International Partnership For Microbicides Research Articles

Transport and Permeation Properties of Dapivirine: Understanding Potential Drug-Drug Interactions.

The dapivirine (DPV) vaginal ring was developed by the nonprofit International Partnership for Microbicides (IPM) for reducing the risk of HIV infection. A clinical study (IPM 028) showed that concomitant use of the DPV ring and miconazole (MIC) altered DPV pharmacokinetic profile. In this work, we investigated whether or not DPV transport and permeation contributed to the observed DPV-MIC interaction. Our study evaluated the interaction between DPV and several transporters that are highly expressed in the human female reproductive tract, including MRP1, MRP4, P-gp, BCRP, and ENT1, using vesicular and cellular systems. We also evaluated the impact of DPV/MIC on cellular tight junctions by monitoring transepithelial electrical resistance with the Ussing chamber. Lastly, we evaluated the effect of MIC on DPV permeability across human cervical tissue. Our findings showed that DPV was not a substrate of MRP1, MRP4, P-gp, BCRP, or ENT1 transporters. Additionally, DPV did not inhibit the activity of these transporters. DPV, MIC, and their combination also did not disrupt cellular tight junctions. MIC did not affect DPV tissue permeability but significantly reduced DPV tissue levels. Therefore, our results suggest that the DPV-MIC interaction is not due to these five transporters, altered tight junction integrity, or altered tissue permeability.

U.S. Women Need the Dapivirine Ring, Too: FDA as Structural Barrier to HIV Prevention for Women.

The dapivirine monthly vaginal ring-a discreet, anti-HIV microbicide created specifically for women-has received a positive scientific opinion by the European Medicines Agency and is included in the WHO HIV prevention guidelines. It has received regulatory approvals in several countries in southern and eastern Africa. During the review of the New Drug Application that was submitted in December 2020, FDA advised the developer, International Partnership for Microbicides, that it was unlikely to be approved in the United States; the application has since been withdrawn. This commentary will present the case for FDA approval for the dapivirine ring. Advocacy is urgently needed to protect U.S. women's access to user-controlled HIV prevention technologies, consistent with both global regulatory decisions to date and with a reproductive justice framework. Women continue to need the fullest range of HIV prevention methods to integrate into their lives in the most practical and effective way possible.

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

BackgroundThe 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.MethodsIn 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.ResultsA 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.ConclusionsAmong 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.)

Contraceptive Preference among HIV High Risk Women Pre-screened for a Phase III Vaginal Microbicide Trial in South-Western Uganda

Background: Womens contraceptive choices vary according to the type of relationships they have and other aspects of their life. We describe the preference of modern contraceptive methods among HIV high risk women screened to participate in a Phase III vaginal microbicide trial. Methods: Medical Research Council/Uganda Virus Research Institute Uganda Research Unit on AIDS in collaboration with International Partnership for Microbicides (IPM) is evaluating safety and efficacy of a dapivirine vaginal ring among healthy HIV negative women in a multicentre Phase III trial (The Ring Study). One of the study eligibility criteria is being on a stable form of contraception in order to reduce the pregnancy rate. As part of the screening process women are identified from townships and fishing communities within 50 km from the centre. Data on use of modern contraception methods (Pills Injectables Implants IUCDs Surgical) are collected and confirmed by a contraceptive card or presence of an implant or IUCD strings. Women who are willing are provided by the research centre with contraception of choice (pills injectables) or referred to a provider (Implants IUCDs Surgical). The proportion of women per method used was determined. Results: A total of 489 women with a mean age of 28 years were pre-screened (age range 18 to 44 years). Most (306 63%) were already using contraception: 55% were on Injectables followed by Implants (28%) IUCDs (8%) Pills (7%) and only 2% had undergone a Surgical method. Of the women who were not on any method 106 (58%) accepted Injectables 40 (22%) preferred Implants 33 (18%) oral Pills and 4 (2%) chose IUCDs. Conclusions: There is high contraceptive use among HIV high risk women and the majority prefer Injectables. This is encouraging and will hopefully reduce discontinuation of volunteers from the trial due to pregnancy.

PRO2000 vaginal gel for prevention of HIV-1 infection (Microbicides Development Programme 301): a phase 3, randomised, double-blind, parallel-group trial

SummaryBackgroundInnovative prevention strategies for HIV-1 transmission are urgently needed. PRO2000 vaginal gel was efficacious against HIV-1 transmission in studies in macaques; we aimed to assess efficacy and safety of 2% and 0·5% PRO2000 gels against vaginal HIV-1 transmission in women in sub-Saharan Africa.MethodsMicrobicides Development Programme 301 was a phase 3, randomised, double-blind, parallel-group trial, undertaken at 13 clinics in South Africa, Tanzania, Uganda, and Zambia. We randomly assigned sexually active women, aged 18 years or older (≥16 years in Tanzania and Uganda) without HIV-1 infection in a 1:1:1 ratio to 2% PRO2000, 0·5% PRO2000, or placebo gel groups for 52 weeks (up to 104 weeks in Uganda). Randomisation was done by computerised random number generator. Investigators and participants were masked to group assignment. The primary efficacy outcome was incidence of HIV-1 infection before week 52, which was censored for pregnancy and excluded participants without HIV-1 follow-up data or with HIV-1 infection at enrolment. HIV-1 status was established by rapid tests or ELISA at screening at 12 weeks, 24 weeks, 40 weeks, and 52 weeks, and confirmed in a central reference laboratory. The primary safety endpoint was an adverse event of grade 3 or worse. Use of 2% PRO2000 gel was discontinued on Feb 14, 2008, on the recommendation of the Independent Data Monitoring Committee because of low probability of benefit. This trial is registered at http://isrctn.org, number ISRCTN 64716212.FindingsWe enrolled 9385 of 15 818 women screened. 2591 (95%) of 2734 participants enrolled to the 2% PRO2000 group, 3156 (95%) of 3326 in the 0·5% PRO2000 group, and 3112 (94%) of 3325 in the placebo group were included in the primary efficacy analysis. Mean reported gel use at last sex act was 89% (95% CI 86–91). HIV-1 incidence was much the same between groups at study end (incidence per 100 woman-years was 4·5 [95% CI 3·8–5·4] for 0·5% PRO2000 vs 4·3 [3·6–5·2] for placebo, hazard ratio 1·05 [0·82–1·34], p=0·71), and at discontinuation (4·7 [3·8–5·8] for 2% PRO2000 gel, 3·9 [3·0–4·9] for 0·5% PRO2000 gel, and 3·9 [3·1–5·0] for placebo gel). Incidence of the primary safety endpoint at study end was 4·6 per 100 woman-years (95% CI 3·9–5·4) in the 0·5% PRO2000 group and 3·9 (3·2–4·6) in the placebo group; and was 4·5 (3·7–5·5) in the 2% PRO2000 group at discontinuation.InterpretationAlthough safe, 0·5% PRO2000 and 2% PRO2000 are not efficacious against vaginal HIV-1 transmission and are not indicated for this use.FundingUK Department for International Development, UK Medical Research Council, European and Developing Countries Clinical Trials Partnership, International Partnership for Microbicides, and Endo Pharmaceuticals Solutions.

Fighting HIV/AIDS, tuberculosis and malaria: one world, one partnership

keywords poverty-related diseases, clinical trials, partnership, EDCTPThe European and Developing Countries Clinical TrialsPartnership (EDCTP) was founded in 2003 in response tothe global burden of HIV/AIDS, tuberculosis and malaria.Its mission is to accelerate the development of new orimproved clinical interventions against these diseases witha focus on supporting phase II and III clinical trialsincluding capacity development. EDCTP organises biennialforums that bring together researchers, programme man-agers, policy makers, funders and other stakeholdersworking on poverty-related diseases. These forums havebecome a major platform for discussing matters pertainingto poverty-related diseases in Africa. The theme of the FifthEDCTP Forum, held in Arusha, Tanzania, from 12 to 14October 2009, was ‘Fighting HIV/AIDS, tuberculosis andmalaria – one world, one partnership’. This underpinnedthe principle of EDCTP of working in partnerships.Four hundred and fifty participants from 49 countriesincluding 26 from Africa, 15 from Europe and others fromAustralia, Cambodia, China, Cuba, Indonesia, Nepal, Peruand the United States attended. There were presentationsfrom many partners from the African AIDS VaccineProgramme (AAVP), the African Malaria Network Trust(AMANET), AERAS Global TB Vaccine Foundation, theBill & Melinda Gates Foundation (BMGF), the EuropeanVaccines Initiative (EVI), the Enhancing Support forStrengthening the Effectiveness of National CapacityEfforts (ESSENCE), the International Partnership forMicrobicides (IPM), the Medicines for Malaria Venture(MMV) and the Wellcome Trust. There were also foursatellite meetings and workshops on Ownership ofResearch Outcomes in sub-Saharan Africa; UniversalStandards for Clinical Trials in Practice; ESSENCE fundersmeeting to explore synergy; and a Round-table Meeting ofAfrican Regional Economic Communities on the Africanrepresentation to EDCTP-EEIG General Assembly. EDCTPlaunched awards for outstanding African scientists: thesenior scientist award went to Alexis Nzila of KenyaMedical Research Institute, Wellcome Trust ResearchCentre. Dominique Pepper from the Institute of InfectiousDiseases and Molecular Medicine, University of CapeTown, South Africa, won the junior scientist award.The forum comprised plenary and parallel sessionsduring which 58 oral presentations, 81 short electronicpresentations and 69 posters were presented, covering awide range of topics. Keynote addresses were delivered onthe current state of affairs in research and control of HIV/AIDS by Dr Anatoli Kamali, of malaria by ProfessorAbdoulaye Djimde´ and of tuberculosis by Professor WillemHanekom. Articles based on these are published as reviewsin this issue of the journal.Forum participants met in the penultimate plenarysession to identify research gaps and needs and madeseveral recommendations to EDCTP. These were asfollows:HIV/AIDS• Continue with research on preventive HIV vaccinesand microbicides including exploring efficacy of anti-retroviral-based combinations.• Conduct more research to answer treatment strategyissues. These should include when to start treatment;effect of treatment on immune reconstitution inflam-matory syndrome (IRIS); when to switch and what toswitch to; management of HIV-TB co-infectionsincluding strategies on prophylaxis, vaccines, diagno-sis and treatment and reduction in mortality prior toand soon after treatment initiation.• High priority should be given to customised inter-ventions and the needs of specific populations such asdiscordant couples.• High priority should be given to research on imple-menting and scaling up interventions of proven

Myron Cohen ponders path to HIV prevention

Myron Cohen ponders path to HIV prevention

Meeting the need for treatment: the initiatives

Many diseases prevail because are old and ineffective, or simply do not exist. Tuberculosis (TB) is a major killer in poor countries, but no new anti-TB drug has been developed since the 1960s. There are rare, often life-threatening diseases, defined in Europe as affecting fewer than one in 2000 people, for which more orphan drugs need to be developed. There are diseases that are highly prevalent, such as HIV/AIDS in southern Africa, but while new, effective medicines exist, millions of people and their governments cannot afford them or they are not available at all. Neglected tropical diseases, such as malaria, affect millions of people, but most are too poor to constitute a market that is lucrative enough to justify drug research and development (RD 46 such projects were in the pipeline in 2005, according to a Wellcome Trust report. The generic industry provides cheap copies of brand-name medicines, has pushed down drug prices overall through competition. Access-to-medicines campaigners and generic companies argue that patents are a major barrier to meet the huge demand for affordable drugs, vaccines and diagnostics in developing countries. In contrast, the R&D-based pharmaceuticals industry, which comes up with innovations and patents them to recoup the R&D costs, argues that the bottleneck is not the fault of patent restrictions, but the lack of funds to buy these products and inadequate infrastructure to deliver them. Generic industry The global generic pharmaceuticals industry produces cheap copies of patented medicines for diseases such as HIV/AIDS, often pushing down the prices of the original patented medicines in the process. India is a major exporter of generic medicines to other developing countries. Of the more than 60 000 HIV/AIDS patients in nearly 30 countries in Medecins Sans Frontieres' projects, 84% receive generic medicines made in India. The generic industry helped establish the US Orphan Drug Act of 1983 to promote the development of medicines for small patient populations by providing incentives, such as tax benefits and exclusive marketing protection. Some say this model could be used to promote the R&D for for neglected diseases. The generic industry sees several threats to its business model, such as evergreening by pharmaceutical companies to extend their patent rights and data exclusivity, i.e. denying the release of information required to advance science. Public-private partnerships Public-private partnerships show that costly drug development can be combined with social responsibility. Under a 2002 agreement with US pharmaceuticals company Chiron Corporation, the Global Alliance for TB Drug Development obtained exclusive world rights to the compound, PA-824, and its derivatives, which may be developed into a new TB medicine. Chiron agreed to make the compounds royalty free in endemic countries, while retaining the right to develop and commercialize them for non-TB indications. Another example is a 2004 agreement between the International Partnership for Microbicides and Tibotec Pharmaceuticals, a Belgian subsidiary of pharmaceutical company Johnson & Johnson, to develop a microbicide to protect women from infection with HIV. …