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The Bangkok Tenofovir Study

Bangkok Metropolitan Administration. Thailand Ministry of Public Health. The Bangkok Tenofovir Study. An HIV pre-exposure prophylaxis trial in Thailand: participant adherence and study results .

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The Bangkok Tenofovir Study

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  1. Bangkok Metropolitan Administration Thailand Ministry of Public Health The Bangkok Tenofovir Study An HIV pre-exposure prophylaxis trial in Thailand: participant adherence and study results A collaborative project involving: The Bangkok Metropolitan Administration, the US Centers for Disease Control and Prevention, and the Thailand Ministry of Public Health • National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention • Division of HIV/AIDS Prevention

  2. Background • 2.5 million people infected with HIV in 2011 • One in ten of these new HIV infections caused by injecting drug use • Thailand, HIV spread rapidly among PWID in late 1980s and prevalence remains high: 30% to 50% Completed PrEP trials showing efficacy 1Grant RM, et al. Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men. NEJM 2010;363: 2587-99. 2Thigpen MC, et al. Antiretroviral Preexposure Prophylaxis for Heterosexual HIV Transmission in Botswana. N Engl J Med 2012;367:423-34. 3Baeten JM, et al. Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women. N Engl J Med 2012;367:399-410.

  3. Objectives and Design Primary Objectives • Determine if tenofovirreduces risk of HIV among PWID • Determine if tenofovir safe among HIV-uninfected PWID Design • Phase 3, randomized, double-blind, placebo-controlled trial • HIV-uninfected PWID • Randomized to receive tenofovir or placebo • BMA and MOPH ERC and CDC IRB approved protocol, consent, and other trial materials • DSMB annual safety reviews and interim efficacy analysis

  4. Services offered to volunteers • Individualized risk reduction education and counseling • Methadone maintenance • Social services and primary medical care with referrals • Needles not provided: illegal, available in pharmacies without prescription

  5. Community Involvement • Focus Group Discussions among PWID • Assess interest, knowledge, concerns about PrEP • Outreach to CBOs and NGOs working with PWID and communities at risk of HIV • Community Relations Committee • Meet every 2 months with investigators • PWID from each of 17 BMA clinics

  6. Bangkok Metropolitan Administration Drug Treatment Clinics TUC Lab BMA Lab Bangkok Thailand

  7. Activities

  8. Participant Flow 4094 Screened 1492 (36%) Ineligible 662 Abnormal lab results 447 HIV-positive 233 Hepatitis B surface antigen 101 Medical conditions 49 Other reasons 189 (5%) Did not return to enroll 2413 (59%) Randomized 1209 assigned to Placebo Included in ITT 1204 assigned to Tenofovir Included in ITT 2 HIV infected at enrollment 1207 Included in mITT analysis 4823 person-years 1204 Included in mITT analysis 4843 person-years

  9. Baseline Characteristics

  10. Baseline Characteristics

  11. Baseline Characteristics

  12. Retention

  13. Efficacy

  14. Modified Intention-To-Treat AnalysisKaplan-Meier estimates of time to HIV infection mITT 48.9% (9.6 – 72.2); P=0.01

  15. Modified Intention-To-Treat AnalysisKaplan-Meier estimates of time to HIV infection mITT 48.9% (9.6 – 72.2); P=0.01

  16. Pre-specified adherence-defined analysis • Adherent defined: DOT participant taking study drug >71% of days with no more than 2 consecutive day off study drug • Efficacy = 56% (-25.1 - 84.5; p=0.12) • Limiting analysis to participants with detectable tenofovir, efficacy = 74% (16.6 – 94.0; p=0.03)

  17. Unmatched case-control studylimited to tenofovir recipients • The odds of HIV infection were 3-times lower (OR 0.30; 95% CI, 0.09 to 0.98; p=0.04) among participants with detectable tenofovir levels, compared to those with undetectable tenofovir • Represents reduction in risk 70% (95% CI, 2.3 to 90.6)

  18. Adherence by treatment group Overall, participants in DOT follow-up 87% of days on study P=0.16 nonDOT DOT

  19. Adherence among HIV infected and not-infected participants P=0.45 P=0.01

  20. Efficacy by level of adherence Efficacy increases with better adherence

  21. Safety

  22. Safety

  23. Genotyping and Resistance • HIV viruses from 49 of the 52 HIV-infected participants were successfully amplified: • 43 (88%) were CRF01_AE • 5 (10%) were subtype B' • 1 (2%) was CRF01_AE/subtype B' strain • No resistance mutations associated with tenofovir (K65R, K70E) were detected

  24. Limitations • We used self reports of risk behaviors • HIV infections may have occurred due to sexual activity [MOLBPE27]

  25. Oral pre-exposure prophylaxis trials mITT results 75% (55-87) 67% (44-81) Partners (serodiscordants): TDF/FTC TDF TDF2 (heterosexuals): TDF/FTC 62% (22-83) Bangkok Tenofovir Study (PWID): TDF 49% (10-72) iPrex (MSM): TDF/FTC 44% (15-63) FemPrEP (women): TDF/FTC VOICE (women): TDF TDF/FTC 0% 10 20 30 40 50 60 70 80 90 100% Efficacy

  26. Oral pre-exposure prophylaxis trials 2° adherence-based results 90% (56-98) 86% (57-95) Partners (serodiscordants): TDF/FTC TDF TDF2 (heterosexuals): TDF/FTC 78% (41-94) 84% Bangkok Tenofovir Study (PWID): TDF 74% (17-94) iPrex (MSM): TDF/FTC 92% (40-99) FemPrEP (women): TDF/FTC VOICE (women): TDF TDF/FTC 0% 10 20 30 40 50 60 70 80 90 100% Efficacy

  27. Conclusions • Daily oral tenofovir, in combination with other HIV prevention strategies, reduced the risk of HIV infection among people who inject drugs • The protective efficacy increased with improved adherence • We did not identify significant safety concerns, and no tenofovir resistance detected

  28. Next Steps • Additional analyses underway: adherence, risk behavior, drug level • Participants will be offered tenofovir for one year • CDC published initial guidance in MMWR • CDC is currently working to finalize full Public Health Service clinical guidelines on PrEPuse

  29. Bangkok Tenfovir Study Group Principal InvestigatorKachit Choopanya Advisory Group SompobSnidvongs Na Ayudhya, Sithisat Chiamwongpaet, KraichackKaewnil, PraphanKitisin, MalineeKukavejworakit, ManojLeethochawalit, PitinanNatrujirote, SaengchaiSimakajorn, WonchatSubhachaturas Study Clinic Coordination Team Lead: Suphak Vanichseni; Members: BoonrawdPrasittipol, UdomsakSangkum, PravanSuntharasamai Bangkok Metropolitan Administration Rapeepan Anekvorapong, ChanchaiKhoomphong, SurinKoocharoenprasit, ParnrudeeManomaipiboon, SiriwatManotham, PirapongSaicheua, Piyathida Smutraprapoot,SravudthiSonthikaew, La-OngSrisuwanvilai, SamartTanariyakul, MontiraThongsari, WantaneeWattana, KovitYongvanitjit Thailand Ministry of Public Health SumetAngwandee, SomyotKittimunkong Thailand MOPH - U.S. CDC Collaboration Wichuda Aueaksorn, Benjamaporn Chaipung, Nartlada Chantharojwong, ThanyananChaowanachan, Thitima Cherdtrakulkiat, Wannee Chonwattana, Rutt Chuachoowong, Marcel Curlin, Pitthaya Disprayoon, Kanjana Kamkong, Chonticha Kittinunvorakoon, Wanna Leelawiwat, Robert Linkins, Michael Martin, Janet McNicholl, Philip Mock, Supawadee Na-Pompet, Tanarak Plipat, Anchala Sa-nguansat, Panurassamee Sittidech, Pairote Tararut, Rungtiva Thongtew, Dararat Worrajittanon, Chariya Utenpitak, Anchalee Warapornmongkholkul, Punneeporn Wasinrapee U.S. CDC Jennifer Brannon, Monique Brown, Roman Gvetadze, Lisa Harper, Lynn Paxton, Charles Rose Johns Hopkins University Craig Hendrix, Mark Marzinke

  30. Community Involvement • Conducted Focus Group Discussions among PWID in 2004 • PREP trial important, why tenofovir, side-effects, access to care • Outreach to organizations working with PWID and communities at risk of HIV/AIDS • Met with 16 CBOs and NGOs: distributed draft protocols, consents, education tools • Met with community representatives at 3 drop-in sites • Meetings informed development of protocol, consent form and consent process, and education materials • Community Relations Committee • PWID from each of the 17 BMA clinics • Committee meets every 2 months with investigators • Raised concerns about study procedures, confidentiality, police harassment, incarceration, side-effects, medical care, compensation, and post-trial access to tenofovir

  31. Injecting and sharing by treatment group Tenofovir -------- Placebo - - - - - - No difference in TDF/placebo groups (p=0.71) Injecting declined (p<0.001) No difference in TDF/placebo groups (p=0.84) Sharing declined (p<0.001)

  32. Sex by treatment group Tenofovir ------------ Placebo - - - - - - No difference in TDF/placebo groups (p=0.28) Sex with casual partners declined (p<0.001) No difference in TDF/placebo groups (p=0.24) Sex with more than one partner declined (p<0.001)

  33. Risk BehaviorResults • Risk behavior (injecting, sharing, sex) declined during follow-up • Participants randomized to tenofovir and placebo reported similar HIV-associated risk behaviors • Multivariable analysis: age (20-29 years) (p=0.02), sharing needles (p<0.001), and prison (p=0.003) associated with HIV infection • Reporting sex with live-in, casual, or men reporting sex with male partner not associated with incident HIV

  34. Needles • Thai law prohibits distribution of needles to inject illicit drugs • Needles and syringes are available in pharmacies at low cost without a prescription • Participants and community representatives reported that access to clean needles and syringes is not a problem

  35. Measures to improve adherence • Offer daily directly observed therapy • Monthly adherence counseling: participant centered and sharing discussed • Pill counts with participant at each monthly study visit • Participants reminded that we understand taking all doses is difficult and that we need them to tell us about missed doses • Medication diary • At monthly visits diaries reviewed, compared to pill count, and discrepancies resolved • Tenofovir plasma and intracellular levels determined • HIV seroconverters – blood collected visit that HIV test reactive and study drug stopped • HIV uninfected – blood collected from volunteers at exit visit at 4 clinics (n=284 specimens matched PBMCs/plasma)

  36. Pre-specified adherence-defined analysis • Adherent defined: DOT participant taking study drug >71% of days with no more than 2 consecutive day off study drug • 17 met the adherent definition • 5 tenofovir/12 placebo = 56% (-25.1 - 84.5; p=0.12) • 2 of 5 undetectable tenofovir; removing these 74% (16.6 – 94.0; p=0.03)

  37. Unmatched case-control studylimited to tenofovir recipients • The odds of HIV infection were 3-times lower (OR 0.30; 95% CI, 0.09 to 0.98; p=0.04) among participants with detectable tenofovir levels, compared to those with undetectable tenofovir • Represents reduction in risk 70% (95% CI, 2.3 to 90.6)

  38. Plasma tenofovir levels 5/13 (38.5%) Detectable 93/138 (67.4%) Detectable Median HIV-positive HIV-negative

  39. Participant Flow 4094 Screened 1681 (41%) ineligible 662 abnormal lab results 447 HIV-positive 233 HBsAg 189 did not return 101 medical conditions 49 other reasons 2413 (59%) Enrolled 1204 Tenofovir 1209 Placebo 2 were HIV-infected at enrollment 1207 followed for HIV infection (mITT) 4823 person-years 1204 followed for HIV infection (mITT) 4843 person-years Annual retention 12 months, 1059/1204 (88%) 24 months, 987/1030 (96%) 36 months, 933/956 (98%) 48 months, 860/893 (96%) 60 months, 769/788 (98%) 72 months, 596/615 (97%) 84 months, 390/399 (98%) Annual retention 12 months, 1079/1209 (89%) 24 months, 1006/1046 (96%) 36 months, 944/978 (97%) 48 months, 849/886 (96%) 60 months, 758/775 (98%) 72 months, 584/595 (98%) 84 months, 375/377 (99%) 176 (15%) Were lost to follow-up 95 (8%) Withdrew from study 58 (5%) Died 25 (2%) Became pregnant 33 (3%) Became HIV-infected 10 (0·8%) Had a falsely reactive HIV test 4 (0·3%) Withdrawn for medical reason 6 (0·5%) Did not meet eligibility criteria 3 (0·3%) Had other reason 179 (15%) Were lost to follow-up 112 (9%) Withdrew from study 49 (4%) Died 33 (3%) Became pregnant 17 (1%) Became HIV-infected 9 (1%) Had a falsely reactive HIV test 4 (0·3%) Withdrawn for medical reason 3 (0·3%) Did not meet eligibility criteria 3 (0·3%) Had other reason

  40. Annual loss to follow-up by study group

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