Anti-herpes therapy reduces genital and plasma HIV viral load in women not taking HIV therapy

Michael Marco, Michael Carter
Published: 16 August 2006

Daily anti-herpes treatment significantly decreased HIV RNA in the blood and genital secretions of women not taking anti-HIV treatment, according to studies presented to the Sixteenth International AIDS Conference in Toronto on Tuesday August 15th. The investigators from France believe that their findings could have important implications for HIV prevention.

Epidemiological and biological studies have suggested a link between genital infection with herpes simplex virus-2 (HSV-2) and the transmission of HIV. HSV-2 infection may increase genital HIV shedding and possibly make co-infected individual more likely to transmit HIV to their sexual partners. However, this causal relationship has never been proven in human studies. To date, no randomised clinical trials employing anti-HSV-2 therapy have been conducted in HIV-positive individuals.

Therefore investigators from the ANRS conducted two proof-of-concept randomised, placebo-controlled trials in Burkina Faso to ascertain if the daily use of the anti-HSV-2 therapy, valaciclovir (the valine ester prodrug of aciclovir), could reduce HIV viral load in genital secretions and blood of HIV-positive women. The first study, ARNS 1285a, included HIV-positive women who did not require antiretroviral therapy; whereas the women in ARNS 1285b were taking potent HIV treatment.

In ARNS 1285a, a total of 140 women not requiring antiretroviral therapy were equally randomised to receive a daily dose of 1mg of valaciclovir or placebo for three months. Twice a week they had swabs taken from their genitals to measure genital shedding of HIV RNA and HSV-2 and blood tests to monitor their levels of HIV RNA. From the 136 women with analysable data, investigators established that the frequency and quantity of genital HIV RNA shedding and plasma HIV RNA were reduced by valaciclovir therapy by approximately 0.510 log. There was also a marked decrease in HSV-2 genital shedding by 65% as well as an 84% reduction in genital ulcers.

ANRS 1285b randomised 60 antiretroviral-taking women to valaciclovir or placebo. Median CD4 cell count in both arms was approximately 230 cells/mm3 and the median time on antiretroviral therapy was approximately 20 weeks. While there was no appreciable decrease in plasma HIV RNA, a reduction of 0.7110 log HIV RNA was seen in genital secretions. In the treatment phase, 23.7% of women had detectable genital HIV RNA compared to 8.6% receiving valaciclovir (OR=0.27; 95% CI : 0.1, 1.0; P=0.05). Thus, the women who received valaciclovir had a 73% reduction in the odds of having detectable HIV RNA in their genital secretions compared to women on placebo.

For detection of HSV-2 in genital secretions, there was a trend towards a significant difference between the groups with 6.6% of women on valaciclovir still having detectable HSV-2 compared to 9.8% of the women on placebo (P=0.06). There were also no significant differences observed in the mean quantity of genital HSV-2 DNA shedding between the groups.

The investigators proposed numerous reasons for their finding. One hypothesis was that valaciclovir treatment drives down the genital shedding of HIV by reducing plasma viral load in women who are not receiving HIV therapy. They suggest that this could be because of the impact of valaciclovir on immune mechanisms; an effect of the drug on HIV-infected cells; or, the inhibition of other herpes-related viruses. The investigators also emphasise that valaciclovir suppresses genital shedding of HSV-2, therefore reducing HIV viral load in the genitals. They caution that these data do not unequivocally demonstrate that valaciclovir is sufficient to reduce HIV-1 transmission. Wisely, they contend that this hypothesis will need to be evaluated in ongoing clinical trials, such as those being conducted by Connie Cellum and the HIV Prevention Trials Network.

They do, however, rightly point out that this is the first randomised controlled trial to demonstrate the biological impact of HSV-2 on the transmission of HIV. Likewise, they are prudent to call for further safe sex promotion to people receiving antiretrovirals after finding that up to two-thirds of the women on antiretroviral therapy still shed HIV RNA after 20 weeks.

Reference

Mayaud P et al. Herpes simplex virus type-2 (HSV-2) suppressive therapy to reduce genital and plasma HIV-1 RNA: overview of the ARNS 1285 trials, potential mechanisms for future interventions. Sixteenth International AIDS Conference, Toronto, abstract TUA0501, 2006.

Nagot N et al. Impact of valacyclovir on genital and plasma HIV-1 RNA: a randomised controlled trial among women taking HAART (ARNS 1285b). Sixteenth International AIDS Conference, Toronto, abstract TUPE0402, 2006.

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