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Antiretroviral chemoprophylaxis: new successes and questions
Comment
Antiretroviral chemoprophylaxis: new successes and questions Published Online March 11, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)60494-9
Robb Cohen/www.RobbsPhotos.com © CROI 2015
For CROI 2015 see http://www. croiconference.org/
2236
The recent Conference on Retroviruses and Opportunistic Infections (CROI 2015) on Feb 23–26, 2015, in Seattle, WA, USA, included several landmark presentations on the use of antiretrovirals for preexposure prophylaxis (PrEP), more than 2 years after the US Centers for Disease Control and Prevention and Food and Drug Administration approved the daily use of coformulated tenofovir–emtricitabine to prevent acquisition of HIV.1 The PROUD study2 followed men who have sex with men (MSM) in the UK who accessed screening services at local genitourinary medicine clinics. The men were randomly assigned to daily oral tenofovir–emtricitabine or deferred PrEP after the trial was over; all participants received HIV risk reduction counselling. Adherence to treatment was excellent and the trial was stopped early because of the significant protection in men on tenofovir–emtricitabine (86% decrease in risk of HIV infection) and the high rate of HIV infection (almost 9% annually) among men in the deferred PrEP group.2 Similarly encouraging results were presented for the IPERGAY trial,3 a placebo-controlled study of event-driven PrEP which mainly enrolled French MSM. Participants were assigned to oral tenofovir– emtricitabine or a matched placebo, and told that they should take two pills between 2 h and 24 h before an anticipated episode of condomless anal intercourse, and then take one pill a day for 2 subsequent days. The protective efficacy of tenofovir–emtricitabine in IPERGAY was 86% and participants used about 16 pills
per month, which suggests that peri-event PrEP dosing could be protective for MSM.3 Given that early initiation of antiretroviral treatment for HIV-infected people can decrease the likelihood of transmission to HIV-uninfected partners by at least 96%,4 the role of PrEP for primary partners of HIV-infected individuals has been questioned. At CROI 2015, the results of a demonstration project that followed HIV serodiscordant couples in east Africa offered some choices: early antiretroviral treatment to the infected partner and/or PrEP to the uninfected partner, particularly while the infected partner’s infection was becoming virologically suppressed.5 The findings of this study showed a substantial decrease in HIV incidence (0·2% compared with 5·2% in historical controls)5 and suggest that clinicians can now offer a menu of effective choices for HIV serodiscordant couples. Not all the news at CROI was so encouraging. A South African team presented the findings of the FACTS 001 study6 on pericoital vaginal tenofovir gel. The rationale for this study design was that the CAPRISA 004 trial7 showed that pericoital tenofovir gel had decreased HIV transmission in southern African women by almost 40%, whereas the VOICE trial8 did not show efficacy of daily tenofovir gel in a similar population, primarily because of suboptimum adherence. FACTS 001 enrolled 2059 HIV-negative women who were randomly assigned to tenofovir gel or a matched placebo.6 HIV incidence did not differ between the placebo and the tenofovir gel groups. A minority of the women used tenofovir gel during most of their sex acts. These findings suggest that daily use of tenofovir-based gel might not be acceptable for some young African women. Surprisingly, the results of another South African study9 showed that when young African women were given a choice of using daily pills for PrEP or less frequent dosing (eg, pericoital), they preferred daily dosing because it was easier to remember. The lack of efficacy seen in these studies might be explained partly by the unwillingness of trial participants to admit non-compliance due to the perceived benefits of taking part in the studies (ie, modest incentives, including free medical services); intercurrent genital tract inflammation impeding local antiretroviral protection;10 and pharmacological findings which indicate that women www.thelancet.com Vol 385 June 6, 2015
Comment
might need to be more adherent to tenofovir-based regimens than MSM, because tenofovir achieves higher concentrations sooner in anorectal mucosa than in cervicovaginal tissues.11 So where do the findings presented at CROI 2015 leave the field? In the partners demonstration project5 adherence to PrEP among African women was high and PrEP prevented HIV transmission. One possible explanation is that altruism in committed couples facilitated adherence to treatment through their desire to protect each other. For MSM, the CROI 2015 findings suggest that access to oral PrEP needs to be scaled up, since it has now been shown to be protective in several studies, and the rates of new HIV infection in diverse groups of MSM remain high globally.12 However, only the USA has approved PrEP for clinical use in MSM, although the results of IPERGAY and PROUD should accelerate change in other countries. For young African women, who have some of the highest rates of HIV acquisition worldwide,13 the findings presented at CROI 2015 suggest that longer duration methods of HIV prevention that do not require daily pills or gel applicators could offer culturally congruent approaches to chemoprophylaxis. Two efficacy studies of dapivirine-containing intravaginal rings, which can be inserted monthly, are underway in southern Africa,14 and earlier phase studies of injectable PrEP, containing rilpivirine or cabotegravir, could lead to the development of formulations that can be administered every 8 weeks or even less frequently.15 Immunoprophylaxis, using longacting broadly neutralising monoclonal antibodies, such as VRC01, could offer another means of parenteral prevention that can be administered every few months.16 One challenge for future studies is that as oral tenofovir–emtricitabine becomes recognised as a prevention standard, it will become increasingly difficult to do placebo-controlled studies among high risk populations. By offering PrEP in future efficacy trials, which may decrease HIV incidence in intervention and control groups, more participants will need to be enrolled and followed for longer intervals, which will increase costs and could slow down assessments of other methods of HIV prevention, such as vaccines and immunoprophylaxis. This is a challenge born of success, now that multiple studies suggest that the selective use of antiretrovirals can prevent HIV transmission.
www.thelancet.com Vol 385 June 6, 2015
However, better understanding of the best prevention approaches for specific populations, together with culturally tailored methods to optimise adherence and community engagement, are needed if the benefits of any prophylactic method are to be fully realised. Kenneth H Mayer Fenway Health, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA [email protected] I have received unrestricted education and research grants from Gilead Science. 1
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CDC, US Department of Health and Human Services. Preexposure prophylaxis for the prevention of HIV infection in the United States—2014 Clinical Practice Guideline. 2014. http://www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014. pdf (accessed March 1, 2015). McCormack S, Dunn D. Pragmatic open-label randomised trial of pre-exposure prophylaxis: the PROUD study. Conference on Retroviruses and Opportunistic Infections (CROI) 2015; Seattle, WA, USA; Feb 23–26, 2015. 22LB. Molina J-M, Capitant C, Spire B, et al. On demand PrEP with oral TDF-FTC in MSM: results of the ANRS Ipergay trial. Conference on Retroviruses and Opportunistic Infections (CROI) 2015; Seattle, WA, USA; Feb 23–26, 2015. 23LB. 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. Baeten J, Heffron R, Kidoguchi L, et al. Near elimination of HIV transmission in a demonstration project of PrEP and ART. Conference on Retroviruses and Opportunistic Infections (CROI) 2015; Seattle, WA, USA; Feb 23–26, 2015. 24. Rees H, Delany-Morelwe SA, Lombard C, et al. FACTS 001 phase III trial of pericoital tenofovir 1% gel for HIV prevention in women. Conference on Retroviruses and Opportunistic Infections (CROI) 2015; Seattle, WA, USA; Feb 23–26, 2015. 26LB. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 2010; 329: 1168–74. Marrazzo JM, Ramjee G, Richardson BA, et al. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med 2015; 372: 509–18. Bekker L-G, Hughes J, Amico R, et al. HPTN 067/ADAPT Cape Town: a comparison of daily and nondaily PrEP dosing in African women. Conference on Retroviruses and Opportunistic Infections (CROI) 2015; Seattle, WA, USA; Feb 23–26, 2015. 978LB. Naranbhai V, Abdool Karim SS, Altfeld M, et al. Innate immune activation enhances HIV acquisition in women, diminishing the effectiveness of tenofovir microbicide gel. J Infect Dis 2012; 206: 993–1001. Trezza CR, Kashuba AD. Pharmacokinetics of antiretrovirals in genital secretions and anatomic sites of HIV transmission: implications for HIV prevention. Clin Pharmacokinet 2014; 53: 611–24. Beyrer C, Sullivan P, Sanchez J, et al. The increase in global HIV epidemics in MSM. AIDS 2013; 27: 2665–78. UNAIDS. The gap report. Geneva: UNAIDS, 2014. http://www.unaids.org/ en/resources/campaigns/2014/2014gapreport/gapreport (accessed March 4, 2014). AVAC. Global Advocacy for HIV Prevention. Dapivirine. 2015. http://www. avac.org/search/node/dapivirine (accessed March 1, 2015). Spreen W, Williams P, Margolis D, et al. Pharmacokinetics, safety, and tolerability with repeat doses of GSK1265744 and rilpivirine (TMC278) long-acting nanosuspensions in healthy adults. J Acquir Immune Defic Syndr 2014; 67: 487–92. Graham BS. Update on clinical development of VRC01 and second generation neutralizing CD4 binding site-specific monoclonal antibodies. HIV Research for Prevention 2014 AIDS Vaccine, Microbicide and ARV-based Prevention Science; Cape Town, South Africa; Oct 28–31, 2014. SY12.01.
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Antiretroviral chemoprophylaxis: new successes and questions Published Online March 11, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)60494-9
Robb Cohen/www.RobbsPhotos.com © CROI 2015
For CROI 2015 see http://www. croiconference.org/
2236
The recent Conference on Retroviruses and Opportunistic Infections (CROI 2015) on Feb 23–26, 2015, in Seattle, WA, USA, included several landmark presentations on the use of antiretrovirals for preexposure prophylaxis (PrEP), more than 2 years after the US Centers for Disease Control and Prevention and Food and Drug Administration approved the daily use of coformulated tenofovir–emtricitabine to prevent acquisition of HIV.1 The PROUD study2 followed men who have sex with men (MSM) in the UK who accessed screening services at local genitourinary medicine clinics. The men were randomly assigned to daily oral tenofovir–emtricitabine or deferred PrEP after the trial was over; all participants received HIV risk reduction counselling. Adherence to treatment was excellent and the trial was stopped early because of the significant protection in men on tenofovir–emtricitabine (86% decrease in risk of HIV infection) and the high rate of HIV infection (almost 9% annually) among men in the deferred PrEP group.2 Similarly encouraging results were presented for the IPERGAY trial,3 a placebo-controlled study of event-driven PrEP which mainly enrolled French MSM. Participants were assigned to oral tenofovir– emtricitabine or a matched placebo, and told that they should take two pills between 2 h and 24 h before an anticipated episode of condomless anal intercourse, and then take one pill a day for 2 subsequent days. The protective efficacy of tenofovir–emtricitabine in IPERGAY was 86% and participants used about 16 pills
per month, which suggests that peri-event PrEP dosing could be protective for MSM.3 Given that early initiation of antiretroviral treatment for HIV-infected people can decrease the likelihood of transmission to HIV-uninfected partners by at least 96%,4 the role of PrEP for primary partners of HIV-infected individuals has been questioned. At CROI 2015, the results of a demonstration project that followed HIV serodiscordant couples in east Africa offered some choices: early antiretroviral treatment to the infected partner and/or PrEP to the uninfected partner, particularly while the infected partner’s infection was becoming virologically suppressed.5 The findings of this study showed a substantial decrease in HIV incidence (0·2% compared with 5·2% in historical controls)5 and suggest that clinicians can now offer a menu of effective choices for HIV serodiscordant couples. Not all the news at CROI was so encouraging. A South African team presented the findings of the FACTS 001 study6 on pericoital vaginal tenofovir gel. The rationale for this study design was that the CAPRISA 004 trial7 showed that pericoital tenofovir gel had decreased HIV transmission in southern African women by almost 40%, whereas the VOICE trial8 did not show efficacy of daily tenofovir gel in a similar population, primarily because of suboptimum adherence. FACTS 001 enrolled 2059 HIV-negative women who were randomly assigned to tenofovir gel or a matched placebo.6 HIV incidence did not differ between the placebo and the tenofovir gel groups. A minority of the women used tenofovir gel during most of their sex acts. These findings suggest that daily use of tenofovir-based gel might not be acceptable for some young African women. Surprisingly, the results of another South African study9 showed that when young African women were given a choice of using daily pills for PrEP or less frequent dosing (eg, pericoital), they preferred daily dosing because it was easier to remember. The lack of efficacy seen in these studies might be explained partly by the unwillingness of trial participants to admit non-compliance due to the perceived benefits of taking part in the studies (ie, modest incentives, including free medical services); intercurrent genital tract inflammation impeding local antiretroviral protection;10 and pharmacological findings which indicate that women www.thelancet.com Vol 385 June 6, 2015
Comment
might need to be more adherent to tenofovir-based regimens than MSM, because tenofovir achieves higher concentrations sooner in anorectal mucosa than in cervicovaginal tissues.11 So where do the findings presented at CROI 2015 leave the field? In the partners demonstration project5 adherence to PrEP among African women was high and PrEP prevented HIV transmission. One possible explanation is that altruism in committed couples facilitated adherence to treatment through their desire to protect each other. For MSM, the CROI 2015 findings suggest that access to oral PrEP needs to be scaled up, since it has now been shown to be protective in several studies, and the rates of new HIV infection in diverse groups of MSM remain high globally.12 However, only the USA has approved PrEP for clinical use in MSM, although the results of IPERGAY and PROUD should accelerate change in other countries. For young African women, who have some of the highest rates of HIV acquisition worldwide,13 the findings presented at CROI 2015 suggest that longer duration methods of HIV prevention that do not require daily pills or gel applicators could offer culturally congruent approaches to chemoprophylaxis. Two efficacy studies of dapivirine-containing intravaginal rings, which can be inserted monthly, are underway in southern Africa,14 and earlier phase studies of injectable PrEP, containing rilpivirine or cabotegravir, could lead to the development of formulations that can be administered every 8 weeks or even less frequently.15 Immunoprophylaxis, using longacting broadly neutralising monoclonal antibodies, such as VRC01, could offer another means of parenteral prevention that can be administered every few months.16 One challenge for future studies is that as oral tenofovir–emtricitabine becomes recognised as a prevention standard, it will become increasingly difficult to do placebo-controlled studies among high risk populations. By offering PrEP in future efficacy trials, which may decrease HIV incidence in intervention and control groups, more participants will need to be enrolled and followed for longer intervals, which will increase costs and could slow down assessments of other methods of HIV prevention, such as vaccines and immunoprophylaxis. This is a challenge born of success, now that multiple studies suggest that the selective use of antiretrovirals can prevent HIV transmission.
www.thelancet.com Vol 385 June 6, 2015
However, better understanding of the best prevention approaches for specific populations, together with culturally tailored methods to optimise adherence and community engagement, are needed if the benefits of any prophylactic method are to be fully realised. Kenneth H Mayer Fenway Health, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA [email protected] I have received unrestricted education and research grants from Gilead Science. 1
2
3
4 5
6
7
8
9
10
11
12 13
14 15
16
CDC, US Department of Health and Human Services. Preexposure prophylaxis for the prevention of HIV infection in the United States—2014 Clinical Practice Guideline. 2014. http://www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014. pdf (accessed March 1, 2015). McCormack S, Dunn D. Pragmatic open-label randomised trial of pre-exposure prophylaxis: the PROUD study. Conference on Retroviruses and Opportunistic Infections (CROI) 2015; Seattle, WA, USA; Feb 23–26, 2015. 22LB. Molina J-M, Capitant C, Spire B, et al. On demand PrEP with oral TDF-FTC in MSM: results of the ANRS Ipergay trial. Conference on Retroviruses and Opportunistic Infections (CROI) 2015; Seattle, WA, USA; Feb 23–26, 2015. 23LB. 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. Baeten J, Heffron R, Kidoguchi L, et al. Near elimination of HIV transmission in a demonstration project of PrEP and ART. Conference on Retroviruses and Opportunistic Infections (CROI) 2015; Seattle, WA, USA; Feb 23–26, 2015. 24. Rees H, Delany-Morelwe SA, Lombard C, et al. FACTS 001 phase III trial of pericoital tenofovir 1% gel for HIV prevention in women. Conference on Retroviruses and Opportunistic Infections (CROI) 2015; Seattle, WA, USA; Feb 23–26, 2015. 26LB. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 2010; 329: 1168–74. Marrazzo JM, Ramjee G, Richardson BA, et al. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med 2015; 372: 509–18. Bekker L-G, Hughes J, Amico R, et al. HPTN 067/ADAPT Cape Town: a comparison of daily and nondaily PrEP dosing in African women. Conference on Retroviruses and Opportunistic Infections (CROI) 2015; Seattle, WA, USA; Feb 23–26, 2015. 978LB. Naranbhai V, Abdool Karim SS, Altfeld M, et al. Innate immune activation enhances HIV acquisition in women, diminishing the effectiveness of tenofovir microbicide gel. J Infect Dis 2012; 206: 993–1001. Trezza CR, Kashuba AD. Pharmacokinetics of antiretrovirals in genital secretions and anatomic sites of HIV transmission: implications for HIV prevention. Clin Pharmacokinet 2014; 53: 611–24. Beyrer C, Sullivan P, Sanchez J, et al. The increase in global HIV epidemics in MSM. AIDS 2013; 27: 2665–78. UNAIDS. The gap report. Geneva: UNAIDS, 2014. http://www.unaids.org/ en/resources/campaigns/2014/2014gapreport/gapreport (accessed March 4, 2014). AVAC. Global Advocacy for HIV Prevention. Dapivirine. 2015. http://www. avac.org/search/node/dapivirine (accessed March 1, 2015). Spreen W, Williams P, Margolis D, et al. Pharmacokinetics, safety, and tolerability with repeat doses of GSK1265744 and rilpivirine (TMC278) long-acting nanosuspensions in healthy adults. J Acquir Immune Defic Syndr 2014; 67: 487–92. Graham BS. Update on clinical development of VRC01 and second generation neutralizing CD4 binding site-specific monoclonal antibodies. HIV Research for Prevention 2014 AIDS Vaccine, Microbicide and ARV-based Prevention Science; Cape Town, South Africa; Oct 28–31, 2014. SY12.01.
2237