Safety, adherence, and HIV-1 seroconversion among women using the dapivirine vaginal ring (DREAM): an open-label, extension study.

BACKGROUND: The Ring Study, a phase 3 trial in 1959 sexually active women (randomised 2:1), showed a favourable safety profile and a 31% HIV-1 infection risk reduction for a vaginal ring containing 25 mg of dapivirine, compared with a placebo ring. We report here the DREAM study, which aimed to evaluate safety, adherence, and HIV-1 incidence in those using the dapivirine vaginal ring (DVR) in open-label use. METHODS: The DREAM study is an open-label extension of The Ring Study, done at five research centres in South Africa and one research centre in Uganda. Former participants from The Ring Study, who remained HIV-negative and who did not discontinue the study due to an adverse event or safety concern that was considered to be related to the investigational product, were eligible. Women who were pregnant, planning to become pregnant, or breastfeeding at screening for DREAM were excluded. All participants received the DVR for insertion at the enrolment visit. Participants attended a 1-month follow-up visit and could either proceed with visits once every 3 months or attend monthly visits up to month 3 and then continue with visits once every 3 months. At each visit, HIV testing and safety evaluations were done, and residual dapivirine measured in used rings (approximately 4 mg is released from the DVR over 28 days of consistent use). HIV-1 incidence was compared descriptively with the simulated incidence rate obtained from bootstrap sampling of participants in the placebo group of The Ring Study, matched for research centre, age, and presence of sexually transmitted infections at enrolment. This study is registered with ClinicalTrials.gov, NCT02862171. FINDINGS: Between July 12, 2016, and Jan 11, 2019, 1034 former participants from The Ring Study were screened, 941 were enrolled and 848 completed the trial. 616 (65·5%) of 941 participants reported treatment-emergent adverse events. Of these, six (0·6%) had events considered to be treatment-related. No treatment-related serious adverse events were reported. Measurements of monthly ring residual amounts in participants enrolled in both trials showed consistently lower mean values in DREAM than in The Ring Study. Arithmetic mean ring residual amounts of participants in The Ring Study DVR group who enrolled in DREAM were 0·25 mg lower (95% CI 0·03-0·47; p=0·027) than the mean ring residual amounts of these participants in The Ring Study. 18 (1·9%) HIV-1 infections were confirmed during DVR use, resulting in an incidence of 1·8 (95% CI 1·1-2·6) per 100 person-years, 62% lower than the simulated placebo rate. INTERPRETATION: Although efficacy estimation is limited by the absence of a placebo group, the observed low HIV-1 incidence and improved adherence observed in DREAM support the hypothesis that increased efficacy due to improved adherence occurs when women know the demonstrated safety and efficacy of the DVR. The feasibility of a visit schedule of once every 3 months was shown, indicating that the DVR can be used in a real-world situation in usual clinical practice. FUNDING: The Ministry of Foreign Affairs (MFA) Denmark, Flanders MFA, Irish Aid, Dutch MFA, UK Aid from the UK Government's Foreign, Commonwealth and Development Office, and the US President's Emergency Plan for AIDS Relief through the US Agency for International Development.

Safety, uptake, and use of a dapivirine vaginal ring for HIV-1 prevention in African women (HOPE): an open-label, extension study.

BACKGROUND: Two phase 3 clinical trials showed that use of a monthly vaginal ring containing 25 mg dapivirine was well tolerated and reduced HIV-1 incidence in women by approximately 30% compared with placebo. We aimed to evaluate use and safety of the dapivirine vaginal ring (DVR) in open-label settings with high background rates of HIV-1 infection, an important step for future implementation. METHODS: We did a phase 3B open-label extension trial of the DVR (MTN-025/HIV Open-label Prevention Extension [HOPE]). Women who were HIV-1-negative and had participated in the MTN-020/ASPIRE phase 3 trial were offered 12 months of access to the DVR at 14 clinical research centres in Malawi, South Africa, Uganda, and Zimbabwe. At each visit (monthly for 3 months, then once every 3 months), women chose whether or not to accept the offer of the ring. Used, returned rings were tested for residual amounts of dapivirine as a surrogate marker for adherence. HIV-1 serological testing was done at each visit. Dapivirine amounts in returned rings and HIV-1 incidence were compared with data from the ASPIRE trial, and safety was assessed. This study is registered with ClinicalTrials.gov, NCT02858037. FINDINGS: Between July 16, 2016, and Oct 10, 2018, of 1756 women assessed for eligibility, 1456 were enrolled and participated in the study. Median age was 31 years (IQR 27-37). At baseline, 1342 (92·2%) women chose to take the DVR; ring acceptance was more than 79% at each visit up until 12 months and 936 (73·2%) of 1279 chose to take the ring at all visits. 12 530 (89·3%) of 14 034 returned rings had residual dapivirine amounts consistent with some use during the previous month (>0·9 mg released) and the mean dapivirine amount released was greater than in the ASPIRE trial (by 0·21 mg; p<0·0001). HIV-1 incidence was 2·7 per 100 person-years (95% CI 1·9-3·8, 35 infections), compared with an expected incidence of 4·4 per 100 person-years (3·2-5·8) among a population matched on age, site, and presence of a sexually transmitted infection from the placebo group of ASPIRE. No serious adverse events or grade 3 or higher adverse events observed were assessed as related to the DVR. INTERPRETATION: High uptake and persistent use in this open-label extension study support the DVR as an HIV-1 prevention option for women. With an increasing number of HIV-1 prophylaxis choices on the horizon, these results suggest that the DVR will be an acceptable and practical option for women in Africa. FUNDING: The Microbicide Trials Network and the National Institute of Allergy and Infectious Diseases, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health, all components of the US National Institutes of Health.

Safety and Efficacy of a Dapivirine Vaginal Ring for HIV Prevention in Women.

BACKGROUND: The incidence of human immunodeficiency virus (HIV) infection remains high among women in sub-Saharan Africa. We evaluated the safety and efficacy of extended use of a vaginal ring containing dapivirine for the prevention of HIV infection in 1959 healthy, sexually active women, 18 to 45 years of age, from seven communities in South Africa and Uganda. METHODS: In this randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned participants in a 2:1 ratio to receive vaginal rings containing either 25 mg of dapivirine or placebo. Participants inserted the rings themselves every 4 weeks for up to 24 months. The primary efficacy end point was the rate of HIV type 1 (HIV-1) seroconversion. RESULTS: A total of 77 participants in the dapivirine group underwent HIV-1 seroconversion during 1888 person-years of follow-up (4.1 seroconversions per 100 person-years), as compared with 56 in the placebo group who underwent HIV-1 seroconversion during 917 person-years of follow-up (6.1 seroconversions per 100 person-years). The incidence of HIV-1 infection was 31% lower in the dapivirine group than in the placebo group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.99; P=0.04). There was no significant difference in efficacy of the dapivirine ring among women older than 21 years of age (hazard ratio for infection, 0.63; 95% CI, 0.41 to 0.97) and those 21 years of age or younger (hazard ratio, 0.85; 95% CI, 0.45 to 1.60; P=0.43 for treatment-by-age interaction). Among participants with HIV-1 infection, nonnucleoside reverse-transcriptase inhibitor resistance mutations were detected in 14 of 77 participants in the dapivirine group (18.2%) and in 9 of 56 (16.1%) in the placebo group. Serious adverse events occurred more often in the dapivirine group (in 38 participants [2.9%]) than in the placebo group (in 6 [0.9%]). However, no clear pattern was identified. CONCLUSIONS: Among women in sub-Saharan Africa, the dapivirine ring was not associated with any safety concerns and was associated with a rate of acquisition of HIV-1 infection that was lower than the rate with placebo. (Funded by the International Partnership for Microbicides; ClinicalTrials.gov number, NCT01539226 .).

Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women.

BACKGROUND: Antiretroviral medications that are used as prophylaxis can prevent acquisition of human immunodeficiency virus type 1 (HIV-1) infection. However, in clinical trials among African women, the incidence of HIV-1 infection was not reduced, probably because of low adherence. Longer-acting methods of drug delivery, such as vaginal rings, may simplify use of antiretroviral medications and provide HIV-1 protection. METHODS: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a non-nucleoside HIV-1 reverse-transcriptase inhibitor, involving women between the ages of 18 and 45 years in Malawi, South Africa, Uganda, and Zimbabwe. RESULTS: Among the 2629 women who were enrolled, 168 HIV-1 infections occurred: 71 in the dapivirine group and 97 in the placebo group (incidence, 3.3 and 4.5 per 100 person-years, respectively). The incidence of HIV-1 infection in the dapivirine group was lower by 27% (95% confidence interval [CI], 1 to 46; P=0.046) than that in the placebo group. In an analysis that excluded data from two sites that had reduced rates of retention and adherence, the incidence of HIV-1 infection in the dapivirine group was lower by 37% (95% CI, 12 to 56; P=0.007) than that in the placebo group. In a post hoc analysis, higher rates of HIV-1 protection were observed among women over the age of 21 years (56%; 95% CI, 31 to 71; P<0.001) but not among those 21 years of age or younger (-27%; 95% CI, -133 to 31; P=0.45), a difference that was correlated with reduced adherence. The rates of adverse medical events and antiretroviral resistance among women who acquired HIV-1 infection were similar in the two groups. CONCLUSIONS: A monthly vaginal ring containing dapivirine reduced the risk of HIV-1 infection among African women, with increased efficacy in subgroups with evidence of increased adherence. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01617096 .).

Recent work on vaginal rings containing antiviral agents for HIV prevention.

PURPOSE OF REVIEW: In response to the need for strategies women can use to protect themselves from HIV infection, a new class of product commonly referred to as vaginal 'microbicides' has been under development for the past few decades. Several leading products currently in development contain antiviral agents delivered in a vaginal ring. RECENT FINDINGS: Research published over the past year reports advances in identification and continued formulation of specific antiviral agents that have potential for delivery in vaginal rings, including drug combinations for HIV, other sexually transmitted infections and contraception. Most products are antiretroviral reverse transcriptase inhibitors. Advances in vaginal ring design have also been reported; some of these are designed to release specific antiviral agents, while other designs could be used for multiple drugs. This review focuses both on antiviral agents and vaginal ring designs. SUMMARY: Over the past year, advances continued to be made in the development of vaginal rings to deliver antiviral agents for prevention of HIV. An array of antiviral agents and vaginal ring designs to deliver these products are at various stages in the product pipeline process. Results from the first efficacy trials of an antiretroviral-containing vaginal ring are expected soon and will inform the continued development of this important product class.

A safety and pharmacokinetic trial assessing delivery of dapivirine from a vaginal ring in healthy women.

OBJECTIVES: Women-initiated HIV-prevention products are urgently needed. To address this need, a trial was conducted to assess the safety and pharmacokinetics of a silicone elastomer matrix vaginal ring containing 25 mg of the antiretroviral drug dapivirine when used continuously for 28 consecutive days. METHODS: A double-blind, randomized, placebo-controlled trial was conducted in 16 healthy, HIV-negative women, 18-40 years of age, who were randomized 1:1 to use either the active or matching placebo ring for 28 days. Participants were followed during and for 28 days after ring use for safety and pharmacokinetic evaluations. RESULTS: The dapivirine vaginal ring was safe and well tolerated with no differences in safety endpoints between the active and placebo ring. The concentration-time plots of dapivirine in vaginal fluid were indicative of a sustained release of dapivirine over the 28 days of use. Dapivirine vaginal fluid concentrations were highest near the ring, followed by the cervix and introïtus (mean Cmax of 80, 67 and 31 µg/g, respectively). Vaginal fluid concentrations of dapivirine on the day of ring removal (day 28) at all three collection sites exceeded by more than 3900-fold the IC99 for dapivirine in a tissue explant infection model. Plasma dapivirine concentrations were low (< 1 ng/ml) and remained well below those observed at the maximum tolerated dose for oral treatment (mean Cmax of 2286  ng/ml). CONCLUSION: The dapivirine vaginal ring has a safety and pharmacokinetic profile that supports its use as a sustained-release topical microbicide for HIV-1 prevention in women.

Development of dapivirine vaginal ring for HIV prevention.

In the continuing effort to develop effective HIV prevention methods for women, a vaginal ring containing the non-nucleoside reverse transcriptase inhibitor dapivirine is currently being tested in two safety and efficacy trials. This paper reviews dapivirine ring's pipeline development process, including efforts to determine safe and effective dosing levels as well as identify delivery platforms with the greatest likelihood of success for correct and consistent use. Dapivirine gel and other formulations were developed and tested in preclinical and clinical studies. Multiple vaginal ring prototypes were also tested, resulting in the current ring design as well as additional designs under consideration for future testing. Efficacy results from clinical trials are expected in 2015. Through ongoing consultations with national regulatory authorities, licensure requirements for dapivirine vaginal ring approval have been defined. This article is based on a presentation at the "Product Development Workshop 2013: HIV and Multipurpose Prevention Technologies," held in Arlington, Virginia on February 21-22, 2013. It forms part of a special supplement to Antiviral Research.

Future strategies in microbicide development.

The reduction in human immunodeficiency virus (HIV) infection in women demonstrated by pericoital use of tenofovir gel has encouraged the continued development of microbicides. Novel approaches include new ways to deliver tenofovir, as well as products that contain different antiretroviral drugs, either as single agents or as combinations of antiretroviral drugs. Indeed, emphasis has renewed on the development of multipurpose prevention technologies, products designed to address multiple sexually transmitted infections. Dual-purpose contraceptive antiretroviral products are also being designed to prevent HIV and pregnancy. Since consistent and correct use of these products will be critical to their effectiveness, the active pharmaceutical ingredients must be delivered in acceptable vaginal dosage forms, such as gels, films and sustained-release vaginal rings. The development of different dosage forms will help ensure that women can find a method to protect themselves from HIV, pregnancy, and potentially other sexually transmitted infections.

Microbicides: topical prevention against HIV.

Microbicides represent a potential intervention strategy for preventing HIV transmission. Vaginal microbicides would meet the need for a discreet method that women could use to protect themselves against HIV. Although early-generation microbicides failed to demonstrate efficacy, newer candidates are based on more potent antiretroviral (ARV) products. Positive data from the CAPRISA 004 trial of tenofovir gel support use in women and represent a turning point for the field. This article reviews current progress in development of ARV-based microbicides. We discuss the consensus on selection criteria, the potential for drug resistance, rationale for drug combinations, and the use of pharmacokinetic (PK)/pharmacodynamic (PD) assessment in product development. The urgent need for continued progress in development of formulations for sustained delivery is emphasized. Finally, as the boundaries between different prevention technologies become increasingly blurred, consideration is given to the potential synergy of diverse approaches across the prevention landscape.

Safety and pharmacokinetics of dapivirine delivery from matrix and reservoir intravaginal rings to HIV-negative women.

Vaginal microbicides for the prevention of HIV transmission may be an important option for protecting women from infection. Incorporation of dapivirine, a lead candidate nonnucleoside reverse transcriptase inhibitor, into intravaginal rings (IVRs) for sustained mucosal delivery may increase microbicide product adherence and efficacy compared with conventional vaginal formulations. Twenty-four healthy HIV-negative women 18-35 years of age were randomly assigned (1:1:1) to dapivirine matrix IVR, dapivirine reservoir IVR, or placebo IVR. Dapivirine concentrations were measured in plasma and vaginal fluid samples collected at sequential time points over the 33-day study period (28 days of IVR use, 5 days of follow-up). Safety was assessed by pelvic/colposcopic examinations, clinical laboratory tests, and adverse events. Both IVR types were safe and well tolerated with similar adverse events observed in the placebo and dapivirine groups. Dapivirine from both IVR types was successfully distributed throughout the lower genital tract at concentrations over 4 logs greater than the EC50 against wild-type HIV-1 (LAI) in MT4 cells. Maximum concentration (Cmax) and area under the concentration-time curve (AUC) values were significantly higher with the matrix than reservoir IVR. Mean plasma concentrations of dapivirine were <2 ng/mL. These findings suggest that IVR delivery of microbicides is a viable option meriting further study.

The future of HIV prevention: prospects for an effective anti-HIV microbicide.

Topical microbicides are self-administered products for prevention of HIV transmission, and they present one of the most promising strategies for combating the HIV-AIDS epidemic. The development of microbicides is a long and complicated process, with many hurdles that are unique to this class of product, including challenges in product design, in the conduct and design of clinical trials, and in obtaining licensure of a new class of products intended for use almost exclusively in developing countries. Once they have been registered, there are additional challenges to the marketing and distribution of microbicides. An overview of the types of microbicide currently in development, and a summary of the issues and the approaches being taken to address them, are provided.

The role of herpes simplex virus type 2 and other genital infections in the acquisition of HIV-1 among high-risk women in northern Tanzania.

BACKGROUND: We examined the role of herpes simplex virus type 2 (HSV-2) and other genital infections on human immunodeficiency virus type 1 (HIV-1) incidence in a cohort study conducted between 2002 and 2005 among female bar/hotel workers in Moshi, Tanzania. METHODS: At baseline and every 3 months thereafter, participants were interviewed, and blood and genital samples were collected. Predictors of HIV-1 incidence were evaluated using a Cox proportional hazards regression model. RESULTS: Of 845 women who were HIV-1 seronegative at baseline, 689 (81.5%) were monitored in the study for a total of 698.6 person-years at risk (PYARs). The overall HIV-1 incidence was 4.6/100 PYARs (95% confidence interval [CI], 3.0-6.2/100 PYARs), and condom use was very low. After adjustment for other risk factors, the risk of HIV-1 was increased among women with HSV-2 at baseline (hazard ratio [HR], 4.3 [95% CI, 1.5-12.4]) and in those who acquired HSV-2 during the study period (HR, 5.5 [95% CI, 1.2-25.4]). Other independent predictors of HIV-1 were baseline chlamydial infection (HR, 5.2), bacterial vaginosis (HR, 2.1), and the occurrence of genital ulcers (HR, 2.7). CONCLUSION: HSV-2 and other genital infections were the most important risk factors for HIV-1. Control of these infections could help to reduce HIV-1 incidence in this population.

Predictors of herpes simplex virus type 2 prevalence and incidence among bar and hotel workers in Moshi, Tanzania.

BACKGROUND: Herpes simplex virus (HSV) type 2 increases the risk of human immunodeficiency virus (HIV) infection, and, in regions with high prevalence of both viruses, control of HSV-2 may be an effective method of HIV prevention. Identification of modifiable factors for prevention of HSV-2 infection is essential. We conducted this study among female bar and hotel workers in Moshi, Tanzania. METHODS: Factors associated with prevalent infection were examined among 1039 women. Predictors of incident infection were examined among 360 women initially HSV-2 negative, with at least 1 follow-up visit. RESULTS: HSV-2 prevalence was 56.3% (95% confidence interval [CI], 53.3%-59.3%). Only 2.5% of women able to name a sexually transmitted infection named herpes. Incidence was 14.2 cases/100 person-years (95% CI, 10.5-18.8 cases/100 person-years). Incident HSV-2 infection was independently associated with HIV infection, younger age of sexual initiation, ethnicity, alcohol consumption, and having a male partner with other sexual partners. CONCLUSIONS: The occurrence of HSV-2 is high in this population, but knowledge is low. Development of education programs to increase awareness of HSV-2 is critical. The control of both HSV-2 and HIV infections is a major public health priority in Moshi. Prevention interventions in this and other high prevalence populations might most effectively target younger women, before initiation of sexual activity.

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.

Microbicides for the prevention of HIV infection in women: an overview of recent trials.

PURPOSE OF REVIEW: As the HIV/AIDS pandemic continues, the development of new prevention technologies is urgently needed. Microbicides, products applied to genital mucosal surfaces, are being developed to reduce the transmission of HIV during sexual intercourse. Microbicides have been designed to inhibit HIV from the time the virus enters the genital tract to any of the multiple steps in local virus replication. RECENT FINDINGS: Preclinical research and development of microbicides has led to the advancement of many candidates into human clinical trials. This research has shown that cervicovaginal irritation is an important safety concern and needs to be evaluated carefully and early. New approaches to measuring local irritation are currently under investigation. SUMMARY: Five broad-spectrum microbicides are now being tested in large-scale effectiveness trials to measure their effects on the reduction of HIV incidence. Next-generation candidates, based on highly active antiretroviral drugs, are currently undergoing safety studies. This paper reviews the findings from trials of these products and discusses several challenges that are encountered in the clinical development of microbicides. Although complex and resource intensive, the successful completion of ongoing studies and the initiation of efficacy trials of next-generation candidates are critical to the successful development of a microbicide.

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.

Topical microbicides for disease prevention: status and challenges.

As the human immunodeficiency virus and sexually transmitted disease epidemics advance relentlessly, it is clear that an armamentarium of therapeutic and preventive methods will be essential to their containment. Topical microbicides--self-administered prophylactic agents applied to the vagina or rectum in various formulations--could be a crucial addition to that necessary armamentarium. This article provides an update on the dramatically broadening array of approaches being pursued in microbicide research and development and identifies critical challenges to progress.

Safety and tolerability of vaginal PRO 2000 gel in sexually active HIV-uninfected and abstinent HIV-infected women.

OBJECTIVES: To evaluate once or twice daily vaginal exposure to 2 and 4% PRO 2000 Gel, a naphthalene sulfonate polymer microbicide, in sexually active HIV-uninfected women to determine the highest tolerated frequency and concentration combination, and to assess this in sexually abstinent HIV-infected women. METHODS: Sixty three women from Providence, Philadelphia, Durban and Johannesburg were enrolled after being screened to exclude pre-existing illnesses and were instructed to use the product once or twice daily for 14 intermenstrual days. They underwent colposcopy prior to product use and after 14 days of product use, with a pelvic examination at day 7. RESULTS: The product was well tolerated, with no serious adverse events, even though 73% of the participants had at least one adverse experience: 82% of these were classified as mild, and over 90% of the findings and symptoms were localized to the genital tract. Women who used the 4% gel twice daily tended to have more adverse events than all the other groups. Three participants did not complete the study; one because of Herpes simplex virus cervicitis, the second because of epithelial disruption, and the third because she became pregnant. The remaining participants adhered to the study protocol and indicated that they would use the product if it were shown to be effective. CONCLUSIONS: PRO 2000 Gel was safe and well tolerated in sexually active HIV-uninfected and sexually abstinent HIV-infected women, enabling the product to be considered for evaluation in efficacy trials.