HIV-1 Drug Resistance in the iPrEx Preexposure Prophylaxis Trial

Abstract

Background. The iPrEx study demonstrated that combination oral emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) as preexposure prophylaxis (PrEP) protects against HIV acquisition in men who have sex with men and transgender women. Selection for drug resistance could offset PrEP benefits.Methods. Phenotypic and genotypic clinical resistance assays characterized major drug resistant mutations. Minor variants with FTC/TDF mutations K65R, K70E, M184V/I were measured using 454 deep sequencing and a novel allele-specific polymerase chain reaction (AS-PCR) diagnostic tolerant to sequence heterogeneity.Results. Control of primer-binding site heterogeneity resulted in improved accuracy of minor variant measurements by AS-PCR. Of the 48 on-study infections randomized to FTC/TDF, none showed FTC/TDF mutations by clinical assays despite detectable drug levels in 8 participants. Two randomized to FTC/TDF had minor variant M184I detected at 0.53% by AS-PCR or 0.75% by deep sequencing, only 1 of which had low but detectable drug levels. Among those with acute infection at randomization to FTC/TDF, M184V or I mutations that were predominant at seroconversion waned to background levels within 24 weeks after discontinuing drug.Conclusions. Drug resistance was rare in iPrEx on-study FTC/TDF-randomized seroconverters, and only as low-frequency minor variants. FTC resistance among those initiating PrEP with acute infection waned rapidly after drug discontinuation.Clinical Trials Registration. NCT00458393.

Sexually transmissible infection control programs for men who have sex with men – what will they look like in 2020?

“…Acquisition of drug-resistant HIV strains in initiators of FTC-TDF for PrEP has been documented in clinical trials. 46,47 Among participants in the FTC-TDF for PrEP treatment arm who seroconverted during the Partner's PrEP study, there were seven cases of detectable FTC-TDF-related mutations. 47 Three of those seven seroconversions were unrecognised at baseline and did not have detectable FTC-TDF-related mutations at that time, which suggests that these mutations were likely caused by treatment rather than acquisition of an already mutated strain.…”

Low Frequency of Drug-Resistant Variants Selected by Long-Acting Rilpivirine in Macaques Infected with Simian Immunodeficiency Virus Containing HIV-1 Reverse Transcriptase

“…These situations may increase the selection of drug-resistant mutations (DRMs), promoting spread of drug resistance and limiting future ART options through cross-resistance (25). Resistance analyses of breakthrough infections in TDF-FTC clinical trials revealed that selection of DRMs was rare in patients who became infected after receiving PrEP, but DRMs did develop in the few individuals that were HIV-1 ϩ before initiating PrEP (26)(27)(28).…”

How Much Do We Know about Drug Resistance Due to PrEP Use? Analysis of Experts' Opinion and Its Influence on the Projected Public Health Impact

“…The values and ranges of the resistance parameters informed by the survey responses are presented in Tables 1 and 2. Projections associated with the M184V mutation have been used in the analysis, as this mutation is the most common mutation found in individuals that become infected despite the use of PrEP [10][11][12]. The aggregated parameter set consists of ranges representing the 90% confidence level of distributions pooled from values and ranges suggested by the experts (find pooling procedure in the S1 Text).…”

“…Drug resistance developed predominantly among participants with unrecognized acute HIV infection who were randomized to start PrEP. [10][11][12] Though this is somewhat reassuring, uncertainty remains regarding the resistance risk once PrEP is implemented widely; patients prescribed PrEP may not have the close monitoring and frequent HIV-testing mandated in clinical trials. As a consequence, a new HIV-infection might not be identified in a timely manner and patients who continue using PrEP may select for drug resistance.…”

“…[13,14] HIV drug resistance due to PrEP is complex and influenced by different processes (Table 1). First, acquired drug resistance (ADR) can emerge in individuals who continue using PrEP after they become infected with HIV [10][11][12]. Second, transmitted drug resistance (TDR) occurs when an individual becomes infected with a drug resistant virus.…”