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Treating HIV infection with drugs for HSV-2 infection? Commentary
 
 
  The Lancet, Early Online Publication, 15 February 2010
 
Anne Buve aEmail Address, Lutgarde Lynen b a Department of Microbiology, Institute of Tropical Medicine, B2000 Antwerp, Belgium b Department of Clinical Sciences, Institute of Tropical Medicine, B2000 Antwerp, Belgium
 
"Further research is needed on the feasibility and cost-effectiveness of suppressive therapy for infection with HSV-2 as a strategy to slow disease progression in HIV- co-infected patients. In the meantime, efforts should be stepped up to ensure that HIV-infected patients in low-income and middle-income countries who have frequent recurrences of genital herpes or severe genital herpes receive suppressive therapy with aciclovir, as recommended in industrialised countries......Adherence to the study drugs was high in today's trial but such high levels of adherence will be difficult to achieve in real life on a large scale....before advocating for an additional possible intervention, such as aciclovir suppressive treatment, we need to define and assess the relative contribution"
 
Jairam Lingappa and colleagues,1 in The Lancet today, present results from the Partners in Prevention HSV/HIV Transmission Study. This study was in HIV-1 discordant couples, and the primary objective was to directly assess the efficacy of suppressive therapy with aciclovir in reduction of onward transmission of HIV-1 from partners co-infected with herpes simplex virus type 2 (HSV-2). In the past few years, other placebo-controlled trials have studied the effects of aciclovir or valaciclovir on HIV-1 transmissibility, with genital shedding of HIV-1 RNA as a proxy of transmissibility.2-6 In these trials, suppressive therapy of HSV-2 reduced genital shedding of HIV-1 RNA. However, the Partners in Prevention Study showed that suppressive therapy with aciclovir did not reduce onward transmission of HIV-1.7
 
In randomised trials,2-6 researchers identified that there could be a clinical benefit because suppressive therapy with aciclovir or valaciclovir seemed to lower HIV-1 RNA plasma levels in co-infected patients. In view of the fact that HIV-1 plasma viral load is related to disease progression, this finding opened up new perspectives for the management of HIV-infected patients. A meta-analysis8 of randomised trials done in industrialised countries in the early 1990s reported that aciclovir offered a survival benefit to HIV-infected patients. Today's report is the first to assess the effects of suppressive therapy for HSV-2 on disease progression in patients co-infected with HIV in sub-Saharan Africa during a 2-year period. In patients assigned to aciclovir, fall of CD4 cell count was slower, start of antiretroviral treatment was delayed, and mortality was reduced, compared with patients in the control group. These findings are exciting, but are we ready to translate them into new guidelines for the management of such co-infected patients?
 
WHO recently revised its guidelines for the treatment of HIV-infected patients in low-income and middle-income countries.9 In line with the recommendations of the International AIDS Society, WHO recommends that antiretroviral treatment is started at a CD4 cell count of 350 per µL. These new guidelines imply that resources for HIV care in countries of low and middle incomes will have to increase substantially, which is unlikely to happen in the present economic crisis.10 Treatment of HIV-infected patients with drugs that are cheap and easy to take, and which slow disease progression, is thus an appealing strategy to save on antiretroviral treatments. Does suppressive therapy of infection with HSV-2 fit this bill? Lingappa and co-workers are cautious and suggest that further studies are needed. There are unresolved issues, and translation of results of this study into real-life programmes would be premature.
 
In patients assigned to aciclovir, the incidence of selected endpoints for HIV-1 disease progression was 16% lower than in patients assigned to placebo. With the assumption that disease progression continued on the same course after the 24 months of the trial, an estimated median time to CD4 cell count of fewer than 350 per µL was delayed by 6·3 months. However, data suggest that, to have an effect on HIV disease progression, at least 90% of the prescribed doses of aciclovir need to be taken. Adherence to the study drugs was high in today's trial but such high levels of adherence will be difficult to achieve in real life on a large scale, because most co-infected patients have asymptomatic herpes infection and will not feel any immediate benefit from taking aciclovir. Efforts to convince these patients to adhere to suppressive therapy might be out of proportion to the expected gains, and cost-effectiveness analyses are needed to resolve this question.
 
Additionally, suppressive therapy for HSV-2 is not the first prophylactic treatment that has been assessed. In the 1990s, before antiretroviral therapy became widely available in low-income and middle-income countries, several prophylactic treatments were assessed in HIV-infected patients with the aim to slow disease progression.11-14 Nowadays, interest has been renewed in the development of care packages given before HIV antiretrovirals, but the focus has somewhat shifted. In many settings, especially in sub-Saharan Africa, concern is growing that patients who have been tested and diagnosed with HIV infection are lost to follow-up and present later with advanced HIV infection.15, 16 A care package given before HIV antiretrovirals could serve a dual purpose: to ensure that people remain under care and start HIV antiretrovirals before they are severely immunocompromised, and to slow disease progression.
 
Such a package could include cotrimoxazole and isoniazid preventive therapy, regular CD4 cell counts, nutritional support, anthelmintic drugs, multivitamins, and insecticide-treated bednets for the prevention of malaria. All these components have adherence issues, and before advocating for an additional possible intervention, such as aciclovir suppressive treatment, we need to define and assess the relative contribution and the specific target group of every component and its cost-effectiveness in retention of patients and delay of disease progression.
 
Further research is needed on the feasibility and cost-effectiveness of suppressive therapy for infection with HSV-2 as a strategy to slow disease progression in HIV- co-infected patients. In the meantime, efforts should be stepped up to ensure that HIV-infected patients in low-income and middle-income countries who have frequent recurrences of genital herpes or severe genital herpes receive suppressive therapy with aciclovir, as recommended in industrialised countries.
17
 
We declare that we have no conflicts of interest.
 
 
 
 
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