HIV Prevention Report at IAS 2011 by Jared Baeten, MD & Connie Cellum, MD
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome, Italy, 17-20 July 2011
Jared Baeten, MD PhD
Connie Celum, MD MPH
University of Washington
Without a doubt, IAS 2011 was a conference about HIV prevention. Extremely exciting, including very late breaking, data were presented regarding new prevention strategies, and notable successes with scale-up of established strategies were reviewed. For perhaps the first time ever, the discussion among researchers, policymakers, and activists at the meeting had a tone raising the possibility that sufficiently powerful HIV prevention tools may now be available to radically change the course of the epidemic. The cover of the medical journal The Lancet for the week of the conference had the following key quote: "The question for attendees in Rome, and the global community, is whether we have the political will to mobilize the resources needed to arrest the HIV epidemic 30 years after it first emerged."
Many important sessions from Rome have slides (and sometimes audio) available for free on the web; we have included links for these.
In an Opening Session keynote address
(http://pag.ias2011.org/flash.aspx?pid=383, abstract SUPL0105), Michel Sidibe, Executive Director of the Joint United Nations Programme on HIV/AIDS (UNAIDS),emphasized the importance of scientific research and implementation science in the fight against new HIV infections. Notably, he called for "universal access to science" - to turn scientific success in prevention and treatment into better health for all populations, even in an era of economic constraints - and he emphasized that the world now recognizes that reaching a "tipping point" for controlling the epidemic is possible.
ART and PrEP: Treatment is prevention
The highlight of the conference was a special oral abstract session on Monday afternoon, devoted to new research on antiretrovirals for HIV prevention (http://pag.ias2011.org/session.aspx?s=98). The session, originally focused on the results of the HIV Prevention Trails Network (HPTN) 052 study, was expanded to include the results of two pre-exposure prophylaxis (PrEP) trials, which reported their results in the week before the conference. The session title was changed from "Treatment as Prevention" to "Treatment is Prevention: The Proof is Here," reflecting tremendous scientific enthusiasm at the meeting for the results of these powerful studies.
HPTN 052 was a randomized clinical trial testing the hypothesis that antiretroviral therapy (ART) would decrease the risk of HIV transmission. Since the intervention (antiretroviral therapy) was provided to an HIV infected person and the outcome (HIV transmission) needed to be measured in their initially-HIV uninfected sexual partners, the trial was conducted among HIV serodiscordant couples, in which one member was HIV infected and the other uninfected. Because clinical standards for initiating ART mandate treatment for HIV infected persons who experience symptomatic HIV disease, only couples in which the HIV infected partner had a CD4 count between 350 and 550 cells/μL at the time of study enrollment (i.e., greater than current international guidelines for initiation of ART; WHO current recommends initiation at 350 cells/μL) were eligible. The design of the study was a 1:1 randomization of couples to immediate versus delayed ART, where HIV infected partners in the delayed arm started ART when their CD4 counts fell to ≤250 cells/μL. The primary endpoint for the study was HIV transmission within the study partnership, established by molecular virology (i.e., HIV sequencing) to determine linkage. The study also evaluated the clinical benefits of early ART initiation, with a primary composite clinical endpoint of WHO stage 4 events, pulmonary tuberculosis, severe bacterial infection, or death. HPTN 052 was conducted in 9 countries (Brazil, Botswana, India, Kenya, Malawi, South Africa, Thailand, United States, Zimbabwe). The study was funded by the United States National Institutes of Health through the HPTN, with study medications donated by a number of companies.
The primary study results were presented by Dr. Myron Cohen from the University of North Carolina, the HPTN 052 protocol chair (http://pag.ias2011.org/flash.aspx?pid=680, abstract MOAX0102). Additional talks in the session focused on the laboratory testing for HIV linkage within the partnerships (http://pag.ias2011.org/flash.aspx?pid=681, Eshleman, abstract MOAX0103) and the clinical and virologic outcomes in the trial (http://pag.ias2011.org/flash.aspx?pid=609, Hosseinipour, abstract MOAX0104 and http://pag.ias2011.org/flash.aspx?pid=612, Grinsztejn, abstract MOAX0105)
In total, HPTN 052 screened 10,838 individuals in order to enroll and randomize 1763 HIV serodiscordant couples, 886 to the immediate ART arm and 877 to the delayed ART arm. The major reason for screen out was that the HIV infected partner's CD4 count was not in the 350-550 cells/μL range required for the study. The majority of enrolled couples (954/1763, 54%) were from Africa. For 49% of the couples, the HIV infected partner was female; most were married. The median CD4 count at enrollment for HIV infected partners was approximately 430 cells/μL.
HIV infected partners randomized to immediate ART underwent intensive adherence counseling and monitoring of viral loads to ensure viral suppression. During follow-up, >90% of HIV infected partners on ART achieved and sustained a viral load of <400 copies/mL.
In April 2011, the HPTN 052 Data and Safety Monitoring Board (DSMB) reviewed data in the study through 21 February 2011. The DSMB recommended that the study results be reported as soon as possible and the delayed arm be offered ART, due to clear transmission benefits of immediate (as compared to delayed) ART initiation.
In total, 39 HIV transmission events were observed in HPTN 052: 4 in the immediate ART and 35 in the delayed arm (p<0.0001). Of these 39 events, 28 were determined to be virologically linked within the partnership (i.e., the transmission occurred within the study partnership rather than from an outside partner): 1 in the immediate arm and 28 in the delayed arm (p<0.001), for incidences of linked HIV transmission of 0.1 and 1.7 per 100 person-years, respectively, indicating a 96% reduction in risk of HIV transmission. 82% of the HIV transmissions occurred in the African sites and 64% of the transmissions were from female HIV infected partners to male HIV uninfected partners. The one linked HIV transmission event in the immediate arm was detected within 3 months of study enrollment and viral sequence analysis suggested that transmission occurred very soon after study enrollment, before viral suppression effects from ART would have been realized.
In multivariate analysis, randomization to the immediate ART arm (hazard ratio 0.04), higher CD4 count (hazard ratio 1.24 per 100 cell increment), higher plasma viral load (hazard ratio 2.84 per log10 increase), and 100% condom use at baseline (hazard ratio 0.33) were associated with transmission risk.
HPTN 052 also demonstrated clinical benefits of early ART initiation - specifically, a 41% decrease in the risk of reaching the composite clinical endpoint (p=0.01), mostly driven by differences in the rate of extrapulmonary tuberculosis (3 in the immediate arm versus 17 in the delayed ART arm). The risk of death was not statistically different between the study arms.
Thus, HPTN 052 definitively demonstrates that antiretroviral therapy is a powerful HIV prevention strategy - reducing the likelihood of transmission by 96%. It is important to note that HIV transmission incidence in the delayed treatment arm of HPTN 052 was less than 2% per year, substantially lower than was seen previously in observational studies of HIV serodiscordant couples.
Indeed, the HPTN 052 study was originally designed anticipating an HIV incidence of approximately 10% per year in the delayed arm. The low HIV incidence in the delayed arm is indicative of the HIV prevention benefits of the package of HIV prevention services - testing as couple, ongoing risk-reduction counseling, access to condoms and condom counseling - that all couples in the trial received, and the potential importance of such combination prevention services. Finally, it is notable that ~25% of incident HIV infections in HPTN 052 were not virologically linked within the partnership, emphasizing that HIV seronegative partners in serodiscordant couples face HIV risk from outside partners, with whom they may be less likely to discuss HIV status and use condoms.
The HPTN 052 study is continuing. Couples in the delayed arm are being offered ART, and all couples will continue to be followed. Median follow-up in HPTN 052 was only 1.7 years, and continued information about the durability of ART adherence, virologic response, and transmission and clinical benefits for persons started on ART at high CD4 counts will be important to gather.
The primary findings of HPTN 052 were simultaneously published online in the New England Journal of Medicine (http://www.nejm.org/doi/full/10.1056/NEJMoa1105243). An important satellite session describing a recent meeting in Vancouver on use of ART for HIV prevention also occurred in Rome (http://pag.ias2011.org/session.aspx?s=99).
The Partners PrEP Study is a phase III, randomized, double-blind, placebo-controlled, three-arm trial of daily oral tenofovir (TDF) and emtricitabine/tenofovir (FTC/TDF) PrEP for the prevention of HIV acquisition by HIV seronegative partner in heterosexual HIV serodiscordant partnerships (disclosure: we are the lead investigators of this study). On 10 July 2011, just a week before the IAS 2011 meeting in Rome opened, the independent DSMB for the Partners PrEP Study recommended that the results of the study be publically reported, nearly 2 years earlier than expected, and the placebo arm discontinued, because of clear demonstration of HIV protection due to PrEP. These surprising results were made public that week and were quickly incorporated into the IAS 2011 schedule (http://pag.ias2011.org/flash.aspx?pid=886, abstract MOAX0106). The study was funded by the Bill and Melinda Gates Foundation.
The Partners PrEP Study enrolled 4758 HIV serodiscordant couples, in which the HIV infected partner was not medically eligible for ART under the national guidelines of their country of residence at the time of study enrollment. HIV uninfected partners were randomized in an equal fashion to receive daily oral TDF, FTC/TDF, or placebo. Couples were followed for up to 36 months, for primary endpoints of HIV acquisition in the initially-seronegative partner and safety. The study was conducted at 9 clinical trial sites in rural and urban Kenya and Uganda. Most couples were married. For HIV infected partners, the average median CD4 count at enrollment was 495 cells/μL.
HIV uninfected participants were seen monthly, for HIV and pregnancy testing, safety monitoring, and individualized adherence counseling. HIV infected participants had quarterly visits for monitoring of HIV clinical status; during the study ~20% initiated ART. All participants received a comprehensive package of HIV prevention services, including individual and couples risk reduction counseling, condoms and condom counseling, and counseling regarding other HIV prevention services (e.g,. male circumcision).
Retention in the Partners PrEP Study was ≥95% throughout the study follow-up period. Adherence to PrEP was high: 97% of dispensed pills were estimated to be taken, based on monthly pill counts of returned, unused study medication.
In total, 78 HIV infections occurred after enrollment in the Partners PrEP Study: 18 among those assigned TDF, 13 among those randomized to FTC/TDF, and 47 among those receiving placebo, for an efficacy for HIV protection of 62% (95% CI 34-78%, p=0.0003) for TDF and 73% (95% CI 49-85%, p<0.0001) for FTC/TDF. The HIV protection effects of TDF versus FTC/TDF were not statistically different (p=0.18).
Both TDF and FTC/TDF reduced HIV risk in both men and women, and the effects in women and men were statistically similar. For TDF, efficacy among women was 68% and was 55% among men; for FTC/TDF, efficacy was 62% in women and 83% in men.
TDF and FTC/TDF PrEP were safe: there was no statistically significant differences in the rate of serious adverse events and important laboratory adverse events between those receiving active PrEP and those receiving placebo. PrEP was also well tolerated - like in previous PrEP trials (e.g., iPrEx, among MSM, reported at CROI this past year and in the New England Journal of Medicine), slightly more participants reported nausea during the first month of PrEP than those receiving placebo, that faded over time, but gastrointestinal symptoms like these occurred in <10% of participants overall. The study found no evidence of risk compensation - in fact, unprotected sex declined during follow-up, similarly across the three study arms.
Ongoing testing in the study is examining antiretroviral resistance in seroconverters, drug levels as a measure of adherence, and plasma viral load in seroconverters, as a measure of early HIV disease.
In summary, the Partners PrEP Study, with results reporting just a week before Rome, demonstrated definitively reduced risk of HIV acquisition for African men and women taking TDF and FTC/TDF PrEP. The degree of HIV protection was statistically similar for TDF versus FTC/TDF, and both medications were robust in HIV protection for women and for men. The medications were well-tolerated.
The Partners PrEP Study is continuing: the DSMB recommended continued follow-up of the active PrEP arms, to gather additional comparative information on the safety, efficacy, and tolerability of TDF and FTC/TDF as PrEP. Placebo arm participants immediately began stopping study medication and will be offered active PrEP at the research clinics.
The TDF2 study was a double-blind, randomized, trial of daily oral FTC/TDF or placebo for prevention of HIV acquisition young (age 18-39) women and men in Botswana (Thigpen, abstract WELBC01, http://pag.ias2011.org/flash.aspx?pid=596). The study was funded by the Centers for Disease Control and Prevention.
A total of 1219 individuals were randomized, about 30% of the study population did not complete follow-up. Adherence to PrEP overall was estimated to be approximately 84%. Overall, 9 HIV infections occurred among those assigned FTC/TDF compared to 24 among those assigned placebo, translating to an efficacy for HIV protection of 63% (95% CI 22-83%, p=0.01). Subgroup analyses by gender included too few cases for definitive results, but the point estimates suggested that PrEP reduced HIV risk substantially in both women and men. One participant in the active PrEP group who was infected at enrollment (and in the window period) developed resistance to both FTC and TDF but was successfully initiated on antiretroviral therapy. PrEP was safe in terms of renal and hepatic function.
Thus, the TDF2 study, like the Partners PrEP Study, found that daily oral PrEP was safe and effective for HIV prevention among heterosexual men and women.
TDF2 participants are being offered 12 months of active PrEP, and CDC is currently reviewing heterosexual PrEP data to develop guidance for PrEP use in the US.
The Partners PrEP Study and the TDF2 study are two of seven placebo-controlled, efficacy trials of tenofovir-based products HIV prevention, including TDF, FTC/TDF, and tenofovir vaginal gel. At AIDS 2010 in Vienna last year, CAPRISA 004, a phase IIb trial, reported that 1% tenofovir gel used with coitus reduced HIV risk by 39% among 889 South African women. In late 2010, iPrEx, a phase III trial among 2499 men who have sex with men from 6 countries, found that daily oral FTC/TDF reduced HIV risk by 42%. The iPrEx team reported updated results from the end of their trial in Rome (Grant, abstract WELBC04, http://pag.ias2011.org/session.aspx?s=43). In both iPrEx and CAPRISA 004, HIV protection from PrEP was closely related to adherence. In iPrEx, the risk of HIV infection overall decreased during the study, suggesting that PrEP and the HIV prevention package that was standard for participants worked in combination to reduce risk of HIV acquisition. In April of this year, the FEM-PrEP trial, among 1950 higher-risk African women, was stopped early due to no HIV protection effect seen from daily oral FTC/TDF in that population. Clearly, the results of FEM-PrEP are in disagreement with the more recent results from the Partners PrEP Study and the TDF2 trial, and final results are expected from FEM-PrEP by the end of this year. A large ongoing study, VOICE, conducted through the US NIH's Microbicides Trials Network, is evaluating the safety and effectiveness of daily application of tenofovir gel as well as oral TDF and FTC/TDF. There are differences between the PrEP studies, including geographic location of the study populations (trial sites are in North and South America, Asia, and East and southern Africa), route of HIV exposure (with populations including injection drug users, men who have sex with men, and heterosexual women and men), as well as the potential for different side effects, adherence, and acceptability. Thus, each will contribute an important "piece of the puzzle" for advancing understanding about the safety and effectiveness of oral and topical tenofovir-based antiretroviral medications for HIV prevention among different populations.
Risk factors for HIV acquisition and transmission and new strategies to reduce HIV risk
Hormonal contraception and HIV risk. A prospective study of 3790 heterosexual HIV serodiscordant couples (in which one partner was HIV seropositive and the other seronegative) from 7 African countries compared rates of HIV acquisition in women and HIV transmission from women to men among hormonal contraceptive users and nonusers. Among 1314 couples in which the HIV seronegative partner was female, HIV acquisition rates were 6.61 and 3.78 per 100 person-years in women currently using and not using hormonal contraception (adjusted hazard ratio 1.98, 95% CI 1.06-3.68, p=0.03). Among 2476 couples in which the HIV seronegative partner was male, HIV transmission rates from women to men were 2.61 and 1.51 per 100 person-years in those whose partners currently used versus did not use hormonal contraception (adjusted hazard ratio 1.97, 95% CI 1.12-3.45, p=0.02). Both injectable and oral hormonal contraceptive methods were associated with increased HIV risk. Genital HIV RNA concentrations were significantly higher in HIV seropositive women using hormonal contraception than those using no contraception, suggesting a potential mechanism for increased transmission risk from women to men. This concerning results suggest that hormonal methods of contraception may double the risk of HIV acquisition and transmission, emphasizing the importance of counseling about dual protection, particularly in high HIV prevalence settings. The remainder of the session included interesting talks on scale-up and integration of family planning with HIV prevention and care, a critically important topic (http://pag.ias2011.org/session.aspx?s=10).
Bacterial vaginosis and HIV risk. Bacterial vaginosis, a common infection in women that has been shown to increase HIV acquisition risk in a number of studies, may also increase HIV transmission risk from HIV-infected women to their male partners (Cohen, abstract MOAC0202 http://pag.ias2011.org/flash.aspx?pid=281). In a study of >2200 HIV infected African women and their male partners, the rate of HIV transmission within the partnership was 2.9 per 100 person-years from women with bacterial vaginosis compared with 0.9 per 100 person-years from women with normal vaginal flora. These are the first results suggesting bacterial vaginosis increases HIV transmission risk, and it further emphasizes the need for strategies to promote vaginal health as an HIV prevention strategy.
HSV-2 suppression. Several abstracts described treatment of herpes simplex virus type 2 (HSV-2), the cause of genital herpes, as a strategy to decrease HIV infectiousness and disease progression. Among145 HIV/HSV-2 co-infected pregnant women randomized to twice daily valacyclovir HSV-2 suppression, post-partum breastmilk and plasma HIV RNA concentrations were significantly lower than those randomized to matching placebo, by 0.51 log10 (Drake, abstract MOAC0201 http://pag.ias2011.org/flash.aspx?pid=282). Other results from this same study showed that daily valacyclovir HSV-2 suppression was safe(Drake, abstract MOPE174) and resulted in increased CD4 counts for post-partum women (Roxby, abstract TUAB0202 http://pag.ias2011.org/flash.aspx?pid=300). A small randomized cross-over trial found that higher-dose HSV-2 suppression (valacyclovir 3 gm daily) could reduce plasma HIV RNA levels by >1 log10 compared to baseline levels and >0.6 log10 compared to acyclovir 400 mg bid (Mugwanya abstract WEPDB0106). A randomized trial from Uganda found that HSV-2 suppression delayed HIV disease progression (Reynolds, TUAB0104 http://pag.ias2011.org/flash.aspx?pid=291), suggesting this treatment strategy could be used to delay time to ART in persons with high CD4 counts. The combined results of these studies indicate that HSV-2 suppression may have benefits in terms of HIV-1 disease progression, vertical and sexual transmission, and that additional studies should evaluate the relative HIV-1 decreases and costs of higher doses of HSV-2 suppression.
Intimate partner violence and HIV risk. A small study (n=160) from an outpatient hospital setting in Uganda found that intimate partner violence was common (32% of women, 9% of men reporting physical violence, 44% and 27% sexual biolence, and 37% and 28% emotional abuse) (Kiene, abstract MOAC0101, http://pag.ias2011.org/flash.aspx?pid=307). Those experiencing partner violence thought themselves more likely to test HIV positive. Interventions to mitigate partner violence remain desperately needed in many settings.
Men who have sex with men. In a late-breaker oral session, a pilot study of couples voluntary counseling and testing for MSM couples in Atlanta was reported (Sullivan abstract WELBC05 http://pag.ias2011.org/flash.aspx?pid=600). A total of 106 couples were enrolled. 28 (26%) reported recent sexual coercion, intimate partner violence, or both in the partnership. 1 in 5 couples were HIV serodiscordant. This pilot evaluation is now following couples after couples testing. It has demonstrated that couples-targeted strategies can be applied to MSM in the US, reaching a population with high prevalence of undiagnosed HIV prevalence and HIV discordance.
HIV testing strategies
With the exciting results of HIV treatment as HIV prevention and PrEP presented at IAS, there is a growing number of effective prevention tools, and HIV testing is clearly central for achieving high uptake of effective HIV prevention and care services. A poster discussion session focused on "Reaching the Hard to Reach with Testing" (http://pag.ias2011.org/session.aspx?s=47). The effectiveness of an opt-out approach to HIV testing was demonsrtated in the Gambela Ethiopia medical male circumcision programs; HIV testing increased from 25% to 77% (Abduljewad, abstract MOPDC0101). Community-based VCT is an effective way to get high coverage of HIV testing, knowledge of HIV serostatus, and to reach men; through Project Accept in the Soweto township in South Africa, 99% of 20,304 persons agreed to HIV testing with equal numbers of men and women (Robertson, abstract MOPDC0102). Provider-initiated HIV testing was found to reach a higher proportion of ethnic minorities in Liangshan province in southwestern China with high HIV prevalence, and to identify HIV+ persons with a higher median CD4 than other testing strategies (Peng, abstract MOPDC0106).
Injection drug users
In Vienna at the International AIDS Society meeting last year, an official declaration for evidence-based interventions for prevention of HIV in injection drug users was made (http://www.viennadeclaration.com/), an important step towards HIV elimination in this population. An important symposium was dedicated to successful prevention in drug users (http://pag.ias2011.org/session.aspx?s=80) as well as a Wednesday plenary (http://pag.ias2011.org/flash.aspx?pid=357).
The prevention benefit of male circumcision in reducing female-to-male HIV transmission risk was demonstrated in three landmark randomized trials completed in 2006. Implementation of circumcision services has become a clear public health priority. In Orange Farm, South Africa, where one of the clinical trials of male circumcision was conducted, a roll-out project has been providing circumcision promotion and services since 2008 (Auvert abstract WELBC02 http://pag.ias2011.org/flash.aspx?pid=597). Uptake has been high: community surveys have shown that, among men aged 15-49, only 15.6% were circumcised in 2007, while 49.4% had circumcised by 2010, including 58.5% of those in the age range of 20-24 years. In the 2010 survey, circumcised men were were younger, more educated, less likely to be married, and more aware of their own HIV status, but they were no more likely to engage in higher-risk sexual practices than uncircumcised men. HIV prevalence was 20.0% in uncircumcised men versus 6.2% in circumcised men, a 55% reduction. Using detuned ELISA testing, it was estimated that HIV incidence was 3.7% per year for uncircumcised men versus 0.6%, a 76% reduction. This impressive work demonstrates, in a real world setting in South Africa that circumcision roll-out can be highly successful, with high uptake among young men, change social norms, and reduce HIV prevalence and incidence.
In a poster discussion (Mahler abstract TUPDC0101) high-volume delivery of male circumcision services in another high HIV prevalence community was reported, from the Iringa region of Tanzania (HIV prevalence 16%, circumcision rates <40%). A six-week campaign in mid 2010 was launched, with demand creation teams, radio advertising, and scale up of clinical and counseling services. In total >10,000 men were circumcised at 5 centers, >99% were tested for HIV, and adverse events were few (<1%). These results show that circumcision can be scaled up successfully, when delivery scale-up and demand creation are linked. In another poster discussion, a longitudinal study from Kenya found no increase in high-risk sexual behaviors of men who became circumcised in that country's roll-out program (Westercamp, abstract WEPDC0102).
The Global Plan to eliminate mother-child transmission of HIV was launched in June 2011, with the ambitious global target to reduce HIV transmission to children by 90%. WHO presented guidance on standardizing methods for impact evaluation for PMTCT, including triangulating information obtained from mathematical modeling, prospective cohorts of HIV-infected pregnant women, immunization clinic assessments of HIV exposure and infection status of infants, population-based surveys, and analysis of early infant diagnosis and testing data (http://pag.ias2011.org/session.aspx?s=23). Scale-up of PMTCT was discussed in pre-conference symposia (http://pag.ias2011.org/session.aspx?s=38 and http://pag.ias2011.org/session.aspx?s=21) and in the Wednesday plenary session (http://pag.ias2011.org/flash.aspx?pid=356).
Antiretroviral prophylaxis, now shown to be an important strategy for prevention of sexual HIV transmission, first demonstrated its potential for HIV prevention in the PMTCT setting, where it is the core of efforts to prevent transmission to infants. A late-breaker abstract presented a pooled analysis of trials of post-partum infant nevirapine prophylaxis for the prevention of breast milk transmission to infants (Van der Horst abstract WELBC03). The data were from the well-known SWEN (6 weeks of post-partum nevirapine), PEPI (14 weeks), and BAN (28 weeks) trials. The analysis was restricted to infants born to women who had CD4 counts >200. The primary outcome was HIV infection at 28 weeks after birth. Overall, the analysis demonstrated the post-partum nevirapine results in a 71% reduction in risk of HIV acquisition for infants, during the period it is given (i.e., longer duration of prophylaxis results in greater reduction in risk). Post-partum prophylaxis for infants is clearly critical for reaching goals to eliminate MTCT, particularly for infants born to women not on HAART.