Delany S, Mlaba N, Clayton T, et al. Impact of aciclovir on genital and plasma HIV-1 RNA in HSV-2/HIV-1 co-infected women: a randomized placebo-controlled trial in South Africa. AIDS 2009;23(4):461-9.
Previous studies have suggested a synergistic relation between HIV and HSV-2. Co-infected persons experience more frequent reactivation of HSV-2 than persons not infected with HIV, and HSV-2 appears to increase the transmission of HIV as well as disease progression.(1,2) Studies demonstrate that treatment with valacyclovir, a HSV-2 suppression drug used less commonly than acyclovir, reduces plasma, genital, and rectal HIV RNA.(3,4)
To measure the effect of oral acyclovir, 400 mg twice daily for 3 months on genital and plasma HIV RNA, CD4 count, and genital HSV-2 DNA among HIV/HSV-2-seropositive women who were not receiving antiretroviral therapy
Johannesburg, South Africa
Randomized, double-blind, placebo-controlled trial
Women aged 18 years or older, HIV-1 and HSV-2 seropositive, asymptomatic for HIV (according to WHO criteria), CD4 count ≥ 250 cells/µL; negative urine pregnancy test, not breastfeeding, without contraindications to using acyclovir, and not eligible for or taking HSV-2 suppressive therapy
Genital and plasma HIV RNA, CD4 count, and genital HSV-2 DNA at study visits and with any occurrence of genital ulcer disease
Women were recruited from community or support groups for HIV-infected persons. Interested women were tested for genital shedding of HIV and HSV-2 at two baseline visits that were separated by 1 week. Baseline demographic, medical, and behavioral data were collected through interviewer-administered questionnaires. Baseline physical and pelvic
examinations were performed and genital and blood specimens were collected.
Participants were randomized 1:1 to acyclovir 400 mg twice daily or matching placebo identical to acyclovir using random permuted blocks of varying size. Study drugs were prepackaged and sequentially numbered by the drug company according to a randomization list prepared by an independent statistician. Treatment packs were assigned consecutively. Both the investigators and participants were unaware of study group assignments. Adherence counseling included instructions in the use of the study drug and storage and handling of missed doses.
At each of the three monthly follow-up visits, the women returned their drug packs for pill counts, were provided with a new supply of medication, had blood and genital specimens collected, and were tested for pregnancy. A study exit visit was conducted 7 days after the third follow-up visit. The study drug was discontinued after the exit visit.
All participants received pre- and post-test, and risk-reduction counseling, condoms, syndromic treatment of sexually transmitted infections (STIs), and referrals to HIV treatment centers. Genital ulcer diseases were treated presumptively with acyclovir 1200 mg daily for 5 days.
The study was conducted between April 2005 and April 2006. A total of 583 women were screened as eligible for participation and 300 were randomized to acyclovir (n=152) or placebo (n=148). Data from 269 (90%, 132 acyclovir and 137 placebo) women were available for analysis of the primary outcome after the third follow-up visit. There were 288 women who provided data for analysis of summary and repeat measures (146 acyclovir and 142 placebo). Five hundred forty-one of the 604 (90%) planned follow-up visits among the acyclovir group were completed and 545 of the 592 (92%) of the visits among the placebo group. Adherence at 3 months was 95% in both groups. Seven hospitalizations due to severe bacterial infections unrelated to treatment occurred, including three in the acyclovir group.
The demographic and risk characteristics of the two arms were similar. The mean age was 32 years and median time since HIV diagnosis was 1 year. The proportion of women who were shedding HIV/HSV-2 was similar in the two groups (30% and 28%, respectively).
At the third follow-up visit, 61 (46%) of women in the acyclovir group and 71 (52%) in the placebo group had detectable HIV RNA (RR 0.89, 95% confidence interval [CI]: 0.70-1.14; P=0.36). The quantity of genital HIV RNA was not appreciably different in the groups (mean difference 0.13 log10 copies/mL, 95% CI: -0.14-0.39).
The proportion of women with detectable genital HIV RNA was lower at each follow-up visit and the summary measurement analysis found that acyclovir significantly reduced the frequency of HIV shedding (adjusted odds ratio [OR] 0.57, 95% CI: 0.36-0.89; P=0.013). The mean detectable quantity of HIV was not statistically lower in the acyclovir group (-0.13 log10 copies/mL, 95%CI: -0.28-0.03; P=0.12). In the repeated measures analysis, genital HIV RNA was detected at fewer visits in the acyclovir group among women who were persistent shedders (RR 0.78, 95% CI: 0.67-0.91) than among intermittent shedders (RR 1.02, 95% CI: 0.71-1.46) (interaction P=0.18). The effect of acyclovir did not depend on the presence of both HIV and HSV-2 at baseline (interaction P=0.88).
Plasma HIV RNA was lower in the acyclovir group at the third follow-up visit (mean difference - 0.34 log10 copies/mL, 95% CI: -0.54-0.15; P<0.001). When the exit visits were included, there was a reduction of 0.27 log10 copies/mL (95% CI: -0.13-0.41; P<0.001).
There was no difference in CD4 counts among the acyclovir and placebo groups (mean difference 7 cells/µL, 95% CI: -24-37; P=0.66).
At the third follow-up visit, 10/133 (8%) of women in the acyclovir group had detectable genital HSV DNA compared to 28/137 (20%) of women in the placebo group (RR 0.37; 95% CI: 0.19-0.73; P=0.002). There was no difference in the quantity of genital HSV DNA between the groups (mean difference 0.16 log10 copies/mL, 95% CI: -1.23-1.54; P=0.82). Overall, 33% of the women in the acyclovir group had detectable genital HSV DNA compared to 54% of women in the placebo group (RR 0.61, 95% CI: 0.46-0.80; P<0.001) and women in the acyclovir group had fewer follow-up visits with detectable HSV DNA than did women in the placebo group (OR 0.40, 95% CI: 0.25-0.64; P<0.001). The proportion of women with genital ulcer disease was significantly lower in the acyclovir group (8%) compared to the placebo group (18%, RR 0.43, 95% CI: 0.22-0.84; P=0.01).
The authors conclude that suppressive acyclovir may contribute to reducing sexual transmission of HIV and may delay the requirement for initiation of antiretroviral therapy by reducing HIV plasma viral load and altering the pattern of genital HIV shedding.
This was a high quality trial. Participants were randomized in an acceptable manner, there was proper concealment of allocation, the outcome measures were objective, and there was minimal loss to follow-up. There was, however, no mention of an intention-to-treat analysis.
The authors state that the primary outcome was the detection and quantity of genital HIV RNA at the third follow-up visit. The results indicate that there was no difference between the acyclovir and placebo groups with respect to this outcome. Additionally the authors examined differences in genital and plasma HIV RNA at each of the follow-up visits and found that acyclovir decreased HIV shedding over all of the visits. Plasma HIV RNA was lower in the acyclovir group at the third follow-up visit and over all of the visits. Acyclovir was effective at HSV-2 and genital ulcer suppression. Although there was a reduction in the frequency of detection of HIV over the three follow-up visits, the implications of this finding are unclear, particularly because the mean genital RNA levels did not differ between groups. Although plasma HIV RNA was lower in the acyclovir group, it may not have an impact on sexual transmission of HIV. The results from clinical trials of daily suppressive therapy with acyclovir on HIV transmission did not demonstrate an effect of therapy on reduced HIV transmission.(5,6) Thus, the programmatic implications of this study are that it is biologically plausible that acyclovir reduces HIV transmission but this result cannot be used to conclude causality.
- Corey L, Wald A, Celum CL, Quinn TC. The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: a review of two overlapping epidemics. J Acquir Immune Defic Syndr 2004;35:435-45.
- LeGoff J, Weiss HA, Gresenguet G, et al. Cervicovaginal HIV-1 and herpes simplex virus type 2 shedding during genital ulcer disease episodes. AIDS 2007;21:1569-78.
- Nagot N, Ouedraogo A, Foulongne V, et al. Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus. N Engl J Med 2007;356:790-9.
- Zuckerman RA, Lucchetti A, Whittington WL, et al. Herpes simplex virus (HSV) suppression with valacyclovir reduces rectal and blood plasma HIV-1 levels in HIV-1/HSV-2-seropositive men: a randomized, double-blind, placebo-controlled crossover trial. J Infect Dis 2007;196:1500-8.
- Celum C, Wald A, Hughes J, et al. Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial. Lancet 2008;371:2109-19.
- Watson-Jones D, Weiss HA, Rusizoka M, et al. Effect of herpes simplex suppression on incidence of HIV among women in Tanzania. N Engl J Med 2008;358:1560-71.