. Erskine Palmer

All subjects received either an intravenous dose of ARC (Arrowhead Research Corporation)-520 (48 patients) or placebo (10 patients). The dose was 1-4 mg/kg, divided and given 2 weeks apart in the HBeAg-neg patients, and was 4 mg/kg in the HBeAg-pos patients.

Knockdown of viral parameters was measured over 85 days.

Viral DNA measures showed levels below the threshold for quantification in all patients on entecavir at study entry. Those who were entecavir naive at entry had reduced viral DNA up to 4.3 log (mean, 2.2 log) after treatment with ARC and entecavir, he noted.

ARC reduced viral antigens with quantitative HBeAg (qHBeAg) with best knockdown of 1.7 log after a single 4 mg/kg dose. In treatment-naive patients, the best observed quantitative hepatitis B surface antigen (qHBsAg) knockdown was 1.9 log (99%) in HBeAg-pos patients, and 0.7 log in HBeAg-neg patients (mean max, 1.2 log and 1.1 log, respectively).

A dose-response was seen for quantitative hepatitis B core-related antigen (qHBcrAg) in HBeAg-neg patients, with best knockdown of 0.18 log at a dose of 1 mg/kg (mean max, 0.15 log), and best knockdown of 1.1 log at 4 mg/kg (mean max, 0.9 log). HbeAg-pos showed best knockdown of 1.1 log (mean max, 0.92 log).

The qHBsAg dose response was less deep in patients treated chronically with entecavir (best observed reduction of 0.3 log at 1 mg/kg (mean max, 0.2 log) vs. 0.5 log at 4 mg/kg (mean max, 0.4 log) in HBeAg-neg, and 0.7 log in HBeAg-pos patients (mean max, 0.3).

Divided doses at 4 mg/kg did not increase antigen knockdown, Dr. Yuen noted.

The duration of qHBsAG knockdown was typically 8 weeks, and two distinct knockdown patterns were noted, including an immediate, direct ARC antiviral effect in about 70% of patients, and a delayed response of several weeks after treatment in about 30% of patients, he said.

Chronic hepatitis B has become an important target for drug development, and ARC-520, which targets covalently close circular DNA (ccc-DNA)-derived messenger RNA, is of particular interest. The findings of the current study, which suggest more ccc-DNA–driven antigen production in HBeAg-pos disease, are consistent with those from studies in chimpanzees, as well as with previously reported chronic entecavir reductions in patients for ccc-DNA, Dr. Yuen said.

Studies are currently underway to evaluate the ability of chronic ARC therapy to produce HBsAG seroclearance, he noted.

Dr. Yuen reported advisory committee or review panel participation with GlaxoSmithKline, Bristol-Myers Squibb, and Pfizer, and grant or research support from Roche, Bristol-Myers Squibb, Pfizer, and Gilead Science.

sworcester@frontlinemedcom.com

SAN FRANCISCO – Response-guided therapy using all-oral, triple direct-acting antiviral (DAA) therapy appears useful for shortening the duration of treatment in noncirrhotic patients with hepatitis C virus genotype 1b infection, according to findings from the randomized proof-of-concept SODAPI study.

The findings of the open-label study strongly suggest that administration of potent triple regimens containing NS3, NS5A, and NS5B HCV inhibitors leads to rapid virologic response within 2 days in a majority of treated patients, Dr. George K. Lau of Emory University, Atlanta, reported at the annual meeting of the American Association for the Study of Liver Diseases.

Courtesy US. Dept of Veterans Affairs

Study subjects were 26 Chinese patients who received either sofosbuvir, ledipasvir, and asunaprevir (group 1, 12 patients); sofosbuvir, daclatasvir, and simeprevir (group 2, 6 patients); or sofosbuvir, daclatasvir, and asunaprevir (group 3, 8 patients) at approved doses. Those who achieved rapid virologic response remained on the regimen for 3 weeks; those who did not were treated for 8-12 weeks.

Rapid virologic response was achieved by 6 of 12 group 1 patients, 6 of 6 group 2 patients, and 6 of 8 group 3 patients. Baseline viral load was lower in those with rapid virologic response vs. those without (5.96 vs. 7.00 log₁₀ IU/mL), Dr. Lau noted.

All 18 subjects with rapid virologic response and 3 weeks of treatment achieved the primary endpoint of plasma HCV RNA below the detectable limit at 12 weeks (SVR12). Median time to plasma HCV RNA less than 25 IU/mL was shortest in group 1 vs. group 3, he said.

Treatment was well tolerated; no patients discontinued therapy and no significant adverse events were reported.

Patients in the study were noncirrhotic patients with chronic hepatitis C genotype 1b infection with a median age of 34 years, median body mass index of 21.7 kg/m², and baseline mean HCV RNA of 6.55 log₁₀ IU/mL. Six were men, 12 were women.

DAAs have a high cure rate and favorable tolerability in persons infected with hepatitis C virus, but shorter courses could improve adherence and affordability and could increase accessibility to DAAs, Dr. Lau said.

He and his colleagues “postulated that the addition of an NS3 protease inhibitor to dual NS5A-NS5B (nucleoside) inhibitors would enhance antiviral efficacy and reduce treatment duration to 3 weeks in those with a rapid virologic response defined as plasma HCV RNA less than 500 IU/mL by day 2.”

Based on these positive early findings, future studies exploring this response-guided approach to therapy are recommended, as this approach has the potential to reduce therapy duration and drug costs, and to improve accessibility and adherence, he concluded.

Dr. Lau is a consultant for Roche and Novartis.

sworcester@frontlinemedcom.com

SAN FRANCISCO – Response-guided therapy using all-oral, triple direct-acting antiviral (DAA) therapy appears useful for shortening the duration of treatment in noncirrhotic patients with hepatitis C virus genotype 1b infection, according to findings from the randomized proof-of-concept SODAPI study.

The findings of the open-label study strongly suggest that administration of potent triple regimens containing NS3, NS5A, and NS5B HCV inhibitors leads to rapid virologic response within 2 days in a majority of treated patients, Dr. George K. Lau of Emory University, Atlanta, reported at the annual meeting of the American Association for the Study of Liver Diseases.

Courtesy US. Dept of Veterans Affairs

Study subjects were 26 Chinese patients who received either sofosbuvir, ledipasvir, and asunaprevir (group 1, 12 patients); sofosbuvir, daclatasvir, and simeprevir (group 2, 6 patients); or sofosbuvir, daclatasvir, and asunaprevir (group 3, 8 patients) at approved doses. Those who achieved rapid virologic response remained on the regimen for 3 weeks; those who did not were treated for 8-12 weeks.

Rapid virologic response was achieved by 6 of 12 group 1 patients, 6 of 6 group 2 patients, and 6 of 8 group 3 patients. Baseline viral load was lower in those with rapid virologic response vs. those without (5.96 vs. 7.00 log₁₀ IU/mL), Dr. Lau noted.

All 18 subjects with rapid virologic response and 3 weeks of treatment achieved the primary endpoint of plasma HCV RNA below the detectable limit at 12 weeks (SVR12). Median time to plasma HCV RNA less than 25 IU/mL was shortest in group 1 vs. group 3, he said.

Treatment was well tolerated; no patients discontinued therapy and no significant adverse events were reported.

Patients in the study were noncirrhotic patients with chronic hepatitis C genotype 1b infection with a median age of 34 years, median body mass index of 21.7 kg/m², and baseline mean HCV RNA of 6.55 log₁₀ IU/mL. Six were men, 12 were women.

DAAs have a high cure rate and favorable tolerability in persons infected with hepatitis C virus, but shorter courses could improve adherence and affordability and could increase accessibility to DAAs, Dr. Lau said.

He and his colleagues “postulated that the addition of an NS3 protease inhibitor to dual NS5A-NS5B (nucleoside) inhibitors would enhance antiviral efficacy and reduce treatment duration to 3 weeks in those with a rapid virologic response defined as plasma HCV RNA less than 500 IU/mL by day 2.”

Based on these positive early findings, future studies exploring this response-guided approach to therapy are recommended, as this approach has the potential to reduce therapy duration and drug costs, and to improve accessibility and adherence, he concluded.

Dr. Lau is a consultant for Roche and Novartis.

sworcester@frontlinemedcom.com

SAN FRANCISCO – Response-guided therapy using all-oral, triple direct-acting antiviral (DAA) therapy appears useful for shortening the duration of treatment in noncirrhotic patients with hepatitis C virus genotype 1b infection, according to findings from the randomized proof-of-concept SODAPI study.

The findings of the open-label study strongly suggest that administration of potent triple regimens containing NS3, NS5A, and NS5B HCV inhibitors leads to rapid virologic response within 2 days in a majority of treated patients, Dr. George K. Lau of Emory University, Atlanta, reported at the annual meeting of the American Association for the Study of Liver Diseases.

Courtesy US. Dept of Veterans Affairs

Study subjects were 26 Chinese patients who received either sofosbuvir, ledipasvir, and asunaprevir (group 1, 12 patients); sofosbuvir, daclatasvir, and simeprevir (group 2, 6 patients); or sofosbuvir, daclatasvir, and asunaprevir (group 3, 8 patients) at approved doses. Those who achieved rapid virologic response remained on the regimen for 3 weeks; those who did not were treated for 8-12 weeks.

Rapid virologic response was achieved by 6 of 12 group 1 patients, 6 of 6 group 2 patients, and 6 of 8 group 3 patients. Baseline viral load was lower in those with rapid virologic response vs. those without (5.96 vs. 7.00 log₁₀ IU/mL), Dr. Lau noted.

All 18 subjects with rapid virologic response and 3 weeks of treatment achieved the primary endpoint of plasma HCV RNA below the detectable limit at 12 weeks (SVR12). Median time to plasma HCV RNA less than 25 IU/mL was shortest in group 1 vs. group 3, he said.

Treatment was well tolerated; no patients discontinued therapy and no significant adverse events were reported.

Patients in the study were noncirrhotic patients with chronic hepatitis C genotype 1b infection with a median age of 34 years, median body mass index of 21.7 kg/m², and baseline mean HCV RNA of 6.55 log₁₀ IU/mL. Six were men, 12 were women.

DAAs have a high cure rate and favorable tolerability in persons infected with hepatitis C virus, but shorter courses could improve adherence and affordability and could increase accessibility to DAAs, Dr. Lau said.

He and his colleagues “postulated that the addition of an NS3 protease inhibitor to dual NS5A-NS5B (nucleoside) inhibitors would enhance antiviral efficacy and reduce treatment duration to 3 weeks in those with a rapid virologic response defined as plasma HCV RNA less than 500 IU/mL by day 2.”

Based on these positive early findings, future studies exploring this response-guided approach to therapy are recommended, as this approach has the potential to reduce therapy duration and drug costs, and to improve accessibility and adherence, he concluded.

Dr. Lau is a consultant for Roche and Novartis.

sworcester@frontlinemedcom.com