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

Background Randomized controlled trials reported that pre-exposure prophylaxis (PrEP) with tenofovir and emtricitabine rarely selects for drug resistance. However, drug resistance due to PrEP is not completely understood. In daily practice, PrEP will not be used under the well-controlled conditions available in the trials, suggesting that widespread use of PrEP can result in increased drug resistance. Methods We surveyed expert virologists with questions about biological assumptions regarding drug resistance due to PrEP use. The influence of these assumptions on the prevalence of drug resistance and the fraction of HIV transmitted resistance was studied with a mathematical model. For comparability, 50% PrEP-coverage of and 90% per-act efficacy of PrEP in preventing HIV acquisition are assumed in all simulations. Results Virologists disagreed on the following: the time until resistance emergence (range: 20–180 days) in infected PrEP users with breakthrough HIV infections; the efficacy of PrEP against drug-resistant HIV (25%-90%); and the likelihood of resistance acquisition upon transmission (10%-75%). These differences translate into projections of 0.6%- 1% and 3.5%—6% infected individuals with detectable resistance 10 years after introducing PrEP, assuming 100% and 50% adherence, respectively. The rate of resistance emergence following breakthrough HIV infection and the rate of resistance reversion after PrEP use is discontinued, were the factors identified as most influential on the expected resistance associated with PrEP. Importantly, 17–23% infected individuals could virologically fail treatment as a result of past PrEP use or transmitted resistance to PrEP with moderate adherence. Conclusions There is no broad consensus on quantification of key biological processes that underpin the emergence of PrEP-associated drug resistance. Despite this, the contribution of PrEP use to the prevalence of the detectable drug resistance is expected to be small. However, individuals who become infected despite the use of PrEP should be closely monitored due to higher risk of virological failure when initiating antiretroviral treatment in the future.


Introduction
The following questions are put together to solicit opinion from expert virologists. Please indicate your answers quantitatively and provide comments which may give rational for your answers. The aim is to determine areas of agreement and uncertainty and to assist the parametrisation of mathematical models.

Definitions
The focus here is specifically on PrEP being a daily oral dose of TDF or TDF/FTC, and ART being TDF-based. Please indicate if you use data that do not correspond to these definitions.

Instructions
For each question there is a line with a scale and we ask for an indication of where on that line the true value lies (location and uncertainty). In the example below, a question is asked about the rate ratio of an event and a scale is provided (note, a logarithmic scale); the respondent has indicated (in red) that the rate is usually less than 1.0, but not usually more than 0.3 and with a typical value of approximately 0.5 Please provide comments which may give rational for your answers (optional) 1 , David van de Vijver

Rate of resistance development for HIV+ PrEP users.
a) What is the average time it takes for resistance to develop (to any detectable level) in users who acquire HIV and subsequently use PrEP with perfect compliance? b) What is the average time it takes for resistance to develop (to any detectable level) in users who acquire HIV and subsequently use PrEP with intermittent compliance (missing doses every other day). c) What is the average time it takes for resistance to develop (to any detectable level) in users who acquire HIV and subsequently use PrEP with low compliance (taking only 1 dose per week).
NB. These guidelines are not drawn to scale.

Transmission from an individual with acquired drug-resistant HIV
a) For an individual that had acquired drug-resistance whilst on PrEP but who now has not used PrEP for one week, what is the relative chance of transmitting a resistant virus compared to a wild-type virus (given that infection has occured).
i. … to someone who is not on PrEP ii. … to someone who is currently taking PrEP (and in good compliance) b) For an individual that acquire drug-resistance whilst on PrEP but who now has not been using PrEP for one year, what is the relative chance of transmitting a resistant virus compared to a wild-type virus (given that infection has occured) . Note: This could change after one year due to reversion i. … to someone who is not on PrEP ii. … to someone who is currently taking PrEP (and in good compliance) c) What is the level of protection of PrEP against drug-resistant HIV (Assumed level of protection against wild type HIV is provided.)

Reversion of Drug Resistance
a) For an individual that had acquired drug-resistance whilst on PrEP but who now has not used PrEP what is the proportion of resistant virus compared to a total viral population over time after discontinue PrEP use. b) For an individual that has transmitted drug-resistance and never used PrEP what is the proportion of resistant virus compared to a total viral population over time after transmission. (Note: Insert graph)

Characteristic of Transmitted Drug Resistance
If drug-resistant HIV is transmitted, what will be relative chance of transmitting to someone else (compared to if the infection has been a wild-type virus: lower/same/ higher), and what is the probability that the transmitted virus is resistant virus: