ArticlesDaily aciclovir for HIV-1 disease progression in people dually infected with HIV-1 and herpes simplex virus type 2: a randomised placebo-controlled trial
Introduction
Recent expansion of access to antiretroviral therapy has had a large effect on disease progression and mortality of people with HIV-1 infection in resource-poor countries. However, only a third of people with HIV-1 who meet international antiretroviral therapy initiation guidelines are given these drugs.1 The number of people needing antiretroviral therapy will continue to grow, despite constraints on antiretroviral programmes and resources—especially if increased CD4 thresholds are adopted for initiation of antiretroviral therapy (eg, 350 cells per μL). Moreover, most people infected with HIV-1 worldwide have counts that are higher than the therapy starting thresholds of 200 or 350 CD4 cells per μL. Thus, low-cost interventions to slow HIV-1 disease progression are needed for those who do not meet present anti-retroviral initiation guidelines.
Infection with herpes simplex virus type 2 is the most common cause of genital ulcer disease worldwide. Seroprevalence of this virus in people with HIV-1 ranges from 70% to more than 90%.2 Reactivation of this herpes virus is common and often asymptomatic in HIV-1-infected people, occurring on about a third of days.3 Plasma and genital HIV-1 concentrations increase during reactivation,4, 5, 6, 7, 8 suggesting that herpes reactivation enhances HIV-1 replication, possibly through binding of herpes simplex virus proteins to the HIV-1 long-terminal repeat, raising concentrations of pro-inflammatory cytokines, or through infiltration of HIV-1 target cells in the genital tract.9, 10, 11
In view of the strong relation between raised plasma HIV-1 concentrations and increased speed of HIV-1 disease progression,12, 13 suppression of herpes virus type 2 has been regarded as a potential strategy to reduce HIV-1 concentrations and slow its progression. Researchers of five randomised trials14, 15, 16, 17, 18 of people dually infected with these viruses who were not taking antiretroviral therapy reported that daily herpes suppressive therapy with aciclovir or valaciclovir for 8–12 weeks reduced plasma HIV-1 concentrations by 0·25–0·5 log10 copies per μL.14, 15, 16, 17, 18 We undertook a multicentre trial of daily suppression of herpes simplex virus type 2 with aciclovir in Africans who were dually infected with HIV-1 and herpes simplex virus type 2 to assess the efficacy of suppressive aciclovir on measures of HIV-1 disease progression.
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Participants
Heterosexual couples who were discordant for HIV-1 infection were recruited at sites in southern Africa (Gaborone Botswana; Cape Town, Orange Farm, and Soweto South Africa; and Kitwe, Lusaka, and Ndola Zambia) and east Africa (Eldoret, Kisumu, Nairobi, and Thika, Kenya; Kigali Rwanda; Moshi Tanzania; and Kampala Uganda) between Nov 23, 2004 and May 16, 2007. Eligible HIV-1 infected partners were 18 years or older, seropositive for HIV-1 and herpes simplex virus type 2, and had a CD4 cell count
Results
Figure 1 shows the trial profile. Baseline demographic and clinical characteristics were similar between the two study groups (table 1). 68% of participants were women. The median baseline CD4 cell count was 462 cells per μL (IQR 347–631) and for HIV-1 plasma RNA was 4·1 log10 copies per μL (3·4–4·7). Most participants had asymptomatic HIV-1 disease, with 5% or fewer reporting pneumonia, tuberculosis, or herpes zoster in the previous year. Retention of participants at 24 months of follow-up was
Discussion
Our results show that standard doses of aciclovir for suppression of herpes simplex virus type 2 in people infected with HIV-1 and herpes type 2 reduced the risk of HIV-1 disease progression by 16%. Fewer participants in the aciclovir group than in the placebo group had CD4 cell counts fall below 200 cells per μL (p=0·06), started antiretroviral therapy (p=0·05), or died from non-trauma-related reasons (p=0·29). Furthermore, fewer of those in the group assigned aciclovir with counts of 350
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