the bangkok tenofovir study an hiv pre-exposure prophylaxis trial in thailand: participant adherence...

The Bangkok Tenofovir StudyAn HIV pre-exposure prophylaxis trial in

Thailand: participant adherence and study results

National Center for HIV/AIDS, Viral Hepatitis, STD, and TB PreventionDivision 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

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.

Trial Risk Group ARV used mITT 2° adherence analyses

iPrEx1 MSM TDF/FTC 44% 92% (Drug level)

TDF22 Heterosexuals TDF/FTC 62% 78% (As-treated)

Partners3 Discordant TDF 67% 86% (Drug level)

Partners3 Discordant TDF/FTC 75% 90% (Drug level)

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

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

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

Bangkok Metropolitan Administration Drug Treatment Clinics

TUC Lab

BMA Lab

Bangkok

Thailand

ActivitiesVisitsss 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

Participant Flow4094 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 TenofovirIncluded in ITT

1209 assigned to PlaceboIncluded in ITT

1204 Included in mITT analysis4843 person-years

1207 Included in mITT analysis4823 person-years

2 HIV infected at enrollment

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 yr 516 (42.9) 517 (42.8) 1033 (42.8) 30-39 yr 458 (38.0) 450 (37.2) 908 (37.6) 40-49 yr 175 (14.5) 183 (15.1) 358 (14.8) 50-60 yr 55 (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-secondary 98 (8.1) 116 (9.6) 214 (8.9)

Baseline CharacteristicsCharacteristicRisk data available on 2405 participants

Tenofovir(N = 1201)

Placebo(N = 1204)

Total(N = 2405)

Incarceration

In police holding cell (jail) in the past 3 months 272 (22.6) 280 (23.3) 552 (23.0)

In prison in the past 3 months 200 (16.6) 189 (15.7) 389 (16.2)

Drug use

Currently in methadone program 257 (21.4) 267 (22.2) 524 (21.8)

Injected drugs in past 3 months 739 (61.5) 768 (63.8) 1507 (62.7)

Injected heroin 268 (22.3) 259 (21.5) 527 (21.9)

Injected methamphetamine 416 (34.6) 385 (32.0) 801 (33.3)

Injected midazolam 270 (22.5) 289 (24.0) 559 (23.2)

Injected other drugs 76 (6.3) 97 (8.1) 173 (7.2)

Injection frequency in the past 3 months — no. (%)

Daily 101 (8.4) 103 (8.6) 204 (8.5)

Weekly 267 (22.2) 274 (22.8) 541 (22.5)

Less than weekly 371 (30.9) 391 (32.5) 762 (31.7)

Shared needles in past 3 months — no. (%) 222 (18.5) 213 (17.7) 435 (18.1)

Baseline Characteristics

Characteristic Tenofovir(N = 1201)

Placebo(N = 1204)

Total(N = 2405)

Sexual behaviours Number of opposite sex sexual partners in past 3 months 0 365 (30·4) 334 (27·7) 699 (29·1) 1 585 (48·7) 599 (49·8) 1184 (49·2) >1 251 (20·9) 271 (22·5) 552 (21·7)Reported sex with live-in partner in past 3 months 526 (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)

Retention

Reason Tenofovir(n=1204)

Placebo(n=1209)

All(n=2413)

Log-rank p-value

Lost to follow-up 179 (14.9) 176 (14.6) 355 (14.7) 0.83

Withdrew consent 112 (9.3) 95 (7.9) 207 (8.6) 0.22

Death 49 (4.1) 58 (4.8) 107 (4.4) 0.34

Ineligible 3 (0.2) 6 (0.5) 9 (0.4) 0.32

Withdrawn for medical reason 4 (0.3) 4 (0.3) 8 (0.3) 0.99Withdrawn because refused study activities or threat to staff 3 (0.2) 3 (0.2) 6 (0.2) 0.99

Pregnant 33 (2.7) 25 (2.1) 58 (2.4) 0.37

False reactive HIV test 9 (0.8) 10 (0.8) 19 (0.8) 0.63

EfficacyInfections/person-years

Incidence/100 pys(95% CI)

Efficacy (95% CI) P-value

mITT

Tenofovir (n=1204)

17/4843 0.35/100 (0.21 – 0.56) 48.9 (9.6 – 72.2) 0.01

Placebo (n=1207)

33/4823 0.68/100 (0.47 – 0.96)

ITT

Tenofovir (n=1204)

17/4843 0.35 (0.21 – 0.56) 51.8 (15.3 – 73.7) 0.01

Placebo (n=1209)

35/4823 0.73 (0.51 – 1.01)

All (n=2411) 50/9665 0.52/100 (0.38 – 0.68)

Modified Intention-To-Treat AnalysisKaplan-Meier estimates of time to HIV infection

0.0

00

.02

0.0

40

.06

0.0

80

.10

1158 1029 948 844 722 500 234 0Placebo1147 1007 933 857 736 521 241 0TDF

Number at risk

0 12 24 36 48 60 72 84Months on study

TDF Placebo

mITT 48.9% (9.6 – 72.2); P=0.01

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)

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)

Adherence by treatment group

Tenofovir Placebo0%

20%

40%

60%

80%

100%

Overall, participants in DOT follow-up 87% of days on study

P=0.16

DOT

nonDOT

Adherence among HIV infected and not-infected participants

HIV-infected Not infected0%

20%

40%

60%

80%

100%

Tenofovir

QuartilesHIV-infected adherence

Not infectedadherence

75% 94.1% 98.6%

Median 76.5% 94.0%

25% 65.3% 77.8%

HIV-infected Not infected0%

20%

40%

60%

80%

100%

Placebo

QuartilesHIV-infected adherence

Not infectedadherence

75% 98.8% 98.8%

Median 94.0% 94.3%

25% 65.0% 81.2%

P=0.01P=0.45

Efficacy by level of adherence

mITT >67% >75% >90% >95% >97.5%20%

40%

60%

80%

100%

49%54%

58%

68%72%

84%

Adherence

Eff

ica

cy

Efficacy increases with better adherence

SafetyTenofovir (n=1204) Placebo (n=1209)

Adverse Event (AE) no. of participants (%) no. events no. of participants (%) no. events † p valueAny AE 1098 (91.2) 10965 1083 (89.6) 11550 0.455

Any serious AE 227 (18.9) 340 246 (20.3) 375 0.352

Death 49 (4.1) 49 58 (4.8) 58 0.369

Any grade 3 or 4 event 156 (13.0) 414 160 (13.2) 389 0.886

Nausea/vomit 96 (8.0) 113 59 (4.9) 71 0.002

Renal disease 13 (1.1) 18 11 (0.9) 15 0.687

Creatinine: grade 1 37 (3.1) 114 28 (2.3) 33 0.268

Creatinine: grade 2 2 (0.2) 3 0 (0) 0 0.249Creatinine: grade 3 or 4 3 (0.2) 4 3 (0.2) 3 0.996

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 240

1

2

3

4

TenofovirPlacebo

Months since randomization

Nau

sea

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

Limitations

• We used self reports of risk behaviors• HIV infections may have occurred due to

sexual activity [MOLBPE27]

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)

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%

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

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

Bangkok Tenfovir Study GroupPrincipal Investigator Kachit ChoopanyaAdvisory Group Sompob Snidvongs Na Ayudhya, Sithisat Chiamwongpaet, Kraichack Kaewnil, Praphan Kitisin, Malinee Kukavejworakit, Manoj Leethochawalit, Pitinan Natrujirote, Saengchai Simakajorn, Wonchat SubhachaturasStudy Clinic Coordination Team Lead: Suphak Vanichseni; Members: Boonrawd Prasittipol, Udomsak Sangkum, Pravan SuntharasamaiBangkok 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 CollaborationWichuda 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 WasinrapeeU.S. CDCJennifer Brannon, Monique Brown, Roman Gvetadze, Lisa Harper, Lynn Paxton, Charles RoseJohns Hopkins University Craig Hendrix, Mark Marzinke

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

Injecting and sharing by treatment group

0 12 24 36 48 60 720%

20%

40%

60%

80%

Study visit (month)

% R

epo

rtin

g No difference in TDF/placebo groups (p=0.71)

No difference in TDF/placebo groups (p=0.84)

TDF 1201 919 840 771 662 521 341

Placebo 1204 960 874 770 667 512 326

Tenofovir --------Placebo - - - - - -

Injecting declined (p<0.001)

Sharing declined (p<0.001)

Sex by treatment group

0 12 24 36 48 60 720%

10%

20%

30%

40%

50%

Study visit (month)

% R

epo

rtin

g



TDF 1201 919 840 771 662 521 341

Placebo 1204 960 874 770 667 512 326

Tenofovir ------------Placebo - - - - - -

Sex with more than one partner declined (p<0.001)

Sex with casual partners declined (p<0.001)

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

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

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)

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)

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)

HIV infected

HIV uninfected

Total

Tenofovir detected 5 (39%) 93 (67%) 98

Tenofovir not detected

8 45 53

Total 13 138 151

Plasma tenofovir levels

0 1 20

100

200

300

400

Teno

fovi

r (ng

/ml)

HIV-positive HIV-negative

5/13 (38.5%) Detectable 93/138 (67.4%) Detectable

Median

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-up112 (9%) Withdrew from study49 (4%) Died33 (3%) Became pregnant 17 (1%) Became HIV-infected9 (1%) Had a falsely reactive HIV test 4 (0·3%) Withdrawn for medical reason3 (0·3%) Did not meet eligibility criteria3 (0·3%) Had other reason

1204 followed for HIV infection (mITT)4843 person-years

1204 Tenofovir

2 were HIV-infected at enrollment

Annual retention12 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 retention12 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-up95 (8%) Withdrew from study58 (5%) Died25 (2%) Became pregnant 33 (3%) Became HIV-infected10 (0·8%) Had a falsely reactive HIV test 4 (0·3%) Withdrawn for medical reason6 (0·5%) Did not meet eligibility criteria3 (0·3%) Had other reason

1209 Placebo

1207 followed for HIV infection (mITT)4823 person-years

Annual loss to follow-up by study group

Tenofovir Placebo Total

Month 12 98 92 190/2413 (7.9%)

Month 24 24 24 48/2072 (2.3%)

Month 36 10 23 33/1943 (1.7%)

Month 48 16 20 36/1856 (1.9%)

Month 60 14 10 24/1749 (1.4%)

Month 72 10 6 16/1685 (1.0%)

Month 84 7 1 8/1623 (0.5%)

the bangkok tenofovir study an hiv pre-exposure prophylaxis trial in thailand: participant adherence...

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