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 was only marginally associated with improved healing on day 7 among participants with recurrent HSV-2 ulcers (adjusted risk ratio [aRR]: 1.14, 95% confidence interval [CI]: 1.00–1.30). Given these findings and their observation that African patients tend to come late for the management of their ulcers, the efficacy of episodic antiviral therapy for recurrent genital herpes among HIV-uninfected persons are clearly limited if not administered at the onset of recurrence.
Several studies have found that HIV-seropositive individuals with herpetic lesions may only have a slight benefit from episodic antiviral therapy as HIV-seronegative persons. Overall, Weiss et al reported a small effect of acyclovir on HIV-1 seropositive individuals with GUD (aRR: 1.16, 95% CI: 1.01–1.32) from their pooled data analyses.13 One of the trials they analyzed from South Africa demonstrated a shorter time to healing among HIV-infected participants treated with 5 days of acyclovir compared with placebo, but the difference between groups was a median of 6 versus 7 days, respectively (P = 0.006).16
The effect of episodic antiviral therapy on HSV-2 transmission is even less promising. Theoretically, antivirals reduce the transmission of HSV-2 by reducing the frequency and duration of virus shedding. A large, multicenter study demonstrated the effectiveness of suppressive once-daily valacyclovir in reducing the risk of sexual transmission of genital herpes among immunocompetent heterosexual monogamous couples who were serologically discordant for HSV-2 infection.17 In this study, viral shedding was detected on 2.9% of days among HSV-2–infected partners who received valacyclovir as compared with 10.8% of days among those who received placebo (P < 0.001). The acquisition of HSV-2 by susceptible partners was reduced by 48% (P = 0.054), and the time to overall acquisition of infection was decreased by 55% with the use of suppressive therapy (P = 0.012). However, episodic antiviral therapy has not been shown to reduce the risk for HSV transmission because the majority of transmission events is believed to occur by asymptomatic viral shedding.18 In fact, national sexually transmitted disease treatment guidelines caution that episodic therapy does not reduce the risk for transmission and its use should be discouraged for this purpose among persons whose partners might be at risk for HSV-2 acquisition.19
Not surprisingly, there have been no reported studies on the use of episodic antiviral therapy to reduce the likelihood of HSV-2 or HIV-1 transmission among HIV-seropositive or -discordant partners. Paz-Bailey et al did show that 5-day acyclovir therapy reduced HSV-2 shedding among HIV- positive participants with a herpetic ulcer, with viral shedding noted in 17.6% in the acyclovir group versus 63.8% in the placebo group (aRR: 0.2, 95% CI: 0.1–0.4) at day 7, which was sustained up to day 14.16 However, given what we know regarding increased genital shedding of HSV-2 in HIV-infected persons,20,21 asymptomatic viral shedding between recurrent episodes, and the failure of daily acyclovir to prevent HIV transmission, we would expect either a marginal or no benefit from episodic therapy on either HSV-2 or HIV-1 transmission between HIV-discordant partners.
The cost of government-procured acyclovir in South Africa has been estimated to be equivalent to United States $0.14 per day (for 2 × 400 mg acyclovir),22 or $0.70 for a 5-day regimen. Although the low cost of individual episodic therapy may warrant its offering and use among symptomatic individuals despite its limited benefits, the real question that warrants further evaluation is no longer the effect of episodic acyclovir on symptoms or HSV shedding but whether this regimen is cost-effective or good public health policy in resource-poor countries for syndromic management of GUD. Considering its limited effect on the duration of symptoms in recurrent genital herpes and its lack of demonstrable impact on HSV or HIV transmission, we believe that there is little utility or potential gain from episodic treatment of HSV-2 in resource-poor settings like Africa.
1.Smith JS, Robinson NJ. Age-specific prevalence of infection with herpes simplex virus types 2 and 1: A global review. J Infect Dis 2002; 186(suppl 1):S3–S28.
2.Weiss H. Epidemiology of herpes simplex virus type 2 infection in the developing world. Herpes 2004; 11:24A–35A.
3.Mbopi-Keou FX, Gresenguet G, Mayaud P, et al. Interactions between herpes simplex virus type 2 and human immunodeficiency virus type 1 infection in African women: opportunities for intervention. J Infect Dis 2000; 182:1090–1096.
4.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 trail. J Infect Dis 2007; 196:1500–1508.
5.Baeten JM, Strick LB, Lucchetti A, et al. Herpes simplex virus (HSV)-suppressive therapy decreases plasma and genital HIV-1 levels in HSV-2/HSV-1 co-infected women: a randomized, placebo-controlled, cross-over trial. J Infect Dis 2008; 198: 1804–1808.
6.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; 356:790–799.
7.Dunne EF, Whitehead S, Sternberg M, et al. Suppressive acyclovir therapy reduces HIV cervicovaginal shedding in HIV and HSV-2-infected women, Chaing Rai, Thailand. J Acquir Immun Defic Syndr 2008; 49:77–83.
8.Delany S, Mlaba N, Clayton T, et al. Impact of acyclovir on genital and plasma HIV-1 RNA in HSV-2/HIV-1 co-infected women: a randomized placebo-controlled trail in South Africa. AIDS 2009; 23:461–469.
9.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; 358:1560–1571.
10.Celum C, Wald A, Lingappa JR, et al. Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2. N Engl J Med 2010; 362:427–439.
11.Crumpacker C, Schnipper L, Zaia J, et al. Growth inhibition by acycloguanosine of herpes virus isolated from human infections. Antimicrob Agents Chemother 1979; 15:642–645.
12.Reichman RC, Badger GJ, Mertz GJ, et al. Treatment of recurrent genital herpes simplex infections with oral acyclovir. A controlled trial. JAMA 1984; 251:2103–2107.
13.Weiss HA, Paz Bailey G, Phiri S, et al. Episodic therapy from genital herpes in sub-Saharan Africa: A pooled analysis from three randomized controlled trials. PLoS One 2011; 6:e22601.
14.Mayaud P, Legoff J, Weiss HA, et al. Impact of acyclovir on genital and and plasma HIV-1 RNA, genital herpes simplex virus type 2 DNA, and ulcer healing among HIV-1-infected African women with herpes ulcers: A randomized placebo-controlled trial. J Infect Dis 2009; 200:216–226.
15.Phiri S, Hoffman IF, Weiss HA, et al. Impact of acyclovir on ulcer healing, lesional, genital and plasma HIV-1 RNA among patients with genital ulcer disease in Malawi. Sex Transm Infect 2010; 86:345–352.
16.Paz-Bailey G, Sternberg M, Puron AJ, et al. Improvement in healing and reduction in HIV shedding with episodic acyclovir therapy as part of syndromic management among men: A randomized, controlled trial. J Infect Dis 2009; 200:1039–1049.
17.Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl Med 2004; 350:11–20.
18.Mertz GJ, Schmidt O, Jourden JL, et al. Frequency of acquisition of first-episode genital infection with herpes simplex virus from symptomatic and asymptomatic source contacts. Sex Transm Dis 1985; 12:33–39.
19.Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2010. Morb Mort Wkly Rep 2010; 59:20–25.
20.Augenbraun M, Feldman J, Chirgwin K, et al. Increased genital shedding of herpes simplex virus type 2 in HIV-seropositive women. Ann Intern Med 1995; 123:845–847.
21.Schacker T, Zeh J, Hu HL, et al. Frequency of symptomatic and asymptomatic herpes simplex virus type 2 reactivations among human immunodeficiency virus-infected men. J Infect Dis 1998; 178:1616–1622.
22.Vickerman P, Devine A, Foss AM, et al. The cost-effectiveness of herpes simplex virus-2 suppressive therapy with daily acyclovir for delaying HIV disease progression among HIV-1-infected women in South Africa. Sex Transm Dis 2011; 38:401–409.