Protease Inhibitor Use & ALT Elevations

As you can see just below, this is a relatively old study. It was submitted initially for publication in October 1999 and modified in January 2000 and finally accepted in August 2000. Most of the overall concepts are not new and repeat what we know already, except for a few new wrinkles. For example, no single PI was associated with worse LFT elevations than others. Only HCV and HBV presence were associated with > 5 times LFT elevations.

A PDF of the full report is also available.

Hepatitis B or Hepatitis C Virus Infection Is a Risk Factor for Severe Hepatic Cytolysis after Initiation of a Protease Inhibitor-Containing Antiretroviral Regimen in Human Immunodeficiency Virus-Infected Patients
      Marianne Sav╦s,1 ▄ Fran┴ois Raffi,2 ▄ Philippe Clevenbergh,3 Bruno Marchou,4 Anne Waldner-Combernoux,5 ▄ Philippe Morlat,6 ▄ Vincent Le Moing,7 ▄ Catherine Rivi╦re,8 ▄ Genevi╦ve Ch╦ne,1 Catherine Leport,7* and the APROCO Study Groupß
[Received 7 October 1999/Returned for modification 18 January 2000/Accepted 25 August 2000]

In a cohort of 1,047 human immunodeficiency virus type 1-infected patients started on protease inhibitors (PIs), the incidence of severe hepatic cytolysis (alanine aminotransferase concentration five times or more above the upper limit of the normal level > 5N) was 5% patient-years after a mean follow-up of 5 months. Only positivity for hepatitis C virus antibodies (hazard ratio [HR], 7.95; P <10-3) or hepatitis B virus surface antigen (HR, 6.67; P <10-3) was associated with severe cytolysis. Before starting patients on PIs, assessment of liver enzyme levels and viral coinfections is necessary. 

Severe cytolysis was defined as ALT 5 times above normal. 23 of 1047 had severe cytolysis. At baseline twice as many patients had elevated ALT in the cytolysis group than those who did not have cytolysis. Three times as many had HCV (Hazard Ratio 7.95, by multivariate analysis) and 7 times as many had HBV (HBs antigen positive 6.67 Hazard Ratio, by multivariate analysis) in the cytolysis group. The authors felt cytolysis could be due to PI use or immune restoration. But the development of cytolysis was not associated with any specific PI.

APROCO was set up to study the clinical and immuno-virological evolution in HIV-1-infected patients started on PI-containing regimens. Patients were enrolled at the initiation of PI therapy from May 1997 to July 1998 and were monitored at month 1 (M1), M4, and then every 4 months in 47 French AIDS centers. Patients eligible for this analysis were those who had a serum alanine aminotransferase (ALT) concentration under fivefold the upper limit of the normal value (<5N) at the baseline. The HBV and HCV infection statuses at the time of inclusion in the study were retrospectively recorded. Clinicians were asked to report the most recent results. For HCV and HBV surface (HBs) antigen, this was part of routine care, but this might have been performed more often if the patient had a potential risk of contamination. 

Among the initial cohort of 1,080 patients, 1,047 (96.9 %) had a baseline ALT of <5N (median age, 35 years; proportion of men, 77%). The main HIV transmission route categories were homosexuality (39%), heterosexuality (34%), and intra-venous drug use (17%). The serological status for hepatitis viruses was known for 613 patients: 26% (n =159) were HCV seropositive and 4% (n =45) had HBs antigen. After a mean follow-up of 5 months, severe cytolysis developed in 23 patients, yielding an incidence of 5 per 100 patient-years (95% confidence interval, 3.2 to 7.6). The median time from cohort entry to an ALT of 5N was 95 days (interquartile range, 34 to 121 days). Median (minimum to maximum) ALT and aspartate aminotransferase (AST) concentration (fold N) were 1.1 (0.5 to 4.8) and 1.1 (0.4 to 5.1) at the initiation of PI, 3.4 (0.6 to 85.6) and 1.8 (0.6 to 55.7) at Month 1, 5.3 (0.4 to 17.8) and 3.8 (0.7 to 7.7) at M4, 1.3 (0.4 to 7.8) and 1.2 (0.5 to 5.5) at M8, 2.0 (0.4 to 5.8) and 2.0 (0.5 to 4.9) at M12, 2.9 (0.7 to 7.7) and 2.6 (0.7 to 4.7) at M16, 1.2 (0.4 to 3.9) and 1.2 (0.7 to 4.1) at M20, and 1.6 (0.3 to 7.4) and 1.1 (0.6 to 3.3) at M24. It was associated with at least one clinical manifestation, mainly jaundice (n 5 6) and abdominal pain (n 5 5), in 11 patients (48%).

 Among the 23 patients with severe cytolysis, intravenous drug use was the most frequent HIV transmission route category (52%); 16 (70%) were positive for HCV antibodies and 5 (22%) were positive for HBs antigen (Table 1). The median change between M0 and M1 was 72  x 106/liter for the CD4+ cell count and -1.84 log10 copies/ml for the HIV RNA level.

At the onset of severe cytolysis, two patients were receiving saquinavir (SQV), five patients were receiving ritonavir (RTV), seven patients were receiving indinavir (IDV), five patients were receiving nelfinavir (NFV), one patient was receiving SQV and RTV, one patient was receiving IDV and NFV, and one patient was receiving RTV and NFV. NFV had been discontinued 17 days before severe cytolysis in one patient, and no other PI was used at the onset of severe cytolysis. The initially prescribed PIs were stopped after the occurrence of severe cytolysis in 17 other patients, among whom 6 were switched to another PI and 1 was switched to nevirapine. Among these 17 patients, the ALT concentration decreased to <5N in the 13 patients for whom follow-up data were available.

 Among the five patients who continued to take PIs, the ALT concentration decreased to < 5N in two patients and the ALT concentration remained at > 5N in three patients. Complete data for variables entered in the multivariate analysis were available for 570 patients (Table 2).

Positivity for HCV antibodies (hazard ratio [HR], 7.95; p< 10-3 ) and positivity for HBs antigen (HR, 6.67; P <10-3) were identified as the only risk factors for severe cytolysis. After adjustment for hepatitis virus status, we found no association between severe cytolysis and the type of PI or the response at M1 in terms of CD4 cell count and plasma HIV RNA level. The interaction between HCV & HBV was not significant. Although an increase in the ALT concentration greater than 5N may not be considered severe from a hepatologistÝs point of view, it seems to be a reasonable threshold considering that it provides an assessment of hepatocellular necrosis and seems to be a reasonable threshold in the context of adverse events surveillance from international standardized toxicity tables (6).

Severe cytolysis in HIV-infected patients may be related to several causes such as drug treatment regimens that include PIs and other antiretroviral drugs, concomitant infections or neoplasms, and immune restoration, which may interact with each other. Drug-related hepatitis may be suggested by a decrease in ALT levels after withdrawal of PI treatment, a positive response upon rechallenge, and the presence of an hepatic eosinophilic infiltrate (1, 2, 10). In the present study, ALT levels decreased to normal after the withdrawal of PI treatment in some patients; however, the observation of a return of ALT levels to normal levels in other patients who continued PI treatment suggests that the drug may not have been the only cause of cytolysis.

A couple of key points from the study: