London School of Hygiene & Tropical Medicine

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 today at 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'.