Antiretroviral combination therapy markedly reduces risk of heterosexual HIV-1 transmission
- 1Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
- 2Department of Medicine and Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Correspondence to Eric S Rosenberg
Department of Medicine and Pathology, Massachusetts General Hospital, Gray J-504, 55 Fruit Street, Boston, MA 02114, USA;
The reduction of HIV-1 transmission remains one of the highest global health priorities. The use of established antiretroviral drugs for preventing HIV-1 transmission was first considered in 1994, after an observational clinical study showed reduced HIV-1 infection rates in partners of HIV-1 infected persons treated with zidovudine monotherapy.1 In 2007, the HIV Prevention Trials Network (HPTN) initiated a randomised-controlled clinical trial (HPTN 052) in which the effect of antiretroviral combination therapy on heterosexual transmission of HIV-1 was evaluated; the results have recently been reported.
HPTN 052 is a phase III, randomised-controlled clinical trial designed to determine if early initiation of antiretroviral therapy could reduce transmission of HIV-1 in serodiscordant partners, compared with delayed treatment (after a decline in CD4 counts or the onset of HIV symptoms). The principal outcome measures were (i) the rates of new HIV-1 infections in partners of infected subjects, (ii) the frequency of HIV-1 associated comorbidities and deaths in HIV-1 index subjects and (iii) the toxicity of antiretroviral agents. Study participants were monitored for a median follow-up time of 1.7 years.
Thirty-nine partners of HIV-1 subjects were infected with HIV-1 during the study. Four infections occurred in the immediate treatment arm; the remaining 35 new infections were in the delayed treatment arm (p<0.0001). In 28 cases, genetic analysis demonstrated direct viral transmission from the index subject to the respective partners; almost all of these genetically linked transmissions (n=27) were observed in the delayed treatment arm, compared with only one transmission in the immediate treatment arm (96% reduction of HIV-1 transmission, p<0.0001). Seventeen HIV-1 subjects with linked HIV-1 transmission to a sexual partner had relatively normal CD4 cell counts (>350/ul).
This clinical trial provides the first clear evidence that antiretroviral treatment can be used as a highly effective HIV-1 prevention strategy. Indeed, the 96% reduction of HIV-1 transmission reported in this study represents the most successful effort against HIV-1 acquisition achieved by any biomedical intervention in a controlled randomised clinical trial. The results of this study provide proof of principle for a ‘treatment as prevention’ approach. The results are particularly striking when compared with a recent HIV-1 vaccine study,2 where only a 31% reduction of HIV-1 transmissions was reported. Representatives of UNAIDS, the joint United Nations Program on HIV/AIDS, called this study as a ‘serious game-changer’ for HIV-1 prevention strategies.
Interestingly, the majority of transmission events in this study occurred in HIV-1 subjects with CD4 cell counts of >350/ul, and CD4 counts of HIV-1 index subjects were not predictive of viral transmission to a sexual partner. This suggests that the current guidelines for initiation of antiretroviral treatment based on CD4 cell counts may not be appropriate when taking prevention of transmission into account. Therefore, alternative criteria may need to be considered for treatment initiation to maximise prevention efforts. Indeed, this study suggests that universal HIV-1 treatment of all infected subjects, independently of CD4 cell counts, could possibly result into a near-complete suppression of sexual HIV-1 transmission, and gives credibility to recent mathematical models suggesting that such a ‘test and treat’ strategy may lead to conditions under which the HIV-1 epidemic could be driven towards elimination.3
An important limitation of this study is the relatively short observation time (ie, 1.7 years), which makes it uncertain whether a preventive effect of antiretroviral therapy could be sustained for prolonged periods of time, particularly with respect to the development of antiviral resistance. Moreover, it is important to recognise that this study only evaluated HIV-1 transmission in heterosexual serodiscordant couples under conditions of a controlled clinical trial. Whether antiretroviral treatment under real-life circumstances and in the setting of a mix of different transmission modes would result in similar high rates of HIV-1 prevention will need further investigation. Finally, it is evident that widespread use of antiretroviral agents for preventive purposes will represent a logistical, financial and infrastructural challenge, specifically since currently available resources are not sufficient to provide these life-saving drugs to all patients who need them. Despite the success of this study, the quest for safe, effective and logistically and economically feasible strategies for HIV-1 prevention continues.