1. Young person with multi-class resistance: follow-up and management (with perspectives from well-resourced and resource-limited settings) Gareth Tudor-Williams Imperial College London UK

2. Where would you prefer to be right now? Langkawi resort?Attending a workshop?

3. Young person with multi-class resistance: follow-up and management (with perspectives from well-resourced and resource-limited settings) Gareth Tudor-Williams Imperial College London UK

4. Context In many resource-rich settings, young people with perinatally acquired HIV who are now in their mid-teens started on sub- optimal regimens in the pre-cART era. Typically dual therapy, such as AZT + 3TC, or d4T and ddI were used. Nelfinavir (unboosted) and ritonavir in therapeutic doses were our early PI’s. NNRTI’s were added to failing regimens.

5. Thankfully, the lessons have been learned! Less chance of selecting triple class resistance with today’s combination therapy

6. Case history 15 year old girl, Zambian parents VL 96,000 c/ml off treatment / CD4=280 Previous treatment: – AZT 3TC DDI TDF NFV RTV EFV Can swallow tablets Weighs 42 kg No known allergies Aware of her HIV status

7. Would you do a resistance test now? I would do a test: I would not do a test now:

8. HIV resistance mutations Adherence has been a long-standing problem and she has never sustained an undetectable VL for any consistent length of time. She has had a number of resistance tests over the years Right now, not much point in repeating resistance test since she has been off treatment Cumulative mutations from previous tests are more helpful, plugged into Stanford data base: http://sierra2.stanford.edu/sierra/servlet/JSierra?ac tion=mutationsInput

12. 15yrs – triple class resistance

13. In a well resourced setting: More information required to help decide what else to offer: –Is she co-infected with HBV or HCV?

14. If she is HBV infected, would you recycle lamivudine in next regimen? I would prescribe 3TC I would not include 3TC

15. In a well resourced setting: More information required to help decide what else to offer: –Is she co-infected with HBV or HCV? NO –HLA B*5701 status?

16. Where you work, do you have access to HLA B*5701 testing? I do have access I do not have access

17. In a well resourced setting: More information required to help decide what else to offer: –Is she co-infected with HBV or HCV? NO –HLA B*5701 status? Negative –HIV tropism?

18. Current co-receptor binding inhibitors work best against which strain of HIV? CXCR4 CCR5

19. Tropism = which co-receptor on the CD4+ lymphocyte is being used by the virus to bind to the cell

20. stageBlocked by 1 Binding & Fusion CCR5 co-receptor inhibitor (Maraviroc) Fusion inhibitor (Enfuvirtide = T20) 2 Reverse transcript’n NRTI’s (3TC, ABC) NNRTI’s (NVP, EFV) 3 Integration Integrase inhibitors (Raltegravir) 4Transcription 5 Assembly Protease inhibitors (Lopinavir / ritonavir) 6Budding and maturation Maturation inhibitors Targets for currently available inhibitors

21. In a well resourced setting: More information required to help decide what else to offer: –Is she co-infected with HBV or HCV? NO –HLA B*5701 status? Negative –HIV tropism? X4

22. ‘Virtual clinic’ recommendation, 2010 Virtual clinic = our HIV team, plus virologist / lab scientist, monthly meeting Darunavir 600mg twice daily Ritonavir 100mg twice daily Raltegravir 400mg twice daily Truvada 1 tablet once daily

23. Management Multi-disciplinary support for adherence Seen every two weeks for first month, plus phone calls from clinical nurse specialist No significant adverse effects Viral load tested 4 weeks after starting new regimen – excellent response, which reinforces her ability to adhere Follow-up visits gradually extended to 3m.

24. 2012: VL<50 for 1 year - would like once daily regimen….

25. Recent FDA approval Darunavir once daily for ARV naïve without DRV resistance mutations: ARV-naive children 3 to under 12 : –10 to under 15 kg: 35/7 mg/kg once daily –15 to under 30 kg: 600/100 mg once daily –30 to under 40 kg: 675/100 mg once daily ARV-naive adolescents 12 to <18 yrs: –40 kg or more: 800/100 mg once daily http://www.natap.org/2013/Pharm/Pharm_13.htm

26. (I54S, V82A) DRV susceptible

27. Virtual Clinic discussion 2012 ?? OD DRV/r +Truvada + Third agent ? – potential low level R to rilpivirine (2 nd generation NNRTI) ? Wait elvitegravir / dolutegravir ?? OD Raltegravir Decided to go for once daily DRV 800 / RTV 100 plus Truvada, with close monitoring of viral load… so far, so good!

28. Resource-limited setting 15 year old girl VL 96,000 c/ml off treatment / CD4=280 Previous treatment: – AZT 3TC DDI TDF NFV RTV EFV Can swallow tablets Weighs 42 kg No known allergies Aware of her HIV status

29. Resource limited setting: More information required to help decide what else to offer: –Is she co-infected with HBV? NO –HLA B57*01 status? Know your population! –HIV tropism? Not (currently) relevant

30. Prevalence of HLA B*5701 varies according to ethnic background

31. HLA B*5701 prevalence Ethnicityn =% positive White / Eurasian6548 Niger / Congo5730.5 Black Caribbean820 South Asian425 East Asian120

32. HLA B*5701 prevalence in African populations

33. Would you treat her with 3TC monotherapy? Yes, I would No, I wouldn’t

34. HIV resistance Much can be inferred without access to resistance testing Need to know what regimens she has had, and how long she was on a failing regimen Failure on 3TC – expect M184V mutation Failure on NNRTI – predictable resistance Trials such as the PENPACT 1 study provide some insights:

35. PENPACT 1 (PENTA 9 / PACTG 390) Antiretroviral therapy initiation with a PI versus an NNRTI combination and switch at higher versus low viral load in HIV-infected children: an open randomised controlled phase 2/3 trial Lancet Infect Dis 2011; 11: 273-283

36. A long-term comparison in ART naïve children of: PI-based versus NNRTI-based initial therapy two different viral load criteria for switching from 1 st to 2 nd line therapy: >1,000 versus >30,000 copies/ml PENPACT 1 trial (PENTA / IMPAACT)

37. Time to Switch by Drug Class At trial endPI (N=131)NNRTI (N=132) On 1 st regimen9673%9270% 0.00 0.25 0.50 0.75 1.00 Proportion of children not switched 024487296120144168192216240264288 Weeks from randomisation p=0.64 PI NNRTI Only 4 (2%) children switched to 3 rd line

38. Time to Switch by Viral Load Switch-point 0.00 0.25 0.50 0.75 1.00 Proportion of children not switched 024487296120144168192216240264288 Weeks from randomisation p=0.04 1,000 30,000 HIV-1 RNA at switch c/ml, median (IQR) 1,00030,000p-value 6,720 (1,380; 26,100)35,712 (8,060; 72,800)<0.01

39. Resistance testing Samples tested for resistance: Last sample with viral load >1000c/ml before switch at confirmed viral load >1000c/ml before re-suppression (to ensure a fair comparison between the 1000 and 30000 groups) at 4 years at trial end

40. If she was ‘failing’ on NVP for a year, would she have accumulated more NVP resistance than if she had switched as soon as VL reached 1,000 c/ml? Yes, more resistance No, no greater resistance

41. Cumulative Resistance at end of follow-up 1,00030,000P-value* Total children Number expected to have tests Number with tests 134 60 51 129 48 40 PI resistance 1 or 2 mutations11 (9%)5 (4%) 0.27 NNRTI resistance 1 or 2 mutations 3 or more mutations 18 (14%) 3 (2%) 16 (13%) 5 (4%) 0.50 High-level etravirine resistance1 (1%)2(2%)** Analysis assumes those without tests were not resistant. *Poisson regression ** score 5 on Stanford scale

42. Cumulative Resistance at end of follow-up PI 1,000 PI 30,000 NNRTI 1,000 NNRTI 30,000 P value Total children Number expected to have tests Number with tests 66 33 28 65 23 18 68 27 23 64 25 22 NRTI resistance 1 or 2 mutations 3 or more mutations 9 (15%) 3 (5%) 6 (10%) 3 (5%) 14 (22%) 0 (0%) 12 (20%) 7 (11%) 0.001 ** ** Driven by more children with ≥ 3 NRTI mutations in NNRTI switch at 30,000 c/ml arm

43. Start NNRTIs: 1000 group Potential NRTIs for second-line n first-line ZDV ddI 3TC ABC 1 3TC ABC EFZ low - - - 2 3TC ABC EFZ - - high pot. low 3 3TC ABC EFZ - inter. high high 4 3TC d4T EFZ - - - - 5 ZDV 3TC EFZ - - - - 6 ZDV 3TC EFZ - - - - 7 ZDV 3TC EFZ - - - - 8 ZDV 3TC EFZ - - - - 9 ZDV 3TC EFZ - - high pot. low 10 ZDV ddI EFZ inter. low - low 11 3TC d4T NVP - low high low 12 3TC d4T NVP - - high pot. low 13 3TC d4T NVP - - high pot. low 14 ZDV 3TC NVP - - high pot. low 15 ZDV 3TC NVP - - - - 16 ZDV 3TC NVP - - high pot. Low 17 ZDV 3TC NVP low low high inter. 18 ZDV 3TC NVP - - high pot. low 19 ZDV ABC NVP inter. low - low 20 ZDV ddI NVP - - - - Stanford score - = 1 fully susceptible pot. low = 2 potential low low = 3 low Inter. = 4 intermediate high = 5 high Example 14 children start on 3TC ZDV/d4T + NNRTI WHO 2010 recommends 2 nd line: ABC 3TC LPV/r : 5 fully susceptible OR ABC ddI LPV/r : 5 fully susceptible

44. Start NNRTIs: 30000 group Potential NRTIs for second-line n first-line ZDV ddI 3TC ABC 1 3TC ABC EFZ - - high pot. low 2 3TC ABC EFZ - high high high 3 ZDV 3TC EFZ - - high pot. low 4 ZDV 3TC EFZ - - high pot. low 5 ZDV 3TC EFZ - pot. low high pot. low 6 ZDV 3TC EFZ - - high pot. low 7 ZDV 3TC EFZ inter. inter. high inter. 8 ZDV 3TC EFZ - pot. low high low 9 ZDV 3TC EFZ inter. pot. low high low 10 ZDV 3TC EFZ low high high high 11 ZDV ddI EFZ inter. inter. - low 12 ZDV ddI EFZ - - - - 13 ZDV ddI EFZ low - - - 14 ZDV ddI EFZ inter. low - low 15 3TC ABC NVP - - high pot. low 16 3TC d4T NVP - - high pot. low 17 3TC d4T NVP pot. low - - - 18 3TC d4T NVP - - high pot. low 19 3TC d4T NVP inter. pot. low high low 20 3TC d4T NVP high inter. high inter. 21 ZDV 3TC NVP - - high pot. low 22 ZDV 3TC NVP high high high high Stanford score: - = 1 fully susceptible pot. low = 2 potential low low = 3 low inter. = 4 intermediate high = 5 high Example 15 children start on 3TC ZDV/d4T +NNRTI WHO 2010 recommends second-line: ABC 3TC LPV/r :1 fully susceptible OR ABC ddI LPV/r :1 fully susceptible

45. Start LPV/r: 30000 group Potential NRTIs for second-line n 1 st line ZDV ddI 3TC ABC 1 3TC d4T LPV - - - - 2 ZDV 3TC LPV - - - - 3 ZDV 3TC LPV - - - - 4 ZDV 3TC LPV inter. low - pot. low 5 ZDV 3TC LPV - - - - 6 ZDV 3TC LPV - - high pot. low 7 ZDV 3TC LPV inter. inter. high inter. Example 7 children started on 3TC ZDV/d4T + LPV/r WHO recommends second- line: ABC 3TC EFV : 4 fully susceptible OR ABC ddI EFV : 4 fully susceptible

46. Management Use boosted PI (i.e. Kaletra, if that’s what is available) Recycle available options Push for access to newer agents – darunavir / atazanavir / raltegravir and in due course dolutegravir…. GOOD LUCK!

47. With many thanks to Dr Caroline Foster and my colleagues in the HIV Family Clinic, Imperial College Healthcare NHS Trust, London UK and colleagues in Paediatric European Network for Treatment of AIDS (PENTA) especially Linda Harrison for PP1 analyses