1. 1 Hepatic Toxicity in Patients Taking ARVs HAIVN Harvard Medical School AIDS Initiative in Vietnam

2. 2 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

3. 3 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

4. 4 Hepatotoxicity and ARVs: Difficulties Diagnosing cause of hepatotoxicity is difficult: No diagnostic test exists for medication- induced 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

5. 5 Hepatotoxicity: Differential Diagnoses (1) ARV toxicity Idiopathic hypersensitivity NNRTI (NVP,EFV) ABC (abacavir) LPV/r (rare) Lactic acidosis with hepatic steatosis NRTIs Non-ARV drugs TB drugs PZA, RIF, INH Antifungal drugs Others Cotrimoxazole Paracetamol Alcohol

6. 6 Hepatotoxicity: Differential Diagnoses (2) Infectious Diseases: Viral: CMV, HAV, HBV, HCV Bacterial, mycobacterial: TB, MAC, sepsis Fungal: Penicillium Cryptococcus Parasitic: Malaria, amoeba Other Causes: IRIS HBV Hepatic Steatosis Tumor: lymphoma Kaposi’s sarcoma

7. 7 Grading Hepatotoxicity GRADE  LFT > normalALT mild 11.25 – 2.550 - 100 22.5 - 5101 - 200 severe 35 - 10201 - 400 4> 10> 400

8. 8 Approach to the Patient with Hepatotoxicity (1) CategorySpecifics 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

9. 9 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)

10. 10 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

11. 11 NNRTIs and Hepatotoxicity

12. 12 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 co- infection NVP has greater risk than EFV

13. 13 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

14. 14 NNRTIs and Hepatotoxicity: Treatment (1) LevelLTFTreatment Mild (grade 1-2) 1-5 x normal  Continue ARV  Follow closely with clinical exam and LFT every 1-2 weeks Moderate (grade 3) 5-10 x normal  Stop NNRTI, continue 2 NRTIs for 1 week  Restart another NNRTI (or PI) if symptoms resolve, and LFT < 2.5 - 5 x normal Severe (grade 4) >10 x normal  Stop all ARV and hepatotoxic drugs  Do not use offending agent (NVP or EFV) again

15. 15 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

16. 16 Lactic Acidosis

17. 17 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

18. 18 Lactic Acidosis: Symptoms Mild: Fatigue Body aches Nausea Vomiting Diarrhea Weight loss Severe: Wasting Dyspnea Abdominal pain Coma

19. 19 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

20. 20 Lactic Acidosis: Treatment Mild symptoms or lactate < 5.0 Severe symptoms or lactate > 5 - 10  Stop NRTI and/or  Switch to NRTI with less mitochondrial toxicity, such as TDF or ABC  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

21. 21 Abacavir Hypersensitivity

22. 22 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

23. 23 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!!

24. 24 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

25. 25 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

26. 26 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?

27. 27 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

28. 28 Thank you! Questions?