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Antiretroviral Therapy for the Prevention of HIV-1 Transmission
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Myron S. Cohen, M.D., Ying Q. Chen, Ph.D., Marybeth McCauley, M.P.H., Theresa Gamble, Ph.D., Mina C. Hosseinipour, M.D., Nagalingeswaran Kumarasamy, M.B., B.S., James G. Hakim, M.D., Johnstone Kumwenda, F.R.C.P., Beatriz Grinsztejn, M.D., Jose H.S. Pilotto, M.D., Sheela V. Godbole, M.D., Suwat Chariyalertsak, M.D., Breno R. Santos, M.D., Kenneth H. Mayer, M.D., Irving F. Hoffman, P.A., Susan H. Eshleman, M.D., Ph.D., Estelle Piwowar-Manning, M.T., Leslie Cottle, B.S., Xinyi C. Zhang, Ph.D., Joseph Makhema, M.B., B.Ch., Lisa A. Mills, M.D., Ravindre Panchia, M.B., B.Ch., Sharlaa Faesen, M.B., B.Ch., Joseph Eron, M.D., Joel Gallant, M.D., Diane Havlir, M.D., Susan Swindells, M.B., B.S., Vanessa Elharrar, M.D., David Burns, M.D., Taha E. Taha, M.B., B.S., Karin Nielsen-Saines, M.D., David D. Celentano, Sc.D., Max Essex, D.V.M., Sarah E. Hudelson, B.S., Andrew D. Redd, Ph.D., and Thomas R. Fleming, Ph.D., for the HPTN 052 Study Team*
N Engl J Med Sept 1 2016
An interim analysis of data from the HIV Prevention Trials Network (HPTN) 052 trial showed that antiretroviral therapy (ART) prevented more than 96% of genetically linked infections caused by human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. ART was then offered to all patients with HIV-1 infection (index participants). The study included more than 5 years of follow-up to assess the durability of such therapy for the prevention of HIV-1 transmission.
We randomly assigned 1763 index participants to receive either early or delayed ART. In the early-ART group, 886 participants started therapy at enrollment (CD4+ count, 350 to 550 cells per cubic millimeter). In the delayed-ART group, 877 participants started therapy after two consecutive CD4+ counts fell below 250 cells per cubic millimeter or if an illness indicative of the acquired immunodeficiency syndrome (i.e., an AIDS-defining illness) developed. The primary study end point was the diagnosis of genetically linked HIV-1 infection in the previously HIV-1–negative partner in an intention-to-treat analysis.
Index participants were followed for 10,031 person-years; partners were followed for 8509 person-years. Among partners, 78 HIV-1 infections were observed during the trial (annual incidence, 0.9%; 95% confidence interval [CI], 0.7 to 1.1). Viral-linkage status was determined for 72 (92%) of the partner infections. Of these infections, 46 were linked (3 in the early-ART group and 43 in the delayed-ART group; incidence, 0.5%; 95% CI, 0.4 to 0.7) and 26 were unlinked (14 in the early-ART group and 12 in the delayed-ART group; incidence, 0.3%; 95% CI, 0.2 to 0.4). Early ART was associated with a 93% lower risk of linked partner infection than was delayed ART (hazard ratio, 0.07; 95% CI, 0.02 to 0.22). No linked infections were observed when HIV-1 infection was stably suppressed by ART in the index participant.
The early initiation of ART led to a sustained decrease in genetically linked HIV-1 infections in sexual partners. (Funded by the National Institute of Allergy and Infectious Diseases; HPTN 052 ClinicalTrials.gov number, NCT00074581.)
Advances in the treatment and care of patients with human immunodeficiency virus type 1 (HIV-1) infection have led to dramatic reductions in the morbidity and mortality associated with this disease.1 However, despite intensive public health initiatives aimed at HIV-1 prevention, more than 2 million new HIV-1 infections were reported in 2014 worldwide.2
The global HIV-1 epidemic is primarily driven by sexual transmission.2 Potent, durable HIV-1 prevention strategies are required to reduce the risk of viral transmission from infected persons to their sexual partners. Observational studies involving serodiscordant couples have suggested that antiretroviral therapy (ART) in persons with HIV-1 infection reduces the risk of sexual transmission of the virus.3,4 The multinational, randomized, controlled HIV Prevention Trials Network (HPTN) 052 trial was designed to determine the effect of ART on the transmission of HIV-1 from infected persons to their sexual partners.5-7
The HPTN 052 trial enrolled 1763 serodiscordant couples at 13 sites in nine countries. Index participants (i.e., those with HIV-1 infection) had CD4+ counts of 350 to 550 cells per cubic millimeter. Couples were randomly assigned to two study groups. In the early-ART group, index participants initiated ART at the time of enrollment. In the delayed-ART group, index participants initiated ART when two consecutive CD4+ counts fell below 250 cells per cubic millimeter or they had an illness indicative of the acquired immunodeficiency syndrome (i.e., an AIDS-defining illness).
In an interim analysis of study data that was performed in May 2011 after a median follow-up of 1.7 years, investigators found that early ART was associated with a 96% lower risk of index-to-partner, genetically linked HIV-1 infections than was delayed ART.5 The interim analysis also showed that early ART provided health benefits to the index participants.8 The data and safety monitoring board requested immediate release of those results. Accordingly, after May 2011, all index participants who were not already receiving ART were offered ART, regardless of the CD4+ count.6The trial continued as prespecified through May 2015 to assess the durability of the effect of ART on HIV-1 transmission. This report presents the final results of the HPTN 052 trial.
Over the course of our study involving HIV-1 serodiscordant couples, there was a 93% lower risk of genetically linked HIV-1 infection among partners in the early-ART group than in the delayed-ART group in the intention-to-treat analysis. Between May 2011 and May 2015, there were only two cases of linked HIV-1 infection per 2573 person-years of follow-up. After May 2011, couples in the delayed-ART group also derived a benefit from the evolving initiation of ART. However, even during the latter part of the study, the risk of linked HIV-1 infection among partners remained higher in the delayed-ART group than in the early-ART group (Table 1 and Figure 2, and Table S2 in the Supplementary Appendix).
Over the course of the study, eight genetically linked partner infections were observed after the index participant had initiated ART (three in the early-ART group and five in the delayed-ART group). In all eight cases, the data indicated that the index participant was most likely viremic at the time of HIV-1 transmission, although it was not possible to measure the viral load at the time of the transmission event. The relationship between viremia and HIV transmission that we observed in this study emphasizes the importance of counseling with respect to the potential for HIV-1 transmission before viral suppression is achieved, of close monitoring of the viral load during treatment, and of responding quickly in cases of ART failure.11 Previous studies have reported the transmission of HIV-1 by only one participant in whom the infection was stably suppressed during receipt of ART.12,13 However, we did not document any such transmission events in this study. After the release of the interim study results, 17% of the index participants in the delayed-ART group initially chose not to start ART, even though they were informed of the personal and public health benefits of such therapy (Fig. S3 in the Supplementary Appendix). This finding probably reflects the relative good health of the participants with HIV-1 infection and the former recommendations of worldwide guidelines that ART was not required for the treatment of infection until there was a decrease in the CD4+ count or a deterioration in health.14,15 We hope that the newly emphasized importance of early initiation of ART16-18 will encourage patients with HIV-1 infection to start such therapy without delay.
Unlinked partner infections (i.e., cases in which the partner was most likely infected by someone other than the enrolled index participant) were observed in the two study groups and represented approximately 30% of partner infections throughout the study; a similar frequency of unlinked infections was reported in another study involving serodiscordant couples.19 We observed one unlinked partner infection for every 300 person-years of follow-up. The prevention of unlinked HIV-1 infections will require the use of combination prevention strategies that target the broader community.20 Data on the frequency of linked and unlinked partner infections may be helpful for advising HIV-1 serodiscordant couples21,22 and clarifying the assumptions that are used in mathematical modeling and cost-effectiveness exercises.23
As expected, index participants who had increased viral loads at baseline were significantly more likely to transmit HIV-1 to their sexual partners.24In contrast, self-reported condom use by either partner was associated with a reduced risk of HIV-1 acquisition. An increased baseline CD4+ count among index participants in the delayed-ART group was associated with a greater probability of linked partner infections, which may reflect a longer delay in the initiation of ART and thus more opportunity for HIV-1 transmission.
Previous observational studies involving participants with HIV-1 infection have shown lower rates of viral transmission both among heterosexual couples3,4 and among men who have sex with men25 when the infected person was receiving ART. The final results of the HPTN 052 trial are consistent with those findings and support the importance of viral suppression for HIV-1 prevention. Recent reports have shown that very early initiation of ART can preserve immune function and reduce complications of HIV-1 infection.16-18 In our study, the early initiation of ART also provided health benefits to the participants receiving treatment.8
In 2015, the World Health Organization revised its guidelines to include recommendations for universal HIV-1 testing and the provision of ART to all persons with HIV-1 infection, regardless of CD4+ count.21 Clinical trials are now evaluating the extent to which the provision of early therapy can reduce the population-level incidence of HIV-1 infection.26-28 The most effective implementation of ART for HIV-1 prevention on a population level will require intensive HIV-1 testing programs and reliable and sustained programs for immediate and universal access to HIV-1 therapy.29
In conclusion, the final results of the HPTN 052 study show that successful treatment of HIV-1 is a highly effective tool for the prevention of sexual transmission of the virus. These findings support the results of observational studies and controlled clinical trials showing the personal and public health benefits of the earliest possible initiation of HIV-1 treatment.

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