Resistance is futile: HIV in the age of integrases

1. Resistance is futile:HIV in the age of integrases

2. Outline • Resistance to ART • Current state of play • Future prospects

3. 1st entry inhibitor approval 1st cases of opportunistic infections described 1st post-attachment inhibitor approval 1st NNRTI approval 1st NRTI approval 1st PI approval 1st INSTI approval 1981 1987 1995 1997 2003 2007 2018 1992 1994 1999 2004 2008 1st NRTI resistance 1st PI resistance 1st T-20 resistance 1st INSTI resistance 1st NNRTI resistance

4. Global perspectives • Antimicrobial resistance

6. Unemo, Shafer Clin Micro Rev 2015

8. How does this translate to HIV?

10. Progress check

11. Massive scale up of ART 20.9 million by June 2017 Global AIDS Update, UN 2016

12. Maintaining ART • As treatment rates increase, levels of drug resistance increase • Occurs with high quality services, but more if there are gaps • Increased rates of drug resistance likely to increase transmitted drug resistance • If NNRTI continues as 1st line treatment and resistance >10% → risk of not achieving goals WHO HIV Drug Resistance Report 2017

13. AMR in HIV • Definitions of drug resistance • Acquired (ADR) • Transmitted (TDR) • Pretreatment (PDR)

14. HIV drug resistance testing

15. WHO HIV Drug Resistance Report 2017

16. NNRTI resistance • PLHIV with NNRTI resistance • 30% less likely to achieve VS • 23 x more likely to experience VF or death • 9 x more likely to stop treatment Mbuagbaw L et al, Guidelines on public health response to pre-treatment drug resistance, WHO 2017

17. WHO HIV Drug Resistance Report 2017

19. Children • Only South Africa has evaluated DR specifically in children • WHO recommendation 2013: • all children younger than 3 yo should get LPV/r based regimens • Poor uptake • Issues with variable dose formulation – only recently not requiring refrigeration and not palatable

20. Management of DR in LMIC • Identify drug resistance • Detect treatment failure • Have robust 2nd/3rd line options • Ascertain when to stop using NNRTI as first line

21. AMR in HIV • HIV replication is highly error prone • Development of multiple “quasi-species” within individual • What are we talking about? • In vitro vs in vivo • Phenotype vs genotype

22. Phenotypic drug susceptibility testing • Developed by ACTG/DoD • PBMCs cultured with various numbers of copies of HIV and various concentrations of AZT • Identified drug-resistant virus • Labour intensive, time consuming, but able to be standardized AAC 1993

23. Developments in phenotypic DST • Sequences of RT and protease from patient samples • Inserted into vector • Cultured with various concentrations of drug • Brightness of luciferase measured (or some other measure of viral growth) Petropoulos et al AAC 2000

24. Developments in phenotypic DST • Various iterations of phenotypic DST – ExaVir TM, PhenoSense TM • Ongoing work to make this more efficient and lower cost

25. Genotypic DST • Sequencing of patient HIV – relevant parts of the virus for drugs • Lab compares the sequence with reference sequence for subtype B virus • Identifies where amino acid changes have occurred • Interprets databases to correlate expected outcome with respect to viral growth

26. Database interpretation of genotype • HIVDB • >90 000 sequences of protease, RT, IN • From published work/GenBank

27. Drug resistance mutations

28. Genotype vs Phenotype • Sensitive to mutations in low frequency • Common mutations • Antagonistic mutations • Rare mutations • Combinations of mutations • Drug tested in isolation • Antagonistic mutations

29. Jacob • 24 year old Australian born cis male • Perinatal infection with HIV • Mother died when he was around 12 • Difficult relationship with father • Challenging engagement with HIV care through teenage years • Current treatment: Descovy 200/10, darunavir 600 bd, ritonavir 100 bd, etravirine 200 bd, raltegravir 400 bd plus azithromycin/pentamidine • CD4 10; VL varies 100-10 000

30. Jacob • Now swears that he has good adherence • Excellent HIV knowledge • Studying and working ~50h per week • In a regular relationship – partner on PrEP, but not clear how effective this would be if a condom broke

31. Previously identified mutations • NRTI: 41L, 67N, 70NRS, 184V, 210W, 215HY • NNRTI: 181C • Other 20R, 60I, 68G, 122E, 137NH, 211RK, 219D, 223KR, 228LH, 245M, 284K, 286A, 292VI, 294PT, 317A, 322T, 324DE, 329IV, 334QL • PI: Major: 54V, 82VA, 90M • Accessory: 33LF, 73S, 88D; Other: 10I, 13V, 20KR, 35ED, 36MI, 37ND, 60DE, 62IV, 63PS, 71AT, 72IT, 93L • Integrase: Nil major/accessory • Other: 31I, 101I, 113L, 119G, 122I, 124N, 201I, 234I (2017) • X4 detected

33. What to do for Jacob? • Established virologic failure • No current clinical consequences • At risk of adverse clinical events including transmission • Extreme limitation of alternate treatment options

34. Current state of play • Australian data • Testing for resistance in Brisbane • What about INSTI?

35. Rates of primary virologic resistance in Australia Reduction in • K103N • M41 • T215 Single case of INSTI resistance (118G/R) Note rapid disappearance of 184V EFV, NVP AZT, d4T D’Costa et al, Sex Health 2017

36. Rafiei N et al, AIDS 2017

37. Integrase resistance Anstett K. et al, Retrovirology 2017

38. Integrase resistance Anstett K. et al, Retrovirology 2017

39. Integrase resistance Anstett K. et al, Retrovirology 2017

40. Integrase resistance Anstett K. et al, Retrovirology 2017

41. Integrase resistance Anstett K. et al, Retrovirology 2017

42. ‡ 1 participant with transmitted INSTI resistance at G140S + Q148H Phenotypically sensitive to BIC and partially sensitive to DTG RT mutations: K70R and K103N Pooled Studies 1489 and 1490: BL Resistance Analysis in ART-Naive Case Study: B/F/TAF in Setting of Transmitted INSTI Resistance • Week 4 • Achieved VL <50 c/mL • Week 72 • Maintained suppression In this first case of an ART-naïve patient with transmitted integrase resistance (G140S + Q148H) on B/F/TAF. Virologic suppression was rapid and maintained from Week 4 to 72. Slide courtesy D. Fagan, Gilead White K, et al . CROI 2018. Boston, MA. Poster 532.

43. Treatment of patients with RAL resistance • VIKING II: 69% achieved UVL • Patients with Q148X plus 2 other mutations did worst • E157Q uncertain significance – reported to increase susceptibility to DTG • G118R has been selected in INSTI failure • R263K – RAL sensitive unless H51Y or E138K present Anstett K. et al, Retrovirology 2017

44. What about PrEP and resistance? • Lots of concern about fostering resistant HIV • Only occurs if you have HIV infection • Likely that PrEP failures will have higher rates of resistance to TDF/FTC • Future PrEP options will have their own vulnerabilities.

45. What to do for Jacob? • Established virologic failure • No current clinical consequences • At risk of adverse clinical events including transmission • Options • Re-evaluate and improve adherence • Repeat the resistance panel * • Improve potency/resistance barrier of INSTI

46. What about the future? • Worldwide • Tipping point for changing first line therapy is approaching • Need for VL testing in face of increasing DR • Locally • Improvement in turnaround time for resistance testing • Baseline INSTI resistance testing? • Failure with first line INSTI… • Potential impact of PrEP failure/change