Liver toxicity induced by non-nucleoside reverse transcriptase inhibitors

Abstract

Liver toxicity is one of the most relevant adverse effects of antiretroviral therapy. Within the non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz can be considered a safer drug for the liver than nevirapine. In fact, the frequency of severe increased liver enzymes in patients on efavirenz ranges from 1 to 8%, whereas in patients treated with nevirapine, it ranges from 4 to 18%. Likewise, nevirapine is more commonly associated than efavirenz with early acute hepatitis, which is produced by a hypersensitivity mechanism and has a defined risk profile that often makes it avoidable. Despite the fact that most cases of NNRTI-induced liver toxicity are asymptomatic, the rates of symptomatic events in patients treated with nevirapine are greater than in subjects on efavirenz. In any case, it is unusual for an NNRTI to be suspended due to liver toxicity.

Stavudine- and nevirapine-related drug toxicity while on generic fixed-dose antiretroviral treatment: incidence, timing and risk factors in a three-year cohort in Kigali, Rwanda

“…As reported before, baseline abnormal liver tests were associated with hepatotoxicity. 6,18 Whether this is related to concurrent use of hepatotoxic drugs, alcohol abuse or associated viral hepatitis infection could not be determined from our data, but has been reported before. 7,8,18 Our data would suggest that, if conditions allow, performing a baseline liver-function test might allow identification of patients requiring closer follow-up and/or avoidance of NVP-based HAART.…”

“…7,8,17 Whereas data from Western countries have not consistently shown specific risk factors for skin rash, it is generally accepted that a high baseline CD4 count and being female are associated with NVP-related liver toxicity. 6 However, African studies have reported different results. 7,8 No single study clearly revealed high CD4 count as a risk factor, and most have not seen an association with sex.…”

“…Of these, 108 (4.9%) were related to skin rash and 29 (1.3%) to hepatotoxicity, which corresponded to incidence rates of 30 and 8/1000 patient-years, respectively (Table 2). Most (93%) of the substitutions due to skin rash occurred within the first 6 months, with a median time of 4 weeks [interquartile range (IQR) [3][4][5][6]. For hepatotoxicity, the median time of substitution was 5 weeks (IQR 3-29), with 28% occurring after 6 months of NVP use.…”

“…1 The availability of a cheap, generic fixed-dose combination (FDC) containing stavudine (d4T), lamivudine and nevirapine (NVP) has played an important higher baseline CD4 counts, above 250 cells/l in particular, are at higher risk of toxicity, with a documented 12-fold increase in risk of severe hepatotoxicity. 6 With ART treatment guidelines tending toward therapy initiation at higher CD4 thresholds (<350 cells/l), an increasing number of patients, particularly women, will initiate NVP-based ART with higher baseline CD4 counts with concerns regarding safety. 7,8 Although d4T-and NVP-related toxicity will remain important clinical challenges in Africa over the next few years, only limited long-term follow-up data on these toxicities from field settings are available.…”

Effect of Host Genetic Variation on the Pharmacokinetics and Clinical Response of Nnrtis

“…The frequency of Grade 3 or 4 increased liver enzymes in patients on NVP (4-18%) appears to be higher than those on EFV (1-8%) based on several clinical trials and cohort studies [46]. Factors associated with hepatotoxicity include female gender, higher baseline and actual CD4 + T-cell counts [47,48], and HLA-DRB1*0101 [49].…”