PrEP use in young African women in HPTN 082: Effect of drug level feedback Connie Celum, Nyaradzo Mgodi, Linda-Gail Bekker, Sybil Hosek, Deborah Donnell, Pete Anderson, Bonnie Dye, Subash Pathak, Yaw Agyei, Jessica Fogel, Mark Marzinke, Keo Makgamathe, Sheetal Kassim, Shorai Mukaka, Heather Noble, Adeola Adeyeye, Sinead Delany-Moretlwe on behalf of the HPTN 082 Study Team Background HIV incidence of 4-6% among young African women in recent HIV prevention trials PrEP is highly effective when taken with good, but not, perfect adherence PrEP use was low (20-25%) in FEM-PrEP and VOICE trials Qualitative research among former VOICE participants indicated drug level feedback could foster more honest discussion about PrEP adherence Given the need for primary HIV prevention among young African women and the high effectiveness of PrEP, it is important to assess the effectiveness of PrEP adherence support strategies Primary Objectives of HPTN 082 To assess the proportion and characteristics of young HIV-uninfected women who accept versus decline PrEP. To assess the difference in PrEP adherence in young women randomized to enhanced adherence support (using drug level feedback) versus standard of care adherence support. HPTN 082: Evaluation of daily oral PrEP as a primary prevention strategy for young African women
Study Population Uninfectedwomen Ages16-25yrs Johannesburg&CapeTown, SouthAfrica Harare,Zimbabwe TargetEnrollment 400womenwhoaccept PrEPat enrollment 200womenwhodecline PrEPat enrollment Standard adherence aryobjectives:support Eligibility criteria: Sexually active in past month;Prim VOICE Assess the proportion andtocharacteristics of women who accept risk score >5; interest in PrEP; access mobile phone; B seronegative Assess hepatitis PrEP adherence
using drug levels in young women Standard adherence support plus drug level feedback versus decline PrEP Standard adherence support in HPTN 082 Weekly two way SMS in first 3 months Monthly adherence clubs Peer support Address concerns & share experiences about PrEP Problem-solve adherence challenges Brief counseling at visits: Months 1,2, 3, 6, 9 and 12 Discrete pill containers Hey sister, howzit? Are you ok? Drug level feedback at months 2 and 3 Women randomized to enhanced counseling have DBS TFV-DP levels obtained at months 1 and 2. Results given at next visit (month 2 and 3)
DBS are a measure of average adherence in prior month Counseling messages for >4 doses/week (green), 1-3 doses/week (yellow) and below detection (red) Lower thresholds used at month 1 before TDFDP levels reached steady-state Anderson P et al. TFV-DP in DBS: DOT-DBS Study. CROI 2017 Anderson P et al Sci Transl Med 2012 Grant R et al Lancet Infect Dis 2014 Analysis: Definitions and methods Primary adherence outcome: TFV-DP >700 fmol/punch at 6 months Predictors of high adherence at 6 months (TFV-DP >700 fmol/punch) Logistic regression, adjusted for site Persistence: Detectable TFV-DP or plasma TFV at 3, 6 & 12 months HPTN 082: PrEP uptake Figure 1: PrEP uptake overall and by site 100% 90% 80% 70% 60% 50% 40% 30% 20% 10%
0% 95% 97% 99% Overall Harare Cape Town PrEP not accepted 88% Johannesburg PrEP accepted 646 were accessed for eligibility 129 were not eligible, including 50 unable to enroll within 45 days of screening 29 HIV positive at screening
21 pregnant or planning pregnancy 10 with VOICE score <5 451 enrolled 24 declined PrEP 427 underwent randomization 215 were assigned to receive drug level feedback plus standard adherence support 26 lost to follow-up 212 were assigned to receive standard adherence support Retention Month 1 Month 2 Month 3 204/215 (95%) 191/215 (89%) 191/215 (89%) Month 6 183/215 (85%)
Month 9 173/214 (81%) Month 12 184/215 (86%) 179 included in the intent-to-treat analysis for month 6 primary outcome 4 missing DBS sample for drug level at month 6 Retention Month 1 Month 2 Month 3 191/212 (90%) 180/212 (85%) 190/212 (90%) Month 6 188/212 (89%) Month 9 180/212 (85%) Month 12 181/212 (85%) 184 included in the intent-to-treat analysis for month 6 primary outcome 4 missing DBS sample for drug level at month 6 28 lost to follow-up 4 HIV infections
Demographics & Sexual Partner Characteristics Standard Adherence Support* N=212 Enhanced Adherence Support* N=215 Age (years) median (IQR) 21 (19, 23) 21 (19, 22) Education Secondary school or higher 184 (98%) 187 (98%) CES-D depression score >10 126 (59%) 133 (62%) Any intimate partner violence, past year
100 (48%) 116 (54%) Trauma symptoms 137 (65%) 152 (71%) Primary sex partner in past 3 months 174 (83%) 182 (85%) HIV negative 112 (79%) 97 (68%) HIV positive 1 (1%) 2 (1%)
27 (19%) 42 (30%) Baseline characteristic HIV status of primary partner Does not know Sexual behavior, risk perception, & PrEP Baseline characteristic Thinks partner has other partners Yes Dont know Vaginal sex past month (median, IQR) Condoms with vaginal sex, past month Always or often Curable STI CT, GC, trichomonas, syphilis Perceived risk of HIV, next year None Small Moderate Great Plan to disclose PrEP use Standard Adherence Support* N=212
Tenofovir levels at 3, 6, & 12 months 3 months 6 months 12 months N=371 N=363 N=347 Detectable 83.6% 56.5% 31.4% >700 fmol/punch* (among those with detectable TFV-DP) 24.8% 20.9%
8.6% Tenofovir diphosphate (TFV-DP), DBS * TFV-DP >700 fmol/punch was associated with 100% efficacy among MSM in the iPrEX OLE study & the 25th percentile of 4 doses/week on average (Grant Lancet HIV 2014) Tenofovir levels at 3, 6, & 12 months 3 months 6 months 12 months N=371 N=363 N=347 Detectable 83.6% 56.5% 31.4% >700 fmol/punch* (among those with
Tenofovir diphosphate (TFV-DP), DBS Plasma tenofovir * TFV-DP >700 fmol/punch was associated with 100% efficacy among MSM in the iPrEX OLE study & the 25th percentile of 4 doses/week on average (Grant Lancet HIV 2014) ** Plasma tenofovir >40 ng/ml associated with daily use and efficacy among women in Partners PrEP (Donnell JAIDS 2014) Effect of drug level feedback on adherence (TFV-DP >700 fmol/p) at 6 months Difference in Standard adherence Enhanced adherence proportion with support support TFV-DP >700 TFV-DP>700 fmol/punch) TFV-DP>700 fmol/punch) fmol/punch Intent to treat 40/184 (21.7%) 36/179 (20.1%) -1.6% 95% CI
P-value -9.9%, 6.7% 0.7 Effect of drug level feedback on adherence (TFV-DP >700 fmol/p) at 6 months Standard adherence Enhanced Difference in support adherence support proportion with TFV-DP>700 TFV-DP>700 TFV-DP >700 fmol/punch fmol/punch fmol/punch 95% CI P-value Intent to treat 40/184 (21.7%) 36/179 (20.1%)
-1.6% -9.9%, 6.7% 0.7 Per protocol analysis* 40/181 (22.1%) 17/115 (14.8%) -7.3% -15.7%, 2.5% 0.2 * Per protocol analysis excluded women who: - were not receiving PrEP due to a clinical or laboratory hold did not receive drug level feedback because DBS results were not available at next visit, or received drug level counselling that did not correspond to the appropriate category based on actual DBS drug levels PrEP adherence & persistence, by arm
DBS Concentration (fmol/punch) 1400 1000 Arm Standard Adherence Support 700 Enhanced adherence support 350 0 Month 3 DBS results Drug hold or stopped PrEP in prior month Detectable TFV-DP among those on PrEP Month 6 Month 12 N=371
N=363 N=7 N=21 N= 26 202 (59%) * 109 (34%)* 305 (84%) *p<0.001 for months 6 and 12 compared to month 3 N=347 Challenges of retrospective drug level feedback 215 191 172 151 Participants randomized to drug level feedback arm Completed visits through month 3 DBS results back before next visit Received correct counseling
Correlates of high adherence at 6 months Univariate Odds Ratio Multivariate Odds Ratio (95% CI) (95% CI) Multivariate Pvalues Perceived risk of HIV (any vs none) 1.9 (1.1, 3.2) 2.4 (1.2, 4.5) 0.008 PrEP readiness score (per unit increase) 1.0 (1.0, 1.1) 1.0 (1.0, 1.1) 0.004 Disclosed to someone about PrEP use
3.3 (1.2, 8.8) 3.0 (1.0, 9.1) 0.06 Number of sexual partners, past 3 months 1.2 (1.0, 1.5) 1.3 (1.0, 1.6) 0.07 Participant ever dropped out of school 1.8 (1.0, 13.1) 2.0 (1.0, 14.1) 0.07 Adherence club participation (per club attendance) 1.7 (1.2, 2.3) 1.3 (1.0, 1.8)
0.10 Covariate HIV seroconversions Four HIV seroconverters (at months 3, 6, and two at 9) observed in 404 person-years of follow-up HIV incidence of 1.0/100 person-years (95% CI 0.3-2.5) 2 had undetectable DBS TFV-DP concentrations and 2 detectable but low concentrations (74 and 243 fmol/punch) in the visit at or prior to when they were first detected HIV seropositive Three had no resistance mutations & one had D67N (NRTI mutation) and four NNRTI mutations (K101E, K103N, E138A, and G109A) No resistance mutations associated with TDF or FTC HPTN 082: Summary Very high PrEP uptake (95%) among young women who were at risk for HIV, a majority of whom took PrEP in the first 6 months No effect of drug level feedback on proportions with detectable TFV-DP or high adherence by arm at 6 months Challenges in operationalizing DBS drug level feedback and counseling about adherence levels 1-2 months ago Research is needed to determine effective adherence support to sustain use including POC adherence assays (eg., urine TFV) Women who perceived themselves to be at risk of HIV and were motivated to use PrEP (HPRM score) had higher adherence at 6 months HPTN 082 Summary (2)
Adherence declined significantly after month 3 Associated with change to quarterly visits, similar to other PrEP studies in youth (ATN 110/113, PlusPills) Low HIV incidence (1%) given risk profile of this cohort; Counterfactual HIV incidence of 3.7% based on modeling (Moore CROI 2019) Will assess whether low incidence was due to higher adherence during periods of risk (prevention-effective adherence) Longer-acting PrEP & choice of options will likely increase uptake, adherence & persistence (i.e., effective coverage) ACKNOWLEDGEMENTS The youth CABs for their engagement, ideas and feedback The young women who participated in HPTN082 HPTN 082 team with special thanks to the site teams at Emavundleni (Cape Town), Spilhaus (Harare) and Ward 21 (Johannesburg) ACKNOWLEDGEMENTS WLEDGEMENTSYouth community advisory boards, participants, and the HPTN 082 team The HIV Prevention Trials Network is funded by the National Institute of Allergy and Infectious Diseases (UM1AI068619, UM1AI068613, UM1AI1068617), with co-funding from the National Institute of Mental Health, and the National Institute on Drug Abuse, all components of the U.S. National Institutes of Health. Gilead Sciences for donation of Truvada for the study
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