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