Utility of episodic acyclovir therapy for HSV-2 in Africa.

Herpes simplex virus type 2 (HSV-2) is a primary cause of genital ulcers in sub-Saharan Africa. In Tanzania, HSV-2 accounted for 83% of all identifiable pathogens in a study of genital ulcer disease (GUD). 1 Recent serological studies in sub-Saharan Africa have further demonstrated that prevalence rates among populations with no specific high-risk sexual behaviors exceed those of similar populations in the United States and Europe.2 In sub-Saharan Africa, up to 70% of high-risk persons who are HIV-1 negative and up to 85% of those who are HIV-1 positive are also seropositive for HSV-2.3 Several clinical trials have demonstrated that daily therapy for HSV-2 can reduce plasma HIV-1 levels by 0.25 to 0.50 log 10 copies per milliliter.4–8 However, 2 randomized trials of acyclovir HSV-2 suppressive therapy failed to demonstrate protection against HIV acquisition in high-risk HIV seronegative populations.9,10 Celum et al10 found a statistically significant reduction in GUD incidence due to HSV-2 among participants who received acyclovir versus placebo in their trial, noting that the lack of efficacy of HSV-2 suppressive therapy in preventing the transmission of HIV-1 did not appear to have been caused by poor activity of acyclovir against HSV-2. To further explore this issue, Baeten et al conducted a randomized trial of episodic acyclovir therapy among 88 HIV-1 seronegative, HSV-2 seropositive African women with recurrent genital herpes, some of whom had participated in the HIV Prevention Trials Network Study 39.10 The authors state that one potential explanation for the findings from Celum et al, which was conducted among 14 sites in Africa, is that African women with HSV-2 may have diminished response to acyclovir therapy. Therefore, they tested this hypothesis by focusing on the study end points of time to complete healing of all genital lesions and time to first negative HSV polymerase chain reaction result. After a course of oral acyclovir at 400 mg 3 times daily for 5 days, Baeten et al found a modestly greater likelihood of lesion healing from a mean of 5.1 day (acyclovir arm) versus 6.0 days (placebo arm), which did not reach statistical significance. They reported a greater likelihood of cessation of HSV shedding from episodic acyclovir, with a statistically significant difference in duration of viral shedding between treated participants with a mean of 3.0 days compared with women on placebo with a mean of 5.0 days. The authors concluded that diminished virologic response to acyclovir among African women did not explain the failure of HSV-2 suppressive therapy to prevent HIV acquisition. Furthermore, they stated that acyclovir has potential when included as part of first-line syndromic management of GUD, as currently recommended by the World Health Organization. In light of the continued focus on antivirals as episodic therapy for recurrent HSV-2, we believe it is time to re-evaluate the benefits and costs of episodic acyclovir in management of chronic HSV-2 infection. Some experts would argue that the benefits from this agent rarely seem to support its utilization, especially among HIV-1 seronegative individuals. We need to consider the effects of episodic acyclovir on several distinct outcomes in chronic genital herpes infection including: (1) symptom resolution in HIV-seronegative and HIV-seropositive persons; (2) HSV-2 sexual transmission among HIV-seronegative and HIV-seropositive persons; and (3) HIV-1 transmission between discordant partners. Acyclovir, an acyclic nucleoside analog, has potent activity against both HSV-1 and HSV-2 in vitro.11 Since the 1980s, oral acyclovir has been reported to significantly reduce viral shedding, improve ulcer healing, and to decrease the incidence of new lesion formation among patients with recurrent genital herpes who received treatment with 48 hours of the onset of new lesions.12 More recently, Weiss et al13 pooled data from 3 individual randomized controlled trials conducted in Ghana and Central African Republic,14 Malawi,15 and South Africa16 to assess the impact of episodic acyclovir therapy on participants with GUD. These authors found that episodic acyclovir