Acyclovir for Prevention of HIV Transmission
Abstract & Commentary
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.
Synopsis: In a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir 400 mg BID) in HIV-1 serodiscordant couples, acyclovir did not reduce the risk of transmission of HIV-1 despite a reduction in the levels of HIV-1 RNA.
Source: Celum C, et al. Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2. N Engl J Med. 2010;362:427-439.
In a study of hiv transmission, 3,408 HIV-1 serodis cordant couples were enrolled at 14 sites in Africa. All patients had CD4+ lymphocyte counts ≥ 250/uL, were also infected with HSV-2, and were not receiving antiretroviral therapy (ARVs). Sixty-eight percent of the HIV-1 infected partners were women. There were 132 HIV-1 seroconversions; 84 were linked within couples by sequencing. Of these, 41 occurred in the acyclovir (ACV) group and 43 in the placebo group. ACV treatment reduced the mean plasma concentration of HIV-1 by 0.25 log10 copies/mL and the occurrence of HSV-2 + genital ulcers by 73%. Ninety-two percent of the partners infected with HIV-1, and 84% of the partners not infected with HIV-1, remained in the study for 24 months. ACV adherence was 96%.
The correlation between genital ulcer disease and HIV-1 infection, especially in heterosexual couples, has been appreciated since the mid-1980s. The logical postulation is that by disrupting normal cutaneous and mucosal barriers, genital ulcer disease directly facilitates the transmission of HIV-1. In addition, a large body of research over the last 25 years has demonstrated that many HSV-encoded proteins can directly promote the transcription of HIV-1, as well as nonspecifically enhancing host cytokine levels, which generally facilitate NFkB-mediated up-regulation of HIV-1 transcription. In fact, earlier clinical studies have demonstrated that daily therapy with ACV for 8-12 weeks reduced plasma HIV-1 RNA levels by 0.25-0.50 log10 copies/mL.
This large, randomized, placebo-controlled trial represented a logical hypothesis that anti-HSV nucleoside analogs, such as ACV, could reduce the transmission of HIV-1 in serodiscordant couples by both reducing genital ulcer disease and by modestly lowering plasma (and genital fluid) levels of HIV-1. This approach is attractive for a number of reasons, since the majority of HIV-1 transmission in Africa is heterosexual and the prevalence of ulcerative genital disease (mostly due to HSV-2) is high. Additionally, the cost of ACV has come down considerably since it is now available as a generic drug, and is certainly less expensive than antiretroviral therapy.
Unfortunately, despite high levels of adherence to daily ACV therapy (and demonstrated reduction in genital ulcer disease and modest reduction in HIV-1 RNA levels), this intervention is just not good enough to reduce HIV transmission. Interestingly, the authors point out that the rate of HIV transmission in both the ACV and placebo groups were relatively low compared to historical data. The authors attribute this low transmission rate to the effect of intervention on promoting condom use and safer sex practices within the study.
The take-home message, from my perspective, is that the only way we are going to significantly reduce HIV transmission is by making universal antiretroviral therapy available throughout the world. While the cost of nucleoside and nucleotide analogue reverse transcriptase inhibitors and non-nucleoside RT inhibitors has come down, HIV protease inhibitors will likely remain unaffordable in much of the developing world. This is actually not due to greedy pharmaceutical companies, but rather the hard fact that PIs require multiple synthetic steps and use generally costly precursor chemicals in their synthesis. Unfortunately, with the rising prevalence of NRTI and nnRTI resistance in transmitted virus, I remain skeptical about our chances of successfully eradicating HIV infection in the developing world using NRTI/nnRTI combinations alone, even if the goal of universal antiretroviral therapy is achieved.