1. Changing Antiretroviral Therapy Unit 9 HIV Care and ART: A Course for Physicians

2. 2 Learning Objectives  Explain the different reasons for changing therapy.  List important drug toxicities that necessitate changing therapy.  Describe the clinical, immunologic, and virologic indicators of ART failure.  Describe the principles of changing therapy in the event of drug toxicity and treatment failure.  List factors to consider when changing ART.

3. 3 Reasons to Change Therapy  Toxicity  Treatment Failure Clinical failure Immunologic failure Virologic failure  Pregnancy  Treatment of active tuberculosis  Non-adherence

4. 4 Changing Therapy Due to Toxicity  Toxicity: Organ dysfunction and/or intolerable side effects of a medication.  Detected as a result of patient report, physical exam, and laboratory tests.  Approximately 50 percent of patients treated for years with good viral suppression will require a change in therapy due to an adverse reaction

5. 5 Principles of Managing Adverse Events  Establish whether the adverse event is due to ARV drugs, other drugs, or diseases.  Try to identify the responsible ARV drug.  Assess the severity using ACTG (AIDS Clinical Trial Group) grading system

6. 6 Lab Grading of Adverse Events in Adults and Adolescents (ACTG) ItemGrade 1Grade 2Grade 3Grade 4 Hgb (g/dl)8 - 9.47 – 7.96.5 - 6.9 < 6.5 ANC(/mm3)1000- 1500 750 -990500 - 749 <500 Platelets(/mm3) -- <49,000 -- ALT (×ULN)*1.25-2.52.5-55-10>10 Bilirubin((×ULN) -- 3-7.5>7.5 Creatinine(mg/dl) -- 1.2-1.5>1.5 * “ULN” = Upper limit of normal value

7. 7 Clinical Grading of Adverse Events in Adults and Adolescents (ACTG) ItemGrade 1Grade 2Grade 3Grade 4 Peripheral neuropathy Mild discomfort &/or impairment Moderate discomfort &/or impairment Severe discomfort &/or impairment; sensory loss to knee and wrist Incapacitating or not responsive to narcotics; sensory loss involves limb & trunk RashErythema, prurius Diffuse maculopap- ular rash or dry desqua- mation Vesiculation, moist desquamation or ulceration Erythema multiforme, SJS, or TEN

8. 8 Changing Therapy Due to Toxicity- Specific Exchanges  d4T induced neuropathy or pancreatitis: switch to AZT  AZT induced anemia: switch to d4T  EFV induced persistent CNS toxicity: switch to NVP  NVP induced hepatotoxicity or non-life threatening severe rash: switch to EFV  NVP induced life threatening rash like SJS: switch to PI

9. 9 Discontinuation for Severe Toxicity  If severe toxicity identified, need to stop ALL HIV drugs  Do not reinitiate ART until toxic effect has resolved  When stopping NVP, do not re-challenge  Substitute new HIV drug for the drug that caused the toxicity, if known (e.g., if NVP hepatotoxicity, substitute EFV)

10. 10 Stopping Drugs with Different Half Lives 0244836 12 Time (hours) Drug concentration Zone of potential replication IC 90 IC 50 Last Dose Day 1 Day 2 MONOTHERAPY Source: S. Taylor et al. 11th CROI Abs 131

11. 11 Introductory Case: Abebe  Abebe, a 30-year- old HIV positive woman has been taking d4T+3TC+NVP for the last 2 months  Her baseline CD4 count was 150/mm3  Gained weight and strength in the first 6 weeks of starting ART  Developed anorexia, nausea and vomiting with jaundice in the last 2 weeks  Became weak and confused in the last 2 days  On exam, she has deep icterus and tender liver; confused, with flapping tremor

12. 12 Introductory Case: Abebe (2)  What are the likely differential diagnosis?  What tests would you request?

13. 13 Introductory Case: Abebe (3)  Lab tests revealed: ALT: 800 IU/L ( normal value = upto 40) Bilirubin( total): 12mg/dl ( normal upto 1mg/dl) HBs Ag and anti HCV Ab: negative  How would you manage her?

14. 14 Causes of ART Failure Preexisting Resistance Limited Potency of Regimen Host Immune Failure Poor Absorption Rapid Elimination Drug-Drug Interactions Imperfect Adherence Persistent Viral Replication Drug Failure

15. 15 Treatment Failure  Treatment failure can be classified as: Clinical failure Immunologic failure Virologic failure

16. 16 Clinical Failure  Clinical Failure: clinical disease progression despite HAART given for a sufficient time to allow immune restoration, or clinical disease following a period of HAART-induced immune restoration. Development of an OI or symptomatic disease Development of an HIV-related malignancy  Should be differentiated from Immune Reconstitution Inflammatory Syndrome

17. 17 Immune Reconstitution Inflammatory Syndrome (IRIS)  Different from clinical failure  IRIS is the clinical manifestation of a sub-clinical infection that was already present at baseline, brought about by HAART-induced reconstitution of the immune system Typically seen within the first several weeks after initiating HAART

18. 18 Immunologic Failure  Fall in CD4 counts more than 30% from peak value or  A return of CD4 count to, or below, the pre- treatment baseline  Not usually not seen for several months or maybe years after starting successful ART. CD4 count can take a long time to come back up even on effective ART, and may never reach a normal level if initially significantly suppressed

19. 19 Virologic Failure  Failure of viral load to become undetectable after 24 weeks of ART (failure to suppress)  Reappearance of detectable virus after a period of undetectability (loss of virologic control)  Less than one log (10-fold) decrease in viral load from baseline after 6-8 weeks of HAART  Need to ensure that failure is not due to lack of adherence.

20. 20 Virologic Failure with non-initial Suppression Courtesy of David H. Spach, MD; NW AETC, University of Washington

21. 21 Virologic Failure after Initial Response Medications Started 50 Courtesy of David H. Spach, MD; NW AETC, University of Washington

22. 22 Causes of Failure of Therapy  Poor adherence – most common and important reason  Viral resistance  Diminished efficacy of ARVs Decreased absorption of ARVs Drug-food interactions (eating/not-eating with meds  malabsorption) Drug-drug interactions Other disease processes in GI tract Colitis, gastritis, diarrhea lead to rapid transit times in intestines Inadequate dosage Increased metabolism

23. 23 Time Course of Treatment Failure Virologic Failure Immunologic Failure Clinical Failure

24. 24 Which Measure of Treatment Failure Should be Used?  Virologic failure precedes immunologic & clinical failure  Periodic viral load screening therefore offers advantage of detecting treatment failure earlier, when more options may exist for subsequent treatment regimens  However, viral load testing is also very expensive: Is the benefit of earlier detection worth the cost?

25. 25 Introductory Case: Abebe (4)  Abebe continued to take d4T+3TC+EFV for the last 2 years  Has been doing well clinically until 3 months back  CD4 count was 220/ mm3 6 months back  In the last 3 months, she started to have recurrent diarrhea and lost weight  On exam, she has oral thrush

26. 26 Introductory Case: Abebe (5) A.What is wrong with Abebe? B.What additional information would you like to know? C.What lab tests are important for managing this patient?

27. 27 Introductory Case: Abebe (6)  Abebe claims that she misses only 1 or 2 doses of ARV drugs in 3 months  CD4 count: 142/mm3  Viral load and resistance testing not available A.What is your assessment? B.How would you manage her?

28. 28 Treatment Failure Approach  Adherence! Adherence! Adherence!  Revisit co-morbid conditions that might be interfering, e.g. mental health; substance abuse  Inquire about side effects that may have contributed to poor adherence  Before moving on to the next regimen, try to identify and correct the cause of treatment failure with the initial regimen

29. 29 Changing Therapy in the Setting of Treatment Failure  In the setting of treatment failure, resistance should be suspected once complete non- adherence (“drug holiday”) is ruled out  A completely new regimen that includes a new class of agents is ideal  Resistance testing, if available, can help to guide the selection of the new regimen  Without resistance testing, empiric decision making based on clinical history is indicated

30. 30 Case Study: Management  Management Strong adherence counseling Start her with 3 new drugs; preferably 1 of which is from a new class of drugs ABC or TDF or AZT and ddI and LPV/r or SQV/r or NFV

31. 31 Second Line Regimens- Ethiopian Guideline First-line RegimenSecond-line Regimen d4T or ZDV and 3TC and NVP/EFV ABC or TDF or ZDV (if not taken) and ddI a and LPV/r b or SQV/r b or NFV

32. 32 Group Discussion  Would it be better to change to a second regimen sooner or later after ART failure and the development of viral resistance?  Ideally, we want to change from a failing regimen as soon as possible

33. 33 CNA3005: Slow Stepwise Appearance of Mutations in Patient With Virologic Failure WTM184V M184V, Y215T/Y M41L/M, M184V, Y215Y M41L, M184V, L210L/W, Y215Y 50 c/mL 400 c/mL D67N/D, K70R/K, M184V ABC=5.9, ZDV=4.1-fold ABC=6.2, ZDV=12.2-fold M41L, M184V, Y215Y 28 weeks of M184V only 5000 c/mL Source: Melby T, et al. 8th CROI; February 4-8, 2001; Chicago, IL. Poster 448.

34. 34 Antiretroviral Resistance Testing  Goal of resistance testing is to identify these resistance- conferring mutations in order to design a ‘salvage’ regimen intelligently  Studies have documented clinical benefit of resistance testing  Expert advice on interpretation of the genotype is vital  Two types: Genotyping (less expensive; can be completed in 1-2 weeks) Phenotyping (more expensive; generally takes 2-3 weeks)

35. 35 Factors to Consider When Changing Regimen  Prior antiretroviral history (assessment of adherence)  Ability to follow-up in clinic  Side effects  Antiretroviral resistance  Barriers to adherence  Patient life-style and preferences  Drug interactions  Cost and sustainability  Ethiopian ARV Guidelines

36. 36 Summary Guidelines for Changing ARV Regimens  Utilize caution when considering ARV change  Assess adherence  At least 2 new drugs  Preferably 1 new drug class  Don’t add one drug to a failing regimen

37. 37 Summary Guidelines for Changing ARV Regimens (2)  Consider resistance & cross resistance  Quality of life in end stage disease  Get advice from experienced clinicians  Consider resistance testing if available  Premature changing in ARV can limit future options

38. Case Study Handout 9.1

39. 39 Key Points  If drug toxicity (grade 3 or 4) occurs, replace the offending agent with a drug which doesn’t cause the specific side effect.  If there is a life threatening toxicity, stop all drugs until patient’s condition is stabilized  In case of treatment failure, first check patient’s adherence and then change all 3 drugs

40. 40 Key Points (2)  The main reasons for changing ART are treatment failure and drug toxicity. Treatment failure may be clinical, immunologic, or virologic.  Other reasons include problems with adherence or other medical conditions, or illnesses that may impact choice of therapy such as pregnancy or TB.  Regular clinical and laboratory monitoring is necessary to detect side effects and to monitor success/failure of therapy.