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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: March 1, 2016; last reviewed: March 1, 2016)

Table 12e. 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.
  • Hepatitis generally occurs within the 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.
  • 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 [Teucrium chamaedrys])

Alcohol use

Underlying liver disease


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.
  • 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.
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., 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 (including repeating AST and ALT and checking total bilirubin). If ALT or AST is more than 5–10 times ULN and felt to be possibly or probably associated with ARVs, the potentially offending ARVs should be discontinued.

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, including ZDV, d4T, and ddI in particular (see also Lactic Acidosis).

Consider viral causes of hepatitis: HAV, HBV, HCV, EBV, and CMV.
Indirect Hyper-bilirubinemia IDV, ATV (with either RTV or COBI) Onset:
  • First months of therapy
  • Jaundice; otherwise asymptomatic elevation of indirect bilirubin levels with normal AST and ALT. Direct bilirubin may be normal or slightly elevated when levels of indirect bilirubin are very high.
HIV-Infected Children Receiving ATV:
  • In long-term follow-up, 9% had at least 1 total bilirubin level > 5 x ULN and 1.4% experienced jaundice
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 ddI, d4t Onset:
  • Generally after years of therapy
  • 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.
  • 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 For example, HLA-DRB1*0101 in whites, HLA-DRB1*0102 in South Africans, and HLA-B35 in Thai and whites.

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; COBI = cobicistat; 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; HLA = human leukocyte antigen; IDV = indinavir; IRIS = immune reconstitution inflammatory syndrome; MVC = maraviroc; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; RAL = raltegravir; RTV = ritonavir; TDF = tenofovir disoproxil fumarate; TPV = tipranavir; ULN = upper limit of normal; ZDV = zidovudine


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