the bangkok tenofovir study an hiv pre-exposure prophylaxis trial in thailand: participant adherence...
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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
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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)
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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
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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
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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
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Bangkok Metropolitan Administration Drug Treatment Clinics
TUC Lab
BMA Lab
Bangkok
Thailand
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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
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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
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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)
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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)
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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)
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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
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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)
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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
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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
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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)
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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)
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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
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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
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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
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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
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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
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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
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Limitations
• We used self reports of risk behaviors• HIV infections may have occurred due to
sexual activity [MOLBPE27]
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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)
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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%
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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
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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
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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
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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
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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)
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Sex by treatment group
0 12 24 36 48 60 720%
10%
20%
30%
40%
50%
Study visit (month)
% R
epo
rtin
g
No difference in TDF/placebo groups (p=0.24)
No difference in TDF/placebo groups (p=0.28)
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)
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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
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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
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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)
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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)
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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
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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
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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
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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%)