1. 1 Treatment Failure HAIVN Harvard Medical School AIDS Initiative in Vietnam

2. 2 Learning Objectives By the end of this session, participants should be able to: Identify the 3 types of treatment failure Explain how to diagnose treatment failure based on clinical, immunological, and virological criteria Explain the indications for viral load testing in Vietnam and interpret a viral load result

3. 3 Overview Estimated frequency of treatment failure in Vietnam is 2-3% in first year of treatment, based on clinical and immunological criteria Highest incidence among patients who took ARVs before enrolling in free ARV program Changing treatment to second line on basis of virological or immunological failure aims to prevent clinical progression

4. 4 Resistance Overview (1) Low levels of drug (caused by nonadherence) or low drug potency (caused by previous resistance) allow viral replication, which generate mutations in viral RNA and DNA New mutations arise and these mutations can confer resistance to current drug Resistant virus will preferentially multiply, gradually leading to treatment failure

5. 5 Resistance Overview (2) Pre- Treatment Initial Response ARV Treatment Wild type HIV Resistant HIV Adherence Problem

6. 6 Three Types of Treatment Failure

7. 7 Typical Order of Treatment Failure Clinical Failure Immunological Failure Virological Failure This is the only part that you “see” (without lab tests)

8. 8 Clinical Treatment Failure MOH criteria: New or recurrent WHO stage IV event Note: Must differentiate from IRIS Some stage 4 conditions can occur even with complete virological suppression and may not indicate treatment failure while some stage 3 conditions may indicate treatment failure

9. 9 Immunological Treatment Failure MOH Criteria: (at least 2 CD4 measurements) CD4 count falls to or below pre-treatment value CD4 count falls to or below 50% on- treatment peak value CD4 persistently below 100 cells/uL for 1 year Other causes of change in CD4 must be considered

10. 10 CD4 Monitoring Check CD4 every 3-6 months Develop a system for reviewing all CD4 count to review and compare every test to previous results The CD4 test is like a lottery ticket: you only get a benefit if you check the numbers later!

11. 11 Virological Treatment Failure MOH criteria: VL > 5.000 copies/ml Confirm virological failure with 2 VL tests at least one month apart before switching to 2nd line ARV

12. 12 Viral Load (VL) Test

13. 13 Viral Load Test – Definition HIV PCR (VL) test: Number of HIV RNA copies per ml of plasma VL testing will be supported in some provinces in Vietnam Best test to assess treatment success or failure

14. 14 Viral Load Test - Best Test to Assess Treatment Effectiveness 2008 HCMC study of ARV resistance in patients with 1st-Line treatment failure 248 patients had VL testing June- December 2007 96% on 1st line regimens (d4T/AZT + 3TC + NVP/EFV) Results: VL undetectable: 100 (41.5%) VL detectable: 148 (58.5%) Positive Predictive Value (PPV) of Clinical or Immunological Criteria for Treatment Failure = 58.5%

15. 15 Targeted Viral Load Objectives: Confirm suspected clinical or immunological failure Maximize clinical benefits of first-line therapy Reduce unnecessary switching to second- line therapy WHO now recommends use of viral load to confirm treatment failure A targeted viral load strategy will be supported in Vietnam

16. 16 When to Do the VL test? After you make sure that patient has: Been on ARV > 6 months Adequate adherence Do the VL test if patient presents with one of the following: Clinical treatment failure criteria Immunological treatment failure criteria Other conditions or risk factors suspecting treatment failure

17. 17 Interpretation of Viral Load Undetectable VL< 250 VL < 48 Low Detectable 250 < VL < 5000 48< VL < 5000 >5000 The results of VL Test will be one of these: Note: Depends on the machine used for VL test, the detectable level can be 250 or 48

18. 18 What to Do if VL Result Is Undetectable? Interpretation: VL suppressed Treatment failure is not confirmed

19. 19 Interpretation: Detectable but below threshold for confirming treatment failure What to Do if VL Result Is Low Detectable?

20. 20 What to Do if VL Result Is > 5000? VL > 5000 copies/ml Initiate Adherence Intervention Repeat VL in 1 month Undetectable Continue current regimen Low detectable - Reinforce adherence - Repeat VL in 3 months (See Low Detectable Algorithm) VL > 5000 Switch to 2 nd Line

21. 21 3 Steps to Diagnose Treatment Failure

22. 22 Clinical Practice: 3 Steps to Diagnose Treatment Failure 1 Before thinking of treatment failure, make sure: ART > 6 months Currently adherent Not acutely ill 2 Check patient based on MOH criteria for: Clinical Failure Immunological Failure 3 Based on this information, make decision

23. 23 Clinical Practice: Step 1 (1) If patient is not adherent? Counsel the patient on adherence Evaluate the patient again after 3 months of good adherence: Clinical exam Repeat CD4 and/or VL if available  Consider switching to 2nd line only if evidence of treatment failure persists while patient is taking ARV with good adherence

24. 24 Clinical Practice: Step 1 (2) Does patient have an acute OI? Acute OI such as TB can temporarily decrease the CD4 count Therefore, before considering switching to second line ARV: Treat the OI first Then reassess the clinical and immunological status of the patient.

25. 25 Clinical Practice: Step 2 Clinical failure New or recurrence of stage 4 diseases or conditions CD4 failure c  CD4 count returns to or falls below pre-therapy baseline level  50% decline from the on-treatment peak value since the initiation of ART (if known)  CD4 count < 100 cells/mm3 after a year without any increase Virological failure d VL > 5,000/ml Check patient based on MOH Criteria for Treatment Failure

26. 26 Clinical Practice: Step 3 – Making a Decision Criteria Clinical Stage 1 - 234 CD4 failure (VL testing not available) Do not switch ARV regimen Follow for appearance of clinical manifestations of treatment failure Repeat CD4 after 3 months Consider switching to 2 nd line ARV Switch to 2 nd line ARV CD4 and VL failure Switch to 2 nd line ARV

27. 27 If Patient Is Confirmed with Treatment Failure, What to Do? Before Switching to 2nd Line ARV: Repeat adherence counseling Treat any acute OI first Provide counseling and patient education about the new regimen Second line ARV is last-line ARV in Vietnam!

28. 28 Switching ARV Due to Treatment Failure 1 st Line ARV2 nd Line ARV TDF + 3TC + NVP/EFV AZT + 3TC or ddI + ABC + LPV/r AZT/d4T + 3TC + NVP/EFV TDF + 3TC or ddI + ABC AZT/d4T + 3TC +TDF/ABCEFV/NVP + ddI Vietnam MOH, HIV/AIDS Treatment Guidelines, 2009.

29. 29 CASE STUDY

30. 30 Key Points Important to recognize resistance and treatment failure Three types of treatment failure are: clinical, immunological, and virological Always evaluate patient’s adherence before changing to second line ARV Diagnose treatment failure through: VL testing (most accurate) If VL not available, use combination of clinical and/or immunological criteria

31. 31 Thank you! Questions?