1. Adherence to topical microbicides and oral pre- exposure prophylactic HIV preventative treatments: what are the barriers and how are they addressed? Felix Muchomba, Robin Gearing, Nabila El-Bassel Columbia University, New York, NY, USA Methods Oral PrEP and topical microbicide randomized controlled trials were searched using Medline, PsycINFO, Cochrane, and conference abstracts databases, and HIV prevention trials websites. Searches were limited to English articles published between January 1, 1987 and January 1, 2012. Studies that did not report treatment efficacy/effectiveness in preventing HIV infection were excluded. A review of the articles by the authors resulted in the inclusion of 19 out of 591 studies retrieved. Results Majority (n = 13) of the studies were microbicide trials (Table 1). Over one third (n = 7) of the studies measured adherence solely through self-report and only 2 studies employed biomarkers. Oral PrEP trials reported higher adherence rates (87%) than microbicide trials (79%) on average. TABLE 1. Treatment and adherence characteristics of microbicide and oral pre-exposure prophylaxis randomized controlled trials Introduction The HIV prevention field has made progress in the use of oral pre-exposure prophylaxis (PrEP) and topical microbicides. 1 For preventive treatments to be effective, adherence to intervention protocols is required. 2 However, adherence to oral PrEP and microbicides has not been sufficiently studied and recommendations on promoting adherence are needed. This systematic review sought to identify: 1) how adherence was measured; 2) barriers to adherence; and 3) strategies used to promote adherence to these HIV preventative treatments. Conclusions HIV preventative treatments need to incorporate multipronged adherence strategies focusing not only on the biological and individual adherence strategies, but incorporating partner, agency and community level strategies. Lacking a gold standard adherence measure, a variety of measures of adherence are recommended. Trials also need to assess adherence among injection drug users and other populations who face social and lifestyle challenges. Literature cited 1. Padian NS, Buve A, Balkus J, Serwadda D, Cates W,Jr. Biomedical interventions to prevent HIV infection: Evidence, challenges, and way forward. Lancet. 2008;372(9638):585-599. 2. Karim SSA, Kashuba ADM, Werner L, Karim QA. Drug concentrations after topical and oral antiretroviral pre-exposure prophylaxis: Implications for HIV prevention in women. Lancet. 2011;378(9787):279-281. 3. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010;329(5996):1168-1174. 4. Abdool Karim SS, Richardson BA, Ramjee G, et al. Safety and effectiveness of BufferGel and 0.5% PRO2000 gel for the prevention of HIV infection in women. AIDS. 2011;25(7):957. 5. Feldblum PJ, Adeiga A, Bakare R, et al. SAVVY vaginal gel (C31G) for prevention of HIV infection: A randomized controlled trial in nigeria. PLoS One. 2008;3(1):e1474. 6. Halpern V, Ogunsola F, Obunge O, et al. Effectiveness of cellulose sulfate vaginal gel for the prevention of HIV infection: Results of a phase III trial in nigeria. PLoS One. 2008;3(11):e3784. 7. McCormack S, Ramjee G, Kamali A, et al. PRO2000 vaginal gel for prevention of HIV-1 infection (microbicides development programme 301): A phase 3, randomised, double-blind, parallel-group trial. The Lancet. 2010;376(9749):1329-1337. 8. Microbicide Trials Network. Microbicide trials network statement on decision to discontinue use of tenofovir gel in VOICE, a major HIV prevention study in women. Microbicide Trials Network Web site. http://www.mtnstopshiv.org/node/3909. Published Nov 25, 2011. Updated 2011. Accessed Dec 17, 2011.http://www.mtnstopshiv.org/node/3909 9. Peterson L, Nanda K, Opoku BK, et al. SAVVY®(C31G) gel for prevention of HIV infection in women: A phase 3, double-blind, randomized, placebo-controlled trial in ghana. PLoS One. 2007;2(12):e1312. 10. Richardson BA, Lavreys L, Martin Jr HL, et al. Evaluation of a low-dose nonoxynol-9 gel for the prevention of sexually transmitted diseases: A randomized clinical trial. Sex Transm Dis. 2001;28(7):394. 11. Roddy RE, Zekeng L, Ryan KA, Tamoufé U, Tweedy KG. Effect of nonoxynol-9 gel on urogenital gonorrhea and chlamydial infection. JAMA: The Journal of the American Medical Association. 2002;287(9):1117-1122. 12. Skoler-Karpoff S, Ramjee G, Ahmed K, et al. Efficacy of carraguard for prevention of HIV infection in women in south africa: A randomised, double-blind, placebo-controlled trial. The Lancet. 2008;372(9654):1977-1987. 13. Van Damme L, Ramjee G, Alary M, et al. Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: A randomised controlled trial. The Lancet. 2002;360(9338):971-977. 14. Van Damme L, Govinden R, Mirembe FM, et al. Lack of effectiveness of cellulose sulfate gel for the prevention of vaginal HIV transmission. N Engl J Med. 2008;359(5):463-472. 15. Kreiss J, Ngugi E, Holmes K, et al. Efficacy of nonoxynol 9 contraceptive sponge use in preventing heterosexual acquisition of HIV in nairobi prostitutes. JAMA: The Journal of the American Medical Association. 1992;268(4):477-482. 16. Roddy RE, Zekeng L, Ryan KA, Tamoufe U, Weir SS, Wong EL. A controlled trial of nonoxynol 9 film to reduce male-to-female transmission of sexually transmitted diseases. N Engl J Med. 1998;339(8):504-510. 17. Baeten J, Celum C. Antiretroviral pre-exposure prophylaxis for HIV-1 prevention among heterosexual african men and women: The partners PrEP study. In: the 6th IAS conference on HIV pathogenesis, treatment and prevention; July 17–20, 2011; Rome, Italy. 18. Family Health International. FEM-PrEP project. FHI 360 Web site. http://www.fhi360.org/en/Research/Projects/FEM-PrEP.htm. Published November 25, 2011. Updated 2011. Accessed December 17, 2011.http://www.fhi360.org/en/Research/Projects/FEM-PrEP.htm 19. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587-2599. 20. Peterson L, Taylor D, Roddy R, et al. Tenofovir disoproxil fumarate for prevention of HIV infection in women: A phase 2, double-blind, randomized, placebo-controlled trial. PLoS Hub for Clinical Trials. 2007;2(5):e27. 21. Thigpen M, Kebaabetswe P, Smith D, et al. Daily oral antiretroviral use for the prevention of HIV infection in heterosexually active young adults in botswana: Results from the TDF2 study. In: the 6th IAS conference on HIV pathogenesis, treatment and prevention; July 17–20, 2011; Rome, Italy. Further Information: Felix Muchomba, MPH, Ph.D. Student. Columbia University School of Social Work. (212) 851-2431. fmm2116@columbia.edu AuthorsPreventive Treatment a Study Findings b Adherence Measurement c Adherence to Treatment Abdool Karim et al. (2010) 3 Gel: TDFSig 1. Self-report 2. Applicator count 72% - Abdool Karim et al. (2011) 4 Gel: BufferGel Gel: PRO2000 Trend Non-sig 1. Self-report81% Feldblum et al. (2008) 5 Gel: SAVVYNon-sig1. Self-report78% Halpern et al. (2008) 6 Gel: Cellulose SulfateTrend1. Self-report81% McCormack et al. (2010) 7 Gel: PRO2000 2% Gel: PRO2000 0.5% Non-sig 1. Self-report 2. Coital diaries 3. Applicator count 4. In-depth interview 89% - MTN (2011) 8 Gel: TDF Oral PrEP: TDF Oral PrEP: FTC & TDF Non-sig NR 1. Applicator count 2. Pill count 3. Self-report 4. In-depth interview 5. Focus group ---------- Peterson et al. (2007) 9 Gel: SAVVYTrend1. Self-report75% Richardson et al. (2001) 10 Gel: Nonoxynol-9Non-sig1. Self-report75% Roddy et al. (2002) 11 Gel: Nonoxynol-9Non-sig1. Self-report76% Skoler-Karpoff et al. (2008) 12 Gel: CarraguardNon-sig 1. Self-report 2. Applicator count 3. Staining assay 96% - 41% Van Damme et al. (2002) 13 Gel: Nonoxynol-9Non-sig1. Self-report79% Van Damme et al. (2008) 14 Gel: Cellulose SulfateNon-sig1. In-depth interview87% Kreiss et al. (1992) 15 Sponge: Nonoxynol-9Non-sig1. Coital diary81% Roddy et al. (1998) 16 Film: Nonoxynol-9Non-sig1. Self-report87% Baeten et al. (2011) 17 Oral PrEP: TDF, Oral PrEP: FTC & TDF Sig 1. Pill count 2. Random pill count 3. MEMS 97% - FHI (2011) 18 Oral PrEP: FTC & TDFNon-sig 1. Self-report 2. Pill count 3. Blood level test 4. In-depth interview 95% - Grant et al. (2010) 19 Oral PrEP: FTC & TDFSig 1. Prescription refills 2. Self-report 3. Pill count 4. Blood level test 91% 95% 86% - Peterson et al. (2007) 20 Oral PrEP: TDFNon-sig1. Pill count69% Thigpen et al. (2011) 21 Oral PrEP: FTC & TDFSig1. Pill count84% a TDF = Tenofovir Disoproxil Fumarate; FTC & TDF = Emtricitabine & Tenofovir Disoproxil Fumarate combination b Sig = protective, statistically significant (p ≤ 0.05); Trend = protective, marginally statistically significant (0.05 0.1); NR = not reported c MEMS = Medication Event Monitoring System (Aprex, Union City, CA, USA) Frequently reported barriers to microbicide adherence were decreased motivation over time, sex with primary (non-commercial/non-casual) partners, and insufficient supply (Fig. 1). Oral PrEP adherence barriers were older age and medication side effects. Most trials (n = 12) did not report whether participants engaged in drug use or not. FIGURE 1. Frequency of adherence barriers in microbicide and oral pre-exposure prophylaxis randomized controlled trials Strategies to promote adherence predominantly focused on the individual level (Fig. 2). FIGURE 2. Frequency of adherence promotion strategies in microbicide and oral pre-exposure prophylaxis randomized controlled trials