Diagnosis>Complications of Therapy>

PATHOGENS

• Distinct mechanisms of ART-related hepatotoxicity:
• Idiosyncratic reactions & dose dependent cytotoxicity: most common cause; most ART agents, NRTI, NNRTI, PI (may be dose dependent)
• Hypersensitivity reaction: early NVP and ABC
• Mitochondrial toxicity: NRTIs; esp. d4T, ddI, AZT
• Immune reconstitution inflammatory syndrome (IRIS): all agents during CD4 increase
• General risk factors: HBV and/or HCV co-infection, previous hepatotoxicity, alcoholism, cirrhosis, obesity, substance abuse, baseline abnormal transaminases, other hepatotoxic medications (eg: anti-tuberculosis therapy)
• 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
• Lactic acidosis risk factors: female, higher BMI

CLINICAL

• Definition of hepatotoxicity: elevation in ALT/AST in the absence of another etiology.
• Hepatotoxicity is predominately hepatocellular (increase in ALT, AST with minimal initial change in bilirubin or alk phos. Consider other Dx if high bilirubin without high ALT or for high alk phos. Indirect hyperbilirubinemia often due to ATV or IDV therapy and not associated with hepatotoxicity. 
• Presentation related to etiology.
• Idiosyncratic reactions: most common: onset < 6mos after ART initiation, often asymptomatic and lasting <3 wks. Dose dependent reactions: generally result of cumulative drug exposure & 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, steatosis, and weight loss.
• IRIS: usually presents after <6 mos of ART & after robust CD4 rise. Associated with reconstituted immune response to antigens (e.g. TB, HBV, MAI)

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, & 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)
• DIAGNOSIS: 
• Measure transaminases before starting HAART. If normal, may be checked monthly for 1st 3 mos. If stable, can be increased to 3 mo. intervals. Most hepatotoxicity diagnosed by routine ALT testing.
• Suspect hepatotoxicity if patients present with malaise, anorexia, nausea, fevers, rash (especially with NVP or ABC hypersensitivity hepatitis), or weight loss.

TREATMENT

• Presence of constitutional Sx, elevated lactate, or evidence of hepatic dysfunction (coagulopathy or elevated ammonia) suggest severe toxicity & is medical emergency; discontinue HAART and provide close monitoring, usually as inpatient. Provide supportive care. 1) Mitochondrial toxicity sometimes treated with riboflavin or thiamine therapy, but no data. Full resolution of hyperlactemia may take months.  2) 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 < 5x ULN can be managed with close clinical monitoring (repeat ALT/AST until elevation resolves)
• If ALT elevated >5x ULN or persistently elevated, evaluate for other causes (see Differential Dx), consider flare of HBV or reactivation even if negative serologies recently obtained
• 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) doesn't increase hepatotoxicity, but greater hepatotoxicity with TPV/RTV 500/200 mg bid.

• 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.

Drug Comments

REFERENCES

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