02.03 adult art monitoring, changing gsn

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  • X1: If clinically indicated Serum Creatinine not needed for standard 1 st line; required more regularly in patients on TDF. Red X are for tests necessitated by those particular drugs. Most patients can be adequately monitored 6 monthly and as clinically indicated
  • Average CD4 count rise
  • 02.03 adult art monitoring, changing gsn

    1. 1. UNIT 3 Monitoring/changing /stopping Highly Active Anti Retroviral Therapy (HAART) and drug interactions:
    2. 2. UNIT 3: Objectives <ul><li>Understand the type of monitoring employed in ART management </li></ul><ul><li>Understand when to change or stop ART </li></ul><ul><li>Know the common drug interactions between ARVs and other drugs </li></ul><ul><li>Understand strategies to avoid or minimize occurrence of drug interactions during ART </li></ul>
    3. 3. Monitoring Antiretroviral Therapy
    4. 4. Monitoring ART <ul><li>Why? </li></ul><ul><li>Assess efficacy of intervention </li></ul><ul><li>Detect other treatable conditions </li></ul><ul><li>Assessment for drug related toxicities </li></ul><ul><li>How? </li></ul><ul><li>Clinical history and examination </li></ul><ul><li>Laboratory markers </li></ul>
    5. 5. Clinical Monitoring <ul><li>Regular clinical evaluation is important to </li></ul><ul><ul><li>Assess efficacy of ART </li></ul></ul><ul><ul><li>Monitor toxicity. </li></ul></ul><ul><li>Frequency of visits for clinical monitoring </li></ul><ul><li>First visit at 2 weeks after initiating therapy </li></ul><ul><ul><li>Ensure that medicines are being taken and stored correctly </li></ul></ul><ul><ul><li>Note and address possible side effects </li></ul></ul><ul><ul><li>Assess adherence </li></ul></ul><ul><li>In stable patients </li></ul><ul><ul><li>Subsequent visits should be monthly </li></ul></ul><ul><ul><li>6-12 months following initiation of ART, clinical appointments may be spaced at 2 to 3 month intervals in compliant and clinically stable patients with an excellent understanding of ART </li></ul></ul>
    6. 6. Clinical Monitoring <ul><li>Plot the patient’s weight and note the trend </li></ul><ul><ul><li>Falling weight may indicate treatment failure/new illness e.g. TB </li></ul></ul><ul><li>Determine the patient’s physical condition. </li></ul><ul><ul><li>Address ongoing medical problems including possibility of failure of treatment through the development of new OIs. </li></ul></ul><ul><ul><li>Treat inter-current infections </li></ul></ul><ul><li>Check drug dosages and adjust according to weight. </li></ul><ul><li>The patients should be given medicines to last for 1 month even when the clinic appointments are less frequent. </li></ul><ul><li>Adherence should be assessed and appropriate counseling provided at each visit. </li></ul>
    7. 7. Clinical Monitoring: Indicators of Treatment Success <ul><li>Look for: </li></ul><ul><li>Patient self assessment of well being </li></ul><ul><li>Decrease or disappearance of symptoms </li></ul><ul><li>Increase in body weight </li></ul><ul><li>Decrease in frequency and severity of OIs </li></ul>
    8. 8. Laboratory Monitoring of ART <ul><li>Laboratory tests are recommended for </li></ul><ul><li>Assessing response to and efficacy of treatment. </li></ul><ul><li>Monitoring toxicity </li></ul>
    9. 9. Laboratory Monitoring of ART <ul><li>Assessing efficacy of treatment </li></ul><ul><li>For effective monitoring of efficacy of treatment, CD4 counts, and viral load are essential. </li></ul><ul><li>Resistance testing where available is a useful adjunct to choice of antiretroviral treatment. </li></ul>
    10. 10. Laboratory Monitoring of ART: CD4 Count <ul><li>Where possible CD4 count should be determined at baseline and thereafter at 6 monthly intervals </li></ul><ul><li>CD4 count should not be measured during a concurrent infection </li></ul><ul><ul><li>Delay until > 2 weeks after recovery </li></ul></ul><ul><li>For consistency CD4 measurements in a patient should be carried out </li></ul><ul><ul><li>In the same laboratory and preferably at the same time of day. </li></ul></ul>
    11. 11. Laboratory Monitoring of ART: Viral Load <ul><li>Viral load measurements are the most timely and sensitive way of assessing treatment response </li></ul><ul><li>Where available viral loads should be done routinely at baseline and then 6-monthly </li></ul><ul><li>Viral load should also be done if possible, when treatment failure is suspected </li></ul><ul><ul><li>CD4 count response less than expected or falling </li></ul></ul><ul><ul><li>Where adherence is judged to be poor </li></ul></ul>
    12. 12. Lab Tests: Monitoring For Toxicity <ul><li>Tests for monitoring toxicity </li></ul><ul><li>Where available the following tests should be done at baseline to enable monitoring ARV drug toxicity </li></ul><ul><ul><li>Complete blood count (CBC) </li></ul></ul><ul><ul><li>ALT/SGPT </li></ul></ul><ul><ul><li>Creatinine </li></ul></ul><ul><ul><li>Pregnancy test for all women of child bearing potential </li></ul></ul><ul><ul><li>Fasting lipid profile and glucose, if Protease inhibitors are to be used </li></ul></ul><ul><ul><li>Serum amylase </li></ul></ul>
    13. 13. Lab tests: Follow up <ul><li>Follow-up laboratory tests: </li></ul><ul><ul><li>ALT after 1-2 months of treatment when NNRTIs are used. If normal, repeat at 3 months, 6 months and thereafter 6-monthly interval or earlier if clinically indicated. </li></ul></ul><ul><ul><li>CBC if Zidovudine is used for treatment. If normal, repeat at 3 months, 6 months and thereafter 6-monthly intervals </li></ul></ul><ul><ul><li>Fasting lipids annually, if a patient is on protease inhibitors. </li></ul></ul><ul><ul><li>Evaluation for pregnancy for women of child-bearing potential and pregnancy tests done when indicated. </li></ul></ul><ul><li>The clinical picture should always be taken into account when monitoring for toxicity </li></ul>
    14. 14. Summary Schedule of Laboratory Monitoring X X 1 X (if on TDF) X X 6m X X X Fasting lipids & glucose (PIs) X X X X (if on NVP) X (if on NVP) X ALT(LFT) X 1 X 1 X 1 X 1 X 1 X Pregnancy test X (if on TDF X (if on TDF) X (if on TDF X (if on TDF) X (if on TDF) X Serum Creatinine X X X X (if on AZT) X (if on AZT) X CBC + Differential X X X X CD4 24m 18m 12m 3m 1-2 months Baseline Test
    15. 15. <ul><li>when to change or stop ART </li></ul>
    16. 16. Three Main Reasons for Altering a Patient’s Regime: <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>
    17. 17. 1. Drug Toxicity and Intolerance <ul><li>Two Broad Groups of Side-effects: </li></ul><ul><li>1. Common “Mild” </li></ul><ul><li>2. Rare and Dangerous </li></ul>
    18. 18. Guidelines When to stop/change I <ul><li>Failure </li></ul><ul><li>Toxicity </li></ul><ul><li>Pregnancy </li></ul><ul><li>Co-morbidity </li></ul><ul><li>Interruption of drug supply </li></ul>
    19. 19. Common “Mild” SE’s <ul><li>Nausea </li></ul><ul><li>Vomiting </li></ul><ul><li>Lethargy </li></ul><ul><li>Headaches </li></ul><ul><li>Dizzyness </li></ul><ul><li>“ Flu” symptoms </li></ul><ul><li>Mild rash </li></ul>
    20. 20. Common “Mild” SE’s <ul><li>Patients should “expect” them </li></ul><ul><li>Usually improve within 1-2 months </li></ul><ul><li>Rarely necessary to change/stop regime </li></ul>
    21. 21. Rare, potentially serious SE’s <ul><li>Severe rash/SJ Syndrome </li></ul><ul><li>Hepatotoxicity </li></ul><ul><li>Peripheral Neuropathy </li></ul><ul><li>Haematotoxicity </li></ul><ul><li>Pancreatitis </li></ul><ul><li>Lactic Acidosis </li></ul>
    22. 22. A Rational Approach to the Management of Serious Side Effects Refer to “The National Clinical Manual for ARV Providers”
    23. 23. Rash <ul><li>National Clinical Manual – </li></ul><ul><li>Most commonly due to NVP </li></ul><ul><li>Also sometimes EFV </li></ul><ul><li>Rarely can be caused by other ARV’s </li></ul><ul><li>Patient Counselling… </li></ul>
    24. 24. Case Study - Rash <ul><li>A 34 year old woman has been commenced on D4T, 3TC 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>
    25. 25. Hepatotoxicity <ul><li>National Clinical Manual – </li></ul><ul><li>NVP most common cause </li></ul><ul><li>Also D4T and ABC (uncommon) </li></ul><ul><li>Check ALT/SGPT if any hepatic symptoms </li></ul><ul><li>Routinely at baseline and 4-6 weeks </li></ul>
    26. 26. 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 RUQ tenderness, but is not clinically jaundiced. </li></ul><ul><ul><li>What test should be performed urgently? </li></ul></ul>
    27. 27. Continued… <ul><li>An SGPT is performed urgently </li></ul><ul><li>The result comes back at 462 </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>
    28. 28. Haematotoxicity <ul><li>National Clinical Manual – </li></ul><ul><li>AZT by far the most common cause </li></ul><ul><li>Can be fatal </li></ul><ul><li>Check Hb if clinical symptoms/signs of anemia </li></ul><ul><li>Also at baseline, 4-6 weeks and 6 monthly routinely </li></ul>
    29. 29. Case Study - Haematotoxicity <ul><li>A 40 year old man before starting ART has a baseline Haemoglobin of 12.4. He is started on AZT/3TC + EFV (by a doctor who has never read the National Guidelines!) and 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>
    30. 30. Peripheral Neuropathy <ul><li>Refer to National Clinical Manual – </li></ul><ul><li>D4T and ddI most common cause </li></ul><ul><li>Especially if used together or with other PN drugs (eg: Isoniazid) </li></ul><ul><li>Can be disabling and irreversible </li></ul><ul><li>Patient Counselling </li></ul><ul><li>Symptomatic management </li></ul>
    31. 31. 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). She walks into the clinic with the assistance of her husband – since the last appointment she has developed progressive 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>
    32. 32. 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>
    33. 33. Pancreatitis <ul><li>Rare, but can be fatal </li></ul><ul><li>Abdo. pain, vomiting, hypovolaemic shock </li></ul><ul><li>D4T and ddI most common causes </li></ul><ul><li>Especially if together or with other pancreas damaging drugs (eg. alcohol) </li></ul><ul><li>If suspicion check serum amylase </li></ul><ul><li>If occurs, probably best to stop all drugs until resolved – seek expert help </li></ul>
    34. 34. First line ARV regimens <ul><li>Regimen d4T/3TC/NVP </li></ul><ul><li>Toxicity Drug Substitution </li></ul><ul><li>d4T-related neuropathy or pancreatitis Switch d4T –› ZDV </li></ul><ul><li>d4T-related lipoatrophy Switch d4T –› TDF or ABC </li></ul><ul><li>NVP-related severe hepatotoxicity Switch NVP –› EFV </li></ul><ul><li>(except in pregnancy) </li></ul><ul><li>NVP-related severe rash Switch NVP –› EFV </li></ul><ul><li>(but not life threatening) </li></ul><ul><li>NVP-related life threatening rash Switch NVP –› PI </li></ul><ul><li>(Stevens-Johnson syndrome) </li></ul>
    35. 35. First line ARV regimens <ul><li>Regimen ZDV/3TC/NVP </li></ul><ul><li>Toxicity Drug Substitution </li></ul><ul><li>ZDV-related persistent GI intolerance Switch ZDV –› d4T </li></ul><ul><li>or severe hematological toxicity </li></ul><ul><li>NVP-related severe hepatotoxicity Switch NVP –› EFV </li></ul><ul><li>(except in pregnancy. </li></ul><ul><li>In this situation switch </li></ul><ul><li>to NFV, LPV/r or ABC.) </li></ul><ul><li>NVP-related severe rash (but not life Switch NVP –› EFV </li></ul><ul><li>threatening) </li></ul><ul><li>NVP-related life threatening rash Switch NVP –› PI </li></ul><ul><li>(Stevens-Johnson syndrome) </li></ul>
    36. 36. First line ARV regimens <ul><li>Regimen d4T/3TC/EFV </li></ul><ul><li>Toxicity Drug Substitution </li></ul><ul><li>d4T-related neuropathy Switch d4T –› ZDV </li></ul><ul><li>or pancreatitis </li></ul><ul><li>d4T-related lipoatrophy Switch d4T –› TDF or ABC </li></ul><ul><li>EFV-related persistent Switch EFV –› NVP </li></ul><ul><li>CNS toxicity </li></ul>
    37. 37. First line ARV regimens <ul><li>Regimen ZDV/3TC/EFV </li></ul><ul><li>Toxicity Drug Substitution </li></ul><ul><li>ZDV-related persistent GI Switch ZDV –› d4T </li></ul><ul><li>intolerance or severe </li></ul><ul><li>hematological toxicity </li></ul><ul><li>EFV-related persistent CNS Switch EFV –› NVP </li></ul><ul><li>toxicity </li></ul>
    38. 38. 2. Drug Interactions It is not possible to remember all the possible drugs interactions with ARV’s Refer to “The National ARV Guidelines”
    39. 39. Main Problems <ul><li>A. Blood levels of ARV’s increased or decreased </li></ul><ul><li>B. Other drugs made ineffective </li></ul><ul><li>C. Additive toxicities </li></ul><ul><li>D. Some ARV’s not compatible with each other </li></ul>
    40. 40. A. Blood levels of ARV’s Increased or Decreased <ul><li>Rifampicin reduces NVP levels (next slide) </li></ul><ul><li>EFV levels affected by: </li></ul><ul><ul><li>Benzodiazepines </li></ul></ul><ul><ul><li>Antihistamines </li></ul></ul><ul><ul><li>High dose Garlic Supplements </li></ul></ul><ul><ul><ul><li>These should all be avoided </li></ul></ul></ul>
    41. 41. TB Drugs <ul><li>Rifampicin reduces blood levels of NVP </li></ul><ul><li>Currently NOT recommended together </li></ul><ul><li>If already on NVP and develops TB, one cannot avoid using Rifampicin </li></ul><ul><li>Therefore change to EFV 600mg OD </li></ul><ul><li>If not yet on ARV’s but requires TB Rx, defer ARV’s until intensive phase completed </li></ul>
    42. 42. B. Drugs which are made Ineffective by ARV’s <ul><li>Oral Contraceptive Pill unreliable with NVP/EFV and PI’s – need alternative/added method </li></ul><ul><li>Ketoconazole ineffective with NVP (use fluconazole) </li></ul>
    43. 43. C. Additive Toxicities <ul><li>Hepatotoxicity – TB drugs, Alcohol </li></ul><ul><li>Haematotoxicity – Cytotoxics </li></ul><ul><li>Peripheral Neuropathy – INH (give Pyridoxine) </li></ul><ul><li> - Also d4T with ddI </li></ul><ul><li>Pancreatitis – Alcohol, Thiazides </li></ul><ul><li>Lactic Acidosis – d4T and ddI (esp in pregnancy) </li></ul>
    44. 44. D. Incompatible ARV’s <ul><li>D4T and AZT </li></ul><ul><li>Always Contraindicated </li></ul><ul><ul><li>Compete for same active sites, therefore reducing efficacy </li></ul></ul><ul><li>3TC and ddC </li></ul><ul><li>TDF+ddI (associated with increased toxicity and treatment failure use with care) </li></ul>
    45. 45. 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 – 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>
    46. 46. 3. Treatment Failure Refer to “The National Clinical Manual for ARV Providers”
    47. 47. Diagnosing Treatment Failure <ul><li>1. Clinical failure while on ART </li></ul><ul><ul><li>Recurrence of prior OI’s or onset/recurrence of WHO stage III or IV conditions after a period of good immunity signifying clinical disease progression. </li></ul></ul><ul><ul><li>Failure unlikely to be responsible for symptoms in an adherent patient in firat 6 months of TX </li></ul></ul><ul><li>See p.38 of the Clinical Manual </li></ul><ul><ul><li>Assess Adherence </li></ul></ul><ul><ul><li>Treat OI’s </li></ul></ul><ul><ul><li>Assess CD4 level – VL if available </li></ul></ul>
    48. 48. 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>> 50% fall in CD4 count from peak level without concomitant infection to explain decrease </li></ul></ul><ul><li>See p.39 of the Clinical Manual </li></ul><ul><ul><li>Assess Adherence </li></ul></ul><ul><ul><li>Recheck CD4 at least twice before committing to a change in ART in a patient who is well </li></ul></ul><ul><ul><ul><li>(Need for a National Quality Control system for CD4’s) </li></ul></ul></ul>
    49. 49. Diagnosing Treatment Failure <ul><li>3. CD4 stabilized <200 in a clinically stable patient after 1 year on ART </li></ul><ul><li>Consider baseline CD4 count </li></ul><ul><li>Assess adherence </li></ul><ul><ul><li>Assess Adherence </li></ul></ul><ul><ul><li>Recheck CD4 to confirm </li></ul></ul><ul><ul><li>Perform Viral Load if available </li></ul></ul><ul><ul><ul><li>If VL not available, better to monitor a well patient closely on 1 st line than to change possibly unnecessarily/prematurely to 2 nd line </li></ul></ul></ul>
    50. 50. Immune reconstitution Inflammatory syndrome <ul><li>Differentiate treatment failure from IRIS </li></ul><ul><li>IRIS is characterized by appearance of signs and symptoms of an opportunistic disease few weeks after the start of ART in a setting of advanced immunodeficiency as an inflammatory response to previously sub-clinical opportunistic infection </li></ul>
    51. 51. CAUSES OF FAILURE OF ART: INFLUENCE OF FOOD ON ART ABSORPTION Drug Fasting Low High Recommen- fat meal fat meal dation Indinavir + + - Fasting Indinavir+Ritovinar) + + + None Nelfinavir - + + Meal Amprinavir + + - No High fat meal Navirapine + + + None Delavaridine + - - Fasting Efavirenz + + + none
    52. 52. CAUSES OF FAILURE OF ART: Pill Burden
    53. 53. CAUSES OF ART FAILURE: ADRs <ul><li>Adverse reactions (ADRS) </li></ul><ul><li>First week- Gastritis Skin rash Hepatitis </li></ul><ul><li>After two weeks Anemia Drug reaction Hepatitis </li></ul><ul><li>After 2-3 months Hepatitis Peripheral Neuropathy Pancreatitis </li></ul><ul><li>After one year Hepatitis Peripheral Neuropathy Pancreatitis  Blood sugar, S. Chl/Trig. Lipodystrophy </li></ul>AZT – Gastritis Anemia & Hepatitis d4T – Peripheral neuropathy NVP - Skin rash Hepatitis SJS PI - Lipodystrophy Renal failure Hepatitis We have not encountered lactic acidosis or Osteopenia/osteoporosis
    54. 55. CAUSES OF ART FAILURE: CONCOMITANT MEDICATION <ul><li>Preferred </li></ul><ul><li>Anti histaminics- Cetirizine </li></ul><ul><li>Antifungal-Fluconazole,AmB </li></ul><ul><li>Anti convulsants- Sodium valproate </li></ul><ul><li>Antacids-Ranitidine,Omeprazole </li></ul><ul><li>Anti psychotic and Anti depressants-Fluoxetine </li></ul><ul><li>Lipid lowering drug- Clofibrate,Fenofibrate,Pravastatin </li></ul><ul><li>Beta-blockers-Atenolol,Metoprolol,Propranolol (except with RTV) </li></ul><ul><li>Non-preffered </li></ul><ul><li>Anti TB (ATT)-Rifampicin </li></ul><ul><li>Ca Channel antagonist-Unsafe </li></ul><ul><li>Oral hypoglycemic agents-Glipizide,Tolbutamide need monitoring </li></ul><ul><li>Analgesics-Aspirin & Paracetamols </li></ul><ul><li>Anti bacterial-Clarithromycin,Rifampicin are avoided </li></ul><ul><li>Drug abuse </li></ul>
    55. 56. CAUSES OF ART FAILURE: CONCOMITANT MEDICATION <ul><li>Possible Options For ART In Active T.B </li></ul><ul><li>Defer ART until TB treatment is completed </li></ul><ul><li>Defer ART until the intensive phase is over and initiate ART along with and ETB & INH as maintenance therapy . </li></ul><ul><li>Treat TB with Rifampicin containing regimen and use Ritonavir + 2NRTIs </li></ul><ul><li>Treat TB with Rifampicin containing regimen & use </li></ul><ul><li>Ritonavir /Saquinavir + 2NRTI </li></ul><ul><li>Treat TB with Rifampicin containing regimen & use Efavirenz + 2 NRTIs </li></ul><ul><li>Treat TB with Rifampicin containing regimen & use a 2 NRTI regimen then change to maximally suppressive ART once TB treatment intensive is completed </li></ul>
    56. 57. Recommended second-line regimens in adults and adolescents for treatment failure on first-line ARV regimens <ul><li>For Failure On: Change To: </li></ul><ul><li>d4T or ZDV TDF or ABC </li></ul><ul><li>+ + </li></ul><ul><li>3TC ddI </li></ul><ul><li>+ + </li></ul><ul><li>NVP or EFV LPV/r or SQV/r </li></ul>
    57. 58. Changing to 2 nd line Regime <ul><li>This should not be done lightly </li></ul><ul><li>It is never an emergency (like starting ART) </li></ul><ul><li>A senior clinician should be involved </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>
    58. 59. Summary <ul><li>When and how to change ARV’s is a complicated subject </li></ul><ul><li>Refer to “The National Clinical Manual for ARV Providers” to assist in decision making </li></ul><ul><li>If unsure, seek advice from a senior clinician </li></ul>

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