Changing Anti-Retroviral Therapy

1. Changing Anti-Retroviral Therapy dr shabeel pn

2. Introductory Case: Mikael • Mikael is a 28 year-old male diagnosed with AIDS who has been taking his triple drug ART regularly for the past 6 months without difficulties. He began therapy one year ago, during a bout of PCP pneumonia and oral thrush • CD4/TLC and VL monitoring is not available in his region • Today Mikael is diagnosed with toxoplasmosis and is hospitalized for treatment with Fansidar

3. Introductory Case: Mikael (cont.) • Which of the following statements about changing therapy are true? • ART should not be changed because this patient is not experiencing side effects from his regimen • A change in ART should be done for a patient who experiences a new opportunistic infection on ART • ART should be changed as soon as a patient starts to miss doses to avoid treatment failure • ART should only be changed when a patient experiences virologic failure

4. Unit Learning Objectives • Identify reasons for changing ART • List factors in ART failure • Determine how to change ART due to toxicity, treatmentfailure or concomitant disease • Describe factors to consider when changing ART • Describe appropriate laboratory monitoring procedures for ART

5. Ethiopia ARV guidelines Prior antiretroviral history Antiretroviral resistance Side effects Number of drugs needing replacement Barriers to adherence Patient life-style and preferences Ability to follow-up in clinic Drug interactions Cost and sustainability Factors to Consider When Changing Regimen

6. Reasons for Changing ART • ART is not changed unless absolutely necessary! • ART may be changed because of: • Treatment Failure • Clinical failure • Immunologic failure • Virologic failure • Toxicity or intolerance • Co-morbid conditions • Non-adherence/compromised quality of life

7. Treatment Failure • Treatment failure is defined by • Clinical failure • New or recurrent OI • Onset or recurrent WHO Stage III condition Note: Should not be confused with immune reconstitution inflammatory syndrome • Immunologic failure • Fall of CD4 count by >50% from the peak • Return of the CD4 count to baseline or below

8. Introductory Case: Mikael (cont.) • ART should not be changed because this patient is not experiencing side effects from his regimen FALSE • Where CD4 counts and viral load tests are unavailable, the WHO recommends using clinical evaluation to define treatment failure • This patient is experiencing clinical failure defined as the development of a new opportunistic infection (in this case toxoplasmosis) while on ART

9. Introductory Case: Mikael (cont.) • A change in ART should be done for a patient who experiences a new opportunistic infection on ART TRUE Where CD4 counts and viral load tests are unavailable, the WHO recommends using clinical evaluation to define treatment failure

10. Treatment Failure (2) • Virologic failure: • Failure to suppress viral load to undetectable • 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 8-12 weeks of ART

11. Antiretroviral Therapy: Failure to Suppress Medications Started 50 50 TIME Courtesy of David H. Spach, MD; NW AETC, University of Washington

12. Antiretroviral Therapy: Viral Failure Medications Started 50 50 TIME Courtesy of David H. Spach, MD; NW AETC, University of Washington

13. Reasons Treatment May Fail Treatment fails if: • Drugs are not strong enough to control the virus • Patient is too sick (clinical failure) or has serious infections which are not treatable • Patient has poor adherence • Missing more than three doses/month increases risk of treatment failure • Missing additional doses causes drug levels to fall, making HIV resistant

14. Treatment Failure and IRIS • Must differentiate treatment failure from Immune Reconstitution Inflammatory Syndrome (IRIS) • Clinical manifestation of a sub-clinical infection present at baseline. Brought on by ART-induced reconstitution of the immune system • Typically seen within several weeks of initiating ART

15. Introductory Case: Mikael (cont.) • ART should be changed as soon as a patient starts to miss doses to avoid treatment failure FALSE • If it is determined that a patient is missing doses, it is best to try to determine the cause and to identify a solution to assist the patient with adherence • Changing ART should only be done when absolutely necessary

16. Reasons Treatment May Fail (2) • Other medicines may stop ART from working • Reduce levels of ARVs in the blood • e.g. TB drug rifampicin is a potent liver enzyme inducer • Important: • Patients must be warned that herbal medicines could reduce ARV drug levels • Traditional healers must be told that their medicines could reduce ARV drug levels

17. Reasons Treatment May Fail (3) • Patient cannot tolerate the available drugs • Liver damage, nerve damage and anemia are possible serious side effects • Diarrhea, nausea and vomiting caused by the drugs may sometimes be too much to bear • Treatment may have to be stopped if these side effects become serious and replacement drugs are not available

18. Introductory Case: Mikael (cont.) • ART should only be changed when a patient experiences virologic failure FALSE • Virologic failure is only one possible reason that a change in therapy may be necessary • Other reasons to change therapy include: • Intolerable toxicities or side effects • Treatment failure (clinical failure or immunologic failure) • Co-morbidities

19. Pre-existing Resistance Poor Absorption Limited Potency of Regimen Rapid Elimination Imperfect Adherence Drug-Drug Interactions Persistent Viral Replication Drug Failure Causes of ART Failure: Summary

20. Toxicity • About 50% of patients treated for three years with good viral suppression will require a change in therapy due to an adverse reaction to antiretroviral drugs • Intolerable side effects • Organ Dysfunction • Interventions: • If the offending drug can be identified, replace just that drug • If the offending drug cannot be identified, replace entire regimen

21. Clinical Indications to Change ART Due to Toxicity

22. Lab Indications to Change ART Due to Toxicity * ULN = Upper Limit of Normal

23. Toxicity: Changing One Drug • Regimen: d4T/3TC/NVP • d4T-related neuropathy or pancreatitis: Switch d4T to ZDV • NVP-related rash or hepatotoxicity: • Switch NVP to EFZ (except pregnancy) • Switch NVP to PI’s (in cases of pregnancy or severe adverse effect) • Regimen: d4T/3TC/EFV • EFZ-related persistent CNS toxicity: Switch EFZ to NVP • Regimen: ZDV/3TC/EFV • ZDV-related anemia or neutropenia: Switch ZDV to d4T

24. Co-morbidities • A change in clinical status of patients may mandate change in ART • Pregnancy: • If on EFV based regimen – change EFV to NVP • Occurrence of active TB: • If on NVP based regimen – change to EFV (with adjusted dose), to LPV/r, or SQV/r

25. Minimizing Viral Resistance • Never prescribe ARVs in the absence of adherence counseling and support • Work with patients and their families to minimize barriers to medication adherence • Never prescribe ARV monotherapy or dual therapy • If ARV medications are to be discontinued, stop all drugs at the same time

26. Minimizing Viral Resistance (2) • Do not prescribe ZDV (zidovudine) and d4T (stavudine) together (antagonistic) • Pay meticulous attention to other medications and treatments and their potential to interact with ARV therapies • Never add a single drug (alone) to a failing regimen

27. Improving Adherence and Enhancing QOL • Reduce pill burden • Changing to fixed dose combinations • Replace PIs with NNRTI’s or abacavir • Minimize food/water restrictions • 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

28. Changing Regimen • When changing regimen due to treatment failure: • Evaluate for resistance through resistance testing or empiric decision-making based on clinical history • Change to an entirely new regimen, with at least one drug from a new class • Anticipate some cross-resistance (e.g. ZDV and d4T) • Try to determine and correct reasons for failure of the first regimen (e.g. adherence issues)

29. Alternative Regimen Source: Guideline for Use of Antiretroviral Drugs in Ethiopia. MOH, January 2005. p. 16

30. Changing Regimen (2) • Second-line therapy for patients with drug failure on d4T/3TC/nevirapine or efavirenz: • ZDV + DDI + IDV/r or • TDF +DDI + LPV/r • Second-line therapy for patients with drug failure on ZDV/3TC/nevirapine or efavirenz: • TDF + DDI + IDV/r or • TDF +DDI + LPV/r

31. Monitoring Therapy

32. First-Line Regimen: Laboratory Monitoring • Baseline: ALT and CD4 or TLC • Additional lab monitoring varies with regimen • NVP: ALT/AST at 2, 4, 6, 8 weeks, 3 months, then q 6 months and symptom directed • EFV: symptom directed thereafter for ALT, pregnancy test at baseline for women of childbearing age • ZDV: CBC/diff at baseline, 2, 4, 8 and 12 wks, then q 3-6 months and symptom directed

33. Laboratory Monitoring Guideline Source: Guideline for Use of Antiretroviral Drugs in Ethiopia. MOH, January 2005. Refer to slide at end of handbook.

34. Second-Line Regimen: Laboratory Monitoring • Baseline: CBC/diff, ALT, SCr and CD4 or TLC • Other lab monitoring varies with regimen • ZDV: CBC/diff at baseline, 2, 4, 8, 12 wks, then q 3-6 months and symptom directed • DDI: amylase at baseline and symptoms of abdominal pain, CBC with diff and LFTs q 12 months • TDF: urine protein dipstick and SCr at baseline, 3 months and q 6 months, CBC/diff and AST/ALT q 12 months • PIs: lipids at baseline and q 12 months, AST/ALT at baseline, 3 months then q 6 months, fasting glucose at baseline, then q 12 months • Indinavir: urine dipstick for RBCs with symptoms of flank pain, SCr at baseline then q 6 months

35. Case Studies

36. Case 1

37. Case Study: Kasahun • Kasahun is a 25 year-old male (CD4 count 56) who presents to clinic for follow-up 2 weeks after starting ZDV, 3TC and NVP. He learned his HIV status two months ago, during a hospitalization with CNS toxoplasmosis. He is currently receiving treatment for toxoplasmosis and has tolerated his medication over the past two months • At diagnosis he had significant lower leg numbness and weakness due to INH therapy for TB • Pyridoxine 40 mg was started to replace his B-complex vitamin. Why would this be necessary?

38. Case Study: Kasahun (2) • He had some nausea the first week on meds, which he has resolved by eating small meals before doses. He claims to take his medications every day as directed. He has lost weight and is now 51 kg • Today he presents complaining of a mildly itchy red rash over his trunk and arms which began 2 days ago. He says he feels tired all day. He proudly states that he has taken his NVP twice daily since his first day on medications

39. Case Study: Kasahun (3) • What do you think is occurring with Kasahun? • Should his ART regimen be changed? • What additional information would you like to know? • What are the laboratory tests that should be done at today’s visit to monitor Kasahun’s therapy?

40. Case Study: Kasahun Follow-up (4) • Laboratory Values • WBC: 5.6 H/H: 6.9 / 27 LFTs: 31 / 26 • How would you interpret these lab results? • He has had only minor headaches over the past 3 weeks. What does this tell us? • He does not have any other areas of the rash, oral blisters, myalgias or fever. What should you do? • Did he take NVP QD x 2 weeks, then increase to BID?

41. Case Study: Kasahun (5) • He has not been having trouble remembering doses • He has been taking doses with meals (breakfast and dinner) • Peripheral neuropathy symptoms have improved • However, he has been missing work due to fatigue

42. Case Study: Kasahun (6) • How would you interpret his results? • Would you change his ART? • How would you counsel Kasahun?

43. Case Study: Kasahun (7) • Follow up at 3 months shows: • CD4 count = 110 (10%) cell/mm3 • Hemoglobin/Hematocrat = 13 / 38% • WBC = 5.8 • 55 kg • He is tolerating medications except for occasional numbness in lower extremities. His symptoms have somewhat improved over last 3 months. Occasional nausea after taking meds • Claims he is taking all his medications. He takes his morning dose at work during his break and takes his evening dose with dinner

44. Case Study: Kasahun (8) • Therapeutic goals are being met • Patient energy increased and he’s feeling better • Appetite is good and he has gained 4 Kg • CD4 increasing (was 56/5% 2 months ago) • H/H normalized • However, he reports side effects: • If possible, decrease dose of stavudine to 30mg BID for neuropathy • Encourage food before doses

45. Case 2

46. Case Study: Yared • Yared is a 30 year-old man who has been stable on stavudine, lamivudine and nevirapine for the past four years • History: PCP pneumonia 4 years ago • Today his CD4 cell count is 140 cells/mm3, his previous CD4 count was 300 and his viral load has risen from undetectable levels to 50,000 copies/ml • He feels well and has no complaints today

47. Case Study: Yared (2) • What do you think is happening to Yared? • What additional information would you like to know? • Does he require a change in his regimen? • What possible regimen can you give to Yared, based on your local situation?

48. Case Study: Yared Follow-up (3) • Yared had been taking his medication as prescribed but missed doses recently while he was visiting his brother in Jimma • What are the factors to consider before starting a new regimen?

49. Case Study: Yared (4) • Side effects • Educate Yared on the potential side effects of each potential regimen • Patient preference • Yared is very fearful of the ABC hypersensitivity syndrome and would prefer to avoid ABC in his next regimen • Review drug-drug interactions • Cost and sustainability • Barriers to adherence • Plan ahead for changes in schedule, vacations, etc

50. Case Study: Yared (5) • He will begin TDF 300 mg qd +DDI 250 mg qd +LPV/r 3 caps bid • How will you monitor his therapy? • Clinical • Laboratory • Does he have to take his DDI apart from LPV/r and/or tenofovir?