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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Management of Medication Toxicity or Intolerance

Hepatic Events

(Last updated:2/12/2014; last reviewed:2/12/2014)

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Table 11e. Antiretroviral Therapy-Associated Adverse Effects and Management Recommendations—Hepatic Events
Adverse Effects Associated ARVs Onset / Clinical Manifestations Estimated Frequency Risk Factors Prevention/ Monitoring Management
Hepatic Toxicity 
Elevated AST, ALT, clinical hepatitis
All ARVs may be associated with hepatitis. NVP and TPV are of particular concern.

NVP, EFV, ABC, RAL, and MVC have been associated with hypersensitivity reactions.

NRTIs (especially ZDV, ddI, and d4T) are associated with lactic acidosis and hepatic steatosis.
Onset:
  • Hepatitis generally occurs within first few months of therapy, but can occur later.
  • Steatosis presents after months to years of therapy.
  • HBV-coinfected patients may develop severe hepatic flare with the initiation, withdrawal, or development of resistance to 3TC, FTC, or TDF (especially in patients receiving only one anti-HBV agent).
  • Hepatitis may also represent IRIS early in therapy, especially in HBV- and HCV- infected patients. 
Presentation:
  • Asymptomatic elevation of AST and ALT.
  • Symptomatic hepatitis with nausea, fatigue, and jaundice.
  • Hepatitis may be component of hypersensitivity reaction with rash, lactic acidosis, and hepatic steatosis. 
Uncommon in children.

Frequency varies with different agents and drug combinations.
 
HBV or HCV coinfection

Elevated baseline ALT and AST

Other hepatotoxic medications (including herbal preparations such as St. John's wort [Hypericum perforatum], Chaparral [Larrea tridentate], Germander [Teudrium chamaedrys])

Alcohol use

Underlying liver disease

Pregnancy

For NVP-Associated Hepatic Events in Adults:
  • Female with pre-NVP CD4 count >250 cells/mm3
  • Male with pre-NVP CD4 count >400 cells/mm3
  • Certain HLA types are also associated with NVP-associated hepatic events but are population-specific.a
Higher drug concentrations for PIs, particularly TPV
Prevention:
  • Avoid concomitant use of hepatotoxic medications. 
  • If hepatic enzymes are elevated >5 to 10 times ULN or chronic liver disease, most clinicians would avoid NVP.
Monitoring:
For ARVs Other than NVP
  • Obtain AST and ALT at baseline and thereafter at least every 3–4 months, or more frequently in at-risk patients (e.g., as HBV- or HCV-coinfected or elevated baseline AST and ALT).
For NVP
  • Obtain AST and ALT at baseline, at 2 and 4 weeks, then every 3 months.
Asymptomatic patients with elevated ALT or AST should be evaluated for other causes and monitored closely. If ALT or AST >5 to 10 times ULN, some would consider discontinuing ARVs.

In symptomatic patients, discontinue all ARVs and other potential hepatotoxic agents and avoid restarting the offending agent.

If a symptomatic hepatic event occurs on NVP, permanently discontinue drug (see also NVP Hypersensitivity).

When clinical hepatitis is associated with lactic acidosis, avoid restarting the most likely agent, and ZDV, d4T, and ddI in particular (see also Lactic Acidosis).

Consider viral causes of hepatitis:  HAV, HBV, HCV, EBV, and CMV.
Indirect Hyperbilirubinemia IDV, ATV Onset:
  • First months of therapy
Presentation:
  • Jaundice; otherwise asymptomatic elevation of indirect bilirubin levels with normal direct bilirubin, AST, and ALT.
HIV-Infected Children Receiving ATV
  • 49% developed increased total bilirubin levels (≥3.2 mg/dL); 13% had jaundice/
    scleral icterus.
N/A Monitoring:
  • No specific monitoring.
Not necessary to discontinue the offending agent except for cosmetic reasons. 

After an initial rise over the first few months of therapy, unconjugated bilirubin levels
generally stabilize; in some patients, levels improve over time.
Non-Cirrhotic Portal Hypertension ARVs, especially ddI, d4T and combination of ddI and d4T Onset:
  • Generally after years of therapy
Presentation:
  • GI bleeding, esophageal varices, hypersplenism.
  • Mild elevations in AST and ALT, moderate increases in ALP, and pancytopenia (because of hypersplenism).
  • Liver biopsy may reveal a variety of findings, most commonly nodular regenerative hyperplasia
    or hepatoportal sclerosis.
Rare:
  • Probably less than 1%
Prolonged exposure to ARV therapy, especially ddI and the combination of ddI and d4T Monitoring:
  • No specific monitoring.
Manage complications of GI bleeding and esophageal varices.

Discontinue/
replace d4T or ddI, if patient is receiving either.
a E.g. HLA-DRB1*0101 in Caucasians, HLA-DRB1*0102 in South Africans, and HLA-B35 in Thai and Caucasians

Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ALP = alkaline phosphatase; ALT = alanine transaminase; , ARV = antiretroviral; AST = aspartate aminotransferase; ATV = atazanavir; CD4 = CD4 T lymphocyte; CMV = cytomegalovirus; d4T = stavudine; ddI = didanosine; EBV = Epstein-Barr virus; EFV = efavirenz; FTC = emtricitabine; GI = gastrointestinal; HAV = hepatitis A virus; HBV = hepatitis B virus; HCV = hepatitis C virus; IDV = iIndinavir; IRIS = immune reconstitution inflammatory syndrome; MVC = maraviroc; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; RAL = raltegravir; TDF = tenofovir disoproxil fumarate; TPV = tipranavir; ULN = upper limit of normal; ZDV = zidovudine

References

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