A Review of Two Studies on Hepatotoxicity and HIV Antiretroviral Drugs

There have been a number of reports about the first study authored by Mark Sulkowski, MD, from Johns Hopkins. Most of the reports are interpretations by others. Often interpretations don't reveal certain facts. Below is the actual abstract published by JAMA. Its important to notice that "severe hepatotoxicity" is defined as a grade 3 or 4 change in levels of serum alanine aminotransferase and aspartate aminotransferase. These are more commonly known as LFTs (liver functions tests). Following this first review is a review of a second study reaching different conclusions: hepatoxicity rates were different.

Hepatotoxicity Associated With Antiretroviral Therapy in Adults Infected With Human Immunodeficiency Virus and the Role of Hepatitis C or B Virus Infection

authors- Mark S. Sulkowski, MD; David L. Thomas, MD, MPH; Richard E. Chaisson, MD; Richard D. Moore, MD


Use of antiretroviral drugs, including protease inhibitors, for treatment of human immunodeficiency virus (HIV) infection has been anecdotally associated with hepatotoxicity, particularly in persons coinfected with hepatitis C or B virus.


To ascertain if incidence of severe hepatotoxicity during antiretroviral therapy is similar for all antiretroviral drug combinations, and to define the role of chronic viral hepatitis in its development.


Prospective cohort study.


University-based urban HIV clinic.


A total of 298 patients who were prescribed new antiretroviral therapies between January 1996 and January 1998, 211 (71%) of whom received protease inhibitors as part of combination therapy (median follow-up, 182 days) and 87 (29%) of whom received dual nucleoside analog regimens (median follow-up, 167 days). Chronic hepatitis C and B virus infection was present in 154 (52%) and 8 (2.7%) patients, respectively.

Main Outcome Measure  

Severe hepatotoxicity, defined as a grade 3 or 4 change in levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), evaluated before and during therapy.


Severe hepatotoxicity was observed in 31 (10.4%) of 298 patients (95% confidence interval [CI], 7.2%-14.4%). Ritonavir use was associated with a higher incidence of toxicity (30%; 95% CI,

17.9%-44.6%). However, no significant difference was detected in hepatotoxicity incidence in other treatment groups, ie, nucleoside analogs (5.7%; 95% CI, 1.2%-12.9%), nelfinavir (5.9%; 95% CI, 1.2%-16.2%), saquinavir (5.9%; 95% CI, 0.15%-28.7%), and indinavir (6.8%; 95% CI, 3.0%-13.1%). Although chronic viral hepatitis was associated with an increased risk of severe hepatotoxicity among patients prescribed nonritonavir regimens (relative risk, 3.7; 95% CI, 1.0-11.8), most patients with chronic hepatitis C or B virus infection (88%) did not experience significant toxic effects. Rate of severe toxicity with use of any protease inhibitor in patients with hepatitis C infection was 12.2% (13/107; 95% CI, 6.6%-19.9%). In multivariate logistic regression, only ritonavir (adjusted odds ratio [AOR], 8.6; 95% CI, 3.0-24.6) and a CD4 cell count increase of more than 0.05  109/L (AOR, 3.6; 95% CI, 1.0-12.9) were associated with severe hepatotoxicity. No irreversible outcomes were seen in patients with severe hepatotoxicity.


Our data indicate that use of ritonavir may increase risk of severe hepatotoxicity. Although hepatotoxicity may be more common in persons with chronic viral hepatitis, these data do not support withholding protease inhibitor therapy from persons coinfected with hepatitis B or C virus. JAMA. 2000;283:74-80

Main Contributing Factors to Severe Hepatic Cytolysis (ALT >201) in HAART-treated patients: history of cytolysis, baseline ALT, HBV, and HCV

Below is a review of a study reported in AIDS Vol 13, Numb 17 Dec 3 1999.  There appear to be some differences in the baseline demographics and study findings in this study versus the JAMA Sulkowski study recently receiving attention. In the JAMA study at baseline 49% (104/211) had prior injection drug use history among those receiving PI regimen, and 60% (56/87) had prior injection drug use history among those receiving dual nucleoside regimen.  In the AIDS study, 27% were reportedly IVDUs. In the JAMA Sulkowski study 48% (102/211) of those receiving PIs were hepatitis C virus antibody positive, and 60% (52/87) among the NRTI group were hep C virus antibody positive. As well, 3.3% (7/211) were hepatitis B surface antigen positive and 1.1% (1/87) in the NRTI group was hep B surface antigen positive. In the AIDS study chronic HBV infection was diagnosed in 7%, HCV in 35%, and triple infection in 2% in the individuals receiving NRTIs. In those receiving PI-HAART chronic HBV was diagnosed in 6%, HCV in 28%, and triple infection in 7%.

I think that the information from these studies can be used to individualize therapy based on patients situation: do they have HBV, HCV, higher baseline ALT, prior or current injection drug use, etc. Such individualization can help in possibly preventing or delaying the development of severe cytolysis (ALT elevations) and possibly the progression of HBV and HCV and cirrhosis. Is dual NRTI therapy complete blasphemy for the patient with HBV and/or HCV, particularly if they have relatively low baseline HIV RNA?

Severe hepatic cytolysis: incidence and risk factors in patients treated by antiretroviral combinations
Aquitane Cohort, France, 1996-1998

Marianne Saves, Stephanie Vandentorren, Valentin Daucourt, Catherine Marimoutou, Michel Dupon, Patrice Couzigou, Noelle Bernard, Patrick Mercie, Francois Dabis, and the Group d'Epidemiologie Clinique du Sida en Auitane (GESCA)


To study hepatic cytolysis in patients treated by HAART with protease inhibitor or with 2 nucleoside reverse transcriptase inhibitors (NRTIs)


Authors selected patients of the Aquitane Cohort who initiated HAART or two NRTIs before Jan 1 1998, had ALTs <201 IU/I at baseline and at least one follow-up measure. Cox model was used to study the association between occurrence of severe hepatic cytolysis (ALT >200IU/I) and age, gender, HIV transmission mode, baseline CD4 and CD8 count, history of hepatic cytolysis, antiretroviral therapy, baseline liver enzymes (WHO classification level 0: <51 IU/I, level 1: 51 to 100, level 2: 101-200. hepatitis B and C co-infection.


Sixty-four of 748 (8.5%) patients treated with HAART and 71 of 1249 (5.7%) treated with 2 NRTIs developed cytolysis. The probability of occurrence was 7.9% after 1 year (95% confidence interval (CI), 5.9-10.4) for patients treated with HAART and 4.8% (95% CI, 3.6-6.4) for patients treated with 2 NRTIs (log rank test, P=0.01). The median time to occurrence was 164 days for HAART-treated patients and 252 days for those treated with 2 NRTIs. In multivariate analysis, the history of cytolysis (hazard ratio (HR)=2.3; 95% CI, 1.2-4.4), baseline ALT value, (HR=2.4; 95% CI, 1.2-4.8 and HR=3.3; 95% CI, 1.4-7.4 for levels 1 and 2, respectively, hepatitis B (HR=3.0; 95% CI, 1.4-6.2) and hepatitis C co-infections (HR=3.2; 95% CI, 1.7-6.2) remained significantly associated with the occurrence of severe hepatic cytolysis among HAART-treated patients. History of cytolysis, hepatitis B and C were associated with cytolysis in patients treated with 2 NRTIs (HR=14.8, 2.6 and 2.7, respectively).
end of abstract. the following was excerpted from the full text of publication.

Risk Factors of severe hepatic cytolysis PIs

Study population.  The most frequently prescribed PI was indinavir (51%), followed by saquinavir (34%), ritonavir (13%), nelfinavir (1%) and ritonavir+saquinavir (1%); 96% had a history of treatment with 2 NRTIs, 3% with 1 NRTI and only 1% were naive of treatment. Median baseline viral load was 4.0 log (10,000 copies/ml) and median CD4 was 144. Chronic HBV co-infection was documented in 6%, HCV in 28% and triple infection in 7%.

Patients who developed severe hepatic cytolysis during HAART with PI differed from those who did not on the following factors in univariate analysis: they were more often IVDUs (48% vs 18%), had more frequently a history of cytolysis prior to the beginning of HAART with PI (36% vs 8%), had higher baseline ALT values and were more often co-infected by HBV and HCV (24% and 73% vs 5% and 32%, respectively). The final multivariate model kept the following risk factors: history of cytolysis (HR=2.3), baseline ALT >50 IU/I (HR=2.4 and 3.3 for grades 1 and 2, respectively), HBV (HR=3.0) and HCV (HR=3.2) co-infections. Higher baseline CD8 lymphocyte count protected against the occurrence of severe hepatic cytolysis (HR= 0.96 for an increase  of 50 CD8 cells. The PI used in the HAART regimen, the history of antiretroviral therapy, and the variables describing the evolution under HAART with PI (plasma viral load, CD4 lymphocytes and serum triglycerides) did not change the risk of occurrence of this adverse event. When restricting the analysis to those subjects with grade 0 baseline ALT values (19 among 486 patients), the only factors associated with occurrence of severe hepatic cytolysis were co-infection with HBV (HR=14.9, 95% CI 5.5-40.7) and HCV (HR=6.1; 95% CI, 2.2-16.7).


Study population. Most frequently NRTI associations were AZT+ddC (43%), AZT+3TC (38%), AZT+ddI (8%), 3TC+d4T (5%), ddI+d4T (4%), and other combinations (2%). Plasma baseline viral load was 4.2 log (16,000 copies/ml), median CD4 234. Chronic HBV diagnosed in 7%, HCV in 35%, and triple infection in 2%. The dual NRTI group was PI-naive.

In univariate analysis, NRTI-treated patients who developed severe hepatic cytolysis differed from those who did not for the following factors: they were more often IVDUs (52% vs 25%) or blood recipients (15% vs 5%), had higher ALTs at baseline, more frequently a history of cytolysis prior to beginning dual therapy (86% vs 11%), and a co-infection with HBV or HCV (21% and 58% vs 6% and 29%, respectively. In the final multivariate model, the following risk factors of severe hepatic cytolysis were: a history of cytolysis (HR=14.8), and HBV (HR=2.6) and HCV (HR=2.7) co-infections. The risk of severe hepatic cytolysis was independent of the NRTIs used, the baseline ALT value, and the follow-up characteristics.

Discussion by authors

Chronic HBV and HCV infections almost tripled the risk of developing severe hepatic cytolysis when combinations of antiretrovirals are used, regardless of the regimen. An underlying hypothesis to explain the increased frequency of cytolysis is the immune restoration induced by PIs. The increase in cytotoxic T-lymphocytes could induce a destruction of HCV-infected hepatocytes, and thus a reactivation of HCV virions demonstrated by an increase in ALT values. The exact role of PIs in this sequence of events is still debated. The only differences between the PI-HAART and NRTI groups in this study were the higher frequency of patients at the AIDS stage and a lower median CD4 at baseline in HAART treated patients whereas plasma viral load was comparable. This can be explained by the initial conditions of prescription of HAART with PI in France. It is therefore possible that the frequency of severe hepatic cytolysis in HAART-treated patients changes once the circumstances of prescription of the PI and antiretroviral regimens evolve. The HBV viral load generally was not available and authors considered HBsAg carriage as a diagnostic criteria for HBV. As liver biopsies were not routinely performed in HCV coinfected patients, they could not identify the subgroups with chronic HCV and  therefore could not study the specific risk factor. There is a risk of underestimating the incidence of severe hepatic cytolysis because ALT values fluctuate over time and their increase is often asymptomatic. Commencement of HAART with PI should be carefully considered in patients with grade 1 or 2 ALT values and a history of cytolysis. Once HAART has been initiated co-infected patients should be carefully followed with repeated ALT measures, especially during first few months of treatment.

I encourage you to read the full text of the publication for complete details.