Elsevier

The Lancet

Volume 382, Issue 9903, 2–8 November 2013, Pages 1515-1524
The Lancet

Review
Antiretroviral treatment of HIV-1 prevents transmission of HIV-1: where do we go from here?

https://doi.org/10.1016/S0140-6736(13)61998-4Get rights and content

Summary

Antiretroviral drugs that inhibit viral replication were expected to reduce transmission of HIV by lowering the concentration of HIV in the genital tract. In 11 of 13 observational studies, antiretroviral therapy (ART) provided to an HIV-infected index case led to greatly reduced transmission of HIV to a sexual partner. In the HPTN 052 randomised controlled trial, ART used in combination with condoms and counselling reduced HIV transmission by 96·4%. Evidence is growing that wider, earlier initiation of ART could reduce population-level incidence of HIV. However, the full benefits of this strategy will probably need universal access to very early ART and excellent adherence to treatment. Challenges to this approach are substantial. First, not all HIV-infected individuals can be located, especially people with acute and early infection who are most contagious. Second, the ability of ART to prevent HIV transmission in men who have sex with men (MSM) and people who use intravenous drugs has not been shown. Indeed, the stable or increased incidence of HIV in MSM in some communities where widespread use of ART has been established emphasises the concern that not enough is known about treatment as prevention for this crucial population. Third, although US guidelines call for immediate use of ART, such guidelines have not been embraced worldwide. Some experts do not believe that immediate or early ART is justified by present evidence, or that health-care infrastructure for this approach is sufficient. These concerns are very difficult to resolve. Ongoing community-based prospective trials of early ART are likely to help to establish the population-level benefit of ART, and—if successful—to galvanise treatment as prevention.

Introduction

Development of many antiretroviral drugs has made HIV infection a treatable chronic disease.1 Initiation of antiretroviral therapy (ART) soon after infection offers near normal quality of life and lifespan.2 Early ART is also associated with a reduced latent viral reservoir,3 reduced viral DNA,4 and normalisation of some immune markers.5

Yet HIV prevention has been a constant struggle. Although the estimated incidence of HIV decreased by 50% in 25 countries between 2001 and 2011, 2·5 million people still became newly infected in 2011.6 Furthermore, encouraging reductions in the global incidence of HIV cannot be fully explained or ascribed to one intervention.

Figure 1 shows several strategies for HIV prevention. However, in the absence of a vaccine (which will probably be the case for the foreseeable future7), combinations of intervention strategies must be used.8, 9 The combination prevention approach was put forward in the US Government's new national HIV/AIDS strategy,10 and in the global President's Emergency Plan for AIDS Relief (PEPFAR).11

Key messages

  • •

    Treatment of an HIV-infected person will greatly reduce the probability of an HIV transmission event

  • •

    Treatment as prevention requires careful attention to the best drug combinations for clinical and public health benefit

  • •

    For treatment to affect the epidemic, improved detection of infection at all stages, universal access to antiretroviral therapy (ART), and excellent adherence are essential

  • •

    Treatment as prevention demands a robust health-care infrastructure

  • •

    Ongoing community-based randomised controlled trials of early ART are measuring population-level benefit of treatment as prevention

Perhaps no part of combination HIV prevention has attracted more attention than the use of antiretroviral drugs. There are three ways in which these drugs can be deployed: as postexposure prophylaxis, as pre-exposure prophylaxis, and to reduce infectiousness of HIV-infected people to their sexual partners (treatment as prevention). First, suspected exposure to HIV can be followed by postexposure prophylaxis with antiretroviral drugs.12, 13, 14 This approach has been accepted as standard policy for both occupational exposure in health-care workers (eg, a needlestick injury)12, 13 and non-occupational exposure (eg, an unprotected sexual encounter).14 Recommendations for postexposure prophylaxis are based on findings from experiments with macaques and an observational study in people who have been exposed to needlesticks.15, 16 Second, gel-formulated and oral-based ART have been used successfully as pre-exposure prophylaxis for people at high risk for HIV infection. The combination of emtricitabine and tenofovir disoproxil fumarate (Truvada; Gilead Sciences, Foster City, CA, USA) has been approved by the US Food and Drug Administration as pre-exposure prophylaxis for particular high-risk groups. However, pre-exposure prophylaxis did not provide protection in all clinical trials, most likely because of poor adherence to study drugs.17, 18, 19 In this Review, we provide a comprehensive, timely, and critical assessment of the third use of ART, as treatment as prevention.

Section snippets

The HIV transmission event

The biology of HIV transmission has been best characterised in the rhesus macaque. Shortly after mucosal exposure, several foci of nascent HIV replication can be seen.20, 21, 22 Yet both in macaques exposed to a physiological dose of simian HIV23, 24, 25 and in people with acute infection25, 26 a very small number of HIV variants (founder viruses) cause infection. These viruses use both CD4 and CCR5 receptors,25, 27 and differ from other variants in envelope properties such as glycosylation and

Antiretroviral drugs and the genital tract

ART can be expected to reduce HIV transmission by reducing the concentration of virus in the blood and genital secretions of the person with HIV infection. Several groups have shown the ability of ART to penetrate the male and female genital tract39, 40 and the ability of these drugs to suppress viral replication in the genital tract. Most (but not all) antiretroviral drugs can be expected to achieve similar or higher concentrations in the genital tract as in blood (figure 2). An important

Preventive use of ART

Findings from ecological studies, observational cohort studies, and one randomised control trial have shown the ability of ART to prevent sexual HIV transmission. Investigators of ecological studies have analysed changes in regional spread of HIV relative to use of ART to assess whether a policy of treatment as prevention (eg, frequent widespread testing coupled with ART initiation at diagnosis48, 49) has slowed population-level HIV transmission. These studies take advantage of natural

Serodiscordant couples

Findings from observational studies of serodiscordant, sexually engaged couples have informed individual-level investigations into the protective effects of ART. By comparing the experiences of serodiscordant couples in which infected partners were either receiving or not receiving ART, results of these studies strengthened the hypothesis that ART could reduce the risk of HIV transmission.56 On the basis of these results, in 2008, Swiss experts recommended that suppressive ART, when properly

Moving from evidence to application

Translation of research findings into public health practice represents an exciting prospect but with many challenges. Efficacy shown in a randomised controlled trial might not lead to an effective intervention in the general population. Accordingly, the population-level benefits of treatment as prevention remain unproven. Although treatment of discordant couples is now standard, the effects of this approach on the overall epidemic are debated for several reasons.69, 70

For example, the

Modelling of the effect of ART on pandemics

Early modelling work of the effects of ART to reduce transmission led to very conservative estimates of benefit.86 However, newer model analyses suggest that the costs and attendant risk of expanding ART programmes will be justified by their benefits, especially in the long term.87

There are three possible ART expansion routes.88 The first is a low-cost, low-impact strategy of expanding treatment eligibility for those who are already attending clinic. A medium-cost, medium-impact strategy would

Implementation challenges

The movement towards treatment as prevention has unmasked a massive gap in the strategy—namely, the difficulty to find and treat people at greatest risk for transmission, who may be hardest to reach. This limitation has both scientific and social underpinnings. Scientifically, routine HIV testing will not identify people with acute infection. In view of the potential importance of such people to the spread of HIV,31, 94, 95 we need to set an even higher scientific priority on finding means to

Conclusion

ART, as a key component of combination prevention, has galvanised the call for an AIDS-free generation.11 In this Review we have provided the rationale for the development of treatment as prevention, described population-level evidence suggesting a chance for success with this approach, and outlined four community randomised trials designed to measure the population-level benefit from earlier or immediate ART. We have also stressed the many limitations and challenges of implementation of

Search strategy and selection criteria

We searched PubMed and PsycInfo databases from Jan 1, 1990, to Aug 31, 2013, with the terms: (“HIV” OR “AIDS”) AND (“antiretroviral” OR “ART” OR “ARV”) AND (“treatment as prevention” OR “TasP” OR “prevent transmission”); and (“HIV” OR “AIDS”) AND (“treatment” OR “antiretroviral” OR “ART” OR “ARV”) AND (“discordant” OR “serodiscordant”) AND (“couples” OR “partners” OR “relationships”). We used no other inclusion or exclusion criteria.

Contributors

MSC conceived of the primary idea and led the

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