Twenty-eight participants collected swabs of genital skin and mucosa during both study arms. The HSV shedding rate did not differ between the study arms: HSV was detected on 55 (7.8%) of 707 days on valacyclovir and 59 (8.2%) of 718 days on acyclovir (relative risk: 0.95; 95% CI: 0.66 to 1.37; P = 0.78). There were 19 HSV shedding episodes on acyclovir and 18 on valacyclovir. No significant difference was seen in the episode duration by treatment arm (P = 0.68). The median quantity of HSV-2 DNA for positive samples was 3.0 log10 copies per milliliter on both arms (range: acyclovir, 2.2–6.4 log10 copies per milliliter; valacyclovir, 2.2–6.8 log10 copies per milliliter; P = 0.67). Genital lesions were present on 7 (1.0%) of 772 days, occurring in only 1 participant during the valacyclovir arm, compared with 27 (4.0%) of 750 days, occurring in 2 participants during the acyclovir arm (P = 0.16). Ninety-three percent of the participants did not report any genital lesion throughout the study, and 94% of all shedding episodes were asymptomatic. There was a significant period effect such that rates of HSV-2 shedding were 76% (range: 60%–85%) lower during the second treatment arm compared with the first treatment arm regardless of the treatment given (P < 0.001). There was no significant drug carryover (P = 0.58). When the participant receiving interferon and ribavirin was excluded from analysis, we still found no significant difference in the rate of HSV detection on valacyclovir compared with acyclovir (relative risk: 0.82; 95% CI: 0.55 to 1.23; P = 0.33).
CMV DNA was detected in 6 plasma samples from 5 participants during treatment with acyclovir and 6 samples from 2 participants during treatment with valacyclovir. The mean quantity of CMV DNA for positive samples was 2.00 log10 copies per milliliter during acyclovir and 1.99 log10 copies per milliliter during valacyclovir treatment.
Our findings are limited by high loss to follow-up, which is especially problematic in crossover studies and decreases power. HIV-1–infected patients with detectable plasma HIV-1 RNA are becoming increasingly difficult to enroll in studies in developed countries where antiretrovirals are available and prescribed early in the course of HIV-1 disease to decrease associated morbidity and mortality, prevent transmission to sexual partners, and reduce community viral load.47 Because persons who remain viremic and not on treatment are often those with psychosocial comorbidities, such as serious mental illness, substance abuse, and poverty,48–50 maintaining high adherence to study protocol has become challenging in this population. As we collected swabs on a daily basis, we may have underestimated the frequency of shedding by missing episodes <24 hours in duration,25 although this would be expected to similarly affect both arms. The crossover design of this trial, with each participant serving as their own control, increased efficiency and decreased potential confounding. This design also mitigated potential ramifications of the period effect that we found for HSV-2 shedding rates, because in the second treatment period, each group received a different drug.
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