NATAP Reports

Highlights from Digestive Disease Week

May 20-23, 2001 Atlanta, Georgia

Platelet Counts; Elevated Lipids; Thymosin alpha-1 for HBV; treating HCV in methadone, psychiatric, and former drug users, Hepatotoxicity in HIV in the ACTG

Platelet Count May Predict HCV Liver Disease Progression

Deanna Oliver and a research group from the University of California, San Diego reported that a person’s platelet count can be predictor of HCV disease progression. But it does not always predict disease severity. The purpose of our study was to examine the utility of platelet count in predicting fibrosis stage in a co-infected sample. The authors concluded platelet count significantly predicted fibrosis stage in co-infected patients. Lower platelet counts are predictive of worsening fibrosis.

69% of patients with platelet count <100,000 (n=11) had cirrhosis and 2 (3%) did not have cirrhosis. 97% of patients (n=63) with >100, 000 platelet count did not have cirrhosis and 5 (31%) did have cirrhosis. Using <100,000 platelet count as a cutoff, the positive predictive accuracy was 85% and the negative predictive accuracy was 95%.

Elevated Cholesterol/Triglycerides May Be Associated With Accelerated Liver Disease Progression; Treatment May Slow Progression

Previous studies have reported that fatty liver (steatosis) may abe associated with accelerate liver disease progression. And that improved weight and fats in diet may slow progression. The purpose of this study (Pierre Gholam, Don Kotler, St Lukes-Roosevelt Hosp, NYC) was to explore the relationship between presence of diabetes, hypertension, dyslipidemia (elevated cholesterol and/or triglycerides) and coronary artery disease, and Body Mass Index (BMI) was calculated from weight and height taken prior to liver biopsy. Records of 126 HCV+ patients evaluated by liver biopsy were reviewed. Patients with current or previous alcohol use were excluded presumablt to exclude alcohol as a cause of the presence of these factors. Data from 82 patients were analyzed (56% male, 6% cirrhotic, age 48±10 yrs, BMI 27.4±4.7 kg/m2 ). Patients were assigned a composite MeS (Metabolic Syndrome) score (1-5) based on the presence or absence of the 4 recorded features plus obesity, defined as BMI >30 kg/m2. Fibrosis and inflammation were scored using the Batts-Ludwig classification. Steatosis (0-3) was graded as per Hourigan et al (Hepatology 1999;29:1215-9) by two pathologists blinded to the subjects clinical information. Analysis was performed using Spearman's Rank correlation coefficients. Results: Patient characteristics were: 56% male, 40% Caucasian, 11% diabetic, 6% cirrhotic. Mean age 48+10 years , Mean BMI 27.4+4.7 kg/m2

The authors concluded the MeS score is associated with steatosis and fibrosis in HCV infected patients. The MeS score correlates better with fibrosis than with the degree of steatosis seen on liver biopsy. The authors said its unclear how much MeS and HCV infection contribute to fibrosis. But they speculate that steatosis in HCV could in part, independent of viral infection, further potentiate inflammation and fibrosis. They speculate further that if this is true effective treatment of MeS could affect the progression of liver disease.

Meta-Analysis of Thymosin Alpha Treatment for Hepatitis B

Thymosin is an immune modulator that may have antiviral effect against HBV although it has never been well studied and clearly established. The authors (Henry Chan, University of Hong Kong) looked at a meta-analysis of 5 studies totaling 430 patients. Thymosin was given for 6 months mostly but in one study for 12 months. Thymosin-aplha 1 treatment for 6-12 months has no effect on HBV DNA suppression at the end of treatment. Virologic response increases after stopping therapy and is superior to placebo at 12 months post treatment. No benefit in biochemical response (ALST/AST) was apparent at the end of treatment and after stopping therapy. The authors said the reason for the delayed anti-viral effect of thymosin is unclear.

Although no serious adverse events were reported, there did not appear to be The role for thymosin in treating HBV seems unclear because interferon and 3TC are effective either in combination or separately. And a number of other drugs are HBV are in development. The furthest along is adefovir, but also included are entecovir, DAPD, LD4T.

Thymosin Alpha for Treatment of Hepatitis B

An Egyptian research group (Murat Saruc, Celal Bayar Univ, Dept of Gastroenterology, Manisa Turkey) reported in abstract 1949 finding that the combination of interferon a-2b with thymosin alpha-1 produced significantly greater sustained response rates than in the interferon monotherapy group although there was not a statistically significant difference between the two groups at the end of 52 week treatment. The authors suggest that adding thymosin may decrease relapse rate.

The aim of this study was to compare the efficacy and safety of interferon_ (IFN_) and thymosin_1 combination with IFN_ monotherapy in the treatment of naive anti-Hbe-positive and HBV DNA-positive chronic hepatitis B patients. Methods: Thirty-one patients were enrolled in the study. Twenty-one patients (group-1) received a 26-week combination course of 1.6 mg thymosin_1 subcutaneously twice a week and 10 MIU IFN_2b subcutaneously three times a week, followed by IFN_ monotherapy at the same dose for another 26 weeks. The other 10 patients (group-2) used 10 MIU IFN_2b three times a week during 52 weeks. The patients were observed for a further 26 weeks without any medication. Endpoints were a normalization of alanine aminotransferase and negativation of HBV DNA at weeks 52 and 78, as well as an improvement in liver histology at week 78. Results: Eighteen (87.7%) of 21 patients in group-1 responded by losing serum HBV DNA and normalizing alanine aminotransferase values at the end of the 52-week treatment period. Sixteen (76.2%) of these patients became sustained responders, with normal alanine aminotranferase and negative HBV DNA at the end of 78 weeks. Two patients were nonresponders, two relapsed and one had a breakthrough during therapy. In group-2, 7 (70%) patients responded to the 52-week IFN monotherapy. But only 4 (40%) of these patients were sustained responders at the and of drug-free 26-week follow-up period. Two were nonresponders, and one had a breakthrough in group-2. Significant improvements in the Knodell histological activity index were observed in the responders of the both groups. There was no statistically significant difference between two groups according to response rates (p>0.05). However sustained response rates were significantly greater in the combination therapy group than in the interferon monotherapy group (p=0.002).

Psychiatric Patients, Methadone Patients, and Earlier Drug Users Can Be Treated for HCV When Given Adequate Support Services

Martin Schaefer (Munich, Germany) reported on treating these patients and the outcomes. Psychiatric complications like depression or suicidal thoughts during treatment with (INF-a) often limit treatment options for psychiatric patients with concomitant chronic hepatits C. We investigated the prevalence of depression during combination treatment of chronic hepatitis C with INF-a and Ribavirin in psychiatric risk groups compared to controls. In a prospective and controlled study, 77 patients were treated with INF-a 3x3 Mio U/week and ribavirin(1000-1200 mg/day). Psychiatric patients (n=16), patients with history of drug addiction (n=20) or with methadone substition (n=18) were compared with controls (n=23). Patients were continuously seen and rated by a psychiatrist for depressive syndromes according to DSM-IV criterias. Depressive syndromes before and during treatment with INF-a are shown in table 1. Other frequently observed side effects were aggressiveness and irritability, which occurred in 65% of earlier drug addicts, 78% of methadone patients, 75% of psychiatric patients and 65% of controls. Also other typical symptoms like sleeping disturbances (50-65%) and difficulties in concentration and memory (26-63%) were frequent, but did not differ between treatment groups. Methadone patients wanted more methadone during therapy and earlier drug addicts wanted alcohol or drugs. In no patient drop-out was due to depression (7 by non-compliance, 3 by severe somatic side effects and 3 by relapse). The dropout was 3/13 in the control group (13%) , 1/16 in the psychiatric patients (7%), 2/16 (13%) in the methadone patients, and 39% (7/18) in the earlier drug users.

The response to treatment after 6 months (intent-to-treat) was 43% in psychiatric patients, 39% in controls, 41% in earlier drug users, and 50% in the methadone patients. Schaefer reported that psychiatric patients showed a better response and better compliance than controls. Patients with earlier addiction have the best response rate if they can be kept in therapy. 7/9 earlier drug users had response if they completed 6 months therapy. 6/13 psychiatric patients had a response if they completed treatment, and 9/21 controls did so as well. He suggested psychiatric contraindications for therapy need to be redefined. For safe and successful treatment of these patients, an interdisciplinary setting with adequate support is needed. One of the most important ways to optimize therapy efficacy is to reduce somatic and psychiatric side effects to increase patient compliance and to keep them in therapy.

Hepatotoxicity in the US Adult Clinicals Trials Group

Ron Reisler reported for the ACTG Liver Diseases Focus Group at the IAS Conference in Buenos Aires. Antiretroviral therapy for HIV includes nucleoside reverse transcriptase inhibitors (AZT, d4T), non-nucleoside reverse transcriptase inhibitors (efavirenz, nevirapine), and protease inhibitors (indinavir, Kaletra). ART has been associated with elevated liver enzymes (ALT). Severe incidence has been reported in a small percentage of patients, particularly those with HCV and/or elevated ALT before treatment.. The purpose of this study was to quantify the frequency of severe ART-related hepatotoxicity, treatment discontinuation, and death in a large representative US HIV cohort.. And to compare the frequency and timing of hepatotoxicity among the classes of drugs. The study findings are limited because: baseline HCV. HBV, and LFT status was not available for this analysis; this was a retrospective analysis pooling data from 21 studies over 9 years; the analysis does not consider adequately related factors; the patient follow-up was variable; HIV status for patients ranged from early to advanced HIV; patient pool consisted of naïve and experienced patients; mortality data (death) may underreport those related to liver causes.

This was a retrospective analysis of 21 ACTG studies from 1991 to 2000. 10,611 patients enrolled into treatment arms: single NRTI, double NRTI, triple therapy (combination of NRTIs, +/- NNRTIs, Pis). The outcomes measured in the study are severe hepatotoxicity defined as grade 3 or 4 (>5x ULN) LFTs, permanent drug discontinuation, and hepatic associated and overall mortality rates.

The overall incidence rate of severe hepatoxicity was 6.2%. In single NRTI studies, the highest hepatoxicity rate was in high dose ddI arms (250-375 mg bid) 10.3% vs low dose 200 mg bid 6.2% vs 5,4% in AZT/d4T arms. Rates in regimens containing an (NNRTI +2NRTIs) were significantly higher than rates in regimens containing a (PI +2NRTIs vs a NNRTI+2 NRTIs) 8.2%vs.5.0%; with higher rates in regimens containing 2 NRTIs and either nevirapine (8.9%)or efavirenz (10.8%), compsred to 3.6% for delavirdine containing regimens. The discontinuation rate was 27% overall: 22% in weeks 0-12, 22% during weeks 13-24, and 54% after 24 weeks of therapy. Median time to severe hepatoxicity (range 0-121) was 21 weeks, and to discontinuation 28 weeks (range 0-123). The liver mortality rate was low 0.40% (42/10,000) but the authors cautioned that this low rate could be underreporting and could be due to the data collection methods not fully capturing when liver was the actual cause of death. This study and a recent publication in AIDS shows that nevirapine hepatoxicity can occur way after the early stages following initiation of therapy. Previously it was thought that hepatoxicity was most likely to occur in the first 2-3 months, but this is not necessarily the case as has been subsequently found.