Background: Standard doses of herpes simplex virus (HSV) suppressive therapy reduce plasma HIV-1 RNA levels (0.25–0.53 log10 copies per milliliter) among HIV-1/HSV-2 coinfected persons. Postulated mechanisms for this effect include direct inhibition of HIV-1 by acyclovir or indirect reduction by decreasing HSV-associated inflammation. We hypothesized that high-dose valacyclovir would further reduce plasma HIV-1 RNA and that the effect would be mediated by greater suppression of HSV shedding.
Methods: Thirty-four participants with HIV-1 and HSV-2 not on antiretroviral therapy were enrolled into a randomized, open-label crossover trial of valacyclovir 1000 mg twice daily or acyclovir 400 mg twice daily for 12 weeks, followed by a 2-week washout, and then the alternate treatment arm for 12 weeks. HSV DNA was measured from daily self-collected genital swabs for the initial 4 weeks of each arm, and HIV-1 RNA was quantified from weekly plasma samples.
Results: Twenty-eight participants provided plasma samples and genital swabs on both acyclovir and valacyclovir. The genital HSV-2 shedding rate was the same on valacyclovir and acyclovir [7.8% vs. 8.2% of days; relative risk: 0.95; 95% confidence interval (CI): 0.66 to 1.37; P = 0.78]. Plasma HIV-1 RNA was 0.27 log10 copies per milliliter lower on valacyclovir compared with acyclovir (95% CI: −0.41 to −0.14 log10 copies per milliliter; P < 0.001); this was unchanged after adjustment for genital HSV-2 shedding.
Conclusions: High-dose valacyclovir reduces plasma HIV-1 RNA levels more than standard-dose acyclovir in HIV-1/HSV-2–seropositive persons not receiving antiretroviral therapy. The incremental reduction in plasma HIV-1 RNA achieved is not mediated by greater genital HSV-2 suppression.