HIV protective efficacy and correlates of tenofovir blood concentrations in a clinical trial of PrEP for HIV prevention.
BACKGROUND
Antiretroviral pre-exposure prophylaxis (PrEP) is a novel HIV prevention strategy for which adherence is a known determinant of efficacy. Blood concentrations of PrEP medications are one objective marker of adherence.


METHODS
In a placebo-controlled PrEP efficacy trial of tenofovir disoproxil fumarate (TDF) and TDF with emtricitabine (FTC/TDF) among 4747 African women and men with an HIV-infected partner, we measured plasma tenofovir concentrations from participants in the active PrEP arms: 29 HIV seroconverters (cases) and 196 randomly selected controls who remained uninfected.


RESULTS
Among controls, 71% of visits had tenofovir concentrations >40 ng/mL, consistent with steady-state daily dosing, compared with 21% of cases at the visit HIV was first detected. Pill count data indicated that 96% of controls and 66% of cases had >80% adherence for these same visits. The estimated protective effect of PrEP against HIV, based on concentrations >40 ng/mL, was 88% (95% confidence interval: 60 to 96, P < 0.001) for individuals receiving TDF and 91% (95% confidence interval: 47 to 98, P = 0.008) for individuals receiving FTC/TDF. Controls had consistent patterns of PrEP concentrations during follow-up; among the 81% with concentrations >40 ng/mL at month 1, 75% maintained this concentration at month 12. Only 5 of 29 seroconverters seemed to be consistently adherent to PrEP. Tenofovir concentrations >40 ng/mL were associated with older age and shorter time on study; concentrations ≤40 ng/mL occurred more commonly when participants reported no sex with their HIV-infected partner.


CONCLUSIONS
Plasma concentrations of tenofovir consistent with daily dosing were highly predictive of protection from HIV acquisition. Most of those who took PrEP seemed to have high and consistent adherence.
*Department of Global Health University of Washington and Vaccine and Infectious Disease Institute Fred Hutchinson Cancer Research Center, Seattle, WA; Departments of †Global Health; ‡Medicine; §Epidemiology, University of Washington, Seattle, WA; Departments of ‖Pharmacology and Molecular Sciences; ¶Medicine, Johns Hopkins University, Baltimore, MD; #Center for Global Health, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, MA; **Department of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda; ††Department of Obstetrics and Gynecology, University of Nairobi and Kenyatta National Hospital, Nairobi; and ‡‡Department of Epidemiology, Johns Hopkins University, Baltimore, MD.
Deborah
D
Donnell
Jared M
JM
Baeten
Namandjé N
NN
Bumpus
Justin
J
Brantley
David R
DR
Bangsberg
Jessica E
JE
Haberer
Andrew
A
Mujugira
Nelly
N
Mugo
Patrick
P
Ndase
Craig
C
Hendrix
Connie
C
Celum
D000225:Adenine / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections / Q000517:prevention & control*; D006679:HIV Seropositivity / Q000097:blood; D006801:Humans; D008297:Male; D063065:Organophosphonates / Q000097:blood / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D000068698:Tenofovir; D055815:Young Adult; D016903:Drug Monitoring
D019380:Anti-HIV Agents; D015415:Biomarkers; D063065:Organophosphonates; D003841:Deoxycytidine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine