Thinking (Re)Productively – September 2013

Commentary: Delivering on MPTs: addressing the needs, rising to the challenges and making the opportunities

R. Karl Malcolm	Susan M. Fetherston

Introduction

The Greek philosopher Plato famously remarked that, “necessity is the mother of invention”. Or, in more contemporary language, difficult situations inspire ingenious solutions. Let’s hope this popular proverb holds true — the (re)emerging and reenergised research area of multipurpose prevention technologies (MPTs) will undoubtedly need a double measure of inspiration, creative thinking and tenacity to help begin address some of the priority issues within reproductive and sexual health. The underlying facts are both startling and sobering: each year, 40% of the >200 million pregnancies worldwide are unintended¹ and 448 million treatable sexually transmitted infections (STIs) [i.e. not including syphilis, HIV, herpes simplex virus (HSV), and human papillomavirus (HPV)] are contracted;² >80% of HIV infections are now acquired through sexual transmission.³ Young women in developing countries disproportionately bear the brunt of these health risks,⁴ although teenage pregnancy and STI rates are also worryingly high and increasing in many developed countrie.⁵

What are MPTs?

Current biomedical interventions for contraception and either prevention or treatment of STIs, including HIV/AIDS, are invariably reliant upon “single-indication” drug delivery or medical device technologies (Table 1). These diverse technologies are administered by a range of routes (vaginal, oral, sub-dermal injection/implant, etc.) and provide different levels and durations of efficacy. MPTs are products, preferably single device products and administered via a single route, that are expressly designed to simultaneously address multiple sexual and reproductive health needs.⁶ Of course, MPTs are nothing new — male and female condoms already provide effective protection against pregnancy and sexually transmitted infections, including HIV (Table 1). However, women will need significantly greater access to both existing and new contraceptive and reproductive health technologies if we are to stand any chance of addressing some of the targets described in UN Millennium Development Goals 5 and 6 (specifically, the unmet need for family planning, and halting and reversing the spread of HIV/AIDS, respectively).⁷ Several major research funding bodies, most notably The Bill and Melinda Gates Foundation (BMGF) and United States Agency for International Development (USAID), have recently expressed interest in supporting the development of new MPT technologies with invitations for submission of concept papers. The BMGF appears to be primarily focused on MPTs that address contraception and HIV, while USAID have a broader remit that specifically includes HSV and HPV infections.

Taking the lead from existing contraceptive technologies

Of the various target clinical indications that define MPTs, contraceptive technologies are by far the most advanced and diverse and are likely to drive future MPT product development. Various distinct types of contraceptive product have already been approved and marketed, including hormonal, spermicidal and barrier devices Table 1). Theoretically, any of these technologies could be exploited for development of an MPT device. However, based on the product assessments summarized within the table (some of which are tentative), there is a clear subset of device technologies (rings, injectables, oral pills, condoms) that holds out the greatest promise, and these are the main focus in the remainder of this article.

Male and female condoms already cover all the bases; with proper and consistent use, these ubiquitous barrier devices provide effective protection against conception, HIV and other STIs. Unfortunately, in an ironic twist of fate and for a variety of reasons, condoms remain unloved and unused.^{8, 9} What of the other existing contraceptive technologies? Rings, injectables and oral pills probably represent the most viable MPT platforms, with rings and injectables offering the possibility of long-acting, high user adherence, controlled release products, and oral pills leaning heavily on their familiarity, ease of administration and encouraging data from recent oral pre-exposure prophylaxis (PrEP) studies.^{10, 11} Oral PrEP does pose a number of challenges, though, including adherence to daily pill intake, the potential for renal and bone toxicities, the potential for decreased condom use, and the development of resistance. Also, very considerable technical hurdles will need to be overcome in developing an oral pill containing a low dose contraceptive hormone and one or more high dose antiretrovirals. Vaginal gels, which have been a major focus within HIV microbicide research, may struggle to provide an acceptable and effective contraceptive function. More realistically, gels may prove useful as a combination anti-infective product (e.g., HIV and HSV)¹² or in conjunction with a cervical barrier device.¹³

Vaginal microbicides for HIV prevention

Although the anti-HIV component of any future MPT strategy is far from certain, both vaginally and orally administered antiretrovirals for PrEP seem to offer the most credible options. Although the concept of a vaginally administered microbicide directed against sexual HIV transmission has been pursued for the past twenty years, an effective product has yet to be demonstrated in late stage efficacy trials. The non-specific microbicide candidates Carraguard, SAVVY (also a contraceptive) and PRO2000 all failed to demonstrate efficacy against HIV transmission,^{14, 15, 16, 17} while a gel-based formulation of the spermicidal agent nonoxynol-9 was shown to damage vaginal tissue and thereby increase susceptibility to HIV infection.¹⁸ The CAPRISA-004 trial provided the first glimmer of hope (and much relief) for microbicide researchers: a 1% tenofovir aqueous gel, applied both before and after sex, was shown to be effective in reducing HIV infection by 39% (54% in highly adherent women) compared to placebo gel.¹⁹ However, the same tenofovir vaginal gel product applied once daily showed no efficacy in the subsequent VOICE (MTN-003) trial.²⁰ The microbicide community is now keeping its fingers very tightly crossed for the dapivirine-releasing vaginal ring,^{21, 22} which recently entered Phase III clinical testing (ASPIRE study).

A major obstacle for single indication vaginal HIV microbicides is that we still do not know how much drug is needed to prevent viral transmission. Given long-term safety concerns with regular use, most microbicide clinical studies have understandably erred on the side of caution in selecting the administered dose for testing. Might there be a rationale for seeking proof-of-concept with higher microbicide doses, knowing that lower doses, if required for safety, can be tested later? The last thing the microbicide field needs is another failed Phase III study. Also, although current antiretroviral microbicide candidates may be sufficiently potent, the surrogates of efficacy are still largely unknown.

Challenges ahead

Major practical considerations for single-device MPTs include the requirement for complementary duration of clinical effect for each of the different clinical indications targeted, and the very significant complexities of evaluating both clinical outcomes at the same time. The former issue is particularly challenging for long-acting, multi-drug MPTs where the actives have different clinical potencies and therefore require very different drug release rates. For example, marketed hormonal intrauterine devices (IUDs) provide excellent contraceptive efficacy for either 3 or 5 years, with 13.5 or 52 mg total levonorgestrel loadings and release rates ranging between 5 and 20 mcg/day, respectively. Incorporation of a second active agent into a hormonal IUD for the purpose of HIV or STI prevention over the same time period may be impractical owing to the limited drug loading capacity (associated with the physical size constraints of the drug reservoir) and the need for higher release rates (given the lower potency of anti-HIV/STI agents compared with contraceptive hormones). Also, the presence of a second active in an MPT IUD device may modify the release characteristics of the primary active. These same concerns also apply to other implantable and injectable devices. Of course, a simple solution would be to reduce the duration of clinical use, although user acceptability may decline as a consequence. By comparison, the larger size of vaginal rings not only offers increased drug loading capacity, but also permits the design of more complex (and more costly) devices with independently controlled release rates for multiple actives.

Where’s the innovation?

Most of the innovation within the MPT arena is stemming from the existing HIV microbicide community — there appears to be significantly less innovation in the much more mature contraceptive arena. A particularly strong emphasis is being placed on products that offer long-acting efficacy, rapid reversibility of activity, and high levels of user adherence. It’s not surprising, therefore, that variants on controlled release vaginal rings, which are already marketed for contraception (NuvaRing and Progering) and are being developed as HIV microbicide products (Table 1), are high up the MPT priority list. Levonorgestrel is widely considered the preferred hormone for incorporation into a ring, and continuous-use combination products with either dapivirine or tenofovir are already in early stage development with the International Partnership for Microbicides and CONRAD, respectively. Fortunately, a large body of literature already exists for levonorgestrel-releasing rings, mostly published during the 1980s and 1990s when the World Health Organization were focused on developing a contraceptive ring to help alleviate spiraling global population growth. Although those early studies demonstrated the considerable clinical promise of the levonorgestrel ring, particularly in terms of efficacy and acceptability, progress was hampered by problems in mass production and in procuring adequate supplies of the silicone elastomer,²³ both of which are largely resolved now. In 1993, clinical data was reported suggesting that use of a levonorgestrel-releasing silicone elastomer vaginal ring caused transient erythematous ulcerations to form on the vaginal tissue, possibly due to epithelial thinning effects under local influence of levonorgestrel, physical factors relating to ring flexibility, and/or reaction to ring excipients.²⁴ Subsequent studies by the Population Council implemented regular colposcopic monitoring to assess the vaginal epithelial surface with use of a number of progestogen-only and estrogen-progestogen vaginal rings, none of which contained levonorgestrel;²⁵ similar findings were observed in a control group of sexually active subjects using non-ring methods of contraception. Further studies with a redesigned and more flexible placebo ring showed no clinically significant lesions among ring users or controls, although a number of minor changes in appearance of the cervicovaginal epithelium were observed in some ring users.²⁶ Interestingly, the effects of NuvaRing use on the cytology/integrity of vaginal tissue have never been reported. Clearly, the potential for vaginal epithelial thinning or damage needs to be carefully assessed in any ring-based MPT strategy, since it may have major implications for transmission of HIV and other STIs. Also, there is the ongoing debate as to whether hormonal contraception is correlated with increased risk of HIV transmission.^{26, 27, 28, 29} A demonstrable correlation would have major implications for the feasibility of any MPT strategy that simultaneously delivers a contraceptive hormone and an HIV microbicide.

Newer contraceptive agents are also being evaluated for use in controlled release vaginal rings, including ulipristal acetate (UPA, a selective progesterone receptor modulator) and nestorone (a highly potent progestogen). A reservoir-type silicone elastomer ring releasing 600–800 mcg/day UPA has recently been reported as not achieving the minimum effective contraceptive dose.³⁰ A redesign of the device to achieve a thinner rate-controlling membrane may provide an increased daily release rate to enhance efficacy. Various nestorone-releasing rings are being evaluated by the Population Council, in both nestorone-only formulations and in combination with ethinyl estradiol. Nestorone-only releasing silicone elastomer rings with different release rates have also been evaluated in women, showing good contraceptive efficacy but also menstrual disturbances.³¹ These contraceptive rings could be further developed to simultaneously deliver an antiretroviral microbicide such as dapivirine.

Given current concerns over hormonal contraception, MPT strategies that include a barrier contraceptive function are gaining traction. For example, a dapivirine-releasing diaphragm device, based on PATH’s SILCS diaphragm, has recently been reported.³² Aside from the re-purposing of existing drug delivery/medical devices, we also need innovation in the development of new MPT technologies. Biodegradable drug-eluting fiber meshes that provide simultaneous release of multiple agents against HIV-1, HSV-2, and sperm represent one such novel approach, underscoring the potential for combining chemical and physical barrier functions within a single MPT device.³³ Like any new technology, there are challenges ahead for these fiber meshes as viable products, not least development and scaling of the manufacturing method and replacing/removing the organic solvents used in their fabrication. But, they are a step in the right direction and offer a new product strategy for moving forward.

There can be no doubt that delivering on MPTs is going to be considerably more complex and challenging than for the corresponding single indication products. We need to learn from our past experiences, both our successes and mistakes. We must leverage the broad expertise of multi-disciplinary teams to best tackle the myriad of issues that will no doubt arise. The clinical need is already with us; the time for action is now.

References

1. Singh S, Sedgh G, Hussain R. Unintended pregnancy: worldwide levels, trends, and outcomes. Stud Fam Plann. 2010;41:241–250
2. Prevalence and incidence of selected sexually transmitted infections. Chlamydia, Neisseria gonorrhoeae, syphilis and Trichomonas vaginalis. Geneva: World Health Organization;2011;
3. Sexual and reproductive health and HIV/AIDS linkages: a framework for priority linkages. Geneva: World Health Organization, United Nations Population Fund, International Planned Parenthood Federation, Joint United Nations Programme on HIV/AIDS;2005;
4. Singh S, Darroch JE. Adding it up: Costs and benefits of investing in family planning and maternal and newborn health. Guttmacher Institute and United Nations Population Fund (UNFPA), 2011.
5. Rompalo A. Preventing sexually transmitted infections: back to basics. J Clin Invest. 2011;121:4580–4583
6. Harrison PF, Hemmerling A, Romano J, Whaley KJ, Young Holt B. Developing multipurpose reproductive health technologies: an integrated strategy. AIDS Res Treat. 2013;[Article ID 790154]
7. United Nations Development Programme. The Millennium Development Goals.
8. Warner L, Gallo MF, Macaluso M. Condom use around the globe: how can we fulfil the prevention potential of male condoms?. Sex Health. 2012;9:4–9
9. Ingham R. Condoms, bloody condoms: yet more problems. Sex Transm Infect. 2012;88:479–480
10. Anderson PL, Glidden DV, Liu A, et al. Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. Sci Transl Med 2012;4:151ra125.
11. Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367:399–410
12. Kenney J, Aravantinou Meropi A, Singer R, et al. An antiretroviral/zinc combination gel provides 24 hours of complete protection against vaginal SHIV infection in macaques. PLoS One. 2001;6(1):e15835
13. Frezieres RG, Walsha T, Kilbourne-Brook M, et al. Couples’ acceptability of the SILCS diaphragm for microbicide delivery.Contraception. 2012;85:99–107
14. Feldblum PJ, Adeiga A, Bakare R, et al. SAVVY vaginal gel (C31G) for prevention of HIV infection: a randomized controlled trial in Nigeria. PLoS One. 2008;3:e1474
15. McCormack S, Ramjee G, Kamali A, et al. PRO2000 vaginal gel for prevention of HIV-1 infection (Microbicides Development Programme 301): a phase 3, randomised, double-blind, parallel-group trial. Lancet. 2010;376:1329–1337
16. Peterson L, Nanda K, Opoku BK, et al. SAVVY (C31G) gel for prevention of HIV infection in women: a phase 3, double-blind, randomized, placebo-controlled trial in Ghana. PLoS One. 2007;2:e1312
17. Skoler-Karpoff S, Ramjee G, Ahmed K, et al. Efficacy of Carraguard for prevention of HIV infection in women in South Africa: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:1977–1987
18. Van Damme L, Ramjee G, Alary M, et al. Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomised controlled trial. Lancet. 2002;360:971–977
19. Abdool Karim SS, Kashuba ADM, Werner L, et al. Drug concentrations after topical and oral antiretroviral pre-exposure prophylaxis: implications for HIV prevention in women. Lancet. 2011;378:279–281
20. Microbicide Trails Network . MTN statement on decision to discontinue use of Tenofovir Gel in VOICE, a major HIV prevention study in women. 
21. Malcolm RK, Woolfson AD, Toner CF, et al. Long-term, controlled release of the HIV microbicide TMC120 from silicone elastomer vaginal rings. J Antimicrob Chemother. 2005;56:954–956
22. Nel A, Smythe S, Young K, et al. Safety and pharmacokinetics of dapivirine delivery from matrix and reservoir intravaginal rings to HIV-negative women. J Acquir Immune Defic Syndr. 2009;51:416–423
23. Elstein M, Jackson R, Hickling D, Assendorp R. Current status of contraceptive vaginal rings [Article in French]. Contracept Fertil Sex (Paris). 1992;20:15–19
24. Bounds W, Szarewski A, Lowe D, Guillebaud J. Preliminary report of unexpected local reactions to a progestogen-releasing contraceptive vaginal ring. Eur J Obstet Gynecol Reprod Biol. 1993;48:123–125
25. Fraser IS, Lacarra M, Mishell DR, et al. Vaginal epithelial surface appearances in women using vaginal rings for contraception. Contraception. 2000;61:131–138
26. Weisberg E, Fraser IS, Baker J, et al. A randomized comparison of the effects on vaginal and cervical epithelium of a placebo vaginal ring with non-use of a ring. Contraception. 2000;62:83–89
27. Mostad SB, Overbaugh J, DeVange DM, et al. Hormonal contraception, vitamin A deficiency, and other risk factors for shedding of HIV-1 infected cells from the cervix and vagina. Lancet. 1997;350:922–927
28. Heffron R, Donnell D, Rees H, et al. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. Lancet Infect Dis. 2012;12:19–26
29. Kiddugavu M, Makumbi F, Wawer MJ, et al. Hormonal contraceptive use and HIV-1 infection in a population-based cohort in Rakai, Uganda. AIDS. 2003;17:233–240
30. Brache V, Sitruk-Ware R, Williams A, et al. Effects of a novel estrogen-free, progesterone receptor modulator contraceptive vaginal ring on inhibition of ovulation, bleeding patterns and endometrium in normal women. Contraception. 2012;85:480–488
31. Brache V, Mishell DR, Lahteenmaki P, et al. Ovarian function during use of vaginal rings delivering three different doses of NES. Contraception. 2001;63:257–261
32. Major I, Boyd P, Kilbourne-Brook M, Saxon G, Cohen J, Malcolm RK. A modified SILCS contraceptive diaphragm for long-term controlled release of the HIV microbicide dapivirine. Contraception. 2013;88(1):58–66
33. Ball C, Krogstad E, Chaowanachan T, Woodrow KA. Drug-eluting fibers for HIV-1 inhibition and contraception. PLoS One.2012;7(11):e49792