Ouedraogo A, Nagot N, Vergne L, Konate I, Weiss HA, Defer MC, Foulongne V, Sanon A, Andonaba JB, Segondy M, Mayaud P, Van de Perre P. Impact of Suppressive Herpes Therapy on Genital HIV-1 RNA among Women Taking Antiretroviral Therapy: A Randomized Controlled Trial. AIDS. 2006 Nov 28;20(18):2305-13.
To demonstrate a causal relationship between herpes simplex virus 2 (HSV-2) and increased genital HIV-1-RNA shedding in women on highly active antiretroviral therapy (HAART).
This was a double-blind randomized controlled trial of valacyclovir (500mg twice a day) in HIV-1 and HSV-2 co-infected women taking HAART in Burkina Faso.
The study took place in Bobo-Dioulasso, Burkina Faso, between August 2004 and January 2005.
Study participants were recruited from the Yerelon cohort of high-risk women, from local organizations of individuals living with HIV, and from the University Hospital in Bobo-Dioulasso. Women aged 16 or older who had serum antibodies to HSV-2 and HIV-1 and were taking HAART for a minimum of four months were eligible for the trial.
The intervention consisted of 500mg of valacyclovir suppressive therapy twice a day for three months.
The primary outcomes included the following: proportion of women with genital HIV-1 RNA detected at least once during the treatment phase, the frequency of HIV-1 shedding during the treatment phase, and the mean quantity of HIV-1 RNA measured at visits during which genital HIV-1 RNA was detected. Other outcomes included plasma HIV-1 RNA levels, proportion of women shedding HSV-2 DNA at least once, clinical ulcer episodes, and plasma and genital HIV-1 RNA levels among baseline genital HIV-1 RNA shedders.
Of the 82 women screened for eligibility, 60 were enrolled in the trial and randomly assigned to the valacyclovir group (n=30) or the placebo group. No women were lost to follow-up, but two women were withdrawn from the study because of pregnancy and censored in the analysis. The mean age of participants was 33 years, and the mean time since HAART initiation was 19 weeks. All women had a mean HAART adherence rate above 90%. Thirty women (50%) had genital tract HSV-2 RNA detectable at baseline. There was no impact of valacyclovir on the proportion of women with genital HIV-1 RNA detected at least once (RR: 1.1, CI: 0.6-2.1), on the frequency of HIV shedding (OR: 0.9, CI: 0.3-2.6), nor on the quantity of HIV-1 RNA detected at visits during which shedding was occurring (p=0.19). The treatment did not significantly reduce the number of women with detectable plasma HIV-1 RNA (RR; 0.6, CI: 0.2-1.5) or the frequency of detectable plasma HIV-1 RNA (OR: 0.2, CI: 0.04-1.21). Valacyclovir did reduce the proportion of women shedding HSV-2 DNA at least once, although not significantly (RR: 0.7, CI: 0.3-1.3); however, on repeated measures analysis, the impact was closer to significant (OR: 0.4, CI: 0.1-1.1), and the effect of treatment on reducing the quantity of HSV-2 DNA also approached significance (p=0.12). Very few women experienced clinical ulcers, so no analysis was done due to low power. Among the predefined group of women with detectable genital HIV-1 RNA at least once during baseline, there was a significant impact of treatment on the proportion of visits with detectable HIV-1 shedding (OR: 0.2, p=0.05), and on the quantity of genital HIV-1 RNA shedding (p=0.01), an effect that increased over time with an average reduction in mean genital HIV-1 RNA of 0.1 log10 copies/µl every two weeks during treatment (p=0.1).
The authors conclude that HSV-2 facilitates residual genital HIV-1 replication among dually infected women taking HAART, perhaps partly explaining the high proportion of women having intermittent genital HIV-1 shedding despite suppression at the systemic level. Overall, valacyclovir had no significant impact on either the frequency or quantity of genital HIV-1 RNA shedding.
Using the Jadad criteria, this study received a quality rating of 5. One point was received for describing the randomization, one for adequate randomization, one for double-blinding, one for appropriate blinding, and one for description of loss to follow-up. The main limitation noted by the authors was the low power of the study.
The efficacy of valacyclovir on HSV-2 DNA had not been reported previously, however one study using HSV-2 culture showed that the related drug famciclovir could reduce the frequency of HSV-2 shedding from 11% to 1% of days.(1) While this study was unable to assess the impact of treatment on clinical ulcer formation, a randomized study in the US among HIV-infected persons, 93% of whom were taking HAART, found that valacyclovir prophylaxis could significantly increase the time to clinical ulcer episodes.(2)
The results of this study suggest that valacyclovir can reduce genital HSV-2 shedding even in women on HAART with detectable HSV-2 genital tract infection. However, given the expense of valacyclovir and the finding that the benefit of valacyclovir was limited to a subset of women with detectable HSV-2 shedding at baseline (as opposed to those who were sero-positive for HSV-2), this intervention requires further evaluation in larger trials (some of which are ongoing) before establishing HSV-2 suppression as a standard of care for HIV and HSV-2 co-infected women in resource-constrained settings. The effects of suppression are likely two-fold and could include both decrease in symptomatic HSV-2 as an opportunistic infection, and decreased genital tract shedding of HIV, which is associated with active HSV-2 infection.
- Schacker T, Hu HL, Koelle DM, et al. Famciclovir for the suppression of symptomatic and asymptomatic herpes simplex virus. reactivation in HIV-infected persons. A double-blind, placebo-controlled trial. Ann Intern Med 1998 Jan 1;128(1):21-8.
- DeJesus E, Wald A, Warren T, et al. Valacyclovir for the suppression of recurrent genital herpes in human immunodeficiency virus-infected subjects. J Infect Dis 2003 Oct 1;188(7):1009-16. Epub 2003 Sep 10. Erratum in: J Infect Dis 2003 Nov 1;188(9):1404.