Lisa Maslankowski

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.

Safety and tolerability of tenofovir vaginal gel in abstinent and sexually active HIV-infected and uninfected women.

Objectives:To establish the highest practical dose and frequency (HPDF) of 0.3% or 1% tenofovir vaginal gel applied once or twice daily by sexually abstinent HIV-uninfected women, and to evaluate the safety, tolerability and systemic pharmacokinetics of the HPDF in abstinent and sexually active HIV-negative and HIV-infected women. Methods:Eighty-four women, enrolled in sequential cohorts, used the study product for 14 consecutive intermenstrual days. Safety laboratory assessments and pelvic examinations were carried out during five study visits, with colposcopy at enrollment and on day 14. Samples for pharmacokinetics were collected before and after the initial tenofovir gel use and at day 13. Results:The 1% tenofovir gel used twice daily was as well tolerated as other regimens used by the 48 HIV-negative sexually abstinent women, establishing the HPDF. Although 92% of the women reported at least one adverse event, the majority were mild (87%) and involved the genitourinary tract (70%). One possibly product-related severe adverse event involving lower abdominal cramping was reported by a sexually abstinent woman who used 0.3% gel twice daily. Serum tenofovir levels were low but detectable in 14 of the 25 women. No new HIV RNA resistance mutations were detected after 2 weeks of tenofovir gel in the 24 HIV-infected participants. No significant systemic toxicity was detected. Conclusion:A 2-week course of 1% tenofovir vaginal gel used twice daily was well tolerated in sexually abstinent and sexually active HIV-negative and HIV-positive women. Systemic tenofovir absorption occurred. Expanded safety and effectiveness testing is warranted.

The acceptability of an investigational vaginal microbicide, PRO 2000 Gel, among women in a phase I clinical trial.

PURPOSE Vaginal microbicides will provide a woman-initiated prevention strategy that could substantially reduce rates of HIV infection. The acceptability of microbicides will greatly influence the use and, hence, effectiveness of such products. In this study, the acceptability of an investigational microbicide, PRO 2000 Gel (Indevus Pharmaceuticals, Inc., Lexington, MA), was assessed, and womens opinions about microbicides and their potential for real world use were gathered. METHODS Quantitative and qualitative data were collected from 30 U.S. and 33 South African women. All sexually active HIV-uninfected women and all sexually abstinent HIV-infected women participating in this phase I clinical trial stated in a survey that they would use PRO 2000 Gel if they had reason to be concerned about HIV and the product were available. Qualitative data, however, provided insight into the nuances of acceptability ratings. Women rated product safety, ease of use, and positive effects on sexual pleasure among the most important characteristics of acceptable microbicides. RESULTS Opinions regarding product leakage, contraceptive capability, and the ability to be used without partners noticing, as well as characteristics of the product itself, varied substantially based on the context of sex and perceptions of risk within each individual womans life. CONCLUSIONS As microbicide development continues and the first investigational products move into efficacy trials, the needs and preferences of those women who constitute the potential users of microbicides become paramount. Providing woman-initiated microbicides that are safe, easy to use, and pleasurable will be key to the impact these products will have on the AIDS epidemic worldwide.

Safety and acceptability of cellulose sulfate as a vaginal microbicide in HIV-infected women.

Objectives:Few studies of topical microbicides have assessed their safety in HIV-infected women. We conducted this study to evaluate the safety and acceptability of 6% cellulose sulfate (CS) gel as a vaginal microbicide in sexually abstinent and active HIV-infected women. Methods:Fifty-nine HIV-infected women were enrolled in a randomized double-blind placebo-controlled study comparing 6% CS to placebo gel used for 14 days. Sexually abstinent women applied gel once or twice daily and sexually active women used gel once daily. Results:CS gel was safe with no reported severe or life-threatening adverse events (AE). Thirty-nine (66%) of the participants experienced urogenital AE judged as probably or possibly related to gel. The majority (51%) of these participants reported only mild events. Fewer women (62%) who used CS experienced urogenital AE than those assigned to placebo gel (70%) (P = 0.59). Eleven (19%) women experienced intermenstrual bleeding judged to be probably or possibly related to gel use (four in the CS and seven in the placebo gel group). There was no increase in AE by frequency of gel use or sexual activity with the exception of abdominal/pelvic pain which was noted more frequently with twice daily use among sexually abstinent women. Women and men found the gel highly acceptable. Conclusions:This Phase I study demonstrated that CS vaginal gel was safe, well tolerated and acceptable by HIV-infected women and their male partners. Thus, further development of CS is warranted as a potential method to prevent HIV transmission and acquisition.

P3.090 Bacterial Vaginosis and the Risk of Trichomonas Vaginalis Acquisition Among HIV-1 Negative Women

Background The vaginal microbiota may play a role in mediating susceptibility to sexually transmitted infections, including Trichomonas vaginalis (TV). This analysis evaluated the association between bacterial vaginosis (BV) and incident TV among women enrolled in a biomedical HIV prevention trial. Methods Data were analysed from HIV-1 seronegative women participating in HIV Prevention Trials Network Protocol 035. At quarterly visits for up to 30 months, participants completed structured interviews and specimens were collected for genital tract infection testing. TV was detected by saline microscopy. BV was characterised by Gram stain using the Nugent score (BV = 7–10; intermediate = 4–6; normal = 0–3 [reference group]). Cox proportional hazards models stratified by study site were used to assess the association between BV at the prior quarterly visit and TV acquisition. Participants were censored at their first TV infection or if they became pregnant or HIV-infected. Results This secondary analysis included 2,804 participants from Malawi, South Africa, USA, Zambia and Zimbabwe who contributed 13,977 follow-up visits. BV was detected at 5,184 (37.1%) visits and TV was detected at 352 (2.5%) visits. After adjusting for age, marital status, hormonal contraceptive use, sexual activity and TV at baseline, intermediate microbiota and BV at the prior visit were independently associated with an increased risk of TV (intermediate microbiota: adjusted hazard ratio [aHR] = 1.74, 95% confidence interval [CI] 1.22, 2.47; BV: aHR = 3.25, 95% CI 2.53–4.17). TV at baseline was also associated with an increased risk of TV (aHR = 2.54; 95% CI 1.91, 3.36). Sensitivity analyses excluding 202 women with baseline TV showed similar results (BV: aHR = 3.18; 95% CI 2.42 – 2.19). Conclusions Women with a Nugent score > 3 were at an increased risk of acquiring TV. If this relationship is causal, interventions that decrease the incidence of BV and promote a normal vaginal microbiota could potentially contribute to reductions in TV incidence.

Impact of targeted counseling on reported vaginal hygiene practices and bacterial vaginosis: the HIV Prevention Trials Network 035 study

The objective of this study was to describe the impact of intense counseling to reduce vaginal hygiene practices and its effect on bacterial vaginosis. A secondary data analysis of the HIV Prevention Trials Network 035 study was undertaken, focusing on HIV-negative, nonpregnant women who were at least 18 years old, in seven African sites and one US site. At enrollment and during follow-up quarterly visits, vaginal hygiene practices were determined by face-to-face administration of a behavioral assessment questionnaire. Vaginal hygiene practices were categorized as insertion into the vagina of (1) nothing, (2) water only, and (3) other substances with or without water. Each practice was quantified by frequency and type/combination of inserted substances. At quarterly visits, diagnosis of bacterial vaginosis was made using the Nugent score. Trends for vaginal hygiene practices and bacterial vaginosis were evaluated using generalized estimating equation models. A total of 3087 participants from the HIV Prevention Trials Network 035 study were eligible for this analysis. At enrollment, 1859 (60%) reported recent vaginal hygiene practices. By one year, this figure had decreased to 1019 (33%) with counseling. However, bacterial vaginosis prevalence remained consistent across the study observation period, with 36%–38% of women testing positive for the condition (p for trend = 0.27). Overall, those who reported douching with water only (AOR = 1.03, 95%CI: 0.94–1.13) and those who reported inserting other substances (AOR= 0.98, 95%CI: 0.88–1.09) in the past quarter were not more likely to have bacterial vaginosis compared to those who reported no insertions. However, in South Africa, an increase in bacterial vaginosis was seen among those who reported inserting other substances (AOR: 1.48, 95%CI: 1.17, 1.88). In conclusion, targeted counseling against vaginal hygiene practices resulted in change in self-reported behavior but did not have an impact on bacterial vaginosis diagnosis in all but one site.

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

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.

The CONRAD/WHO Update 2000 Colposcopy Manual: how well is it working?

with the Update 2000 manual. Their responses had many commonalities and have been combined into this single manuscript. The panelists’ experience came from clinical trials of Pro2000, BufferGel, cellulose sulfate, dextrin sulfate, nonoxynol-9, K-Y Jelly, tenofovir, Praneem, and vaginal diaphragms. In general, it was felt that the Update 2000 manual was clear, concise, and easy to follow. The procedure is short (5–7 min) and simple once the colposcopist has been properly trained. The use of digital imaging was endorsed as a way to reduce both inter and intra-observer variability, and to ensure good image quality when the examination was still in progress. The need for equipment, reliable electricity, and training were limitations of the procedure. The most common recommendation was the reintroduction of ‘terms’, namely clinical labels for changes seen, such as erythema, edema, abrasion, ulcer, etc. These had been removed from the Update 2000 manual in favor of simply recording the status of the epithelium and blood vessels as either intact or not intact. The latter was felt to be more meaningful in terms of HIV/sexually transmitted infection risk, and the previously used terms had for some time been analysed only with respect to the intactness they represented. However, the panelists pointed out that the terms were still being used during discussions among clinicians and study staff, as they were more easily visualized than descriptions of intactness. CONRAD has found that in studies in which both the intactness and terms were recorded and there were discrepancies, it was usually the term that was correct. As a result of this feedback, the new Update 2004 includes places for recording both terms and intactness. Several aspects of the lavage step were discussed. Different types of syringes for lavaging were described, with each having different merits that are somewhat dependent on the type of study being carried out. As a result, the type of syringe is no longer specified in the Update 2004 manual, but can be protocol-specific. Several panelists reported that lavage was often inadequate for the removal of product, and that saline-moistened swabs had to be used. This was added to the Update 2004 manual. Also, when microbiology specimens from the endocervix were taken before lavage, the lavage samples were frequently contaminated with blood, which confounded the results of viral load and cytokine analyses when the lavage was used for this purpose. The Update 2004 manual states that if the collection of lavage fluid for the measurement of inflammatory markers is felt to be of higher priority than the collection of cervical or vaginal specimens, it may be collected first. It was suggested that the degree of cervical ectopy be recorded, and the recording of findings such as cervical polyps be addressed; both were added to in Update 2004. The recording of blood observed on the examination was also added. Possible changes in colposcopically observed vascular patterns because of the day of the menstrual cycle or other hormonal influences were brought up as an area deserving investigation. Several panelists brought up the cumbersome nature of the reporting forms, which required many pages for each finding. One speaker had redesigned the form so that up to 10 findings could be recorded on one form. This change was incorporated into the Update 2004 manual. In addition, the numbering of the anatomical sites was changed so that a single numbering sequence incorporated both the vagina and cervix, rather than having separate sequences for each. The date of first observation and the date when findings were noticed to have resolved was added. Other suggestions included examining the anterolateral and posterolateral fornices rather than the anterior, posterior, and lateral fornices, and always starting with the same fornix. It was also reported that rotating the speculum 90° was well tolerated by some women and allowed the examination of the