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
Context
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.
Objectives
To
ascertain if incidence of severe hepatotoxicity during
Design
Prospective
cohort study.
Setting
University-based
urban HIV clinic.
Patients
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.
Results
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.
Conclusions
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)
Objective
To
study hepatic cytolysis in patients treated by HAART with protease inhibitor or
with 2 nucleoside reverse transcriptase inhibitors (NRTIs)
Methods
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.
Results
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).
NRTIs
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.