- Distinct mechanisms of ART-related hepatotoxicity:
- Idiosyncratic reactions & 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; NVP>>EFV; TPV, full dose RTV >> other PIs.
- Hypersensitivity reaction: early NVP and ABC (ABC hepatotoxicity can occur in absence of ABC hypersensitivity reaction & among HLAB*5701 -negative pts)
- 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 (esp. genotype 3), older age, previous hepatotoxicity, alcoholism, cirrhosis, obesity, substance abuse, baseline abnormal transaminases, other hepatotoxic medications (eg: anti-tuberculosis therapy). Note: sustained virologic response on HCV therapy decreases HCV-associated risk.
- 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
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