Daily Acyclovir Use in HIV-1/HSV-2 Coinfected Women
Daily Acyclovir Use in HIV-1/HSV-2 Coinfected Women
Objectives Several clinical trials have demonstrated that daily treatment of HIV-infected individuals with the antiherpes drug acyclovir slightly decreases HIV-1 viral load and slows disease progression. This study examines if this slowing in clinical progression is a direct cause of the decrease in viral load or an indirect effect of lower immune activation due to lower levels of herpetic reactivation.
Methods Women who participated in a randomised clinical trial of daily acyclovir use (n=301) were monitored every 6 months for changes in immune activation. Soluble CD14 (sCD14), a marker for monocyte activation, and C-reactive protein (CRP), a marker for general immune activation, were measured by ELISA.
Results Initial levels of sCD14 and CRP were not predictive of HIV disease progression when controlling for initial CD4+ cell count and HIV viral load. sCD14 levels, but not CRP, decreased in the acyclovir treatment arm at a significantly faster rate than the placebo group, which was independent of changes in HIV viral load and CD4+ cell count in a multivariant mixed-effects model (p=0.039). However, the magnitude of this decrease was relatively small with a total estimated decrease of sCD14 of 15% of initial levels.
Conclusions These data suggest that decreased monocyte activation may play a minor role in the ability of daily acyclovir use to slow HIV disease progression.
Clinical trial registration number NCT00405821
Herpes simplex virus type 2 (HSV-2) has been shown to upregulate HIV-1 replication and is associated with increased HIV-1 viral load (VL). Acyclovir treatment, which effectively blocks HSV replication, was shown to also significantly reduce HIV VL, as well as decrease the rate of disease progression in two separate randomised controlled trials. This effect was most prominent in individuals with high HIV VLs. It is unclear if the protective effect of acyclovir use in HIV disease progression is due to its direct effect of decreasing HIV replication or a secondary effect caused by decreased immune activation associated with less herpetic reactivation.
A placebo-controlled trial of the use of valacyclovir, a derivative of acyclovir, in HIV-1/HSV-2 coinfected adults found that 18 weeks of treatment did not decrease cellular or inflammatory immune activation. However, these individuals were on fully suppressive highly active antiretroviral therapy (HAART), which may have masked some of the effects of suppressing HSV replication. The same investigators performed a similar trial in HIV-uninfected women and found that 2-month valacyclovir treatment did not reduce cellular activation or levels of proinflammatory cytokines in the female genital tract. In contrast to these smaller shorter studies, the randomised controlled trial of daily acyclovir use in Rakai district, Uganda, was performed over 2 years on 440 participants, allowing for greater power to examine subtle and long-term changes in immune activation.
C-reactive protein (CRP), a marker for general immune activation, has been shown to increase during HIV disease in this population. Soluble CD14 (sCD14) is a marker for monocyte activation and has been shown to be predictive of HIV disease progression. It is not fully understood how long-term acyclovir treatment may alter these markers. This study examined if acyclovir-induced changes in general immune activation account for a proportion of the protective effect seen in HIV disease progression or if it is due more to the direct effect of decreased HIV VL.
Abstract and Introduction
Abstract
Objectives Several clinical trials have demonstrated that daily treatment of HIV-infected individuals with the antiherpes drug acyclovir slightly decreases HIV-1 viral load and slows disease progression. This study examines if this slowing in clinical progression is a direct cause of the decrease in viral load or an indirect effect of lower immune activation due to lower levels of herpetic reactivation.
Methods Women who participated in a randomised clinical trial of daily acyclovir use (n=301) were monitored every 6 months for changes in immune activation. Soluble CD14 (sCD14), a marker for monocyte activation, and C-reactive protein (CRP), a marker for general immune activation, were measured by ELISA.
Results Initial levels of sCD14 and CRP were not predictive of HIV disease progression when controlling for initial CD4+ cell count and HIV viral load. sCD14 levels, but not CRP, decreased in the acyclovir treatment arm at a significantly faster rate than the placebo group, which was independent of changes in HIV viral load and CD4+ cell count in a multivariant mixed-effects model (p=0.039). However, the magnitude of this decrease was relatively small with a total estimated decrease of sCD14 of 15% of initial levels.
Conclusions These data suggest that decreased monocyte activation may play a minor role in the ability of daily acyclovir use to slow HIV disease progression.
Clinical trial registration number NCT00405821
Introduction
Herpes simplex virus type 2 (HSV-2) has been shown to upregulate HIV-1 replication and is associated with increased HIV-1 viral load (VL). Acyclovir treatment, which effectively blocks HSV replication, was shown to also significantly reduce HIV VL, as well as decrease the rate of disease progression in two separate randomised controlled trials. This effect was most prominent in individuals with high HIV VLs. It is unclear if the protective effect of acyclovir use in HIV disease progression is due to its direct effect of decreasing HIV replication or a secondary effect caused by decreased immune activation associated with less herpetic reactivation.
A placebo-controlled trial of the use of valacyclovir, a derivative of acyclovir, in HIV-1/HSV-2 coinfected adults found that 18 weeks of treatment did not decrease cellular or inflammatory immune activation. However, these individuals were on fully suppressive highly active antiretroviral therapy (HAART), which may have masked some of the effects of suppressing HSV replication. The same investigators performed a similar trial in HIV-uninfected women and found that 2-month valacyclovir treatment did not reduce cellular activation or levels of proinflammatory cytokines in the female genital tract. In contrast to these smaller shorter studies, the randomised controlled trial of daily acyclovir use in Rakai district, Uganda, was performed over 2 years on 440 participants, allowing for greater power to examine subtle and long-term changes in immune activation.
C-reactive protein (CRP), a marker for general immune activation, has been shown to increase during HIV disease in this population. Soluble CD14 (sCD14) is a marker for monocyte activation and has been shown to be predictive of HIV disease progression. It is not fully understood how long-term acyclovir treatment may alter these markers. This study examined if acyclovir-induced changes in general immune activation account for a proportion of the protective effect seen in HIV disease progression or if it is due more to the direct effect of decreased HIV VL.
