The intervention and control arm men were comparable with respect to sociodemographic and behavioral characteristics at enrollment (). The prevalence of HR-HPV at enrollment was 39.1% in the intervention arm and 38.6% in the control arm (p = 0.17).
Participant characteristics at enrollment
At enrollment, and prior to circumcision, the proportions of samples with amplifiable cellular DNA were 78.0%% (344/441) in the intervention and 76.7% (306/399) in the control arm. Among the intervention arm men, the proportion of samples with amplifiable cellular DNA declined over time to 63.0% (208/330) at twelve months and 60.8% (240/395) at 24 months (p <0.001). However, there was no decline in the proportion of samples with amplifiable cellular DNA among uncircumcised controls at 12 months (76.8%, 241/314) or 24 months (75.3%, 272/361), and this difference between study arms at 24 months was statistically significant (p<0.001).
The incidence of new HR-HPV infections or genotypes was determined for samples with amplifiable cellular or viral DNA at sequential study visits (). In an intention to treat analysis over the 24 months follow up, 70 intervention arm men acquired one or more new HR-HPV infections (incidence 19.7/100 py), whereas among controls 125 men acquired one or more HR-HPV infections with an incidence rate of 29.4/100 py (IRR = 0.67, 95%CI 0.50-0.90). During the first year of follow up, the incidence rate was significantly lower in the intervention group (IRR= 0.61, %95CI 0.44-0.85), while during the second year of follow up, the effect was of borderline statistical significance (IRR=0.64, 95%CI 0.38-1.07). HR-HPV incidence declined over time in both study arms, partly because participants with higher risk sexual behaviors acquired infections in the first follow up year, and thus could not contribute to incident infections with the same genotype during the second follow up year. There were no significant differences in HR-HPV incidence between study arms among men who only acquired a single HR-HPV infection (IRR=0.89, 95%CI 0.60-1.30). However, the acquisition of multiple HR-HPV infections over 24 months was markedly lower among men in the intervention arm (6.7/100 py) than in the control arm (14.8/100 py) with an IRR = 0.45 (95%CI 0.28-0.73). In an as treated analysis, the incidence of any HR-HPV infection was 20.6/100 py (72/350) in the intervention arm and 28.6/100 py (123/430.5 py) in the control with an IRR of 0.72 (95%CI 0.54-0.96). The as treated incidence of multiple (two or more) HR_HPV infections was 7.1/100 py (25/350 py) in the circumcised men and 14.4/100 py (62/430.5 py) in the controls with an IRR = 0.50, 95%CI 0.31-0.79).
HR-HPV Incidence by study arm and follow up interval for participants with amplifiable cellular or viral DNA at sequential study visits.
The incidence of type-specific HR-HPV over 24 months was lower in intervention than control arm men for all high risk genotypes examined (), and these differences were statistically significant for HR-HPV genotypes 18 (IRR = 0.30, 95%CI 0.10-0.75) and 33 (IRR = 0.17, 95%CI 0.19-0.0.74).
Type-specific HR-HPV Incidence over 24 Months, by Study Arm
The rates of HR-HPV acquisition were lower in the intervention than the control arm in all sociodemographic and behavioral subgroups (). Among controls, HR-HPV incidence was higher in younger men and declined with age, but no age-related trend was observed among intervention arm men. The effect of circumcision on HR-HPV acquisition was statistically significant among men reporting high risk sexual behaviors such as non-use of condoms (IRR=0.67, 95%CI 0.46-0.98), and multiple sex partners (IRR=0.56, 95% 0.36-0.87). After adjustment for covariates associated with HR-HPV at enrollment (age, education, condom use, alcohol consumption with sex, and number of sex partners), the adjusted incidence rate ratio of HR-HPV acquisition in circumcised relative uncircumcised men was 0.67 (95%CI 0.50-0.91, p = 0.008.)
The incidence of High Risk HPV (HR-HPV) over 24 months stratified by sociodemographic and behavioral covariates
We also assessed acquisition of low risk HPV genotypes (LR-HPV). The 24 month incidence of any LR-HPV genotype was 29.9/100 py (102/341.5 py) in the intervention arm and 35.0/100 py (144/411 py) in the control arm (IRR 0.84, 95%CI 0.66-1.10). For single LR-HPV infections, the incidence was 19.3/100py (36/41.5py) in the intervention arm and 17.8/100 py (73/411 py) in the controls (IRR = 1.09, 95%CI 0.78-1.52). However, the incidence of multiple LR-HPV infections was 10.5/100 py (36/341.5py) in the intervention and 17.3/100 py (71/411 py) in the controls (IRR = 0.61, 95%CI 0.41-0.91).
Clearance of HR-HPV infections is shown in . Clearance rates per 100 py observation were higher in the intervention (215.8/100 py) than the control arm (159.1/100 py), with a RR=1.36 (95%CI 1.13-1.63). The rates of clearance per 100 py were increased for most genotypes and this was statistically significant for types 39, 51 and 58 (Table 7). After adjustment for age, education, number of sex partners and condom use, the ratio of clearance rates in the intervention relative to the control arm was 1.39 (95%CI 1.17-1.64). Among men in the intervention arm, 77.7% (205/264) of pre-existing HR-HPV infections were cleared over the 24 months observation period, whereas clearance was 66.9% (255/381) among the controls (RR = 1.16, 95%CI 1.05-1.28). In multivariate analyses, the adjusted RR of percent clearance was 1.17 (95%CI 1.05-1.31).
Clearance of genotype-specific pre-existing HR-HPV infection as a rate per 100 person years, by study arm