Long-term safety of anti-TNF treatment in patients with rheumatic diseases and chronic or resolved hepatitis B virus infection.

OBJECTIVES: The aim of this prospective study was to examine the safety of anti-tumour necrosis factor (TNF) therapy in patients with rheumatic disease and hepatitis B virus (HBV) infection. METHODS: 14 patients with chronic HBV infection, 19 HBV-vaccinated patients and 19 patients with resolved HBV infection were included in the study. All HBV-infected patients received combination therapy with oral antivirals and anti-TNF agents. During treatment the levels of hepatitis B surface antibodies (anti-HBs) in HBV-vaccinated patients and of serum HBV DNA in patients with chronic or resolved HBV infection were monitored. RESULTS: No viral reactivation was observed in patients with resolved HBV infection while anti-HBs titres decreased during anti-TNF treatment in vaccinated patients, similarly to patients treated with methotrexate alone. None of the HBV-infected patients developed liver decompensation or a significant increase in alanine aminotransferase levels. One patient (7%) treated with lamivudine and etanercept showed viral reactivation due to the emergence of a lamivudine-resistant mutant strain. CONCLUSIONS: Anti-TNF agents represent a safe option for patients with chronic HBV infection when combined with antiviral therapy, as well as in patients previously exposed to HBV receiving no HBV prophylaxis. Resistant HBV strains may arise in patients with chronic hepatitis B, necessitating the initial use of anti-HBV agents with a low risk of resistance.

Serum hepcidin levels are related to the severity of liver histological lesions in chronic hepatitis C.

Hepcidin is synthesized in the liver and has a crucial role in iron homoeostasis. Its synthesis is up-regulated in chronic inflammation and iron excess. We examined the determinants of serum hepcidin and liver hepcidin mRNA levels and their association with histological lesions in patients with chronic hepatitis C (CHC) and healthy controls. We studied 96 patients with CHC and 30 controls. Serum hepcidin levels were measured by an in-house competitive ELISA. Hepcidin mRNA levels were determined by a one-step qRT-PCR in total RNA extracted from liver biopsy specimens of 27 patients with CHC and six disease controls. Histological lesions were evaluated according to Ishak's classification. Serum hepcidin was significantly lower in patients with CHC than healthy controls (14.6 ± 7.3 vs 34.6 ± 17.3 ng/mL, P < 0.001). In patients with CHC, serum hepcidin correlated positively with aspartate aminotransferase (r = 0.334, P = 0.001) and insulin resistance (r = 0.27, P = 0.016) and had a trend for correlation with alanine aminotransferase (r = 0.197, P = 0.057) and serum haemoglobin (r = 0.188, P = 0.067) but not with ferritin. A significant positive correlation was also found between serum hepcidin levels and both necroinflammation (r = 0.259, P = 0.011) and fibrosis (r = 0.214, P = 0.036). Serum hepcidin was among others an independent predictor of cirrhosis (odds ratio: 1.145, P = 0.039). Liver hepcidin mRNA levels did not differ between patients and controls and were relatively lower in patients with than without cirrhosis (19.3 ± 21.7 vs 38.3 ± 26.0, P = 0.067). Patients with CHC have reduced serum hepcidin levels, which correlate with worse necroinflammation and fibrosis. The previously mentioned observations suggest a viral effect on hepatic hepcidin production, but might also support its involvement in the inflammatory process.

Serum HCV RNA levels and HCV genotype do not affect insulin resistance in nondiabetic patients with chronic hepatitis C: a multicentre study.

BACKGROUND: Chronic hepatitis C (CHC) induces insulin resistance (IR) and subsequently diabetes. AIM: To examine viral, metabolic and histological predictors of IR in 275 CHC patients to test the hypothesis that IR differs among HCV genotypes and that viral replication directly affects IR. METHODS: We studied 275 nondiabetic treatment-naïve CHC patients. Histological lesions were evaluated according to Ishak. IR was assessed using homeostasis model assessment for insulin resistance (HOMA-IR). RESULTS: HOMA > 3.0 was found in 37% of patients, independently associated with higher BMI and GGT. In genotype non-3 patients, HOMA > 3.0 was associated with higher BMI and GGT values, while no significant association was noted in genotype 3 patients. In non-obese patients with minimal fibrosis, HOMA > 3.0 was found in 20% of cases without significant differences among genotypes. No association between HOMA > 3.0 and HCV-RNA levels was found. Severe fibrosis (stage 5-6) related to older age (OR:1.048), HOMA-IR (OR:1.177), necroinflammation (OR: 2.990) and higher ALT (OR: 1.009) and GGT (OR:1.006). CONCLUSIONS: IR develops at early stages of CHC without significant differences among genotypes. It is more frequent in obese patients with steatosis and contributes to fibrosis progression. However, IR does not seem to be associated with viraemia and therefore its exact pathogenetic mechanism in CHC remains elusive.

Prevalence of glucose intolerance in patients with chronic hepatitis B or C: a prospective case-control study.

Despite several studies, the association of glucose intolerance with chronic hepatitis B (CHB) or C (CHC) virus infection remains controversial. We evaluated the prevalence of glucose intolerance by oral glucose tolerance test (OGTT) in patients with CHB or CHC in comparison with matched controls. In total, 189 consecutive outpatients with CHB or CHC and 189 subjects individually matched for age, sex and body mass index (BMI) were included. OGTT was performed in all cases, except in known diabetics, and glucose intolerance was defined as impaired glucose tolerance (IGT), OGTT-diabetes or known diabetes. Most patients with abnormal OGTT had normal fasting glucose (IGT: 69.8%, OGTT-diabetes: 54.5%). Compared with their own controls, CHB patients had a higher prevalence of IGT (13.6% vs 2.5%, P = 0.018) and family history of diabetes (34.6% vs 16.0%, P = 0.011), while CHC patents had higher prevalence of glucose intolerance (37.0% vs 15.7%, Rho = 0.001), mostly because of more frequent IGT (21.3% vs 6.5%, Rho = 0.003). After age and BMI adjustment, patients with CHC compared with those with CHB had significantly higher prevalence of glucose intolerance (37.0% vs 29.6%, P = 0.037). In conclusion, increased prevalence of glucose intolerance is documented by OGTT both in CHC and CHB patients compared with age, sex and BMI matched controls. Glucose intolerance is more frequent in CHC than CHB patients, regardless of known risk factors. An OGTT might be necessary at the baseline work-up of CHB or CHC patients, as a normal fasting glucose value does not exclude IGT or OGTT-diabetes.

Natural course of treated and untreated chronic HCV infection: results of the nationwide Hepnet.Greece cohort study.

BACKGROUND: Interferon (IFN-alpha)-based regimens have been used with varying success in the treatment of chronic hepatitis C (CHC) for over two decades. The effect of such treatments on the natural course of CHC has been evaluated in small clinical trials with conflicting results. AIM: To investigate the natural course of IFNalpha-based-treated and untreated patients with CHC by analysing data from the HEPNET.GREECE study. METHODS: We retrospectively analysed 1738 patients from 25 Greek Centres (median age 40.1; males 57.6%; cirrhosis 9.2%), 734 untreated and 993 treated with IFNalpha-based regimens [44.7% sustained viral response (SVR)], followed-up for median 25.2 and 46.8 months, respectively. RESULTS: During follow-up, 48 patients developed liver decompensation and 24 HCC. Older age was significantly related to disease progression (HR = 2.6 per 10 years of increasing age). Stratified by baseline cirrhosis, Cox analysis showed that patients with SVR, but not without SVR, had significantly lower hazard for events compared with nontreated patients (HR = 0.16; P < 0.001), whereas the detrimental effect of older age remained highly significant. Separate group analysis demonstrated that in cirrhosis, the beneficial effect of treatment was evident even without SVR. Treatment effect interacted significantly with age, indicating that older patients, mainly noncirrhotic, gained the most benefit. CONCLUSIONS: IFNalpha-based treatment does alter the natural course of CHC. A protective effect is mostly present in patients with SVR, but older patients, at higher risk of events, gain the greatest benefit. In established cirrhosis, treatment carries a protective effect even among those without SVR.

Longitudinal changes in serum HBV DNA levels and predictors of progression during the natural course of HBeAg-negative chronic hepatitis B virus infection.

We evaluated the longitudinal changes of viraemia and predictors of progression in a prospectively followed cohort of 150 untreated patients with HBeAg-negative chronic hepatitis B virus (HBV) infection. According to the first year of follow-up, 85 patients were classified into inactive carrier state and 65 into chronic hepatitis B (CHB). Serum HBV DNA levels were determined at baseline in all patients, at year-1 in carriers or last pretherapy visit in CHB patients and during alanine aminotransferase (ALT) elevations in carriers progressing to CHB. HBV DNA levels at any occasion were > or =80, > or =2000 or > or =20 000 IU/mL in 81%, 23% or 0% of carriers and 100%, 95% or 83% of CHB patients. The cumulative progression rate from carrier to CHB was 11%, 16%, 24% at 2-, 3-, 4 years and was independently associated with higher baseline ALT (always within traditional normal range) and baseline HBV DNA > or =2000 or > or =5000 IU/mL. In 12 carriers progressed to CHB, HBV DNA increased by >1 log(10) IU/mL. During 7.5 months of median follow-up, HBV DNA change > or =1 log(10) IU/mL was observed in 49% of CHB patients. In conclusion, serum HBV DNA levels are detectable in the majority of inactive HBV carriers exceeding 2000 IU/mL in only 23% and 20 000 IU/mL in none of them. Carriers have approximately 15% 3-year risk of progression to CHB, which is associated with higher baseline ALT and viraemia > or =2000-5000 IU/mL, and thus should be closely followed. Approximately 20% of HBeAg-negative CHB patients have HBV DNA <20 000 IU/mL with fluctuations >1 log(10) occurring in many of them.

Metabolic syndrome is associated with severe fibrosis in chronic viral hepatitis and non-alcoholic steatohepatitis.

BACKGROUND: The prevalence of metabolic syndrome and its possible impact on the severity of liver histological lesions have not been studied prospectively in chronic liver diseases. AIM: To investigate the prevalence of metabolic syndrome in patients with chronic viral hepatitis or non-alcoholic steatohepatitis, and to determine its associations with histological severity. METHODS: We prospectively included 317 patients (hepatitis B e antigen-negative chronic hepatitis B: 95, chronic hepatitis C: 176, non-alcoholic steatohepatitis: 46) with liver biopsy. Metabolic syndrome was defined using the Adult Treatment Panel III criteria. Histological lesions were evaluated according to Ishak's or Brunt's classification. RESULTS: Metabolic syndrome was present in 10.4% of patients being significantly more prevalent in non-alcoholic steatohepatitis than in chronic viral hepatitis (41.3% vs. 5.1%, P < 0.001). In chronic viral hepatitis, cirrhosis (stages 5-6) was independently associated with increasing age, higher aspartate aminotransferase and gamma-glutamyl-transpeptidase levels, severe necroinflammation and metabolic syndrome (P = 0.016). In non-alcoholic steatohepatitis, severe fibrosis (stages 3-4) was independently associated with severe necroinflammation and metabolic syndrome (P = 0.033). Presence of metabolic syndrome was not associated with presence or severity of steatosis both in chronic viral hepatitis and in non-alcoholic steatohepatitis. CONCLUSION: Metabolic syndrome is more prevalent in non-alcoholic steatohepatitis than in chronic viral hepatitis; it is associated independently with more severe fibrosis but not with the severity of steatosis, both in chronic viral hepatitis and in non-alcoholic steatohepatitis.

Serum apoptotic caspase activity as a marker of severity in HBeAg-negative chronic hepatitis B virus infection.

BACKGROUND AND AIMS: In chronic hepatitis C and non-alcoholic fatty liver disease, apoptotic caspases are activated in liver, and serum caspase activity has been suggested as a sensitive marker of early liver injury. An investigation was carried out into whether the serum levels of caspase-generated fragments of cytokeratin-18 (CK-18) are associated with the severity of liver lesions in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) infection. Patients/ METHODS: CK-18 fragment serum levels were determined in 115 treatment-naive, consecutive HBV patients and 30 healthy controls. Hepatic-expression of CK-18 fragments was evaluated by immunocytochemistry in chronic hepatitis B patients. RESULTS: CK-18 fragment levels (U/l) were significantly lower in healthy controls (mean (SD), 154 (31)) than in 53 inactive carriers (172 (24), p = 0.003) and in 62 chronic hepatitis B patients (474 (488), p<0.001). The receiver operating characteristic curve showed excellent diagnostic accuracy (c-statistic: 0.87) for differentiating inactive carriers from chronic hepatitis B patients. A CK-18 fragment cut-off level of 240 U/l gave a sensitivity of 60%, and a specificity and positive predictive value of 100% for chronic hepatitis B diagnosis. CK-18 fragment levels were also lower in inactive carriers than in 16 chronic hepatitis B patients with transiently normal alanine aminotransferase (ALT; 327 (256), p = 0.001), offering good accuracy for such a differentiation (c-statistic: 0.78). In chronic hepatitis B patients, serum CK-18 fragments correlated positively with ALT/aspartate aminotransferase (AST), viraemia, grading score and their immunohistochemical hepatic expression, and negatively with platelet counts, but not with fibrosis or steatosis severity. CONCLUSIONS: Serum apoptotic caspase activity is strongly associated with the presence of liver injury in patients with HBeAg-negative chronic HBV infection. CK-18 fragment levels seem to be a very useful marker for differentiation between the inactive HBV carrier state and HBeAg-negative chronic hepatitis B, but not for estimation of the severity of liver histological lesions among HBeAg-negative chronic hepatitis B patients.

Hepatic steatosis in chronic hepatitis B develops due to host metabolic factors: a comparative approach with genotype 1 chronic hepatitis C.

BACKGROUND/AIMS: Hepatic steatosis has not been adequately studied in chronic hepatitis B, while it is considered to be a cardinal feature in chronic hepatitis C and to be mainly metabolically induced in patients infected with genotype 1. We investigated the prevalence of and the parameters associated with steatosis in HBeAg-negative chronic hepatitis B. METHODS: We studied 213 patients with HBeAg-negative chronic hepatitis B and compared them with 163 patients with genotype-1 chronic hepatitis C. Steatosis was semi-quantitatively graded. RESULTS: Steatosis was significantly less frequent in chronic hepatitis B than chronic hepatitis C (60% versus 72%, P=0.016), but there was no difference in the prevalence of moderate/severe steatosis. In chronic hepatitis B, steatosis was associated only with higher body mass index (P=0.002), while moderate/severe steatosis was associated only with higher body mass index (P=0.043) and diabetes (P=0.031). Steatosis was relatively less frequent in chronic hepatitis B than chronic hepatitis C non-diabetic, normal-weight patients (45.6% versus 62.5%, P=0.063), but it did not differ in diabetic and/or overweight/obese patients with chronic hepatitis B or chronic hepatitis C. CONCLUSIONS: Hepatic steatosis in HBeAg-negative chronic hepatitis B (a) is less frequent than in genotype-1 chronic hepatitis C, (b) is mainly associated with presence of host metabolic factors, such as high body mass index and diabetes and (c) does not seem to be associated with the severity of liver histological lesions.

Liver transplantation in Greek patients: epidemiological data, morbidity, and mortality of 71 patients from a single center with 6 years of mean follow-up.

Liver transplantation remains an underdeveloped technique in Greece; currently there is no information on outcomes in Greek patients. In this study, data were provided on the outcomes of liver transplantation in 71 patients with a mean follow-up of 6 (0.1 to 16) years in our center. Mean age at transplantation was 46 +/- 13 years, while the main cause for transplantation was hepatitis B (16 patients, 23%) or C (six patients, 8%) virus. In the first posttransplantation year, three patients died, while 18 (25%) required at least one hospitalization with a median stay of 30 days. At the end of follow-up, 56 patients (79%) are alive. The leading cause of death was de novo malignancies (40%), appearing at a mean of 5.2 +/- 3.3 years. Late adverse effects of immunosuppressive therapy included hypertension (42%), hyperlipidemia (24%), chronic renal failure (21%), and diabetes mellitus (24%). With the exception of diabetes, all the above abnormalities were significantly associated with cyclosporine-based but not with tacrolimus-based immunosuppressive regimens. Relapse of primary disease in liver transplants occurred in 21 (29.6%) patients at a mean time of 1.5 +/- 1.4 years, of whom 67% were related to viral hepatitis. The quality of life (Karnofsky scale 1 to 6) was excellent in 64% of surviving patients, affordable in 21%, and poor in 15%. In conclusion, after 6 mean years, the majority of Greek liver transplant recipients conduct a normal life, although metabolic abnormalities are often observed. A national registry is needed to provide more solid evidence of outcomes.

Diabetes mellitus in chronic hepatitis B and C: prevalence and potential association with the extent of liver fibrosis.

Diabetes mellitus has been reported to have an increased prevalence and to be associated with more severe fibrosis in patients with chronic hepatitis C. We evaluated the prevalence of diabetes mellitus in patients with chronic hepatitis B or C as well as the possible association between presence of diabetes and extent of liver fibrosis. In total, 434 consecutive patients with histologically documented hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (n = 174) or chronic hepatitis C (n = 260) were studied. The relationships of diabetes and epidemiological, somatomorphic, laboratory and histological patient characteristics were evaluated. Liver histological lesions were blindly evaluated according to the Ishak's classification. Diabetes was present in 58 (13%) patients, without any difference between those with chronic hepatitis B (14%) or C (13%). Diabetes was observed significantly less frequently in patients with fibrosis score 0-2 (7.7%) than 3-4 (10.4%) than 5-6 (29.2%) (P < 0.001). The presence of diabetes was independently associated with higher gamma-glutamyl-transpeptidase (GGT) levels and more severe fibrosis or presence of cirrhosis (P < 0.001) as well as with presence of hepatic steatosis and increased serum triglycerides levels (P < 0.02). In the noncirrhotic patients, diabetes was significantly associated with older age and higher GGT levels, but not with the extent of fibrosis. In conclusion, diabetes mellitus is observed in more than 10% of patients with either HBeAg-negative chronic hepatitis B or chronic hepatitis C. The presence of diabetes is strongly associated with more severe liver fibrosis, but such an association may be related to the high prevalence of diabetes in patients with cirrhosis.

A partially overlapping treatment course with lamivudine and interferon in hepatitis B e antigen-negative chronic hepatitis B.

BACKGROUND: Treatment of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHBe-) with interferon or lamivudine alone is inefficient and reports of combination treatment with both drugs, equivocal so far. AIM: To investigate the efficacy of a lamivudine-interferon combination therapy in 36 patients HBeAg-negative CHBe-. METHODS: Lamivudine was administered from 1 to 12 months and interferon-alpha2b from 7 to 18 months. A historical control group of 36 CHBe- patients, matched for age and sex and treated with the same dosage of interferon-alpha2b was used. All patients were followed up for > or =12-month post-treatment. RESULTS: The biochemical response rate at the end of treatment was 78% in lamivudine-interferon and 52.8% in interferon-control group (P = 0.026) and at 12-month post-treatment 38.9% and 22.2%, respectively (P = 0.125). Alanine aminotransferase normalization and serum HBV-DNA levels < or =30 000 cp/mL were observed in 50.0% of lamivudine-interferon-treated and 30.6% of interferon-treated patients at the end of treatment (P =0.093) and in 22.2% and 13.9% of patients, respectively, at 12-month post-treatment (P = 0.358). Moreover, alanine aminotransferase normalization and undetectable serum HBV-DNA (<400 cp/mL) was observed in 30.6% of lamivudine-interferon-treated and 8.3% of interferon-treated patients at the end of treatment (P = 0.017) and in 8.3% and 0% of patients, respectively, at 12-month post-treatment (P = 0.076). CONCLUSIONS: In CHBe-, 12 months after ending a lamivudine-interferon partially overlapping 18-month combination course, 22% of patients still maintain normal alanine aminotransferase and HBV-DNA levels < or =30 000 cp/mL. However, a 12-month interferon monotherapy course may achieve similar responses.

Impact of interferon-alpha therapy on liver fibrosis progression in patients with HBeAg-negative chronic hepatitis B.

The possible effect of interferon-alpha (IFNa) on liver fibrosis progression has not been adequately studied in chronic hepatitis B. We evaluated 147 patients with HBeAg-negative chronic hepatitis B who had > or =2 liver biopsies and had been treated with IFNa (n = 120) or had remained untreated (n = 27). The median interval between the two biopsies was 24 (12-160) months. All biopsies were scored blindly by a single liver histopathologist according to the classification of Ishak et al. (J Hepatol 1995; 22: 696-699). IFNa induced sustained biochemical response in 30, initial response and subsequent relapse in 57 and no response in 33 patients. Fibrosis improved in 17.5% of treated (sustained responders: 40%, relapsers: 9%, nonresponders: 12%) and 4% of untreated patients and worsened in 34% (sustained responders: 7%, relapsers: 40%, nonresponders: 48%) and 70% of cases, respectively (P = 0.002). The annual rate of fibrosis progression was worse in the untreated (0.427 +/- 0.119) than in treated patients (0.067 +/- 0.052, P = 0.001). However, the fibrosis progression rate in the untreated patients was not significantly different than the net fibrosis progression rate (after subtraction of IFNa duration) in nonresponders or relapsers. In multivariate analysis, worse fibrosis progression rate was associated with older age (P = 0.010), worse baseline grading score (P < 0.001), lower baseline fibrosis (P = 0.035) and the type of response to IFNa (P = 0.032). In conclusion, in HBeAg-negative chronic hepatitis B, IFNa significantly reduces the rate of fibrosis progression, but such an effect is mainly observed in patients with sustained biochemical responses. In relapsers and nonresponders, fibrosis benefit equals the treatment period. The strongest factor associated with fibrosis progression is the change in necroinflammatory activity.

Deep sinus aspergillosis in a liver transplant recipient successfully treated with a combination of caspofungin and voriconazole.

We describe the rare case of a diabetic patient who was successfully treated for cytomegalovirus viremia and leishmaniasis following liver transplantation for hepatitis C virus-related cirrhosis, but also developed invasive sinus Aspergillus infection, while still on liposomal amphotericin B (AmBisome). The patient refused radical surgery including eye enucleation, and received a combination of intravenous caspofungin and voriconazole, along with repeated, conservative, local surgical debridement. At follow-up, 15 months after the onset of sinusitis, the patient remains culture-negative, fully active, and without evidence of local recurrence.

Interferon alpha treatment and retreatment of hepatitis B e antigen-negative chronic hepatitis B.

BACKGROUND AND AIMS: In hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHBe-), interferon (IFN) achieves very low biochemical sustained response rates. No information exists on retreatment. METHODS: Two hundred sixteen CHBe- patients treated for 5 or 12 months with 3 MU IFN-alpha2b thrice weekly and retreated (51 patients, 60 courses) because of no response or relapse were retrospectively analyzed. RESULTS: After 7.0 years of median follow-up, 39 naive patients (18.1%) were still in biochemical and virologic remission after a single IFN course. Longer treatment and a biochemical response within 4 months were significant predictors, inversely related to relapse by multivariate analysis (relative hazard [RH], 0.611; 95% confidence interval [CI], 0.448-0.834 and RH, 0.290; 95% CI, 0.192-0.438, respectively). Retreatment resulted in 18.4% sustained response by intention-to-treat (18 of 98 patients). Patients with sustained response had persistently normal alanine aminotransferase levels, undetectable hepatitis B virus (HBV) DNA by molecular hybridization, and significant improvement of histologic grade, and 32% of them lost hepatitis B surface antigen. In sustained responders, serum HBV DNA was undetectable or very low at the end of treatment and at the end of follow-up (median 3934 and 903 copies/mL, respectively) by quantitative polymerase chain reaction. CONCLUSIONS: IFN induced long-term biochemical and virologic remission in approximately 18% of naive or retreated patients with CHBe-. Sustained responders exhibited significant histologic improvement and a high rate of HBsAg loss.

Induction interferon therapy in naïve patients with chronic hepatitis C: increased end-of-treatment virological responses but absence of long-term benefit.

BACKGROUND AND AIMS: The low efficacy of interferon monotherapy and data from viral kinetic studies led us to evaluate the efficacy of interferon administered daily in chronic hepatitis C. PATIENTS AND METHODS: Thirty-eight naïve patients with chronic hepatitis C and active liver disease randomly received 3 or 5 MU IFN-alpha daily for 1 month, followed by the same dose three times a week for 11 months. Results were compared to a three-times-a-week scheme of 3 MU IFN-alpha for 1 year. RESULTS: At the end of the induction period, 27 out of 38 (71%) patients had cleared HCV-RNA with a significantly higher rate in the 5 MU than in the 3 MU group (17 out of 18 or 94% vs. 10 out of 20 or 50%, P=0.003). The end-of-treatment virological response rate was 66% (25 out of 38) in the induction groups and 40% (10 out of 25) in the control group (P=0.04). Six months after completion of therapy, the sustained response rate dropped to 29% (11 out of 38) compared to 28% (7 out of 25) in the standard regimen. CONCLUSIONS: In chronic hepatitis C, treatment with 5 or 3 MU IFN-alpha daily during the first month of a standard IFN regimen leads to significantly increased end-of-treatment virological responses, but long-term responses are similar to those of standard IFN monotherapy.

Oral ganciclovir treatment in chronic hepatitis B virus infection: a pilot study.

BACKGROUND/AIMS: Ganciclovir is a nucleoside analogue with an excellent safety record; it is effective against cytomegalovirus infection in both its intravenous and its oral form. Intravenous administration of ganciclovir is active against hepatitis B virus but the efficacy of oral ganciclovir is unknown. The aim of this study was to evaluate the tolerability and primary efficacy in reducing HBV DNA levels and liver enzymes of 2 dosing schedules of oral ganciclovir in HBeAg-positive and -negative patients with chronic hepatitis B. METHODS: Oral ganciclovir was administered to 15 consecutive patients with active chronic hepatitis B (age 43+/-12 years; 73% males; seven HBeAg-positive and eight negative; no cirrhosis) in a pilot, phase I, open-label study. Before treatment, all patients were screened for 8 weeks to ascertain the persistence of biochemical and virological activity, and then randomized to receive 3 g (eight patients), or 6 g (seven patients) of oral ganciclovir daily for 8 weeks; following therapy, they were closely observed for 8 more weeks. RESULTS: Baseline HBV DNA declined by 99% or 2 log10 at the end of treatment (405.0 vs 3.9 MEq/ml, respectively) and in four patients serum HBV DNA became undetectable by the Monitor assay. Oral ganciclovir suppressed HBV equally well in HBeAg-positive and -negative patients, and the 3- and 6-g daily dose regimens were equally effective. The pre-treatment viral load, however, was a determinant of response, with patients in the lowest quartile of baseline HBV DNA levels responding significantly better than those in the upper quartile (3.0 vs 0.6 log10 respectively, p=0.002). Serum alanine aminotransferase levels became normal or declined in most patients. Oral ganciclovir was very well tolerated. Within 8 weeks after stopping medication, a relapse in serum HBV DNA levels occurred in nine of the 15 patients (60%). CONCLUSIONS: These findings suggest that ganciclovir administered orally at a dose of 3 g can achieve sufficient suppression of HBV replication. This dose, and even higher doses, are well tolerated and could be used as an alternative or in combination with other antivirals for the treatment of chronic hepatitis B.

Neurovisual impairment: a frequent complication of alpha-interferon treatment in chronic viral hepatitis.

Following our earlier observation of clinically evident optic tract neuropathy in patients receiving low-dose interferon (IFN) therapy, we prospectively evaluated 53 consecutive patients treated for chronic hepatitis B or C with a median dose of 3 MU of IFN-a2b thrice weekly. Measurements included routine ophthalmologic evaluation and recordings of visual evoked responses (VER), electroretinograms (ERG), visual acuity, and visual fields, before, at the end of IFN treatment, and at follow-up visits. Baseline P100 latencies of VERs (base-VER) were abnormally prolonged in 24 patients (32 of 106 eyes, 30.2%); age was the only significant covariate associated with increased risk for an abnormal base-VER by multiple logistic regression (relative risk [RR] 5.3 per each 5-year increase in age). In 45 patients (74 eyes) with normal baseline P100 latencies, the end-of-treatment VERs (end-VER) were significantly prolonged compared with baseline, becoming abnormal in 11 (15 of 74 eyes, 20.3%) (138.8+/-8.7 vs. 117.7+/-5.2 ms, P < .001). This subgroup had older age (59.1+/-11.0 vs. 47.5+/-15.3, P=.007) and reduced visual sensitivity compared with their own pretreatment measurements (24.5+/-1.6 vs. 23.0+/-1.2db, P=.019). Changes of end-VERs by age had a sigmoid distribution with a steep increase of values beyond the 5th decade (R2=.326, P < .001). In a logistic regression model, significant predictors of abnormal end-VERs were, patients' age (RR 5.6 per each 5-year increase), presence of hepatitis B virus (HBV) infection (RR 15.1 compared with hepatitis C virus [HCV] infection) and serum cholesterol levels above 240 mg% (RR 7.1 compared with values < 240 mg%). Subconjunctival hemorrhages were seen in 2 cases and funduscopic examination revealed cotton wool spots in one other. ERG recordings and the P100 amplitude remained unchanged. After stopping IFN, the treatment-associated neurovisual abnormalities reversed to normal in 7 patients (10 of 15 eyes) and persisted in 5 (5 of 15 eyes, 33.3%) for up to 37 (median 7.3) months observation, all patients remaining clinically asymptomatic. In conclusion, subclinical neurovisual impairment is a frequent, largely unrecognized complication of low-dose IFN therapy, and patients with chronic hepatitis B and older age appear to be most susceptible. This apparently innocuous complication is long lasting, possibly irreversible in some patients, with yet undetermined consequences on visual function.

Biochemical and virological outcome of patients with chronic hepatitis C treated with interferon alfa-2b for 6 or 12 months: a 4-year follow-up of 211 patients.

To compare two interferon (IFN) schedules for the treatment of chronic hepatitis C, we followed 211 patients who received 3 million units IFN-alpha2b thrice weekly for either 6 months (group 1; 85 patients) or 12 months (group 2; 126 patients), with a median follow-up of 3.4 (0.1-8.4) and 4.2 (0.7-8.7) years, respectively. The biochemical and virological responses at the end of treatment were 34.1% and 16.5% versus 62.7% and 41.2% for the 6- and the 12-month regimens, respectively. Late biochemical responses (after the third month of treatment) occurred in 30.6% of responding patients, and they were not particularly associated with an adverse long-term treatment outcome. In a multivariate analysis, patients with a primary response were significantly more frequently infected with a non-1b HCV genotype (relative risk [RR]: 14.4), had been treated for 12 months (RR: 6.0), and had an early stage of liver fibrosis (RR: 5.2). Baseline serum HCV-RNA and ferritin levels also bore a significant, though weaker, association with a primary response. Using a set of pretreatment variables in a model of discriminant analysis, we could correctly predict the long-term virological outcome in 86.6% of the individual cases. At the end of follow-up, a biochemical and virological sustained response was observed in 14.1% and 11.8% versus 40.5% and 31% of groups 1 and 2, respectively. Significant predictors of a virological sustained response were a virological primary response (RR: 41.2) and the pretreatment level of serum HCV-RNA (RR: 10.3 per each 10(6)-Eq/mL decrease). Patients with a "good treatment profile," including an early stage of liver fibrosis, a non-1b genotype and serum HCV-RNA <0.35 x 10(6) Eq/mL, had a 66.7% rate of observed virological SR, compared with a zero response for those with the opposite, a "bad treatment profile." We conclude that a 12-month IFN treatment, along with a non-1b genotype and the absence of advanced stage of fibrosis, are the main determinants for the induction of a virological primary response in chronic hepatitis C. Such response, along with a low pretreatment serum HCV-RNA level, are the main predictors for a 4-year virological response to IFN.