Fifty-eight of 128 participants enrolled in the 3 trials were eligible for inclusion in this analysis (). Thirty-one of 60 persons were excluded from study 1 (13 because they did not have evidence of HHV-8 infection, 10 because they only completed one study arm, and 8 because they collected less than 30 days of oral swabs in one or both study arms), 7 of 20 persons were excluded from study 2 (6 because they did not have evidence of HHV-8 infection and 1 because they only completed one study arm), and 32 of 48 persons were excluded from study 3 (15 because they did not have evidence of HHV-8 infection, 14 because they collected less than 30 days of oral swabs in one or both study arms, and 3 because they only completed one study arm).
Participants from study 1 tended to be older (median age of 44) than those from the other two studies (median ages of 31 for study 2 and 36 for study 3; ).
Study participant demographic and clinical characteristics including those completing only one study arm.
Participants in studies 1 and 3 were primarily white, while those from study 2 were Peruvian (reflecting study location). Ninety-two percent of participants in all three studies were men who have sex with men (MSM). Participants in study 1 tended to have a greater time since HIV diagnosis than those in study 3 (this information was not available for participants in study 2). Antiretroviral use was markedly different across studies, with 59% of participants from study 1 on HAART and the remaining participants not taking any antiretroviral treatment. Median CD4 count was similar across studies, whereas median HIV viral load was lower in study 1, reflecting inclusion criteria of that study.
Fifty-eight participants contributed 6036 oropharyngeal swabs for analysis (). Thirty-four (59%) of 58 men had HHV-8 detected in at least three oral swabs. Of the 58 participants, 11 (19%) were PCR positive only, 24 (41%) were only positive by serology, and 23 (40%) were positive by both measures. The median person-level oral HHV-8 shedding rates during placebo sessions were 0% (IQR: 0 – 34%) for study 1, 2% (IQR: 0 – 4%) for study 2, and 8% (IQR: 1 – 69%) for study 3. The overall frequency of HHV-8 detection during placebo administration was 19% of days (269/1449) for study 1, 12% (85/716) for study 2, and 32% (264/827) for study 3.
HHV-8 shedding rates and quantities detected in oropharyngeal swabs collected among participants completing both study arms, for A. by study arms, and B. by HAART use.
Effect of valacyclovir and famciclovir on the detection of HHV-8 in the oropharynx
HHV-8 was detected in 34 (59%) of 58 participants receiving placebo, 26 (62%) of 42 receiving valacyclovir, and 5 (31%) of 16 receiving famciclovir. Overall, HHV-8 was detected in 1128 (19%) of 6036 oropharyngeal swabs, including 618 (21%) of 2992 swabs from participants receiving placebo, 323 (15%) of 2221 swabs from those on valacyclovir treatment and 187 (23%) of 823 swabs from those on famciclovir ().
There was a wide distribution of shedding frequencies among participants from all three groups (); however, median shedding frequency was slightly lower among participants on famciclovir compared to those on valacyclovir and placebo (, ).
Change in HHV-8 Oropharyngeal Detection Rates between Placebo and Antiviral Drug Arms, by Participant
Valacyclovir decreased HHV-8 shedding frequency by 18% (95% confidence interval [CI], 4%–29%; P = 0.01) and famciclovir by 30% (95% CI, 16%–42%; P < 0.001; ), respectively, compared to placebo. These estimates did not substantially change in the multivariate model ().
Univariate and multivariate model of HHV-8 shedding rate for persons completing both study arms.
The reduction in HHV-8 shedding frequency was not associated with a reduction in viral copy number on days with detectable shedding. On days that HHV-8 was detected, the median log10 copies of HHV-8 DNA/ml detected in oral swabs was somewhat greater among participants on valacyclovir (5.26) compared to placebo (4.44) and famciclovir (4.68, ). Valacyclovir and famciclovir increased HHV-8 log10 copies/ml by 0.132 (95% CI 0.016 lower to 0.280 higher; P = 0.081) and 0.218 (95% CI 0.049–0.387; P = 0.012), respectively, compared to placebo. No other covariates were associated with HHV-8 quantity.
Effect of antiretroviral therapy on the detection of HHV-8 in the oropharynx
Seventeen participants on HAART contributed 1761 oropharyngeal swabs for analysis. Four participants on non-HAART ART and 35 participants not taking any ART contributed 4074 oropharyngeal swabs for analysis. HAART regimens included 5 participants taking a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, 11 participants taking a protease inhibitor (PI)-based regimen, and 1 participant who was on a NNRTI-based regimen during the placebo arm and a PI-based regimen during the drug arm. Among participants taking a PI-based regimen, 10 were on dual PIs and 1 was on three PIs. All participants taking a NNRTI-based regimen were on only one NNRTI.
HHV-8 was detected in 93 (5%) of 1761 oropharyngeal swabs on HAART compared to 1034 (25%) of 4074 oropharyngeal swabs not on HAART (, above).
HHV-8 oral shedding rates were 89% (95% CI 58%–97%; P = 0.001) lower among participants on HAART compared to those not taking HAART (, ). This estimate did not change substantially in the multivariate model; however, the strength of the association was attenuated (). Of note, HIV viral load was the only other covariate associated with HHV-8 shedding in a univariate model, but this association was not statistically significant after adjusting for HAART use and study drug (). The combination of ART and antiviral therapy showed no synergistic benefit in reducing HHV-8 shedding though numbers of observations in each stratum were small.HHV-8 copy number on days with detectable shedding was significantly different by HAART use (Table IIb; data not shown).
Change in HHV-8 Oropharyngeal Detection Rates by Highly Active Antiretroviral Therapy Use