ADR-12739; No of Pages 9 Advanced Drug Delivery Reviews xxx (2015) xxx–xxx

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Acceptability and preferences for vaginal dosage forms intended for prevention of HIV or HIV and pregnancy☆ Cynthia Woodsong ⁎, Jonathon D.S. Holt International Partnership for Microbicides, 8401 Colesville Rd., Ste 200, Silver Spring MD 20910, USA

a r t i c l e

i n f o

Available online xxxx Keywords: Vaginal microbicides Multipurpose prevention technologies Microbicide acceptability HIV prevention Vaginal dosage form preferences

a b s t r a c t This paper reviews key issues found to affect acceptability and preferences for vaginal products to prevent HIV infection or HIV and pregnancy. We focus on the interplay between the biological and physico-chemical aspects of formulation and the social and behavioral issues that may affect use. The need for an HIV prevention product that women can use is driven by women's increased biological and social vulnerability to HIV infection, and thus social and behavioral research on microbicide acceptability has been conducted alongside, as well as separate from, the earliest product development efforts. Some acceptability and preference issues are specific to a product's dosage form, use-requirements, and/or use indications, while others pertain to any vaginal product used for prevention of HIV or pregnancy. Although most of the work cited here was published since 2010, it draws on a much longer trajectory of research. © 2015 Elsevier B.V. All rights reserved.

1. Introduction The vagina is an appropriate site for local and systemic delivery of a number of drugs, and vaginal products have been formulated for treatment of sexually transmitted infections and post-menopausal symptoms, to prevent pregnancy, or to induce labor. Products are also used in the vagina to improve sexual performance, such as increasing sexual pleasure for one or both parties, or easing pain during intercourse (e.g. lubes), and for cleaning before or after sex [1–3]. Vaginal healthcare products for treatment and prevention of health conditions encompass a wide range of formulation types and use durations including vaginal gels or creams for daily or twice daily administration, fast dissolving tablets or soft-gel capsules, extended-release drug device combinations such as a contraceptive vaginal ring worn for 21 days (Nuvaring®) and a 90-day estradiol acetate ring for estrogen replacement in postmenopausal women (Femring®, Estring®), and physical barriers for contraception such as the diaphragm and the SILCS® cervical barrier. Two new classes of vaginal products currently under development, called vaginal microbicides and multipurpose prevention technologies (MPTs), could have a significant impact on global health by reducing sexual transmission of HIV, other sexually transmitted infections (STIs) and/or unintended pregnancy [4,5]. However, the potential global health impact of these products will only be realized if they are sufficiently acceptable and accessible to at-risk populations so that they are used

☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Vaginal Drug Delivery”. ⁎ Corresponding author at: International Partnership for Microbicides, 8401 Colesville Rd., Ste 200, Silver Spring, MD 20910, USA. E-mail address: [email protected] (C. Woodsong).

correctly and consistently. It is important to bear in mind that unlike treatment therapies, use of an HIV prevention product is not driven by a medical diagnosis or symptoms needing relief, but rather an assessment of the potential risks and costs of infection, which has been particularly problematic for HIV. Development of acceptable vaginal products for prevention of HIV, STIs or pregnancy will require consideration of a range of social and behavioral issues, since product use requires enactment of preventive health behaviors within social (e.g., sexual) relationships, influenced by social and cultural norms in order for the product's biological effects to have a chance to be effective [6–9]. This paper reviews key issues pertaining to the acceptability of vaginal microbicides and MPTs, with a focus on the interplay between the biological and physico-chemical aspects of formulation, and the social and behavioral issues that may affect use. Although most of the work cited here was published since 2010, it draws on a much longer trajectory of research.

2. Terms and concepts pertaining to microbicide “acceptability” A number of vaginal products that have demonstrated good in vitro profiles for prevention of HIV have failed to demonstrate efficacy in vivo, and a major cause of this is attributed to poor use adherence in clinical trials [10–12]. Thus, the clinical safety and potential efficacy of a number of products that have been tested in clinical trials remains unknown. Social and behavioral research provides important insights into why women may or may not use these products, and how the product could possibly be improved to meet their needs and preferences. Key concepts and terminology used in this body of research are described below, including references to publications that focus on the concept.

http://dx.doi.org/10.1016/j.addr.2015.02.004 0169-409X/© 2015 Elsevier B.V. All rights reserved.

Please cite this article as: C. Woodsong, J.D.S. Holt, Acceptability and preferences for vaginal dosage forms intended for prevention of HIV or HIV and pregnancy, Adv. Drug Deliv. Rev. (2015), http://dx.doi.org/10.1016/j.addr.2015.02.004

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C. Woodsong, J.D.S. Holt / Advanced Drug Delivery Reviews xxx (2015) xxx–xxx

2.1. Acceptability Acceptability is a term used to describe willingness to use or willingness to try a product, and usually includes caveats about expected efficacy and perception of risk (of HIV infection or pregnancy) [6,13–15]. For example, a product may be deemed acceptable if a woman states she is willing to use it as directed to protect herself from HIV, once it is proven effective. Acceptability may imply “likeability” of a product or product attributes, but an acceptable product may only be the “least disliked” option [16] among the choices. Aspects of a product's acceptability include experiences and perceptions of the physical attributes of the product and its use requirements within the context of sexual relationships, all of which may be influenced by larger social and cultural norms, and the infrastructure within which the product is delivered. 2.2. Adherence This concept is similar to the term “compliance,” used in medical treatment, but is considered less paternalistic. Participants in microbicide and MPT clinical trials are expected to adhere to protocol requirements (e.g., study visit schedules, HIV tests, condom use, etc.) as well as product use regimens. Although it is often assumed that acceptability is positively associated with adherence, this relationship has not been clearly demonstrated [14]. Microbicide trial participants may adhere to protocol or product-use requirements without finding either to be acceptable, and they may not use an acceptable product for a variety of reasons. Efforts are expended to motivate adherence to study protocol and product use, and measure adherence to product use through a variety of measures including self-report, bio-markers and mechanical means (e.g., product counts, dye-stain assays) [9,17–19]. 2.3. Use experience Since no vaginal microbicide is currently on the market, women's experiences with these products and their views on product acceptability, preferences, and adherence are necessarily hypothetical. These concepts have been investigated in clinical trials where women use candidate products and placebos, studies that ask women to use proxy products (e.g., over the counter lubricants in various formulations) during sex or with no sex, as well as studies that provide verbal descriptions, photos or actual examples of products [20]. Actual use experience with a vaginal product may be more likely to provide women with a better sense of what they might like and not like about a product's physical attributes. However, the clinical trial environment, with its repeated statements about unknown efficacy, regular study visits and medical testing, and recommendations for condom use may affect women's use experience and overall product acceptability, both positively and negatively. 2.4. User-preferences User-preference describes the characteristics most desired out of a range of options [21–24]. For example, users could be asked about their preferences for a vaginal product that is more or less viscous, has a faster or slower rate of dispersion in the vagina, uses a plastic or paper applicator, or is a colored or clear polymer ring, etc. Users may also have preferences for use requirements, use indications and where to access products. A product may be acceptable and yet have some attributes that are less preferred than others. 2.5. User-perspectives The perspectives of those who are intended to be users of vaginal microbicides and MPTs are of key interest for research on acceptability, adherence and preferences. These perspectives should be elicited from women and men within the targeted risk groups, by persons who are

knowledgeable about the social, cultural and behavioral factors that influence preferences and acceptability, and skilled in collection of such data. User-perspectives also include health professionals who will prescribe microbicides and MPTs, and advise women and men about their use. Health professionals are gatekeepers to product access, and their acceptability and perspectives can greatly influence uptake and sustained use of new methods to prevent HIV and pregnancy [25–27]. 2.6. Conceptual framework The conceptual frameworks most often proposed for the study of microbicide acceptability are variations of “ecological” models, which recognize the importance of considering multiple spheres influencing acceptability, usually beginning with individual behavior which is influenced by the views and perspectives of the partner, the clinical trial environment or health care setting as well as the larger environment of family and friends, situated in a community and even larger cultural, social, political and economic context [6,14,28]. Hayes' [29] conceptualization of an ecological model for HIV prevention begins at the microbiological and cellular level, acknowledging the host defenses and biological reactions in the human body. Such an extension of a conceptual model would be appropriate for considering how the formulation of a product causes physiological interactions that can affect women's bodies and what will be required for the correct use of a product. 3. The pipeline, and attributes key to acceptability Development of the microbicide and MPT pipelines has involved an array of academic, governmental and nongovernmental agencies and organizations and pharmaceutical companies. A number of working groups and committees have been convened with the goal of achieving efficiencies and establishing priorities in the product development process [30,31]. In 2010 there were 75 candidate products in the microbicide pipeline, including formulations for vaginal gels, rings, films, tablets and soft-gel capsules [32]. The microbicide product pipeline is often organized according to the mechanism of action of the active pharmaceutical ingredient(s) (API). When considering acceptability and user preferences, it is helpful to indicate attributes of potential importance for user acceptability, which include dosage form, use requirements, and use indications. Table 1 provides an overview of products that have advanced furthest in the development process, as well as some that are at early stages of development and those that are no longer candidates, and includes information on key acceptability issues. We next discuss acceptability and preference issues reported for these acceptability issues. 3.1. Semi-solid and film dosage forms Gel formulations in single-use pre-filled applicators are the most widely studied, with dose volumes ranging from 1 to 4.5 mL (see Table 1). Aspects of gel formulation that users reported as problematic include leakage/discharge before, during and after sex, and the appearance of the product when discharged from the vagina [61,62]. Leaking and clumping have been reported as messy and inconvenient for cleaning, worrisome for those who feel that product which has been discharged is not providing protection, and make it difficult for women to use without telling the partner. On the other hand, some women welcome product discharge, considering that this demonstrates that the microbicide has cleansed the vagina [63,64]. Semi-solid formulations potentially change the way the vagina feels to one or both partners during sex, and concerns about increased vaginal wetness continue to receive attention in the literature [62,65,66]. There is no clear finding about the ideal viscosity or volume of a semisolid vaginal microbicide or MPT [21]. Although some cultural groups value the sensation of a tight or dry vagina during sex [1], and research has reported that gel detracted from sexual pleasure for some study

Please cite this article as: C. Woodsong, J.D.S. Holt, Acceptability and preferences for vaginal dosage forms intended for prevention of HIV or HIV and pregnancy, Adv. Drug Deliv. Rev. (2015), http://dx.doi.org/10.1016/j.addr.2015.02.004

C. Woodsong, J.D.S. Holt / Advanced Drug Delivery Reviews xxx (2015) xxx–xxx

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Table 1 Selected vaginal products and details, including use indication, dosage form and use requirements. Product

Use indication

Semi-solid, immediate release dosage forms Nonoxynol-9 (N-9) HIV-1, Neisseria gonorrhea, Chlamydia trachomatis Cellulose sulfate (CS) Pro 2000

HIV-1, Neisseria gonorrhea, Chlamydia trachomatis HIV

Vaginal dosage form

Use Mechanism of action requirements

1.5 g of 3.5% N-9 gel in pre-filled Before each applicator [33] sex act Film, sponge, soft-gel capsule [34,35] Gel, 6% CS in 3.5 mL [36] Within 1 h before sex Gel, 2% and 0.5% in 2 mL [37] Within 1 h before sex Gel, 0.5% in 2 mL [38] Within 1 h before sex 2 mL of gel per dose [38] Within 1 h before sex Gel, 7 mL of gel to dispense Within 1 h approximately 4 mL per dose [39] before sex Gel, 1% in 3.5 mL [40] Within 1 h before sex Gel, 1% tenofovir in 2.5 mL [41,42] BAT 24

Buffer gel

HIV

Carraguard

HIV-1

Savvy (C31G)

HIV-1, HIV-2

Tenofovir

HIV-1, HSV-2

Cellulose acetate phthalate (CAP) Dapivirine

HIV

Dapivirine & darunavir VivaGel MIV 150, zinc acetate, carrageenan Maraviroc IQP-0528 IQP-0528 & tenofovir

HIV-1 HIV, HSV-2 HIV-1, HSV

13% CAP in glycerin-based gel, 3 mL dose volume [43] Gel, 0.05% in 2.5 g [44] Film, 1.25 mg Dapivirine [45] Gel [46] Gel, 3% SPL7013 [47] Gel [48]

HIV-1 HIV-1 HIV-1

Gel cite [49] Gel [50,51] Gel [52]

Solid, extended release dosage forms Dapivirine HIV-1

Ring [53,54]

Dapivirine & maraviroc Tenofovir–levonorgestrel Dapivirine–levonorgestrel

HIV-1 HIV-1, HSV-2 and pregnancy HIV-1 and pregnancy

Ring [46] Ring [46]; nanofiber [46] Ring [46]

Dapivirine & darunavir Maraviroc MIV 150, zinc acetate, carrageenan, levonorgestrel MIV 150, zinc acetate, carrageenan IQP-0528, IQP 0532

HIV-1 HIV-1 HIV-1, HSV, pregnancy

Ring [55] Spun nanofiber [46] Ring [56]

Various Daily use

HIV-1, HSV

Ring [15,57]

Daily use

HIV-1

Exploratory dosage forms DS003 Lemon/lime juice

HIV HIV

Lactin V Mucocept Maraviroc Pyrimidine-diones

HIV, BV, UTI HIV, BV, Candida, UTI HIV-1 HIV

a

HIV-1

Daily use Daily use Daily use Daily use Daily use

28 days 90 days 28 days 60 days (or longer)

Surfactant

Polyanion that inhibits entry and attachment Polyanion that inhibits entry and attachment

Development stage

Terminated Terminated Terminated Terminated Terminated

Vaginal defense enhancer (pH)

Inactive

Polyanion that inhibits entry and attachment Surfactant

Terminated as single agent product Inactive

NRTIa

Proof of concept; phase III (current) Terminated

Polyanion that inhibits entry and attachment NNRTIa NNRTI & protease inhibitor Dendrimer that binds virus NNRTI, polyanion and zinc

Inactive Pre-clinical Early clinical Early clinical Pre-clinical

CCR5a antagonist NNRTI NNRTI & NRTI

Pre-clinical Pre-clinical Pre-clinical

NNRTI

Phase III (current) pre-clinical NNRTI and CCR5 antagonist Phase I NRTI and contraceptive hormone Pre-clinical NNRTI & contraceptive hormone Pre-clinical NNRTI & protease inhibitor CCR5 antagonist NNRTI with polyanion, zinc and contraceptive hormone NNRTI with polyanion and zinc

Pre-clinical Pre-clinical Pre-clinical

Ring [50,51]

RTIa

Pre-clinical

Vaginal tablet; gel [46] Various concentrations of juice [58,59] Capsule/soft-gel capsule [60] Capsule/soft-gel capsule [10] Film [46] Film [50,51]

gp120 binder pH

Pre-clinical Terminated

Lactobacillus Lactobacillus, Cyanovirin-N, CCR5 antagonist Multiple

Early clinical Early clinical Pre-clinical Pre-clinical

Pre-clinical

NRTI: nucleoside reverse transcriptase inhibitor; NNRTI: non-nucleoside reverse transcriptase inhibitor; CCR5: chemokine receptor type 5; RTI: reverse transcriptase inhibitor.

participants, most studies report gel lubrication contributes to sex that is more pleasurable, or less painful, to one or both partners [2,15,63, 64,67,68]. Research on vaginal films report that lack of leakage, quick absorption, and ability for discrete use are favorable attributes of this dosage form [69–72]. Innovative new work specifically links dosage form considerations with user perceptions and preferences. Morrow's research on sensory perceptions with semi-solid formulations investigates what users perceive about the spread, absorption and discharge of semi-solids, what meaning they make of these sensory perceptions, and what they like and dislike about these sensations [73,74]. Morrow observes that “… drug delivery systems, product properties and users' sensory perceptions interact in ways that may alter the use and, ultimately effectiveness and public health impact of microbicides.” [73]. Best et al. [22]

use a conjoint analysis approach to present women with descriptions of different MPT gel attributes and ask them to choose preferences for use indication, efficacy in relation to condoms, timing of use and gel texture. Verguet et al. [21] propose a “biophysical framework” to investigate gel acceptability, in which rich descriptions of gel viscosity and the time needed for gel to coat the vagina are presented to women, who are asked to indicate preferences for these attributes in reference to use with their sex partners. Li and colleagues [75] have conducted ex vivo studies to assess user preferences for the shape of vaginal softgel capsules, and find that women's preferences for shape include considerations about the size and firmness of capsules. Morrow and colleagues note that many of the acceptability and use concerns for semi-solids can be incorporated into product design to optimize product development decisions [73,76].

Please cite this article as: C. Woodsong, J.D.S. Holt, Acceptability and preferences for vaginal dosage forms intended for prevention of HIV or HIV and pregnancy, Adv. Drug Deliv. Rev. (2015), http://dx.doi.org/10.1016/j.addr.2015.02.004

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3.2. Solid dosage forms Cervical barrier devices, vaginal rings and spun nanofiber products are also being developed for vaginal dosing of microbicides and MPTs [46,77,78]. Previously, product developers hoped that by combining protection of the cervix with a physical barrier and a microbicidal semi-solid, the product would be more effective than either one used alone. A large study of diaphragms for HIV prevention failed to demonstrate efficacy, although user acceptability for the product was high, and many asked to keep their diaphragms when the study ended [79]. While the diaphragm was designed to prevent pregnancy only, Duet® and SILCS® are cervical barriers developed as one-size-fits-most, with additional design features specific to HIV prevention. With Duet, gel is applied to both sides of the device — one side conveys the gel to the cervical area while the outer band of the device has a rim to enhance gel distribution within the vaginal vault [72]. The SILCS diaphragm, originally developed for use with a gel for HIV and HIV-pregnancy prevention, is now being developed to deliver an API from the outer rim of the product, in a similar manner to the drug-loaded vaginal rings [80]. Vaginal rings that have advanced furthest in clinical trials for HIV prevention are based on the basic design of hormonal rings for postmenopausal symptoms, with a similar appearance. Unlike contraceptive rings, which are designed to be removed for a menstrual bleed, HIV prevention rings and MPT rings are meant to be worn continuously for sustained release of the API(s). Vaginal rings have been commercially available in the U.S. and Europe since 1993 [46,72,81], and in late 2013 were introduced in the private sector in South Africa. Users in the U.S., Canada and Europe have found the devices to be acceptable [82], as have clinical trial participants in sub-Saharan Africa [83,84]. Although initial reactions to seeing the products are often negative, women in clinical trials report that experience using the rings quickly dispels concerns about size and comfort. A frequent question is whether or not the male partner will be able to feel the ring during sex. Contraceptive ring studies report that about 25% of male partners feel the ring [85], and similar levels have been reported in clinical trials in subSaharan Africa [83,84,86]. Data thus far indicate that male partners generally do not find the sensation of feeling the ring during sex to be problematic. Ring expulsions are another concern of potential ring users, and again, expulsion rates for sub-Saharan African women in clinical trials are similar to the 8% reported for the commercially available contraceptive rings [82]. In the clinical trial settings, vaginal rings are meant to be removed only at the monthly study visits, but self-report data from clinical studies indicate that removals and expulsions occur, and at roughly equal rates. Since self-report is known to over-report adherence, it is possible that some expulsions are actually cases of removal, and removals may be higher than reported in trials. These concerns have prompted ring developers to consider ring designs that will be less likely to be expelled, yet easy for users to remove, while providing sufficient drug release for the indicated period of time. A final acceptability concern specific to dosage form is that the device will get “lost” within the woman's body [83]. There is a long history of such concern for reproductive health products, and studies of condoms and contraceptives continue to report this [87,88]. Education about the woman's reproductive system and human anatomy, and taking steps to correct misinformation and rumors will be an essential component of any plan to develop and introduce a vaginal device [89].

3.3. Use requirements, experiences and preferences The physical attributes of a vaginal dosing form are particularly salient to users when considered in the context of the use requirements. These include daily use, coitally-associated use and continuous use.

3.3.1. Daily use As indicated in Table 1, the microbicide pipeline has shifted over time to focus on antiretrovirals (ARVs). Concomitant with this shift was increased interest in developing use requirements less sensitive to user-failure than those requiring application within a short period before sex. Building on contraceptive experiences, it was believed that routinization of microbicide application should improve adherence, and daily use products were proposed as one strategy [90]. Several small early phase clinical trials of ARV gels testing daily use for two weeks [91] and six months [92] initially showed promise for a daily use regimen. However, the large scale VOICE trial of daily use tenofovir gel failed to demonstrate efficacy [93], and this is considered due to high levels of non-adherence [28,94]. Problems with long-term daily use included fear of side effects and other worries and concerns about product safety, as well as misunderstandings about the clinical research process [93,95]. Failure to achieve long term adherence to daily use, coupled with the forecasted costs of this use regimen has contributed to a decreased interest in development of daily use vaginal gels. 3.3.2. Coitally-associated use The first trial to test and demonstrate efficacy of a microbicide was CAPRISA 004, conducted in South Africa and testing tenofovir gel in a coitally-associated use regimen called “BAT-24” [41]. Importantly, the design of this unique use regimen was based on review of sexual behavior data and discussions with women in the expected participant communities, to reflect reported patterns of sexual behavior [96,97]. Women were instructed to insert the gel within 12 h before and again 12 h after sex, and although adherence waned over the 12 month use period, a statistically significant 39% reduction in HIV infection was demonstrated. Effectiveness was higher among women reporting higher adherence [96]. Unfortunately, the FACTS 001 confirmatory trial of tenofovir gel with BAT-24 use, also conducted in South Africa, did not report positive results, which was attributed to low adherence [42]. 3.3.3. Continuous use Adherence problems with daily and coitally associated use have strengthened interest in continuous dosing [98]. Currently, the majority of HIV microbicides and MPTs advancing in the clinical trial pipeline are formulated for delivery in vaginal rings, to provide continuous release of ARVs over 28 days or longer. A consensus-driven target product profile for an MPT for HIV and pregnancy prevention specifies critical aspects of a product and targets vaginal ring as the priority dosage form [5,99]. A platinum catalyzed silicone matrix ring delivering dapivirine for HIV prevention, developed by IPM [100], is currently in two large efficacy trials scheduled for completion in 2015–2016 [53,54]. Alternative ring designs are being explored to improve API delivery as well as extend the product use period for several months, up to a year [101–104]. Since these alternate ring designs may be more expensive to manufacture, extended use periods and/or multipurpose protection could justify the cost. Although it is hoped that extended-use rings may also improve use adherence, this has not yet been investigated. The popularity of longacting injectable contraceptives in sub-Saharan Africa suggests that a sustained release product, such as a vaginal ring providing extended HIV and/or pregnancy protection, could be acceptable to users. Less frequent action would be simpler for users. There would be less frequent need for privacy to insert the product, which has been observed to negatively impact consistent use of vaginal gels [105]. Continuous protection would also be valued by those who fear that they are at risk for unplanned sex and unwanted sex [106–108]. In addition to being easier for users, extended-use products could represent a substantial decrease in annual per-user costs by reducing materials, manufacturing and distribution needs, and decreasing the burden on health care delivery systems as well as the environmental impact of used rings or gel applicators [11]. Reducing the frequency of resupply could also improve adherence by

Please cite this article as: C. Woodsong, J.D.S. Holt, Acceptability and preferences for vaginal dosage forms intended for prevention of HIV or HIV and pregnancy, Adv. Drug Deliv. Rev. (2015), http://dx.doi.org/10.1016/j.addr.2015.02.004

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avoiding the loss of protection due to missed appointments for collection of new rings. However, unlike injections and gels, vaginal rings are a new dosage form, particularly in sub-Saharan Africa, and an understanding of user acceptability and preferences for ring formulations is much more limited than for gels. Studies of hypothetical ring acceptability conducted in several African countries, report interest in this method [108–110], and two clinical trials testing active and placebo rings for HIV prevention have been completed in several sub-Saharan African countries [83,84]. Although acceptability and adherence were reportedly high in both trials, 16% of participants reported at least one removal or expulsion between visits [86,111]. Ring expulsions and removals were reported at roughly equal rates, and cleaning and menses (including a desire to clean after or during menses) were the most common reasons given for non-adherent ring removal. Cleaning and menses appear to be important acceptability considerations for development of extended release rings. Contraceptive rings are removed to allow for menses. NuvaRing is worn for 21 days and removed for a withdrawal bleed, and is currently being tested for contraceptive acceptability in Rwanda and Kenya. The Population Council is developing a contraceptive ring to be worn for a year, with monthly removal for a withdrawal bleed, and a threemonth ring similar to Progering®, which extends the period of lactational amenorrhea [110,112]. Vaginal rings with extended use periods and multiple indications for use are promising delivery platforms, but it remains to be seen if women in sub-Saharan Africa will use them for prevention of HIV and/or pregnancy, what their preferences are for use requirements and use duration, and if they will wear them for extended periods of time without periodic removal for cleaning/rinsing [113]. 3.4. Use indications In the African context, the most familiar indications for use of vaginal products are maintenance of vaginal cleanliness and improving sexual experience, followed by treatment of STIs and bacterial infections using traditional as well as pharmaceutical products [114,115]. Vaginal dosing for prevention of HIV or pregnancy is a new concept, and women's willingness and ability to use a vaginal product and adhere to use requirements may vary according to the indication for which it is being used. The continued HIV pandemic should provide a strong motivation for microbicide use among populations in high-incidence settings and/or high-risk groups. Since the options of abstinence, mutual monogamy, male circumcision and condom use are not acceptable or practical for many who would like to prevent infection, development of vaginal microbicides for HIV prevention continues to generate significant interest and support [4,116]. A vaginal MPT with a use indication for prevention of pregnancy as well as HIV infection may have better adherence than a product preventing only HIV, since most women believe they are at risk of pregnancy, regardless of their awareness or acceptance of risk for HIV infection. Contraceptive use has become normalized in most countries, although men may object to their partner's use of contraceptives, and

women may use them secretly. Studies indicate that women consider pregnancy prevention less problematic to discuss with partners than HIV prevention, and thus pregnancy prevention could be the stated reason for use of an MPT product [22,113]. The leading dosage form for MPTs for HIV and pregnancy prevention is vaginal rings, combining an anti-retroviral (ARV) with a hormonal method, as indicated in Table 1. Given what is known about user concerns about safety, product formulation decisions most likely to influence user acceptability include the effect on menses and time to resume fertility after ring removal. IPM and CONRAD are developing MPT rings combining an ARV with levonorgestrel. Both rings are intended for 90-day continuous use with no removal for a withdrawal bleed. However, some users may prefer to remove the ring periodically as they may prefer to have menses, and breakthrough bleeding may be an unacceptable side effect. Contraceptive-related amenorrhea was originally a concern for African populations, and although the high levels of method use indicate that many women accept amenorrhea, many do not [116,117]. Disruptions in bleeding patterns and breakthrough bleeding are common reasons for contraceptive method discontinuation [118–120], and the perceived need for cleaning a ring, often associated with menses, has been reported as a main reason for ring removal [111]. When women want to conceive, or husbands don't want them to use contraceptives, a single-purpose formulation should also be available. For some products, a single purpose HIV-prevention product could be easily formulated. For example, the dapivirine ring could provide an alternative to a dapivirine–levonorgestral MPT ring. Users will need clear information about how quickly the products become effective for each indication, and how quickly the drugs will clear from the body. In addition, users must be able to easily differentiate single from multipurpose products. 4. Key acceptability issues (or “What do users want?”) Since the earliest products were semi-solids (primarily gels), and formulated for coitally-associated use, microbicide and MPT acceptability research focused on these dosage forms and use requirements. It quickly became clear that user acceptability was influenced by more than product attributes such as color, smell and taste. Although the formulations and use requirements varied, and studies were conducted in different countries with a range of participant populations and risk factors, women reported similar factors influencing their willingness to use a future microbicide product. When a vaginal ring dosage form entered clinical testing, these concerns continued to be reported. The most frequently documented acceptability and preference issues pertain to efficacy, safety, ease of use and the male partner. In 2004, the International Working Group for Microbicides (IWGM) published a list of “essential characteristics for a topical microbicide” [121] to guide further development of vaginal microbicide products. Although the IWGM's focus was not specifically aimed at acceptability and user preferences, the essential characteristics are relevant to key issues and concerns that have emerged in social and behavioral science

Table 2 Comparison of user preferences and recommendations for essential characteristics for a topical microbicide. User preferences for topical microbicide characteristics

(IWGM) Essential characteristics for a topical microbicide [89]

Effective against HIV

“High level of in vitro activity, in the presence of semen, against cell-free and cell-associated HIV-1, and multiple HIV-1 strains/subtypes” “No or low activity against vaginal lactobacilli in vitro and no effect on vaginal pH; no or low irritation to vagina and nonimmunotoxic” “No low systemic toxicity, low cytotoxicity in vitro, nongenotoxic, noncarcinogenic” “No adverse effects on reproductive health in animals” “Formulation suitable for vaginal application in an effective, appealing, and efficient delivery system; stable under the conditions likely to be encountered”

Safe

Few side effects

No long term effects No long term effect on fertility Easy to use Easy to insert/apply Does not impede sexual intercourse Easy to clean-up and dispose after use Partner-related issues

5

(not expressly mentioned in IWGM's “Essential” or “Desirable” characteristics)

Please cite this article as: C. Woodsong, J.D.S. Holt, Acceptability and preferences for vaginal dosage forms intended for prevention of HIV or HIV and pregnancy, Adv. Drug Deliv. Rev. (2015), http://dx.doi.org/10.1016/j.addr.2015.02.004

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studies of acceptability, as illustrated in Table 2. We discuss each, in turn, below. 4.1. Effective When people are asked about desirable characteristics of a potential microbicide or MPT, of paramount concern is that they “really work” to prevent HIV. Users may indicate that while they would prefer microbicides to be as effective as condoms, the urgency of their needs should not delay development of microbicides with lower efficacy [122]. Although acceptability may be tempered when it is explained that microbicides will be less effective at preventing HIV and/or pregnancy, and may not provide any protection to the male partner, users still express interest in the products [113]. Data will be needed to provide users with clear comparative information about potential efficacy and effectiveness under typical use for both condoms and a microbicide, and for both partners. The target product profile for MPTs [5,99] establishes that the contraceptive efficacy of these products should be no less than that for the contraceptive used alone, so that women do not switch to a less effective contraceptive method in their efforts to prevent HIV infection. 4.2. Safe User preferences for microbicide safety can be further divided into concern about side effects, long term effects, and particularly the potential effects on fertility. As could be expected, and consistent with the IWGM recommendations, potential users prefer such effects to be minimal or non-existent. Women do not want to experience vaginal irritation or discharge. Women and their partners are concerned about using products over the long term, and if they might increase vulnerability to cancers or other health conditions. Concern about the safety of using ARVs for prevention rather than treatment is reported to be a key factor in the adherence problems for the VOICE trial [28]. A frequently reported concern is the effect on fertility [28,68,108,123]. Since microbicide research is targeting those most at risk of infection, and these are women of reproductive age, it is not surprising that people are concerned that a product used in the vagina may have long term effects on fertility. The ability to quickly resume fertility is one advantage of a user-initiated vaginal dosing strategy. When pregnancy is desired, product use can be suspended and drug levels will fall quickly, unlike an injection which may take months to clear, or an intrauterine device or implant, which must be removed by a health professional. 4.3. Easy to use Ease of use is an obviously desirable characteristic for any medical product, but people's conceptions of this are variable. At the most basic level, the product must be easy to apply, and devices must also be easy to remove. As seen in Table 1, most clinical studies of microbicides have tested gels in pre-filled single use applicators. Alternate applicator designs have been developed by PATH and CONRAD, with the aim of lowering cost and environmental impact, yet maintaining high user acceptability [124,125]. Reusable and/or user-filled applicators could represent a significant cost savings, but the intended users may have limited access to clean water and the ability to safely clean and store such products. Vaginal ring studies report that women may be initially skeptical about their ability to insert a vaginal ring, but this has not proven challenging for women [83]. Ease of use also refers to clean up and disposal of the product. Studies have reported that product leakage on clothing and bedding can be troublesome to users, both for practical reasons of needing additional cleaning and because such leakage makes the product more noticeable for both partners [62,126]. Disposal of used applicators has been problematic for some clinical trial participants who were allowed to dispose applicators at home (e.g., they worried that a child would play with them, such disposal is less discrete), and for those required to return

used applicators to the research center (e.g., storing used applicators at home, transporting to the research center) [125]. Women using vaginal rings have also been required to return used rings to the research center, but it is not yet known what will be required for return or disposal of rings if they are made available outside of a clinical trial. 4.4. Partner issues An important concern of users that is more challenging to articulate with product development efforts is a wide range of partner related issues. Some of these issues have implications for dosage forms, and some concern the very concept of microbicides and MPTs as products that women can use to protect themselves from HIV infection and pregnancy. In this regard, the ecological frameworks that recognize partner influences within larger social and cultural gender norms are particularly salient, since in much of the world, women's ability to make decisions that affect sexual practices and microbicide product use is constrained. A recent study conducting analysis of data from six microbicide trials confirms findings from earlier studies that key factors influencing women's acceptability of microbicides is their perception of the partner's reaction to the product, and their decisions about what or if to tell him about use [68,108,127]. CAPRISA 004 reported higher adherence among women whose partners knew about the study [128]. Studies that have explored women's concerns about product attributes, such as additional lubrication of gels, or the physical size of a ring have found a general preference for the product to not be noticeable during sex, and if it is noticeable, that it not decrease sexual pleasure, primarily for the male partner [15,129,130]. If a woman feels that the partner will not notice the gel, or the ring, she may then consider using the product without disclosing use [108,129]. In many cultural settings, it is felt that the obligation to tell a partner varies somewhat by partner type — married women should disclose use while women with casual and/or paying partners may have more discretion. Regardless of partner type, disclosure of microbicide or MPT use could surface questions of sexual fidelity, and discovery of covert use could further compound these problems. 5. Conclusion A vaginal product developed for prevention of HIV and/or pregnancy must be sufficiently safe, effective and acceptable for women to use for an extended period of time, perhaps many years. One of the longstanding problems with contraceptive efficacy is achieving correct and continued use, and microbicides and MPTs will likely face similar issues. The behaviors and use patterns that have been observed in clinical trial settings may be quite different from what will happen when effective products are made available to those who seek to access and use them. However, the research field recognizes that users need options for microbicide and MPT products, and that these options will ideally include different use requirements, use indications, and/or dosage forms. Although it is unlikely that a panoply of products will be proven effective and licensed within a narrow time window, maintaining a robust pipeline with a range of product modalities as well as active ingredients is a necessary prerequisite for eventually meeting the diverse needs of human beings across the globe. Balancing what people want (e.g., easy to use, minimal effect on sex, no side effects, protect partners, low-cost, etc.) with what is feasible (e.g., APIs with appropriate dose–response that can be formulated to be safe for vaginal use in a variety of conditions) will continue to challenge product development efforts. These options are further constrained by access issues, which include the final cost per unit, where they may be obtained (e.g., over-the counter, private sector, public sector) and the need to test negatively for HIV infection in order to get a resupply of product [131–133]. Access will likely be more restrictive than condoms and contraceptives, and condoms will be more effective at HIV prevention, so users and health professionals will make choices and recommendations based on issues beyond product characteristics. Such choices may be

Please cite this article as: C. Woodsong, J.D.S. Holt, Acceptability and preferences for vaginal dosage forms intended for prevention of HIV or HIV and pregnancy, Adv. Drug Deliv. Rev. (2015), http://dx.doi.org/10.1016/j.addr.2015.02.004

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driven by user perception of the “least worst” options [16], but ideally users will be able to choose products that are appealing and acceptable. Counseling messages can be provided to help users understand the necessity of the less favorable attributes of vaginal products [73,89]. Counseling must also make it clear that condoms may be used concurrently with these products, and that condoms remain the most effective HIV prevention method when they are used correctly and consistently Social and behavioral scientists must continue to grapple with how best to assess the magnitude of user preferences, and collaborate with product development scientists to create microbicides and MPTs that can have a positive impact on the reduction of HIV and unintended pregnancy. In 1990, Zena Stein's [134] landmark call for HIV prevention methods to be used by women articulated the need for a health technology that would require integrated work from biological and pharmaceutical sciences with social and behavioral sciences. Microbicides are needed specifically because of women's increased biological and social vulnerability to HIV infection, and research on microbicide acceptability has been conducted alongside, as well as separate from, the earliest product development efforts. The understanding of microbicide acceptability and preferences is concentrated most heavily in vaginal gel dosing forms, and it is now incumbent on the research community to make use of this knowledge and apply it to development of new products in the pipeline.

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Please cite this article as: C. Woodsong, J.D.S. Holt, Acceptability and preferences for vaginal dosage forms intended for prevention of HIV or HIV and pregnancy, Adv. Drug Deliv. Rev. (2015), http://dx.doi.org/10.1016/j.addr.2015.02.004