T Cell Activation in HIV-1/Herpes Simplex Virus-2-Coinfected Kenyan Women Receiving Valacyclovir.
Abstract Herpes simplex virus-2 (HSV-2) suppression with acyclovir or valacyclovir reduces HIV-1 viral RNA levels; one hypothesis is that HSV-2 suppression reduces immune activation. We measured T cell immune activation markers among women participating in a randomized placebo-controlled trial of valacyclovir to reduce HIV-1 RNA levels among pregnant women. Although valacyclovir was associated with lower HIV-1 RNA levels, the distribution of both CD4(+) and CD8(+) CD38(+)HLA-DR(+) T cells was not different among women taking valacyclovir when compared to women taking placebo. Further study is needed to understand the mechanism of HIV-1 RNA reduction following herpes suppression among those coinfected with HIV-1 and HSV-2.
Available from: PubMed Central
- "The purported explanation for this negative finding is the considerably lower concentrations of acyclovir achieved in the clinical setting compared with the laboratory studies. Still another possibility is that acyclovir could attenuate HIV disease progression by decreasing HSV-2-related immune activation, although two studies have recently shown no benefit of valacyclovir on a variety of inflammatory markers [32,33]. Further data are needed to clarify the relationship between HSV-2, anti-herpes medications and HIV viral load. "
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ABSTRACT: Herpes simplex virus type 2 (HSV-2) is a common co-infection among HIV-infected adults that is hypothesized to accelerate HIV disease progression.
We searched Medline, EMBASE, relevant conference proceedings (2006--12) and bibliographies of identified studies without language restriction for cohort studies examining the impact of HSV-2 on highly active antiretroviral therapy-untreated HIV disease in adults. The exposure of interest was HSV-2 seropositivity or clinical/laboratory markers of HSV-2 activity. The primary outcome was HIV disease progression, defined as antiretroviral initiation, development of AIDS/opportunistic infection, or progression to CD4 count thresholds (<=200 or <=350 cells/mm3). Secondary outcomes included HIV plasma viral load and CD4 count.
Seven studies were included. No definitive relationship was observed between HSV-2 seropositivity and time to antiretroviral initiation (n=2 studies), CD4<=350 (n=1), CD4<=200 (n=1), death (n=1), viral load (n=6) or CD4 count (n=3). Although two studies each observed trends towards accelerated progression to clinical AIDS/opportunistic infection in HSV-2 seropositives, with pooled unadjusted hazard ratio=1.85 (95%CI=1.12,3.06; I2=2%), most OIs observed in the study for which data were available can occur at high CD4 counts and may not represent HIV progression. In contrast, a single study HSV-2 disease activity found that the presence of genital HSV-2 DNA was associated with a 0.4 log copies/mL increase in HIV viral load.
Despite an observation that HSV-2 activity is associated with increased HIV viral load, definitive evidence linking HSV-2 seropositivity to accelerated HIV disease progression is lacking. The attenuating effects of acyclovir on HIV disease progression observed in recent trials may result both from direct anti-HIV activity as well as from indirect benefits of HSV-2 suppression.
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ABSTRACT: Combination antiretroviral therapy (cART) has resulted in tremendous gains in survival among HIV-infected patients, but as a group those who achieve undetectable viral loads on cART experience a greater degree of immune activation and inflammation than the general population. HIV-infected patients continue to experience premature immune senescence with earlier and more frequent non-AIDS events compared to HIV-uninfected individuals. Chronic immune activation during suppressive cART derives from a variety of sources mediated by cytokines, chemokines, coagulation, microbial translocation, immune regulators and T(effector) cell activation abnormalities, among others. Current investigational strategies to control immune activation target potential causes of persistently heightened immune activation during cART such as microbial translocation, co-infections, and comorbidities or mediators along a common final pathway. Although several interventions have shown promise in vitro or in preliminary clinical trials, no intervention has sufficient evidence for routine use, making control of immune activation during cART an unmet need.
Available from: cid.oxfordjournals.org
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Human immunodeficiency virus (HIV) is associated with increased systemic inflammation and immune activation that persist despite suppressive antiretroviral therapy (ART). Herpes simplex virus type 2 (HSV-2) is a common coinfection that may contribute to this inflammation.
Sixty HIV type 1 (HIV-1)/HSV-2-coinfected adults on suppressive ART were randomized 1:1:1 to 12 weeks of placebo, low-dose valacyclovir (500 mg twice daily), or high-dose valacyclovir (1 g twice daily) in this 18-week trial. Co-primary outcome measures were the percentage of activated (CD38(+)HLA-DR(+)) CD8 T cells in blood, and highly sensitive C-reactive protein, interleukin 6, and soluble intercellular adhesion molecule 1 in plasma. Secondary outcomes included additional immune, inflammatory cytokine, and endothelial activation markers. The impact of valacyclovir (both groups combined) on each outcome was estimated using treatment × time interaction terms in generalized estimating equation regression models.
Participants were mostly white (75%) men who have sex with men (80%). Median age was 51 (interquartile range [IQR], 47-56) years, median duration of HIV infection was 15 (IQR, 8-21) years, median CD4 count at enrollment was 520 (IQR, 392-719) cells/µL, and median nadir CD4 count was 142 (IQR, 42-240) cells/µL. Valacyclovir was not associated with significant changes in any primary or secondary immunological outcomes in bivariate or multivariable models. Medication adherence was 97% by self-report, 96% by pill count, and 84% by urine monitoring. Eight patients had adverse events deemed possibly related to the study drug (5 placebo, 1 low-dose, 2 high-dose), and 6 patients reported at least 1 HSV outbreak (3 placebo, 3 low-dose, 0 high-dose).
Valacyclovir did not decrease systemic immune activation or inflammatory biomarkers in HIV-1/HSV-2-coinfected adults on suppressive ART.
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