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HIV Resistance in the Context of PrEP

Explore concerns, incidence, and effectiveness of HIV drug resistance with PrEP use. Learn about potential risks and implications for long-acting PrEP formulations.

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HIV Resistance in the Context of PrEP

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

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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

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

  13. 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

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

  15. 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

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

  17. 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

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

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

  20. 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

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