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 protective 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 concentrations 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, and two pharmaco- ly measured in clinical trials by self-reported product kinetics studies with the ring were recently completed use and counting of returned used and unused gel ap- in belgium. plicators [29]. this provides only an estimate of true adherence and no information on the time of product MaRavIRoc insertion. others have explored “daily monitored adherence” and found that daily contact with trial partic- Maraviroc, a ccR5 co-receptor antagonist marketed as ipants can improve adherence to the microbicide regi- selzentry® (Pfizer labs, new York, nY, Usa) for men [30]. treatment of ccR5-tropic HIv-1 infection, is in devel- Use of aRv-based vaginal microbicides could po- opment as a vaginal microbicide [20]. vaginal gels and tentially induce drug resistance in individuals who are rings containing a combination of dapivirine plus mar- unaware that they are HIv infected if subtherapeutic aviroc are in development; phase I clinical trials are drug levels consistent with the selection of resistance planned for 2011. these products have the potential in vivo are attained. systemic drug exposure after vagi- advantage of blocking HIv infection at two different nal dosing with nRtI- and nnRtI-based microbi- steps in the replication cycle, attachment and reverse cides has been shown to be low [13, 14, 16, 17, 18, 31, transcription. vaginal gels and rings containing mar- 32], while concentrations in cervicovaginal fluids have aviroc as a single agent are in development in parallel been shown to be many logs greater than in vitro con- with the combination dosage forms and will be includ- centrations at which resistance mutations were noted ed in the phase I clinical trials planned for 2011. In ad- [13]. combination microbicides with two drugs that dition, a combination vaginal film with maraviroc and target different steps in the HIv replication cycle may tenofovir is in preclinical development. reduce the potential for development of HIv resistance by increasing the barrier to infection [28, 33]. MIv-150 furthermore, combination microbicides may help prevent the transmission of virus resistant to a specific MIv-150 is an nnRtI with potent activity against drug via the mechanism of action of the other drug HIv-1 and HIv-2, including free HIv-1 and HIv-1 in the combination. development of resistance is be- strains that are resistant to other aRvs [21-22]. MIv- ing studied in the clinical context through the imple- 150 is currently under development at Population mentation of seroconvertor protocols [12, 13]. the council in both microbicide gel (Pc-815 and Pc- monitoring of microbicide users for HIv infection is 1005) and ring formulations [23-25]. Population therefore important, and recommended timetables for council researchers are also developing vaginal rings HIv testing are under development. Monthly HIv that contain both MIv-150 and a contraceptive to testing is generally used in microbicide trials; however, protect women against both HIv infection and preg- this schedule may not be feasible after product ap- nancy. proval.

cHallEngEs facEd In MIcRobIcIdE PRIoRItIEs In MIcRobIcIdE dEvEloPMEnt dEvEloPMEnt now that proof-of-concept for an aRv-based vaginal the establishment of surrogate markers for determi- microbicide has been established through the success- nation of clinical efficacy and survival-enhancing ef- ful completion of the caPRIsa trial [12], interest in fects of aRvs (rises in cd4 cell counts and decreases new HIv prevention tools has received a boost. It is in HIv viral load) dramatically enhanced the develop- now a priority to set-up the necessary confirmatory ment of new medicines for the treatment of HIv in- and supporting studies for the continued clinical de- fection [26, 27]. to date, no surrogate markers have velopment of tenofovir gel, which could then lead to been identified for measurement of the efficacy of the approval and launch of the first aRv-based micro- HIv prevention tools; therefore, microbicide clinical bicide. other aRv-based microbicides that hold trials are designed to measure the difference in infec- promise for increasing potency and addressing prod- tion rates between the active and control groups. for uct adherence concerns need to be prioritized for de- this reason, trial settings must have sufficiently high velopment, including products ready for efficacy test- HIv incidence rates (typically over 2%) to show a sig- ing such as the dapivirine-containing vaginal ring. nificant reduction with the intervention. furthermore, optimizing implementation programs and measur- careful selection of microbicide candidates to test in ing the real-life public health impact will be further clinical trials is imperative because of shared trial sites milestones. Establishment of a comprehensive post- and high trial expenses. because of the lack of surro- approval drug safety surveillance system is important gate markers, in vitro assays, cervical explant models, when microbicides are introduced into the markets in and animal models have been utilized to estimate the developing countries because there is no experience potential for preventive efficacy of new microbicide with the use of these products in regions under the ju- compounds in women. these models are experimental risdiction of the fda or EMa. also, since these and have not been validated. the development of products will be used by otherwise healthy women, pharmacokinetic/pharmacodynamic models is being monitoring product safety is paramount. further de- explored [28] and ideally would be able to predict the velopment of aRv-based microbicides (including 4 EURoPEan JoURnal of MEdIcal REsEaRcH January 27, 2011 d n

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e l x y m n I n n 8 P l g f I c e f a t n d M u c E t H 5 b e f i v n r t E r u I r o t e 1 a a d M a r E t t R N a M a P T b T P s v ( ( P i ( t I f c a t f n * R January 27, 2011 EURoPEan JoURnal of MEdIcal REsEaRcH 5 drug combinations) with longer-acting formulations Effectiveness of col-1492, a nonoxynol-9 vaginal gel, and in multiple dosage forms remains a priority to of- on HIv-1 transmission in female sex workers: a ran- fer women choices, a strategy that has proven to be domised controlled trial. lancet. 2002 sep 28; 360(9338): 971-7. very successful in the field of contraception [34, 35]. 5. feldblum PJ, adeiga a, bakare R, wevill s, lendvay a, obadaki f, olayemi Mo, wang l, nanda k, Rountree PRE-ExPosURE PRoPHYlaxIs (PREP) w. savvY vaginal gel (c31g) for prevention of HIv infection: a randomized controlled trial in nigeria. Plos In addition to HIv microbicide development, oral one. 2008 Jan 23; 3(1): e1471. PrEP of HIv infection with aRv drugs approved for 6. van damme l, govinden R, Mirembe fM, guédou f, treatment of HIv and aIds is currently under inves- solomon s, becker Ml, Pradeep bs, krishnan ak, alary tigation [36-39]. the voIcE trial described above is M, Pande b, Ramjee g, deese J, crucitti t, taylor d; cs one such trial. other PrEP trials being conducted study group. lack of effectiveness of cellulose sulfate gel worldwide are shown in table 2. all but one of these for the prevention of vaginal HIv transmission. n Engl J Med. 2008 Jul 31; 359(5): 463-72. trials is with oral tenofovir disoproxil fumarate and/or 7. skoler-karpoff s, Ramjee g, ahmed k, altini l, Pla- oral emtricitabine plus tenofovir disoproxil fumarate. gianos Mg, friedland b, govender s, de kock a, cas- Intramuscular injection of tMc278la, an nnRtI sim n, Palanee t, dozier g, Maguire R, lahteenmaki P. for HIv prevention, is presently being tested in a Efficacy of carraguard for prevention of HIv infection phase I trial in the Uk. the results of the first oral in women in south africa: a randomised, double-blind, PrEP trials in women are expected in 2010 and placebo-controlled trial. lancet. 2008 dec 6; 372(9654): 2011. 1977-87. the findings of these PrEP trials should hopefully 8. Morris gc, lacey cJn. Microbicides and HIv preven- demonstrate the efficacy, safety, and tolerability of tion: lessons from the past, looking to the future. curr aRvs in HIv-negative individuals. In addition, the re- opin Infect dis. 2010 feb; 23(1): 57-63. 9. nuttall J. Microbicides in the prevention of HIv infec- sults will be used to develop public health guidelines tion: current status and future directions. drugs. 2010 Jul for prevention of HIv transmission in different popu- 9; 70(10): 1231-43. lations such as heterosexual couples, serodiscordant 10. friend dR. Pharmaceutical development of microbicide couples, men who have sex with men, and injection drug products. Pharm dev technol. 2009 dec 17; 1-20. drug users. If proven safe and effective, PrEP could 11. Romano J, Malcolm Rk, garg s, Rohan lc, kaptur PE. help address the urgent need for a female-initiated Microbicide delivery: formulation technologies and strate- prevention method for women worldwide. gies. curr opin HIv aIds. 2008 sep; 3(5): 558-66. 12. karim Qa, karim ssa, frohlich Ja, grobler ac, baxter conclUsIons c, Mansoor lE, kharsany abM, sibeko s, Mlisana kP, omar Z, gengiah tn, Maarschalk s, arulappan n, Mlotshwa M, Morris l, taylor d, on behalf of the there is an immediate need for female-initiated HIv caPRIsa 004 trial group). Effectiveness and safety of prevention tools. Microbicide research, like most HIv tenofovir gel, an antiretroviral microbicide, for the pre- prevention research, has faced many hurdles over the vention of HIv infection in women. sciencexpress. 2010 past two decades, but proof-of-concept in the Jul 19; 1-13. caPRIsa trial has reignited the hope of obtaining 13. nel aM, smythe sc, Habibi s, kaptur PE, Romano Jw. safe and effective HIv microbicides that are accept- Pharmacokinetics of 2 dapivirine vaginal microbicide gels able to the women who will use these products. sever- and their safety vs. hydroxyethyl cellulose-based universal al aRv-based microbicides are in clinical trials at this placebo gel. J acquir Immune defic syndr. 2010 oct 1; time, and many others are in preclinical stages of de- 55(2): 161-9. velopment. oral PrEP with aRvs approved for treat- 14. nel aM, coplan P, smythe sc, Mccord k, Mitchnick M, kaptur PE, Romano J. Pharmacokinetic assessment of ment of HIv/aIds is currently under investigation dapivirine vaginal microbicide gel in healthy, HIv-nega- with the first trial results expected in 2010 and tive women. aIds Res Hum Retroviruses. 2010 sep 21 2011. {Epub ahead of print]. 15. nel a, kamupira M, Hetro c, nuttall J, Romano J. safety and pharmacokinetics trial of dapivirine matrix vaginal ring. 18th International aIds conference, vienna, aus- REfEREncEs tria, July 18-23, 2010, #PE0391. 16. Romano J, variano b, coplan P, van Roey J, douville k, 1. aIds epidemic update 2009. Joint United nations Pro- Rosenberg Z, temmerman M, verstraelen H, van bortel gramme on HIv/aIds (UnaIds) and world Health l, weyers s, Mitchnick M. safety and availability of organization (wHo) 2009. 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Microbicides 2010 – building telephone: 1-301-608-2221 bridges in HIv Prevention, Pittsburgh, Pa, Usa, May fax: 1-301-608-2241 22-25, 2010, abstract #58. Email: [email protected]