Multipurpose prevention technologies: the future of HIV and STI protection

Review

Multipurpose prevention technologies: the future of HIV and STI protection Jose´ A. Ferna´ndez-Romero1*, Carolyn Deal2*, Betsy C. Herold3*, John Schiller4*, Dorothy Patton5*, Thomas Zydowsky1*, Joe Romano6*, Christopher D. Petro3*, and Manjulaa Narasimhan7* 1

Center for Biomedical Research, Population Council, New York, NY, USA National Institute of Allergy and Infectious Diseases, Bethesda MD, USA 3 Albert Einstein College of Medicine, Bronx, NY, USA 4 Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, MD, USA 5 Obstetrics and Gynecology, University of Washington Seattle, WA, USA 6 NWJ Group, Wayne, PA, USA 7 Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland 2

Every day, more than 1 million people are newly infected with sexually transmitted infections (STIs) that can lead to morbidity, mortality, and an increased risk of human immunodeficiency virus (HIV) acquisition. Existing prevention and management strategies, including behavior change, condom promotion, and therapy have not reduced the global incidence and prevalence, pointing to the need for novel innovative strategies. This review summarizes important issues raised during a satellite session at the first HIV Research for Prevention (R4P) conference, held in Cape Town, on October 31, 2014. We explore key STIs that are challenging public health today, new biomedical prevention approaches including multipurpose prevention technologies (MPTs), and the scientific and regulatory hurdles that must be overcome to make combination prevention tools a reality. Evolving epidemiology of STIs: approaching new technologies to prevent them HIV, other STIs, and unintended pregnancy are global health crises that together affect hundreds of millions of women and men worldwide. These health concerns share a common means of exposure, which is important to recognize when planning for prevention and care services because there is great benefit to addressing them jointly through MPTs (Box 1). MPTs are new, all-in-one tools being developed to protect against HIV, other STIs, and, in some cases, unintended pregnancy. Much of the work on MPTs to date has focused on unintended pregnancy and HIV, but there are important reasons for ensuring that other STIs are addressed as well (Box 2). The prevalence of STIs represents a significant public health burden, and curable STIs are on the rise (Figure 1) Corresponding author: Ferna´ndez-Romero, J.A. ([email protected]). Keywords: multipurpose prevention technologies; STI; HIV; HSV-2; HPV; Trichomonas vaginalis. * All authors contributed equally to this work. 0966-842X/ ß 2015 Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). http://dx.doi.org/10.1016/ j.tim.2015.02.006

[http://www.who.int/mediacentre/factsheets/fs110/en/]. In Asia, numbers of viral STIs such as herpes simplex virus 2 (HSV-2) and human papillomaviruses (HPV) continue to increase, and fear of these appears to be higher than fear of HIV acquisition [http://www.who.int/reproductivehealth/ publications/rtis/stisestimates/en/]. Maternal and child health, mortality, and morbidity, as well as HIV prevalence, are also significant concerns in both Sub-Saharan Africa and South East Asia [http://www.who.int/ reproductivehealth/publications/monitoring/maternalmortality-2013/en/]. Infections with sexually transmitted pathogens other than HIV, as well as persistent reproductive tract infections, such as bacterial vaginosis, impose an enormous burden on morbidity and mortality in both resourceconstrained and developed countries. They directly impact on quality of life, reproductive health, and child health, and augment the risk of acquiring and transmitting HIV [1] or alter the course of other infections. As examples, HIV-positive women and men are more likely to have oncogenic HPV types and develop cervical or anal intraepithelial neoplasias [2], have higher HIV plasma viral load with HSV-2 seropositivity [3], and decreased HIV-1 shedding in cervicovaginal lavages due to STI treatment [4]. Despite their common route of transmission, STIs are a diverse group of infections with multiple different causative agents. These can be differentiated into viral infections (e.g., HIV, HSV, HPV, or hepatitis B), bacterial infections (e.g., gonococcal, chlamydial, or syphilis) or protista infections (e.g., trichomoniasis). This is an important concept because the active agent necessary to control and prevent each infection may be very different based on the pathogen(s) involved [5]. The combination of indications may vary by prevalence of infections seen in differing geographic locations around the world. The next sections will review some of the STIs (other than HIV) that were discussed at the satellite session at HIVR4P, strategies to prevent them, and the potential to combine multiple active agents into one delivery method for broad protection not only against STIs but also against unintended pregnancy. Trends in Microbiology, July 2015, Vol. 23, No. 7

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Review Box 1. Qualities of ideal MPTs     

Represent the next generation of measures for STI control. Be customized for the infections in a targeted geographic area. Control various STIs. Control one or more STIs and reduce unintended pregnancies. Result in multi-faceted, positive outcomes.

HSV-2: major cofactor in the HIV epidemic HSV continues to be a global health concern in its own right, but also in conjunction with HIV (Box 2) [6]. In developed countries, HSV-1 has emerged as the principal cause of genital disease, with a prevalence at 54% of HSV-1 cases in the USA, whereas HSV-2 predominates globally. Both HSV serotypes are lifelong, persistent infections. Notably, HSV-2 infection in Sub-Saharan Africa (70% prevalence of HSV-2 cases) could increase HIV-1 acquisition and further spread [6–8]. Furthermore, HSV-2/HIV-1 co-infected individuals tend to have more severe herpetic lesions and increased HSV-2 shedding [9]. These findings, combined with the absence of any approved prophylactic drug and recent vaccine failures, highlight the importance of developing new HSV prevention strategies as a public health priority [10]. Tenofovir (TFV) and its prodrug tenofovir disoproxil fumarate (TDF), which function as reverse transcriptase inhibitors (RTI) after being converted by cellular kinases to TFV-diphosphate, are being evaluated for prevention of HIV. These drugs do not require viral kinases for phosphorylation and, surprisingly, recent studies suggest that TFV-DP may provide partial protection against HSV. TFV 1% gel (Table 1) reduced HSV-2 incidence by 51% in women applying the product before and after sex (BAT24 dosing) in the CAPRISA-004 pre-exposure prophylaxis (PrEP) trial [11]. A 30% reduction in HSV-2 was also observed in men and women using daily oral TFV-based PrEP in a secondary analysis [12]. Notably, TDF is 160-fold more active than TFV against HSV-2, and a 0.3% gel formulation of TDF provided significantly greater protection than 1% TFV gel against vaginal HSV-2 in mice [13,14]. The greater potency of TDF compared to TFV likely reflects the enhanced cellular uptake of the former. A polyurethane intravaginal ring (IVR) designed to deliver TDF recently completed a Phase I safety study (Table 1), and future studies should explore whether IVRs [containing either TDF or acyclovir (ACV)] distribute a sufficient quantity of drug to sites such as the external genital skin to protect against HSV acquisition. Griffithsin (GRFT), a homodimeric lectin derived from red alga, has been previously reported to bind to gp120 (the HIV envelope glycoprotein that mediates virus interaction with cellular receptors and coreceptors) via N-linked mannose-rich glycosylation clusters and to have potent antiHIV activity in vitro [15,16]. Recently, GRFT was shown to have modest inhibitory activity against HSV entry, but was highly potent when added to cultures post-entry and prevented cell-to-cell spread [17]. These in vitro findings translated to significant protection against genital herpes in mice treated with 0.1% GRFT gel (Table 1). Importantly, the drug retained activity when virus was added in seminal plasma [17]. The latter findings are distinct from results 430

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obtained with polyanion drugs, such as PRO 2000 and cellulose sulfate, which lost activity when the virus was added in seminal plasma, reflecting a competition between seminal proteins and the drug for the HSV envelope glycoproteins [18,19]. By contrast, the MZC gel or MZCL IVR (Table 1) combines carrageenan (CG) and zinc (in addition to MIV-150, an anti-HIV non-nucleoside RTI), and showed potent and durable synergistic anti-HSV-2 activity [20– 22]. This MPT formulation retains antiviral activities when virus is added in seminal plasma [23]. Poly-[1,4-phenylene-(1-carboxy) methylene] (PPCM), another candidate microbicide that targets the viral envelope, is currently being evaluated for its anti-HSV and contraceptive activity, and is a potential candidate for MPT [24,25]. Thus, both GRFT and PPCM are candidate drugs for coformulation with TDF/TFV or dapivirine. These combinations would target HIV by two different mechanisms (entry and reverse transcription), and provide activity against HSV (GRFT and PPCM) and contraception (PPCM). However, currently these anti-HSV drugs have been only formulated as gels, and there are challenges to IVR formulation. In addition, the formulation of GRFT with CG (in IVR or nanofibers, Table 1) is being explored to target not only HIV and HSV but also HPV. Combining ACV with a RTI also holds promise, and it may be easier to coformulate ACV for IVR delivery (Table 1). An MPT to block HSV as well as HIV would provide both a direct and indirect means of HIV prevention and could have a major impact on the HIV epidemic. HPV prevention strategies: learning from success and moving forward Papillomaviruses, including the HPV types that are the central cause of cervical cancer, have a unique life cycle in that virion production only occurs in the stratified squamous epithelium of the skin or mucosal surfaces [26]. Presumably because infection of the basal cells of the tissue is necessary, they have also evolved a unique mechanism of infection. In HPV16 pseudovirion-based mouse and rhesus macaque cervicovaginal challenge models, mature virions in solution are unable to directly bind to any epithelial cells [27,28]. They must first attach to heparan sulfate proteoglycans (HSPGs) on the basement membrane that divides the epithelium from the dermis, at sites in which the integrity of the epithelium is compromised, such that the virions have direct access to its surface, and can enter

Box 2. STI key factsa  >1 million people acquire a STI every day.  >530 million people are infected with HSV-2, with an incidence rate of 20 million cases annually.  >290 million women are infected with HPV.  500 million people become ill with curable STIs every year.  Some STIs can increase the risk of HIV acquisition or transmission.  Some STIs can negatively impact upon the course of HIV infection. a

Modified from WHO Fact Sheet 110 [http://www.who.int/mediacentre/factsheets/ fs110/en/].

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47 million 126 million 128 million 26 million 79 million

93 million

Key: WHO Region of the Americas WHO African Region WHO Eastern Mediterranean Region WHO European Region WHO SE Asian Region WHO Western Pacific Region

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Figure 1. Global total incidence of selected curable sexually transmitted infections (STIs). The figure shows the incidence of four curable STIs (Trichomonas vaginalis, Treponema pallidum, Neisseria gonorrhoeae, and Chlamydia trachomatis) in the six global regions in 2008. The global estimates, especially for these curable STIs, have relied on the few regions with systematic STI surveillance along with a relatively small number of prevalence studies among discrete populations. The World Health Organization (WHO) estimates do not include viral STIs, which are often longstanding or lifelong, and comprise a large proportion of prevalent STIs. Modified from WHO Fact Sheet 110 [http://www.who.int/mediacentre/factsheets/fs110/en/].

Table 1. MPTs in the pipeline that target more than one STI (including HIV) Product 1% TFVa TDF

Delivery method Gel IVR

APIs TFV TDF

Stage Phase III Phase I

Developer CONRAD Albert Einstein College of Medicine Population Council CONRAD CONRAD

MZC (PC-1005) TFV TFV + LNG

Gel IVR IVR

MIV-150, zinc, CG TFV TFV, LNG

Phase I Phase I Phase I

TFV Truvada TFV

Vaginal tablet Vaginal tablet Film

TFV TFV, Emtricitabine TFV

Phase I Phase I Phase I

1%TFV + SILCS diaphragm MZCL

Gel IVR

TFV MIV-150, zinc, CG, LNG

Phase I Preclinical

CONRAD CONRAD CONRAD, University of Pittsburgh CONRAD, PATH Population Council

Mapp66 (monoclonal antibodies) TFV + ACV TFV + IQP-0528 (pyrimidinedione analog) TDF + non-nucleoside reverse transcriptase inhibitor (NNRTI) GRFT

Film IVR IVR

Monoclonal antibodies TFV, ACV TFV, IQP-0528

Preclinical Preclinical Preclinical

Mapp Biopharmaceutical Auritec Pharmaceuticals ImQuest BioSciences

IVR

TDF, NNRTI

Preclinical

Gel

GRFT

Preclinical

GRFT CG GRFT CG

IVR Nanofibers

GRFT, CG GRFT, CG

Preclinical Preclinical

PPCM

Gel

Poly-[1,4-phenylene(1-carboxy) methylene]

Preclinical

Albert Einstein College of Medicine University of Louisville, University of Pittsburgh Population Council Population Council, University of Washington Yaso Biotechnologies

Stanford Research Institute two-polymer (SR-2P)

Gel

TFV, ACV

Preclinical

SRI International

Indications HIV, HSV HIV, HSV HIV, HSV, HPV HIV, HSV HIV, HSV, unintended pregnancy HIV, HSV HIV, HSV HIV, HSV HIV, HSV HIV, HSV, HPV, unintended pregnancy HIV, HSV HIV, HSV HIV, HSV HIV, HSV HIV, HSV HIV, HSV, HPV HIV, HSV, HPV HIV, HSV, HPV, chlamydia, gonorrhea, unintended pregnancy HIV, HSV

a

The result of the 1% TFV gel Phase III trial was announced at the time of publication of this manuscript. Adherence in the overall study population was too low to show TFV gel effectiveness in this trial. A reduced glycerin version of this gel is currently in Phase II trial as a potential rectal microbicide.

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Review basal keratinocytes only after undergoing conformational changes on the basement membrane [29,30]. Understanding the mechanism of HPV infection can help to explain the high efficacy of virus-like particles (VLP)induced antibodies at preventing HPV infection in clinical trials of commercial vaccines [31]. The requirement for sufficient epithelial disruption to expose the basement membrane implies that the virus must transit through an increasing gradient of exudated antibodies to reach its target tissue for attachment. A high level of systemic antibodies, as induced after intramuscular VLP vaccination, effectively prevents virion binding to the basement membrane in the mouse cervicovaginal challenge model [32]. The extended time of exposure of the virions to neutralizing antibodies after basement-membrane binding is likely to be a crucial factor in the susceptibility of the virus to low levels of neutralizing antibodies in that it would both promote accumulation of the antibodies on the virions and engulfment of the virus/antibody complexes by the phagocytic leukocytes attracted to the site of trauma. The highly-effective HPV vaccines to prevent HPV 6, 11, 16, and 18 (Gardasil and Cervarix), and the recently approved nonavalent vaccine (Gardasil 9) [33], are without a doubt an excellent start for curbing HPV prevalence, especially knowing that HPV 16 and 18 are together responsible for 70% of cervical cancer and >90% of other non-cervical HPV-related cancers [34]. However, the current vaccines have several features that limit their potential impact. There has been overall low uptake owing to relatively high cost, lack of provider recommendations, parental concerns, and limited enthusiasm from some healthcare providers and public health officials. In addition, protection is type-restricted, and other HPV types with anogenital tropism, some which are associated with increased HIV susceptibility [35,36], need to be addressed in alternative prevention strategies (such as broader-spectrum vaccines or microbicides). The discovery that HSPGs are the crucial initial attachment factors for HPVs, and the development of cell-based and in vivo assays that supported the HPV vaccine efficacy [32], led to a targeted screen for potential inhibitors that might serve as topical microbicides. Several sulfated polysaccharides that could potentially compete for HSPG, including heparin, inhibited HPV infection [37]. CG, however, was by far the most potent, with an IC50 of 2 ng/ml, and it was active against a broad spectrum of genital HPV types. Importantly, it retains high activity in the presence of seminal plasma [23]. Interestingly, several commercial sexual lubricants are formulated using CG as the primary gelling agent. These commercial lubricants generated inhibition curves that were similar to 1% CG, exhibiting IC50s of 5 million-fold dilution [37]. CG gels were also potent inhibitors of cervicovaginal infection in mouse and rhesus macaque models [22,27,28]. In a clinical trial of a CG-based microbicide primarily directed at HIV prevention, one-third fewer genital HPV infections were detected at study exit in the most adherent subgroup of women, compared to controls [38]. Two randomized placebo-controlled clinical trials evaluating a commercial CG-based product, Divine #9, as a topical microbicide to specifically prevent genital HPV infection in young women are now 432

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underway. Developing an MPT with a broad spectrum anti-HPV agent would overcome the limitations of the current HPV vaccines as well as the increased HIV susceptibility in HPV-infected individuals. Trichomonas vaginalis: curable but not under control T. vaginalis is more common than Chlamydia trachomatis, Neisseria gonorrhoeae, and Treponema pallidum combined, making it the most prevalent non-viral STI [39]. Trichomoniasis infects both men and women throughout their reproductive lives. Adverse reproductive outcomes, more severe in women, include premature rupture of membranes and preterm birth as well as increased risks of acquisition and transmission of HIV. Given the reproductive consequences, treatment limitations, and economic impact of this STI, the potential role of MPTs and/or therapeutic products in preventing this infection must be pursued. Systemic treatment for trichomoniasis, commonly referred to as metronidazole, became available in 1959 [40]. The Centers for Disease Control and Prevention (CDC) recommended regimes with metronidazole or tinidazole that are effective, inexpensive, and widely available as single-dose therapy. Nevertheless, treatment failure remains problematic due to noncompliance, reinfection, or inaccurate diagnosis because symptoms mimic other STIs and, in addition, there is possible lack of treatment of sexual partners. Furthermore, resistance of T. vaginalis to metronidazole treatment is currently found in 2.5–10% of isolates tested [41], and this argues in favor of new prevention tools. Potential prevention strategies for T. vaginalis infections include development of a vaccine or the application of microbicides, preferably in MPTs. Vaccine development for humans has been hampered by a lack of understanding of the host immune response to T. vaginalis infections. Only two vaccines have progressed to clinical trials in the past 50 years. Neither candidate proved to be effective. Research continues as we learn more about the surface proteins that might be viable targets for a vaccine. In the absence of a vaccine, others are developing MPTs for prevention of non-ulcerative STIs including T. vaginalis. The HPTN 035 Phase II/IIB safety and efficacy study of vaginal microbicides recently evaluated BufferGel and 0.5% PRO 2000 for prevention of T. vaginalis, C. trachomatis, and N. gonorrhoeae. Regrettably, neither candidate microbicide had any protective effect against trichomoniasis, chlamydia, or gonorrhea [42]. The lack of good animal models for T. vaginalis has made it difficult to conduct standardized studies to support microbicide and vaccine development. While a variety of animals have been evaluated as potential models [43], the mouse is the most frequently used species. The modified mouse model has been used extensively in both immunization and MPT prevention experiments. This model uses young mice pretreated with estradiol, to promote initial infectivity of T. vaginalis, and also vaginally pre-colonizes with lactobacilli before challenge with vaccine candidates [44] or topical microbicide candidates [45]. The murine model has shown limited utility in predicting clinical efficacy.

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More recently, the pigtailed macaque was evaluated as a suitable nonhuman primate model for T. vaginalis infections. The pigtailed macaque is naturally susceptible to human strains of T. vaginalis, hosts lactobacilli in its vagina, has a vaginal pH of 5.5–8.0, and sustains infection for up to 5 weeks without any pretreatment required to initiate, enhance, or sustain infection. The pigtailed macaque also responds to metronidazole treatment, and signs of pathogenesis have been colposcopically documented [46], making it a promising step forward for testing prevention tools against T. vaginalis. Research to control the spread of T. vaginalis, the world’s most common, non-viral STI, continues to lag. Applying new knowledge and using new approaches, preferably within the context of MPTs, may provide opportunities to effectively reduce the spread of T. vaginalis. Developing all-in-one technologies to target multiple STIs and unintended pregnancy MPTs have been primarily designed as woman-initiated products (although some formulations can be used by men) that simultaneously reduce the risk of the sexual acquisition/transmission of HIV, other bacterial, viral, or protista STIs (especially those that increase the risk of HIV acquisition/transmission), and unintended pregnancy. MPTs can potentially fill significant unmet sexual and reproductive health needs. In addition, compelling economic and practical arguments for MPT development include greater efficiency in terms of cost, access, and delivery of sexual and reproductive health (SRH) products, and increased demand for one product type to achieve uptake of a second (e.g., effective contraception might attract women to use products that also target HIV and other STIs). There is consensus that MPTs are worth pursuing [47] [http://resource.cami-health.org/resources/ipsos.php] [http://resource.cami-health.org/documents/2012SAWGReport-FinalReport.pdf], but there are no objective and

quantitative data regarding the best mix of indications and delivery devices (Figure 2) to pursue. In addition, the best mix of indications may vary in different regions of the world based on local patterns of infections and contraceptive need as well as user-related social and behavioral dimensions [48]. Based on survey data collected, the Initiative for Multipurpose Prevention Technologies and the Coalition Advancing Multipurpose Innovations (IMPT/ CAMI) propose sustained release devices (e.g., IVRs), long-acting injectables, and on-demand/pericoital products (e.g., films and gels) as the highest priorities [http:// mpts101.org/mpt-database]. Because MPT development has evolved from HIV-targeting products, most MPT developers are initially focusing on familiar territory: pursuing indications, active pharmaceutical ingredients (APIs), and delivery devices with which they have the most experience or for which there is a significant body of literature [e.g., Levonorgestrel (LNG) as the contraceptive] (Table 1). Importantly, MPT development will be informed by testing these early-phase MPTs in rigorous clinical trials designed to identify the best candidates. This general strategy makes sense initially because the perceived/much-discussed complexity and additional challenges of MPT product development can be more easily understood and overcome using experience derived from non-MPT products. However, in the long run we will need to take a different approach, moving beyond prioritizing delivery options and working in familiar territory to deciding which specific indications, API combinations, and delivery devices make the most sense – based on objective and quantitative criteria such as impact and value (in economic and human terms) of the intervention, market size, and potential return on investment [important to both manufacturers and the non-governmental organization (NGO) community], cost of the MPT, and the likelihood of success (risk mitigation).

(A)

(B)

(C)

(D)

(E)

(F)

(G)

(H)

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Figure 2. Multipurpose prevention technology (MPT) delivery devices. (A) Male and female condom. (B) Vaginal/rectal gels. (C) Implants. (D) Injectables. (E) Intravaginal rings. (F) Nanofibers (photograph courtesy of A. Steger and K.A. Woodrow, University of Washington, Seattle, WA, USA). (G) SILCS (silicone barrier contraceptive device) diaphragm (photograph courtesy of PATH, Seattle, WA, USA. All rights reserved). (H) Vaginal tablet (photograph courtesy of M. Clark and D. Friend, CONRAD, Arlington, VA, USA). Images (A, B, D, E) by Julie Sitney (Population Council).

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Review Regulatory challenges in MPT development The regulatory process for MPT products will involve additional challenges in comparison to single-indication products. Because MPTs will target at least two of multiple possible indications, the development and licensure process will involve multiple groups within the relevant regulatory agencies. With the Food and Drug Administration (FDA), the regulatory process will involve multiple groups within the Center for Drug Evaluation and Research (CDER). If the MPT also involves a drug delivery device, interactions with the Center for Devices and Radiological Health will also be required. In addition to the interactions with a stringent regulatory authority such as the FDA or the European Medicines Agency (EMA), MPTs will also likely need to go through WHO prequalification, as well as local country regulatory authority review. Further complications may arise depending on the status of the component drugs included in the MPT. For example, the process and requirements for MPTs with APIs that have previously been approved by the authority for related indications [e.g., approved antiretroviral (ARV) drugs for HIV treatment] may be simpler than for a product that includes multiple experimental drug entities. There are several unique issues that will need to be addressed from a regulatory perspective, particularly for MPTs that are designed to prevent HIV infection and unintended pregnancy. For example, particular ARV products can impact on the metabolism of hormonal contraceptive (HC) agents, resulting in decreased plasma levels and potentially reducing the contraceptive efficacy [49–51]. Thus, MPTs will need careful evaluation of drug–drug interactions. In addition, observational data from several HIV prevention product studies have shown a potential enhanced risk of HIV infection in women using particular HC products [52]. Therefore, the impact of HC components in MPT products on HIV transmission risk will also be an issue of interest to regulatory agencies. An additional set of safety issues for ARV-based MPTs will be the risk of reduced efficacy against drug-resistant virus and the risk of selection for resistance in HIV-positive women who use an MPT. Perhaps the most significant regulatory challenges will concern the design and implementation of clinical efficacy studies for MPTs. Adherence issues observed in HIV prevention product trials [53–55] will certainly need to be addressed in MPT trials. Another challenge will be in determining the control products in these trials, or if oral pre-exposure prophylaxis (PrEP) will need to be incorporated into these trials. Trial design will also need to consider the local standard of care with regard to use and acceptance of oral PrEP [56,57] [http://www.proud. mrc.ac.uk/]. It is also not known if superiority or noninferiority design studies will be required, or what the comparator product would be. Lastly, it is not clear if bioequivalence-based regulatory strategies will be viable. Interaction with regulatory agencies on these and additional issues will be a crucial element of all MPT development plans. Concluding remarks This review elaborates on the importance of targeting different STIs in MPTs, with particular emphasis on 434

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non-curable STIs, while also acknowledging the extreme relevance of preventing unintended pregnancy in these potential combination products. There are hypothetical advantages to MPTs: increased demand/uptake for HIV prevention in MPTs versus HIV prevention-only products; incremental increase in adherence resulting in cost savings; efficiencies in delivery and access; policy support for MPT in relevant parts of the world and procurement bodies purchasing MPTs. It is important to demonstrate along the way that those perceived advantages are true, and that is worth the investment in time and resources to advance into Phase III clinical trials and beyond. MPTs need to be carefully conceived in the context of the entire breath of regulatory complexities and risks that will potentially apply. The use of more than one drug, novel devices, potential drug interactions, and clinical trials (design and adherence) are some of the most complicated issues that MPT developers will face in satisfying regulatory requirements. We need to inform our early product decisions by carefully considering the requirements that will arise in later stages of development, such that we advance the most promising candidates. The MPT field at present is heavily reliant on the public health and NGO communities for support. The limits to funding emphasize the need to design affordable but complex Phase I trials that will inform not only on MPT safety but also potential efficacy, such as post-coital PK studies using high-risk populations. In addition, it would benefit the MPT field to work closely and collaboratively to share findings, avoid duplications, and ensure that MPTs with high quality, impact, and value are based on sound scientific principles and are available in the shortest time possible [58]. MPT developers need to understand where the diseases are, what the incidence rates are, and what the unmet medical needs are – to then be able to elaborate the best strategies to develop a particular combination that will finally reach a receptive market. Public health communities and end-users may also look closely into pricing targets for MPTs, trying to achieve the lowest possible price without asking for impossible goals or missing the advantages that these technologies may bring in terms of cost, access, and delivery. There are many outstanding questions (Box 3) to MPT development, but the benefits of a safe and effective MPT will overshadow all the hurdles that must be overcome [59]. MPTs could be feasible (from a regulatory point of Box 3. Outstanding questions  How can the community inform MPT product development investment and effort from the perspective of hypothetical justifications?  What is the best and most-affordable approach and design to test MPTs in Phase III clinical trials?  How can the community assist in adding the concept of valueadded product into the cost-effectiveness equation?  What are the best objective criteria to decide which indications, devices, and API combinations to prioritize?  How can the public health community best inform MPT developers as to their optimal requirements for MPTs?  How can MPT developers work together and with donors and regulators to accelerate MPT development?

Review view), and several examples of multipurpose vaccines [measles, mumps and rubella (MMR); diphtheria, tetanus, and pertussis (DTP); pentavalent (DTaP, IPV, and Hib); and hexavalent (DTaP, IPV, Hib, and HBV)] show us that is not impossible to reach our common goal: protect those most in need of MPTs for improved sexual and reproductive health. Acknowledgments We would like to thank Jennifer Brunet and Susanna Grecky at Population Council for their valuable input. This work was made possible by the generous support of the American people through the US Agency for International Development (USAID; grant AID-OAA-A-14-00009. This work was also supported by the National Institutes of Health (NIH; grant U19-AI103461). The contents of this paper are the sole responsibility of the authors and do not necessarily reflect the views of the funding agencies.

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