London School of Hygiene & Tropical Medicine

Treating women who are infected with both the HSV-2 and HIV viruses with anti-herpes treatment can reduce the amount of HIV in the blood and genital secretions, according to the results of a trial published today in the New England Journal of Medicine.

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. The results showed that having the herpes virus increased the replication of HIV, and also revealed that the quantity of HIV in the blood and in the vagina was reduced by continuous anti-herpes treatment over 3 months.

These findings open new avenues for the prevention of HIV transmission and for the management of patients co-infected by the two viruses.

In 2005, an estimated 4.1 million people were newly infected with HIV, mostly through heterosexual intercourse¹. This alarming number of infections highlights the urgent need to intensify and expand proven prevention methods, and further, to identify and implement new methods of HIV prevention.

A number of observational studies have indicated that HSV-2 enhances the risk of HIV-1 acquisition by around three-fold². HSV-2 infection may also increase HIV-1 infectiousness by disrupting the genital mucosa and increasing the levels of HIV in the genital tract³, allowing easier transmissibility of the virus. In addition, the HIV viral load in the blood of HIV-1 infected patients increases, at least temporarily, during episodes of HSV reactivation.

Lead author Dr Nicolas Nagot, of the London School of Hygiene & Tropical Medicine (LSHTM), explains: 'Behavioural interventions are not always successful, as knowledge does not necessarily translate into sexual behaviour change. Therefore, innovative methods that target the biological susceptibility of individuals to acquire or transmit HIV are also required. A number of options to prevent HIV transmission are currently being investigated, including the role of vaginal microbicides, pre-exposure HIV prophylaxis, male circumcision, and - in the future - an HIV vaccine.'

'The results of the trial are striking', he adds. 'They show that valacyclovir significantly reduces the frequency and quantity of HIV detectable in genital secretions and, in addition, reduces the quantity of HIV in the plasma. As expected, there was also dramatic reduction in the detection of symptomatic and asymptomatic presence of HSV-2. The effects appeared to gradually increase over the 3 month follow-up period, with no sign of abating.'

These results indicate a new way to possibly reduce the sexual transmission of HIV from already infected individuals to their partners, since the frequency and quantity of HIV in the female genital tract are closely related to the transmission of the virus.

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.

Dr Philippe Mayaud, one of Dr Nagot's colleagues at the LSHTM concludes: 'Our results have important potential implications for public health and clinical practice, as HSV-2 control could become a new form of HIV prevention targeting HIV-infected individuals, as well as providing clinical benefits. Importantly, an HSV vaccine that would either prevent HSV infection or diminish the clinical and sub-clinical manifestations of HSV with a similar efficacy on HIV as HSV suppressive therapy, would represent a long-lasting form of HIV prevention. The development and evaluation of an HSV vaccine should rank high on the international research agenda.'

Gareth Thomas, UK Minister for International Development, whose department DFID has provided supplementary funding for the research, said: "These exciting initial findings demonstrate why research into reducing HIV/ AIDS transmission is such a vital element of the fight against the disease. The UK Government has pledged to spend £1.5 billion tackling HIV/AIDS in developing countries between 2005 and 2008. We will follow the next stages of this research with interest."

Notes:
1. Herpes simplex virus type-2 (HSV-2), a sexually transmitted virus, is one of the most common pathogens worldwide⁴. HSV-2 is a lifelong infection and is found in nearly 80% of HIV-infected patients. 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. The herpes virus can be targeted by specific HSV-2 antiviral drugs such as acyclovir, valacyclovir or famciclovir, which are relatively affordable medications with few side effects, and to which the herpes virus rarely becomes resistant. 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.