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Effect of HSV-2 Suppressive Therapy on HIV-1 Genital Shedding and Plasma Viral Load: A Proof of Concept Randomized Double-Blind Placebo Controlled Trial (ANRS 1285 Trial)
Nicolas Nagot*1,2, A Ouedraogo2, P Mayaud1, I Konate2, L Vergne2, H Weiss1, V Foulongne3, D Djagbare2, M Segongy3, P Vande Perre3, and ANRS 1285 Study Group
1London Sch of Hygiene and Tropical Med, UK; 2Ctr Muraz, Bobo-Dioulasso, Burkina Faso; and 3Univ Hosp, Montpellier, France
Background: Epidemiological data suggest that HSV-2
infection can increase HIV-1 genital shedding, thus potentially increasing
HIV-1 transmissibility from co-infected individuals. Although biologically
plausible, this causal relationship has never been proven.
Methods: We conducted a proof-of-concept, randomized controlled trial of
Valacyclovir (VACV) suppressive treatment (1.0 g daily for 3 months) among
HIV-1/HSV-2 co-infected women not eligible for HAART in Burkina Faso.
We evaluated effect on HIV-1 genital shedding (primary outcome), as well as
HSV-2 genital shedding and HIV-1 plasma viral load (secondary outcomes). Participants
were followed bi-weekly for 3 months prior to, and 3 months after randomization
for a total of 12 visits. At each visit, a cervicovaginal
lavage enriched by cervical swabbing (eCVL) was collected for HSV-2 DNA and HIV-1 RNA quantitation by real time PCR. Primary statistical analyses
were based on an intention-to-treat approach, censoring women who became
pregnant during the trial. For each woman, the outcome was the difference in
mean quantity of shedding (log copies/mL) between the
treatment and the baseline phases. The mean of these differences (∆) was
then compared between the 2 arms. The effect of the intervention on frequency
and persistence of viral shedding was estimated using logistic regression.
Results: We randomized 140 women (70 in each arm) to
VACV or placebo (mean CD4 count 519 and 482/µL, respectively). Overall, 93% of
visits were attended, with a mean treatment compliance of 97%. The reduction in
HIV-1 RNA genital shedding was significantly greater in the VACV group than in
the placebo group (∆= –0.26 vs +0.09 log copies/mL, p =
0.003). HIV-1 shedding
was significantly less persistent in the VACV group (14.3% vs
27.1% shed at each visit; 27.1% vs 44.3% shed at ≥50%
of visits; 32.9% vs 14.3% shed at <50% of visits;
and 25.7% vs 14.3% never shed, p = 0.007). HIV-1 PVL was also reduced in the VACV group (∆=
– 0.39 vs +0.12 log copies/mL,
p <0.001), as was HSV-2 DNA shedding
(∆= –0.22 vs +0.18 log
copies/mL, p <0.001). The proportion of women shedding
HSV-2 at least once was 18.6% in the VACV arm and 54.3% in the placebo arm (p <0.001).
Conclusions:
Active HSV-2 infection is causally related to increased HIV-1 genital shedding, with implications at the
systemic level. HSV-2 control interventions may contribute to reduce sexual
transmissibility of HIV-1 and may delay HAART eligibility in dually infected
women.
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