Benefits and Risks of Antiretroviral Therapy for Perinatal HIV Prevention.

BACKGROUND: Randomized-trial data on the risks and benefits of antiretroviral therapy (ART) as compared with zidovudine and single-dose nevirapine to prevent transmission of the human immunodeficiency virus (HIV) in HIV-infected pregnant women with high CD4 counts are lacking. METHODS: We randomly assigned HIV-infected women at 14 or more weeks of gestation with CD4 counts of at least 350 cells per cubic millimeter to zidovudine and single-dose nevirapine plus a 1-to-2-week postpartum "tail" of tenofovir and emtricitabine (zidovudine alone); zidovudine, lamivudine, and lopinavir-ritonavir (zidovudine-based ART); or tenofovir, emtricitabine, and lopinavir-ritonavir (tenofovir-based ART). The primary outcomes were HIV transmission at 1 week of age in the infant and maternal and infant safety. RESULTS: The median CD4 count was 530 cells per cubic millimeter among 3490 primarily black African HIV-infected women enrolled at a median of 26 weeks of gestation (interquartile range, 21 to 30). The rate of transmission was significantly lower with ART than with zidovudine alone (0.5% in the combined ART groups vs. 1.8%; difference, -1.3 percentage points; repeated confidence interval, -2.1 to -0.4). However, the rate of maternal grade 2 to 4 adverse events was significantly higher with zidovudine-based ART than with zidovudine alone (21.1% vs. 17.3%, P=0.008), and the rate of grade 2 to 4 abnormal blood chemical values was higher with tenofovir-based ART than with zidovudine alone (2.9% vs. 0.8%, P=0.03). Adverse events did not differ significantly between the ART groups (P>0.99). A birth weight of less than 2500 g was more frequent with zidovudine-based ART than with zidovudine alone (23.0% vs. 12.0%, P<0.001) and was more frequent with tenofovir-based ART than with zidovudine alone (16.9% vs. 8.9%, P=0.004); preterm delivery before 37 weeks was more frequent with zidovudine-based ART than with zidovudine alone (20.5% vs. 13.1%, P<0.001). Tenofovir-based ART was associated with higher rates than zidovudine-based ART of very preterm delivery before 34 weeks (6.0% vs. 2.6%, P=0.04) and early infant death (4.4% vs. 0.6%, P=0.001), but there were no significant differences between tenofovir-based ART and zidovudine alone (P=0.10 and P=0.43). The rate of HIV-free survival was highest among infants whose mothers received zidovudine-based ART. CONCLUSIONS: Antenatal ART resulted in significantly lower rates of early HIV transmission than zidovudine alone but a higher risk of adverse maternal and neonatal outcomes. (Funded by the National Institutes of Health; PROMISE ClinicalTrials.gov numbers, NCT01061151 and NCT01253538 .).

Safety and acceptability of the Reality condom for anal sex among men who have sex with men.

OBJECTIVES: To assess safety and acceptability of Reality condoms for anal sex among men who have sex with men. METHODS: Crossover study among HIV-seroconcordant (33 HIV-negative and 5 HIV-positive) monogamous male couples, randomized to latex male and Reality condom use with anal sex. RESULTS: Slippage with removal was reported more frequently with Reality than male latex condoms [odds ratio (OR), 2.7; 95% confidence interval (CI), 1.2-5.8 for receptive partners and OR, 34.1; 95% CI, 13.8-84.1 for insertive partners]. Receptive partners more frequently reported pain or discomfort (OR, 5.0; 95% CI, 2.6-9.4) and rectal bleeding (OR, 1.9; 95% CI, 0.9-4.1) with Reality condoms than male condoms. Over 20% reported willingness to use the Reality condom in the future with a partner of unknown HIV status; willingness was associated with past problems with male condoms and no problems with Reality condoms among receptive partners, and with past use of Reality condoms and HIV seropositivity among insertive partners. CONCLUSIONS: Men reported more frequent problems with Reality condoms than male latex condoms used for anal intercourse, particularly slippage, discomfort, and rectal bleeding. Design modifications, training, and research on the clinical significance of safety outcomes are needed for use of Reality condoms with anal sex.

Utility of colposcopy in a phase 2 portion of a microbicide clinical trial of BufferGel and 0.5% PRO 2000 Gel.

BACKGROUND: The majority of new HIV infections are acquired through heterosexual transmission. There is urgent need for prevention methods to compliment behavior change and condom use. Topical microbicide represent a potential strategy for reduction of HIV transmission in women. METHODS: Monthly Colposcopy evaluations were performed during pelvic examinations among 299 women enrolled in the Phase 2 portion of HPTN 035 study at four sites (1 in USA, 3 in Southern Africa). This was a phase 2/2b, multisite, randomized, and controlled clinical trial with four arms: BufferGel, 0.5% PRO2000 Gel, placebo gel and no gel. At two of the sites, pelvic examinations were conducted by the use of naked eye without colposcopy. RESULTS: A colposcopy finding of any kind was detected in 48% of participants at baseline compared to 40% at 3 months (p =0.04). The lower rates were also observed in vaginal discharge (22% at baseline, 16% at 3 months, p=0.06), erythema (15% at baseline, 8% at 3 months, p=0.004). The trend towards significance at p=0.05 disappear when utilizing stringent statistical significance levels. A pelvic finding of any kind was detected in 71% of colposcopy participants compared to 41% of participants who had naked eye examination only conducted at two sites that performed both colposcopy and naked eye without colposcopy. Use of colposcopy yielded significantly higher rates of participants with deep epithelial disruption, erythema and ecchymosis. We observed no cases of incident Chlamydia, Gonorrhea, or Syphilis during the three month follow up. There were 2 cases of incident HIV during 3-month study period neither of which was associated with any abnormal colposcopy evaluation findings. CONCLUSION: No safety signals were observed in the 4 study arms, allowing seamless transition from phase 2 to 2b. Colposcopy utility in microbicide clinical trials has minimal value given high rates of background noise findings of no relevant clinical significance.

Randomized, controlled evaluation of a prototype informed consent process for HIV vaccine efficacy trials.

Procedures must be developed to ensure that valid informed consent is obtained from participants in HIV vaccine efficacy trials. A prototype informed consent process was evaluated among 4,892 persons at high risk for HIV infection in the HIV Network for Prevention Trials Vaccine Preparedness Study (VPS), a prospective cohort study of HIV seroincidence in eight U.S. metropolitan areas. Twenty percent of VPS participants were selected at random to undergo the prototype informed consent process at VPS month 3. Participants' knowledge of 10 key HIV vaccine trial concepts and willingness to participate in HIV vaccine efficacy trials were assessed and compared at baseline and semiannually thereafter for 18 months. Knowledge of HIV vaccine trial concepts was low at baseline. Participation in the prototype process was associated with substantial and sustained increases in knowledge (relative risks for the 10 items, 1.04-2.26), which were of similar magnitude across HIV risk groups, race/ethnicity, and educational levels. It is recommended that the prototype informed consent process be adopted for future HIV vaccine efficacy trials as well as for clinical trials in other research areas.

Safety and acceptability of penile application of 2 candidate topical microbicides: BufferGel and PRO 2000 Gel: 3 randomized trials in healthy low-risk men and HIV-positive men.

OBJECTIVES: To assess safety and acceptability of penile application of BufferGel (ReProtect, Baltimore, MD) and PRO 2000 Gel (Indevus Pharmaceuticals, Lexington, MA)compared with placebo among low-risk sexually abstinent men and HIV-positive sexually abstinent men. DESIGN: Seventy-two healthy low-risk men (36 uncircumcised) and 25 HIV-positive men (12 uncircumcised) were enrolled in 3 double-blind, single-center studies as follows: 36 low-risk men in a study of BufferGel and K-Y Jelly (McNeil-PPC, Skillman, NJ) placebo; 36 low-risk men in a study of PRO 2000 Gel and vehicle placebo; and 25 HIV-positive men in a crossover study of BufferGel, PRO 2000 Gel, and K-Y Jelly placebo. METHODS: Participants applied product to the penis on 7 consecutive nights, kept study diaries, and were then interviewed and examined. Urine was tested for inflammation by leukocyte esterase. RESULTS: No serious adverse events (AEs) or urethral inflammation was detected. During use of BufferGel, 3 low-risk men (13%) reported 6 AEs and 2 HIV-positive men (8%) reported 3 AEs. During use of PRO 2000 Gel, 4 low-risk men (17%) reported 6 AEs and 1 HIV-positive participant (4%) had 1 AE. AE rates during use of BufferGel and PRO 2000 Gel use were not significantly different from rates observed during placebo. One low-risk man (4%) would object to his partners using BufferGel and 3 (13%) to PRO 2000 Gel. Two HIV-positive men (8%) reported they would object to partners using either BufferGel or PRO 2000 Gel. CONCLUSIONS: Daily application of BufferGel and PRO 2000 Gel directly to the penis consecutively for 7 days was generally safe and well tolerated among healthy low-risk men and HIV-positive men. These microbicides have acceptable safety profiles to proceed with planned phase 3 vaginal microbicide trials.