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Microbicides for HIV Prevention Pamina M. Gorbach, Epidemiology & Infectious Diseases UCLA MTN, ATN What is a microbicide? ….a product applied inside the vagina or rectum that are intended to protect against HIV though sex. Microbicides that incorporate antiretroviral (ARV) drugs are showing particular promise. Microbicides First generation: Gels & creams for rectum or vagina Inserted daily or before and after sex Current generation: Vaginal rings: Inserted and remain in place for > 1 month Pills: PrEP (Pre-exposure prophylaxis) Future: Injectables, film? What Do Participants Need from HIV Prevention Methods? To reduce risk of HIV and other STIs To prevent pregnancy and not prevent pregnancy! To be safe and non-irritating To be inexpensive and available over the counter To be possibly used without partner’s cooperation or even awareness Photo courtesy of http://www.mtnstopshiv.org/ If microbicides work… 1. Only taken if you KNOW you are HIV negative. So regular HIV testing is necessary. 2. May be available by prescription only. So access to a qualified health care provider is necessary. 3. Only the dosing used in trials is known to work. For now, must be applied daily or before and after sex. Why would HIV+ people want microbicides? Reduce risk of: Infection with multiple strains of HIV Infection with other STIs, yeast or bladder infections Women can get pregnant while still protecting their partner from HIV. Findings from Recent Microbicide Trials: Acceptabilty Product Acceptability (MTN-006) Only 3 of 12 participants in the tenofovir arm liked the gel very much. 5 of 12 felt discomfort Nevertheless, 9 of 12 indicated they were very likely to use the gel in the future. This could mean participants are concerned enough about HIV to tolerate discomfort & unpleasant product characteristics. Gel vs Pill MTN 001: Phase 2 Adherence and Pharmacokinetics Study of Oral and Vaginal Preparations of Tenofovir Enrolled144 sexually active HIV-negative women at sites in Uganda, South Africa and the United States for 21-weeks. Each follow each regimen (pill & gel) for six weeks, with one week between when no study product is used. 72 women enrolled at the two U.S. sites Oral/Vaginal acceptability (MTN 001) Factors that facilitated use: Product properties increased lubrication improved sexual intercourse due to (gel) African sites Reduced vaginal dryness (gel) Discreetness of pill taking (especially relative to gel insertion) Cultural and personal familiarity with pills - US sites Ease of use (tablet) Products bestowed unanticipated benefits: cleansing, menstrual cramps stopped Product properties disliked Gel: Consistency and leakiness; External irritation; Vaginal tightness; Insertion and disposal of product applicators Tablets: Side-effects (nausea, hunger, fatigue); Pill size Qualitative Findings: MTN 001 End of Study In-depth Interviews Product preferences and barriers to use differed among women; clear interest in both products. Gel perceived to improve sex by many women at Ugandan and South African sites, suggesting broader perceived sexual health benefits: “Since I started using it, the love with my husband increased…because he thinks I love him so much yet it’s the gel.” –Ugandan participant. Minor side effects numerous, but subsided swiftly. Product Acceptability in MTN-001 Vaginal Gel Oral Tablets Dual All sites† 83 93 82 African sites 100 100 99 United States sites 64 87 65 Future product use likely if proven effective † p=0.002 (conditional logistic regression, controlling for period and sequence) Geographic differences in reporting future willingness to use products. Participants less comfortable with interviews? Did this affect their responses/behavior? Lessons Learned: Acceptability Cultural differences need further study Puerto Rico vs. U.S. (MTN-004/ATN-062): better acceptability in Puerto Rico Africa vs. U.S. (MTN-001) – More gel preference in Africa; US women prefer pills The risk environment may be as important as gel characteristics Women may “forgive” characteristics if a product is effective or they perceive themselves at high risk (segue to next slide) Findings from Recent Microbicide Trials: Effectiveness – Do they work? Outcomes of first trials – not good Signs of efficacy Safe Trend toward harm No efficacy Carraguard® BufferGel® PRO 2000 0.5% Nonoxynol-9 Savvy Cellulose sulphate VOICE 2.0 (MTN 003) 5,000 Women Tablet (3,000) Truvada (1,000) Tenofovir (1,000) Vaginal Gel (2,000) Placebo Tablet (1,000) Tenofovir Gel (1,000) Placebo Gel (1,000) Marrazzo, J. et al. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir, oral tenofovir/emtricitabine, or vaginal tenofovir gel in the VOICE study (MTN 003). 20th Conference on Retroviruses and Opportunistic Infections. Atlanta. March 3–6, 2013. Abstract #26LB. Marrazzo, J. et al. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir, oral tenofovir/emtricitabine, or vaginal tenofovir Conclusions: VOICE Incidence of HIV substantially higher than anticipated No study drug significantly reduced risk of HIV Adherence to study products was low, especially among younger, unmarried women Results consistent with FEM-PrEP Consider PrEP agents/delivery systems that are long acting and require minimal daily adherence Understanding HIV risk perception and biomedical, social and cultural determinants of adherence in this high-risk population urgently needed Marrazzo, J. et al. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir, oral tenofovir/emtricitabine, or vaginal tenofovir Adherence in FemPrEP ADAPTED FROM Van Damme L, CorneliA, Ahmed K, Agot K, Lombaard J, Kapiga S, et al. The FEM-PrEP Trial of Emtricitabine/ Tenofovir Disoproxil Fumarate (Truvada) among African Women. In: Conference on Retroviruses and Opportunistic Infections (CROI), . Seattle; 2012. Rectal Microbicides Anal Intercourse: Lifetime (ever) NSFG US General Population Chandra A, Mosher WD et al. Sexual Behavior, Sexual Attraction, and Sexual Identity in the United States: Data From the 2006–2008 National Survey of Family Growth. National Health Statistics Reports n Number 36 n March 3, 2011 International: Women Reporting Ever AI Brazil: Silveira MF, 2002; Caetano ME, 2010 South Africa – Lane, Pettior et al 2006 Peru: Caceres C et al. 1997 Kenya: Schwandt M et al. 2006 China (Anhui) : Lui H et al 1998 Nigeria: Bamidele et al 2009 (combined gender) MSM Throughout the World Need HIV Prevention Lubricants are Popular for AI Peri-sexual behaviors: Rectal Douching Common Rectal and Vaginal Mucosa Are Very Different Histology Immunology Microbiology Differential susceptibility to candidate microbicides So Where Now? Issues with Microbicides Many provide only partial protection : How will people interpret this? How will consistent use be maintained & supported? How could different medication schedules (daily, weekly, activity-based) be introduced? How often & who will track: Adherence/consistent use Drug resistance New HIV infections by users (seroconversion) Other Issues Who will get the products? Should adolescents? Pregnant women? Transgender? For how long should/could they be used? Who Will will pay for them? there be an increase in risk behavior? What is drug resistance? HIV makes thousands of copies of itself daily. Every time HIV copies itself, errors can occur, like typing errors on a page. These are mutations—changes that can make the virus weaker or stronger. A mutation that makes HIV able to resist an ARV drug = drug-resistant HIV. Drug resistance from microbicides? Most likely when using only one drug or one type of ARV. Can become HIV+ while using microbicide. Continued use (you don’t know you’re HIV+) may lead to resistance. Options for treatment may be more limited—you might pass on resistant virus. There are unanswered questions at this point. In a nutshell: Acceptability The Positive result from one topical gel trial (CAPRISA 004) Rectal Microbicides looking promising The Bad News Some participants may not satisfied with current product characteristics and dosing Adherence vastly under-reported & products not used in trails enough to detect effectiveness The Good News “Ugly” news Not everyone (dis)likes the same things, and there will need to be product choices Creating Desire for Microbicides To enjoy (the gel) first you need to use it Who is doing the research? Research entity Examples Funding sources Not-for-profit health groups and academic institutions MTN, Governments (South CONRAD, Africa DST, US NIH, UK FHI, CAPRISA DFID), philanthropic foundations Public-private partnerships IPM European/US/Canadian governments, philanthropic foundations, UNFPA, World Bank Smaller pharmaceutical companies Endo StarPharma Venture capital, some government grants Summary: State of the Science Vaginal gel---effective in preventing HIV in women if used before and after sex (CAP 004) Rectal gel---shown to prevent HIV in Phase I trial in men and women Cultural differences: African women may prefer a vaginal gel U.S. women may prefer a pill Bottom Line: People may have choices!