Treatment Failure, Resistance, and 2 nd line ART in Resource-Limited Settings

1. Treatment Failure, Resistance, and 2nd line ART in Resource-Limited Settings Chris Behrens, MD July 2010

2. Questions this talk will address • How should patients in resource-limited settings be screened for treatment failure? • What is the optimal 2nd line HAART regimen for patients in resource-limited settings who fail a typical first-line regimen?

3. Some Key Definitions • 1st line regimen: “the initial regimen prescribed for a naïve patient when the patient fulfills national clinical and laboratory criteria to start ART.” • 2nd line regimen: “the next regimen used in sequence immediately after first-line therapy has failed” • Treatment failure: “the loss of antiretroviral efficacy [that] triggers the switch of the entire regimen from first to second line” • Note: single substitutions of ARVs (usually within the same class) for toxicity, drug-drug interactions, or intolerance to not indicate a 2nd line regimen is being used. WHO: Prioritizing Second Line ART within a Public Health Approach, 2007

4. Key Definitions, continued • Treatment Failure: • “loss of antiretroviral (ARV) efficacy, prompting a switch of the entire regimen from first- to second-line.” - WHO, 2007 • “absence of a sustained favourable response to antiretroviral therapy” - 2007 Caribbean Guidelines • How do we recognize Treatment Failure? • Clinical Failure • Immunologic Failure • Virologic Failure

5. Detecting Treatment Failure Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings (WHO, 2006)

6. Time-Sensitivity of different failure definitions for detecting Tx Failure Viral Load Clinical Status CD4 Count Time Tx Failure Immunologic detection Clinical detection Virologic detection

7. Time-Sensitivity of different failure definitions for detecting Tx Failure Viral Load Clinical Status CD4 Count ~ 4 months* Time Tx Failure Immunologic detection Clinical detection Virologic detection * Rawizz et al. 17th CROI, 2010, Abstract 111

8. How should patients in RLS be screened for treatment failure? What combination of clinical, immunological, and virological monitoring is most appropriate?

9. Clinical trials comparing different methods of screening for treatment failure DART HBAC

10. DART: Routine versus clinically driven monitoring of HIV ART • Randomized trial in Uganda, Zimbabwe involving 3321 symptomatic, ART-naïve adults with CD4 < 200 • randomized to • Laboratory + clinical monitoring (LCM); vs • Clinically driven monitoring (CDM) • Hematology, biochemistry, and CD4 counts performed every 12 weeks • Lab Results available immediately to providers of patients in the LCM group, only if clinically indicated to the CDM group • Endpoints: • New WHO stage 4 HIV events or death; • Serious adverse events Lancet. 2010 January 9; 375(9709): 123–131.

11. DART: Results Lancet. 2010 January 9; 375(9709): 123–131.

12. HBAC: Rakai, Uganda • Setting: rural Uganda • 1094 HIV-infected adults with CD4 < 250 or WHO stage 3/4 given ART and randomized to one of 3 monitoring arms: • Clinical + quarterly CD4 and viral loads; • Clinical + quarterly CD4 • Clinical only • Median f/u 3 years Coutinho A et al. 15th CROI, Boston, MA, USA; Feb 3–6, 2008. Abstract 125

13. HBAC: results • Rate to new AIDS-defining event or death was higher in arm C (clinical monitoring only) than arm A or B (clinical + CD4 +/- viral load) • No difference in time to new AIDS-defining event or death was found between arm A vs B (presence/absence of VL monitoring was only difference between arms A & B) Coutinho A et al. 15th CROI, Boston, MA, USA; Feb 3–6, 2008. Abstract 125

14. Detecting and Managing Treatment Failure in the absence of routine virologic monitoring • Access to routine viral load testing remains scarce in resource-limited settings • HBAC trial failed to show a clear benefit of including routine viral load monitoring in terms of mortality or clinical disease progression • Many clinicians are therefore obliged to monitor patients on HAART using only clinical & immunologic criteria to detect treatment failure • How effective is this approach in terms of diagnosing treatment failure and preventing the evolution of drug resistance?

15. Case 1 • 33 yo male on HAART after being diagnosed with pulmonary TB, CD4 = 220 • Now has completed TB therapy, doing well on HAART with rise in CD4 count • You do not have access to viral load monitoring, hence for this (and all your other patients) you rely on WHO clinical and immunological (CD4) criteria to detect treatment failure • How sensitive is this screening method for detecting treatment failure? How likely is it that your patients are failing therapy, but failure is not being picked up by checking CD4 counts?

16. Case 2 • 27 yo female on HAART for past year, seen for routine follow-up • Initial CD4 count 180, WHO Stage III • Reports excellent adherence. Feeling well. PE unremarkable • CD4 counts: • How should you manage this patient? How likely is it that this patient is truly failing treatment?

17. Performance of WHO clinical and immunological criteria to identify treatment failure Current Opinion in HIV and AIDS 2010, 5:1–5

18. Performance of WHO clinical and immunological criteria to identify treatment failure How likely is it that your patient is truly failing treatment? Current Opinion in HIV and AIDS 2010, 5:1–5

19. Performance of WHO clinical and immunological criteria to identify treatment failure How likely is it that your patient is failing therapy, but failure is not being picked up by clinical & CD4 status? Current Opinion in HIV and AIDS 2010, 5:1–5

20. Problems associated with clinical/immunologic screening for ART treatment failure • Overdiagnosis: most patients who meet WHO criteria for failure will not truly be failing • Solution: use VL testing to confirm/refute treatment failure that is suspected on the basis of CD4 counts and/or clinical disease progression • Cost-effective given high cost of 2nd line ART • Underdiagnosis: some patients who are truly failing therapy will be missed • These patients will eventually be diagnosed by CD4 drop and/or clinical disease progression, but the delay in diagnosis risks the accumulation of additional resistance mutations that could compromise the success of 2nd line ART. • How significant a problem is this?

21. Time-Sensitivity of different failure definitions for detecting Tx Failure Viral Load Clinical Status CD4 Count ~ 4 months* Time Tx Failure Immunologic detection Clinical detection Virologic detection * Rawizz et al. 17th CROI, 2010, Abstract 111

22. Resistance profile of patients failing First Line ART in Malawi when using Clinical and Immunologic Monitoring • Clinical ART failure • New WHO Stage IV condition • Progressive WHO Stage IV condition • Immunological ART failure • > 50% Decline from peak or below pre-treatment value • ART failure confirmed with HIV-RNA > 400 copies/ml • Resistance test if viral load >1000 copies ml • Genotypic analysis (TruGene) • Phenotype (Monogram) for complex genotypes 17th IAC, Mexico City 2008, Abstract TUAB0105

23. Malawi: resistance patterns in patients failing first line ART • On d4T/3TC/NVP or alternative first line (ZDV for d4T toxicity, EFV for NVP toxicity) • Enrollment from Dec 2005 to Jun 2007 • 96 patients identified as ART Failure with VL>1000 copies • 16 clinical (WHO Stage IV), 87 Immunological (CD4 decline) • 66 on d4T/3TC/NVP, 30 on ZDV/3TC/NVP • 2 samples did not amplify => 94 samples for analysis 17th IAC, Mexico City 2008, Abstract TUAB0105

24. Common Mutations • M184V or M184I 81% • NNRTI mutations 93% • Median 2 (range 0-3) • 181C 55%, 190A 30%, 103N 28% • Wild Type Virus 5% • M184 only 0% • NNRTI mutations only 2% • M184V & NNRTI mutations only 16% 17th IAC, Mexico City 2008, Abstract TUAB0105

25. Thymidine Analogue Mutations (TAMs) • 56% of patient samples had TAMs • 28% with one • 28% with 2 • 44% with 3 or more 17th IAC, Mexico City 2008, Abstract TUAB0105

27. Multivariate analysisemergence K65R or K70E resistance OR 95% CI CD4 count <100 cells/ml 6.1 1.47 – 25.0 Use of AZT 0.18 0.04-0.94 17th IAC, Mexico City 2008, Abstract TUAB0105

28. Multivariate analysisemergence PAN-NRTI resistance OR 95% CI CD4 count <100 cells/ml 9.8 1.16 – 82.9 Use of AZT 0.12 0.014 – 0.978 17th IAC, Mexico City 2008, Abstract TUAB0105

29. Implications • High level resistance to 3TC/FTC and to NNRTIs very common in patients who fail 1st line therapy • 2nd line regimen will need to be ‘anchored’ by a ritonavir-boosted PI • Challenge is to design a useful 2nd line NRTI backbone to complement the r/PI • Use of AZT rather than d4T in first line ART regimen better preserves 2nd line NRTI options • AZT prevents emergence of mutations associated with TDF resistance (K65R, K70E), which d4T can select for especially in HIV subtype C strains • Resistance to AZT associated with TAM II pathway, which confers less pan-NRTI resistance

30. What is the best empiric 2nd line ART regimen for patients whose treatment failure was initially detected by immunologic & clinical criteria? Theoretical considerations WHO Guidelines Experience to date

31. What is the best empiric 2nd line ART regimen for patients whose treatment failure was initially detected by immunologic & clinical criteria? Theoretical considerations WHO Guidelines Experience to date

32. 2nd line ART NRTI backbone: theoretical resistance considerations AIDS 2008, 22:2053–2067

33. Synergy of TDF and AZT in 2nd line regimens for patients failing typical 1st line regimen • Unless HIV has evolved multiple TAMs before switch to 2nd line regimen, the virus will likely be at least partially sensitive to both AZT and TDF • Combining AZT and TDF in the 2nd line regimen makes it very difficult for HIV to evolve resistance to both agents simultaneously • K65R mutation reverses TAM-mediated AZT resistance* • Only option for HIV would be to evolve more TAMs, which is difficult with TDF and an active PI in the regimen • This strategy may not work, however, for patients in whom failure is detected relatively late, as multiple TAMs impart high-level resistance to AZT and TDF (as well as d4T, ddI, and ABC) * Antivir Ther. 2006;11(2):155-63

34. Retain 3TC/FTC in 2nd line regimens? • The M184V mutation ‘hobbles’ HIV in two important ways: • Reduced replication capacity (approximately 1/2 log) - virus is less ‘fit’ • Partially reverses TAM-induced resistance to AZT, d4T, and TDF • Keeping 3TC (or FTC) in the 2nd line regimen forces HIV to maintain this inconvenient M184V mutation • 3TC (as well as FTC) is relatively well-tolerated, can be dosed once-daily, is present in many FDCs • Clinical outcomes data from a RCT suggests benefit of keeping 3TC in ‘salvage’ regimens* *Castagna A et al. E-184V study. Third IAS Conference, abstract WeFo0204, 2005.

35. 2nd line ART options for Malawi patients failing 1st line HAART • Based on resistance analysis, most potent 2nd line regimen among would be: TDF + AZT + 3TC/FTC + r/PI • Highest percentage of patients with 2 fully active NRTIs • Lowest percentage of patients with no fully active NRTIs 17th IAC, Mexico City 2008, Abstract TUAB0105

36. What is the best empiric 2nd line ART regimen for patients whose treatment failure was initially detected by immunologic & clinical criteria? Theoretical considerations WHO Guidelines Experience to date

37. WHO ART Rapid Advice: 2009

38. WHO ART Rapid Advice: 2009

39. Which regimen is most appropriate for 2nd line ART? • In the setting of failure of a typical 1st line regimen of (AZT or d4T) + 3TC + NNRTI, where resistance testing is not available: • WHO guidelines suggest TDF + 3TC + r/PI • Malawi data & theoretical considerations suggest AZT + TDF + 3TC + r/PI • Which 2nd line regimen is more appropriate? • Public Health approach • Individual patient approach

40. What is the best empiric 2nd line ART regimen for patients whose treatment failure was initially detected by immunologic & clinical criteria? Theoretical considerations WHO Guidelines Experience to date

41. 2nd line ART Responses: Malawi • 101 patients switched to 2nd line ART on the basis of WHO clinical/immunological criteria for failure • 2nd line ART regimen: AZT/3TC/TDF/r-LPV • 12 months of follow-up: • 10 patients died; • 3 lost to follow-up; • 85% of remaining had VL < 400 at 12 months • Resistance patterns in these patients did not predict response! 16th CROI, Montreal, 2009, abstract 605

42. 2nd line ART Responses: South Africa • N = 382 patients from Themba Luthu clinic (Johannesburg) switched to 2nd line ART regimen of AZT/ddI/r-LPV • 89% of patients alive and in care one year after switch • 78% had undetectable viral load • No data on response according to resistance profile 16th CROI, Montreal, 2009, Abstract 606

43. 2nd line ART Responses: Cambodia • N = 113 patients switched to 2nd line HAART regimen of ddI/3TC/r-LPV • 89% of patients had undetectable viral load a median of 10 months later • No data on response according to resistance profile 14th CROI, Los Angeles, 2007, abstract 36LB

44. Favorable responses to r/PI 2nd line ART - does the NRTI backbone matter? • Success of 2nd line ART in these settings may mostly reflect potency of r-LPV • Several studies suggest high efficacy of r-LPV monotherapy in patients who are naïve to ART or well-controlled on HAART • MONARK*: r-LPV monotherapy not as potent as traditional HAART in non-clade B HIV subtypes *11th European AIDS Conference, Madrid 2007, abstract PS1/2

45. Conclusions Monitoring for 1st line treatment failure Empiric 2nd line ART regimen design

46. Conclusions: monitoring for 1st line treatment failure • Clinical + CD4 monitoring superior to clinical monitoring alone (HBAC, DART trials) • Addition of routine VL monitoring has not been shown to reduce morbidity/mortality (HBAC) • addition of routine VL monitoring may diagnose failure sooner => less evolution of resistance, potentially less transmission of resistance in population • VL testing is expensive and technically difficult; putting eligible patients on ART a higher public health priority • Use of selective VL testing to confirm suspected treatment failure is required to reduce unnecessary switches to 2nd line ART

47. WHO ART Rapid Advice: 2009

48. Conclusions: Empiric 2nd line ART regimen design • For typical 1st line regimen (AZT or d4T)+3TC+NNRTI: • Theoretical considerations favor AZT + TDF + 3TC + r/PI • WHO Guidelines and (limited) practical experience suggest that TDF + 3TC + r/PI may be sufficient • Further studies necessary to clarify this question • For newer 1st line regimens of TDF + 3TC + NNRTI • AZT + 3TC + r/PI recommended by WHO and makes sense from a theoretical standpoint • No data yet from RLS regarding efficacy of this regimen in this scenario

49. Extra slides

50. Resistance patterns associated with failure of 1st line HAART regimens, where patients were virologically monitored for failure • Review of 36 articles and six abstracts involving patients failing 1st line HAART in sub-Saharan Africa • Most studies defined VF as VL>1000 c/mL • Wide range of HIV subtypes; C most common • 27 studies reported specific genotypic resistance mutations in 734 patients with VF • Failed first-line HAART regimens: • NRTIs + NNRTI (82%) • NRTIs + PI (16%)