WHAT ARE MICROBICIDES AND WHY ARE THEY IMPORTANT?
Microbicides are promising prophylactic agents under development for use in the vagina or rectum to prevent sexual acquisition of HIV. It is likely that in the future effective microbicides will include an array of products delivered in several formulations, such as gels, creams, suppositories, films, sponges and vaginal rings (akin to the array of fertility control options) and/or meet multiple sexual reproductive health needs enabling users to choose what suits them best at a particular time in their life course.
Their development is critical as it addresses an important gap in HIV prevention options for vulnerable groups such as young women at high risk of acquiring HIV infection sexually but unable to implement current HIV prevention strategies, such as abstinence, use female condoms, or negotiate safer sex practices such as monogamy, medical male circumcision or use of male condoms with their partner. Microbicides, when used rectally, also have the potential to expand the HIV prevention options available to men who have sex with men (MSM) and women who practice anal sex and although less advanced than topical vaginal products, research is already underway to meet this need.
HISTORY OF MICROBICIDE EFFICACY TRIALS
Early Microbicides: Surfactants, Blockers, and Buffers
Notwithstanding their importance, efforts to find an effective microbicide has been hampered by limited investments in the development of candidate products for clinical testing; an unchartered product development pathway; formulation and delivery method challenges; methodological, ethical, and design challenges; limited understanding of mechanism of HIV acquisition in the female genital tract; insufficient advocacy efforts; and uncertainty about user acceptability and demand.
Over the past 20 years of microbicide development, 11 advanced clinical trials of 6 candidate products (some tested as multiple doses and formulations) have been completed. The first microbicides to enter phase III trials were surfactants that act by inactivating pathogens, including HIV, in the lumen of the vagina. The best-known product in this category is nonoxynol-9 (Advantage 24; Columbia Research Laboratories, Rockville Center, NY), an FDA licensed vaginal contraceptive and widely distributed impregnated in condoms for HIV prevention. In its definitive trial among sex workers in gel formulation, it was shown to increase the risk of HIV infection among women who used the product more frequently.1 Several years later, another surfactant, SAVVY (C31G; Cellegy Pharmaceuticals, Inc., Huntingdon Valley, PA), tested in 2 separate studies in Ghana and Nigeria, was shown to be safe but had no significant effect on HIV prevention, primarily as a result of lower-than-expected HIV incidence rates in the target population2,3 (Fig. 1).
Studies of the polyanionic sulfated polymers, which have a more limited spectrum of activity, followed. These included cellulose sulfate (Ushercell; Polydex Pharmaceuticals, Nassau, Bahamas), Carraguard (product number PDR98-15; FMC, Philadelphia, PA), and PRO2000. The cellulose sulfate trial conducted in several African countries and a site in India was stopped early because of safety concerns. Cellulose sulfate did not prevent HIV infection and may have increased the risk of HIV acquisition.4 Carraguard, which was tested among 6202 South African women, was also shown to have no effect on HIV.5 In 2009, the HIV Prevention Trials Network 035 study showed a 33% lower HIV incidence in women using 0.5% PRO2000 compared with placebo, although the results were not statistically significant.6 The initial optimism was dampened by subsequent findings from the much larger MDP 301 trial,7 comparing 0.5% PRO2000 with placebo groups in 6268 women with 253 HIV infections, which showed no protective effect against HIV infection (risk ratio: 1.05).
BufferGel (ReProtect LLC, Balitmore, MD), designed to maintain a healthy vaginal milieu, was tested alongside 0.5% PRO2000 in the HIV Prevention Trials Network 035 trial but had no effect on HIV acquisition.6 Given the disappointing clinical trial results with surfactants, blockers, and buffering agents, these candidates developed by small start-up entities have essentially disappeared from the HIV prevention product development pipeline.
How Antiretroviral-Based Topical Products and Formulations Have Instilled New Hope in Microbicide Development
Currently, the clinical development pathway of microbicides is dominated by antiretroviral (ARV) agents. These agents, originally developed and used successfully as HIV therapeutics, are being tested in clinical trials as potential topical and oral prophylactic agents because their mechanism of action suggests that when used, they may also be able to prevent HIV infection (supported by proof-of-concept in preventing vertical transmission). The topical formulations of the ARV agents/microbicides act locally in the reproductive tract mucosa, have a long half-life, and generally have specific activity against HIV only, and therefore the potential for unwanted side effects is limited, particularly where systemic absorption is low—all desired characteristics of a prophylactic agent to be used by HIV-uninfected, healthy individuals.
Most advanced in this class of product development is tenofovir gel. Developed by Gilead Sciences, Inc. (Foster City, CA), it was the first ARV-based microbicide to enter clinical testing and provided proof-of-concept that an ARV agent can prevent sexual transmission of HIV in women.8 In 2010, the CAPRISA 004 trial showed that tenofovir gel, applied before and after sex, reduced HIV incidence by 39% (95% confidence interval: 6 to 60), providing hope that a safe and effective microbicide would soon be available.
Following the results of the CAPRISA 004 study, and the fact that the VOICE (Vaginal and Oral Interventions to Control the Epidemic)9 trial, that included daily use of tenofovir gel, was already in the field, there was much optimism that the first microbicide would soon be licensed and made available. Modeling the modest effects of CAPRISA 004 demonstrated that, in South Africa alone, tenofovir gel could avert 1.3 million new HIV infections and more than 800,000 deaths over the next 2 decades.10 Disappointingly, none of the 3 products—tenofovir gel, oral tenofovir disoproxil fumarate, or oral co-formulated emtricitabine and tenofovir (Truvada)—tested in the VOICE trial were effective in preventing HIV.11 The effectiveness of oral tenofovir and Truvada was less than 0% and the tenofovir gel was 14.7% (95% confidence interval: −21 to 40)11 The reason for the lack of protection against HIV in the VOICE trial is partially explained by the low levels of adherence estimated, based on detectable drug levels, to be 23%, 28%, and 29% in the tenofovir gel, oral tenofovir, and oral Truvada arms, respectively.11
The next steps for tenofovir gel, thusfar the only product in the most advanced stage of product development, is dependent on the FACTS 001 trial12 currently in the field across multiple sites in South Africa and testing the effectiveness of tenofovir gel using the same coitally linked dosing regimen used in the CAPRISA 004 trial. It could provide the data needed for regulatory approval of tenofovir gel. A rectal safety study of 1% tenofovir gel has been initiated in young MSM in the United States and Puerto Rico (Project gel)13 and a range of pharmacodynamics and pharmacokinetic (PK) studies of various dosing strategies using tenofovir,14 a reformulated tenofovir gel for rectal use,15 and a safety study of using 1% tenofovir gel in pregnant and lactating women16 are ongoing.
Next Steps in Product Development
New ARV Agents and Novel Delivery Mechanisms
Consistent with advances in AIDS treatment regimens that combine ARVs from different classes, microbicides based on a combination of products are seen as offering a potential for synergy, reduced drug resistance, and multiple targeting.
Long-acting, slow release, monthly vaginal rings and/or 2 monthly injectable formulations impregnated with novel ARV agents are currently being assessed as potential microbicides and may have the added advantage of improving adherence as they are less dependent on user compliance linked with oral or gel formulations. The product in the most advanced stage of development is dapivirine (TMC-120), a nonnucleoside reverse transcriptase inhibitor. Two large phase III dapivirine vaginal ring studies were initiated independently in 2012 by the International Partnership for Microbicides and the Microbicides Trial Network and will enroll more than 5000 women from 6 African countries. Preclinical studies of the vaginal ring containing the tenofovir disoproxil fumarate prodrug has been shown to provide complete protection in pigtail macaques after repeat simian human immunodeficiency virus (SHIV) challenge for more than 16 weeks and may soon enter clinical trials.17 A safety and PK study of the combination of dapivirine and maraviroc in a vaginal ring is also underway in the United States.18 A long-acting parenteral formulation of GSK744, an analog of the investigational new drug, dolutegravir, has been shown to provide complete protection in macaques following repeated intrarectal challenge with simian human immunodeficiency virus. GSK744 could become a next-generation pre-exposure prophylaxis (PrEP)/microbicide agent suitable for monthly to quarterly injections.19
The Importance of the Biobehavioral Nexus
Recent developments in the PrEP and microbicide fields have clearly shown that a successful microbicide product will require more than just an effective anti-HIV product. Despite extensive animal data, a clinical trial,8 and PK evidence20 showing that tenofovir gel should be highly protective against HIV, the VOICE and FEMPrEP trials produced contradictory results11,21 to CAPRISA 004 and other PrEP trials.
Data from the CAPRISA 004 trial8 demonstrate how adherence can impact on effectiveness. In the CAPRISA 004 trial, HIV incidence among high adherers (gel adherence > 80%) was 54% lower (P = 0.025) in the tenofovir gel arm compared with 38% in intermediate adherers (gel adherence 50%–80%) and 28% in low adherers (gel adherence < 50%).8 More recent modeling estimates, using adherence data from CAPRISA 004, have demonstrated a 90% protection by tenofovir gel in high adherers.22 A much better understanding of what motivates people to use a product as prescribed and how to objectively measure compliance is needed.
Objectively measuring adherence in microbicide trials has been challenging and is the Achilles heel of microbicide trials, even before the development of ARV-based products. Many of the early microbicide trials relied exclusively on self-reported data, which has several limitations.23 Dye staining of applicators has been shown to be a reliable and objective method to test vaginal insertion in clinical microbicide trials,24 but differences in composition of plastics, dyes, and product formulations may impact the accuracy and utility of this method.25 Other novel technologies, such as UV light assessment of vaginal applicators26 and wireless technologies, for example, Wisebag,27 are also being considered for microbicide trials to monitor adherence. Trials of microbicides containing ARV drugs have made it possible to more objectively assess whether the product has been used or not, albeit at study completion. Results of recent trials that have measured levels of drug in the vaginal tract or in the plasma have provided us with a better understanding on the level of drug needed for protection28 or why some products have not worked.11,21 The limitation of this method, however, is that we are still unable to measure adherence in the placebo group. The recent approval by the US FDA of Truvada for HIV prevention29 and anticipated wider access, including provision as standard of care for HIV prevention in microbicide trials, will limit the measurement of drug levels as an indicator of compliance.
The inclusion of an easily detectable marker in the product and the placebo to obtain objective measures of adherence in clinical trials is likely to be required. Exploratory studies have shown that the alcohol and ketone metabolites from vaginal products and condoms that were tagged with esters could be detected using a breath test, suggesting that a breath test for microbicide gel use is physiologically and technically possible.30,31 The limitation of this approach, however, is that the product being tested will not be the same as the one intended to be marketed, which will result in regulatory hurdles.
Better assessments of exposure to HIV and the ability to measure this will be needed. It is not sufficient to assess exposure to semen as current assays such as Prostate Specific Antigen or Y-chromosome set out to do; it is also essential to develop markers of HIV exposure. New HIV polymerase chain reaction assays that are able to measure low levels of virus in the vagina may make it possible to measure HIV exposure in the vagina. There is a need for a better correlate of risk or protection other than HIV infection in the microbicide field that can be assessed in real-time analogous to the monitoring of viral load and CD4 counts for therapeutic success.
Although strategies for enhancing adherence through novel delivery mechanisms and ARV agents together with better ways to support and measure adherence is critical, these efforts need to be complemented with a better understanding of HIV acquisition vaginally. The establishment of, for example, the role of genital inflammation in HIV acquisition could require a different product development pathway than that used to develop highly active ARV therapy for patients with AIDS. A cellular and immunological analysis of how other biological factors blunt the effectiveness of tenofovir gel will be critically important for new product development and drug delivery systems. Empiric studies of breakthrough infections following prophylactic use of ARV-based microbicides that monitor disease progression, viral evolution, and resistance patterns are also urgently needed for evidence-based decisions on prophylactic use of ARVs.
As PrEP29 and Treatment as Prevention32 become standard of care, the conduct of placebo-controlled microbicide trials may become a challenge and underscores the importance of finding novel markers of safety and efficacy other than HIV infection. The need for a correlate of protection analogous to CD4+ T-cell count and viral load monitoring in treatment is urgently needed, particularly as newer and novel drugs enter clinical testing and placebo-controlled trials become more limited.
Another important and emerging field includes products that are capable of meeting multiple sexual reproductive health needs of women, such as HIV risk reduction, fertility control, and treatment of other sexually transmitted infections. Examples of such products, also known as multipurpose prevention technologies, are CONRAD's A10-114 study that combines tenofovir with contraceptives33 and a reformulated tenofovir gel containing sperm-immobilizing agents that is being tested with the SILCS diaphragm. Although the development of microbicide candidates with multiple mechanisms of action or dual-purpose products is already being tested in early clinical trials, no products have advanced to clinical effectiveness trials. Notwithstanding uncertain regulatory pathways, and logistical and intellectual property challenges of combining biophysically diverse products, effectiveness of each component needs to be demonstrated in separate trials before they can be co-formulated as a combination product. The uncertainty relating to the role of hormonal contraceptives on HIV acquisition is an additional complexity for combining HIV prevention products with a fertility control product.
Options to Reduce HIV Infection in Adolescent Women
Women in the 15- to 20-year age group living in sub-Saharan Africa have a 3- to 6-fold higher rate of HIV infection and acquire HIV infection 5 to 7 years earlier than their male counterparts. This age–sex difference in HIV acquisition patterns between men and women continues to fuel the epidemic in this region through sustaining high HIV incidence rates.34 A complex interplay of biology, gender–power disparities, and social, political, and economic factors contribute to the excess vulnerability of young women to HIV infection compared with men.35,36 Despite their greater vulnerability, young women particularly in the 15- to 17-year-old age group currently have limited HIV prevention options available to them and would be an ideal target population for the introduction of an effective microbicide for individual and population level benefit. However, none of the microbicide studies to date have been conducted in this important age group, making the evaluation of microbicides in this group a high priority. Notably no topical or oral PrEP trials have demonstrated safety concerns, and large numbers of HIV-infected adolescents are on ARV treatment. The first trial of daily tenofovir gel use among 16- and 17-year-olds (FACTS 002) is planned and will provide important safety and effectiveness data for the use of microbicides in this group, paving the way for adolescent girls to have access to a licensed microbicide.
Rectal Use Studies and Product Formulation
Rectal microbicide development has lagged behind the development of microbicides for vaginal use but are no less important. The mucosal surfaces in the rectum are vulnerable to physical damage during sex and potentially increase the risk of HIV infection. Several surveys indicate that heterosexual anal intercourse is far more common than generally acknowledged37–40 and women who engage in anal intercourse may be less likely to use condoms and more likely to engage in risky behaviors.39
Although vaginal microbicide products may also be beneficial if used rectally, the distinct differences between the vagina and rectum may mean that separate products will be needed specifically for vaginal or rectal use. With some candidate microbicide products, formulations specifically for vaginal or rectal are already available, such as a low osmolality tenofovir gel that has been specifically formulated for rectal use. Clinical trials evaluating the safety and effectiveness of rectal microbicides are under way in MSM populations13,15 and a number of pharmacodynamics/PK studies are planned using 3 rectally applied tenofovir gel formulations.
Blueprint for Product Development Pathway—Licensure, Policy Formulation, and Programmatic Scale-up and Access to Microbicides
In anticipation of licensure of tenofovir gel and to prepare for the implementation of tenofovir gel into the public health service, an open-label implementation study (CAPRISA 008) is being undertaken as part of posttrial access of tenofovir gel for CAPRISA 004 trial participants. The CAPRISA 008 trial will assess the feasibility of integrating tenofovir gel provision into family planning services as one mechanism of rapidly translating policy to practice pending licensure of tenofovir gel.
Draft normative guidance has already been developed by World Health Organization/Joint United Nations Programme on HIV/AIDS (UNAIDS), and the South African government, who owns the royalty-free license for production of tenofovir gel, has established a public–private partnership with CIPLA-MEDPRO for manufacturing of product. The US Food and Drug Administration have also issued a draft guidance document that provides recommendations for the development of vaginal microbicides for the prevention of HIV infection. Specifically, this guidance addresses the overall development program and clinical trial designs to support the development of vaginal microbicide drug products.41
Investments in Microbicide Development Still Largely in Public Sector
Although funding of microbicide research has significantly increased over the years, it still lags far behind research and development funding for other HIV prevention technologies, such as HIV vaccines. In 2011, the total global investment for microbicide research and development was US$186 million. This is compared with funding of US$845 million for HIV vaccine–related research and development in the same year: 4.5 times more than microbicides.42 A successful microbicide product will require extensive and sustained investment in research and development. The product pipeline in general needs a large number of products in phase I because of the high attrition rate before a product warrants assessment for efficacy against HIV infection.
Anecdotal concerns about increased pressure for the emergence of resistant strains of HIV in breakthrough infections in individuals using oral or topical ARVs prophylactically have remained unfounded but attention and investments need to continue for ongoing monitoring in both the therapeutic and the prophylactic use contexts because the life span for both indications could be limited as a result of increases in circulating drug-resistant strains. A pipeline of new products will be necessary to address the declining utility of previous microbicides because of drug resistance. At present, the dearth of new classes of products in the phase I pipeline is a source of major concern.
Funding for microbicide research and development may become even scarcer in the future if limited financial resources are redirected to implementation of PrEP, other HIV prevention strategies, HIV treatment, or other diseases. The widespread availability and accessibility of PrEP and treatment as prevention may take several years to realize as the targeting and implementation of this strategy in different epidemic contexts needs to be unraveled. Even when PrEP is widely available, individuals will need access to a range of methods to protect themselves from HIV to ensure the majority of sex acts are protected. The development of other HIV prevention technologies like microbicides therefore remains important particularly for young women in sub-Saharan Africa who have limited negotiating power to implement the current and new HIV prevention options that are dependent on use by their sexual partner.
ARV-based microbicides provide real potential to influence the course of the HIV epidemic because they fill an important gap for women-initiated anti-HIV–specific prevention methods and could potentially offer an alternative HIV prevention option for MSM. Thusfar, only coitally linked use of tenofovir gel has demonstrated moderate effectiveness in preventing HIV infection, and the findings of a confirmatory trial, FACTS 001, are eagerly awaited as an important next step toward licensure of tenofovir gel. Studies of new antiviral agents, novel delivery mechanisms, combination/multipurpose products, and the role of biological factors in blunting efficacy of ARV agents that address challenges of adherence and enhance the effectiveness of tenofovir gel are already underway to further enhance sexual and reproductive health needs of men and women and efforts to prevent HIV infection.
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