Correspondence
studies and judged the aggregate data to be of low quality.2 Specifically, they found the evidence was inconclusive to conclude that DMPA was causally related to HIV acquisition. The experts proposed no new restrictions on the use of injectable progestins in women at high risk of HIV, but because of the uncertainty, recommended the use of condoms for women using these methods. They also recommended that further research was necessary to provide the higher-quality evidence necessary for both greater scientific certainty and informing international guidelines. Only a randomised trial would provide high quality evidence to help resolve this uncertainty. Second, to be ethical, all trials require clinical equipoise among the experimental groups. In a randomised trial, alternative contraceptives would be compared with the DMPA standard to determine if they have different risks for HIV acquisition. This is precisely the ethical foundation for other HIVprevention trials, such as the MIRA trial cited in the Comment,1 which compared alternative prophylactic methods for which little or no data existed with standard products. Third, Ralph and colleagues question whether women will agree to be randomised to different contraceptives, and if so, whether they will continue the family planning methods to which they have been allocated. We agree that these are potential threats to trial quality and generalisability. However, different feasibility studies show the willingness of women to be randomised to similarly effective contraceptive groups.3,4 Through close attention to eligibility criteria, counselling before and after enrolment, contraceptive method continuation, and participant retention, we believe a randomised trial can be successfully implemented. Finally, we agree with Ralph and colleagues that much greater emphasis needs to be placed on increasing the contraceptive method mix, especially WHO Tier 1 methods. Implants and intrauterine devices are usually 304
20 times more effective in preventing unintended pregnancy than are DMPA and oral contraceptive pills.5 Women in countries with high HIV incidence need access to effective contraception and protection against HIV infection. We should simultaneously advance family planning programmes and assure these newer, more effective methods are as safe or safer than are other methods they might replace. The ambiguity of the current situation has left policy makers in countries with high HIV incidence unsure about the safety of continuing to provide DMPA. Any alleged increased risk associated with hormonal methods could be due to a combination of selection bias, different condom usage, or other flaws inherent to observational research. A randomised controlled trial offers the best hope to find out which of the most effective contraceptive methods might lead to the lowest risk of HIV acquisition. The ECHO Consortium is a multiorganisational collaborative team developing a protocol for a randomised controlled trial of hormonal contraception and HIV. The ECHO Consortium comprises: Jared Baeten, Ward Cates, Connie Celum, Tsungai Chipato, Stephanie Combes, Deborah Donnell, Peter Gichangi, G Justus Hofmeyr, Charles Morrison, Nelly Mugo, Kavita Nanda, Sharon Phillips, Helen Rees, Douglas Taylor, and Marleen Temmerman.
*Ward Cates, on behalf of the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Consortium [email protected] FHI 360, Durham, NC 27513, USA 1
2
3
4
5
Ralph LJ, McCoy SI, Hallett T, Padian N. Next steps for research on hormonal contraception and HIV. Lancet 2013; 382: 1467–69. WHO. Hormonal contraception and HIV: technical statement. Geneva, Switzerland; Research DoRHa, 2012. Hubacher D, Raymond ER, Beksinka M, et al. Hormonal contraception and the risks of STI acquisition: results of a feasibility study to plan a future randomized trial. Contraception 2008; 77: 366–70. Feldblum PJ, Caraway J, Bahamondes L, et al. Randomized assignment to copper IUD or depot medroxyprogesterone acetate: feasibility of enrollment, continuation, and disease ascertainment. Contraception 2005; 72: 187–91. Winner B, Peipert JF, Zhao Q, et al. Effectiveness of longer-acting reversible contraception. N Engl J Med 2012; 366: 1998–2007.
Available long-acting reversible contraceptives (LARC)—intrauterine devices, implant, injections, patches— are numerous and highly efficacious against pregnancy. Under ideal conditions of access and quality counselling, they give women the power to control fertility to an extent barely imagined by previous generations. Nevertheless, none of them protect against HIV. In their Comment, Lauren Ralph and colleagues1 integrate this tragic circumstance into their reasoning and recommendations, whereas this theme is given less emphasis by Ward Cates advocating for a randomised controlled trial between these effective contraceptives. 2 Thus, these two very influential and experienced parties debate the ethics and feasibility of carrying out a formal trial to estimate the additional risk of HIV infection incurred by users of depot medroxyprogesterone acetate (DMPA) versus other LARCs, with Ralph and colleagues downplaying its importance compared with Cates.2 We agree with Ralph and colleagues on the difficulties involved in a trial;1 moreover, pilot studies do not promise uniform enrolment across sites (44% in Brazil, 69% in Vietnam, 72% in Guatemala , and 82% in Egypt),3 and at least two studies show more dropouts in DMPA users than in users of other LARCs.4,5 Nor are there any possibilities of blinding—neither among those enrolled in the trial, nor among those assessing adherence. Moreover, recent analyses of the behavioural demands that affect adherence certainly emphasise caution.6 Like Ralph and colleagues,1 we think it is more important to improve the options and coverage for HIV protection, achieved via exploring further oral or vaginal methods, and expanding access and improving adherence to male or female condom. We should focus on these questions and accept as inevitable a level of uncertainty about DMPA, as other LARCs with a better safety profile are developed. www.thelancet.com Vol 383 January 25, 2014
Correspondence
We declare that we have no conflicts of interest.
*Erica L Gollub, Zena Stein egollub@fiu.edu Department of Epidemiology, Stempel College of Public Health, Florida International University, Miami, FL 33199, USA (ELG); and Department of Epidemiology, Mailman School of Public Health, Columbia University and HIV Center for Clinical and Behavioral Studies, NY State Psychiatric Institute, New York, NY, USA (ZS) 1
2
3
4
5
6
Ralph LJ, McCoy SI, Hallett T, Padian N. Next steps for research on hormonal contraception and HIV. Lancet 2013; 382: 1467–69. Cates W. Hormonal contraception and HIV: what a difference a year makes! HPTN/IMPAACT meeting, May 8, 2013, Washington, DC, USA. http://www.hptn.org/web%20documents/ AnnMtgPrstns2013/JointPlenary/05CatesHPTN_ HC_HIV.pdf (accessed Sept 23, 2013). Feldblum PJ, Caraway J, Bahamondes L, et al. Randomized assignment to copper IUD or depot-medroxyprogesterone acetate: feasibility of enrollment, continuation and disease ascertainment. Contraception 2005; 72: 187–91. Hubacher D, Raymon ER, Beksinska M, et al. Hormonal contraception and the risks of STI acquisition: results of a feasibility study to plan a future randomized trial. Contraception 2008; 77: 366–70. Stringer EM, Kaseba C, Levy J, et al. A randomized trial of the intrauterine contraceptive device vs hormonal contraception in women who are infected with the human immunodeficiency virus. Am J Obstet Gynecol 2007; 197: 144. Amico KR, Mansoor LE, Corneli A, Torjesen K, van der Straten A. Adherence support approaches in biomedical HIV prevention trials: experiences, insights and future directions from four multisite prevention trials. AIDS Behav 2013; 17: 2143–55.
Lauren Ralph and colleagues1 highlight some of the logistical and bioethical issues with a proposed randomised controlled trial of various methods of hormonal contraception and their potential association with HIV risk. 1 Observational evidence for many hormonal contraceptions and HIV acquisition risk is mixed and inconclusive.2 For example, oral hormonal contraception pills have not been associated with increased HIV acquisition, but the possibility exists that some hormonal contraception www.thelancet.com Vol 383 January 25, 2014
methods, particularly the injectable depot medroxyprogesterone acetate, might increase HIV acquisition risk.2 To minimise the potential risk of HIV acquisition to women who choose to enrol in any randomised trial, while simultaneously obtaining high-quality randomised data, I propose that all proven means of HIV prevention be offered to all study participants, including couples counselling and testing, immediate anti-retroviral therapy for any HIV-positive partners,3 and pre-exposure prophylaxis (PrEP) for those who wish to participate. The test-and-treat approach reduces HIV transmission by 96% in discordant couples.4 The success of PrEP in southern Africa is mixed, but it can be highly effective in adherent individuals.5 Thus, if any group have an increased HIV risk, this could be countered by lowering risk in the overall study population due to the addition of a full combination prevention package. At a minimum, the advantages and disadvantages of including these interventions as part of standard clinical counselling and care on the logistics, possible results, and subsequent recommendations of the randomised trial should be considered.6 I declare that I have no conflicts of interest. The opinions expressed here are mine and do not reflect the view of the NIH, DHHS, or the US Government.
Andrew D Redd [email protected] NIH, NIAID, Baltimore, MD 21205, USA 1
2
3
4
5
6
Ralph LJ, McCoy SI, Hallett T, Padian N. Next steps for research on hormonal contraception and HIV. Lancet 2013; 382: 1467–69. Polis CB, Curtis KM. Use of hormonal contraceptives and HIV acquisition in women: a systematic review of the epidemiological evidence. Lancet Infect Dis 2013; 13: 797–808. WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, 2013. http://www.who.int/hiv/ pub/guidelines/arv2013/en/ (accessed Jan 7, 2014) Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; 365: 493–505. Sugarman J, Mayer KH. Ethics and pre-exposure prophylaxis for HIV infection. J Acquir Immune Defic Syndr 2013; 63: S135–39. Haire B, Folayan MO, Hankins C, et al. Ethical considerations in determining standard of prevention packages for HIV prevention trials: examining PrEP. Dev World Bioeth 2013; 13: 87–94.
Authors’ reply These Correspondences reflect the complexities of studying hormonal contraception and HIV. They highlight several points on which we agree, most importantly that the existing body of observational evidence is inconclusive. Where we differ is how to handle this uncertainty.1 Although Ward Cates suggests that a randomised trial is the best way to achieve clarity, we, along with Erica Gollub and Zena Stein, question whether a trial will generate sufficiently definitive new information. On the critical question of whether such a trial is feasible, Cates cites a number of studies in which randomisation has been proposed or used.2,3 However, our understanding is that such studies2–4 indicate that just more than half (56%) of women approached about such a trial would agree to random assignment to depot medroxyprogesterone acetate (DMPA) or intrauterine devices, 2 showing substantial levels of non-participation (34–39%), method discontinuation (12–31%), and loss to follow-up or study withdrawal (18–28%),3,4 and have limited applicability because they differ from the proposed trial (eg, women outside of sub-Saharan Africa,3 HIV-positive women4). Thus, there is little compelling evidence that such a trial is feasible in the general population and, therefore, would be able to offer evidence superior to that obtained in observational studies to date. We agree however, that such feasibility questions will be addressed in the trial itself. Nevertheless, were the outcomes of the trial ones of feasibility and not efficacy, it would certainly have a different sample size and cost. The ethical issues are extremely complex, but the comparison with the MIRA trial cited by Cates is non-illustrative. In that trial, there was no previous evidence that the interventions in either group (condoms, or condoms plus diaphragms) increased women’s risk of HIV, whereas here, evidence suggests a small but increased risk of HIV in DMPA users.
Dr P Marazzi/Science Photo Library
A randomised trial appears to be a high-risk (for failure) venture for marginal gain. By comparison, efforts to close the HIV protection gap for women have far better odds of success and stand to bring indisputable gains for women’s health.
305
studies and judged the aggregate data to be of low quality.2 Specifically, they found the evidence was inconclusive to conclude that DMPA was causally related to HIV acquisition. The experts proposed no new restrictions on the use of injectable progestins in women at high risk of HIV, but because of the uncertainty, recommended the use of condoms for women using these methods. They also recommended that further research was necessary to provide the higher-quality evidence necessary for both greater scientific certainty and informing international guidelines. Only a randomised trial would provide high quality evidence to help resolve this uncertainty. Second, to be ethical, all trials require clinical equipoise among the experimental groups. In a randomised trial, alternative contraceptives would be compared with the DMPA standard to determine if they have different risks for HIV acquisition. This is precisely the ethical foundation for other HIVprevention trials, such as the MIRA trial cited in the Comment,1 which compared alternative prophylactic methods for which little or no data existed with standard products. Third, Ralph and colleagues question whether women will agree to be randomised to different contraceptives, and if so, whether they will continue the family planning methods to which they have been allocated. We agree that these are potential threats to trial quality and generalisability. However, different feasibility studies show the willingness of women to be randomised to similarly effective contraceptive groups.3,4 Through close attention to eligibility criteria, counselling before and after enrolment, contraceptive method continuation, and participant retention, we believe a randomised trial can be successfully implemented. Finally, we agree with Ralph and colleagues that much greater emphasis needs to be placed on increasing the contraceptive method mix, especially WHO Tier 1 methods. Implants and intrauterine devices are usually 304
20 times more effective in preventing unintended pregnancy than are DMPA and oral contraceptive pills.5 Women in countries with high HIV incidence need access to effective contraception and protection against HIV infection. We should simultaneously advance family planning programmes and assure these newer, more effective methods are as safe or safer than are other methods they might replace. The ambiguity of the current situation has left policy makers in countries with high HIV incidence unsure about the safety of continuing to provide DMPA. Any alleged increased risk associated with hormonal methods could be due to a combination of selection bias, different condom usage, or other flaws inherent to observational research. A randomised controlled trial offers the best hope to find out which of the most effective contraceptive methods might lead to the lowest risk of HIV acquisition. The ECHO Consortium is a multiorganisational collaborative team developing a protocol for a randomised controlled trial of hormonal contraception and HIV. The ECHO Consortium comprises: Jared Baeten, Ward Cates, Connie Celum, Tsungai Chipato, Stephanie Combes, Deborah Donnell, Peter Gichangi, G Justus Hofmeyr, Charles Morrison, Nelly Mugo, Kavita Nanda, Sharon Phillips, Helen Rees, Douglas Taylor, and Marleen Temmerman.
*Ward Cates, on behalf of the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Consortium [email protected] FHI 360, Durham, NC 27513, USA 1
2
3
4
5
Ralph LJ, McCoy SI, Hallett T, Padian N. Next steps for research on hormonal contraception and HIV. Lancet 2013; 382: 1467–69. WHO. Hormonal contraception and HIV: technical statement. Geneva, Switzerland; Research DoRHa, 2012. Hubacher D, Raymond ER, Beksinka M, et al. Hormonal contraception and the risks of STI acquisition: results of a feasibility study to plan a future randomized trial. Contraception 2008; 77: 366–70. Feldblum PJ, Caraway J, Bahamondes L, et al. Randomized assignment to copper IUD or depot medroxyprogesterone acetate: feasibility of enrollment, continuation, and disease ascertainment. Contraception 2005; 72: 187–91. Winner B, Peipert JF, Zhao Q, et al. Effectiveness of longer-acting reversible contraception. N Engl J Med 2012; 366: 1998–2007.
Available long-acting reversible contraceptives (LARC)—intrauterine devices, implant, injections, patches— are numerous and highly efficacious against pregnancy. Under ideal conditions of access and quality counselling, they give women the power to control fertility to an extent barely imagined by previous generations. Nevertheless, none of them protect against HIV. In their Comment, Lauren Ralph and colleagues1 integrate this tragic circumstance into their reasoning and recommendations, whereas this theme is given less emphasis by Ward Cates advocating for a randomised controlled trial between these effective contraceptives. 2 Thus, these two very influential and experienced parties debate the ethics and feasibility of carrying out a formal trial to estimate the additional risk of HIV infection incurred by users of depot medroxyprogesterone acetate (DMPA) versus other LARCs, with Ralph and colleagues downplaying its importance compared with Cates.2 We agree with Ralph and colleagues on the difficulties involved in a trial;1 moreover, pilot studies do not promise uniform enrolment across sites (44% in Brazil, 69% in Vietnam, 72% in Guatemala , and 82% in Egypt),3 and at least two studies show more dropouts in DMPA users than in users of other LARCs.4,5 Nor are there any possibilities of blinding—neither among those enrolled in the trial, nor among those assessing adherence. Moreover, recent analyses of the behavioural demands that affect adherence certainly emphasise caution.6 Like Ralph and colleagues,1 we think it is more important to improve the options and coverage for HIV protection, achieved via exploring further oral or vaginal methods, and expanding access and improving adherence to male or female condom. We should focus on these questions and accept as inevitable a level of uncertainty about DMPA, as other LARCs with a better safety profile are developed. www.thelancet.com Vol 383 January 25, 2014
Correspondence
We declare that we have no conflicts of interest.
*Erica L Gollub, Zena Stein egollub@fiu.edu Department of Epidemiology, Stempel College of Public Health, Florida International University, Miami, FL 33199, USA (ELG); and Department of Epidemiology, Mailman School of Public Health, Columbia University and HIV Center for Clinical and Behavioral Studies, NY State Psychiatric Institute, New York, NY, USA (ZS) 1
2
3
4
5
6
Ralph LJ, McCoy SI, Hallett T, Padian N. Next steps for research on hormonal contraception and HIV. Lancet 2013; 382: 1467–69. Cates W. Hormonal contraception and HIV: what a difference a year makes! HPTN/IMPAACT meeting, May 8, 2013, Washington, DC, USA. http://www.hptn.org/web%20documents/ AnnMtgPrstns2013/JointPlenary/05CatesHPTN_ HC_HIV.pdf (accessed Sept 23, 2013). Feldblum PJ, Caraway J, Bahamondes L, et al. Randomized assignment to copper IUD or depot-medroxyprogesterone acetate: feasibility of enrollment, continuation and disease ascertainment. Contraception 2005; 72: 187–91. Hubacher D, Raymon ER, Beksinska M, et al. Hormonal contraception and the risks of STI acquisition: results of a feasibility study to plan a future randomized trial. Contraception 2008; 77: 366–70. Stringer EM, Kaseba C, Levy J, et al. A randomized trial of the intrauterine contraceptive device vs hormonal contraception in women who are infected with the human immunodeficiency virus. Am J Obstet Gynecol 2007; 197: 144. Amico KR, Mansoor LE, Corneli A, Torjesen K, van der Straten A. Adherence support approaches in biomedical HIV prevention trials: experiences, insights and future directions from four multisite prevention trials. AIDS Behav 2013; 17: 2143–55.
Lauren Ralph and colleagues1 highlight some of the logistical and bioethical issues with a proposed randomised controlled trial of various methods of hormonal contraception and their potential association with HIV risk. 1 Observational evidence for many hormonal contraceptions and HIV acquisition risk is mixed and inconclusive.2 For example, oral hormonal contraception pills have not been associated with increased HIV acquisition, but the possibility exists that some hormonal contraception www.thelancet.com Vol 383 January 25, 2014
methods, particularly the injectable depot medroxyprogesterone acetate, might increase HIV acquisition risk.2 To minimise the potential risk of HIV acquisition to women who choose to enrol in any randomised trial, while simultaneously obtaining high-quality randomised data, I propose that all proven means of HIV prevention be offered to all study participants, including couples counselling and testing, immediate anti-retroviral therapy for any HIV-positive partners,3 and pre-exposure prophylaxis (PrEP) for those who wish to participate. The test-and-treat approach reduces HIV transmission by 96% in discordant couples.4 The success of PrEP in southern Africa is mixed, but it can be highly effective in adherent individuals.5 Thus, if any group have an increased HIV risk, this could be countered by lowering risk in the overall study population due to the addition of a full combination prevention package. At a minimum, the advantages and disadvantages of including these interventions as part of standard clinical counselling and care on the logistics, possible results, and subsequent recommendations of the randomised trial should be considered.6 I declare that I have no conflicts of interest. The opinions expressed here are mine and do not reflect the view of the NIH, DHHS, or the US Government.
Andrew D Redd [email protected] NIH, NIAID, Baltimore, MD 21205, USA 1
2
3
4
5
6
Ralph LJ, McCoy SI, Hallett T, Padian N. Next steps for research on hormonal contraception and HIV. Lancet 2013; 382: 1467–69. Polis CB, Curtis KM. Use of hormonal contraceptives and HIV acquisition in women: a systematic review of the epidemiological evidence. Lancet Infect Dis 2013; 13: 797–808. WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, 2013. http://www.who.int/hiv/ pub/guidelines/arv2013/en/ (accessed Jan 7, 2014) Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; 365: 493–505. Sugarman J, Mayer KH. Ethics and pre-exposure prophylaxis for HIV infection. J Acquir Immune Defic Syndr 2013; 63: S135–39. Haire B, Folayan MO, Hankins C, et al. Ethical considerations in determining standard of prevention packages for HIV prevention trials: examining PrEP. Dev World Bioeth 2013; 13: 87–94.
Authors’ reply These Correspondences reflect the complexities of studying hormonal contraception and HIV. They highlight several points on which we agree, most importantly that the existing body of observational evidence is inconclusive. Where we differ is how to handle this uncertainty.1 Although Ward Cates suggests that a randomised trial is the best way to achieve clarity, we, along with Erica Gollub and Zena Stein, question whether a trial will generate sufficiently definitive new information. On the critical question of whether such a trial is feasible, Cates cites a number of studies in which randomisation has been proposed or used.2,3 However, our understanding is that such studies2–4 indicate that just more than half (56%) of women approached about such a trial would agree to random assignment to depot medroxyprogesterone acetate (DMPA) or intrauterine devices, 2 showing substantial levels of non-participation (34–39%), method discontinuation (12–31%), and loss to follow-up or study withdrawal (18–28%),3,4 and have limited applicability because they differ from the proposed trial (eg, women outside of sub-Saharan Africa,3 HIV-positive women4). Thus, there is little compelling evidence that such a trial is feasible in the general population and, therefore, would be able to offer evidence superior to that obtained in observational studies to date. We agree however, that such feasibility questions will be addressed in the trial itself. Nevertheless, were the outcomes of the trial ones of feasibility and not efficacy, it would certainly have a different sample size and cost. The ethical issues are extremely complex, but the comparison with the MIRA trial cited by Cates is non-illustrative. In that trial, there was no previous evidence that the interventions in either group (condoms, or condoms plus diaphragms) increased women’s risk of HIV, whereas here, evidence suggests a small but increased risk of HIV in DMPA users.
Dr P Marazzi/Science Photo Library
A randomised trial appears to be a high-risk (for failure) venture for marginal gain. By comparison, efforts to close the HIV protection gap for women have far better odds of success and stand to bring indisputable gains for women’s health.
305
