skip navigation

Skip Nav

Clinical Guidelines Portal

Clinical Guidelines Portal

Table of Contents

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Management of Medication Toxicity or Intolerance

Hepatic Events

(Last updated: March 5, 2015; last reviewed: March 5, 2015)

Table 13e. 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 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. If ALT or AST is more than 5–10 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, 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 Onset:
  • First months of therapy
  • 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.
  • 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
  • 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; 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; TDF = tenofovir disoproxil fumarate; TPV = tipranavir; ULN = upper limit of normal; ZDV = zidovudine


    1. Aceti A, Pasquazzi C, Zechini B, De Bac C, Group L. Hepatotoxicity development during antiretroviral therapy containing protease inhibitors in patients with HIV: the role of hepatitis B and C virus infection. J Acquir Immune Defic Syndr. Jan 1 2002;29(1):41-48. Available at
    2. Baylor MS, Johann-Liang R. Hepatotoxicity associated with nevirapine use. J Acquir Immune Defic Syndr. 2004;35(5):538-539. Available at
    3. Buck WC, Kabue MM, Kazembe PN, Kline MW. Discontinuation of standard first-line antiretroviral therapy in a cohort of 1434 Malawian children. J Int AIDS Soc. 2010;13:31. Available at
    4. Bunchorntavakul C, Reddy KR. Review article: herbal and dietary supplement hepatotoxicity. Aliment Pharmacol Ther. Jan 2013;37(1):3-17. Available at
    5. Busti AJ, Hall RG, Margolis DM. Atazanavir for the treatment of human immunodeficiency virus infection. Pharmacotherapy. Dec 2004;24(12):1732-1747. Available at
    6. Cotte L, Benet T, Billioud C, et al. The role of nucleoside and nucleotide analogues in nodular regenerative hyperplasia in HIV-infected patients: a case control study. J Hepatol. Mar 2011;54(3):489-496. Available at
    7. Gray D, Nuttall J, Lombard C, et al. Low rates of hepatotoxicity in HIV-infected children on anti-retroviral therapy with and without isoniazid prophylaxis. J Trop Pediatr. Jun 2010;56(3):159-165. Available at
    8. Kovari H, Ledergerber B, Battegay M, et al. Incidence and risk factors for chronic elevation of alanine aminotransferase levels in HIV-infected persons without hepatitis b or c virus co-infection. Clin Infect Dis. Feb 15 2010;50(4):502-511. Available at
    9. Kovari H, Ledergerber B, Peter U, et al. Association of noncirrhotic portal hypertension in HIV-infected persons and antiretroviral therapy with didanosine: a nested case-control study. Clin Infect Dis. Aug 15 2009;49(4):626-635. Available at
    10. Levy V, Grant RM. Antiretroviral therapy for hepatitis B virus-HIV-coinfected patients: promises and pitfalls. Clin Infect Dis. Oct 1 2006;43(7):904-910. Available at
    11. McDonald C, Uy J, Hu W, et al. Clinical significance of hyperbilirubinemia among HIV-1-infected patients treated with atazanavir/ritonavir through 96 weeks in the CASTLE study. AIDS Patient Care STDS. May 2012;26(5):259-264. Available at
    12. McKoy JM, Bennett CL, Scheetz MH, et al. Hepatotoxicity associated with long- versus short-course HIV-prophylactic nevirapine use: a systematic review and meta-analysis from the Research on Adverse Drug events And Reports (RADAR) project. Drug Saf. 2009;32(2):147-158. Available at
    13. Nunez M. Clinical syndromes and consequences of antiretroviral-related hepatotoxicity. Hepatology. Sep 2010;52(3):1143-1155. Available at
    14. Ouyang DW, Shapiro DE, Lu M, et al. Increased risk of hepatotoxicity in HIV-infected pregnant women receiving antiretroviral therapy independent of nevirapine exposure. AIDS. Nov 27 2009;23(18):2425-2430. Available at
    15. Phillips E, Bartlett JA, Sanne I, et al. Associations between HLA-DRB1*0102, HLA-B*5801, and hepatotoxicity during initiation of nevirapine-containing regimens in South Africa. J Acquir Immune Defic Syndr. Feb 1 2013;62(2):e55-57. Available at
    16. Schouten JN, Van der Ende ME, Koeter T, et al. Risk factors and outcome of HIV-associated idiopathic noncirrhotic portal hypertension. Aliment Pharmacol Ther. Nov 2012;36(9):875-885. Available at
    17. Stern JO, Robinson PA, Love J, Lanes S, Imperiale MS, Mayers DL. A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients. J Acquir Immune Defic Syndr. Sep 2003;34 Suppl 1(Suppl 1):S21-33. Available at
    18. Van Dyke RB, Wang L, Williams PL, Pediatric ACTGCT. Toxicities associated with dual nucleoside reverse-transcriptase inhibitor regimens in HIV-infected children. J Infect Dis. Dec 1 2008;198(11):1599-1608. Available at
    19. Vispo E, Morello J, Rodriguez-Novoa S, Soriano V. Noncirrhotic portal hypertension in HIV infection. Curr Opin Infect Dis. Feb 2011;24(1):12-18. Available at
    20. Wit FW, Weverling GJ, Weel J, Jurriaans S, Lange JM. Incidence of and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy. J Infect Dis. Jul 1 2002;186(1):23-31. Available at

    Back to Top