Treating herpes simplex virus-2 (HSV-2) with valaciclovir reduces genital shedding of HIV in women, according to the results of a proof-of-concept study presented to the Thirteenth Conference on Retroviruses and Opportunistic Infections in Denver on Monday. This is the first randomised controlled trial to demonstrate a causal relationship between HSV-2 and HIV replication.
Over the past few years, evidence has been accumulating that suggests a strong causal relationship between infection with herpes simplex virus-2 (HSV-2) and both HIV transmission and infection.
However, since this causal relationship has never been proven, researchers from France and the United Kingdom collaborated with the Centre Muraz in Bobo-Dioulasso - Burkina Faso's second largest city - on a double-blinded randomised controlled trial evaluating the effect of the anti-herpes drug, valaciclovir (Valtrex), on the genital shedding of HIV. Valaciclovir, a pro-drug of aciclovir that can be taken once daily, is also known by the generic name netivudine.
A total of 195 HIV-positive women with HSV-2 infection were screened for the study and those women who required anti-HIV therapy, those already taking anti-HSV-2 therapy and those with contraindications to valaciclovir were excluded. Any screened woman eligible for anti-HIV therapy according to World Health Organization (WHO) criteria was offered anti-HIV therapy and four months later entered a companion study, ANRS 1285b. This is examining the impact of the combination of valaciclovir and anti-HIV therapy on HIV transmission, and will report at a later date.
The remaining 150 HIV-positive women with HSV-2 infection who did not require anti-HIV therapy were enrolled in the baseline phase of the study, which consisted of six bi-weekly study visits over twelve weeks during which a cervicovaginal lavage enriched by cervical swabbing was collected in order to quantify HSV-2 DNA and HIV RNA by real time PCR.
Eligibility criteria were then rechecked and a total of 140 women were randomised to the treatment phase, with 70 women receiving oral valaciclovir (1g/day for three months) and 70 women receiving placebo. Another six bi-weekly study visits over twelve weeks collected HSV-2 DNA and HIV RNA data via cervicovaginal lavage enriched by cervical swabbing.
At randomisation, the mean CD4 cell count in the treated and placebo arms of the study was 519 cells and 482 cells/mm3, respectively. Overall, 93% of expected visits were attended, with a mean treatment compliance of 97% in both arms. The investigators found a "very low prevalence" of other sexually transmitted infections in both arms, according to Dr Nicolas Nagot from the London School of Hygiene and Tropical Medicine, presenting. In total, eleven women were censored during the treatment phase of the study, "primarily due to pregnancy", he reported. Consequently, statistical analyses were based on a modified intention-to-treat approach.
The investigators found that genital shedding of HIV was significantly less in the valaciclovir group (HIV RNA decreased from a mean of 2.41 log copies/ml during the baseline phase to a mean of 2.15 log copies/ml during the treatment phase) than in the placebo group (where HIV RNA slightly increased by 0.09 log copies/ml; p = 0.003). The difference in the reduction of mean HIV RNA in plasma levels between the two arms was found to be even greater: -0.39 log copies/ml vs. +0.12 log copies/ml, respectively (p
The investigators also assessed the impact of valaciclovir on the frequency and pattern of HIV shedding during the study. HIV shedding was found to be significantly less persistent in the valaciclovir group (14% vs. 27% of women shed HIV at each visit; 27% vs. 44% shed at ≥50% of visits; 33% vs. 14% shed at
As expected, valaciclovir had a significant impact on HSV-2 shedding and HSV-2 DNA levels. The proportion of women shedding HSV-2 at least once was 18.6% in the valaciclovir arm compared with 54.3% in the placebo arm (p
Dr Nagot hypothesised that the reduction seen in genital HIV RNA in the study "is probably linked to the parallel decrease in the systemic compartment", although the valaciclovir may also have had an impact at a genital level. He said that more data regarding the mechanism of valaciclovir on HIV shedding at a genital level will come from the companion study.
He concluded that although this proof-of-concept study had no direct public health implications, the investigators "believe that our results can provide a good rationale for potential interventions. A sustained HSV-2 strategy could at the same time decrease HIV genital transmissibility," he argued, adding that treating HSV-2 could also have individual benefits "probably on [HIV] viral load and perhaps on immunity as well."
In response to questions from the audience, Dr Nagot conceded that the impact on HIV transmission of the small but significant reductions in HIV genital shedding seen in this study is unknown at this time. He added that trials are ongoing that will examine the impact of anti-HSV-2 therapy on HIV transmission, and that "we may have answers later."
Nagot N et al. Effect of HSV-2 Suppressive Therapy on HIV-1 Genital Shedding and Plasma Viral Load: A Proof of Concept Randomized Double-Blind Placebo Controlled Trial (ANRS 1285 Trial) Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, abstract 33LB, 2006.