Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Hepatic Toxicity in Patients Taking ARVs HAIVN Harvard Medical School AIDS Initiative in Vietnam 1 Learning Objectives By the end of this session, participants should be able to: Outline the differential diagnoses of hepatitis in a patient on ARVs Describe the major types of hepatic toxicities from ARVs Explain how to manage a patient on ARVs with hepatic toxicity 2 Overview of Hepatotoxicity and ARVs Up to 50% of patients taking ARVs will have transient elevations in LFTs Most patients are asymptomatic and LFTs will return to normal without stopping ARVs Less than 5% of patients will need to stop or change ARV due to hepatotoxicity 3 Hepatotoxicity and ARVs: Difficulties Diagnosing cause of hepatotoxicity is difficult: • No diagnostic test exists for medicationinduced hepatotoxicity • HIV patients often take multiple medications harmful to the liver • Alcohol use is common and can cause hepatitis Co-infection with Hepatitis B or C increases risk for hepatotoxicity 4 Hepatotoxicity: Differential Diagnoses (1) ARV toxicity Idiopathic hypersensitivity • NNRTI (NVP,EFV) • ABC (abacavir) • LPV/r (rare) Lactic acidosis with hepatic steatosis Non-ARV drugs TB drugs • PZA, RIF, INH Antifungal drugs Others • Cotrimoxazole • Paracetamol Alcohol • NRTIs 5 Hepatotoxicity: Differential Diagnoses (2) Infectious Diseases: Viral: • CMV, HAV, HBV, HCV Bacterial, mycobacterial: • TB, MAC, sepsis Fungal: • Penicillium • Cryptococcus Other Causes: IRIS • HBV Hepatic Steatosis Tumor: • lymphoma • Kaposi’s sarcoma Parasitic: • Malaria, amoeba 6 Grading Hepatotoxicity LFT > normal ALT 1 1.25 – 2.5 50 - 100 2 2.5 - 5 101 - 200 3 5 - 10 201 - 400 4 > 10 > 400 GRADE mild severe 7 Approach to the Patient with Hepatotoxicity (1) Category Specifics to Ask About History of illness Alcohol Use Risk factors for acute hepatitis Medication history What medications, how long Hepatotoxic meds: • anti-TB, ARVs • antifungals • antibiotics Physical Exam Jaundice, rash Abdomen: • liver size • tenderness 8 Approach to the Patient with Hepatotoxicity (2) Laboratory Testing: • AST, ALT, bilirubin, CBC • Hepatitis serology (A,B,C) if previously negative or not yet done • Consider: US Abdomen, blood culture for bacteria, TB/MAC, fungus • If concerned about Lactic Acidosis: Lactic acid, pH, electrolytes (Na, K, Cl, HCO3) 9 Management of the Patient with Hepatotoxicity General Principles Counsel patient to stop alcohol use Stop any non-essential drugs that may cause hepatic toxicity (e.g. CTX, fluconazole) If toxicity to ARV is likely, then consider stopping or changing ARV 10 NNRTIs and Hepatotoxicity 11 NNRTIs and Hepatotoxicity: Overview 5-10% of patients on NNRTI will have grade 3-4 elevation in AST/ALT Many patients are asymptomatic Increased risk with HBV or HCV coinfection NVP has greater risk than EFV 12 NNRTIs and Hepatotoxicity: Adverse Reactions More Severe Reaction (grade 3-4): Usually occurs in first 1-2 months of treatment Higher risk for NVP with: • female CD4>250 • male CD4>400 Other symptoms: rash, fever, body aches Stevens-Johnson Syndrome: severe allergic reaction with mucous-membrane involvement 13 NNRTIs and Hepatotoxicity: Treatment (1) Level LTF Treatment Continue ARV 1-5 Mild (grade 1-2) x normal Follow closely with clinical exam and LFT every 1-2 weeks Moderate (grade 3) Stop NNRTI, continue 2 NRTIs for 1 5-10 week x normal Restart another NNRTI (or PI) if • symptoms resolve, and • LFT < 2.5 - 5 x normal Severe (grade 4) Stop all ARV and hepatotoxic drugs >10 x normal Do not use offending agent (NVP or 14 EFV) again NNRTIs and Hepatotoxicity: Treatment (2) Liver-supporting drugs Fortec, Bidipa, BDD, Legalon, Silybean No research has shown these drugs to be effective in treatment of hepatotoxicity in patients on ARV However, most of these drugs have few side effects and are probably safe to use in HIV infected patients 15 Lactic Acidosis 16 NRTI: Mitochondrial Toxicity and Lactic Acidosis NRTIs inhibit mitochondrial DNA polymerase gamma Leads to decreased ability to use oxygen to produce energy Anaerobic metabolism leads to build up of fat in the liver and lactic acid in blood Incidence 0.5%-1.5% per year Risk of lactic acidosis: D4T+DDI > D4T > DDI > AZT Very low risk: 3TC, TDF, ABC 17 Lactic Acidosis: Symptoms Mild: Fatigue Body aches Nausea Vomiting Diarrhea Weight loss Severe: Wasting Dyspnea Abdominal pain Coma 18 Lactic Acidosis: Diagnosis Diagnosis: elevated lactic acid levels Lactic acid testing only available at large hospitals If lactic acid levels not available: • Increased anion gap [Na-(Cl+HCO3)] > 16 • LFT, CPK, LDH • pH, HCO3 19 Lactic Acidosis: Treatment Mild symptoms or lactate < 5.0 Stop NRTI and/or Switch to NRTI with less mitochondrial toxicity, such as TDF or ABC Severe symptoms or lactate > 5 - 10 Stop all ARVs, hospitalize Hydration, bicarbonate IV IV riboflavin (50 mg/day) or IV Vitamin C When stable restart ARV: • switch d4T/AZT to TDF 20 Abacavir Hypersensitivity 21 Abacavir Hypersensitivity (1) Occurs in about 5% of patients taking ABC • Associated with HLA B*5701 • May be less common in Asian populations* Usually presents within first 6 weeks of treatment *Martin AM, PNAS, 2004 22 Abacavir Hypersensitivity (2) Symptoms: • Rash, fever, nausea, vomiting, fatigue, arthralgia, headache, abdominal pain, dyspnea, cough Laboratory: • AST/ALT, lymphocytes, CPK Treatment: Stop ABC Important never to use ABC again: can cause death!! 23 Case Study: Tuan (1) Tuan is a 30 year old male with HIV/HCV co-infection • Takes cotrimoxazole for PCP prophylaxis and fluconazole for oral thrush • Reports active intravenous drug use and has been sharing needles with friends • Reports drinking alcohol frequently as well 24 Case Study: Tuan (2) 3 weeks after starting AZT/3TC/NVP he develops nausea, vomiting and abdominal pain • Examination shows right upper quadrant abdominal pain and icteric sclera. There is no fever or rash • Lab testing shows ALT 650, AST 625 • Baseline ALT (at registration to OCP) was 89 and baseline CD4 was 175 25 Case Study: Tuan (3) Discussion What is the differential diagnosis? What is the grade of liver toxicity? How would you manage this patient? What put this patient at risk for liver toxicity? 26 Key Points Elevated LFTs are very common in patients on ARVs For most patients, LFTs will return to normal while continuing to take ARVs Hepatotoxicty due to NVP can be managed by switching to EFV (or LPV/r or TDF) Lactic acidosis can be managed by changing to less toxic NRTI A patient with ABC hypersensitivity should never take ABC again 27 Thank you! Questions? 28