Anne Coletti

Safety and effectiveness of BufferGel and 0.5% PRO2000 gel for the prevention of HIV infection in women

Objective:To determine the safety and effectiveness of BufferGel and 0.5% PRO2000 microbicide gels for the prevention of male-to-female HIV transmission. Design:Phase II/IIb, randomized, placebo-controlled trial with three double-blinded gel arms and an open-label no gel arm. Methods:Study participants from Malawi, South Africa, Zambia, Zimbabwe, and the USA were instructed to apply study gel up to 1 h before each sex act and safety, sexual behavior, pregnancy, gel adherence, acceptability, and HIV serostatus were assessed during follow-up. Results:The 3101 enrolled women were followed for an average of 20.4 months with 93.6% retention and 81.1% self-reported gel adherence. Adverse event rates were similar in all study arms. HIV incidence rates in the 0.5% PRO2000 gel, BufferGel, placebo gel, and no gel arms were 2.70, 4.14, 3.91, and 4.02 per 100 women-years, respectively. HIV incidence in the 0.5% PRO2000 gel arm was lower than the placebo gel arm (hazard ratio = 0.7, P = 0.10) and the no gel arm (hazard ratio = 0.67, P = 0.06). HIV incidence rates were similar in the BufferGel and both placebo gel (hazard ratio = 1.10, P = 0.63) and no gel control arms (hazard ratio = 1.05, P = 0.78). HIV incidence was similar in the placebo gel and no gel arms (hazard ratio = 0.97, P = 0.89). Conclusion:The 0.5% PRO2000 gel demonstrated a modest 30% reduction in HIV acquisition in women. However, these results were not statistically significant and subsequent findings from the Microbicide Development Programme (MDP) 301 trial have confirmed that 0.5% PRO2000 gel has little or no protective effect. BufferGel did not alter the risk of HIV infection. Both products were well tolerated.

Determinants of enrollment in a preventive HIV vaccine trial: hypothetical versus actual willingness and barriers to participation.

Objective:To compare hypothetical and actual willingness to enroll in a preventive HIV vaccine trial and identify factors affecting enrollment. Methods:Participants previously enrolled in an HIV vaccine preparedness study (VPS) in 8 US cities were invited to be screened for a phase 2 HIV vaccine trial. Demographic and risk characteristics of those enrolling, ineligible, and refusing enrollment were compared using the χ2 or Fisher exact test. Multivariable logistic models were used to identify independent predictors of refusal. Results:Of 2531 high-risk HIV-uninfected former VPS participants contacted for the vaccine trial, 13% enrolled, 34% were ineligible, and 53% refused enrollment. Only 20% of those stating hypothetical willingness during the VPS actually enrolled in this vaccine trial. In multivariate analysis, refusal was higher among African Americans and lower in persons >40 years of age, those attending college, and those with ≥5 partners in the prior 6 months. All racial ethnic groups cited concerns about vaccine-induced seropositivity; African Americans also cited mistrust of government and safety concerns as barriers to enrollment. Conclusions:Steps can be taken to minimize potential social harms and to mobilize diverse communities to enroll in trials. Statements of hypothetical willingness to participate in future trials may overestimate true enrollment.

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.

Home collection for frequent HIV testing: Acceptability of oral fluids, dried blood spots and telephone results

ObjectiveTo assess the feasibility and acceptability of bimonthly home oral fluid (OF) and dried blood spot (DBS) collection for HIV testing among high-risk individuals. DesignA total of 241 participants [including men who have sex with men (MSM), injecting drug users (IDU), and women at heterosexual risk] were recruited from a randomly selected subset of study participants enrolled at four sites in the HIV Network for Prevention Trials (HIVNET) cohort, and assigned at random to bimonthly home collection of OF or DBS specimens over a 6 month interval. Participants could select telephone calls or clinic visits to receive HIV test results. MethodsBimonthly specimens were tracked for adherence to the schedule, were evaluated for adequacy for testing, and tested using antibody assays and polymerase chain reaction (PCR) for DBS. The acceptability of bimonthly home OF and DBS collection and telephone counseling was assessed in an end-of-study questionnaire. ResultsThe laboratory received 96 and 90% of expected OF and DBS specimens, respectively; 99% of each specimen type was adequate for testing. Almost all (95%) participants chose results disclosure by telephone. The majority of participants (85%) reported that bimonthly testing did not make them worry more about HIV, and almost all (98%) judged that with bimonthly testing their risk behavior remained the same (77%) or became less risky (21%). ConclusionBimonthly home specimen collection of both OF and DBS with telephone counseling is acceptable and feasible among study participants at high risk. These methods will be useful for the early detection of HIV infection and remote follow-up of research cohort participants in HIV vaccine and prevention trials.

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.

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

Objectives: To assess safety and acceptability of RealityTM 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.

Appropriateness of hydroxyethylcellulose gel as a placebo control in vaginal microbicide trials: A comparison of the two control arms of HPTN 035

Objective:To compare the 2 control arms of HPTN 035 [a hydroxyethylcellulose (HEC) gel control arm and a no-gel control arm] to assess the behavioral effects associated with gel use and direct causal effects of the HEC gel on sexually transmitted infections (STIs), pregnancy, and genital safety. Design:Randomized trial with 1 blinded (HEC gel) and 1 open-label (no-gel) control arms. Methods:HIV-uninfected, sexually active women were randomized into the HEC gel arm (n = 771) and into the no-gel arm (n = 772) in 5 countries. Participants in the HEC gel arm were instructed to insert the study gel intravaginally <1 hour before each vaginal sex act. Data on sexual behavior, adherence, safety, pregnancy, and STIs were collected quarterly for 12–30 months of follow-up. Results:During follow-up, mean reported condom use in the past week was significantly higher in the no-gel arm (81% versus 70%, P < 0.001). There were no significant differences, after adjusting for this differential condom use, between the 2 arms in the rates of genital safety events, pregnancy outcomes, or STIs, including HIV-1. Conclusions:In this large randomized trial, we found no significant differences between the no-gel and HEC gel arms in the rates of genital safety events, pregnancy outcomes, or STIs. These results aid interpretation of the results of previous vaginal microbicide trials that used the HEC gel as a control. The HEC gel is suitable as a control for ongoing and future vaginal microbicide studies.

Oral and injectable contraceptive use and HIV acquisition risk among women in four African countries: A secondary analysis of data from a microbicide trial

OBJECTIVE To assess the effect of oral and injectable contraceptive use compared to nonhormonal contraceptive use on HIV acquisition among Southern African women enrolled in a microbicide trial. STUDY DESIGN This is a prospective cohort study using data from women enrolled in HIV Prevention Trials Network protocol 035. At each quarterly visit, participants were interviewed about self-reported contraceptive use and sexual behaviors and underwent HIV testing. Cox proportional hazards regression was used to assess the effect of injectable and oral hormonal contraceptive use on HIV acquisition. RESULTS The analysis included 2830 participants, of whom 106 became HIV infected (4.07 per 100 person-years). At baseline, 1546 (51%) participants reported using injectable contraceptives and 595 (21%) reported using oral contraceptives. HIV incidence among injectable, oral and nonhormonal contraceptive method users was 4.72, 2.68 and 3.83 per 100 person-years, respectively. Injectable contraceptive use was associated with a nonstatistically significant increased risk of HIV acquisition [adjusted hazard ratio (aHR)=1.17; 95% confidence interval (CI) 0.70, 1.96], while oral contraceptive use was associated with a nonstatistically significant decreased risk of HIV acquisition (aHR=0.76; 95% CI 0.37,1.55). CONCLUSION In this secondary analysis of randomized trial data, a marginal, but nonstatistically significant, increase in HIV risk among women using injectable hormonal contraceptives was observed. No increased HIV risk was observed among women using oral contraceptives. Our findings support the World Health Organizations recommendation that women at high risk for acquiring HIV, including those using progestogen-only injectable contraception, should be strongly advised to always use condoms and other HIV prevention measures. IMPLICATIONS Among Southern African women participating in an HIV prevention trial, women using injectable hormonal contraceptives had a modest increased risk of HIV acquisition; however, this association was not statistically significant. Continued research on the relationship between widely used hormonal contraceptive methods and HIV acquisition is essential.