54th Annual Meeting of
The American Association for
the Study of Liver Diseases
October 24, 28- 2003
Boston, Massachusetts
Page Seven
African Americans
Epidemiology
Pathogenesis
Toxicities and Side Effects
Adverse Drug Reactions: liver toxicity
|
http://www.hivandhepatitis.com/2003icr/03_assld/main.html
Pegasys/Ribavirin Treatment in African American and
Caucasians with Chronic HCV Genotype 1
Background:
Response rates to interferon (IFN) therapy appear to be lower in African
American (AA) patients with chronic hepatitis C than in Caucasians (Ca). The
lower response has been attributed, in part, to the high prevalence of
infection with hepatitis C virus (HCV) genotype 1 among the AA population.
However, low numbers of AA patients in prospective clinical trials has
hampered meaningful evaluation of antiviral therapy. The objective of this study was to determine the efficacy and safety of Pegasys (peginterferon alfa-2a/40KD) in combination with ribavirin (RBV) in non-Hispanic AA HCV genotype 1 patients.
The trial enrolled
patients in a 3:1 ratio of AA to Ca patients and was powered only to
estimate sustained virologic response (SVR) in the AA group to within ± 10%
of a 95% confidence interval. Patients with previously untreated chronic HCV genotype 1 and elevated ALT received Pegasys 180 µg sc once weekly plus RBV 1000 or 1200 mg orally based on body weight (<75 kg or >75 kg) for 48 weeks, with 24 weeks of treatment-free follow-up. High viral load (HVL) was defined as HCV RNA >1 X 106 IU/mL. Early virologic response (EVR) at 12 weeks of therapy (defined as HCV RNA <50 IU/mL, or >2-log10 drop in HCV RNA from baseline) was assessed. SVR was defined as undetectable HCV RNA at week 72; sustained biochemical response (SBR) was defined as normal serum ALT at Week 72.
Histologic responses were
reported as Knodell HAI scores of liver biopsies obtained prior to treatment
and within 4 weeks of completion of the 24-week untreated follow-up period. Study Results A total of 106 patients received at least one dose of study medication. Baseline characteristics of AA patients were: mean age 46 years, 56 male (72 %), mean ALT 63 U/L, high viral load 45 (58%). Baseline characteristics of Ca patients were: mean age 45 years, 17 male (61%), mean ALT 64 U/L, high viral load 12 (43%). Sixty-two of 78 (80%) AA patients and 22 of 28 (79%) Ca patients completed treatment. The table below shows an SVR rate of 26% for AA patients and 39% for Ca patients. A larger proportion, 45 of 78 AA patients had high viral loads prior to the initiation of therapy, contrasting with only 12 of 28 Ca patients. SVR was achieved by 9 (20%) and 3 (25%) of patients with HVL in each group respectively. Of 47 AA patients who had EVRs, 20 patients went on to achieve an SVR.
The negative predictive
value of EVR was 100% for both AAs and Cas. SBR was observed with similar
frequency for both racial groups (36% for AA and 39% for Ca). Histologic
analyses of a subgroup of patients for whom paired biopsies were available
showed that 13 of 53 (25%) AA patients and 1 of 16 (6%) Ca patients had
fibrosis improvement. No unexpected adverse events (AEs) occurred during the
study. Four of 78 (5%) AA patients and 4 of 28 (14%) Ca patients withdrew
prematurely for AEs or laboratory abnormalities. ConclusionsThe SVR of 26% in AA with genotype 1 HCV after therapy with Pegasys plus RBV is the highest response to combination therapy yet reported in this population. The SVR rate in the AA population is nonetheless lower than in other studies with patients of diverse ethnic backgrounds and may be explained by the higher viral titers observed in these patients. Failure to achieve EVR has a high negative predictive value for SVR with continuing therapy. This study demonstrates that Pegasys with RBV is a safe and tolerable treatment for AA patients with chronic HCV genotype 1 infection. In addition, the SVR rate and histologic benefit observed in this trial provide a basis for future efforts to increase efficacy in this difficult to treat population . Summary of Efficacy Analyses
Louisiana State University
Health Sciences Center, University of Maryland School of Medicine,
University of Pennsylvania, Roche Laboratories, Inc., Nutley, NJ.
Reference
Pegasys/Ribavirin Treatment in African American and
Caucasians with Chronic HCV Genotype 1
Background:
Response rates to interferon (IFN) therapy appear to be lower in African
American (AA) patients with chronic hepatitis C than in Caucasians (Ca). The
lower response has been attributed, in part, to the high prevalence of
infection with hepatitis C virus (HCV) genotype 1 among the AA population.
However, low numbers of AA patients in prospective clinical trials has
hampered meaningful evaluation of antiviral therapy. The objective of this study was to determine the efficacy and safety of Pegasys (peginterferon alfa-2a/40KD) in combination with ribavirin (RBV) in non-Hispanic AA HCV genotype 1 patients.
The trial enrolled
patients in a 3:1 ratio of AA to Ca patients and was powered only to
estimate sustained virologic response (SVR) in the AA group to within ± 10%
of a 95% confidence interval. Patients with previously untreated chronic HCV genotype 1 and elevated ALT received Pegasys 180 µg sc once weekly plus RBV 1000 or 1200 mg orally based on body weight (<75 kg or >75 kg) for 48 weeks, with 24 weeks of treatment-free follow-up. High viral load (HVL) was defined as HCV RNA >1 X 106 IU/mL. Early virologic response (EVR) at 12 weeks of therapy (defined as HCV RNA <50 IU/mL, or >2-log10 drop in HCV RNA from baseline) was assessed. SVR was defined as undetectable HCV RNA at week 72; sustained biochemical response (SBR) was defined as normal serum ALT at Week 72.
Histologic responses were
reported as Knodell HAI scores of liver biopsies obtained prior to treatment
and within 4 weeks of completion of the 24-week untreated follow-up period. Study Results A total of 106 patients received at least one dose of study medication. Baseline characteristics of AA patients were: mean age 46 years, 56 male (72 %), mean ALT 63 U/L, high viral load 45 (58%). Baseline characteristics of Ca patients were: mean age 45 years, 17 male (61%), mean ALT 64 U/L, high viral load 12 (43%). Sixty-two of 78 (80%) AA patients and 22 of 28 (79%) Ca patients completed treatment. The table below shows an SVR rate of 26% for AA patients and 39% for Ca patients. A larger proportion, 45 of 78 AA patients had high viral loads prior to the initiation of therapy, contrasting with only 12 of 28 Ca patients. SVR was achieved by 9 (20%) and 3 (25%) of patients with HVL in each group respectively. Of 47 AA patients who had EVRs, 20 patients went on to achieve an SVR.
The negative predictive
value of EVR was 100% for both AAs and Cas. SBR was observed with similar
frequency for both racial groups (36% for AA and 39% for Ca). Histologic
analyses of a subgroup of patients for whom paired biopsies were available
showed that 13 of 53 (25%) AA patients and 1 of 16 (6%) Ca patients had
fibrosis improvement. No unexpected adverse events (AEs) occurred during the
study. Four of 78 (5%) AA patients and 4 of 28 (14%) Ca patients withdrew
prematurely for AEs or laboratory abnormalities. ConclusionsThe SVR of 26% in AA with genotype 1 HCV after therapy with Pegasys plus RBV is the highest response to combination therapy yet reported in this population. The SVR rate in the AA population is nonetheless lower than in other studies with patients of diverse ethnic backgrounds and may be explained by the higher viral titers observed in these patients. Failure to achieve EVR has a high negative predictive value for SVR with continuing therapy. This study demonstrates that Pegasys with RBV is a safe and tolerable treatment for AA patients with chronic HCV genotype 1 infection. In addition, the SVR rate and histologic benefit observed in this trial provide a basis for future efforts to increase efficacy in this difficult to treat population . Summary of Efficacy Analyses
Louisiana State University
Health Sciences Center, University of Maryland School of Medicine,
University of Pennsylvania, Roche Laboratories, Inc., Nutley, NJ.
Reference
Pegasys/Ribavirin Enhances HCV Specific T-cell Responses
by Restoration of Dendritic Cell Functions Pegasys (peginterferon alfa-2a/40KD)/ribavirin combination therapy markedly improves the sustained virological response in chronic hepatitis C compared to conventional interferon alfa therapy. This research group has previously demonstrated that Pegasys alone or in combination with ribavirin enhances HCV specific CD4+ T helper 1 responses in patients with chronic hepatitis C but the underlying mechanism by which the HCV-specific responses are restored is not yet fully understood. Dendritic cells (DCs) are the most efficient type of cells involved in antigen presentation (APC), however HCV proteins affect DC function resulting in abnormal priming of anti-HCV-specific T cells and defective antiviral immunity. The investigators hypothesized that peginterferon activates CD4+ T cells through restoration of the DC antigen-presenting function. Monocyte-derived dendritic cells (DCs) generation (magnatic sorting and positive selection), phenotypic analysis and allogeneic stimulatory capacity of DC (S.I.) as well as HCV-specific CD4+ T-cell proliferative responses and cytokine production to HCV proteins (ELISPOT assay using autologous DCs as APCs) were prospectively assessed in 64 patients with chronic hepatitis C (genotypes 1 and 4) before, during and after treatment with either conventional IFN-alfa-2a therapy, or Pegasys/ribavirin combination therapy and the results were correlated to the therapy outcome. Study Results The SVR in genotype 1 was 49% with Pegasys/ribavirin, and 26% with conventional IFN alfa-2a ribavirin while in genotype 4 the SVR was 54% in subjects treated with Pegasys/ribavirin combination therapy vs 28% of HCV in subjects treated with conventional IFN alfa-2a/ribavirin. Before induction of therapy, DCs from HCV infected subjects exhibited a pattern of incomplete activation and the stimulatory capacity of HCV-DCs was significantly lower than that of the normal-DCs (7.8± 3.9 vs. 67.2± 19.7, respectively; P < 0.001) The same pattern of incomplete activation was observed in CD4+ T cells in the form of absent or weak pre-treatment HCV specific CD4+ responses. Initiation of Pegasys/ ribavirin therapy markedly ameliorated the allostimulatory capacity in DCs of HCV patients and induced significant increase in the frequency, strength and breadth of HCV-specific CD4+T-h1 responses; compared to conventional IFN-alfa-2a-based regimen. The stimulatory capacity of HCV-DC was restored to normal in subjects who achieved SVR (62.05 ± 17.7 in SR versus 11.88 ± 2.55 in NR; P = 0.007). Sustained responders developed early restoration of DC functions and strong multi-specific persistent HCV specific CD4+T- cell responses with preferential IFN-γ production and IL-10 suppression. Interestingly patients who had breakthrough or relapse had transient increase in DC stimulatory capacity, which coincided with the absence of HCV viremia; however DC abnormalities were detected with recurrence of viremia. Viral clearance and HAI improvement but not HCV genotype correlated with the DC stimulatory capacity and HCV-specific CD4+ responses. The authors conclude, Pegasys in combination with ribavirin enhances HCV specific CD4+ T responses through restoration of the antigen presenting functions of dendritic cells. This finding has important implications for development of novel immunotherapeutic strategies. Harvard Institutes Of Medicine, Boston, Ma, USA, University Of Freiburg, Germany, Ain Shams University, Egypt. 10/26/03
Reference
Untreated Patients with Chronic Hepatitis C (CHC)
and Normal ALT Levels Have Distinct Biological and Virological Features and
a Majority Report CHC Symptoms Associated with Interferon Treatment
A large
proportion of patients with chronic hepatitis C (CHC) have alanine
aminotransferase (ALT) levels persistently within normal range, but the
natural history of these patients is not well defined.
The purpose
of this study was to characterize the clinical and virological features and
the evolution of disease in untreated patients with CHC and normal ALT
levels. An international, multicenter study evaluating efficacy and safety of treatment with peginterferon alfa-2a (40KD) (PEGASYS®) and ribavirin (COPEGUS®) in normal ALT CHC patients was performed. Patients in the control group were observed untreated for 72 weeks. All patients were required to have CHC infection documented by positive anti-HCV antibody test and detection of HCV RNA by PCR. Persistently normal ALT was defined by at least 3 determinations ≤ the upper limit of normal (ULN) a minimum of 4 weeks apart, with one value within the 42-day screening period and another between 6 and 18 months before the study onset. Patients with ALT levels >ULN during the 18 months preceding baseline were excluded from the study. Liver disease consistent with CHC was confirmed by biopsy within 36 months before the study.
Patients
with cirrhosis or other chronic liver disease, or those coinfected with
human immunodeficiency virus, were also excluded from the trial. Study Results Sixty-nine patients were randomized to the untreated control group and were monitored for the 72 weeks of the study. Demographic characteristics were: male gender 38%, mean age 41 years, and mean weight 71 Kg. Mode of infection, iv drug use 35%, transfusion 20%, unknown 32%, other percutaneous exposure 10% and sexual transmission 3%. Sixty-eight percent (68%) of the patients had HCV genotype 1 infection (38% 1a, and 30% 1b), 19% and 9% of the patients had genotype 2 and 3, respectively, and 3% had genotype 4. Histological activity (Ishak score): 81% of the patients had a score ≤4 for necroinflammatory changes, 93% had a fibrosis score ≤2; only 5 patients had a fibrosis score of 3. The mean baseline viral load was 1.3 x 106 IU/mL. Viremia levels were stable during the study period with mean values fluctuating between 1.3 and 1.8 x 103 IU/mL. No patient spontaneously cleared HCV. ALT values remained within normal limits throughout the trial in 48% of the patients. Occasional ALT elevations of <2 x ULN occurred in 45% of patients, and of <5 x ULN in 6% of patients. One patient had an isolated 12 x ULN ALT flare accompanied by a moderate AST increase.
Fifty-three
patients (77%) reported adverse events during the study, such as fatigue,
headache, insomnia, and depression. Conclusions CHC patients with persistently normal ALT values appear to have distinct biological and virological features. In comparison to a previous multinational trial performed in patients with elevated ALT levels (Hadziyannis et al. J Hepatol. 2002;36 [suppl 1]:3A), the male to female ratio was inverted, with a female predominance in normal ALT patients, the HCV genotype distribution was different, baseline viremia was lower, and liver disease was mild. During the 72-week observation period, viremia was stable but no patient cleared HCV RNA. ALT values remained within the normal or near-normal range in most patients. A majority of individuals reported CHC symptoms often believed to be associated with IFN treatment. Transient, generally low-grade ALT elevations were noted in over 50% of control patients. 10/27/03
Reference
Patients with Increased Symptoms of Depression During
Interferon/Ribavirin Therapy Are Less Likely to Clear HCV Interferon (IFN)-alfa plus ribavirin is an effective treatment for chronic hepatitis C virus (HCV) infection, but is associated with a high rate of depression. Depressive symptoms have been linked to a worse outcome in a number of medical disorders.
To determine whether
increased depressive symptoms during IFN alfa/ribavirin therapy were
associated with reduced clearance of HCV, a prospective cohort design was
used to evaluate HCV-infected patients at baseline and after 4, 8, 12 and 24
weeks of pegylated IFN-alfa-2b/ribavirin therapy. The sample was derived from patients enrolled in a larger multi-center, randomized clinical trial of PEG-Intron (pegylated IFN-alfa-2b) plus fixed-dose versus weight-based ribavirin. 102 HCV-infected subjects who volunteered to participate and completed 24 weeks of IFN alfa/ribavirin treatment followed by viral load testing were included.
Severity of depressive
symptoms was measured by the Zung Self-Rating Depression Scale (SDS). Viral
clearance was defined as polymerase chain reaction (PCR) negative (less than
29 HCV IU/ml) at 24 weeks. Study Results Increased depressive symptoms during IFN-alfa/ribavirin therapy were associated with reduced viral clearance (P=0.006). Only 34% of subjects with a 20-point or greater increase in SDS Index (N=29) were HCV PCR negative at 24 weeks, compared to 63% of patients without a 20-point increase (N=73). These results remained significant after adjusting for ribavirin dose assignment, viral genotype, age, antidepressant usage, IFN-alfa/ribavirin dosage reduction and knowledge of viral load status during treatment.
Cumulative depressive
symptoms over the 24 weeks of IFN-alfa/ribavirin therapy also predicted
failure to clear virus (P=0.026). Conclusions HCV patients who experience significant increases in symptoms of depression during IFN-alfa/ribavirin therapy are less likely to clear virus, highlighting the potential importance of identifying and treating depressive symptoms in this patient population. 10/27/03
References
Peginterferon Commonly Causes Clinically Significant
Depressive Symptoms, but Not Major Depression, and Ribavirin May Contribute
to Depression in a Dose-dependent Manner Interferon (IFN)-alfa plus ribavirin is the only FDA-approved treatment for hepatitis C (HCV) infection. Unfortunately, IFN-alfa/ribavirin therapy is associated with depression in a high percentage of patients.
To further examine the
development of depression during treatment for HCV and the risk factors
involved, researchers conducted a 24-week prospective cohort study of
patients receiving PEG-Intron (pegylated IFN-alfa-2b/PEG IFN) and ribavirin
for the treatment of HCV. The study sample was derived from a larger multi-center, randomized clinical trial designed to compare the efficacy of standard versus weight based dosing of ribavirin plus PEG IFN. 150 patients from this trial volunteered to participate in the study, completed 24 weeks of treatment with PEG IFN/ribavirin and were included in data analysis. Subjects were evaluated at baseline (prior to start of PEG IFN/ribavirin) and following 4, 8, 12 and 24 weeks of therapy. At baseline, subjects were screened for past or current major depression and substance abuse by telephone. Subjects also completed the Zung Self Rating Depression Scale (SDS), a 20-item self-report instrument widely used to evaluate depressive symptoms in the medically ill.
The development of
clinically relevant depressive symptoms was considered to have occurred if
patients developed an SDS score equal to or greater than 60 (consistent with
the presence of moderate to severe depression) at any point during the 24
week treatment period. Study Results Mean SDS score at baseline for the study sample as a whole was 41.8 (SD 10.0). During 24 weeks of IFN-alfa/ribavirin treatment, mean maximum SDS score for the group as a whole increased to a maximum of 55.6 (SD 10.2), with the majority of the increase from baseline occurring in the first 4 weeks of treatment. Thirty eight percent of patients developed SDS scores equal to or greater than 60 during treatment, while 11% of patients met criteria for major depression. In a univariate analysis, factors that correlated with the development of clinically significant depressive symptoms included weight-based dosing of ribavirin and past history of major. Weight-based ribavirin dosing continued to predict the development of depressive symptoms after adjustment for age, gender, past history of depression, antidepressant use at baseline or during treatment, history of substance abuse and baseline SDS score. Past history of major depression did not predict the development of depressive symptoms after adjustment for these factors, suggesting that the effect of past major depression may be mediated in part by an increased likelihood of patients with a history of depression having elevated SDS scores at baseline. Consistent with this, patients with a past history of major depression had significantly higher baseline SDS scores. Baseline SDS score predicted the development of significant depressive symptoms. Conclusions Results from this study suggest that the development of clinically significant depressive symptoms, but not major depression, is common in patients receiving pegylated PEG IFN plus ribavirin for HCV infection. Moreover, while PEG IFN has traditionally been viewed as the causative agent for depression during combined therapy, these data indicate that ribavirin may also contribute to the development of depressive symptoms, and that the effect may be dose related. Finally, the association between past depression and the development of depressive symptoms during treatment appears to be mediated by the increased likelihood for patients with a past history of depression to demonstrate increased depressive symptoms just prior to commencing IFN-alfa/ribavirin therapy. This finding highlights the importance of evaluating a patients mood status prior to commencing treatment for HCV. 10/27/03
Reference
Visual Problems May Not Completely Resolve in All Patients
After Discontinuing Treatment with Peginterferon and Ribavirin: Observations
from the WIN-R Trial
Ophthalmologic side effects (visual changes) of interferon therapy have been
reported but there are limited data on their frequency and pathogenesis.
The aim of
this retrospective analysis was to assess the frequency and clinical
presentation of serious ophthalmologic events during hepatitis C (HCV)
therapy with pegylated interferon (PEG) and ribavirin (RBV) Study Results Approximately 4800 patients have received at least one dose of pegylated interferon and ribavirin in this study. Of these patients, 20 patients with ophthalmologic events reported as SAEs were identified. Fourteen patients were male and the patients ranged in age from 26-69 years (mean- 48 years). Fifteen patients were Caucasian, 2 were African-American, 1 was Hispanic, and 2 were of other races. Eleven patients were HCV genotype 1. On liver biopsy, 14 patients were Metavir stage 0-2 and 6 patients were Metavir stage 3-4. Thirteen patients received fixed dose ribavirin and 7 patients received weight-based ribavirin. Two patients had hypertension and 2 were diabetic. Four patients had a prior history of ophthalmologic disorders including myopia, lasik surgery, bilateral intraocular implants, and a history of visual field defects. No patient had a known history of retinopathy before PEG and RBV initiation. The eye symptoms occurred after a mean period of 15 weeks of therapy (range 3-36 weeks). Nineteen patients had visual symptoms. Impaired vision was the most common symptom (15 patients). Two patients had photophobia, 1 complained of floaters, 1 experienced halos, and 1 complained of a headache. In the one asymptomatic patient, the visual changes were found on routine eye examination. The most common findings on ophthalomologic exam were cotton wool spots, intraretinal hemorrhages, and papilledema. The diagnosis of the ophthalmologic injury was available in 16 patients: interferon retinopathy (8), optic neuritis (1), optic nerve infarct (1), retinal artery thrombosis (2), presbyopia (1), retinal vein occlusion (1), retinal detachment (1), and focal vasculitic event involving the retina (1). One patient with optic neuritis required steroids, and 1 patient with retinal detachment required surgery. Seventeen patients discontinued PEG and RBV at the time of the adverse event, one patient delayed discontinuation for 20 weeks after symptoms first occurred, 1 patient continued therapy for 36 weeks to complete 48 weeks of therapy, and 1 patient held PEG and RBV for 4 weeks and then resumed therapy for 8 more weeks before permanently discontinuing therapy because of fatigue. Symptoms resolved in 11 patients including 9 patients who discontinued therapy, the patient who continued therapy, and the patient who restarted therapy one month later. Three patients have not had complete resolution of their ophthalmologic disorders including 2 patients who discontinued therapy and the patient who delayed treatment discontinuation.
Of the 3
patients with persistent injury, 1 had interferon retinopathy, 1 had optic
neuritis and the diagnosis was not available in 1 patient. None of the 3
patients with persistent injury had diabetes or hypertension. Data on the
final outcome of visual symptoms is not available in 6 patients. Conclusions
11/10/03
Reference
Viramidine, a Prodrug of Ribavirin, May Have Increased
Efficacy and Reduced Red Blood Cell Toxicity Compared to Ribavirin Ribavirin (Rebetol, Copegus) forms part of current combination therapy for chronic hepatitis C, but its red blood cell (RBC) toxicity represents a challenge in clinical management. Viramidine, a prodrug of ribavirin, can readily convert to ribavirin and exert antiviral activity. Oral dosing of [3H] ribavirin in portal vein-cannulated monkey gave 2X RBC radioactivity, but 1/3 the amount of radioactivity retained in the liver than oral dosing of [3H] viramidine, indicating that viramidine may have better efficacy with reduced RBC toxicity as compared to ribavirin. The aim of the current study was to compare disposition and metabolic profile in monkey liver after single and multiple oral dosing of [14C] viramidine or [14C] ribavirin. Cynomolgus monkeys received oral dose (10 mg/kg) of [14C] viramidine or [14C] ribavirin once daily for 10 days. At 24 hours after single dose or the 10th dose, liver samples were collected, immediately extracted with 0.5 M EDTA/methanol and centrifuged. Radioactivity in the liver was determined using liquid scintillation spectrometry. The metabolic profile in the liver was analyzed by HPLC equipped with radioactivity flow detection. Study ResultsLiver radioactivity concentration was 8.3 and 16.6 microgramequivalent/g, respectively, after single and multiple dosing of [14C] ribavirin. The concentration was 25.9 and 50.7 microgram.equivalent/g, respectively after single and multiple dosing of [14C] viramidine. Metabolic profiles (expressed as % of total radioactivity) in the monkey liver are summarized below:
After oral dosing of viramidine, viramidine monophosphate (VMP) is the predominant metabolite, followed by RMP, TCONH2, R, RDP, RTP, viramidine, viramidine monophosphate (VMP), viramidine diphosphate (VDP) and viramidine triphosphate (VTP). The total R (R+RMP+RDT+RTP) accounted for 21.5 % of the liver radioactivity after single dosing and 43.8 % after multiple dosing of viramidine. B> Conclusions
11/14/03
Reference
Predictors of Antiretroviral-related Severe Liver Toxicity
in 21 AACTG Studies The use of antiretroviral therapy (ART) for HIV has been associated with severe, grade 3+ hepatotoxicity (SH), liver failure and death. Researchers at Massachusetts General Hospital previously presented results from our retrospective analysis on the incidence of SH and mortality in 21 Adult AIDS Clinical Trials Group (AACTG) studies. The studies enrolled subjects into arms that included single and multiple nucleoside reverse transcriptase inhibitors (NRTI), and triple drug regimens that included varying combinations of NRTIs, non-nucleoside reverse transcriptase inhibitors (NNRTI), and protease inhibitors (PI). (Gastroenterology 2001; 120: A54.). The investigators found that 10% of subjects developed SH (AST, ALT, total bilirubin > 5xULN) in all treatment regimens (12% single NRTI, 7.9% multiple NRTIs, 8.6% PI (-) triple drug, 12% PI (+) triple drug). The overall and liver-related death rates were 15% and 0.3%, respectively. Factors associated with SH were not included in our initial analysis. This report identifies baseline predictors for SH in those receiving single NRTI, multiple NRTI, NNRTI, and PI-based regimens. 9,017 subjects were analyzed. Stepwise, multi-covariate, logistic regression was used to determine baseline factors associated with the development of SH occurring in the first 6 and 6-12 months of single NRTI, multiple NRTI, NNRTI, and PI therapy. ART included: NRTIs AZT, ddI, ddC, d4T, and 3TC; NNRTIs nevirapine (NVP) and delavirdine; and the PI indinavir. Baseline factors included age, gender, ethnicity, history of intravenous drug use (IVDU), ART, entry CD4+ < 300 cells/mm3, hepatotoxic potential of concomitant medications (CMEDS), concomitant medical problems at entry, and baseline laboratory values (AST, ALT, total bilirubin (TB), hemoglobin, WBC, absolute neutrophil count, creatinine, platelet count (plt), cholesterol, triglyceride, and glucose). Baseline hepatitis B and C status were not recorded. Study ResultsHigh AST (>1.25xULN) was associated with early SH among all regimens. High triglyceride (> 400 mg/dL) was associated with late SH among subjects on single NRTI regimens. Elevated creatinine (> 1.5xULN) and low plts (<99,000/mm3) were risk factors for those on multiple NRTI regimens, as was NVP use for those on NNRTI-based regimens. CMEDS predicted late SH for those on multiple NRTIs or indinavir. d4T was a predictor of early SH among subjects on indinavir. Low CD4+ (<300 cells/mm3) was associated with a decreased risk of early and late SH for those on multiple NRTIs, while black race was associated with decreased risk of late SH for those receiving indinavir.
ConclusionsIn the largest U.S. HIV cohort ever studied, (1) There was a high rate of SH irrespective of ART class with an overall rate of 10%; (2) Among all ART regimens, high baseline AST and/or ALT (>1.25xULN) were predictors of SH, confirming results from other cohorts; (3) NVP-containing regimens were associated with both early and late SH; (4) Previously unreported risk factors for SH among subjects on multiple NRTIs included plt <99,000/mm3, creatinine >1.5xULN and concomitant hepatotoxic medications. (5) Concomitant hepatotoxic medications, d4T use, and history of IVDU were risk factors for those on indinavir-based regimens. These findings suggest that in addition to baseline ALT and AST, other factors should be considered prior to initiating ART. 11/07/03
Reference
Description of Liver Toxicity Associated with HIV Protease
Inhibitors with or without Low-dose Ritonavir Boosting The HIV protease inhibitors (PIs), in particular full dose Norvir (ritonavir/RTV) have been associated with hepatotoxicity (liver toxicity). Increasingly, clinicians use low-dose RTV (200 400 mg/d) to alter the pharmacokinetics of other PIs such as Kaletra (lopinavir/LPV) and Crixivan (indinavir/IDV).
This allows
less frequent dosing and increased efficacy. Despite increasing use, few
data are available regarding hepatotoxicity associated with these boosted PI
regimens.
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. Study Results Between 1/96- 3/03, 1,061 eligible patients (pts) started PI-containing ART including Viracept (nelfinavir/NFV), 605 pts; Kaletra (LPV + RTV) 200 mg/d, 89 pts; IDV + RTV (200 400 mg/d), 94 pts; Fortovase/Invirase (saquinavir/SQV) + RTV (800 mg/d). At baseline, subjects had the following characteristics: median age 37 yrs; male, 73%; African-American, 77%; HCV positive, 46%; HBsAg positive, 10%; median ALT, 30 IU/L, median CD4 count, 166/mm3; median HIV RNA level, 4.7 log10. Subjects were followed for a median 224 365 days. The incidence of grade 3/4 hepatoxicity is shown in the Table below. In multivariate Cox proportional hazard analysis, grade 3/4 hepatotoxicity was independently associated with IDV/ RTV, SQV/ RTV, HCV positivity, CD4 cell count greater than 50/mm3 and HIV RNA level greater than 400 copies/mL (3.18, 0.86 11.8). Conclusions The highest risk of grade 3/4 hepatoxicity was observed in pts receiving SQV/ RTV (800mg/d) and IDV/RTV (200 400mg/d). However, no increased risk of hepatotoxicity was detected in pts receiving NFV or LPV/RTV (200mg/d). In addition, while HCV positive pts had a 2-fold higher risk of hepatotoxicity, 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.
11/07/03
Reference
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||