Summary: Objectives: A randomized, double-blind, placebo-controlled trial (RCT) of herpes simplex virus type 2 suppressive therapy with acyclovir 400 mg twice daily conducted among women in northwestern Tanzania reported a similar rate of HIV acquisition in both trial arms (Current Controlled Trials number ISRCTN35385041). A collaborative group of scientists from the Centre Muraz (Burkina Faso), the University of Montpellier (France) and the London School of Hygiene & Tropical Medicine (UK) carried out the trial among women co-infected with the human immuno-deficiency virus (HIV) and the virus that causes genital herpes (HSV-2) in Burkina Faso. METHODS: Female workers at recreational facilities in northwestern Tanzania who were 16 to 35 years of age were interviewed and underwent serologic testing for HIV and HSV-2. In 2005, an estimated 4.1 million people were newly infected with HIV, mostly through heterosexual intercourse1. Results: Overall, 821 herpes simplex virus type 2 seropositive, HIV seronegative women were randomized, 400 to acyclovir and 421 to placebo; 659 (80.3%) completed follow-up. A number of observational studies have indicated that HSV-2 enhances the risk of HIV-1 acquisition by around three-fold2. We used a modified intention-to-treat analysis; data for participants who became pregnant were censored.
In addition, the HIV viral load in the blood of HIV-1 infected patients increases, at least temporarily, during episodes of HSV reactivation. 30-35: hazard ratio = 4.02; 95% CI 1.67-9.68), alcohol consumption at enrolment (≥30 drinks/week vs. The findings will need to be confirmed by further research, and there is already a large ongoing trial that is measuring direct transmission of HIV between discordant couples in several sites worldwide. The incidence of HIV infection was 4.27 per 100 person-years (27 participants in the acyclovir group and 28 in the placebo group), and there was no overall effect of acyclovir on the incidence of HIV (rate ratio for the acyclovir group, 1.08; 95% confidence interval, 0.64 to 1.83). Herpes simplex virus type-2 (HSV-2), a sexually transmitted virus, is one of the most common pathogens worldwide4. Interventions are needed to address the risk associated with alcohol use and to sustain control of other sexually transmitted infections. Once acquired, the virus cycles between latency (hidden in nerves), asymptomatic genital excretion of the virus (‘shedding’), and clinical reactivations that can produce painful ulcers in and around the genitalia.
CONCLUSIONS: These data show no evidence that acyclovir (400 mg twice daily) as HSV suppressive therapy decreases the incidence of infection with HIV. These drugs are effective in preventing the recurrence of disease and in curbing the transmission of HSV-2 from infected to uninfected partners5. 2. In 2001, an international workshop organised by WHO, UNAIDS and LSHTM called for randomised controlled trials of HSV-2 therapy to definitely establish a causal relationship between HSV-2 and HIV-1 infectivity and acquisition6. We have now completed the first two randomised placebo-controlled trials of herpes suppressive treatment (with valacyclovir at a dose of 500 mg twice daily for 3 months) among HIV-infected individuals. The studies were conducted in Burkina Faso among women who were dually seropositive for HIV and HSV-2. In the first trial (ANRS1285a) published in today’s issue of the New England Journal of Medicine7, we report on the impact of HSV suppressive treatment on plasma and genital HIV-1 levels among women who did not require ART and who did not require a treatment for their HSV infection (they had less than 6 episodes per year).
In the companion trial (ANRS1285b), which has been published recently in AIDS8, we reported the impact of herpes suppressive therapy on plasma and genital HIV-1 levels among women who were taking highly active antiretroviral therapy (HAART). The ANRS 1285b trial was conducted among 60 women who had been taking HAART for at least 4 months. This trial showed that valacyclovir had an additional impact on the residual shedding of HIV-1 despite good systemic control of the virus. This supports an effect of HSV-2 on independent mucosal HIV-1 replication – an important contribution to the HSV/HIV co-activation hypothesis. This research was sponsored by France’s Agence Nationale de Recherches sur le Sida et les Hepatites (ANRS), with supplementary financial support from the United Kingdom’s Department for International Development (DFID). The ANRS, created in 1992 to specifically respond to the many scientific challenges posed by the extension of the HIV/AIDS pandemic, coordinates research activities that span several disciplines from fundamental research, to clinical research, public health and socio-anthropological research. DFID has been funding research on HIV/AIDS through a series of research programmes formerly called ‘Knowledge Programmes’ and currently ‘Research Programme Consortia’.
The purpose of the current LSHTM-based Consortium on Sexual and Reproductive Health and HIV is to strengthen the evidence base to enable policy makers to identify and prioritise interventions that will improve reproductive and sexual health and reduce HIV incidence among economically poor populations in Africa and Asia; and to ensure that the research results are made available to policy makers at national and international levels in an intelligible and relevant form. 6 – World Health Organisation. Herpes simplex virus type 2: Programmatic and research priorities in developing countries. Report of a WHO/UNAIDS/LSHTM workshop (London, 14-16 February 2001). Document WHO/HIV AIDS/2001.05. Geneva: WHO, 2001. 7 – Nicolas Nagot, Abdoulaye Ouedraogo, Vincent Foulongne, Issouf Konate, Helen A.
Weiss, Laurence Vergne, Marie-Christine Defer, Didier Djagbare, Anselme Sanon, Jean-Baptiste Andonaba, Pierre Becquart, Michel Segondy, Roselyne Vallo, Adrien Sawadogo, Philippe Van de Perre, and Philippe Mayaud for the ANRS 1285 Study Group. Reduction of HIV-1 RNA Levels with Therapy to Suppress Herpes Simplex Virus. New Engl J Med 2007;356 (8): 790-9. 8 – Abdoulaye Ouedraogo, Nicolas Nagot, Laurence Vergne, Issouf Konate, Helen A. Weiss, Marie-Christine Defer, Vincent Foulongne, Anselme Sanon, Jean-Baptiste Andonaba, Michel Segondy, Philippe Mayaud and Philippe Van de Perre. Impact of suppressive herpes therapy on genital HIV-1 RNA among women taking antiretroviral therapy: a randomized controlled trial. AIDS 2006; 20: 2305-13.