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

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 1 Grant RM, et al. Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men. NEJM 2010;363: 2587-99. 2 Thigpen MC, et al. Antiretroviral Preexposure Prophylaxis for Heterosexual HIV Transmission in Botswana. N Engl J Med 2012;367:423-34. 3 Baeten JM, et al. Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women. N Engl J Med 2012;367:399-410. TrialRisk GroupARV usedmITT2° adherence analyses iPrEx 1 MSMTDF/FTC44%92% (Drug level) TDF2 2 HeterosexualsTDF/FTC62%78% (As-treated) Partners 3 DiscordantTDF67%86% (Drug level) Partners 3 DiscordantTDF/FTC75%90% (Drug level)

3. Objectives and Design Primary Objectives Determine if tenofovir reduces 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 Visitsss Activities Monthly 3 Monthly Daily visits (DOT) Study drug diary DOT vs. nonDOT Adherence and risk reduction counseling Oral HIV test All monthly activities, plus: Assessed risk behavior Blood collected for safety testing Staff watch participant take study drug

8. Participant Flow 4094 Screened 2413 (59%) Randomized 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 1204 assigned to Tenofovir Included in ITT 1209 assigned to Placebo Included in ITT 1204 Included in mITT analysis 4843 person-years 1207 Included in mITT analysis 4823 person-years 2 HIV infected at enrollment

9. Baseline Characteristics Characteristic Tenofovir (N = 1204) Placebo (N = 1209) Total (N = 2413) Male — no. (%)958 (79.6)966 (79.9)1924 (79.7) Female — no. (%)246 (20.4)243 (20.1)489 (20.3) Age group — no. (%) 20-29 yr516 (42.9)517 (42.8)1033 (42.8) 30-39 yr458 (38.0)450 (37.2)908 (37.6) 40-49 yr175 (14.5)183 (15.1)358 (14.8) 50-60 yr55 (4.6)59 (4.9)114 (4.7) Education level — no. (%) Primary or less (<6 years)561 (46.6)593 (49.0)1154 (47.8) Secondary (7 - 12 years)545 (45.3)500 (41.4)1045 (43.3) Post-secondary98 (8.1)116 (9.6)214 (8.9)

10. Baseline Characteristics Characteristic Risk data available on 2405 participants Tenofovir (N = 1201) Placebo (N = 1204) Total (N = 2405) Incarceration In police holding cell (jail) in the past 3 months272 (22.6)280 (23.3)552 (23.0) In prison in the past 3 months200 (16.6)189 (15.7)389 (16.2) Drug use Currently in methadone program257 (21.4)267 (22.2)524 (21.8) Injected drugs in past 3 months739 (61.5)768 (63.8)1507 (62.7) Injected heroin268 (22.3)259 (21.5)527 (21.9) Injected methamphetamine416 (34.6)385 (32.0)801 (33.3) Injected midazolam270 (22.5)289 (24.0)559 (23.2) Injected other drugs76 (6.3)97 (8.1)173 (7.2) Injection frequency in the past 3 months — no. (%) Daily101 (8.4)103 (8.6)204 (8.5) Weekly267 (22.2)274 (22.8)541 (22.5) Less than weekly371 (30.9)391 (32.5)762 (31.7) Shared needles in past 3 months — no. (%)222 (18.5)213 (17.7)435 (18.1)

11. Baseline Characteristics CharacteristicTenofovir (N = 1201) Placebo (N = 1204) Total (N = 2405) Sexual behaviours Number of opposite sex sexual partners in past 3 months 0365 (30·4)334 (27·7)699 (29·1) 1585 (48·7)599 (49·8)1184 (49·2) >1251 (20·9)271 (22·5)552 (21·7) Reported sex with live-in partner in past 3 months526 (43·8)518 (43·0)1044 (43·4) Reported sex with casual partner in past 3 months 433 (36·0)481 (40·0)914 (38·0) Male participants (n=1913) reporting sex with male partner in past 3 months 35 (3·7)56 (5·8)91 (4·8)

12. Retention Reason Tenofovir (n=1204) Placebo (n=1209) All (n=2413) Log-rank p-value Lost to follow-up179 (14.9)176 (14.6)355 (14.7)0.83 Withdrew consent112 (9.3)95 (7.9)207 (8.6)0.22 Death49 (4.1)58 (4.8)107 (4.4)0.34 Ineligible3 (0.2)6 (0.5)9 (0.4)0.32 Withdrawn for medical reason4 (0.3) 8 (0.3)0.99 Withdrawn because refused study activities or threat to staff 3 (0.2) 6 (0.2)0.99 Pregnant33 (2.7)25 (2.1)58 (2.4)0.37 False reactive HIV test9 (0.8)10 (0.8)19 (0.8)0.63

13. Efficacy Infections/ person-years Incidence/100 pys (95% CI) Efficacy (95% CI)P-value mITT Tenofovir (n=1204) 17/48430.35/100 (0.21 – 0.56)48.9 (9.6 – 72.2)0.01 Placebo (n=1207) 33/48230.68/100 (0.47 – 0.96) ITT Tenofovir (n=1204) 17/48430.35 (0.21 – 0.56)51.8 (15.3 – 73.7)0.01 Placebo (n=1209) 35/48230.73 (0.51 – 1.01) All (n=2411)50/96650.52/100 (0.38 – 0.68)

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

15. Modified Intention-To-Treat Analysis Kaplan-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 study limited 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 DOT nonDOT

19. Adherence among HIV infected and not-infected participants Quartiles HIV-infected adherence Not infected adherence 75%94.1%98.6% Median76.5%94.0% 25%65.3%77.8% Quartiles HIV-infected adherence Not infected adherence 75%98.8% Median94.0%94.3% 25%65.0%81.2% P=0.01 P=0.45

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

21. Safety Tenofovir (n=1204)Placebo (n=1209) Adverse Event (AE) no. of participants (%)no. eventsno. of participants (%)no. events † p value Any AE1098 (91.2)109651083 (89.6)115500.455 Any serious AE227 (18.9)340246 (20.3)3750.352 Death49 (4.1)4958 (4.8)580.369 Any grade 3 or 4 event156 (13.0)414160 (13.2)3890.886 Nausea/vomit96 (8.0)11359 (4.9)710.002 Renal disease13 (1.1)1811 (0.9)150.687 Creatinine: grade 137 (3.1)11428 (2.3)330.268 Creatinine: grade 22 (0.2)30 (0)00.249 Creatinine: grade 3 or 43 (0.2)4 30.996

22. Safety Tenofovir (n=1204)Placebo (n=1209) Adverse Event (AE) no. of participants (%)no. eventsno. of participants (%)no. events † p value Any AE1098 (91.2)109651083 (89.6)115500.455 Any serious AE227 (18.9)340246 (20.3)3750.352 Death49 (4.1)4958 (4.8)580.369 Any grade 3 or 4 event156 (13.0)414160 (13.2)3890.886 Nausea/vomit96 (8.0)11359 (4.9)710.002 Renal disease13 (1.1)1811 (0.9)150.687 Creatinine: grade 137 (3.1)11428 (2.3)330.268 Creatinine: grade 22 (0.2)30 (0)00.249 Creatinine: grade 3 or 43 (0.2)4 30.996

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

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

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 PrEP use

29. Bangkok Tenfovir Study Group Principal Investigator Kachit Choopanya Advisory Group Sompob Snidvongs Na Ayudhya, Sithisat Chiamwongpaet, Kraichack Kaewnil, Praphan Kitisin, Malinee Kukavejworakit, Manoj Leethochawalit, Pitinan Natrujirote, Saengchai Simakajorn, Wonchat Subhachaturas Study Clinic Coordination Team Lead: Suphak Vanichseni; Members: Boonrawd Prasittipol, Udomsak Sangkum, Pravan Suntharasamai Bangkok Metropolitan Administration Rapeepan Anekvorapong, Chanchai Khoomphong, Surin Koocharoenprasit, Parnrudee Manomaipiboon, Siriwat Manotham, Pirapong Saicheua, Piyathida Smutraprapoot, Sravudthi Sonthikaew, La-Ong Srisuwanvilai, Samart Tanariyakul, Montira Thongsari, Wantanee Wattana, Kovit Yongvanitjit Thailand Ministry of Public Health Sumet Angwandee, Somyot Kittimunkong Thailand MOPH - U.S. CDC Collaboration Wichuda Aueaksorn, Benjamaporn Chaipung, Nartlada Chantharojwong, Thanyanan Chaowanachan, 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

31. 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

32. Injecting and sharing by treatment group No difference in TDF/placebo groups (p=0.71) No difference in TDF/placebo groups (p=0.84) TDF1201919840771662521341 Placebo1204960874770667512326 Tenofovir -------- Placebo - - - - - - Injecting declined (p<0.001) Sharing declined (p<0.001)

33. Sex by treatment group No difference in TDF/placebo groups (p=0.24) No difference in TDF/placebo groups (p=0.28) TDF1201919840771662521341 Placebo1204960874770667512326 Tenofovir ------------ Placebo - - - - - - Sex with more than one partner declined (p<0.001) Sex with casual partners declined (p<0.001)

34. Risk Behavior Results 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

35. 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

36. 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)

37. 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)

38. Unmatched case-control study limited 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) HIV infected HIV uninfected Total Tenofovir detected5 (39%)93 (67%)98 Tenofovir not detected 84553 Total13138151

39. Plasma tenofovir levels HIV-positiveHIV-negative 5/13 (38.5%) Detectable93/138 (67.4%) Detectable Median

40. Participant Flow 2413 (59%) Enrolled 4094 Screened 1681 (41%) ineligible 662 abnormal lab results 447 HIV-positive 233 HBsAg 189 did not return 101 medical conditions 49 other reasons 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 1204 followed for HIV infection (mITT) 4843 person-years 1204 Tenofovir 2 were HIV-infected at enrollment 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 1209 Placebo 1207 followed for HIV infection (mITT) 4823 person-years

41. Annual loss to follow-up by study group TenofovirPlaceboTotal Month 129892190/2413 (7.9%) Month 2424 48/2072 (2.3%) Month 36102333/1943 (1.7%) Month 48162036/1856 (1.9%) Month 60141024/1749 (1.4%) Month 7210616/1685 (1.0%) Month 84718/1623 (0.5%)