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03.03 management of patients on antiretroviral drugs changi


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03.03 management of patients on antiretroviral drugs changi

  1. 1. Module 3 Unit 3: Changing/stopping ART A Rational Approach to a Complicated Subject
  2. 2. Objectives <ul><li>By the end of this session, the participants should be able to: </li></ul><ul><li>Describe the side effects of ARV drugs and their management </li></ul><ul><li>Describe interactions between ARV drugs and other drugs </li></ul><ul><li>Describe when to change or stop ART </li></ul>
  3. 3. Three Main Reasons for Altering a Patient’s ARV Drug Regimen: <ul><li>1. Drug Toxicity or Intolerance </li></ul><ul><ul><li>Single drug substitutions appropriate </li></ul></ul><ul><li>2. Drug Interactions </li></ul><ul><ul><li>Single drug substitutions appropriate </li></ul></ul><ul><li>3. Treatment Failure </li></ul><ul><ul><li>Entire regimen must be changed </li></ul></ul>
  4. 4. Other reasons for altering a patient’s regimen <ul><li>Pregnancy </li></ul><ul><li>Interruption of drug supply </li></ul>
  5. 5. 1. Drug Toxicity and Intolerance <ul><li>Adverse drug reactions (ADRs) are the most common reason for treatment discontinuation </li></ul><ul><ul><li>All classes of ARVs associated with ADRs </li></ul></ul><ul><li>Two Broad Groups of Side-effects: </li></ul><ul><ul><li>Common “Mild” </li></ul></ul><ul><ul><li>Rare and Dangerous </li></ul></ul>
  6. 6. ARV Drug Class Adverse Effects <ul><li>NRTIs </li></ul><ul><li>Peripheral neuropathy </li></ul><ul><li>Pancreatitis </li></ul><ul><li>Lipoatrophy </li></ul><ul><li>Hepatitis </li></ul><ul><li>Lactic acidosis </li></ul><ul><li>Mitochondrial toxicity </li></ul><ul><li>NNRTIs </li></ul><ul><li>Rash </li></ul><ul><li>Fever </li></ul><ul><li>Nausea </li></ul><ul><li>Diarrhea </li></ul><ul><li>Hepatoxicity </li></ul><ul><li>PIs </li></ul><ul><li>Lipodystrophy </li></ul><ul><li>GI Intolerance </li></ul><ul><li>Hyperglycaemia </li></ul><ul><li>Lipid abnormalities </li></ul><ul><li>Common Adverse Effects </li></ul><ul><li>Peripheral Neuropathy – d4T,ddI </li></ul><ul><li>Hematotoxicity - AZT </li></ul><ul><li>Hepatotoxicity - NVP </li></ul><ul><li>Diarrhea – NFV </li></ul><ul><li>Skin rash – NVP </li></ul><ul><li>Lipodystrophy – PIs, NRTIs </li></ul><ul><li>CNS disturbance – EFV </li></ul><ul><li>Hypersensitivity – ABC </li></ul><ul><li>Hyperlipidemia-PIs, d4T </li></ul>
  7. 7. Common “Mild” Side Effects <ul><li>Many patients are asymptomatic when treatment is started </li></ul><ul><li>Minor ADRs may therefore be as distressing to patients as major grade 3 or 4 ADRs </li></ul><ul><ul><li>Include </li></ul></ul><ul><ul><li>Nausea </li></ul></ul><ul><ul><li>Vomiting </li></ul></ul><ul><ul><li>Lethargy, fatigue </li></ul></ul><ul><ul><li>Headaches </li></ul></ul><ul><ul><li>Dizziness </li></ul></ul><ul><ul><li>Flu-like symptoms </li></ul></ul><ul><ul><li>Mild rash </li></ul></ul>
  8. 8. Common “Mild” Side Effects <ul><li>Occur soon after initiation of treatment; patients should be warned about them </li></ul><ul><li>Usually improve within 1-2 months </li></ul><ul><li>If necessary give supportive treatment to manage or reduce symptoms </li></ul><ul><li>Rarely necessary to change/stop treatment regimen </li></ul>
  9. 9. Rare, potentially serious ADRs <ul><li>May be acute occurring early in treatment </li></ul><ul><ul><li>Severe rash/Steven Johnson Syndrome </li></ul></ul><ul><ul><li>Hepatotoxicity </li></ul></ul><ul><ul><li>Peripheral Neuropathy </li></ul></ul><ul><ul><li>Hematological toxicity </li></ul></ul><ul><ul><li>Pancreatitis </li></ul></ul><ul><ul><li>Lactic Acidosis </li></ul></ul><ul><li>Late occurring months or years into treatment </li></ul><ul><ul><li>Metabolic complications – hyperinsulinism, dyslipidemia, lipodystrophy, cardiovascular events </li></ul></ul>
  10. 10. Toxicity: Anticipate <ul><li>Proactive assessment for predictable toxicity </li></ul><ul><li>Use of well tolerated regimens as much as possible associated with low toxicity early in treatment </li></ul><ul><li>Avoiding drug combinations likely to be associated with toxicity as much as possible </li></ul>
  11. 11. Management of Adverse Drug Effects <ul><li>Try and establish the ARV drug responsible for the adverse effect </li></ul><ul><li>Consider duration of ARV use, other disease processes, other treatments (including self administered) </li></ul><ul><li>If it is necessary to stop ART, discontinue all ARV drugs simultaneously* </li></ul><ul><li>Grade 1 or 2 reactions: continue ART under observation. </li></ul><ul><ul><li>Single drug substitution may be necessary </li></ul></ul><ul><li>Grade 3 or 4- Stop ART, manage Adverse Event and re-introduce ART. </li></ul>
  12. 12. A Rational Approach to the Management of Serious Side Effects Refer to “The National Clinical Manual for ARV Providers”
  13. 13. Rash <ul><li>Most commonly due to Nevirapine </li></ul><ul><li>Also sometimes Efavirenz, Abacavir and Cotrimoxazole </li></ul><ul><li>Patient information and counseling on predictable ADRs should done </li></ul>
  14. 14. Case Study - Rash <ul><li>A 34 year old woman has been commenced on d4T, 3TC (BD) and NVP (OD). She returns after 2 weeks with a dry, itchy rash over her entire body. </li></ul><ul><ul><li>What grade is her rash? </li></ul></ul><ul><ul><li>What action should be taken? </li></ul></ul>
  15. 15. Hepatotoxicity <ul><li>Nevirapine is most likely to cause hepatotoxicity </li></ul><ul><ul><li>More likely in women than in men </li></ul></ul><ul><ul><li>More likely at CD4 >250 in women >400 in men </li></ul></ul><ul><li>Other ARVs can also cause liver toxicity including NRTIs and PIs </li></ul><ul><li>Check ALT/SGPT routinely at baseline, 4-6 weeks and at 3 months </li></ul><ul><li>Check ALT/SGPT if any hepatic symptoms/signs </li></ul><ul><li>Consider other causes </li></ul><ul><ul><li>Other drugs (e.g. anti-TB) </li></ul></ul><ul><ul><li>Infectious hepatitis, other infections </li></ul></ul>
  16. 16. Case Study - Hepatotoxicity <ul><li>A 27 man has been taking d4T/3TC/NVP twice a day for 6 weeks. He presents with abdominal pain, nausea and malaise. He has marked right upper quadrant tenderness, but is not clinically jaundiced. </li></ul><ul><ul><li>What test should be performed urgently? </li></ul></ul>
  17. 17. Continued… <ul><li>An ALT/SGPT is performed urgently </li></ul><ul><li>The result comes back at 462 U/L </li></ul><ul><ul><li>What grade is this? </li></ul></ul><ul><ul><li>What is the most likely cause? </li></ul></ul><ul><ul><li>What action should be taken? </li></ul></ul>
  18. 18. Hematological Toxicity <ul><li>AZT by far the most common cause </li></ul><ul><ul><li>Most likely in women, those with pre-existing anemia and low baseline CD4 count </li></ul></ul><ul><ul><li>Peaks at 4-12 weeks after treatment initiation </li></ul></ul><ul><ul><li>AZT can also cause neutropenia, thrombocytopenia </li></ul></ul><ul><li>Check Hb at baseline, 4-6 weeks at 3 months, thereafter 6 monthly routinely </li></ul><ul><li>Check Hb if clinical symptoms/signs of anemia </li></ul><ul><li>Remember other possible causes of bone marrow suppression </li></ul><ul><ul><li>Cotrimoxazole </li></ul></ul>
  19. 19. Case Study – Hematological Toxicity <ul><li>A 40 year old man before starting ART has a baseline Hb of 12.4. He is started on AZT/3TC + EFV. His routine Hb check at 1 month is 6.8 – an urgent repeat Hb confirms the result. </li></ul><ul><ul><li>What is the grade of adverse drug reaction? </li></ul></ul><ul><ul><li>What drug is the most likely cause? </li></ul></ul><ul><ul><li>What action should be taken? </li></ul></ul>
  20. 20. Peripheral Neuropathy <ul><li>d4T and ddI most common cause </li></ul><ul><ul><li>Especially if used together or with other drugs likely to cause PN (e.g. Isoniazid) </li></ul></ul><ul><li>Can be disabling and irreversible </li></ul><ul><li>Patient education and counseling on adverse drug reactions should be done </li></ul><ul><li>Symptomatic management if mild </li></ul>
  21. 21. Case Study - Neuropathy <ul><li>A 24 year old woman has been on TB treatment for 5 months and d4T/3TC/NVP for 3 months (started after the intensive phase). </li></ul><ul><li>She walks into the clinic with the assistance of her husband – since the last appointment she has developed progressive pain and weakness in her legs. She cannot rise from a chair without help and greatly reduced sensation below her knees. </li></ul><ul><ul><li>What grade neuropathy does she have? </li></ul></ul><ul><ul><li>What action should be taken? </li></ul></ul>
  22. 22. Continued… <ul><li>She is given Pyridoxine 50mg TDS </li></ul><ul><li>After 2 weeks she returns – the pain has reduced a little but she still needs assistance to walk </li></ul><ul><ul><li>What action should be taken now? </li></ul></ul>
  23. 23. Pancreatitis <ul><li>Rare, but can be fatal </li></ul><ul><li>Abdominal pain, vomiting, hypovolemic shock; may be asymptomatic </li></ul><ul><li>ddI and d4T most common causes </li></ul><ul><ul><li>Especially if together or with other pancreas damaging drugs (e.g. alcohol) </li></ul></ul><ul><li>If suspicion check serum amylase </li></ul><ul><li>If occurs, best to stop all drugs until resolved – seek expert help; supportive treatment needed </li></ul>
  24. 24. Late Toxicity <ul><li>Management of late metabolic toxicities can be difficult </li></ul><ul><li>Lipodystrophy </li></ul><ul><ul><li>Lipoatrophy (LA) associated with thymidine analogs (d4T >> AZT) </li></ul></ul><ul><ul><li>Very common after long periods on stavudine containing regimen </li></ul></ul><ul><ul><li>Associated fat loss in the face and limbs with central fat accumulation </li></ul></ul><ul><ul><li>Distressing to patients and may increase stigma </li></ul></ul>
  25. 25. Late Toxicity <ul><li>Lipodystrophy </li></ul><ul><ul><li>Lipohypertophy associated with PIs </li></ul></ul><ul><ul><li>Fat accumulation centrally with large belly and buffalo hump </li></ul></ul><ul><li>Lipid abnormalities – all classes </li></ul><ul><li>Insulin resistance including frank diabetes (PIs) </li></ul><ul><li>Cardiovascular disease PIs and also NRTIs </li></ul>
  26. 26. Management of late toxicity <ul><li>Management </li></ul><ul><ul><li>Exercise and diet </li></ul></ul><ul><ul><ul><li>Useful for fat accumulation, insulin resistance and cardiovascular disease; less so for LA </li></ul></ul></ul><ul><ul><li>Smoking cessation (cardiovascular risk) </li></ul></ul><ul><ul><li>Switching ARV treatment </li></ul></ul><ul><ul><ul><li>Where possible substitute d4T with ABC or TDF in case of d4T associated LA. </li></ul></ul></ul><ul><ul><ul><ul><li>Not always possible and patient counseling to support continued treatment essential </li></ul></ul></ul></ul><ul><ul><li>Standard treatment of hyperlipidemia and diabetes mellitus </li></ul></ul>
  27. 27. 2. Drug Interactions It is not possible to remember all the possible drugs interactions with ARV Drugs Refer to “The National ARV Guidelines”
  28. 28. Main Problems <ul><li>Blood levels of ARVs may be increased or decreased </li></ul><ul><li>Reduction/increase in concentrations of other drugs </li></ul><ul><li>Additive toxicities </li></ul><ul><li>Some ARV drugs are not compatible with each other </li></ul>
  29. 29. 1. Blood levels of ARVs Increased or Decreased <ul><li>Plasma concentration of NVP increased by 100% by Fluconazole; avoid combination </li></ul><ul><li>Rifampicin, a potent CYP450 enzyme inducer, reduces NVP, IDV, NFV levels (next slide) </li></ul><ul><li>These combinations should be avoided </li></ul>
  30. 30. TB Drugs <ul><li>Rifampicin reduces blood levels of NVP </li></ul><ul><ul><li>Currently NOT recommended together </li></ul></ul><ul><li>If a patient is already on NVP and develops TB, change to EFV 600mg OD </li></ul><ul><li>If not yet on ARVs but requires anti-TB defer ARVs until intensive phase completed or use EFV </li></ul>
  31. 31. 2. Reduction/increase in concentrations of other drugs (making them ineffective/toxic) <ul><li>Oral contraceptive pill unreliable with NVP/EFV and PIs – reduced concentration thus need alternative or additional method of contraception </li></ul><ul><ul><li>Metabolism of Medroxyprogesterone (Depo-Provera) not affected by NNRTIs and NFV </li></ul></ul><ul><li>EFV, RTV, other PIs increase plasma concentration of the following: </li></ul><ul><ul><li>Benzodiazepines (respiratory arrest) </li></ul></ul><ul><ul><li>Antihistamines (cardiac arrhythmias) </li></ul></ul><ul><li>Avoid these combinations </li></ul>
  32. 32. 3. Additive/Overlapping Toxicities <ul><li>BONE MARROW DEPRESSION </li></ul><ul><li>AZT </li></ul><ul><li>Ganciclovir </li></ul><ul><li>Cotrimoxazole </li></ul><ul><li>NEPHROTOXICITY </li></ul><ul><li>Indinavir- stones </li></ul><ul><li>Aminoglycosides </li></ul><ul><li>PERIPHERAL NEUROPATHY </li></ul><ul><li>ddI </li></ul><ul><li>d4T </li></ul><ul><li>Isoniazid </li></ul><ul><li>DIARRHOEA </li></ul><ul><li>ddI </li></ul><ul><li>NFV </li></ul><ul><li>RTV </li></ul><ul><li>Cotrimoxazole </li></ul><ul><li>RASH </li></ul><ul><li>ABC, EFV, NVP, Dapsone, Cotrimoxazole </li></ul><ul><li>HEPATOTOXICITY </li></ul><ul><li>EFV ,NVP , NRTIs </li></ul><ul><li>Rifampicin/ Rifabutin </li></ul><ul><li>Isoniazid </li></ul><ul><li>Fluconazole /Ketoconazole/Itraconazole </li></ul><ul><li>PANCREATITIS </li></ul><ul><li>ddI </li></ul><ul><li>3TC in children </li></ul><ul><li>d4T </li></ul><ul><li>RTV </li></ul><ul><li>OCCULAR EFFECTS </li></ul><ul><li>ddI </li></ul><ul><li>Rifabutin </li></ul><ul><li>Ethambutol </li></ul>
  33. 33. 4. Incompatible ARV Drugs <ul><li>D4T and AZT or 3TC and ddC </li></ul><ul><ul><li>Always contraindicated </li></ul></ul><ul><ul><li>Compete for same active sites reducing efficacy </li></ul></ul><ul><li>3TC and FTC (Emtricitabine). Should not be used together or sequentially </li></ul><ul><ul><li>Same single mutation causes resistance to both </li></ul></ul><ul><li>TDF and ddI (associated with increased ddI toxicity and treatment failure) </li></ul>
  34. 34. Minimizing Drug Interactions <ul><li>Warn patients about potential interactions e.g. Alcohol, over the counter pills, Rifampicin </li></ul><ul><li>Ask what other medicines the patient is taking including herbals– always check at each visit </li></ul><ul><li>Check with up-to-date reference materials </li></ul><ul><li>Educate patient to consult before taking any other medicines </li></ul><ul><li>Avoid drugs which interact wherever possible </li></ul>
  35. 35. 3. Treatment Failure Refer to “The National Clinical Manual for ARV Providers”
  36. 36. Changing to 2 nd line Regime <ul><li>This should not be done lightly </li></ul><ul><li>It is never an emergency </li></ul><ul><li>A senior clinician should be involved and multidisciplinary team decision made (counselor, social worker, nutritionist) </li></ul><ul><li>Adherence Assessment Mandatory </li></ul><ul><ul><li>Changing to 2 nd line regime will achieve nothing if the cause of treatment failure is not addressed </li></ul></ul><ul><li>Change in therapy should take into account drug history and National Guidelines </li></ul>
  37. 37. Diagnosing Treatment Failure <ul><li>1. Clinical failure while on ART </li></ul><ul><ul><li>Recurrence of prior OIs or onset/recurrence of WHO stage III or IV conditions after a period of no symptoms, signifying clinical disease progression. </li></ul></ul><ul><ul><li>Failure unlikely to be responsible for symptoms in an adherent patient in first 6 months of treatment </li></ul></ul><ul><ul><ul><li>Immune recovery still on-going </li></ul></ul></ul>Treat OIs Assess adherence Assess CD4 Count if possible
  38. 38. Diagnosing Treatment Failure <ul><li>2. Immunologic failure while on ART </li></ul><ul><ul><li>Return of CD4 cell to pre therapy baseline or below without concomitant infection to explain transient CD4 cell decrease </li></ul></ul><ul><ul><li>> 30% fall in CD4 count from peak level without concomitant infection to explain decrease </li></ul></ul><ul><ul><ul><ul><li>Assess Adherence </li></ul></ul></ul></ul><ul><ul><ul><ul><li>2. Recheck CD4 before changing ART in a patient who is clinically well </li></ul></ul></ul></ul><ul><ul><ul><ul><li>3. Viral load if available </li></ul></ul></ul></ul>
  39. 39. Diagnosing Treatment Failure <ul><li>3. Virological </li></ul><ul><ul><li>Failure to suppress fully by 24 weeks (6m) of potent antiretroviral therapy </li></ul></ul><ul><ul><li>Sustained increase in viral load after full suppression on ART </li></ul></ul><ul><ul><li>1. Assess adherence </li></ul></ul><ul><ul><li>2. Recheck viral load prior to changing therapy in a patient who is well </li></ul></ul>
  40. 40. Immune Reconstitution Inflammatory Syndrome (IRIS) <ul><li>Need to differentiate this from treatment failure </li></ul><ul><li>Development of symptoms of OIs associated with recovery of immune function, </li></ul><ul><ul><li>Usually 1-3 months after initiation of effective ART </li></ul></ul><ul><li>Clinical presentations vary according to causative organism and the organ system involved </li></ul><ul><li>Management includes specific antimicrobial therapy and symptomatic treatment </li></ul><ul><li>In severe reactions OR where vital organs involved (e.g. CNS or eyes ) adjunctive steroid therapy may be necessary </li></ul>
  41. 41. Summary <ul><li>When and how to change antiretroviral drugs is a complex subject </li></ul><ul><li>Refer to “The National Clinical Manual for ARV Providers” and “National Antiretroviral Treatment Guidelines” to assist in decision making </li></ul><ul><li>If unsure, seek advice from a senior clinician </li></ul>