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Changing Antiretroviral Therapy

Changing Antiretroviral Therapy. Unit 9 HIV Care and ART: A Course for Physicians. Learning Objectives. Explain the different reasons for changing therapy. List important drug toxicities that necessitate changing therapy.

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Changing Antiretroviral Therapy

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

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

  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. 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. Lab Grading of Adverse Events in Adults and Adolescents (ACTG) * “ULN” = Upper limit of normal value

  7. Clinical Grading of Adverse Events in Adults and Adolescents (ACTG)

  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. 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. Last Dose Day 1 Day 2 Drug concentration IC90 MONOTHERAPY Zone of potential replication IC50 12 0 24 36 48 Time (hours) Stopping Drugs with Different Half Lives Source: S. Taylor et al. 11th CROI Abs 131

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

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

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

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

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

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

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

  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 • What is your assessment? • How would you manage her?

  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. 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. 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. Second Line Regimens- Ethiopian Guideline

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

  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. 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. 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. 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. 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. 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.

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