HIV Resistance in the Context of PrEP Daniel R. Kuritzkes, M.D. Division of Infectious Diseases Brigham and Women’s Hospital Harvard Medical School

Disclosures The speaker is a consultant to and/or has received research grant support from AbbVie Gilead Janssen Merck ViiV

Outline Concerns about PrEP and ART resistance Incidence of HIV drug resistance in the setting of PrEP use Effectiveness of PrEP against drug-resistant HIV Potential for resistance with long-acting PrEP Conclusions

Background Oral PrEP is highly effective at preventing transmission of HIV Concerns about resistance in the setting of PrEP: Drugs used for PrEP are the same as those used for ART Selection of drug resistance after PrEP failure could compromise ART efficacy Overall prevalence of pre-existing drug resistance could be increased by PrEP

The PrEP “Paradox” PrEP could reduce HIV transmission but increase drug resistance in newly infected persons ANI ratio surface (Absolute number of drug-resistant versus drug-sensitive infections over 10 years in the absence/presence of PrEP) No behavioral change Behavioral risk compensation Supervie et al PNAS 2010 DRK.US-Japan Mtg.9/23/11

Another model of PrEP and resistance Different parameters effect PrEP efficacy and resistance prevalence due to PrEP Extent of uptake and adherence explain ~50% of efficacy Duration of inadvertent use and PrEP uptake in previously infected persons explains ~50% of resistance prevalence DRK.US-Japan Mtg.9/23/11 Abbas et al PLoS One 2011

Potential risks for resistance PrEP regimens may select resistance in cases where PrEP fails Intermittent adherence could allow infection and inadvertent suboptimal ART PrEP could select for transmission of resistant variants from partners with failing ART or pre-existing drug-resistant variants Long-acting PrEP formulations raise new concerns regarding possible selection of drug-resistant HIV

Resistance to common PrEP drugs Drugs approved for PrEP require only a single mutation to confer high-level resistance Tenofovir (TDF): K65R Emtricitabine (FTC): M184I/V Low genetic barrier may be mitigated by fitness cost of resistance mutations Low prevalence in virus populations from untreated persons Some mutations (e.g., M184V) increase susceptibility to other drugs (e.g., TDF) High tissue concentrations may provide added pharmacologic barrier to resistance

ARV resistance after PrEP failure Systematic review identified 699 participants with HIV seroconversion in 13 PrEP trials (TDF ± FTC) 77 with acute infection at time of enrollment 622 with incident infection during follow-up Drug resistance mutations detected in 18/77 participants (23%) with acute HIV infection Drug resistance mutations detected in 19/622 participants (3%) with incident infection Gibas KM et al Drugs 2019

ARV resistance in acutely infected participants in PrEP Trials 15 had resistance to FTC (M184V/I) One received placebo 2 had TFV resistance (K65R) One received TDF alone One received TDF + FTC 1 participant had resistance to FTC and TFV Received TDF/FTC Gibas KM et al Drugs 2019

ARV resistance in PrEP trial participants with incident HIV infection 15 had resistance to FTC (M184V/I) 4 received placebo; 1 received TDF alone 2 had resistance to TFV (K65R) Both received placebo 2 had resistance to FTC and TFV Both received TDF/FTC Gibas KM et al Drugs 2019

Case reports of ARV resistance after PrEP failure Gibas KM et al Drugs 2019

High rates of K65R after first-line ART failure 23 of 33 (69.7%) patients at McCord Hospital failing TDF-containing first-line ART had K65R1 A study of 1000 patients initiating first-line ART in peri-urban/rural KZN found 30% prevalence (27/89) of K65R at treatment failure2 1Sunpath H et al AIDS 2012 2Brijkumar J et al HIVDRW 2018

Implications of drug resistance after failure of 1st-line ART for PrEP TenoRes Study Group Lancet Infect Dis 2016

Efficacy of TDF/FTC against rectal challenge with M184V SHIV 10 macaques challenged with SHIV162p3(M184V)1 5 received TDF/FTC; 5 controls All 5 control animals infected No treated animals infected Increased TDF susceptibility may have contributed to protection Virus infectivity to virion particle ratios were 4- and 10-fold lower in SHIV162p3(M184V) and SHIV162p3(K65R), compared to WT SHIV162p32 1Cong et al J Virol 2011 2Cong et al Virol 2011

Efficacy of TDF/FTC PrEP against rectal challenge with K65R SHIV Cong ME et al J Infect Dis 2013

Risk of resistance with long-acting PrEP Long-acting formulations offer potential advantages for PrEP Infrequent dosing Better adherence? The long half-life and extended tail of these formulations carry unknown risk of resistance if HIV exposure occurs during tail Similar concerns may pertain to bNAbs with the LS modification

Cabotegravir-LA single-dose PK Spreen W et al JAIDS 2014

Drug resistance after exposure to long-acting RPV Penrose KJ et al J Infect Dis 2016

Conclusions PrEP may select for drug-resistant HIV To date, the incidence of resistance has been low Greatest risk for persons with unrecognized recent infection who initiate PrEP FTC resistance more likely to emerge than TFV resistance But dual resistance has been reported Increasing prevalence of K65R after 1st-line ART failure may blunt efficacy of TDF/FTC prep The prolonged tail of long-acting formulations may pose additional risks for resistance in persons infected after stopping PrEP More data will permit better modeling of the risk-benefit ratio of PrEP with respect to resistance