Hepatotoxicity

Christopher J. Hoffmann, M.D., M.P.H.

PATHOGENS

  • ART-related hepatotoxicity (also known as drug-induced liver injury - DILI):
    • INSTIs have very low hepatotoxicity RAL < DTG, ELV/c, BIC.
    • Idiosyncratic reactions and dose-dependent cytotoxicity: most common cause; most ART agents, NRTI, NNRTI, PI (may be dose dependent). Order of risk: ddI>d4T>AZT>ABC>3TC, FTC, TDF (TDF, 3TC, FTC, have minimal liver toxicity);NVP>>EFV=ETR>RPV; TPV>> other PIs (all others similar, including DRV, NFV may be lower)
    • Hypersensitivity reaction: early NVP and ABC (ABC hepatotoxicity can occur in absence of ABC hypersensitivity reaction and among HLAB*5701 -negative pts)
    • Mitochondrial toxicity & lactic acidosis: d4T, ddI, AZT (risk factors: female, higher BMI)
    • Immune reconstitution inflammatory syndrome (IRIS): can lead to hepatocellular injury particularly if known infection is present with liver involvement (not true DILI)
  • General risk factors: HBV and/or HCV ongoing untreated infection (increase risk from 2-5% to 10-25%), pregnancy, older age, previous hepatotoxicity, alcohol use, cirrhosis, obesity, substance abuse, baseline abnormal transaminases, other hepatotoxic medications (eg: anti-tuberculosis therapy). Note: sustained virologic response on HCV therapy decreases or eliminates HCV-associated risk.
  • Other agents that are common causes of DILI (see https://www.ncbi.nlm.nih.gov/books/NBK547852 for searchable database on drug-induced liver injury)
    • Anti-TB therapy
    • Cotrimoxazole
    • Amoxacillin-clavulanate
    • Acetominophen
    • Herbal supplements
    • Alcohol
    • High-dose statin
  • NVP hypersensitivity risk factors: female sex and higher CD4 (>250 for women, >400 for men) at time of ART initiation
  • ABC hypersensitivity risk factor: HLA B*5701 haplotype
  • ddI causes non-cirrhotic portal hypertension

CLINICAL

  • Definition of hepatotoxicity / DILI: drug-related elevation in ALT/AST in absence of another etiology (although no strict criteria, typically ALT >5x upper limit of normal (ULN), alk phos >2xULN, or ALT>3x ULN and bilirubin >2x ULN).
  • Biochemical patterns of hepatobiliary disease: cholestatic (elevated alk phos [and bilirubin] with less elevation in AST, ALT), mixed, hepatocellular (elevation in ALT, AST much greater than alk phos). ART-related hepatotoxicity / DILI is most commonly hepatocellular injury. R factor helps distinguish between patterns (R factor = (ALT/ULN) / alk phos/ULN); >5 hepatocellular, 2-5 mixed, < 2 cholestatic).
  • ART hepatotoxicity predominately hepatocellular (increase in ALT, AST with minimal initial change in bilirubin or alk phos). Isolated indirect hyperbilirubinemia often due to ATV or IDV therapy and not associated with hepatotoxicity.
  • Presentation related to etiology.
    • Idiosyncratic reactions: most common: onset < 6 mos after ART initiation, often asymptomatic and lasting < 3 wks. Dose-dependent reactions: generally result of cumulative drug exposure and occur >6 mos on drug. Both often asymptomatic with spontaneous resolution but can progress to severe livery injury.
    • Hypersensitivity: onset 4-6 wks after ART initiation, presents with fever, rash, & constitutional symptoms. (Note: can be confused with acute viral infection such as influenza).
    • Mitochondrial toxicity: onset usually >6 mos after initiation of d4T, ddI, or AZT; presents with lactic acidosis, nausea, anorexia, dyspnea, hepatomegaly, hepatic steatosis, and weight loss.
  • IRIS: usually presents after < 6 mos of ART and after robust CD4 rise. Associated with reconstituted immune response to antigens and may be indistinguishable from drug related hepatotoxicity (e.g. TB, HBV, MAC).
  • In the setting of persistent elevation in liver enzymes or an acute rise, acute infection (viral hepatitis, other) and hepatic steatosis and other chronic non-infectious liver diseases should be considered (auto-immune hepatitis, granulomatous hepatitis, hemochromatosis, etc).

DIAGNOSIS

  • DIFFERENTIAL DIAGNOSIS:
    • Viral hepatitis: acute infection or flare with HAV, HBV, HCV, HDV. HBV can lead to flare spontaneously, with reactivation during waning immunity, and with loss of suppression of HBV DNA by 3TC or other anti-HBV agents due to discontinuation or resistance.
    • Acute viral infection: CMV, EBV
    • Bacterial infections: TB, MAC, and Bartonella henselae/quintana
    • Malignancy: lymphoma
    • Toxins: acetaminophen, alcohol, other medications (including naturopathic products)
    • Influenza (rash, fever, constitutional Sx; no significant elevation in ALT)
    • Chronic non-infectious liver disease (esp. hepatic steatosis)
  • DIAGNOSIS:
    • Measure transaminases before starting ART. If normal, may be checked monthly with other labs for 1st 3 mos. If stable, can be increased to 3-6 mo. intervals. Most hepatotoxicity is diagnosed by routine ALT testing.
    • Suspect hepatotoxicity if patients present with malaise, anorexia, nausea, fevers, rash (these symptoms especially common with NVP or ABC hypersensitivity hepatitis), or weight loss.

TREATMENT

ART

  • Stop or Modify ART if: (1) symptomatic hepatitis; (2) lactic acidosis; (3) jaundice (elevated bilirubin + elevated ALT requires close monitoring / hospital care); (4) evidence of ABC or NVP hypersensitivity; or (5) ALT>10x. ART regimens in current use very rarely cause hepatotoxicity and even more rarely need to be stopped for hepatotoxicity.
  • Presence of constitutional Sx, elevated lactate, or evidence of hepatic dysfunction (coagulopathy or elevated ammonia) suggest severe toxicity and is medical emergency; discontinue ART and provide close monitoring, usually as inpatient. Provide supportive care.
  • Mitochondrial toxicity sometimes treated with riboflavin or thiamine therapy, but no data. Full resolution of hyperlactemia may take months.
  • Hypersensitivity sometimes treated with prednisone, but no data. Do not restart causative medication (NVP or ABC). Attempt to identify cause, usually continue ART and underlying OI, may treat with NSAIDs or prednisone to control Sx. Evaluate carefully to avoid missing other cause and stopping ART unnecessarily.
  • Asymptomatic elevations < 10x ULN can be managed with close clinical monitoring (repeat ALT/AST until elevation resolves)
  • Asymptomatic elevations 5-10x ULN must be managed on case-by-case basis. Pts without liver disease may do well without discontinuation of therapy but with close monitoring until ALT elevation is resolved.
  • Elevations >10x ULN require close monitoring and generally discontinuation of ART until ALT elevation has resolved.
  • If drugs stopped or switch needed, switch to drugs with less hepatotoxicity: NRTIs: 3TC, FTC, TDF, ABC; NNRTIs: EFV; PI: no conclusive data, except that TPV/r more hepatotoxic than others. No drug absolutely contraindicated in pts with chronic hepatitis, though ABC contraindicated in patients with severe hepatic disease (because of hepatic metabolism), and dose reduction of some PIs recommended. Dual PIs more hepatotoxic than singe PIs. Boosting with low-dose RTV (100-200 mg/day) does not increase hepatotoxicity, but greater hepatotoxicity with TPV/r 500/200 mg twice-daily.
  • Always also consider and evaluate for other causes (see Differential Dx); consider flare of HBV or reactivation even if negative serologies recently obtained.

Anti-TB Therapy

  • Clinical assessment monthly when receiving treatment for TB disease. Warn pts of Sx of hepatitis (dark urine, fever > 3 days, malaise).
  • Obtain transaminases with any Sx consistent with hepatitis and routinely at 1 and 3 mos.
  • If ALT/AST >5x ULN: discontinue INH, rifampin, PZA; consider use of ethambutol, streptomycin, and fluoroquinolone.
  • When transaminases have normalized, reintroduce primary drugs one at a time.

Selected Drug Comments

Drug

Recommendation

Stavudine (d4T)

Hepatotoxicity due to hepatic steatosis resulting from mitochondrial toxicity: more common with d4T than with other NRTIs. Incidence estimates vary (9%-13%)

AZT (Zidovudine)

Hepatotoxicity due to hepatic steatosis resulting from mitochondrial toxicity. Estimated incidence ~7%

Didanosine (ddI)

Hepatotoxicity due to hepatic steatosis resulting from mitochondrial toxicity. Also increased risk for chronic fibrotic liver disease.

Protease inhibitors

Incidence varies, but in a recent study: NFV 11%, LPV/r 9%, IDV13%, IDV/r (1600/200-400 mg/d), 12.8%, SQV/RTV (800/800 mg/day), 17.2%. Pts with chronic hepatitis B or C at greatest risk

Nevirapine

Early hepatotoxicity due to hypersensitivity; can be life-threatening. Incidence varies, but increased in women and pts with elevated CD4 counts (>250). Risk of later (non-hypersensitivity) hepatotoxicity greatest in pts with chronic hepatitis B or C (as with PI toxicity).

Efavirenz (EFV)

Associated with early and generally mild hepatotoxicity possible from hypersensitivity. Also report of liver necrosis with ALT >10x ULN and elevated bilirubin. injury.

Rilpivirine (RPV)

Similar hepatotoxicity to comparitors in clinical trials. Single case report of RPV associated hepatotoxicity, possible hypersensitivity reaction.

Lamivudine

Risk for flare of HBV in HIV/HBV coinfected pts when 3TC withdrawn or when 3TC resistance develops

Emtricitabine (FTC)

Risk for flare of HBV in HIV/HBV coinfected pts when FTC withdrawn or when FTC resistance develops

Tenofovir (TDF)

Risk for flare of HBV in HIV/HBV coinfected pts when TDF withdrawn or when TDF resistance develops

Tipranavir

At standard dose of TPV/r 500/200 mg twice-daily, this is only PI shown to have greater hepatotoxicity than other RTV-boosted PIs.

Abacavir (ABC)

Hypersensitivity among approx 6% of whites, lower among other racial groups (risk predicted by presence of HLA B*5701, screen for this haplotype before initiating ABC)

Raltegravir (RAL)

Similar to better hepatoxocity profile to comparitors in clinical trials. Case reports of improved ALT after switch to RAL and case report of RAL associated hepatotoxicity during pregnancy.

Elvitegravir (EVG)

Similar hepatotoxicity profile to comparitors in clinical trials. No evidence of direct hepatotocity.

Dolutegravir (DTG)

Similar hepatotoxicity profile to comparitors in clinical trials. No evidence of direct hepatotocity.

Pathogen Specific Therapy

Pathogen

1st Line Agent

2nd Line Agent

References

  1. Pelchen-Matthews A, Larsen JF, Shepherd L, et al. Hypersensitivity reactions, hepatotoxicity, and other discontinuations in persons receiving integrase strand transfer inhibitors: results from the EuroSIDA study. HIV Res Clin Pract. 2021;22(6):160-168.  [PMID:34779362]
  2. Heil EL, Pandit NS, Taylor GH. Probable hepatotoxicity from two second-generation integrase strand transfer inhibitors. AIDS. 2021;35(13):2232-2233.  [PMID:34602594]
  3. Rivera CG, Otto AO, Zeuli JD, et al. Hepatotoxicity of contemporary antiretroviral drugs. Curr Opin HIV AIDS. 2021;16(6):279-285.  [PMID:34545037]

    Comment: Excellent overview of ART hepatotoxicity.
    Rating: Important

  4. Sonderup MW, Maughan D, Gogela N, et al. Identification of a novel and severe pattern of efavirenz drug-induced liver injury in South Africa. AIDS. 2016;30(9):1483-5.  [PMID:26959511]

    Comment: Case series of EFV related hepatotoxicity

  5. Kovari H, Sabin CA, Ledergerber B, et al. Antiretroviral Drugs and Risk of Chronic Alanine Aminotransferase Elevation in Human Immunodeficiency Virus (HIV)-Monoinfected Persons: The Data Collection on Adverse Events of Anti-HIV Drugs Study. Open Forum Infect Dis. 2016;3(1):ofw009.  [PMID:26925429]

    Comment: Comparison of early and late hepatotoxicity by agent in the D:A:D cohort.

  6. Morse CG, McLaughlin M, Matthews L, et al. Nonalcoholic Steatohepatitis and Hepatic Fibrosis in HIV-1-Monoinfected Adults With Elevated Aminotransferase Levels on Antiretroviral Therapy. Clin Infect Dis. 2015;60(10):1569-78.  [PMID:25681381]
  7. Björnsson ES, Bergmann OM, Björnsson HK, et al. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013;144(7):1419-25, 1425.e1-3; quiz e19-20.  [PMID:23419359]

    Comment: Analysis of drug associated liver injury in general population in Iceland (non-HIV). Amoxicillin-clavulanate, azothiprine, inflixamab, and diclofenac among most common causes.

  8. Renet S, Closon A, Brochet MS, et al. Increase in transaminase levels following the use of raltegravir in a woman with a high HIV viral load at 35 weeks of pregnancy. J Obstet Gynaecol Can. 2013;35(1):68-72.  [PMID:23343800]
  9. Soni S, Churchill DR, Gilleece Y. Abacavir-induced hepatotoxicity: a report of two cases. AIDS. 2008;22(18):2557-8.  [PMID:19005287]

    Comment: Case reports of ABC associated hepatotoxicity in HLA B*5701-negative patients.

  10. Sanne I, Mommeja-Marin H, Hinkle J, et al. Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects. J Infect Dis. 2005;191(6):825-9.  [PMID:15717255]

    Comment: South African study identified low BMI, low albumin and female gender associated with increased risk of hepatotoxicity from NVP.

Last updated: March 12, 2023