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Hepatic Toxicity in Patients Taking ARVs

HAIVNHarvard Medical School AIDS

Initiative in Vietnam

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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

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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

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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

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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

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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

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Grading Hepatotoxicity

GRADE LFT > normal ALT

mild

1 1.25 – 2.5 50 - 100

2 2.5 - 5 101 - 200

severe

3 5 - 10 201 - 400

4 > 10 > 400

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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

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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)

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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

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NNRTIs and Hepatotoxicity

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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

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NNRTIs and Hepatotoxicity: Adverse Reactions

More Severe Reaction (grade 3-4):Usually occurs in first 1-2 months of treatmentHigher risk for NVP with:

• female CD4>250• male CD4>400

Other symptoms: rash, fever, body achesStevens-Johnson Syndrome: severe allergic reaction with mucous-membrane involvement

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NNRTIs and Hepatotoxicity: Treatment (1)

Level LTF Treatment

Mild(grade 1-2)

1-5x normal

Continue ARV Follow closely with clinical exam and

LFT every 1-2 weeks

Moderate(grade 3)

5-10x 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)

>10x normal

Stop all ARV and hepatotoxic drugs Do not use offending agent (NVP or

EFV) again

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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

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Lactic Acidosis

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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

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Lactic Acidosis: Symptoms

Mild: Fatigue Body aches Nausea Vomiting Diarrhea Weight loss

Severe: Wasting Dyspnea Abdominal pain Coma

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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

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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

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Abacavir Hypersensitivity

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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

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Abacavir Hypersensitivity (2)

Symptoms: • Rash, fever, nausea, vomiting, fatigue,

arthralgia, headache, abdominal pain, dyspnea, cough

Laboratory: • AST/ALT, lymphocytes, CPK

Treatment: Stop ABCImportant never to use ABC again:

can cause death!!

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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

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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

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Case Study: Tuan (3)

DiscussionWhat 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?

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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

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Thank you!

Questions?