Celum C, Wald A, Hughes J, Sanchez J, Reid S, Delany-Moretlwe S et al.Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial. Lancet 371:2109-2119

Department of Global Health, University of Washington, Seattle, WA, USA.
The Lancet (Impact Factor: 45.22). 07/2008; 371(9630):2109-19. DOI: 10.1016/S0140-6736(08)60920-4
Source: PubMed


Across many observational studies, herpes simplex virus type 2 (HSV-2) infection is associated with two-fold to three-fold increased risk for HIV-1 infection. We investigated whether HSV-2 suppression with aciclovir would reduce the risk of HIV-1 acquisition.
We undertook a double-blind, randomised, placebo-controlled phase III trial in HIV-negative, HSV-2 seropositive women in Africa and men who have sex with men (MSM) from sites in Peru and the USA. Participants were randomly assigned by block randomisation to twice daily aciclovir 400 mg (n=1637) or matching placebo (n=1640) for 12-18 months, and were seen monthly for dispensation of study drug, adherence counselling and measurement by pill count and self-reporting, and risk reduction counselling, and every 3 months for genital examination and HIV testing. The primary outcome was HIV-1 acquisition and secondary was incidence of genital ulcers. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00076232.
3172 participants (1358 women, 1814 MSM) were included in the primary dataset (1581 in aciclovir group, 1591 in control group). The incidence of HIV-1 was 3.9 per 100 person-years in the aciclovir group (75 events in 1935 person-years of follow-up) and 3.3 per 100 person-years in the placebo group (64 events in 1969 person-years of follow-up; hazard ratio 1.16 [95% CI 0.83-1.62]). Incidence of genital ulcers on examination was reduced by 47% (relative risk 0.53 [0.46-0.62]) and HSV-2 positive genital ulcers by 63% (0.37 [0.31-0.45]) in the aciclovir group. Adherence to dispensed study drug was 94% in the aciclovir group and 94% in the placebo group, and 85% of expected doses in the aciclovir group and 86% in the placebo group. Retention was 85% at 18 months in both groups (1028 of 1212 in aciclovir group, 1030 of 1208 in placebo group). We recorded no serious events related to the study drug.
Our results show that suppressive therapy with standard doses of aciclovir is not effective in reduction of HIV-1 acquisition in HSV-2 seropositive women and MSM. Novel strategies are needed to interrupt interactions between HSV-2 and HIV-1.

Download full-text


Available from: Stewart E Reid, Mar 22, 2014
  • Source
    • "Under the intervention model, men also may opt for circumcision. Behavioral parameters are derived from multiple studies, predominantly the Peru 2008 Sentinel Surveillance [35] and the baseline of HPTN-039 (a trial of daily oral HSV-2 suppressive therapy with acyclovir to prevent HIV acquisition) [36], and are summarized in the Appendix in [15]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Three trials have demonstrated the prophylactic effect of male circumcision (MC) for HIV acquisition among heterosexuals, and MC interventions are underway throughout sub-Saharan Africa. Similar efforts for men who have sex with men (MSM) are stymied by the potential for circumcised MSM to acquire HIV easily through receptive sex and transmit easily through insertive sex. Existing work suggests that MC for MSM should reach its maximum potential in settings where sexual role segregation is historically high and relatively stable across the lifecourse; HIV incidence among MSM is high; reported willingness for prophylactic circumcision is high; and pre-existing circumcision rates are low. We aim to identify the likely public health impact that MC interventions among MSM would have in one setting that fulfills these conditions—Peru—as a theoretical upper bound for their effectiveness among MSM generally. Methods and Findings We use a dynamic, stochastic sexual network model based in exponential-family random graph modeling and parameterized from multiple behavioral surveys of Peruvian MSM. We consider three enrollment criteria (insertive during 100%, >80% or >60% of UAI) and two levels of uptake (25% and 50% of eligible men); we explore sexual role proportions from two studies and different frequencies of switching among role categories. Each scenario is simulated 10 times. We estimate that efficiency could reach one case averted per 6 circumcisions. However, the population-level impact of an optimistic MSM-MC intervention in this setting would likely be at most ∼5–10% incidence and prevalence reductions over 25 years. Conclusions Roll-out of MC for MSM in Peru would not result in a substantial reduction in new HIV infections, despite characteristics in this population that could maximize such effects. Additional studies are needed to confirm these results for other MSM populations, and providers may consider the individual health benefits of offering MC to their MSM patients.
    PLoS ONE 07/2014; 9(7):e102960. DOI:10.1371/journal.pone.0102960 · 3.23 Impact Factor
  • Source
    • "However, lack of effect may have been the result of poor adherence to study drug, suboptimal drug concentrations at the given dose, or ineffective study drug (Celum et al. 2008; Watson-Jones et al. 2008; Zhu et al. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To assess the long-term effects of population-level HSV-2 infection on HIV incidence. Data from a population-based cohort in south-western Uganda were used to estimate HIV incidence from 1990 to 2007. Stored blood samples were tested for HSV-2, and the impact of HSV-2 prevalence and incidence on HIV incidence was estimated by calculating population attributable fractions (PAFs). The association between population-level annual HIV incidence and annual HSV-2 incidence/prevalence was analysed using linear regression. HIV incidence declined over time among men, from 8.72/1000 person-years (pyr) in 1990 to 4.85/1000 pyr in 2007 (P-trend <0.001). In contrast, there was no decline in HIV incidence among women (4.86/1000 pyr in 1990 to 6.74/1000 pyr in 2007, P-trend = 0.18). PAFs of incident HIV attributable to HSV-2 were high (60% in males; 70% in females). There was no evidence of an association between long-term trends in HIV incidence and HSV-2 prevalence or incidence. Assuming a causal relationship, a substantial proportion of new HIV infections in this population are attributable to HSV-2. The study did not find an effect of HSV-2 prevalence/incidence on trends in HIV incidence. HIV incidence did not vary much during the study period. This may partly explain the lack of association.
    Tropical Medicine & International Health 10/2013; 18(10):1257-66. DOI:10.1111/tmi.12176 · 2.33 Impact Factor
  • Source
    • "Within each adherence category, we examined the effect of treatment arm on a biological outcome: for HPTN 039, genital ulcer disease (GUD) with HSV-2 aetiology confirmed by HSV DNA PCR, based on quarterly genital exams [22], and for Mwanza, genital HSV-2 DNA shedding at the 6, 12 and 24 month visits, when samples were collected [21]. Random-effects logistic regression was used to estimate odds ratios (OR) for the association of treatment with the detection of GUD or HSV-2 shedding at each visit. "
    [Show abstract] [Hide abstract]
    ABSTRACT: For trials of user-dependent HIV prevention products, accurate adherence measurements are essential to interpret and compare results across trials. We used pill count data from two recent HIV prevention trials of herpes simplex virus type 2 (HSV-2) suppression, to show that estimates of adherence vary substantially depending on assumptions that are made in analysing pill count data. We associate calculated adherence with biological markers of anti-HSV-2 activity. In both trials, calculated adherence varied considerably, depending on the summary measure used, and the handling of intervals with apparent 'over-adherence' (fewer pills returned than expected), and unreturned pills. Intervals of apparent over-adherence were associated with reduced antiviral effects on biological markers of herpes reactivation, indicating these are likely to represent periods of non-adherence. Our results demonstrate the clear need for standardisation in reporting of adherence data that are based on pill counts.
    AIDS and Behavior 06/2013; 17(9). DOI:10.1007/s10461-013-0542-9 · 3.49 Impact Factor
Show more