Among HIV infected men undergoing medical male circumcision (MC), resumption of sexual intercourse prior to wound healing is associated with increased risk of HIV transmission to female partners. We previously reported that penile HIV shedding increases post-MC. In this study, we examined the association between pro-inflammatory cytokines and penile HIV shedding.
A prospective cohort study of 223 HIV-infected men undergoing dorsal slit MC was conducted between June 2009 and April 2012 in Rakai, Uganda. Preoperative and weekly penile lavages from 1-4 weeks post-MC (n=1034 visits) were tested for pro-inflammatory cytokines (IFN-γ, IL-10, IL-12p70, IL-13, IL-1β, IL-2, IL-4, IL-6, IL-8, and TNF-α) by an electrochemiluminescence immunoassay (Meso Scale Discovery Inc.). Cytokines with <1% detection (IFN-γ, IL-12p70, & IL-4) were excluded from analyses. Modified Poisson regression with generalized estimating equations and robust variance estimators were used to estimate prevalence risk ratios (PRRs) for penile HIV shedding at weeks 1-4 post-MC. Models were run for each cytokine individually. Among detectable samples, log10 cytokine levels were compared by penile HIV shedding status using the Wilcoxon rank-sum test and correlations with penile log10 HIV RNA were determined by Spearman’s rank-order test corrected for multiple comparisons (Bonferroni method).
Penile HIV and HSV-2 shedding was detected among 13.7% (141/1026) and 10.8% (87/805) of sample visits, respectively. Relative to baseline, detection of each cytokine was higher during wound healing weeks 1-3 post-MC (P<0.01), except for IL-2 (P=0.072; n=1031). Detection of all cytokines was lower among healed wounds (P<0.01; n=791). Baseline plasma HIV VL, CD4 count, genital ulcer disease, and antiretroviral therapy were not associated with cytokine detection. HIV shedding 1-4 weeks post-MC was associated with the detection of IL-1β, IL-2, IL-6, IL-8, IL-13, and TNF-α after adjusting for HSV-2 shedding and study visit (P<0.05; n=630). Log10 IL-1β and IL-8 levels were higher among visits with HIV shedding than non-shedding visits 1-4 weeks post-MC (P<0.01). Log10 IL-1β, IL-6, IL-8, IL-13, and TNF-α levels were positively correlated with penile log10 HIV RNA levels (P<0.01).
An increase in genital pro-inflammatory cytokines is associated with HIV shedding from MC wounds. Strategies to reduce genital inflammation post-MC and HIV shedding during wound healing may help to prevent male to female transmission.