This systematic review did not identify conclusive evidence of an association between HSV-2 seropositivity and HIV disease progression, changes in plasma viral load, or CD4 cell count. Although two studies observed trends towards an accelerated progression to clinical AIDS or first OI [17, 18], most of the OIs observed in the study for which data were available can occur at high CD4 counts and may not represent progression of HIV ; further, compelling data linking HSV-2 seropositivity to other disease progression outcomes were lacking. One study found evidence that HSV-2 disease activity, defined as the presence of genital HSV-2 using PCR, is associated with increased viral load among HSV-2 seropositive individuals.
These observations must be considered in light of unequivocal data from interventional studies linking anti-HSV medications to decreased HIV viral loads and attenuated disease progression. In a meta-analysis of seven randomized trials of acyclovir or valacyclovir among HAART-untreated, HIV, HSV-2 co-infected persons, the summary treatment effect for HSV-2 suppression on plasma HIV RNA was −0.33 log copies/mL (95% CI=−0.56,-0.10) . Further, this effect appears to be dose-responsive; stratification by drug demonstrated greater decreases in viral load with valacyclovir than acyclovir in the meta-analysis . A meta-analysis from the pre-HAART era suggested that >3200 mg per day of acyclovir offered a significant survival benefit (hazard ratio, HR for mortality=0.78, 95% confidence interval, CI=0.65,0.93) , but it is unclear whether the improved survival was only related to eradication of herpesviruses (including HSV and CMV) or whether there could have been a secondary impact on HIV replication. Most recently, in the Partners in Prevention HSV/HIV Transmission Study of acyclovir 400 mg twice daily, the HR for the composite primary endpoint of CD4 count ≤200 cells/mm3, antiretroviral initiation, or death from non-traumatic causes, was 0.84 (95% CI=0.71,0.98) . In a similar trial from the Rakai district of Uganda, the composite primary endpoint was slightly different (CD4 count ≤250 cells/mm3 or the occurrence of any WHO stage 4 clinical event not including esophageal candidiasis), and the HR associated with acyclovir use was 0.75 (95% CI=0.58,0.99) .
Indirect benefits of HSV-2 suppression are thought to primarily underlie these effects, and the observation of increased HIV viral load with HSV-2 disease activity in the Burkina Faso study supports this hypothesis . But how might these findings be reconciled with the lack of convincing evidence of an effect of HSV-2 seropositivity on markers of HIV disease progression observed in this review? One explanation may be that all HSV-2 serology assays have limited sensitivity in early infection [21, 22], and no studies repeated testing on seronegative participants to test for seroconversion. However, the magnitude of this effect should be minimal, given the reported incidence of HSV-2 in HIV-infected populations of 1.8 to 7.3 per 100 person-years [14, 23]. A more plausible hypothesis is that considering only HSV-2 serostatus ignores the duration and activity of HSV-2 infection. Since the natural history of HSV-2 is characterized by a decreasing frequency of reactivations over time [24–27], overrepresentation of individuals with longstanding infection may produce HSV-2 seropositive cohorts with relatively inactive HSV-2. The magnitude of HIV upregulation by HSV-2 may instead depend on the degree of HSV-2 activity and be greatest during symptomatic herpes, as has been observed elsewhere . Studies of HSV-2 seropositivity cannot distinguish between periods of viral latency and reactivation, such that any impact of HSV-2 activity on HIV replication may have been diluted in some of the studies we included. In support of this notion, symptomatic genital ulcer disease of any etiology has been linked to accelerated HIV disease progression [2, 17, 29]. It is also likely that the positive relationship between HIV viral load and HSV-2 activity is partially confounded by HIV-related immunosuppression.
In contrast to the 0.4 log copies/mL increase in viral load associated with HSV-2 activity in the Burkinabé study , a recent randomized trial observed larger viral load decreases of −1.23 log copies/mL using valacyclovir 1.5g twice daily . Taken together, these observations suggest that reversing HSV-2 associated increases in HIV viral load may not be the only mechanism by which such drugs attenuate HIV. Direct antiretroviral effects of acyclovir and related drugs may also contribute, as have been observed in vitro by two independent groups [7, 8]. Arguing against this possibility, however, an evaluation of 168 HIV infected clinical trial participants receiving either acyclovir 400 mg twice daily or valacyclovir 500 mg twice daily for 8–104 weeks failed to identify the V75I reverse transcriptase mutation that confers acyclovir resistance most commonly observed in vitro . 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.
Strengths of this systematic review include our broad, multi-modality search strategy and the lack of language restrictions. There are also limitations that warrant consideration, and the robustness of our conclusions is dependent on the available evidence. First, few studies addressed our primary research question, restricting our ability to quantify the impact of HSV-2 seropositivity on HIV disease progression. Second, the measures used to define HSV-2 seropositivity and HSV-2 activity differed between studies. Although most type-specific serology assays have high, comparable levels of sensitivity and specificity when compared against the Western Blot gold standard, uncertainty regarding the optimal cutoff values in different populations and limitations of all assays in detecting early HSV-2 seroconversion may result in misclassification . Third, our assessment of the risk of study bias was necessarily subjective. However, we systematically applied criteria based on the STROBE statement as has been advised elsewhere, because of the lack of a single obvious candidate tool for this purpose in systematic reviews of observational studies . Fourth, differences in study populations and HIV clades may explain some observed differences between studies. Finally, inadequate control for confounding by variables such as anti-HSV drug use could have biased studies towards the null; further, no study systematically excluded HIV long-term non-progressors.