Normal Baseline Alanine Aminotransferase Research Articles

1105-P: The Effect of Canagliflozin on Alanine Aminotransferase (ALT) Levels: Data from the Association of British Clinical Diabetologists (ABCD) Nationwide Audit Programme

Background: Nonalcoholic fatty liver disease (NAFLD) is common amongst those with type 2 diabetes (T2DM). Alanine aminotransferase (ALT) is known to correlate with levels of liver inflammation and fibrosis. Recent data from our audit programme showed promising reductions in ALT with dapagliflozin. Our aim was to test the same hypothesis, that canagliflozin may improve ALT levels in patients with T2DM, therefore possibly providing benefit in NAFLD. Methods: Data were extracted from the ABCD nationwide audit programme and then stratified into 4 groups based on gender and elevated or normal baseline ALT levels using gender specific references ranges (Prati et al). Baseline and follow-up ALT measurements in the 12-month (6-18months) period were required as a minimum. Data were analysed using Stata 16. Results: 730 datasets were included with mean (±SD) age 61.3yrs (±10.8), 60.1% male, 76% Caucasian (where known), BMI 32.5kg/m2 (±6.5), baseline HbA1c 8.9% (±1.6%) and weight 97.6kg (±22.2) and were broadly similar across all 4 sub-groups. For the entire population, median ALT decreased by 3U/L (95% CI -2, -3; P<0.01). Both male and female subgroups with normal ALT at baseline showed no significant change in ALT. In those with raised ALT at baseline (female ≥19U/L; male ≥30U/L) a change in ALT of -8U/L (95% CI -6, -9U/L; P<0.001) in men and -4U/L in women (95% CI -2, -5; P<0.05). Kruskal-Wallis test confirmed the difference between all groups was significant to P<0.01. No statistically significant correlation was noted between change in weight and change in ALT, which may suggest a weight-loss independent mechanism. Conclusion: Our data show that ALT decreases with canagliflozin, similar to that demonstrated with dapagliflozin. This decrease is greatest in those with elevated baseline levels. Weight-loss is not a predictor of change in ALT suggesting a potential weight-loss independent mechanism. Disclosure T.S.J. Crabtree: None. S.M. Phillips: None. A. Evans: Other Relationship; Self; AstraZeneca. D.K. Sennik: Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. A. Rohilla: None. A. Bickerton: None. K.H. Darzy: None. P. Winocour: Advisory Panel; Self; AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Napp Pharmaceuticals, Sanofi. M.L. Cull: None. A. Strzelecka: None. R.P. Raghavan: Research Support; Self; Allergan plc. Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Napp Pharmaceuticals, Takeda UK. Other Relationship; Self; Napp Pharmaceuticals. I.W. Gallen: None. M. Yadagiri: None. R.E. Ryder: Consultant; Self; GI Dynamics Inc. Other Relationship; Self; Novo Nordisk A/S.

Clinical significance of fatty liver disease induced by tamoxifen and toremifene in breast cancer patients

Background and AimThe aim of this study was to identify the effect of selective estrogen receptor modulator (SERM) on non-alcoholic fatty liver disease (NAFLD) in Asian women. MethodsWe retrospectively evaluated fatty liver development and/or serum alanine aminotransferase (ALT) elevation during SERM treatment in 1061 women who were diagnosed and treated with breast cancer in 2005 at Asan Medical Center. Results45 of 618 SERM-treated patients with normal ALT at baseline experienced ALT elevation during SERM treatment. Among the 112 SERM-treated patients who underwent liver imaging test, fatty liver was observed in 47 and both fatty liver and ALT elevation developed in 16 of 102 SERM-treated patients with normal baseline ALT. The cumulative rates of ALT elevation (10.7 vs. 4.3%; P = 0.002), fatty liver (48.5 vs. 20.9%; P < 0.001), and both fatty liver and ALT elevation (17.7 vs. 7.1%; P = 0.02) at 60 months were significantly higher in the SERM group than non-SERM group. By multivariate analysis, SERM treatment increased the risk of ALT elevation (hazard ratio [HR], 2.20; P = 0.01), fatty liver development (HR, 3.59; P < 0.001), and both fatty liver and ALT elevation (HR, 4.98; P = 0.01). After discontinuation of SERM, elevated serum ALT normalized in 39 (92.9%) and there were no instances of liver-related death or progression to liver cirrhosis in patients who experienced fatty liver or ALT elevation. ConclusionsAlthough SERM treatment is significantly associated with NAFLD in Asian women, considering the tolerability and reversibility of NAFLD induced by SERM, it can be continued with liver function monitoring in relevant patients.

Prevalence and incidence of liver dysfunction and assessment of biomarkers of liver disease in HIV-infected Asian children.

We determined the prevalence and incidence of liver dysfunction before and after initiation of combination antiretroviral therapy (cART) in the TREAT Asia Pediatric HIV Observational Database. Data from children initiated on cART between 2 and 18 years of age with baseline alanine aminotransferase (ALT) available before and at least once after cART initiation in TREAT Asia Pediatric HIV Observational Database between 2008 and 2012 were analyzed. Prevalence and incidence of liver dysfunction and biomarkers including the aspartate aminotransferase to platelet ratio index and FIB4 index (a noninvasive panel to stage liver disease) were assessed. Data from 1930 children were included. Their median age was 6.9 years; 49% were male; 98% were perinatally infected and 94% were initiated on non-nucleoside reverse transcriptase-based cART regimens. Before cART, the prevalence of ALT ≥3 times the upper limit of normal (×ULN) was 5.8%. There were 8.5% of children with aspartate aminotransferase to platelet ratio index >1.5 (suggestive of liver fibrosis) and 2.7% with FIB4 index >1.3 (predictive of possible cirrhosis). Among the 1143 cases with normal baseline ALT (≤1×ULN), the incidence of ALT 3×ULN after cART was 1.19 of 1000 person-months (95% confidence interval: 0.93-1.51). Two of 350 with available tests (0.6%) met Hy's law (ALT >3×ULN and total bilirubin >2×ULN). By multivariate analysis, baseline hemoglobin <7.5 g/dL was a predictor of ALT >3×ULN, whereas age 5-9 years at cART initiation was protective for liver dysfunction. We demonstrated a low prevalence and incidence of liver dysfunction before and after cART initiation in children with normal baseline chemistries. In this population facing life-long cART, prospective surveillance for emergence of liver disease is warranted.

Effect of intensive lipid lowering with atorvastatin on cardiovascular outcomes in coronary heart disease patients with mild-to-moderate baseline elevations in alanine aminotransferase levels

Statins may reduce cardiovascular (CV) morbidity in patients with mild-to-moderate elevations in liver enzyme levels. This post-hoc analysis of the IDEAL study compared intensive versus moderate statin therapy for the prevention of CV events in coronary heart disease patients with normal and elevated baseline levels of serum alanine aminotransferase (ALT). Cox regression analysis was used to investigate the effect of atorvastatin 80 mg/day versus simvastatin 20-40 mg/day on the risk of IDEAL study end points in patients with normal baseline ALT (defined as ALT < ULN [upper limit of normal]) versus elevated baseline ALT (ALT ≥ ULN). Of 8863 IDEAL patients with non-missing baseline ALT values, 7782 (87.8%) had an ALT < ULN and 1081 (12.2%) had an ALT ≥ ULN. In patients with elevated baseline ALT, major CV event rates were 11.5% for simvastatin and 6.5% for atorvastatin, indicating a significant risk reduction with intensive statin therapy (hazard ratio, 0.556; 95% confidence interval, 0.367-0.842; p = 0.0056). Significant heterogeneity of treatment effect was observed for major CV events, cerebrovascular events, and major coronary events, with a trend towards treatment difference for the other outcomes, indicating a greater benefit with atorvastatin in the elevated ALT group. The CV benefit of intensive lipid lowering with atorvastatin compared with a more moderate regimen with simvastatin was generally greater in patients with mildly-to-moderately elevated baseline ALT than patients with normal baseline ALT. Moderate elevations in liver enzyme levels should not present a barrier to prescribing statins, even at higher doses, in high-risk patients.

The Dronedarone Shared-Care Clinical Model and Database: A Coordinated Paradigm to Optimize Management of Evolving Clinical Recommendations

Dronedarone, a non-iodinated derivative of amiodarone, has been approved for use as a second-line agent for atrial fibrillation (AF). Following reports of possible liver injury during routine post-license monitoring, the European Medicines Agency (EMA) recommended regular liver function test (LFT) monitoring. Despite this recommendation, an audit of patients in our multi-center region who were prescribed dronedarone found that on-going LFT monitoring was inconsistent or absent, leading to potential safety concerns. Thus, we assessed whether the setting up of a clinical database of all patients prescribed dronedarone and a dedicated monitoring clinic would improve coordination of follow-up between primary and secondary care, and the implementation of monitoring guidelines. Baseline demographics, pre-treatment and follow-up renal function and LFTs, baseline left ventricular ejection fraction (LVEF), and cardiac rhythm analysis were recorded according to evolving EMA guidelines. Significant transaminitis was defined as alanine aminotransferase (ALT) >3× upper limit of normal. During the study period, 107 patients currently taking dronedarone were identified. Once enrolled in the clinic, prospective serial LFT data were obtained in all patients. Of the 107 patients, 6 had elevated baseline ALT, of whom 1 had a further small ALT rise after commencing dronedarone (from 41 to 79 U/L by 9 months). Of the 101 patients with normal baseline ALT, 6 developed a small ALT rise (mean rise 25 U/L, range 11-36 U/L), but none developed significant transaminitis. After new heart failure guidance was issued 6/107 (7%) patients with baseline LVEF < 35% required therapy discontinuation. Drugs with complex prescribing monitoring requirements are often managed via a shared-care method. Commencement of a dedicated dronedarone clinic optimized consistency of LFT monitoring and facilitated rapid implementation of further EMA guidance. In typical clinical practice, the need to stop dronedarone therapy is more frequently due to reduced LVEF or persistent/permanent AF than development of elevated LFTs.

Histological improvement of long‐term antiviral therapy in chronic hepatitis B patients with persistently normal alanine aminotransferase levels

The aim of this study was to evaluate the histological outcomes of chronic hepatitis B (CHB) patients with persistently normal alanine aminotransferase (ALT) levels after long-term antiviral therapy. Paired liver biopsies before and after lamivudine (LAM) treatment in CHB patients with normal and elevated ALT levels were compared. Histological response was defined as a 1-point decrease according to the Scheuer scoring system, without worsening of fibrosis between pretreatment and posttreatment biopsies. Among the 48 patients who underwent paired liver biopsies, 17 had persistently normal baseline ALT level and 31 had elevated ALT level. The median age of the patients was 44years and 72.9% of the patients were male. The median duration of antiviral treatment was 44.5months (range 14-104). Long-term follow-up of liver biopsies revealed that 82.4% of patients in the normal ALT group and 61.3% in the elevated ALT group had a baseline fibrosis score of 4, which was reduced to 17.6% and 38.7% after long-term therapy, respectively, indicating reversal of cirrhosis in a large proportion of both groups, especially in patients with normal baseline ALT levels. Long-term antiviral treatment could achieve significant histological improvement in CHB patients with fibrosis or cirrhosis, regardless of ALT level.

Abstract 18079: Among CHD Patients in the IDEAL Study, Those with Elevated Levels of Alanine Aminotransferase at Baseline Had a Lower Rate of Major Coronary Events

Background: Previous evidence suggests that statin therapy can reduce cardiovascular (CV) morbidity in patients with mild-to-moderately abnormal liver tests. In this post hoc analysis of the IDEAL study, we investigated the relationship of elevated baseline levels of the liver enzyme alanine aminotransferase (ALT) on CV events, and compared the effects of atorvastatin (ATV) 80 mg versus simvastatin (SIM) 20-40 mg in patients with normal and elevated baseline ALT levels. Methods: IDEAL was a large randomized trial comparing ATV 80 mg with SIM 20-40 mg in 8888 patients with CHD over 4.8 years of follow-up. Cox regression analysis was performed to investigate the relationship of normal levels of ALT (defined as baseline ALT &lt;ULN [upper limit of normal]; 87.8% of subjects) vs elevated ALT (baseline ALT ≥ULN; 11.5% of subjects had ALT ≥ULN-&lt;2 ULN and 0.74% had ALT ≥2 ULN-&lt;3 ULN) on the risk of major coronary events (MCE: CHD death, non-fatal MI or resuscitated cardiac arrest). In addition, treatment effect (ATV 80mg vs SIM 20-40 mg) was examined for subjects with normal and elevated ALT at baseline. Results: Over the course of the study, mean ALT levels increased among patients with normal baseline ALT (n=7782) and decreased for those with ALT ≥ULN at baseline (n=1081). Overall, those patients with normal ALT levels at baseline experienced significantly more MCE than patients with higher baseline ALT levels (≥ULN) (HR=0.76; 95% CI 0.61, 0.96; p=0.02). This finding was consistent in patients treated with ATV (HR=0.60; 95% CI 0.42, 0.87; p=0.007) but not those receiving SIM (p=0.464). In patients with elevated ALT baseline levels, ATV significantly reduced the risk of MCE compared with SIM (HR=0.62; 95% CI 0.40, 0.96; p=0.03), but in patients with normal baseline ALT the difference between treatment groups did not reach statistical significance. Conclusions: In the overall population of CHD patients treated with ATV or SIM, those with normal baseline ALT levels experienced significantly more MCE than those with baseline ALT ≥ULN. The clinical benefits of intensive lipid lowering with ATV compared with a more moderate regimen with SIM were generally greater in patients with abnormal liver tests than in patients with normal liver tests.

Deferasirox (Exjade®) in Pediatric Patients with β-Thalassemia: Update of 4.7-Year Efficacy and Safety from Extension Studies

Background: As pediatric patients with β-thalassemia will require lifelong iron chelation therapy, it is important to evaluate the long-term efficacy, safety and growth during treatment with any iron chelator. This analysis presents cumulative efficacy and safety data from a cohort of pediatric patients treated with the once-daily, oral chelator deferasirox during two 1-year core and 4-year extension trials.Methods: β-thalassemia patients aged 2–<16 years with transfusional iron overload were enrolled in two extension studies (107E and 108E) evaluating the long-term safety, tolerability and efficacy (by serum ferritin [SF] levels) of deferasirox; only patients who received deferasirox from the beginning of the core trial are included in this analysis. Deferasirox doses in the extension trials were initially based on end-of-core liver iron concentration, and were adjusted according to trends in SF levels. Efficacy was monitored by monthly SF levels; safety was assessed by the incidence and type of adverse events (AEs) and laboratory parameters.Results: 168 patients (153 patients from study 107 and 15 from study 108) aged 2–<6 (n=30), 6–<12 (n=74) and ≥12–<16 (n=64) years entered the extensions. To date, patients have received deferasirox for a median of 56.1 months (4.7 years) at an average daily dose of 22.5 ± 6.6 mg/kg/day. Mean iron intake during treatment was 0.4 ± 0.1 mg/kg/day. Mean actual dose at month 3 was 19.8 ± 8.8 mg/kg/day, which increased to 28.3 ± 7.3 mg/kg/day by month 54. Median SF levels at baseline were 2419 ng/mL and were maintained to around month 18, reflecting the mean dose of ~20 mg/kg/day (Figure 1). Following dose titration, SF levels began to decrease with an overall median decrease in SF by month 54 of −947 ng/mL.At the time of analysis 137 patients (81.5%) continue to receive deferasirox. Of 31 discontinuations, 13 (7.7%) were due to AEs (drug-related AEs leading to discontinuation included glycosuria [n=3] and proteinuria [n=2]), eight (4.8%) to unsatisfactory therapeutic effect, five (3.0%) to consent withdrawal and four (2.4%) to other reasons. One death (septicemia in a splenectomized patient) occurred, considered by the Program Safety Board unrelated to treatment. Over the study period, the most common drug-related (investigator-assessed) AEs were abdominal pain and vomiting (n=12, 7.1% for both), nausea (n=10, 6.0%) and rash (n=9, 5.4%). The annual frequency of drug-related AEs decreased from year to year. In total, 13 patients (7.7%) had an increase in serum creatinine >33% above baseline and the upper limit of normal (ULN) on two consecutive visits; however, there were no progressive increases. Six patients (3.6%) with a normal baseline alanine aminotransferase (ALT), and five (3.0%) with a baseline ALT >ULN had an ALT increase >10×ULN on at least one visit. Growth, as assessed by height, proceeded normally in this population.Conclusions: Over a median period of 4.7 years, deferasirox treatment provided a dose-dependent overall reduction in iron burden in transfusion-dependent children with β-thalassemia, as measured by SF levels. Deferasirox was generally well tolerated with the frequency of investigator-reported AEs decreasing over long-term treatment. [Display omitted]

Efficacy and Safety of Deferasirox (Exjade®) during 1 Year of Treatment in Transfusion-Dependent Patients with Myelodysplastic Syndromes: Results from EPIC Trial

Background: Many patients (pts) with myelodysplastic syndromes (MDS) [particularly those with Low- or Int-1-risk] are susceptible to iron overload from ongoing blood transfusions and increased dietary iron absorption. Deferasirox (Exjade®) has shown efficacy in maintaining or reducing body iron (assessed by liver iron concentration [LIC] and serum ferritin [SF]) in MDS pts. More recently, the efficacy and safety of deferasirox in pts with various underlying anemias, including MDS, was evaluated in the large EPIC study. Data for MDS pts are presented here.Methods: The EPIC study was a 1-yr, openlabel, single-arm, multicenter trial. Pts with transfusion-dependent MDS and SF ≥1000 ng/ mL, or SF <1000 ng/mL but requiring >20 transfusions or 100 mL/kg of blood and an R2 MRI-confirmed LIC >2 mg Fe/g dry weight (dw), received an initial deferasirox dose of 10–30 mg/kg/day. SF was assessed monthly and protocol-specified dose adjustments in steps of 5–10 mg/kg/day (range 0–40 mg/kg/day) were done every 3 mths based on SF trends and safety markers. Primary efficacy endpoint was the change in SF from baseline at 12 mths. Safety assessments included monitoring of adverse event (AE) and laboratory parameters.Results: 341 MDS pts (204 M, 137 F; mean age 67.9 yrs, range 11–89 yrs) with median baseline SF of 2730 (range 951–9465) ng/mL were enrolled. Mean transfusion duration was 3.6 yrs, and pts received a mean of 116.4 mL/kg of blood in the previous yr. Almost half (48.4%) of all pts had not received any prior chelation therapy; 40.0% had previously received deferoxamine (DFO), 4.1% deferiprone, 7.0% combination DFO/ deferiprone, and 0.3% other therapy. Overall, mean actual dose of deferasirox over 1 yr of treatment was 19.2±5.4 mg/kg/day. At 12 mths, there was a significant reduction in median SF from baseline (by LOCF: –253.0 ng/mL; P=0.0019). Median SF (range) ng/mL values at baseline, 3, 6, 9 and 12 mths were 2729.5 (951–9465; n=336), 2358.0 (534–46569; n=263), 2209.5 (357–10066; n=230), 2076.0 (358–25839; n=197) and 1903.5 (141–10155; n=174), respectively. Overall, 48.7% of pts (n=166) discontinued therapy. Reasons for withdrawal included AEs [n=78, 23% (n=44, 13% for drug-related AEs)], consent withdrawal (n=33, 10%), unsatisfactory therapeutic effect (n=6, 2%), lost to follow-up (n=2, <1%), death (n=26, 8%, none treatment-related as per investigators' assessments) and other (n=21, 6%). Most common investigator-assessed drug-related AEs were diarrhea (n=110, 32%), nausea (n=45, 13%), vomiting (n=26, 8%), abdominal pain (n=26, 8%), upper abdominal pain (n=25, 7%), rash (n=23, 7%), and constipation (n=21, 6%). Only 25 pts discontinued study drug for drug-related GI AEs. Most AEs were mild-to-moderate (95%) in severity. In total, 14.7% had two consecutive serum creatinine values >33% above baseline (in normal range), 10.6% had two values above ULN, and 24.9% had both two consecutive values >33% and >ULN; 19 pts had dose decreases and 10 dose interruptions due to abnormal creatinine; there were no progressive increases. One patient (<1%) with normal baseline alanine aminotransferase had an increase that exceeded >10xULN on two consecutive visits.Conclusions: In this large cohort of MDS pts with iron overload, deferasirox provided significant reduction in SF levels over 1-yr treatment with appropriate dose adjustments every 3 mths based on SF trends and safety markers. The AE profile in this study is consistent with previously reported deferasirox data in MDS pts. The discontinuation rate was higher in this subgroup. Investigations are ongoing to assess possible contributing factors including associated comorbidities, age of pts, and others.

Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: An interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials

Background: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes mellitus (T2DM), reduced glycosylated hemoglobin (HbA 1c) and weight in 30-week placebo-controlled trials. Some patients were followed up in open-label extensions to provide ‘real-world’ exenatide clinical experience. Objective: The purpose of this study was to examine the metabolic effects of 2 years of exenatide treatment in patients with T2DM. Methods: For this interim analysis, data were pooled from patients who completed 1 of three 30-week, multicenter, double-blind, placebo-controlled trials and their open-label extensions. In the initial trials, subjects were randomized to BID 5-pg exenatide, 10-pg exenatide, or placebo for 30 weeks. All subjects who enrolled in the extension phase then received 5-pg exenatide BID for 4 weeks, followed by open-label treatment with 10-pg exenatide BID. Subjects continued their existing metformin and/or sulfonylurea regimens. Analyses were conducted on data from all subjects who had the opportunity to achieve 2 years of exenatide exposure, irrespective of their treatment arm in the 30-week placebo-controlled trials. Results: A total of 974 patients entered the open-label, extension phase of the trial. Two hundred eighty-three subjects (mean [SD] age, 57 [10] years; mean [SD] weight, 100 119 kg; sex, 63% male; mean [SD] body mass index, 34 [6] kg/m2; mean [SD] HbA 1c, 8.3% [1.0%1] completed 2 years of exenatide treatment. Reductions in mean (SE) HbA 1c from baseline to week 30 (−0.9% [0.1%]) were sustained through 2 years (−1.1% [0.1%]; P < 0.05 vs baseline), with 50% of the population achieving HbA 1c ≤ 7%. At week 30, exenatide was associated with a significant reduction in mean (SD) body weight from baseline (−2.1 [0.2] kg), with progressive reductions after 2 years (−4.7 [0.3] kg; P < 0.001 vs baseline). Patients with normal baseline alanine aminotransferase (ALT) (132/283 [47%]; normal: female ≤19 IU/L; male ≤30 IU/L) had no significant ALT change. However, patients with elevated ALT at baseline (151/283 [53%]) had a mean (SEM) reduction of ALT (−11 [1] IU/L from baseline 38 [1] IU/1,; P < 0.05) and 39% achieved normal ALT by week 104. Patients with elevated ALT at baseline lost significantly more weight than patients with normal ALT at baseline ( P = 0.04). However, weight change was minimally correlated with baseline ALT ( r = −0.09) or ALT change ( r = 0.31). Also, homeostasis model assessment of the β-cell function (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. The most frequently reported adverse event was mild-to-moderate nausea. Conclusions: In these patients with T2DM, adjunctive exenatide treatment for 2 years was generally well tolerated and resulted in a sustained reduction of HbA 1c, progressive reduction in weight, and improvements in HOMA-B, blood pressure, and the hepatic injury biomarkers, AST and ALT.

Histological progression during short-term follow-up of patients with chronic hepatitis C virus infection.

Assessment of prognosis from hepatitis requires liver histology. When the fibrosis stage is known, and if the fibrosis progression rate can be established, time to development of cirrhosis can be calculated. The fibrosis progression rate can be calculated from a single biopsy when duration of infection prior to biopsy is known. Sequential biopsies can also be examined. In this work, we studied histological activity and fibrosis stage in liver biopsies of 157 hepatitis C virus (HCV)-infected patients, including 92 for whom the approximate duration of infection was known. The mean fibrosis progression rate was 0.09 units per year, and was not influenced by mode of infection or viral genotype. Forty-six patients who had very mild histological changes in the initial biopsy underwent repeat biopsy 2 years later (with no intervening anti-viral treatment). Comparison of paired biopsies confirmed a tendency to histological progression and increasing hepatic fibrosis (mean, 0.15 fibrosis units per year). A normal baseline alanine aminotransferase (ALT) value was associated with slow fibrosis progression before baseline biopsy and between biopsies. These data do not differ from published cross-sectional and longitudinal studies, and suggest that histological progression will be observed during follow-up of most patients, including those with mild histological changes at time of initial assessment.