Long-term herpes treatment may reduce HIV infectivity

Long-term anti-herpes treatment of women infected with both HIV and HSV2, the virus that causes genital herpes, may reduce the proportion of women with detectable HIV virus in their genital secretions according to the results of a trial in Tanzania presented the International AIDS Society Conference in Sydney.

A collaborative group of scientists from the London School of Hygiene and Tropical Medicine (UK), African Medical and Research Foundation (Tanzania) and National Institute for Medical Research (Tanzania), in collaboration with INSERM Unit 743 in Paris and the Institute of Tropical Medicine Antwerp, carried out the trial which was the first anywhere in the world to measure the effects of herpes treatment on HIV acquisition, as well as the long-term effects on the infectivity of people with HIV infection.

Although the results for HIV-positive women taking part in the trial were promising, the findings in HIV-negative women were unclear and more data from larger trials will be needed to establish whether long-term herpes treatment can protect individuals against HIV infection.

1,305 women were recruited in small towns and roadside settlements near Mwanza in North-Western Tanzania, and asked to take the anti-herpes drug acyclovir, or a placebo, twice daily. They were followed for up to 30 months to examine the effects on the incidence of HIV infection in 821 women who were initially HIV-negative, or on markers of HIV infectivity in 484 women who were HIV-positive. In the HIV-positive group, the proportion with HIV detected in their genital secretions after six months and twelve months was 20-25% lower in those taking acyclovir.

The research followed on from observational studies showing that HSV2 infection was associated with around a three-fold higher risk of HIV acquisition 1. HSV2 is a lifelong incurable viral infection, but can be effectively controlled using acyclovir or similar drug treatments. This suggests that controlling herpes might be an effective indirect method of protecting against HIV infection, but trials were needed to test whether this approach works in practice.

HSV2 infection also seems to increase the infectivity of HIV-positive individuals by disrupting the genital mucosa and increasing the levels of HIV in the genital tract. Recent trials in Africa and elsewhere have shown that short-term herpes treatment for up to 3 months successfully reduced genital HIV levels 2, 3 , but further research was needed to measure long-term effects.

Disappointingly, among HIV-negative women there was no overall effect of herpes treatment on the acquisition of HIV, with similar rates seen in both treatment groups. However, there was some evidence that the effect varied according to adherence with treatment. Among women who took at least 90% of their prescribed doses, the HIV rate was 42% lower in those taking acyclovir, but numbers of infections in this subgroup were small, and the difference may have been a chance finding.

Lead author Dr Deborah Watson-Jones, of LSHTM and AMREF, explains: 'Persuading women to take acyclovir twice a day for two years or more, when they are basically healthy, is obviously difficult although 70% of women did manage to take at least three-quarters of their tablets. However, despite intensive counselling, we were unable in this long-term trial to maintain the very high levels of treatment adherence of over 90% reported in the shorter trials. This may explain why there was no overall effect on HIV acquisition. However our finding of a protective effect in women with the best adherence, even though not statistically significant, leaves us with hope that this could still be an effective strategy in populations where high adherence can be achieved. We need to wait for data from a larger US-funded trial next year to find out whether this approach works as an HIV prevention tool'.

Whatever the results in HIV-negative women, the trial in Tanzania adds to the growing evidence that herpes treatment of HIV-positive individuals reduces their infectivity to sexual partners. The new data suggest that this effect extends for at least 6 to 12 months, and further analyses are now being carried out on specimens taken after 24 months. Data on plasma viral load will also be analysed to see whether there is any evidence that herpes treatment reduces HIV viral replication, as suggested by the results of the shorter-term trials.

Work will continue on the role of herpes control as an indirect preventive measure against HIV. 'We need every tool we can find to fight the HIV epidemic in Africa', comments Professor Richard Hayes, a senior investigator on the project. 'Safer sexual behaviour is of central importance, but we also need to look at ways of cutting the risk of transmission when sexual exposure occurs. We know that male circumcision is one approach and herpes control may be another. We must also press ahead with work to develop effective vaginal microbicides and vaccines'.

'One thing that this study makes clear is that maintaining adherence to acyclovir over a long period is challenging', adds Deborah Watson-Jones. 'An effective HSV2 vaccine would obviously be a more practical way of controlling this virus, and the development of a vaccine needs to be given a higher priority'.

In 2006, an estimated 4.3 million people were newly infected with HIV, of which more than two-thirds lived in sub-Saharan Africa. This high rate of new infections emphasises the need to expand the implementation of proven prevention methods, at the same time as identifying new approaches to prevention.

1. Herpes simplex virus type-2 (HSV2) is the most common sexually transmitted infection and is the main cause of genital herpes. In some parts of sub-Saharan Africa, 70% of women are infected with HSV2 before reaching 30 years of age. HSV2 is an incurable lifelong infection which is asymptomatic for much of the time but causes occasional episodes of genital ulcers and blisters. Genital ulcers are known to be an important risk factor for HIV infection. Even when there are no symptoms, asymptomatic genital excretion of HSV2 may occur, and there is evidence that this also increases the excretion of HIV, thus enhancing the infectivity of HIV-infected individuals.
2. The herpes virus can be targeted by specific antiviral drugs such as acyclovir, valacyclovir or famciclovir. 'Herpes suppressive therapy', where one of these drugs is taken daily over a prolonged period, is known to be effective in reducing HSV2 expression and cutting the frequency and severity of clinical episodes of herpes. Acyclovir is a relatively affordable medication, with few side effects and to which the herpes virus rarely becomes resistant. However, its effectiveness in reducing the rate of HIV infection has not been directly tested prior to this trial.
3. In 2001, an international workshop organised by WHO, UNAIDS and LSHTM called for randomised controlled trials of HSV2 therapy to definitively establish a causal relationship between HSV2 and HIV infectivity and acquisition 4 . The first such trials to be reported looked at the effects of short-term herpes treatment (up to 3 months) in HIV-infected individuals in Burkina Faso, South Africa, Peru and Thailand. Taken together, the results showed a clear effect on HIV genital excretion and there was also evidence of an effect on HIV plasma viral load, suggesting that herpes treatment might also reduce the clinical progression of HIV infection. The trial in Tanzania is the first to look at the effects of herpes treatment on HIV acquisition in HIV-negative individuals, as well as long-term effects (up to 30 months) on HIV infectivity in HIV-positive individuals.
4. Two trials of long-term therapy are still in progress. An NIH-funded trial in the US, Peru and Africa (HPTN039) will provide additional data on the effect of herpes suppressive therapy on HIV acquisition and will be completed in 2008. A further multi-centre trial ("Partners in Prevention"), funded by the Bill and Melinda Gates Foundation, is looking at the effect of herpes suppressive therapy in discordant couples (where one partner is HIV-infected and the other is HIV-negative). This trial is scheduled for completion in 2009.

Notes on funding and sponsorship

This research was sponsored by the Wellcome Trust and the UK Medical Research Council, with supplementary support from the UK Department for International Development.

The Wellcome Trust was formed in 1936 and its mission is to foster and promote research in developed and developing countries with the aim of improving human and animal health.

The Medical Research Council is a publicly-funded organisation dedicated to improving human health through world-class medical research.

The Department for International Development funds research on HIV/AIDS through a series of 'Research Programme Consortia'. The LSHTM-based Consortium on Sexual and Reproductive Health and HIV aims 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.

Footnotes/References

1. Freeman EE, Weiss HA, Glynn JR, Cross PL, Whitworth JA, Hayes RJ. Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS 2006; 20: 73-83.
2. Nagot N, Ouedraogo A, Foulongne V, Konate I, Weiss HA, Vergne L, Defer M-C, Djagbare D, Sanon A, Andonaba J-B, Becquart P, Segondy M, Vallo R, Sawadogo A, Van de Perre P, Mayaud P 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: 790-9.
3. Ouedraogo A, Nagot N, Vergne L, Konate I, Weiss HA, Defer M-C, Foulongne V, Sanon A, Andonaba J-B, Segondy M, Mayaud P, Van de Perre P. Impact of suppressive herpes therapy on genital HIV-1 RNA among women taking antiretroviral therapy: a randomized controlled trial. AIDS 2006; 20: 2305-13.
4. World Health Organization. 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.

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