Adherence in HIV Type 1 Prevention Trials

Herpes simplex virus type 2 (HSV-2), the principal cause of genital herpes, infects the majority of human immunodeficien-cy virus type 1 (HIV-1)–infected persons worldwide [1]. HIV-1 is shed at high titers in genital ulcers caused by HSV-2 [2], and genital ulcer disease (GUD) increases the risk of HIV-1 transmission [3]. Asymp-tomatic HSV-2 reactivation (ie, viral shedding in the absence of genital lesions) occurs commonly in persons with HIV-1 infection [4], and symptomatic and asymptomatic HSV-2 reactivations have been associated with increased HIV-1 concentrations in plasma and genital secretions [5]. Together, these results suggest that HSV-2 reactivation, both with and without GUD, heightens the infectious-ness of individuals with HSV-2 and HIV-1 dual infection. Acyclovir and its prodrug valacyclovir are routinely and safely used as episodic and daily suppressive treatment against symptomatic GUD due to HSV-2, and suppressive therapy also substantially decreases asymptomatic genital HSV-2 shedding [6]. Five short-term, randomized trials among persons with HIV-1 and HSV-2 dual infection who were not receiving an-tiretroviral therapy found that daily HSV-2 suppressive therapy for 8–12 weeks with acyclovir or valacyclovir reduced plasma HIV-1 levels by 0.25–0.5 log 10 copies/mL and also reduced HIV-1 concentrations in endocervical, rectal, and semen samples [7–12]. These proof-of-concept studies suggest that HSV-2 suppressive therapy could be a long-term intervention to reduce HIV-1 transmission risk. In this issue of the Journal, Tanton et al [13] report the results of a long-term randomized trial of acyclovir suppressive therapy among women from Tanzania with dual HSV-2 and HIV-1 infection. The trial was a considerable undertaking. Nearly 500 women were randomized to daily acyclovir or placebo, seen quarterly, and followed-up for up to 24 months. In contrast with the results of the previous short-term studies, acyclovir did not significantly reduce plasma and genital HIV-1 levels when measured at 6, 12, and 24 months after initiation of suppressive therapy. These results are surprising and disappointing, given the consistency of the previous observational and placebo-controlled interventional studies that have demonstrated a strong relationship between HSV-2 reactivation and systemic and genital HIV-1 levels, and they suggest that acyclovir HSV-2 suppression is unlikely to be an effective long-term strategy to reduce HIV-1 infectiousness. Several possible factors may explain the failure of acyclovir to reduce systemic and genital HIV-1 levels in the trial reported by Tan-ton et al [13], including the dosage of HSV-2 suppressive therapy, the development of viral resistance, and suboptimal study drug adherence. An HSV-2 …