Reducing HIV incidence and prevalence: Where are we and where are we going?

In 2011, 6,850 new HIV infections occurred every day, even though several efficacious HIV prevention options are now available: male and female condoms, voluntary medical male circumcision, timely management of other sexually transmitted infections (STI), and more than 20 antiretroviral drugs in 6 different drug classes [1]. The latter can be used to prevent mother to child transmission, for oral pre- and post-exposure prophylaxis in those who are not infected (see further), and to suppress HIV viral load in those already infected for treatment as well as prevention of onward transmission.

Current programmes

The good news is that these HIV prevention strategies are working. HIV incidence peaked in 1996, with 3.5 million new HIV infections in that year, and has declined to 2.5 million in 2011 [1]. The bad news is that they have not succeeded in decreasing HIV prevalence: HIV prevalence increased steadily from 7 million in 1990 to 34 million at the end of 2011 [1]. The reason for this is that, in addition to 2.5 million new cases per year, HIV patients are surviving longer due to improved access to combination antiretroviral therapy (cART). Eight million patients were receiving cART by the end of 2011, which is 54% of those eligible for cART according to the current World Health Organization guidelines. The vast majority of them live in low- and middle-income countries [1]. It may be possible to reduce HIV incidence even further by improving access to existing prevention strategies and cART, and by removing structural barriers prohibiting evidence-based HIV prevention programmes. However, health systems in low- and middle-income countries and international budgets are struggling to cope with current programmes, and structural barriers are not easily removed. Furthermore, not all groups at risk currently have access to prevention technologies that are suitable for them. New HIV prevention technologies are therefore still needed.

Pre-exposure prophylaxis

The latest addition to the HIV prevention mix is daily oral pre-exposure prophylaxis (PrEP). In 2010 and 2011, three pivotal randomized controlled trials (RCTs) showed a reduction of HIV incidence in participants who had received the drug Truvada (tenofovir disoproxil fumarate plus emtricitabine) for daily oral PrEP: 44% in men who have sex with men (MSM) in the Americas, Thailand and South Africa (iPrEx trial), 63% in heterosexual men and women in Botswana (CDC TDF2 trial), and 73% in HIV discordant couples in several African countries (Partners PrEP trial) (reviewed in 2). Subsequently, in 2012, the United States (US) Food and Drug Administration approved Truvada for oral PrEP, and the US Centers for Disease Control and Prevention issued interim guidance for clinicians interested in prescribing PrEP [2]. The guidance stipulates that PrEP should be targeted to those confirmed to be HIV-negative (and not pregnant) but at very high risk of acquiring HIV, should always be delivered as part of a comprehensive prevention package, and should be monitored closely (i.e. regular HIV, STI and toxicity testing, and adherence evaluation). Demonstration projects have now been initiated in the US and the United Kingdom to evaluate if PrEP will also work in real-world situations. Furthermore, studies to assess the efficacy of intermittent PrEP with Truvada, and of PrEP with other antiretroviral drugs (including the injectable drug TMC278), are ongoing.

HIV virus

While most Truvada PrEP trials to date have been successful, the two trials that enrolled young African women without their male sex partner(s) were not [3, 4]. The FemPrEP and VOICE trials were prematurely terminated due to futility in 2011 and 2013, respectively. Pharmacokinetic testing of drug levels and other trial data suggest that few trial participants used the products as directed. This low adherence explains the lack of benefit and is consistent with data from the successful PrEP trials that found a correlation between higher levels of adherence and protection from HIV. Perhaps the most disturbing finding of the FemPrEP and VOICE trials was the very high HIV incidence in these young women (5 per 100 person-years of follow-up or higher) despite the fact that they were offered several HIV prevention services in an RCT setting.

Microbicides

While daily oral PrEP is a welcome addition to the HIV prevention toolbox in some very high risk populations, it is clearly not suitable for roll-out in many other populations. This is why research on other delivery mechanisms of (lower doses of) antiretroviral drugs is continuing, such as vaginal rings and vaginal and rectal gels. These so-called vaginal and rectal microbicides allow for local dosing at the HIV portal of entry instead of systemic dosing, which may increase efficacy and reduce toxicity [5]. Furthermore, the efficacy of vaginal rings is likely to be less dependent on user-adherence because the rings can stay in place for at least one month. Vaginal microbicide development has a long history. Six different products (none of them antiretroviral drugs) were tried in efficacy trials but failed [6]. The breakthrough came in 2010, when the South African CAPRISA 004 trial showed that 1% tenofovir vaginal gel (2 doses within 12 hours before and 12 hours after sex) reduced HIV incidence by 50% during 12 months of gel use [7]. Overall adherence in the trial was poor, and efficacy increased with higher levels of adherence (as assessed by vaginal drug levels). Unfortunately, hopes were tempered by the negative results of the VOICE trial. The VOICE trial included a 1% tenofovir vaginal gel arm with daily dosing in addition to the above-mentioned oral PrEP arms [4]. This vaginal gel arm was also terminated prematurely due to futility. At the moment, the results of three pivotal RCTs are anxiously awaited: the FACTS 001 trial in South Africa (same product and dosing as CAPRISA 004), and two trials of a vaginal ring containing the non-nucleoside reverse transcriptase inhibitor dapivirine (the Ring and ASPIRE trials). All three RCTs are being conducted in young African women and results are expected in 2014 and 2015.

Vaccin

Perhaps the only way to reduce HIV incidence and prevalence significantly is to develop a highly efficacious vaccine and/or a cure. Many vaccines have been developed and tested but with disappointing results thus far. Only one RCT (the RV 144 trial) has shown a statistically significant but modest (31%) reduction in HIV incidence [8]. This RCT was conducted in Thailand between 2003 and 2009 by the US Military HIV Research Program (MHRP). Participants were primed 4 times with the ALVAC-HIV vaccine (a canary-pox vector containing three genetically engineered HIV genes) and boosted twice with the AIDSVAX B/E vaccine (genetically engineered gp120). MHRP is currently trying to improve the immunogenicity of these vaccines, and is preparing for another large trial based on the RV 144 vaccine strategy in Thailand and South Africa. Recent experiences with adenovirus-based HIV vaccines (the STEP/ Phambili and HVTN 505 trials) have been worrisome: not only were the vaccines not efficacious, they also showed trends towards harm [9-11]. While the vaccine itself cannot cause HIV infection, it is plausible that vaccination recruits and activates target cells for HIV at mucosal surfaces. If the vaccine does not elicit strong protective immune response directed at HIV (such as neutralizing antibodies) at the same time, HIV entry could be facilitated instead of blocked [12]. In the STEP trial, vaccinated MSM with pre-existing antibodies to adenovirus as well as uncircumcised vaccinated MSM had statistically significantly higher rates of HIV infection than circumcised MSM without adenovirus antibodies or unvaccinated controls (the latter two groups did not differ from one another); this effect waned after the first 18 months of follow-up [10]. The HVTN 505 trial, however, was conducted in circumcised MSM without pre-existing adenovirus immunity, and also showed a trend towards harm [1]. Vaccine researchers therefore have to go back to the drawing board once again. One glimmer of hope is the recent discovery of a number of highly potent neutralizing antibodies, which might be incorporated into future vaccine strategies [13].

A cure for HIV

Research on a cure for HIV gained attention after three observations were made suggesting that a cure might be feasible: ‘the Berlin Patient’ (free of replicable HIV since a bone marrow transplant from a donor whose immune system was resistant to HIV due to a delta 32 mutation in the gene coding for the CCR5 co-receptor), ‘the Mississippi Baby’ (treated with cART within hours of infection for 18 months and now free of replicable HIV) and ‘the Visconti Cohort’ (14 HIV patients in France treated with cART within 10 weeks of infection for a median of 37 months who had an HIV viral load of <400 copies/ml in the absence of cART for a median of 89 months) [14]. In all of these cases, the patients were functionally cured (HIV is most likely still present in reservoirs but is controlled without cART) as opposed to a sterilizing cure (no HIV genetic material can be found in the entire body). A cure for HIV will probably consist of a combination of interventions (such as antiretroviral drugs, vaccines and/or gene therapy) to not only kill accessible free virus and virus-infected cells but also hard-to-reach reservoirs. While this area of research is gathering speed, a cure is still years away. In the mean time, the world should continue to focus on improving access to existing HIV prevention strategies and CART.

References

1. UNAIDS. Global report: report on the global AIDS epidemic 2012. Geneva: UNAIDS. Available: http://www.unaids.org/en/resources/publications/2012/name,76121,en.asp. Accessed on 6 May 2013.
2. Smith DK, Thigpen MC, Nesheim SR, MD, et al. Interim guidance for clinicians considering the use of pre-exposure prophylaxis for the prevention of HIV infection in heterosexually-active adults. MMWR 2012; 61:586-9.
3. Van Damme L, Corneli A, Ahmet K, et al. Pre-exposure prophylaxis for HIV infection among African women. New Eng J Med 2012; 367:411-22.
4. Marrazzo J, Ramjee G, Nair G et al. Pre-exposure prophylaxis for HIV in women: Daily oral tenofovir, oral tenofovir/emtricitabine, or vaginal tenofovir gel in the VOICE study (MTN 003). 20th Conference on Retroviruses and Opportunistic Infections 2013, Atlanta, GA, US. Available at: http://www.retroconference.org/2013b/Abstracts/47951.htm. Accessed on 6 May 2013.
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8. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med 2009; 361:2209-20.
9. Buchbinder SP, Mehrotra DV, Duerr A, et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 2008; 372:1881-93.
10. Duerr A, Huang Y, Buchbinder SP, et al. Extended follow-up confirms early vaccine-enhanced risk of HIV acquisition and demonstrates waning effect over time among participants in a randomized trial of recombinant adenovirus HIV vaccine (Step Study). J Infect Dis 2012; 206:258-66.
11. National Institute of Allergy and Infectious Diseases (NIAID). Press release: NIH discontinues immunizations in HIV vaccine study. Available at: http://www.niaid.nih.gov/news/newsreleases/2013/Pages/HVTN505April2013.aspx. Accessed at 6 May 2013.
12. Tenbusch M, Ignatius R, Temchura V, et al. Risk of immunodeficiency virus infection may increase with vaccine-induced immune response. J Virol 2012; 86:10533-9.
13. Walker LM, Huber M, Doores KJ, et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 2011; 477:466-70.
14. Katlama C, Deeks SG, Autran B, et al. Barriers to a cure for HIV: new ways to target and eradicate HIV-1 reservoirs. Lancet 2013; Mar 28 epub ahead of print.