Toxicity & Resistance

Transkript

1 Toxicity & Resistance HIV[e]EDUCATION Dr. Guido van den Berk December 2009 Sint Maarten

2 PI NRTI NRTI + or (the NRTI backbone ) NNRTI

3 Combination of at least 3 drugs, usually: 2 NRTIs (the NRTI backbone ), plus: 1 NNRTI or 1-2 PIs Therapy with only one or two agents allows HIV to overcome therapy through resistance mutations

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5 According to the November 2008 DHHS guidelines for the use of ART. Which of the following statements is true regarding initial ART: A. Zidovudine-lamivudine (Combivir) plus efavirenz B. Tenofovir-emtricitabine (Truvada) plus ritonavir (norvir) plus Darunavir C. Abacavir plus tenofovir plus lamivudine D. Stavudine plus lamivudine plus lopinavir-ritonavir Zidovudine-lam... 0% 0% 0% 0% Tenofovir-emtr... Abacavir plus... Stavudine plus...

6 A. Zidovudine-lamivudine (Combivir) plus efavirenz B. Tenofovir-emtricitabine (Truvada) plus ritonavir (norvir) plus Darunavir C. Abacavir plus tenofovir plus lamivudine D. Stavudine plus lamivudine plus lopinavir-ritonavir

7 Class specific Drug specific

8 Patients A,B and C recently started HAART : A) AZT, 3TC, Nevirapine B) Abacavir, 3TC, Lopinavir/ritonavir C) Tenofovir, Emtricitabin, Efavirenz Patient A develops anemia. What is the most probable cause? 1. AZT 2. 3tc 3. nevirapine

9 Patient A develops anemia. What is the most probable cause? 1. AZT 2. 3tc 3. nevirapine 0% 0% 0% AZT 3tc nevirapine

10 Patients A,B and C recently started HAART : A) AZT, 3TC, Nevirapine B) Abacavir, 3TC, Lopinavir/ritonavir C) Tenofovir, Emtricitabin, Efavirenz Patient A develops rash. What is the most probable cause? 1. azt 2. 3tc 3. nevirapine

11 Patient A develops rash. What is the most probable cause? 1. azt 2. 3tc 3. nevirapine 0% 0% 0% azt 3tc nevirapine

12 Patients A,B and C recently started HAART : A) AZT, 3TC, Nevirapine B) Abacavir, 3TC, Lopinavir/ritonavir C) Tenofovir, Emtricitabin, Efavirenz Patient B develops diarrhea. Which medicine is the most probable cause? 1. abacavir, 2. 3tc 3. lopinavir / ritonavir

13 Patient B develops diarrhea. Which medicine is the most probable cause? 1. abacavir, 2. 3tc 3. lopinavir / ritonavir 0% 0% 0% abacavir, 3tc lopinavir / ri...

14 Patients A,B and C recently started HAART : A) AZT, 3TC, Nevirapine B) Abacavir, 3TC, Lopinavir/ritonavir C) Tenofovir, Emtricitabin, Efavirenz Patient c develops night mares. What is the most probable cause? 1) his wife 2) tenofovir 2) emtricitabin 3) efavirenz

15 Patient c develops night mares. What is the most probable cause? 1. His wife 2. tenofovir 3. emtricitabin 4. efavirenz 0% 0% 0% 0% His wife tenofovir emtricitabin efavirenz

16 Patients A,B and C recently started HAART : A) AZT, 3TC, Nevirapine B) Abacavir, 3TC, Lopinavir/ritonavir C) Tenofovir, Emtricitabin, Efavirenz Patient C develops renal insufficiency. What is the most probable cause? 1) tenofovir 2) emtricitabin 3) efavirenz

17 Patient C develops renal insufficiency. What is the most probable cause? 1. tenofovir 2. emtricitabin 3. efavirenz 0% 0% 0% tenofovir emtricitabin efavirenz

18 Rash Nevirapine > Efavirenz Hepatotoxicity Nevirapine > Efavirenz Efavirenz: Psychogenic side effects Teratogenic effects

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21 Синдром Стивенса-Джонсона 90

22 GI effects Lipodystrophy Lipoatropy dyslipidemia Insulin resistance, diabetes

23 Changes in fat distribution Subcutaneous fat wasting Fat accumulation intra-abdominal abdominal fat localised breast enlargement buffalo hump lipomata Metabolic complications Dyslipidemia Insulin resistance Objective measures (DEXA, CT) crucial End points should be considered separately Diabetes mellitus (rare)

24 Lipoatrophy - hollow cheeks

25 Lipoatrophy - loss of subcutaneous fat in the legs of a woman 80

26 GI problems Mitochondrial toxicity with: Lactic acidosis Myelopathy (Cardio) myopathy Distal polyneuropathy ( d-drugs ) Pancreatitis Hepatitis Lipodystrophy

27 Nucleoside action in mitochondria N O R M A L Polymerase -Gamma Proteins encoded by mtdna mtdna mtdna ndna N R T I s mtdna mtdna ndna Brinkman K et al. Lancet 1999; 354:

28 Neuropathy Myopathy Cardiomyopathy Pancreatitis Hepatitis Lactic acidosis Bone marrow depression ZDV 3TC D 4 T DDC DDI / /- + +

29 Events PYFU Incidence of Myocardial Infarction according to cart Exposure MIs per 1000 PY (95% CI) NEJM April None < >7 cart-exposure (yrs) RR per year of cart: Univariable: 1.16 [ ] Adjusted: 1.16 [ ] Total

30 8 Relative Rate of MI according to PI Exposure Adjusted for NNRTI Adjusted RR* per year of PI: 1.16 [ ] RR (95% CI) None < >6 PI-Exposure (yrs) : Adjusted for sex, age, cohort, calendar year, prior CVD, family history of CVD, smoking, body-mass index, NNRTI exposure

31 8 Relative Rate of MI according to NNRTI Exposure Adjusted for PI RR (95% CI) Adjusted RR* per year of NNRTI: 1.05 [ ] 0.5 None < >4 NNRTI-Exposure (yrs) : Adjusted for sex, age, cohort, calendar year, prior CVD, family history of CVD, smoking, body-mass index, PI exposure

32 Effect of Exposure to PI and NNRTI before and after Adjusting for Lipids PI exposure (per additional year) RR 1.16 RR 1.10 NNRTI exposure (per additional year) RR 1.05 RR Relative Rate of MI (95% CI) : Adjusted for sex, age, cohort, calendar year, prior CVD, family history of CVD, smoking, body-mass index, the other drug class Friis-Møller et al NEJM 2007

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34 patiënts ( patiënt years) 517 first myocardial infarction Out of the 517, in the 6 months before MI: 192 used abacavir 124 used ddi TA`s not associated with increased risk MI Recent (<6 mnths) or current abc or ddi use associated with higher risk MI Higher risk no longer observed in patients who had discontinued abc or ddi > 6 months Sabin CA et al. Lancet april 2008

35 ZDV ddi CHD (n = 639) Stroke (n = 195) RR: 1.40 (P =.005) d4t 3TC ABC RR: 1.63 (P =.0001) Adjusted Relative Rate (95% CI) 2.25 Sabin CA et al. Lancet april 2008

36 Sabin CA et al. Lancet april 2008

37 EMEA : After examination of all currently available data, the EMEA and the national competent authorities have considered that, presently, no definitive conclusion can be drawn on the potential association between abacavir or didanosine use and the risk of myocardial infarction FDA: The FDA has stated that it regards the D:A:D study findings as incomplete as they did not include an analysis of abacavir s chief competitor, tenofovir (Viread), nor another important antiretroviral drug, FTC (emtricitabine, Emtriva)

38 RR 95% CI ddi d4t ddi / d4t ddi / HU d4t / ddi / HU

39 Neurotoxic agents d-drugs (ddc, ddi, d4t) Isoniazid, dapsone, vincristine Diabetes mellitus Alcoholism Vitamin B12 deficiency (rare)

40 Pinprick Normal Diminished Lost Hyperesthesia contact sensitivity or normal knee reflexes Strength normal ankle reflexes pin, temperature, vibration

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43 The common reasons to switch: Toxicity Virological failure

44 Causes of treatment failure include: Patient factors (CD4 nadir, comorbidities) Drug resistance Suboptimal adherence ARV toxicity and intolerance Pharmacokinetic problems Suboptimal drug policy

45 Virologic failure: HIV RNA >400 copies/ml after 24 weeks >50 copies/ml after 48 weeks >400 copies/ml after viral suppression Immunologic failure: Failure to achieve and maintain adequate CD4 increase despite virologic suppression

46 Resistance

47 ????

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51 Most copies of HIV are the same in the body Part of HIV will be naturally resistant to ARV

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57 General principles: Add at least 2 (preferably 3) fully active agents to an optimized background ARV regimen Determined by ARV history and resistance testing 1 active drug should not be added to a failing regimen (drug resistance is likely to develop quickly)

58 3TC has a unique mutation, M184V, which is commonly seen when failing regimen with 3TC A single mutation is enough to significantly decrease 3TC antiviral effect If mutation M184V is present emtricitabine is also failing (identical mutation) AZT and d4t have almost identical mutations and universal cross resistance K65R (Tenofovir resistance)

59 The K103N or Y188L mutation alone prevents the clinical utility of all NNRTIs NVP and EFV have universal cross resistance NVP or EFV should not be part of second line regimen after failing NNRTI first line treatment