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Seeking New Hiv Prevention Tools for Women

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Seeking New Hiv Prevention Tools for Women January 27, 2011 EU Ro PE an JoUR nal of MEd I cal RE sEaRcH 1 Eur J Med Res (2011) 16: 1-6 © I. Holzapfel Publishers 2011 UPdatE on MIcRobIcIdE REsEaRcH and dEvEloPMEnt – sEEkIng nEw HIv PREvEntIon tools foR woMEn t. Mertenskoetter, P. E. kaptur International Partnership for Microbicides, silver spring, Md, Usa Abstract out an apparent lack of HIv prevention methods, women and girls are especially vulnerable to HIv in- specifically for women. sixty-eight percent of the 2.3 fection in sub-saharan africa, and in some of those million adults newly infected with HIv in 2008 live in countries, prevalence among young women can be up sub-saharan africa, where approximately 60% of in- to 3 times higher than among men of the same age. fected individuals are women [1]. women and adoles- Effective HIv prevention options for women are cent girls are especially vulnerable to HIv infection in clearly needed in this setting. several aRv-based vagi- sub-saharan africa not only because of their increased nal microbicides are currently in development for pre- physiological susceptibility to heterosexual transmis- vention of HIv transmission to women and are dis- sion, but also because of social, legal, and economic cussed here. the concept of pre-exposure prophylaxis disadvantages [1]. according to the most recent esti- for the prevention of HIv transmission to women is mate, the number of people living with HIv is 33.4 introduced. million [1]. In the nine countries in southern africa af- fected most by HIv (botswana, lesotho, Malawi, Key words: microbicides, HIv prevention, pre-expo- Mozambique, namibia, south africa, swaziland, Zam- sure prophylaxis (PrEP), antiretrovirals, vaginal gel, bia, and Zimbabwe), prevalence among young women vaginal ring aged 15-24 years was reported to be approximately 3 times higher than among men of the same age [2]. Abbreviations: HIv prevention options for women are presently lim- aRv = antiretroviral (drug) ited in this setting. atn = adolescent Medicine trials network Microbicides to prevent HIv infection in women bMgf = bill & Melinda gates foundation are vaginally applied topical products that interfere caPRIsa = centre for the aIds Programme of Re- with HIv infection at one or more steps in the replica- search in south africa tion cycle. this paper summarizes research to date on EMa = European Medicines agency early generation product development efforts (polyan- fda = U.s. food and drug administration ions, surfactants, acidifying agents) and next genera- fHI = family Health International tion antiretroviral (aRv)-based HIv microbicides and ftc = Emtricitabine introduces the concept of pre-exposure prophylaxis HEc = Hydroxyethyl cellulose (PrEP) for the prevention of HIv transmission. IavI = International aIds vaccine Initiative IPM = International Partnership for Microbicides tHE nEEd foR a fEMalE-InItIatEd HIv Mtn = Microbicide trials network PREvEntIon MEtHod nIaId = national Institute of allergy and Infectious diseases Half of the exposed population currently has no ef- nIcHd = national Institute of child Health & Hu- fective means of self-initiated HIv prevention; and al- man development though condoms provide good protection from HIv nnRtI = non-nucleoside reverse transcriptase in- infection, their regular use is not always negotiable by hibitor women. the effectiveness of an HIv prevention nRtI = nucleoside reverse transcriptase inhibitor method is impacted by its correct and consistent use. PrEP = Pre-exposure prophylaxis therefore, microbicide research and development has tdf = tenofovir disoproxil fumerate also focused on the topic of adherence, and factors af- UsaId = United states agency for International de- fecting adherence, such as preferred dosage forms and velopment regimens, stigma associated with microbicide use, male voIcE = vaginal and oral Interventions to control perception of microbicide use, and various dosage the Epidemic (trial) forms and regimens. an ideal microbicide product would be highly effec- IntRodUctIon tive against HIv transmission and potentially other pathogens, have a very good safety profile, create no current HIv incidence rates in highly impacted re- drug-drug interactions with other vaginal products, gions reflect the magnitude of the epidemic and point and could be easily and discreetly used on a regular ba- 2 EURoPEan JoURnal of MEdIcal REsEaRcH January 27, 2011 sis. the half-life of the active pharmaceutical ingredi- pared with the HEc-based universal placebo gel, 1% ent ideally would be long enough so that protective tenofovir gel was 39% effective (incidence rate ratio drug levels would be maintained in tissues even with 0.61, p = 0.017) at reducing new HIv infection after lapses in product use. dosing regimens should accom- 30 months of coitally-dependent use by sexually-active modate the range in female sexual behavior from regu- women aged 18 to 40 years. the effectiveness in- lar intercourse to periods of abstinence. long-acting creased to 54% (p = 0.025) when only data for women dosage forms such as vaginal rings may be an attrac- who used the gel correctly were analyzed. the protec- tive feature for women as well as improve adherence tive effect of tenofovir gel was evident at 6 months, and therefore the effectiveness of the product. Prod- 50% at 12 months (p = 0.007), and was 40% at 24 uct formulations that combine HIv prevention with months (p = 0.013). tenofovir gel had a favorable contraception are in early stages of development and safety profile: only diarrhea and gastrointestinal infec- would offer women additional options [3]. tions were significantly higher in the tenofovir gel vs. placebo gel group (17% vs. 11%, p = 0.02). ovERvIEw of REsEaRcH and dEvEloPMEnt an ongoing study (Mtn 003, also referred to as EffoRts wItH non-aRv-basEd the “vaginal and oral Interventions to control the MIcRobIcIdEs Epidemic” or “voIcE” trial) funded by nIaId and sponsored by the Microbicide trials network is being several early generation microbicide gels were evaluat- conducted in africa (Malawi, south africa, Uganda, ed for efficacy in phase IIb and phase III trials with Zimbabwe) to test the effectiveness of daily 1% teno- disappointing results. these include the surfactants fovir gel vs. placebo gel as well as the effectiveness of nonoxynol-9 [4] and savvY (cellegy Pharmaceuti- oral tenofovir disoproxil fumarate (viread®, gilead cals, Huntington valley, Pa, Usa) [5]; three polyan- sciences, foster city, ca, Usa) and oral emtric- ions, cellulose sulfate [6], carraguard® (Population itabine/tenofovir disoproxil fumarate (truvada®, council, new York, nY, Usa) [7], and PRo 2000 gilead sciences) vs. oral placebo measured by HIv se- (Endo Pharmaceuticals, chadds ford, Pa, Usa) [8]; roconversion. Extended safety of the products in and an acidifying agent, buffergel (ReProtect llc, women at risk for sexually transmitted HIv infection baltimore, Md, Usa) [8]. none proved to inhibit HIv will also be assessed. the results of this study may an- infection, and in fact with three of the gels, swer the question whether daily dosing (used in the nonoxynol-9, cellulose sulfate, and savvY, a trend to- voIcE trial) improves adherence and effectiveness of ward increased risk of HIv infection was observed [4- tenofovir gel compared with coitally-associated dosing 6]. (used in the caPRIsa trial) without compromising the safety profile. the results of the voIcE trial are ovERvIEw of REsEaRcH and dEvEloPMEnts expected in 2013. EffoRts wItH aRv-basEd MIcRobIcIdEs daPIvIRInE Microbicide research has now shifted to development of next-generation, aRv-based formulations in multi- dapivirine, an nnRtI initially developed by tibotec ple dosage forms such as vaginal gels, rings, films, Pharmaceuticals in belgium, has been tested for safety soft-gel capsules, and tablets [9-11]. formulations of in sexually active, HIv-negative women in both vaginal aRvs that target reverse transcriptase are furthest gel (daily dosing) and vaginal ring (monthly dosing) along in development as topical microbicides (table formulations. both dosage forms have been shown to 1). Proof-of-concept was shown recently with a vagi- have similar safety profiles to their respective placebos nal gel containing tenofovir, an nRtI. and to release dapivirine into the lower female genital . tract at concentrations well above those shown to be tEnofovIR protective in vitro and ex vivo, and well above concen- trations in plasma that have been shown to reduce vi- In July 2010, positive results were reported from the ral load [13-19]. two more recently developed formu- caPRIsa 004 trial in south africa [12]. when com- lations of 0.05% dapivirine gel have been tested in Table 1. aRv-based Microbicides Products in development. Product MOA License Holder(s) Phase of Development tenofovir gel nRtI conRad and IPM Phase IIb dapivirine gel and ring nnRtI IPM Phase I/II dapivirine–maraviroc combination gel and ring nnRtI + ccR5 blocker IPM Phase I planned Maraviroc ring and gel ccR5 blocker IPM Phase I planned Maraviroc–tenofovir combination film ccR5 blocker + nRtI IPM late preclinical MIv-150 gel and ring nnRtI Population council late preclinical January 27, 2011 EURoPEan JoURnal of MEdIcal REsEaRcH 3 safety studies in kenya, Malawi, Rwanda, south africa, pharmacodynamic effect of a microbicide candidate and the United states. a safety study with the current from the pharmacokinetic profile. dapivirine ring formulation (25 mg) is ongoing in adherence with the microbicide regimen is general- south africa, kenya, and Malawi,
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