Clifton W. Kelly

phase 1 Trial of the Topical Microbicide Buffergel: Safety Results From Four International Sites

Aim: To evaluate the safety of BufferGel (ReProtect LLC, Baltimore, MD), a spermicidal microbicide that acidifies semen and maintains the protective acidity of the vagina, in a high‐dose tolerance trial. Methods: HIV/STD negative, sexually abstinent, and sexually active women in India, Thailand, Malawi, and Zimbabwe were asked to insert one applicator (˜5 ml) of BufferGel vaginally twice per day for 14 days. Sexually active women agreed to have sex (while using BufferGel and nonlubricated condoms) at least twice per week. Results: In total, 98 women (30 sexually abstinent and 68 sexually active) were enrolled. Overall compliance with product use was 93%. Epithelial abnormalities detected by pelvic examination or colposcopy were uncommon (8 cases in 271 examinations). Irritation was reported by approximately one quarter of the women (0.58 events per woman‐week) but was generally mild and of short duration. The prevalence of bacterial vaginosis (BV) fell significantly, from 30% at enrollment to 6% at one week, and 7% at two weeks of BufferGel use. Thirty‐two women acquired microscopically detectable yeast during BufferGel exposure, but only 3 developed symptomatic vaginitis. Conclusion: BufferGel appears to be safe and well tolerated by the cervicovaginal epithelium. Its effect on BV and yeasts merits further study.

Safety and toxicity of nonoxynol-9 gel as a rectal microbicide.

BACKGROUND AND OBJECTIVES Methods of HIV and STD prevention, which can be controlled by the receptive partner, are a high priority for research and development. Studies on the safety of Nonoxynol-9 (N-9) on the vaginal mucosa have yielded conflicting results. No Phase I study has evaluated the effect of N-9 on the rectal mucosa. GOALS To assess the safety of 52.5 mg of N-9 in a 1.5-g gel when applied one to four applicators per day to the rectum and penis. STUDY DESIGN The study included 25 HIV-negative and 10 HIV-positive, monogamous gay male couples in which each partner was exclusively insertive or receptive while using N-9 gel. Each participant served as his own control during placebo gel use compared to during N-9 gel use. Receptive partners underwent anoscopic examination after 1 week of placebo use and after 2, 5, and 6 weeks of N-9 gel use, with rectal biopsies obtained after 1 week of placebo use and after 5 and 6 weeks of N-9 gel use. Insertive partners had safety monitoring after 1 week of placebo use and after 2, 5, and 6 weeks of N-9. RESULTS No rectal ulcers were detected; superficial rectal erosions were noted in two HIV-negative participants. Abnormal or slightly abnormal histologic abnormalities of rectal biopsies were detected in 31 (89%) receptive participants after N-9 gel use compared to 24 (69%) participants after 1 week of placebo gel use. Meatal ulceration, not caused by herpes simplex virus, was detected in one HIV-negative participant. CONCLUSION Low-dose N-9 gel was not associated with macroscopic rectal and penile epithelial disruption or inflammation, but histologic abnormalities were commonly observed during N-9 gel as well as during placebo gel use.

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.

Acceptability of a bioadhesive Nonoxynol-9 gel delivered by an applicator as a rectal microbicide

BACKGROUND AND OBJECTIVES Potential rectal microbicides, as an adjunct to condoms for HIV/STD prevention, have not been studied previously. GOAL OF THIS STUDY Advantage 24 (1.5 ml of a bioadhesive gel containing 52.5 mg nonoxynol-9 administered by single-use applicator)-under investigation as a vaginal microbicide-was evaluated for acceptability among male couples. STUDY DESIGN Twenty-five HIV-negative and 10 HIV-positive male couples participated in a frequency use escalation trial. Diaries and self-administered questionnaires assessed product use, acceptability, sexual behavior, and gastrointestinal and urologic side effects. RESULTS Excluding participants who felt no need for an HIV prevention method, 58% said they would use Advantage 24 if approved for rectal use; 69% of receptive users reported rectal fullness and related side effects after insertion of the gel, and 68% reported applicator-related discomfort; 59% of insertive participants found the gel too sticky. CONCLUSIONS Acceptability remains inconclusive and warrants further study of redesigned applicators and ways to minimize rectal side effects.

HIV Incidence Among Women of Reproductive Age in Malawi and Zimbabwe

Objective: The objective of this study was to determine the incidence of HIV-1. Goal: The goal of this study was to inform HIV prevention and vaccine trials by conducting a multisite study in Malawi and Zimbabwe. Study Design: Women of reproductive age were enrolled in a prospective study. They received 5 intensive HIV counseling and condom promotion sessions over 2 months. Subsequently, HIV-negative women completed quarterly follow-up visits. HIV incidence rates and predictors of HIV acquisition were assessed. Results: A total of 2016 HIV-negative women were enrolled in the condom promotion and counseling phase of the study. Of these, 1679 were tested for HIV during follow up and 113 women seroconverted, resulting in an overall HIV incidence rate of 4.7 per 100 women-years (95% confidence interval = 3.8–5.6). Incidence rates were similar across sites. The major predictors of HIV acquisition were young age, presence of sexually transmitted infections, being unmarried, and higher educational level. Conclusion: The incidence of HIV continues to be high among women in both Malawi and Zimbabwe despite counseling and condom promotion.

Nonoxynol-9 100 mg gel: multi-site safety study from sub-Saharan Africa.

Objectives: To evaluate the safety of 100 mg nonoxynol-9 (N-9) gel, a vaginal microbicide, on the genital mucosa of women from Malawi and Zimbabwe in preparation for a phase III efficacy study. Methods: HIV-uninfected women (180) were enrolled and randomized to either N-9 or placebo gel and instructed to insert gel into the vagina twice daily for 14 days. Follow up examinations were conducted at 7 and 14 days. Results: The number of adverse events in the N-9 gel group was higher than in the placebo group (40% versus 13%; P < 0.01). Reported number of any genital symptoms was significantly higher in the N-9 group (38% N-9, 13% placebo; P = 0.01). The number of total epithelial disruptions was higher in the N-9 group (20% versus 3%; P < 0.01); however, the number of genital ulcers and abrasions in the N-9 group was low (2% and 3%, respectively) and not different from that in the placebo group (1% and 2%, respectively). Conclusions: N-9 gel 100 mg caused a significant increase in the rate of genital symptoms and epithelial disruptions compared with placebo. The clinical significance of these epithelial disruptions is unknown. Although these findings alone were not sufficient to cancel the planned phase III study, when considered together with the negative results from the COL-1492 effectiveness trial of 52.5 mg N-9 gel, the decision was made to cancel the planned phase III trial of 100 mg N-9 gel.

Bone Mineral Density Changes Among Young, Healthy African Women Receiving Oral Tenofovir for HIV Preexposure Prophylaxis

Background:Limited data exist on effect of tenofovir disoproxil fumarate (TDF) when used for preexposure prophylaxis (PrEP) on bone mineral density (BMD) in HIV-negative women. We evaluated the effect of daily oral TDF and emtricitabine/TDF compared with placebo on BMD among women enrolled in an HIV-1 PrEP trial. Methods:HIV-uninfected women in Uganda and Zimbabwe had BMD measurements of lumbar spine (LS) and total hip (TH) by dual-energy x-ray absorptiometry at baseline and every 24 weeks for 48 weeks of active treatment and for 48 weeks after discontinuation of study medication. Plasma tenofovir levels were assessed every 12 weeks for the first 48 weeks. Results:Of 518 women enrolled, 432 had dual-energy x-ray absorptiometry results at baseline and week 48. In the primary analysis, no significant differences in percent BMD change in hip or spine between arms observed, likely because of low product adherence. Among the subset with tenofovir detection in 75%–100% of plasma samples, the mean percent BMD change from baseline to week 48 in the LS was 1.4% lower for TDF or emtricitabine/TDF recipients than for placebo (P = 0.002) and TH BMD was 0.9% lower (P = 0.018). BMD changes from end of active treatment to 48 weeks were significantly greater in the active arm participants compared with placebo participants with a net difference of approximately +0.9% at the LS (P = 0.007) and +0.7% (P = 0.003) at the TH. Conclusions:TDF-containing oral PrEP resulted in small but significant reversible decreases in hip and spine BMD among young African women.

Impact of Sex on the Pharmacokinetics and Pharmacodynamics of 1% Tenofovir Gel

BACKGROUND Tenofovir (TFV) gel partially protected against human immunodeficiency virus (HIV) in one but not subsequent trials. The disappointing results were attributed largely to poor adherence. However, timing of gel application relative to sex may impact pharmacokinetics and contribute to outcomes. Thus, we conducted a single-dose pharmacokinetic study of TFV gel applied 1 or 24 hours before or 1 hour before and 1 hour after (BAT) sex and compared results with dosing without sex. METHODS Twenty-four couples were enrolled; cervicovaginal lavage (CVL) and tissue were collected 2 hours after sex with matching timed collections at no sex visits and assayed for drug concentrations and CVL anti-HIV activity. RESULTS Compared with dosing without sex, median TFV concentrations after sex decreased 72% and 78% (P < .001) in CVL, 75% and 71% (P < .001) in vaginal tissue, and 75% (P = .06) and 55% (P < .001) in cervical tissue with -1 hour and -24 hour dosing, respectively. Median concentration of TFV-diphosphate also decreased significantly in cervical tissue with -1 hour, dosing. BAT dosing resulted in drug levels at least as great as those in the absence of sex. Percent inhibition of HIV infection by post-coital CVL increased significantly from median (interquartile range) of 55% (54%) in the absence of gel to 99% (7%), 77% (57%), and 100% (0.4%) with -1 hour, -24 hour, or BAT dosing, respectively, and correlated significantly with drug concentration. CONCLUSIONS Timing of TFV gel application relative to sex significantly impacts drug levels. BAT dosing or sustained delivery may be optimal for preexposure prophylaxis.