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

2. 2 Learning Objectives At the end of this presentation, participants should be able to: Recognize the importance of diagnosing treatment failure Know the definitions of treatment failure Understand how to diagnose ARV treatment failure based on clinical, immunological, and virological criteria Recite the recommended second line regimens after first line treatment failure in Vietnam

3. 3 Content Overview Treatment failure definitions Diagnosing treatment failure Changing to 2 nd line Case examples

4. 4 Overview The frequency of treatment failure among children on ART in Vietnam is currently unknown. Studies from other settings (i.e. South Africa) suggest a relatively high rate of treatment failure  11% probability of treatment failure at three years When treatment failure occurs, it is often not recognized  Approximately 50% of children with virologic failure were not switched to 2 nd line therapy  When switching occurred there was a significant delay (median 5 months) between treatment failure and switching

5. Overview Proper and prompt recognition of treatment failure is important:  Prevent progression of disease and clinical event (OI)  Prevent accumulation of drug resistance mutations  Avoid unnecessary switching to second- line drugs 5

6. Causes of treatment failure Problems with patient adherence Pre-existing or acquired drug resistance Problems with absorption or metabolism of a drug leading to sub-therapeutic drug levels; due to:  inherent characteristics of the individual  pharmacokinetic interactions with concomitant medications 6

7. 7 Lower limit of effective drug concentration in blood Regular medication Wild-type HIVResistant HIV HIV resistance: ARV Exposure

8. 8 Before diagnosing treatment failure:  ART > 6 months  Currently adherent  Not acutely ill

9. 9 If the patient (or care provider) is not adherent: Counsel the patient (or care provider) on adherence Evaluate the patient again after 3 months of good adherence  Clinical exam  Repeat CD4 and/or VL if available Consider switching to second line ARV only if evidence of treatment failure persists while the patient is taking ARV with good adherence

10. 10 CD4 Monitoring Check CD4 every 3-6 months. Every test must be reviewed and compared to previous results.  Develop a system for reviewing all CD4 test results  Patients with dropping CD4: Consider other causes of low CD4 (acute OI, poor adherence) Evaluate for possible treatment failure The CD4 test is like a số vế: you only get a benefit if you check the numbers later!

11. 11 Types of Treatment Failure Virological Failure Immunological Failure Clinical Failure

12. 12 Virological Treatment Failure Definition:  Increase of viral load (VL) caused by resistant virus  Adult guidelines: VL > 5.000 copies/ml  Pediatric threshold not defined  If no evidence of clinical or immunological treatment failure, then confirm virological failure with 2 VL tests at least one month apart before switching to 2 nd line ARV HIV PCR (VL) test:  Number of HIV RNA copies per ml of plasma  Available at some sites in the North and South  Best test to assess treatment success or failure

13. 13 Immunological Treatment Failure Immunological failure: Decline in CD4 count due to ongoing destruction of T cell  CD4 count falls to or below the level of severe immunodeficiency by age after initial recovery response  CD4 count falls rapidly below the level of severe immunodeficiency by age (confirmed by at least two consecutive measurements)  CD4 count falls to or below the baseline CD4 count  CD4 count falls below more than 50% of the peak level Vietnam MOH HIV/AIDS Treatment Guidelines, 2009.

14. 14 Clinical Treatment Failure Clinical Failure:  Lack of or decline in growth rate in children who initially respond to treatment  Loss of neuro-developmental milestones or development of encephalopathy  Severe or recurrent infection or illness: Recurrence or persistence of AIDS-defining conditions or other serious infections. Notes:  Before considering a change in treatment because of growth failure it should be ensured that the child is receiving adequate nutrition.  Some stage III conditions (pulmonary and lymph node TB, bacterial pneumonia) can occur even with complete virological suppression and may not indicate treatment failure* *Vietnam MOH HIV/AIDS Treatment Guidelines, 2009.

15. 15 Making the decision to switch to 2 nd line ARV ClinicalLaboratoryManagement Clinical Stage 1 – 2 CD4 not available Do not switch CD4 available Consider switching only if at least 2 CD4 results are below severe immunodeficiency level by age Clinical Stage 3 CD4 not available Consider switching CD4 available Switch if CD4 is below severe immunodeficiency level, especially if children have ever had good immunological response to ART Clinical Stage 4 CD4 not available Switch to 2 nd line CD4 available Switch to 2 nd line Vietnam MOH HIV/AIDS Treatment Guidelines, 2009.

16. Consider causes of treatment failure Assess medication adherence  Inadequate adherence is the most common cause of antiretroviral treatment failure  Assess barriers to adherence  Explore interventions to improve adherence Assess medication intolerance Assess issues related to pharmacokinetics  Recalculate doses for individual medications using weight or body surface area  Identify concomitant medications including prescription, private pharmacy, and traditional therapies  Assess for drug-drug interactions

17. 17 Before switching to 2 nd Line ARV… Repeat adherence counseling: only change the ARV regimen when the patient has the ability to take it with good adherence. Treat any acute OI first. Provide counseling and patient education about the new regimen. REMEMBER: There is no 3 rd line ARV regimen in Vietnam. Second line ARV is last-line ARV!

18. Switching from 1st line to 2nd line regimens Failure on 1 st regimensChange to 2 nd regimens AZT or d4T + 3TC + NVP AZT or d4T + 3TC + EFV ddI + ABC + LPV/r AZT or d4T + 3TC + ABCddI + EFV + LPV/r ddI + NVP + LPV/r ABC + 3TC + NVP or EFVAZT + 3TC (+/- ddI) + LPV/r d4T + 3TC + LPV/r

19. 19 Key Points It is important to recognize resistance and treatment failure Always evaluate adherence before changing to second line ARV There are 3 types of treatment failure: clinical, immunological, and virological Viral load testing is the most accurate way of diagnosing treatment failure If viral load not available, treatment failure can be determined by a combination of clinical and/or immunological criteria

20. Thank you! Questions?