Download Hepatotoxicity of ARVs

Hepatic Toxicity in
Patients Taking ARVs
HAIVN
Harvard 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 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
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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
Non-ARV drugs
 TB drugs
• PZA, RIF, INH


Antifungal drugs
Others
• Cotrimoxazole
• Paracetamol

Alcohol
• NRTIs
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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
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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
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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 coinfection
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
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
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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
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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
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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
 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
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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 ABC
Important 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)
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?
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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?
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