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

This study presents interesting data. Firstly, the study data suggests that ALT level may be predictive in reflecting disease status and progression. I would still maintain that ALT is not a substitute for a biopsy. Persons with normal ALT appear to have less liver damage (mild and slowly or non-progressive HCV) than individuals with abnormal ALT. Following 4 years follow-up persons with normal ALT had not progressed or not significantly. While individuals with abnormal ALT who were untreated or non-responders saw worsening fibrosis. In HCV/HIV coinfection this information may not apply (ALT may not reflect mild disease or slow progression) because HIV has been shown to accelerate HCV progression in a number of studies.

In fact, at ICAAC 2000 Hoffman-Terry reported 8/10 co-infected individuals with normal ALT had biopsy proven inflammation/fibrosis. As well, all 14 patients with abnormal ALT had biopsies revealing inflammation with or without fibrosis. The number of individuals in the study was not large enough to achieve statistical significance.

Interestingly, Estaban's data in the program abstract shown below indicated patients with elevated ALT saw increased fibrosis if untreated or non-responders to HCV treatment. And, 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 is effective for some individuals. This study also suggests maintenance therapy including RBV maybe more beneficial than IFN alone).

OUTCOME OF HEPATITIS C IN BLOOD DONORS AND ASYMPTOMATIC OUTPATIENTS: AN EIGHT-YEAR FOLLOW-UP STUDY
     Juan I Esteban, Hosp Vall d'Hebron, Barcelona Spain; Silvia Sauleda, Banc de Sang i de Teixits, Inst Catala de la Salut, Barcelona Spain; Alberto Juarez, Liver Unit, Hosp Vall d'Hebron, Barcelona Spain; Rafael Esteban, Jaume Guardia, Hosp Vall d'Hebron, Barcelona Spain

Background: The natural history of hepatitis C in symptom-free patients remains largely unknown.

Aims: To investigate the long-term clinical and histological outcome in asymptomatic HCV-infected patients covering most of the spectrum of HCV-associated liver damage.

Subjects and methods: Four-hundred forty-three HCV RNA + patients representing 80% of HCV positive blood donors (BD) and 75% of asymptomatic outpatients referred for evaluation of positive serology and abnormal ALT(OP), seen at the liver unit between 1991 and 1994 were enrolled in a long-term follow-up study. Baseline evaluation included LFTs, liver US, viral load, genotype, monthly ALT for 6 months and a liver biopsy (LBx). Patients were followed every six months (mean follow up 7.8 to 2 y.)and antiviral treatment (IFN or IFN+RBV) was offered when indicated. Follow-up biopsies were performed after 4.3 to 1.8 y. in 295 (67%)patients without cirrhosis in the first biopsy. Biopsies were scored according to Ishak et al. and fibrosis progression rate per year estimated as the ratio between fibrosis score in the first biopsy and duration of infection (indirect estimate) and difference between fibrosis scores divided by the time interval between biopsies (direct estimate)

Results: Of the 443 patients, 47 were BD with persistently normal ALT (mean 22 to7 IU/L, group I), 271 BD with abnormal ALT (mean 75 to 49 IU/L, group II) and 125 outpatients with abnormal ALT (mean 102 to 67 IU/L, group III).

The 3 groups were similar in:

• age (47 to14 y.),
• gender (50% male),
• risk factor (Tx 40%),
• duration of infection (24-11 y.),
• alcohol intake (>40 g, 11%),
• viral load (6.2-0.9) and
• genotype distribution (1: 86%; 2: 5%; 3: 5%, 4: 4%).

However, significant differences were seen in liver damage in all 3 groups at baseline (group I normal ALT: 55% mild, 36% moderate, 6% severe chronic hepatitis, 2% cirrhosis; group II: 29% mild; 48% mod.; 19% severe chronic hepatitis, 5% cirrhosis; group III: 24% mild; 32% mod.; 27% severe CAH; 17% cirrhosis; P<0.01).

Of the 396 group II and III patients, 153 (39%) received IFN, alone (42%) or with RBV (56%), for 14 to 7 months and 38 (25%) became sustained responders (SR). Among group I patients, ALT remained normal in 91% and repeat biopsies in 32 showed no change or improvement in 55% and slight worsening in 45% with no significant change in mean fibrosis score (1.7 to to to .1 vs. 1.9 to 0.9). Indirect and direct estimates of fibrosis progression rate per year were similar (0.097 to 1.252 and 0.062 to 0.267 FU) and equivalent to a mean interval to cirrhosis of > 60 years.

Among the 257 patients with elevated ALT (189 from group II and 70 from group III), fibrosis increased (from 2.5 to 1.5 at baseline to 2.7 to 1.4 at follow up; p<0.001) in untreated and non responder patients and decreased in the 38 sustained responders (2.5 to 1.1 vs. 2.1 to 1.5;p<0.001).

However, the proportion of patients who improved or remained unchanged was higher in non-responders than in untreated patients (18% and 49% versus 8% and 44%; p=0.03)and fibrosis progression rate decreased from 0.215 to 0.241 before treatment to 0.057 to 0.350 at follow up (p=0.02) in non-responders treated with IFN and RBV, while it remained unchanged in untreated patients and non-responders to interferon alone (0.143 to 0.142 vs. 0.141 to 0.232 and 0.122 to 0.09 vs. 0.144 to 0.347, respectively; p= NS).

The difference persisted after adjusting for age, sex, age at infection, duration of infection, alcohol consumption, viral load, genotype and ALT level. In multivariate analysis, age, ALT level and antiviral combination treatment were the only independent factors associated with fibrosis progression in our cohort.

Conclusions:

1. HCV-infected patients with normal ALT levels have mild and slowly or non-progressive disease.

2. Disease progression is strongly influenced by age and outcome may be predicted by ALT levels.

3. Antiviral combination treatment slows disease progression in virological non-responders although duration of the effect remains unknown.