Paul J. Feldblum

The acute phase of HIV infection carries substantial risk of transmission; identification of acute-phase infections may offer opportunities to reduce that risk. SMARTube incubation of blood specimens is designed to stimulate in vivo-primed HIV-specific lymphocytes to produce HIV antibodies in vitro. The resulting supernatant (S-plasma) can be tested to identify acute infections with commercially available HIV assays. We assessed the performance of the SMARTube to identify acute HIV infections in studies at three developing country sites. We conducted HIV incidence studies in Ho Chi Minh City, Vietnam, and Bloemfontein and Rustenburg, South Africa. We estimated HIV incidence in cross-sectional samples, and measured prospective incidence in uninfected women followed for up to 12 months. We incorporated SMARTube into the HIV testing algorithm at cross-sectional screening and monthly follow-up visits. We tested 1384 persons in Vietnam, 1145 women in Bloemfontein, and 538 persons in Rustenburg. Cross-sectional samples from 11 participants that tested positive with SMARTube after an un-incubated initial-test negative result (11 of 2472; 0.4% of all specimens) were considered “potential acute” infections. Matching samples from 3 of the 11 (27.3%) were confirmed by PCR testing. In follow-up of 355, 401 and 223 uninfected women in Vietnam, Bloemfontein and Rustenburg, respectively, 11 seroconversions occurred in Bloemfontein and Rustenburg. In four of these incident infections (36.4%), SMARTube testing had resulted in earlier detection of HIV infection than the eventual seroconversion visits. In our field studies, pre-treatment with SMARTube allowed the identification of acute HIV-1 infection in some new infections, but with a positive predictive value of 27%. Larger studies are needed to evaluate SMARTube as an alternative to technically challenging and costly EIA and PCR testing to detect acute HIV infection.

To assess the safety, effectiveness, and acceptability of providing a reduced number of ShangRing sizes for adult voluntary medical male circumcision (VMMC) within routine service delivery in Lusaka, Zambia. We conducted a randomized controlled trial and enrolled 500 HIV-negative men aged 18–49 years at 3 clinics. Participants were randomized to 1 of 2 study arms (Standard Sizing arm vs Modified Sizing arm) in a 1:1 ratio. All 14 adult ShangRing sizes (40–26 mm inner diameter, each varying by 1 mm) were available in the Standard Sizing arm; the Modified Sizing arm used every other size (40, 38, 36, 34, 32, 30, 28 mm inner diameter). Each participant was scheduled for 2 follow-up visits: the removal visit (day 7 after placement) and the healing check visit (day 42 after placement), when they were evaluated for adverse events (AEs), pain, and healing. Four hundred and ninety-six men comprised the analysis population, with 255 in the Standard Sizing arm and 241 in the Modified Sizing arm. Three men experienced a moderate or severe AEs (0.6%), including 2 in the Standard Sizing arm (0.8%) and 1 in the Modified Sizing arm (0.4%). 73.2% of participants were completely healed at the scheduled day 42 healing check visit, with similar percentages across study arms. Virtually all (99.6%) men, regardless of study arm, stated that they were very satisfied or satisfied with the appearance of their circumcised penis, and 98.6% stated that they would recommend ShangRing circumcision to family/friends. The moderate/severe AE rate was low and similar in the 2 study arms, suggesting that provision of one-half the number of adult device sizes is sufficient for safe service delivery. Effectiveness, time to healing, and acceptability were similar in the study arms. The simplicity of the ShangRing technique, and its relative speed, could facilitate VMMC program goals. In addition, sufficiency of fewer device sizes would simplify logistics and inventory.

Objectives: To explore factors associated with healing requiring more than 6 weeks after placement of the PrePex device for adult medical male circumcision. Methods: We enrolled 427 men ages 18–49 years in an observational study of PrePex at 1 urban and 2 peripheral clinics in western Kenya. Participants were scheduled for device removal at day 7 and a follow-up visit at day 42 (allowable range, 40–44) at which the provider recorded wound status, with complete healing defined as a dry wound without any scab, later confirmed by site investigator review of digital penile photographs. We performed univariate and multivariate logistic regression to explore associations between selected demographic, surgical, and follow-up factors and delayed healing (not healed by day 42 visit). Results: Of the 427 men, 341 completing a day 42 visit with physical examination and recorded healing status were included. Fifty-four percent of included men were healed by day 42 visit. Factors associated with delayed healing in univariate analysis and remaining significant in the multivariate analysis were as follows: age 25 years or older [odds ratio (OR): 1.8; 95% confidence interval (CI): 1.4 to 2.4], an adverse event by day 44 (OR: 1.4; 95% CI: 1.03 to 2.0), and severe pain during device removal (protective association: OR: 0.7; 95% CI: 0.5 to 0.99). Conclusions: Older age (25+ years), occurrence of an adverse event, and lesser self-reported pain at device removal were associated with delayed wound healing. If confirmed by larger surveillance studies, these results should be incorporated into the counseling given to male circumcision clients.

To ascertain clinical sequelae, client satisfaction and sexual behavior 2+ years after male circumcision using the ShangRing device. We enrolled 199 men from the Kenya sites (Homa Bay district) participating in a 2012 study of the ShangRing device used in routine male circumcision services (N = 552). We enrolled men who had had the ShangRing placed successfully, and over-sampled men who had had an adverse event and/or were HIV-positive during the field study. In the present study, each participant was examined and interviewed by a study clinician, and penile photographs were taken to document longer-term cosmetic results and any abnormal findings. 194 men were included in the analysis. The mean and median times between circumcision and the longer-term follow-up visit in this study were 31.8 and 32 months, respectively. Four men (2.1%) had signs/symptoms of a sexually transmitted infection (STI). Virtually all (99.5%) of the men were very satisfied with the appearance of their circumcised penis, and all would recommend a ShangRing circumcision to friends or family members. The most prevalent reported advantage of the circumcision was the ease of bathing and enhanced cleanliness of the penis (75.8%). 94.3% of the men did not cite a single negative feature of their circumcision. 87.5% of men reported more sexual pleasure post-MC, the most common reason being more prolonged intercourse. The majority of men (52.6%) reported one sexual partner post-MC, but more than a quarter of the men (28.1%) reported an increased number of partners post-MC. Less than half of the men (44.3%) reported using condoms half of the time or more, but the great majority of condom users stated that condom use was much easier post-MC, and 76.9% of users said they used condoms more after circumcision than before. This study supports the safety and acceptability of ShangRing male circumcision during 2–3 years of follow-up. It should allay worries that the ShangRing procedure could lead to delayed complications later than the observation period of most clinical studies. ClinicalTrials.gov NCT01567436

Reliable HIV incidence estimates for Mozambique are limited. We conducted a prospective HIV incidence study as part of a clinical research site development initiative in Chókwè district, Gaza Province, southern Mozambique. Between June 2010 and October 2012, we recruited women at sites where women at higher risk of HIV infection would likely be found. We enrolled and tested 1,429 sexually active women in the screening phase and 479 uninfected women in the prospective phase. Participants were scheduled for 12+ months follow-up, when they underwent face-to-face interviews, HIV counseling and testing, and pregnancy testing. We observed a total of 373.1 woman-years (WY) of follow-up, with mean (median) of 9.4 (9.7) women-months per participant. The prevalence of HIV was 29.4% (95% confidence interval [CI]: 27.0–31.8%). In multivariable logistic regression analysis, factors that remained significantly associated with prevalent HIV were: older age (OR: 0.6; 95% CI: 0.4–0.7), lower educational level (OR: 0.4; 95% CI: 0.3–0.7), and using hormonal contraception (OR: 0.6; 95% CI: 0.4–0.7) or condoms (OR: 0.5; 95% CI: 0.3–0.7). We observed an HIV incidence rate of 4.6 per 100 WY (95% CI: 2.7, 7.3). The HIV incidence was 4.8 per 100 WY (95% CI: 2.5, 8.3) in women aged 18–24 years, 4.5 per 100 WY (95% CI: 1.2, 11.4) in women aged 25–29 years and 3.2 per 100 WY (95% CI: 0.1, 18.0) in the 30–35 years stratum. None of the demographic factors or time-varying behavioral factors examined was significantly associated with incident HIV infection in bivariable analysis at p≤0.10. We found a high HIV incidence among sexually active young women in Chókwè, Mozambique. HIV prevention programs should be strengthened in the area, with more comprehensive reproductive health services, regular HIV testing, condom promotion, and messaging about multiple sexual partners.

To assess the safety, effectiveness and acceptability of the PrePex device for adult medical male circumcision (MMC) in routine service delivery in Kenya. We enrolled 427 men ages 18–49 at one fixed and two outreach clinics. Procedures were performed by trained clinical officers and nurses. The first 50 enrollees were scheduled for six follow-up visits, and remaining men were followed at Days 7 and 42. We recorded adverse events (AEs) and time to complete healing, and interviewed men about acceptability and pain. Placement and removal procedures each averaged between 3 and 4 minutes. Self-reported pain was minimal during placement but was fleetingly intense during removal. The rate of moderate/severe AEs was 5.9% overall (95% confidence interval [CI] 3.8%–8.5%), all of which resolved without sequelae. AEs included 5 device displacements, 2 spontaneous foreskin detachments, and 9 cases of insufficient foreskin removal. Surgical completion of MMC was required for 9 men (2.1%). Among the closely monitored first 50 participants, the probability of complete healing by Day 42 was 0.44 (95% CI 0.30–0.58), and 0.90 by Day 56. A large majority of men was favorable about their MMC procedure and would recommend PrePex to friends and family. The PrePex device was effective for MMC in Kenya, and well-accepted. The AE rate was higher than reported for surgical procedures there, or in previous PrePex studies. Healing time is longer than following surgical circumcision. Provider experience and clearer counseling on post-placement and post-removal care should lead to lower AE rates. ClinicalTrials.gov NCT01711411

Objectives The primary objective was to measure HIV incidence in two prospective cohorts of HIV-negative women. Secondary objectives included measuring pregnancy rates and participant retention rates. Design Cross-sectional HIV screening of women selected for higher risk behaviours, with a subsequent prospective study of uninfected women, followed monthly for up to 6 months. Setting Clinics established for research purposes in Bloemfontein and Rustenburg, South Africa. Participants The authors enrolled women 18–35 years old and presumed at higher risk of sexual acquisition of HIV as indicated by self-reported sexual behaviour or recent sexually transmitted infection symptoms. In Bloemfontein, 1364 women were screened, 1154 were eligible for HIV testing and 1145 agreed to be tested. The prospective study enrolled 401 HIV-negative women. In Rustenburg, 946 women were screened, 540 were eligible and underwent HIV testing and 223 HIV-negative women entered the prospective study. Primary and secondary outcomes Baseline prevalences of HIV infection and HIV incidence rates in the prospective cohorts, according to a double rapid test algorithm with a third rapid test for discrepant or indeterminate results. Pregnancy prevalences and pregnancy incidence rate in Bloemfontein. Participant retention rates in the prospective cohort until the study end. Results In Bloemfontein, 1145 women were tested, 391 entered follow-up and 92.3% of participants completed six study visits. In Rustenburg, 540 women were tested, 194 entered follow-up and retention up to the point of early study termination was 88.6%. Overall HIV prevalence was 21.2% (95% CI 18.9% to 23.6%) in Bloemfontein and 23.5% (95% CI 19.9% to 27.1%) in Rustenburg. Overall HIV incidence was 5.5/100 person-years (95% CI 2.5 to 10.4) in Bloemfontein and 3.0/100 person-years (95% CI 0.4 to 10.8) in Rustenburg. Cross-sectional pregnancy prevalences were 6.5% in Bloemfontein and 8.6% in Rustenburg. Conclusions The authors observed substantial HIV incidence rates in both cohorts. Vigorous prevention efforts are needed in these smaller cities.

Vaginal microbicide gel trials for HIV prevention may require withdrawal of study product when a woman becomes pregnant. We assessed the potential impact of withdrawals in four trials by comparing self-reported sexual behavior pre- and post-pregnancy detection: (1) behavior in the month prior to positive pregnancy test versus behavior reported at the subsequent monthly visit; (2) behavior changes according to pregnancy status at the subsequent visit (continuing pregnancy versus not); (3) average sexual behaviors reported for all months prior to pregnancy detection versus all months after pregnancy was no longer detected; and (4) behavior changes among participants never testing positive for pregnancy. Pregnancy detection was associated with immediate reductions in self-reported numbers of partners and sex acts. The proportion of acts in which study gel was used following a negative pregnancy test did not return to pre-pregnancy levels. Pregnancies complicate the conduct and interpretation of vaginal microbicide trials when product must be withdrawn.