The reduction in human immunodeficiency virus (HIV) infection in women demonstrated by pericoital use of tenofovir gel has encouraged the continued development of microbicides. Novel approaches include new ways to deliver tenofovir, as well as products that contain different antiretroviral drugs, either as single agents or as combinations of antiretroviral drugs. Indeed, emphasis has renewed on the development of multipurpose prevention technologies, products designed to address multiple sexually transmitted infections. Dual-purpose contraceptive antiretroviral products are also being designed to prevent HIV and pregnancy. Since consistent and correct use of these products will be critical to their effectiveness, the active pharmaceutical ingredients must be delivered in acceptable vaginal dosage forms, such as gels, films and sustained-release vaginal rings. The development of different dosage forms will help ensure that women can find a method to protect themselves from HIV, pregnancy, and potentially other sexually transmitted infections.
Introduction
A proof-of-concept for human immunodeficiency virus (HIV) prevention by antiretroviral (ARV)-based microbicides was achieved when 1% tenofovir gel was found to reduce the HIV infection rate by 39% in women using the gel up to 12 h before sex and again within 12 h after sex, compared with women using a placebo gel. It is evident that this approach to prevention has the potential to transform the response to the HIV and acquired immune deficiency syndrome (AIDS) pandemic. Further research, however, is needed on vaginal microbicides, including studies of different dosing strategies, different formulations, and products containing other ARV compounds with alternative targets in the HIV infection process, in order to build upon the level of effectiveness observed with tenofovir gel.
The successful development of vaginally applied products for the prevention of HIV infection requires significant levels of protection against HIV acquisition, demonstrated safety in healthy populations, and no adverse interactions with commonly used vaginal drugs or other HIV prevention approaches. Approaches to the vaginal delivery of microbicides have been based on products used to deliver drugs for the treatment of vaginal infections, contraception and hormone replacement, as well as oral personal care products. These delivery systems commonly include semi-solid gels and creams, intravaginal rings, fast-dissolving films, tablets and capsules, foams and suppositories. The two dosage forms most commonly used in the development of candidate microbicides are shown in Fig. 1 . A product’s effectiveness will depend on its consistent use, therefore, the design of formulations that women find routinely easy to use is of paramount importance in microbicide development. Demographic characteristics such as age, socioeconomic status and culture, among others, will all play a role in a microbicide’s acceptability in any given population, similar to that seen for contraceptives. Data from a market research study in several countries in Africa suggest that the availability of microbicides in multiple dosage forms may increase acceptability, adherence and, therefore, effectiveness.
The development of an effective microbicide for HIV prevention involves the selection of potent drugs that can interfere with HIV replication and delivering the drug to the site of replication at the appropriate time. Thus, both the drug and the drug-delivery system are crucial components of a successful product. The physical and chemical properties of ARV-based compounds allow for their delivery in formulations designed for flexible dosing, including daily or monthly use, in addition to coitally related application. In this chapter, we will review the ARVs and the most common vaginal delivery systems currently being developed for HIV prevention, and will describe those products under development for multiple indications, including contraception and other sexually transmitted infections.
Microbicides in clinical development
Dapivirine
Dapivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) originally developed as an oral therapeutic before being selected for microbicide evaluation owing to poor bioavailability. Dapivirine is specific for, and binds directly to, HIV-1 reverse transcriptase, thereby blocking reverse transcriptase activity and preventing HIV-1 replication. Multiple in vitro studies have shown that dapivirine is able to inhibit both cell free- and cell-associated HIV-1 infection. Dapivirine is also able to inhibit direct infection of mucosal tissue in human cervical explant cultures and to prevent spread of virus by migratory cells. Inhibition of virus by dapivirine was not significantly affected by the presence of either semen or cervical mucus stimulant. Dapivirine has potent activity against a wide range of NNRTI-resistant isolates compared with nevirapine, delavirdine, efavirenz and emivirine. In severe combined immunodeficient mouse-human mice reconstituted with human peripheral blood lymphocytes, application of dapivirine gel was able to block vaginal infection with both CCR5 and CCR5/CXCR4-infected cells.
Dapivirine gels
Given the long history of use of gels as vaginal delivery dosage forms, gel formulations of dapivirine were developed and evaluated pre-clinically and clinically. Dapivirine gels have shown good safety profiles in rabbit vaginal irritation studies of up to 39 weeks duration, in in vitro and in vivo mutagenicity studies, and in reproductive toxicity studies in rats and rabbits (Nuttall J, personal communication).
Results from pharmacokinetic and safety studies of dapivirine vaginal gels in healthy, HIV-negative women showed good distribution of dapivirine in the lower genital tract with low systemic absorption. The gels were safe and well tolerated, with no differences in side-effects between dapivirine gel and matching or universal placebo gel groups. Concentrations of dapivirine in the genital tract were approximately 4–5 logs higher than the 50% inhibitory concentration against HIV-1 in vitro and 3 logs higher than plasma concentrations after oral dapivirine administration, which resulted in at least a 10-fold reduction in viral load.
Dapivirine vaginal rings
Vaginal rings are devices designed to provide sustained delivery of drugs to the vagina for either local or systemic effect. The first ring product to reach the market in 1993 was Estring ® , a silicone elastomer reservoir device providing release of 7.5 μg 17-β-estradiol daily over 3 months for the local treatment of menopausal urogenital atrophy. Two other rings have also been licensed for use; Nuvaring ® , an ethylene vinyl acetate ring delivering the contraceptive steroids etonogestrel and ethinylestradiol over 21 days, and Femring ® (Menoring ® in the UK), a silicone ring delivering a 3-month dose of an estradiol prodrug, estradiol-3-acetate.
For vaginal rings to be suitable for microbicide delivery in women who are at risk of HIV, the physical presence of the vaginal ring should not cause deleterious effects on the local vaginal and cervical epithelium. After a report of chronic erythematous and ulcerative lesions in the posterior vaginal fornix with an early prototype contraceptive ring, several studies examining the local clinical safety of vaginal rings have shown few, if any, adverse effects (including clinical lesions and vaginal flora changes) attributable to the presence of the ring itself. Minor colposcopic findings have been reported, with most resolving despite continued use of the ring. The incidence of ulcerations, abrasions and ecchymoses greater than 0.5 cm, or field of five or more petechiae, was not statistically different between ring users and sexually active historical controls. In a recent safety and acceptability study of a placebo silicone ring, in which women were randomised to either the ring followed by a no treatment observation period or vice versa, adverse events occurred with similar frequency in the treatment and observation periods (Nel A, personal communication).
Several dapivirine vaginal rings have been developed using different polymers and manufacturing processes. The initial dapivirine vaginal rings evaluated clinically contained either 25 mg or 200 mg dapivirine in a tin-catalysed silicone reservoir ring, containing a central drug-filled core enclosed by an non-medicated outer ring. The vaginal rings were found to be safe and well tolerated, successfully delivering the drug in vaginal fluids and tissue in the vagina and cervix, with low systemic absorption. Concentrations of dapivirine throughout the lower genital tract were greater than three logs higher than the in vitro EC 50.
A subsequent study compared a tin-catalysed dapivirine reservoir vaginal ring to a matrix-type configuration, in which the drug is uniformly distributed throughout the silicone. Similar to the reservoir ring, the dapivirine matrix vaginal ring had a good safety profile with low systemic exposure and high concentrations of drug throughout the lower genital tract. A platinum-catalysed silicone ring (Ring-004), designed to improve stability, has been evaluated in phase I and phase II clinical studies involving more than 300 women, and has confirmed the good safety and a pharmacokinetic profiles of earlier prototypes (Nel A, personal communication).
The ability of vaginal rings to release the drug over prolonged periods of time allows for a monthly (or less frequent) dosage form that may contribute to greater consistency in product use. Studies assessing the acceptability of vaginal rings for contraception showed that they can be successfully used by women. Favourable characteristics most often reported by women in these studies included individual control over ring insertion and removal; not needing to remember to take a daily pill; and comfort and ease of use. Compared with other contraceptive dosage forms (oral pills and skin patches), women reported convenience, frequency of use and lower risk of unintentional non-use as being the primary reasons for choosing the vaginal ring. A pattern of more consistent use is supported by the results from a cross-sectional multicentre study of 26,250 typical users of a combined hormonal contraceptive showing that emergency contraception was requested by 14% of pill users, 11% of patch users and 6.3% of ring users.
More recently, several studies have been conducted in an effort to determine the acceptability of vaginal rings for HIV prevention in populations at high risk of HIV infection, specifically in sub-Saharan Africa. In a study of attitudes towards hypothetical use of vaginal rings among female sex workers and their clients in Kenya, perceived benefits of vaginal ring use included a lack of required preparation and inhibition of sexual spontaneity, and compatibility with dry sex preferences. Potential concerns included comfort, detection by male partner, and vaginal hygiene during prolonged use. Acceptability during actual use of a placebo vaginal ring in a clinical safety and acceptability study in South Africa and Tanzania was high, with most women reporting that the ring was comfortable, easy to insert and remove, and could be used without male partner knowledge. A minority of women were concerned about the ring getting lost within the body or being expelled (Woodsong C, personal communication).
Given its ease of use, stability for more than 2 years in zone 4 conditions (30 °C and 65% relative humidity), and relatively low manufacturing cost, dapivirine ring-004, if safe and effective against HIV, would be suitable for use in developing countries, especially in sub-Saharan Africa where HIV incidence in women is high. Randomised, placebo-controlled studies to determine efficacy and long-term safety of dapivirine ring-004 in about 5000 women are planned to begin in several countries in sub-Saharan Africa in early 2012. Additional studies evaluating safety in adolescents and peri-menopausal and post-menopausal women are also planned.
Dapivirine film
Dapivirine has also been formulated into small fast-dissolving films, designed to release drug following dissolution by vaginal fluids. Flexible, translucent polyvinyl alcohol-based vaginal films containing 1.25 mg dapivirine per film were designed to dissolve rapidly upon exposure to an aqueous environment with greater than 50% of the loaded dapivirine being released from the film within 10 mins. In addition, dapivirine was shown to permeate target tissue in vitro and inactivate HIV-1 in ex-vivo models using human cervical explant tissue. The advantages of vaginal films as a microbicide dosage form include the potential for improved drug stability compared with water-based gels, especially for hydrophobic drugs such as dapivirine. As a result of their small size, vaginal films may also have economic advantages over vaginal rings and gels in manufacturing, storage and shipping costs. Vaginal leakage observed with frequent use of microbicide gels may also be eliminated by vaginal films that do not require exogenous fluids for dissolution. Acceptability of vaginal films as a contraceptive dosage form has been evaluated in several studies that reported similar levels of satisfaction for vaginal films compared with contraceptive gels, foams and suppositories. Women have also reported acceptability of vaginal films for microbicide delivery.
Maraviroc
Maraviroc, belongs to a pharmacological class of antiretroviral agents known as CCR5 antagonists, marketed as Selzentry ® (Pfizer Labs, New York, NY, USA) for treatment of CCR5-tropic HIV-1 infection, which acts by blocking the CCR5 co-receptor on human cellular targets to prevent infection of the cell by HIV-1. As CCR5 is the primary co-receptor involved in sexual transmission of HIV, blocking CCR5 has the potential to prevent the establishment of infection in individuals exposed to the virus. Maraviroc has demonstrated efficacy in vitro against a wide range of CCR5-tropic clinical isolates from multiple clades of HIV-1, as well as those resistant to other classes of antiretroviral medicinal products. Maraviroc delivered vaginally has been shown in non-human primates (NHP) to prevent transmission of simian human immunodeficiency virus (SHIV) infection when delivered within a few hours before infection.
Maraviroc and maraviroc-dapivirine vaginal rings
Maraviroc’s short duration of effect in NHP suggests that vaginal rings would be a suitable dosage form for maraviroc-based microbicides. Pre-clinically, maraviroc has been shown to be safe after topical gel application for 4 weeks in rabbit vaginal irritation studies (Nuttall J, personal communication). Vaginal rings containing maraviroc, and a combination of maraviroc and dapivirine, are currently being tested in a phase I safety and pharmacokinetics study (Hillier S, personal communication). Although maraviroc is a licensed therapeutic, a significant body of data support the safety of maraviroc delivered orally. This is the first clinical study utilizing maraviroc in women for vaginal use. The maraviroc vaginal ring contains 100 mg of maraviroc, and the combination vaginal ring contains an additional 25 mg dapivirine, dispersed in a platinum-catalysedcured silicone matrix. In vitro , similar amounts of each drug are released from the vaginal rings over a 28-day period despite the four-fold difference in initial concentration, suggesting a lower solubility of maraviroc in silicone (Devlin B, personal communication). The rationale for developing microbicides containing combinations of ARVs is discussed later in this chapter.
Tenofovir vaginal ring, film and tablet
Tenofovir (Viread ® , Gilead Sciences, Inc.) is a nucleotide reverse transcriptase inhibitor approved for the treatment of HIV infection. In addition to 1% tenofovir gel, currently being tested in a phase III confirmatory efficacy trial for coitally associated use, other dosage forms of tenofovir are also under development. A polyurethane-based tenofovir vaginal ring, designed to release at least 10 mg tenofovir daily over several months to help improve adherence, is planned to enter phase I clinical testing in 2012. Additional formulations in development include a fast-dissolving film and tablet, which both have potential economic and acceptability advantages over the gel dosage form.
Microbicides in clinical development
Dapivirine
Dapivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) originally developed as an oral therapeutic before being selected for microbicide evaluation owing to poor bioavailability. Dapivirine is specific for, and binds directly to, HIV-1 reverse transcriptase, thereby blocking reverse transcriptase activity and preventing HIV-1 replication. Multiple in vitro studies have shown that dapivirine is able to inhibit both cell free- and cell-associated HIV-1 infection. Dapivirine is also able to inhibit direct infection of mucosal tissue in human cervical explant cultures and to prevent spread of virus by migratory cells. Inhibition of virus by dapivirine was not significantly affected by the presence of either semen or cervical mucus stimulant. Dapivirine has potent activity against a wide range of NNRTI-resistant isolates compared with nevirapine, delavirdine, efavirenz and emivirine. In severe combined immunodeficient mouse-human mice reconstituted with human peripheral blood lymphocytes, application of dapivirine gel was able to block vaginal infection with both CCR5 and CCR5/CXCR4-infected cells.
Dapivirine gels
Given the long history of use of gels as vaginal delivery dosage forms, gel formulations of dapivirine were developed and evaluated pre-clinically and clinically. Dapivirine gels have shown good safety profiles in rabbit vaginal irritation studies of up to 39 weeks duration, in in vitro and in vivo mutagenicity studies, and in reproductive toxicity studies in rats and rabbits (Nuttall J, personal communication).
Results from pharmacokinetic and safety studies of dapivirine vaginal gels in healthy, HIV-negative women showed good distribution of dapivirine in the lower genital tract with low systemic absorption. The gels were safe and well tolerated, with no differences in side-effects between dapivirine gel and matching or universal placebo gel groups. Concentrations of dapivirine in the genital tract were approximately 4–5 logs higher than the 50% inhibitory concentration against HIV-1 in vitro and 3 logs higher than plasma concentrations after oral dapivirine administration, which resulted in at least a 10-fold reduction in viral load.
Dapivirine vaginal rings
Vaginal rings are devices designed to provide sustained delivery of drugs to the vagina for either local or systemic effect. The first ring product to reach the market in 1993 was Estring ® , a silicone elastomer reservoir device providing release of 7.5 μg 17-β-estradiol daily over 3 months for the local treatment of menopausal urogenital atrophy. Two other rings have also been licensed for use; Nuvaring ® , an ethylene vinyl acetate ring delivering the contraceptive steroids etonogestrel and ethinylestradiol over 21 days, and Femring ® (Menoring ® in the UK), a silicone ring delivering a 3-month dose of an estradiol prodrug, estradiol-3-acetate.
For vaginal rings to be suitable for microbicide delivery in women who are at risk of HIV, the physical presence of the vaginal ring should not cause deleterious effects on the local vaginal and cervical epithelium. After a report of chronic erythematous and ulcerative lesions in the posterior vaginal fornix with an early prototype contraceptive ring, several studies examining the local clinical safety of vaginal rings have shown few, if any, adverse effects (including clinical lesions and vaginal flora changes) attributable to the presence of the ring itself. Minor colposcopic findings have been reported, with most resolving despite continued use of the ring. The incidence of ulcerations, abrasions and ecchymoses greater than 0.5 cm, or field of five or more petechiae, was not statistically different between ring users and sexually active historical controls. In a recent safety and acceptability study of a placebo silicone ring, in which women were randomised to either the ring followed by a no treatment observation period or vice versa, adverse events occurred with similar frequency in the treatment and observation periods (Nel A, personal communication).
Several dapivirine vaginal rings have been developed using different polymers and manufacturing processes. The initial dapivirine vaginal rings evaluated clinically contained either 25 mg or 200 mg dapivirine in a tin-catalysed silicone reservoir ring, containing a central drug-filled core enclosed by an non-medicated outer ring. The vaginal rings were found to be safe and well tolerated, successfully delivering the drug in vaginal fluids and tissue in the vagina and cervix, with low systemic absorption. Concentrations of dapivirine throughout the lower genital tract were greater than three logs higher than the in vitro EC 50.
A subsequent study compared a tin-catalysed dapivirine reservoir vaginal ring to a matrix-type configuration, in which the drug is uniformly distributed throughout the silicone. Similar to the reservoir ring, the dapivirine matrix vaginal ring had a good safety profile with low systemic exposure and high concentrations of drug throughout the lower genital tract. A platinum-catalysed silicone ring (Ring-004), designed to improve stability, has been evaluated in phase I and phase II clinical studies involving more than 300 women, and has confirmed the good safety and a pharmacokinetic profiles of earlier prototypes (Nel A, personal communication).
The ability of vaginal rings to release the drug over prolonged periods of time allows for a monthly (or less frequent) dosage form that may contribute to greater consistency in product use. Studies assessing the acceptability of vaginal rings for contraception showed that they can be successfully used by women. Favourable characteristics most often reported by women in these studies included individual control over ring insertion and removal; not needing to remember to take a daily pill; and comfort and ease of use. Compared with other contraceptive dosage forms (oral pills and skin patches), women reported convenience, frequency of use and lower risk of unintentional non-use as being the primary reasons for choosing the vaginal ring. A pattern of more consistent use is supported by the results from a cross-sectional multicentre study of 26,250 typical users of a combined hormonal contraceptive showing that emergency contraception was requested by 14% of pill users, 11% of patch users and 6.3% of ring users.
More recently, several studies have been conducted in an effort to determine the acceptability of vaginal rings for HIV prevention in populations at high risk of HIV infection, specifically in sub-Saharan Africa. In a study of attitudes towards hypothetical use of vaginal rings among female sex workers and their clients in Kenya, perceived benefits of vaginal ring use included a lack of required preparation and inhibition of sexual spontaneity, and compatibility with dry sex preferences. Potential concerns included comfort, detection by male partner, and vaginal hygiene during prolonged use. Acceptability during actual use of a placebo vaginal ring in a clinical safety and acceptability study in South Africa and Tanzania was high, with most women reporting that the ring was comfortable, easy to insert and remove, and could be used without male partner knowledge. A minority of women were concerned about the ring getting lost within the body or being expelled (Woodsong C, personal communication).
Given its ease of use, stability for more than 2 years in zone 4 conditions (30 °C and 65% relative humidity), and relatively low manufacturing cost, dapivirine ring-004, if safe and effective against HIV, would be suitable for use in developing countries, especially in sub-Saharan Africa where HIV incidence in women is high. Randomised, placebo-controlled studies to determine efficacy and long-term safety of dapivirine ring-004 in about 5000 women are planned to begin in several countries in sub-Saharan Africa in early 2012. Additional studies evaluating safety in adolescents and peri-menopausal and post-menopausal women are also planned.
Dapivirine film
Dapivirine has also been formulated into small fast-dissolving films, designed to release drug following dissolution by vaginal fluids. Flexible, translucent polyvinyl alcohol-based vaginal films containing 1.25 mg dapivirine per film were designed to dissolve rapidly upon exposure to an aqueous environment with greater than 50% of the loaded dapivirine being released from the film within 10 mins. In addition, dapivirine was shown to permeate target tissue in vitro and inactivate HIV-1 in ex-vivo models using human cervical explant tissue. The advantages of vaginal films as a microbicide dosage form include the potential for improved drug stability compared with water-based gels, especially for hydrophobic drugs such as dapivirine. As a result of their small size, vaginal films may also have economic advantages over vaginal rings and gels in manufacturing, storage and shipping costs. Vaginal leakage observed with frequent use of microbicide gels may also be eliminated by vaginal films that do not require exogenous fluids for dissolution. Acceptability of vaginal films as a contraceptive dosage form has been evaluated in several studies that reported similar levels of satisfaction for vaginal films compared with contraceptive gels, foams and suppositories. Women have also reported acceptability of vaginal films for microbicide delivery.
Maraviroc
Maraviroc, belongs to a pharmacological class of antiretroviral agents known as CCR5 antagonists, marketed as Selzentry ® (Pfizer Labs, New York, NY, USA) for treatment of CCR5-tropic HIV-1 infection, which acts by blocking the CCR5 co-receptor on human cellular targets to prevent infection of the cell by HIV-1. As CCR5 is the primary co-receptor involved in sexual transmission of HIV, blocking CCR5 has the potential to prevent the establishment of infection in individuals exposed to the virus. Maraviroc has demonstrated efficacy in vitro against a wide range of CCR5-tropic clinical isolates from multiple clades of HIV-1, as well as those resistant to other classes of antiretroviral medicinal products. Maraviroc delivered vaginally has been shown in non-human primates (NHP) to prevent transmission of simian human immunodeficiency virus (SHIV) infection when delivered within a few hours before infection.
Maraviroc and maraviroc-dapivirine vaginal rings
Maraviroc’s short duration of effect in NHP suggests that vaginal rings would be a suitable dosage form for maraviroc-based microbicides. Pre-clinically, maraviroc has been shown to be safe after topical gel application for 4 weeks in rabbit vaginal irritation studies (Nuttall J, personal communication). Vaginal rings containing maraviroc, and a combination of maraviroc and dapivirine, are currently being tested in a phase I safety and pharmacokinetics study (Hillier S, personal communication). Although maraviroc is a licensed therapeutic, a significant body of data support the safety of maraviroc delivered orally. This is the first clinical study utilizing maraviroc in women for vaginal use. The maraviroc vaginal ring contains 100 mg of maraviroc, and the combination vaginal ring contains an additional 25 mg dapivirine, dispersed in a platinum-catalysedcured silicone matrix. In vitro , similar amounts of each drug are released from the vaginal rings over a 28-day period despite the four-fold difference in initial concentration, suggesting a lower solubility of maraviroc in silicone (Devlin B, personal communication). The rationale for developing microbicides containing combinations of ARVs is discussed later in this chapter.
Tenofovir vaginal ring, film and tablet
Tenofovir (Viread ® , Gilead Sciences, Inc.) is a nucleotide reverse transcriptase inhibitor approved for the treatment of HIV infection. In addition to 1% tenofovir gel, currently being tested in a phase III confirmatory efficacy trial for coitally associated use, other dosage forms of tenofovir are also under development. A polyurethane-based tenofovir vaginal ring, designed to release at least 10 mg tenofovir daily over several months to help improve adherence, is planned to enter phase I clinical testing in 2012. Additional formulations in development include a fast-dissolving film and tablet, which both have potential economic and acceptability advantages over the gel dosage form.
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