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Hepatotoxicity and Protease Inhibitors: nelfinavir, Kaletra, IDV/r, SQV/RTV
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Reported by Jules Levin
"Hepatoxicity Associated with Antiretroviral Therapy Containing Protease Inhibitors with or without Pharmacokinetic Boosting by Low-dose Ritonavir"
Mark Sulkowski and colleagues (Johns Hopkins University School of Medicine) reported this study at the AASLD liver conference in November 2003 (poster 1125).
BRIEF SUMMARY: This study looked at 1000 patients starting a PI regimen: nelfinavir, Kaletra, indinavir/r, and SQV/RTV with 400mg of ritonavir; for the purpose of evaluating the rates for developing severe hepatotixicity. The study authors found that the rates of severe hepatoxicity occurred in patients receiving nelfinavir regimen at 11%, Kaletra (LPV/rtv) 9%, IDV/RTV (200-400mg/day) 12.8%, SQV/RTV (400mg/day) 17.2%. Overall 12% of patients experienced hepatoxicity when on a PI regimen in this study. Having HCV was associated with experiencing severe hepatoxicity. Hepatoxicity was defined as grade 3 or 4 changes in ALT/AST. For patients with normal ALT/AST at baseline grade 3 was 5 x the upper limit of normal and grade 4 was 10 x the upper limit of normal. For patients with elevated ALT/AST before the study grade 3 was defined as 3.6-5 x baseline and grade 4 as >5 x baseline.
Protease inhibitors, particularly full dose ritonavir (RTV) have been associated with hepatoxicity. As well, all other HIV antiretroviral medications can be associated with hepatoxicity, which means elevated liver enzymes (ALT, AST). Increasingly doctors and care providers use low doseRTV (200-400 mg/day) to alter the pharmcokinetics ("boost") of other PIs such as lopinavir (LPV) and indinavir (IDV), allowing lessfrequent dosing and increased antiivral effectiveness. Few data are available regarding hepatoxicity associated with these boosted PI regimens.
This study prospectively evaluated the incidence of severe hepatoxicity, defined as a grade 3 or 4 change in serum alanine/asparate aminotransferase (ALT/AST) levels following initiation of ART-containing PIs with or without low-dose RTV in a university-based, urban HIV clinic. Changes in serum ALT/AST levels were graded as previously described (JAMA 283;74:80). The incidence was calculated as the number of events per 100-persons exposed.
SUMMARY: Between 1/96-3/03, 1061 eligible patients (pts) started PI-containing ART including nelfinavir (NFV)—605 pts, LPV+RTV 200mg/day—89 patients, IDV+RTV (200-400mg/day—94 pts; saquinavir (SQV)+RTV 800mg/day.
At baseline, subjects had the following characteristics: median age 37 yrs; male 73%; African-American 77%; HCV+ 46%; HBsAg+ 10%; median ALT 30 IU/L; median CD4 count 166; median HIV RNA 4.7 log.
Subjects were followed for a median 224-365 days. The incidence of of grade 3/4 hepatotoxicity was: NFV, 11%; LPV/rtv (200mg/day), 9%; IDV/rtv (200-400mg/day), 12.8%; SQV/rtv (400 mg/day), 17.2%.
Overall, the incidence of grade 3/4 hepatoxicity was higher in HCV+ subjects (8.7%) compared to HCV negative subjects (4%) [RR 2.0, 95% CI 1.44-2.78]. In multivariate Cox proportional hazard analysis, grade 3/4 hepatoxicity was independently associated with use of IDV/rtv (HR 2.97, 95% CI 1.44-6.12), SQV/rtv (2.41, 95% CI 1.48-2.83), HCV positivity (1.82, 95% CI 1.17-2.83), CD4 count >50 (0.58, 0.32-1.0) and HIV RNA level >400 copies/ml (3.18, 0.86-11.8).
The authors concluded the highest risk for grade 3/4 hepatoxicity was observed in pts receiving SQV/rtv (800mg/day) and IDV/rtv (200-400mg/day). However, no increased risk of hepatotoxicity was detected in pts receiving NFV or LPV/rtv (kaletra). In addition, while HCV+ pts had a 2-fold higher risk of hepatoxicity, 83% of such pts did not experience toxicity, suggesting PIs should not be withheld. Further research is needed to elucidate the mechanism of ART-related liver injury.
Patients in this study with pretreatment AST & ALT within the normal ranges (AST <35 IU/L and ALT <31 IU/L) were classified based on changes relative to the upper limit of normal (ULN): grade 0 (<1.25 ULN); grade 1 (1.25-2.5 x ULN); grade 2 (2.6-5 x ULN); grade 3 (5.1-10 x ULN); grade 4 (>10 x ULN). To avoid bias, pts with elevated pretreatment serum AST & ALT (>ULN) were classified based on changes relative to baseline value rather than to the upper limit of normal: grade 0 (<1.25-2.5 x baseline); grade 2 (2.6-3.5 x baseline); grade 3 (3.6-5 x baseline); grade 4 (>5 x baseline). Severe hepatotoxicity was defined as grade 3 or 4 change in either serum AST or ALT levels during antiretroviral treatment.
RESULTS
Prior to initiation of therapy, HCV-infected pts had significantly higher pretreatment AST & ALT levels than HCV-uninfected subjects did. The median pretreatment AST & ALT levels were 44.5 U/L and 37 U/L for HCV-infected pts and 28 U/L and 25 U/L for HCV-uninfected pts. During follow-up, serum AST & ALT levels increased significantly in all treatment groups, however, the magnitude of increase in serum AST & ALT was greater among SQV/rtv users compared to those using other PIs (p<.001) and among HCV-infected compared to HCV-uninfected persons (p<.0001).
Following initiation of PI-containing HAART, serum ALT levels remained less than 1.25 x the ULN of their pretreatment levels in 54% of LPV/rtv users, 62% of IDV/rtv users, and 54% of NFV users compared to only 42% of RTV/SQV users (p<.0001 for comparison of RTV/SQV to other PI regimens). Overall, severe (grade 3 or 4) hepatotoxicity was observed in 135 of 1061 (12.1%; 95% CI 10.6%-14.9%) of pts prescribed PIs. However, the incidence of severe hepatoxicity varied significantly according to the specific PI prescribed: NFV, 67 of 607 pts (11.1%; 95% CI, 6.8-21.2%); LPV/rtv, 8 of 89 pts (9.0%, 95% CI, 4.0-16.9%); IDV/rtv, 12 of 94 pts (12.8%, 95% CI, 6.8-21.2%); and SQV/RTV, 47 of 273 pts (17.2%, 95% CI 12.9-22.2%) (RR=1.55, 95% 1.12-2.16 for the comparison of RTV/SQV to other PI regimens).
In addition to the 89 pts for whom LPV/rtv was their first PI-based ART regimen, 119 pts switched from another PI-based ART regimen to one containing LPV/rtv. Grade 3/4 hepatotoxicity was observed in 10 of 119 (8.4%; 95% CI, 4.1-14.9) pts switching to LPV/rtv; of whom, two pts had experienced severe hepatoxicity on their prior PI-based ART regimen (NFV, SQV/RTV). Thus, among all pts (PI-naïve and experienced) prescribed LPV/rtv based ART, grade 3 or 4 hepatotoxicity developed in 18 of 208 pts (8.4%; 95% CI, 5.2-13.3).
The median duration of treatment before the detection of severe hepatoxicity was: NFV, 253 days (IQR, 77 --669 days); LPV/rtv, 122 days (IQR, 58-158); IDV/RTV, 228 days (IDR 55-318); SQV/RTV, 105 days (IQR 63-224) (p=.13). The detection of severe hepatoxicity was more rapid among pts prescribed SQV/RTV compared to those prescribed other PI-based regimens.
Development of Hepatoxicity and Chronic Viral Hepatitis
Hepatotoxicity (any grade) was observed in 58% of HCV-infected persons compared to 41% of HCV-uninfected than (p<.0001). The detection of severe hepatoxicity was more rapid among HCV among HCV-infected than HCV-uninfected pts. While 62% (84 of 135) of severe hepatotoxicity cases were observed in HCV-infected pts, 82.6% (400 of 484) of HCV-infected pts did not experience severe hepatoxicity.
Risk Factors for the Development of severe Hepatoxicity
Cox proportional hazards regression was used to determine factors associated with the development of severe hepatoxicity during PI-based ART. In univariate analysis, the presence of HCV antibody (RR 1.82, 95% CI 1.20-2.74), baseline CD4 >200 (RR 0.31, 95% CI 0.19-0.51), baseline HIV RNA >10,000 copies/ml (RR 4.81, 95% CI 1.51-15.3), baseline ALT levels >35 U/L (RR 1.58 95% 1.04-2.40), IDV/RTV use (RR 2.02, 95% CI 1.0-4.06). SQV/RTV use (2.63, 95% CI 1.67-4.15), and d4T use (RR 1.68, 95% 1.07-2.65) were associated with the development of severe hepatotoxicity. No significant associations were detected between the development of severe hepatoxicity and race, gender, age, or change in HIV RNA level or CD4 count during treatment.
In multivariate analysis, HCV infection (RR 1.82, 95% CI 1.17-2.83), baseline CD4>200 (RR 0.52 95% CI 0.30-0.90), baseline HIV RNA >10,000 copies/ml (RR 4.77, 95% CI 1.51-15.3), IDV/RTV use (RR 2.97, 95% CI 1.44-6.12), SQV/RTV use (2.41, % CI 1.48-3.92) were associated with the development of severe hepatotoxicity.
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