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HIV Prevention at AIDS 2010 Vienna
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Jared Baeten, MD PhD
Connie Celum, MD MPH
University of Washington
Extremely exciting data related to HIV prevention were presented at the XVIII International AIDS Conference (AIDS 2010). The field has achieved some true successes in the past year, some of which were newly reported in Vienna, and enthusiasm for discovery of new prevention strategies and successful implementation of known effective strategies was high. Of course, in an era of increasingly tight funding for HIV, both research and programs, prevention must be recognized as central to turning the tide in the epidemic. Many key sessions are available for free on the web; we have included links for these.
In an Opening Session plenary (http://globalhealth.kff.org/AIDS2010/July-18/Opening-Session-LIVE-WEBCAST.aspx), Yves Souteyrand from WHO presented an overview on the state of the global epidemic (abstract SUPL0104). The global prevalence of HIV stands at 0.8%, with the number of persons living with HIV continuing to increase, as a result of global population growth, continued transmission, and reduced mortality among persons with HIV as a result of antiretroviral therapy. Each day, an estimated 7400 infections, 1200 in children, 5000 persons die of HIV/AIDS, and 3000 are initiated on antiretroviral therapy. Thus, the epidemic continues to outpace treatment and prevention efforts.
There have been clear positive steps. UNAIDS recently reported that an estimated 200,000 HIV infections in children have been prevented in the past 12 years due to antiretroviral medications used for prevention of mother-to-child transmission (PMTCT), a number that is expected to increase with continued expanded access to treatment. More than five million persons are on antiretroviral therapy in low and middle income countries, resulting in reduced mortality. Prevention efforts have had substantial impact on new sexually-transmitted infections in high prevalence countries. However, the speaker emphasized that stigma, discrimination, and violations of human rights threaten HIV prevention efforts, particularly for most at risk populations, including men who have sex with men, drug users, prisoners, migrants, transgendered persons, women and girls, and sex workers. Failure of countries to act on "knowing your epidemic" - i.e., measuring and understanding the distribution of new infections by risk group within a population and targeting prevention efforts accordingly - results in unachieved prevention potential.
On Monday, Bill Gates spoke in a special plenary session that emphasized the importance of improving efficiencies in delivery and scale-up of HIV prevention (http://globalhealth.kff.org/AIDS2010/July-19/Building-on-Success.aspx). Known effective strategies for HIV prevention, including male circumcision, PMTCT, and antiretroviral treatment, need to be delivered more efficiently and effectively to populations at risk. Moreover, as new potential strategies for prevention, including antiretroviral-based prevention strategies like microbicides or pre-exposure prophylaxis (PrEP) demonstrate efficacy, it will be essential to turn research knowledge into implementation rapidly and efficiently. Combining effective strategies may be most efficient - a single "magic bullet" for HIV prevention does not exist at this time but implementing several strategies together may be able to cross the tipping point to dramatically reduce new infections, in both concentrated and generalized epidemics. Preliminary mathematical modeling results were shown suggesting that, together, current and new tools for prevention could cut new infections by 90% in next 20 years. The session ended with a call for thinking about now being a turning point in HIV prevention, with new opportunities, and an urgent need to get the most out of research and implementation funding. At the beginning of the session, activists called for a "Robin Hood" tax of 0.005% on all worldwide financial transactions, to fund HIV prevention and care.
CAPRISA 004: Efficacy & safety of coitally-dependent tenofovir gel in South African women
The highlight of the entire conference was clearly the results of the CAPRISA 004 study, presented in a special session on Tuesday (http://globalhealth.kff.org/AIDS2010/July-20/Safety-and-Effectiveness.aspx).
CAPRISA 004 was a phase IIb (proof of concept), randomized, double-blind, placebo-controlled clinical trial of the safety and effectiveness of 1% tenofovir vaginal gel (i.e., a microbicide) for preventing HIV infection in women conducted by the Centre for the AIDS Programme of Research in South Africa (CAPRISA). Safety studies done before CAPRISA 004 found tenofovir gel to be well-tolerated and safe for women and men. Tenofovir gel was developed by Gilead Sciences, Inc., of Foster City, California, USA, the manufacturer of tenofovir and emtricitabine/tenofovir tablets. In 2006 tenofovir gel was assigned by a royalty-free license to the International Partnership for Microbicides of Silver Spring, Maryland, and CONRAD, of Arlington, Virginia. The CAPRISA 004 study was done as a collaboration between CAPRISA at the University of KwaZulu-Natal in Durban, South Africa, Family Health International, and CONRAD. It was funded by USAID and the Technology Innovation Agency in South Africa. The study was led by Drs. Quarraisha and Salim Abdool Karim from CAPRISA, the University of KwaZulu-Natal, and Columbia University.
CAPRISA 004 enrolled 889 sexually active HIV uninfected women at two sites in and around Durban, South Africa - one within the city of Durban and a second in rural Vulindlela. Women were randomized to one of two study groups - in the final anaylsis, 444 to placebo gel with no active ingredient and 445 to 1% tenofovir gel - and instructed to use the study product before and after sex, up to a maximum of 2 doses in a 24 hour period. All participants received condoms, intensive counseling and other routine interventions for reducing HIV-1 risk throughout the 12-18 months they were in the trial. The study started in May 2007, enrollment was completed in January 2009, and the final study visits were completed in November 2009.
Retention was high - 95% of women completed the study. Based on self-reported sexual frequency and counts of used and unused gel applicators, on average, 72% of sex acts were covered by two doses of gel.
The study found the tenofovir gel resulted in a 39% reduction in the risk of HIV: 38 women in the tenofovir arm acquired HIV, compared with 60 women in the placebo arm. The result of 39% effectiveness of tenofovir gel was statistically significant (p=0.017), although the 95% confidence interval around the efficacy estimate, which defines a range of reliability for the study finding, found that the true effectiveness of tenofovir gel could be as low as 6% or as high as 60%. There was some suggestion that women who had higher adherence had greater protection from HIV than women with lower adherence - among those who had >80% gel adherence, HIV risk was reduced 54%. Women in the tenofovir arm were also half as likely to acquire herpes simplex virus type 2 (HSV-2), the virus that causes genital herpes, an interesting and important secondary finding, particularly as HSV-2 is an important risk factor for acquiring HIV.
Among the women in the tenofovir arm who acquired HIV, none had HIV that was resistant to tenofovir, as measured by standard genotyping analysis. Pharmacokinetics data presented in the session were in agreement with both the efficacy and resistance findings of the study - vaginal biopsies revealed high concentrations of tenofovir and tenofovir diphosphate (its active intracellular form), concentrations were lower in women who acquired HIV compared with those who did not, and plasma levels of tenofovir were low, indicating low systemic absorption (likely at least in part explaining lack of resistance). Importantly, CAPRISA 004 found that tenofovir gel was safe - there was no increase in adverse events in women randomized to tenofovir gel compared with those randomized to placebo gel.
CAPRISA 004 is a pivotal HIV prevention trial. The study demonstrated that tenofovir gel is safe and reduces the risk of a woman becoming HIV infected. An important secondary finding is that tenofovir gel reduces the risk of a woman becoming HSV-2 infected. The study was conducted with high quality, and it provides a critical "proof of concept" in the path to using antiretroviral medications for HIV prevention. More research is required. Because CAPRISA 004 involved ~900 women from a single region of South Africa, the same approach tested in more women or in women from different regions of Africa could feasibly have a different outcome. That is why evaluation of any new intervention almost always requires more than one study - often several - to gain as much information as possible about its safety and effectiveness in different populations who could potentially benefit.
CAPRISA 004 is one of six placebo-controlled, efficacy trials of tenofovir-based products HIV prevention. Five trials are evaluating tenofovir and/or emtricitabine/tenofovir tablets. One large ongoing study, VOICE, run through the US NIH's Microbicides Trials Network, is also evaluating the safety and effectiveness of daily application of tenofovir gel. The studies evaluating oral tablets are often called PrEP studies while the gel studies seem to be more commonly thought of as microbicide studies; however, the concepts of using tenofovir as a gel or as a tablet for HIV prevention are similar in many ways. There are differences between the oral PrEP studies and the studies evaluating tenofovir gel, 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 antiretroviral medications for HIV prevention among different populations.
Finally, it is important to note the high HIV incidence in the population of women in CAPRISA 004 - more than 5% per year even among those receiving tenofovir gel. Clearly, even with a successful intervention like that used in this trial, additional HIV prevention strategies are necessary for highest-risk populations.
The primary findings of CAPRISA 004 were simultaneously published online in the journal Science (http://www.sciencemag.org/cgi/content/abstract/science.1193748).
Other studies of antiretrovirals for HIV prevention: pre-exposure prophylaxis (PrEP) and treatment for prevention
In a late breaker presentation (Grohskopf abstract FRLBC102), the US Centers for Disease Control and Prevention reported preliminary results of a phase II extended safety study study of oral tenofovir PrEP. The study enrolled 400 HIV seronegative men who have sex with men from the US between February 2005 and July 2007. Participants were randomized to daily oral tenofovir tablets or matching placebo, and then further randomized to immediate versus delayed initiation of tablets, to assess sexual behavior while taking versus not taking study tablets. Study follow-up completed in August 2009. Tenofovir was shown to be safe. There was no statistically significant difference in the frequency of serious adverse events between the tenofovir and the placebo arms. The rate of creatinine and phosphate laboratory abnormalities was similar between the study arms - for example, 1.1% of tenofovir participants vs. 3.2% of placebo participants experienced a creatinine increase of ≥0.5 mg/dL above baseline (p=0.28). A total of 3 HIV-1 infections occurred after enrollment in participants taking study drug, all in the placebo arm; the study, however, was not sufficiently statistically powered to assess the efficacy of tenofovir for preventing HIV-1 infection.
The International AIDS Vaccine Initiative (IAVI) reported preliminary results from two linked placebo-controlled studies of oral emtricitabine/tenofovir PrEP among female sex workers, men who have sex with men, and HIV serodiscordant couples in Kenya and Uganda (Mutua abstract MOPE0369). These small studies (<100 participants in total) evaluated the safety of the study product and adherence to daily versus scheduled intermittent (Monday and Friday doses), and post-coital dosing. Adherence to the daily and intermittent dosing was relatively high and similar, while adherence to the post-coital dosing was lower. Adverse events were mild or moderate, with most felt by the investigators to be unlikely to be related to the study drug and the number of adverse events similar between those who received active drug and those who received placebo. No significant renal problems were observed.
A symposium was devoted to looking ahead to microbicides and PrEP for HIV prevention (http://globalhealth.kff.org/AIDS2010/July-22/Understanding-HIV-Transmission-Mechanisms.aspx).
Arguably the strongest predictor of HIV transmission risk in epidemiologic studies is the level of HIV in blood. When HIV infected persons are treated with antiretroviral therapy, plasma and genital viral concentrations decrease, usually to extremely low levels, which is expected to substantially reduce the infectiousness of HIV infected persons. Mathematical modeling studies have argued that increasing the number of persons on therapy could substantially reduce new HIV transmissions, particularly if the number of persons who know their HIV serostatus is substantially increased, if they are effectively linked to HIV care, and if treatment is initiated (together called the 'test and treat' strategy). Previously-reported observational data from HIV serodiscordant couples has suggested that initiation of antiretroviral therapy substantially reduces HIV transmission risk (as high as 92% reduction).
Among MSM in Denmark, stable HIV incidence over the past 15 years, in spite of rising prevalence as a result of increased treatment access suggests declining transmission (Cowan abstract MOAC0103). Similar ecologic data from San Francisco and Vancouver have been reported.
One limitation to treatment for HIV prevention is the contribution of acute HIV infection to the epidemic, as persons with acute infection are usually unaware they have acquired HIV but they may be highly infectious due to high viral loads. A mathematical modeling study, using data from Malawi, estimated that 38% of new transmissions were a result of transmission from persons with acute infection (Powers abstract FRLBC105). A study from Mozambique found high prevalence of previously-undiagnosed HIV (38%) among persons presenting with fever to an outpatient ward, including 3% acute HIV (Serna-Bolea abstract FRAX0102). Strategies to find and intervene in acute infection remain challenging.
A special symposium was done on antiretroviral-based HIV prevention (http://globalhealth.kff.org/AIDS2010/July-21/Use-of-Antiretrovirals-for-Prevention.aspx).
Cash transfer
In a satellite session on Sunday, The World Bank released the results of two studies, from Malawi and Tanzania, of cash payments (cash transfer) as a behavioral intervention to prevent HIV and other sexually transmitted infections. In the first study, called Schooling, Income, and HIV Risk (SIHR), from Malawi, nearly 4000 girls aged 13 to 22 were enrolled. If girls remained in school, they and their parents were given cash payments, up to ~$15 per month. The study was began in 2008. After 18 months of follow-up, 1.2% of girls who received cash payments had HIV, versus 3% in a control group of girls who did not receive cash payments. The prevalence of genital herpes infection (HSV-2) was also lower (0.7% vs. 3%). Girls who received cash payment had less sex than those in the control group, and were less likely to have sex with older men, who may provide gifts or money to girls and may be more likely to be infected with HIV than younger men - "intergenerational sex" has been described as a risk factor transmission of HIV to young girls in southern Africa. It is unclear - and probably impossible to distinguish - whether staying in school versus increased family income (and some independent income to girls) was responsible for the decreased HIV and HSV-2 incidence. This conditional cash transfer program offers an exciting new HIV prevention strategy for young African women, who are at very high risk for HIV.
The second study, called the RESPECT Study, enrolled 2400 young men and women, aged 18 to 30, in southwest Tanzania. Participnats were tested every four months for common sexually transmitted diseases, including Chlamydia, gonorrhea, trichomoniasis, and syphilis. After a year of providing cash payments (up to $60 over 12 months) to those who remained free of sexually transmitted diseases, the program found a 25% drop in the numbers of cases of sexually transmitted infections.
More information about these studies can be found on the World Bank's website: http://econ.worldbank.org/WBSITE/EXTERNAL/EXTDEC/0,,contentMDK:22649337~pagePK:64165401~piPK:64165026~theSitePK:469372,00.html) .
Most at risk populations
Injection drug users. An important theme of the conference was the continued epidemic among persons who use drugs. An official declaration from the conference - only the second time this has been done - called for incorporating evidence-based practices into illicit drug policies (http://www.viennadeclaration.com/).
High prevalence of HIV in drug users from disparate populations was reported. In one study from 8 cities in Russia, HIV prevalence ranged from 3 to 70% (Lyubimova abstract MOAC0202). More than 30% of women and 40% of men had sex partners who were not injection drug users, suggesting high risk for bridging to heterosexual populations. Greater attention to drug use in African countries has recently received attention. In one study, respondent-driven sampling was used to recruit injection drug users from Zanzibar, Tanzania; HIV prevalence was 16% and HCV prevalence was 26% (Broz abstract MOAC0401).
Prevention of HIV in drug users has the potential for real success. In Estonia, large-scale syringe exchange was associated with HIV incidence decreasing by more than half (from 18 to 8 per 100 person-years) (Uusküla abstract MOAC0402). In Australia, a mathematical modeling study found that for every dollar spent on needle exchange, four dollars were returned in healthcare cost-savings (Wilson abstract MOAC0403).
Two symposia were devoted to the global epidemic among drug users (http://globalhealth.kff.org/AIDS2010/July-20/The-Lancet-Series.aspx and http://globalhealth.kff.org/AIDS2010/July-23/Prevention-and-Treatment-of-HIV-Among-Drug-Using-Populations.aspx).
Youth. UNAIDS reported an analysis of HIV prevalence data among young persons aged 15-24. Of 30 countries participating, 10 (Botswana, Côte d'Ivoire, Ethiopia, Kenya, Malawi, Namibia, South Africa, Tanzania, Zambia, and Zimbabwe, had a decline of 25% or more in HIV prevalence between 2000 and 2008 (Gouws abstract TUAC0204). For 8 of these 10 countries, there were concurrent declines in sexual risk behaviors in young persons. These data suggest falling HIV incidence in some countries in this very high risk stratum of the population; still, interventions remain desperately needed to prevent HIV in young people.
Men who have sex with men. High prevalence and incidence of HIV in men who have sex with men in low and middle income countries is increasingly recognized. A number of presentations focused on this important population. In a study from Uganda (Barker abstract TUAC0304), where MSM activity has recently received international attention after legislative efforts with severe criminal penalties were proposed, a survey of 303 MSM demonstrated HIV prevalence of 14%, with higher HIV risk among men reporting abuse as a result of MSM activity. In a cohort of >1200 MSM from Bangkok, an HIV incidence of 6% per year was reported (van Griensven abstract TUAC0301). Further discussion of MSM HIV risk and prevention in low and middle income countries, and in Africa specifically, occurred in a special symposia (http://globalhealth.kff.org/AIDS2010/July-21/Homophobia-and-HIV-in-Africa.aspx and http://globalhealth.kff.org/AIDS2010/July-22/Know-Your-Epidemic-Know-Your-Response.aspx).
HIV serodiscordant couples. High prevalence of HIV discordancy and high HIV risk in discordant couples, particularly in Africa, is increasingly recognized. A systematic review of data from ~14,000 African couples found that female partners were as likely as male partners to be HIV infected in a discordant relationship, emphasizing the opportunity for testing and counseling couples together (Eyawo abstract TUAC0205). A retrospective review of discordant couples in TASO indicated high levels of sexual activity, and reliance on condoms for family planning (Malinzi abstract CDC0529). In-depth interviews of HIV discordant couples in Nairobi identified reproductive needs and concerns and the benefit of couples-level counseling in increasing dual contraceptive use (Marx TUPE0789). In-depth interviews from Vulindlela and Soweto, South Africa, couples often face challenges discussing HIV risk (Mindry abstract MOAD0102). Desire to have children was one avenue to discuss HIV risk. One third of HIV discordant couples in Kampala indicated that they wanted to conceive in the future (Nakijoba abstract WEPE0386).
Counseling and provision of social support services is essential for HIV serodiscordant couples (Wmala WEPE0578). A multisite randomized trial of an 8-session counseling intervention among African-American discordant couples found increased condom use (Jemmott abstract TUAD0104).
Accessing effective prevention services may also be challenging for couples. In an observational study of HIV discordant couples from Nairobi, over half of those HIV infected members who came to meet national guidelines to initiate antiretroviral therapy did so (Guthrie abstract TUAB0206). Women tended to initiate therapy later than men, and lower socioeconomic status was a barrier to initiation. In a study from an HIV care program in Uganda, ongoing counseling, condom promotion, discussion of disclosure of HIV status, and home based testing resulted in high adherence to antiretroviral therapy and 50% disclosure to partners (Odeke abstract MOAC0105). Data from Porto Alegre in south Brazil, identified a high proportion (14%) of HIV serodiscordant couples among persons testing through a VCT program, and low condom use, indicating that the priority of identifying HIV serodiscordant couple and providing targeted risk reduction is not restricted to Africa (Paganella abstract WEPE0375). A cross-sectional study of HIV serodiscordant couples who were former plasma donors in Henan, China, most of whom were on antiretroviral therapy indicated the importance of adherence counseling, psychosocial support services, and health education (Ge abstract THPDC102 and Ge abstract WEPE0688).
Poverty. Data from the US National HIV Behavioral Surveillance system were analyzed for 23 cities in which ≥20% households were below the US poverty level (Denning abstract WEPDD101). HIV prevalence was significantly higher among residents below the poverty line (2.4%) compared with those in the same neighborhoods but who had incomes above the poverty level (1.1%). The generalized HIV epidemic (prevalence >1%) in poor urban areas of the US deserves continuing attention.
Sex workers. Encouraging data from the Avahan program among female sex workers in Karnataka, south India were reported (Moses abstract MOAC0301). In this large-scale combination prevention program, significant reductions in HIV prevalence (19.6% to 16.4%, p=0.004) were seen after implementation, with concurrent reductions in sexually transmitted infections and increased condom use with clients (66.1% to 84.1% with last client, p<0.001). Among female sex workers in Kampala, Uganda, 40% of 1027 women were infected with HIV, of whom 39% had CD4 counts that would qualify them for antiretroviral therapy by Uganda national guidelines; scale-up of treatment services for this high-risk core group could be an important prevention strategy (Nnakate Bukenya abstract MOAC0104).
Male circumcision
The prevention benefit of male circumcision in reducing female-to-male HIV transmission risk was demonstrated in three landmark randomized trials completed in 2006. Long-term observational follow-up from one of those trials, from Kisumu, Kenya, showed that the protective benefit has extended to 54 months of follow-up - men who chose to receive circumcision had a 63% reduced risk compared with those who chose to remain uncircumcised (Bailey abstract FRLBC101).
Implementation of circumcision services has become a clear priority. Rapid scale-up can be accomplished: in Kenya, >36,000 men were circumcised in one month in late 2009 (Odoyo-June abstract THAC0102). Thirty-eight percent of men were tested for HIV. Task shifting did not jeopardize safety of procedure - the adverse event rate was <2%. In a random household survey from Kisumu, Kenya of >1700 persons found high acceptability of the procedure in this traditionally noncircumcising area (Westercamp abstract THAC0101). Higher-risk men appeared to be more willing to be circumcised but there was not clear evidence that circumcision resulted in higher-risk behaviors that could undermine its effectiveness.
PMTCT
Data from the antiretroviral pregnancy registry, now with 11,000 live births, no overall increase in birth defects for women exposed to antiretroviral medications has been seen compared with general population expected rates, including for first trimester exposures (Vannappagari abstract WEAX0104).
A symposium was dedicated to elimination of mother-to-child transmission HIV (http://globalhealth.kff.org/AIDS2010/July-22/Prevention-of-Mother-to-Child-Transmission.aspx).
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