HIGHLIGHTS of AASLD POSTGRADUATE COURSE
     Written by Marion Peters, MD, UCSF Chief of Hepatology Research, contributions by Jules Levin

The NATAP web site contains 12 reports from AASLD

An excellent course was presented on viral hepatitis which included all types of hepatitis with epidemiology, virology, clinical and therapy combined. Dr. Miriam Alter presented data on hepatitis B vaccination. In a study of Alaskan Natives, 25 -50% of non-responders responded to one additional dose of hepatitis B vaccination and 40-50% responded after three more doses. There was no added benefit in additional vaccination. In immunocompetent patients, immunity lasted 10-15 years even though anti-HBs was lost in 10-50% of patients, there was no disease noted. In immunocompromised patients, it is unclear how long immunity lasts and there is some discussion of whether a booster should be given when anti-HBs falls below 10 I.U. per ml. Pre-S vaccinations that include larger surface proteins have been shown to have a higher response: 60% response in those who have previously not responded to recombinant vaccinations.

NATURAL HISTORY of HCV:

New Research Found HCV Disease Progressed Less Severely and More Slowly

The data reported below was from studies of individuals with HCV alone, not of individuals with HCV/HIV co-infection.

Excellent data were presented on the natural history of Hepatitis C. This is a new and emerging area showing that Hepatitis C disease may be much less severe than previously thought. These are data from Ireland. Dr Kenny Walsh reported on pregnant women who had received Rhogam for treatment of Rh-incompatibility . Subjects were studied 17 years after infection with genotype 1 and only 2% of patients had cirrhosis. Vogt studied 458 German children (New England journal) 20 years after infection. They found that 45% of them had recovered and lost RNA and only 0.3% had cirrhosis. Leonard Seeff studied patients 23 years after acquisition of hepatitis C. There was no difference in all cause mortality between the 500 patients who have had hepatitis and 1000 case controls. However, liver related deaths were higher in the hepatitis C group at 3.1% compared to 1.3% in case controls. However, 56% of individuals died (2% of liver disease). Patients died of causes related for their need for transfusion. This brings up the question: "Is the natural history of hepatitis C after transfusion with a large amount of virus worse than that after acquisition through other parenteral routes?"

Seeff and Alter discussed an algorithm that after acute infection at least 20% of individuals recovered. 80% developed persistent infection of whom 1/3 have stable chronic hepatitis, 1/3 have severe progression, and 1/3 have variable progression. This lead to a favorable outcome overall in 2/3 of patients and 1/3 of patients having on-going progressive disease. In prospective studies, after 10-20 years of exposure, the incidence of cirrhosis was 7-15%. In cohort studies, 17-45 years from exposure, the incidence of cirrhosis was 0.3-21%. This is much lower than previously thought.

David Thomas in JAMA this year studied 1667 patients who were HCV antibody positive and followed them for 8 years. 2.4% had end-stage liver disease. 374 people died of non-liver related problems, and 22.4% had damage related to alcohol. He biopsied 210 patients, two of whom who had cirrhosis. Rogers who described 95 patients from Australia in Hepatology (2000). 95 patients acquired hepatitis C between 1971 and 1975. Twenty years later, 6% were PCR negative, only 51% were PCR positive and four of those 51% had cirrhosis. No individuals had hepatocellular carcinoma.

The rates of spontaneous recovery varied. In transfusion related HCV adults studied by Seeff the spontaneous recovery rate was 24%; in the NHANES 3 Study by Alter 26%; in leukemic children by Losasciulli, 29%; in the Irish Rogam Study 45% and the transfusion related HCV study in children in Germany, the rate was 45%. Lessons from these studies are that 1) there is a higher spontaneous recovery than previously thought. 2) There is a favorable outcome in 64% of patients who develop hepatitis C with either recovery or stable benign disease. 3) There is a severe outcome in less than 1/3 of patients who develop progressive disease of whom somewhere between 7-15% develop cirrhosis.

Norah Terrault presented chronic liver disease and viral hepatitis in the US. Chronic liver disease is the 10th most common cause of death in the USA. In patients with chronic hepatitis C infection, 65% occurs in ages 30-39 years. Victor Navarro looked at a GI community practice in the northeast and found that 52% of patients with chronic liver disease had hepatitis C with or without alcohol. Looking in a large managed care group in California, abnormal LFTs for longer than 6 months was the definition of chronic liver disease and it occurred in 72 patients per 100,000 case subjects. 47 of these 72 were seen by gastroenterologists, but the rest were not referred. It was unclear whether they did not have liver disease or were not deemed suitable patients for therapy.

Weight Based Dosing of Ribivarin: Higher Ribivarin Dose Appears More Effective

John McHutchison presented data on interferon and ribavirin therapy. His group evaluated the dosing of ribavirin and its affect on the overall benefit from combination therapy with interferon. He showed data from Schering that Ribavirin at 400 mg dose led to a 1.6 log decrease in serum HCVRNA, and hemoglobin decreased 1.2. A Ribavirin dose of 600mg led to 1.7 log decrease in HCV RNA, and hemoglobin declined 1.4. Ribavirin at 800mg/ day led to 2.09 decrease in HCV RNA, and a 1.7 decline in hemoglobin. Ribivarin at 1000/1200mg per day had a 2.22 log decrease in HCV RNA, and a 2.2 decline in hemoglobin. Thus, at Ribavirin doses under 800mg there is less anemia but also the dose is less effective, unless as you will see below its used in a person with low body weight <65 kg). Hemoglobin declined 3 or more grams in 7% of patients receiving 800 mg ribivarin per day and 32% in patients receiving 1000/1200 mg per day. McHutchison said 600 mg has less efficacy and more RBV is better per weight basis. Thus, he recommended to start with 1000/1200 mg per day and dose reduction to 800 is better than to 600 per day.

The NATAP Report on weight based dosing is reprinted at the end of this report, but much of the data is in the Peg Intron 72 week Study Report.

PEG-INTRON RIBIVARIN & INTERFERON ADJUSTED DOSING BY BODY WEIGHT
     Reported by Marion Peters and Jules Levin

Michael Manns presented the sustained virologic response of 1530 patients treated with 12 kd pegylated interferon and ribavirin in an oral presentation subsequent to the postgraduate course. 65% of the patients were male, 68% had genotype 1, 69% had HCV RNA >2,000,000 copies per ml and 10% of the patients were cirrhotic. The overall SVR response to 48 weeks of interferon was evaluated for standard therapy with interferon alpha-2B plus ribavirin or pegylated IFN low dose (that is, 0.5 g/kg) or high dose (1.5g/kg of pegylated interferon) plus ribavirin. In all patients, the results were around 50% for all groups (54% Peg 1.5 ug/kg vs 47% standard IFN 3MU-3x/day; p=0.01): genotype-1 patients had a 33% response to standard ribavirin and a 42% response to high dose pegylated IFN. In genotype 2/3 about 80% of patients responded. Manns reported findings that response rates improved after dosing ribivarin by body weight. Everyone in the high dose Peg arm was receiving Peg 1.5 ug/kg arm but they were receiving a fixed dose of 800 mg per day of RBV: 62% of patients <65 kg had a SVR, 55% between 65-85 kg had a SVR, and 49% > 85 mg/kg had a SVR. Manns also reported that for individuals in the Peg 1.5 ug/kg dose arm 50% had a SVR when receiving RBV <10.6 mg/kg per day versus 61% who received >10.6 mg/kg per day RBV. Manns recommended the following dosing for RBV: 800 mg/day if <65 kg, 1000 mg/day if 65-85 kg, and 1200 mg/day if >85 kg. This data suggests that the prior held notion that lower RBV dosing may be equally effective in achieving a SVR may not be true. The high Peg Intron dose of 1.5 ug/kg had better response rates than the other dose regimens and appears to be the dose that will be used after FDA approval. But, the incidence of side effects were slightly higher in the high dose pegylated interferon with neutropenia double that of standard interferon. For more details on this presentation by Manns see the reports on the NATAP web site in AASLD Reports on ribivarin weight dosing and 72 week Peg Intron data:

     http://www.natap.org/2000/oct/Dallas/dallas_rpt_04_Pegylated%20_Intron_a-b_110300.htm

Treating Non-Responders

Dr J. Heathcote reviewed re-treatment of non-responders. She found that retreatment of those who had initially responded to therapy and then relapsed resulted in a 10-70% response to 6 or 12 months of interferon. However this was not seen in non responders to IFN. Regardless of the dose, the length of interferon retreatment of non-responders up to 12 months lead to less than 10% sustained virologic response in the majority of patients. Genotype 2 or 3 patients had a 22% response in data reported by Dr. Solko Schalm.

ALT and HCV Progression; IFN+RBV & Fibrosis in Non-Responders

The effect of response to therapy and normal ALT were studied by Estaban in Abstract 205. 249 patients were followed for over 8 years and had two liver biopsies 4 years apart. He compared those with normal ALT and those with abnormal ALT and found a higher percentage of females in the normal ALT (71%) compared to abnormal ALT (47%). Any alcohol intake was noted in 21% of those with normal ALT and 40% of those with abnormal ALT. Heavy alcohol use greater than 50g/day occurred in 6% of those with normal ALT and 17% of those with abnormal ALT. Liver biopsies differed between those with normal and abnormal ALT. In those with normal ALT, 64% were mild, 34% were moderate and 2% severe. In those with abnormal ALT, 34% had mild biopsies, 64% moderate and 20% severe. Four years later, a repeat biopsy in normal ALT patients showed no cirrhosis, decompensation, hepatocellular carcinoma or death. In 114 patients with abnormal ALT, 8% had progressed to cirrhosis, 2% decompensated, 2% had hepatocellular carcinoma and 2% had died.

(Ed Note from Jules Levin: Interestingly, Estaban's data in the program abstract indicated patients with elevated ALT saw increased fibrosis if untreated or non-responders to HCV treatment. But, some non-responders to IFN improved (18%) or stopped fibrosis progression (49%). The proportion of patients whose fibrosis improved or remained unchanged was higher in non-responders than in untreated patients. Additionally in follow-up, non-responders treated with IFN+RBV saw their fibrosis progression rates decrease (from 0.215± 0) .241 to 0.057± 0.350; p=0.02), while it remained unchanged in untreated patients and non-responders treated with IFN alone. Esteban concluded that combination treatment slows disease progression in virologic non-responders but the duration of benefit remains unknown. This study supplies more evidence that maintenance therapy may be beneficial and it suggests that maintenance therapy including RBV maybe more beneficial than IFN alone. Esteban also suggests in his conclusions that ALT may predict disease progression, but ALT is no substitute for a biopsy). More details on this study are available on the NATAP web site where the abstract will be available.

"More Evidence Supporting Maintenance Therapy, and May Be More Effective If It Includes Ribivarin. ALT May Reflect Liver Damage But Maybe Not In Coinfection"

     http://www.natap.org/2000/oct/Dallas/dalrpt11_more_evidence.html

HCV Progression in HIV Co-infection & Liver Transplantation

In this study HCV/HIV co-infected persons with cirrhosis progressed more quickly than HCV-infected individuals with cirrhosis. The authors made the point that co-infected individuals need to be considered for liver transplants. Up until recently co-infected individuals received a low priority for transplants, and in fact many doctors and institutions refused to offer HIV-infected individuals liver transplants. De Martino from France in Abstract 203 studied 299 patients of whom 50 were coinfected with HIV and HCV. Patients were followed over 28 months. The three-year survival was 47% in HIV positive HCV patients and 72% in HIV negative HCV patients. 56% of HIV and HCV positive patients decompensated compared to 19% of HIV negative HCV patients. 29% of HIV positive patients had ascites whereas 10% of HIV negative did. Variceal bleeds and portal systemic encephalopathy occurred in 20% and 9% of HIV positive compared to 4% of HIV negative HCV positive patients. Analysis revealed that HIV positive and HCV positive patients were younger at the time of diagnosis. There were more males, more history of IV drug abuse, a higher alcohol intake, and prothrombin time. One-third of the patients had CD4 counts less than 200. There was no difference in virologic markers, metavir score , Childs Pugh score or biochemistry. In multivariate analysis, the relative risk of HIV was 3.4 and of alcohol>50g/day, 2.3.

(editorial note from Jules Levin: Despite HIV+ patients in this study having 320 CD4s, 29% had CD4s <200, and everyone was receiving antiretroviral therapy for HIV, the mortality rate after 3 years was 47% in the HIV+ patients vs 13% in the HIV- patients (p=0.02). See the detailed NATAP report on this study:

     http://www.natap.org/2000/oct/Dallas/dalrpt10_frenchresrchgrp.html

Histologic Response: non-responders to interferon achieve 47% rate of histologic response

Abstract 246 by Jenny Heathcote looked at histologic response to 40KD pegylated interferon and compared it with standard interferon. The overall histologic response in pegylated IFN was 57% compared to 41% noted in those receiving standard IFN. In those with sustained virologic response, the histologic response was seen in 83% versus 79%. In virologic non-responders, histologic improvements was noted in 47% of patients receiving pegylated IFN and 30% of those receiving interferon 2A. Histologic improvement was assessed by greater than 2 HAI units on the Knodell score.

Thus these snapshots of AASLD showed that there are new therapies available, that fibrosis can be reversed to some extent with therapy and that the natural history of the disease is less severe than previously thought.
      See detailed NATAP report on this study ("Pegylated Interferon --Pegasys-- Non-Responders Still Appear to Improve Histology (liver condition) 50% of the Time"):

     http://www.natap.org/2000/oct/Dallas/dallas_rpt_02_peg_histologic_103100.htm

Peg Intron + Ribivarin & Dosing by Body Weight

The full details of the 72 week data on Peg-Intron + ribivarin is reported in the NATAP report on that study.

Schering Plough reported data at Dallas saying that ribivarin should be dosed by weight to achieve maximal antiviral benefit. This suggests the old notion that 600 mg per day of RBV may be equivalent antivirally may not be true. Will this prove true in Pegasys + RBV studies? We don't have data on this yet.

Michael Manns, professor and chairman in the Dept. of GI and Hepatology at Hannover medical School in Hannover Germany, reported at Dallas the 72 week data for PegIntron+RBV. Manns issued these recommendations:

Schering reported that in this study when patients received optimized weight dosing (>10.6 mg/kg/daily Ribivarin*) the response rates appeared better.

OPTIMIZED WEIGHT BASED DOSING

For genotype 1 in the Peg 1.5 dose arm:

Overall:

Mans also reported weight based dosing mattered in the other arms:

SUSTAINED VIROLOGIC RESPONSE
 
Peg 1.5/R
Peg 0.5/R
IFN/R A vs C
Overall
54%
47%
47% p=0.01
SVR Geno 1
42%
34%
33% p=0.02
SVR Geno 2/3
82%
80%
79%
OPTIMIZED WEIGHT-BASED DOSING (>10.6 mg/kg/daily Ribivarin*)
SVR (overall)
61%
48%
47%
(slide said 57%)
SVR Geno 1 48% 34% 34%
48%
34%
34%
SVR Geno 2
88%
80%
80%

*10.6 mg/kg/daily Ribivarin is about 800 mg/daily for patient weighing 75 kg.

According to a logistic regression analysis Manns reported that 10.6 mg/kg /daily is the optimal dosing.

In the Peg 1.5 ug/kg arm the SVR by weight was

In the standard IFN arm where patients received 1000/1200 mg/day RBV:

This suggests that weight based dosing of RBV affected the response because all patients were receiving the same dosing for Peg IFN.