Characterization of HIV Seroconverters in a TDF/FTC PrEP Study: HPTN 067/ADAPT

Abstract

Background HPTN 067/ADAPT evaluated tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) pre-exposure prophylaxis (PrEP) in women (South Africa) and men who have sex with men (Thailand, US). Participants received once-weekly directly observed TDF/FTC (DOT), and were then randomized to daily, time-driven, or event-driven PrEP. This report describes characterization of 12 HIV seroconversion events in this trial. Methods HIV rapid testing was performed at study sites. Retrospective testing included: 4th generation assays; HIV RNA testing; Western blot; an HIV-1/2 discriminatory assay; resistance testing; and antiretroviral (ARV) drug testing. Results Six of the 12 seroconverters received TDF/FTC in the DOT phase, but were not randomized (3 were acutely infected at enrollment; 2 were infected during the DOT phase; one was not randomized due to pregnancy). One of the six randomized participants had acute infection at randomization but was not diagnosed for 3–4 months because HIV rapid tests were non-reactive; continued daily PrEP use was associated with false-negative antibody tests and low HIV RNA levels. The five participants infected after randomization included four with low adherence to the PrEP regimen, and one who reported a 7-day period without dosing prior to infection. Three participants had TDF/FTC resistance (M184I, K65R), including two who received only four once-weekly TDF/FTC doses; most TDF/FTC mutations were detected by next generation sequencing only. Conclusions In HPTN 067/ADAPT, participants who acquired HIV infection had infrequent PrEP dosing or low/suboptimal adherence. Sensitive assays improved detection of HIV infection and drug resistance. Drug resistance was observed with limited PrEP exposure.

Challenges of HIV diagnosis and management in the context of pre‐exposure prophylaxis (PrEP), post‐exposure prophylaxis (PEP), test and start and acute HIV infection: a scoping review

“…Case reports have detailed atypical HIV‐antibody test results in those taking PrEP , with the possibility of a delayed or reduced antibody response to HIV infection and suppressed viral replication. In the ADAPT trial (HIV Prevention Trials Network (HPTN) 067) that evaluated TDF/FTC PrEP in women in South Africa and men who have sex with men (MSM) in Thailand and USA, there were 12 new HIV infections . In 9 of the 12 cases, both of two POCTs were non‐reactive at the first HIV‐positive visit, including eight cases of AHI.…”

“…The viral load was ≤ 400 copies/mL in four of the eight AHI cases, but all were positive on a sensitive HIV RNA qualitative assay. In eight cases there was continuation of PrEP, including one case where PrEP was continued for three to four months post HIV infection; there were three cases of drug resistance to ART . In an assessment of HIV diagnostic tests in the ANRS‐IPERGAY study, the Abbott Architect ® Ag/Ab Combo test detected 85% of AHI but failed to detect two early infections, both which had HIV RNA of < 500 copies/mL .…”

Drug Resistance During HIV Pre-Exposure Prophylaxis

“…Thirteen randomized studies have investigated the efficacy and/or optimal dosing schedule of oral TDF with or without FTC as PrEP and have reported rates of antiretroviral drug resistance observed during study follow-up [3][4][5][6][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. These studies demonstrated that PrEP is safe, well tolerated and able to decrease HIV transmission in multiple priority populations.…”

PrEParing for the Unexpected: Mechanisms and Management of HIV pre-exposure Prophylaxis Failure

“…There is general agreement that the vast majority of cases of PrEP failure are simply due to poor adherence to the drug, as evidenced by the low PrEP drug levels seen in seroconverters within the main PrEP efficacy trials (Table 2) [14,23,30]. For instance, in the iPrEx trial, a subgroup analysis among those randomized to active drug showed that 8% of those who developed HIV infection had detectable levels of study drug in either plasma or peripheral blood mononuclear cells (PBMCs), compared with 54% of individuals who did not develop infections and were considered to be 'on treatment' (taking drug on >50% of days) [6].…”