Long-Term Clinical Remission Induced by Corticosteroid Withdrawal Therapy (CSWT) in Patients with Chronic Hepatitis B Infection: A Prospective Randomized Controlled Trial—CSWT with and Without Follow-Up Interferon-α Therapy

The effectiveness of corticosteroid withdrawal therapy (CSWT), with or without follow-up interferon- (IFN-), has not been reported for HBe antigen (HBeAg) -positive patients with chronic hepatitis B. We conducted a prospective randomized controlled trial in 42 patients with HBeAg- and HBV-DNA-positive chronic hepatitis B (HBV genotype C: 38 patients) to assess the possible additive effect of follow-up IFN- after CSWT compared with CSWT alone. HBeAg seroconversion rates in the CSWT-alone and the combination group were 11.1% vs 11.8% at 24 weeks, 27.8% vs 12.5% at 52 weeks, 33.3% vs 18.8% at 76 weeks, and 38.9% vs 18.8% at 104 weeks, respectively. The final HBeAg seroconversion rates after CSWT alone were twice those following combination therapy. We conclude that CSWT alone is a very short-term treatment of just three weeks that may be more effective for long-term clinical remission than CSWT followed by IFN- in Japanese genotype C-dominant hepatitis B patients.     

Combination Therapy of Active HBsAg Vaccination and Interferon-α in Interferon-α Nonresponders with Chronic Hepatitis B

Treatment with interferon- leads to cessation of viral replication in 30–40% of patients with chronic hepatitis B. Preliminary data suggest that therapeutic vaccination in patients with chronic HBV infection may be beneficial. The present trial was conducted to assess the efficacy of combination therapy of interferon- with HBsAg vaccination in patients who previously failed to respond to interferon- alone. Eighteen patients positive for HBsAg and HBeAg were included. Mean ALT was 81 ± 23 units/liter and 7 (39%) patients had HBV-DNA levels >2000 pg/ml. Patients received 5 million IU interferon- 2b (Intron A) thrice weekly for six months and recombinant HBsAg (Gen H-B-Vax) at the beginning and 4 and 12 weeks after initiation of interferon therapy. No serious side effects were seen during the trial period. Loss of HBeAg was seen in 39% (7/18), HBV DNA was undetectable in 50% (9/18), and ALT was normal in 56% 10/18) of patients six months after completion of therapy. Simultaneous administration of interferon- and HBsAg vaccination in patients previously not responding to interferon alone appears to be safe, well-tolerated, and it achieved response rates similar to or even higher than interferon in treatment naive patients. This combination therapy seems to offer a new and promising approach for patients with chronic hepatitis B virus infection.     

Differences Between Interferon-α and-β Treatment for Patients with Chronic Hepatitis C Virus Infection

To compare virological, biochemical, and immuneresponses to human lymphoblastoid interferon(IFN-) and human fibroblast interferon(IFN-) in patients with chronic hepatitis C virus(HCV) infection, 120 patients were randomly assigned to threegroups (group A, 60 patients receiving IFN-, 6million units (MU) once a day, daily for one month andthrice weekly for five months; group B, 40 patients receiving 6 MU IFN- once a day daily fortwo months; and group C, 20 patients receiving 3 MUIFN- twice a day (6 MU/day) daily for two months).Serum soluble interleukin-2 receptor (sIL-2R) and interleukin-6 (IL-6) levels were measured byenzyme-linked immunosorbent assay. Patients withsustained clearance of serum HCV RNA detected bypolymerase chain reaction (PCR) at six months after IFNtreatment were defined as having complete response to IFNtreatment. A low level of HCV RNA (10^-4copies/50 mul, measured by competitive PCR) and HCV RNAof genotype 2a were favorable factors for a completeresponse to both IFNs. Complete response in group Atreatment was strongly associated with early HCV RNAclearance, in contrast with group B. A significantlyhigher HCV RNA negativity at the second week from start of treatment was noted in group C (80.0%),compared with groups A (41.6%) and B (27.5%). sIL-2Rlevels rose in each group during IFN administration. Ingroup C, alanine aminotransferase (ALT) and IL-6 levels were remarkably elevated. These findingsindicate that timing of serum HCV RNA negativity insustained response differs between IFN- andIFN- administrations and that early HCV RNAclearance was induced by twice-a-day IFN-treatment.     

Randomized Trial Assessing Gastric Emptying in Patients with Chronic Hepatitis C During Interferon-α or -β Therapy and Effect of Cisapride

We examined the effects of interferon- or - therapy on gastric emptying and digestive symptoms. The effects of cisapride on gastric emptying and digestive symptoms were also evaluated. The subjects were 48 patients with chronic hepatitis C. All patients were randomly assigned to one of four groups (A, interferon- group; B, interferon- and cisapride group; C, interferon- group; D, interferon- and cisapride group). Gastric emptying was measured before initiation of interferon therapy and two weeks after initiation of therapy. The half-time of gastric emptying (T1/2) was calculated. The T1/2 ratio was calculated by dividing the T1/2 after interferon therapy by the T1/2 before interferon therapy. Digestive symptom scores were determined at the time of the gastric emptying tests. The T1/2 after interferon therapy was higher than that before therapy in groups A and C (P = 0.002 and 0.059, respectively). The digestive symptom score after interferon therapy was higher than that before therapy in groups A and C (P = 0.012 and 0.093, respectively). The T1/2 ratio in group B was significantly lower than that in group A (P = 0.021), and the T1/2 ratio in group D was lower than that in group C, but the difference did not reach statistical significance (P = 0.057). Interferon- is associated with a greater delay in gastric emptying and a higher symptom score than is interferon-. Administration of cisapride corrects the delayed gastric emptying and relieves associated digestive symptoms.     

Comparative Effects of Different Doses of Ribavirin Plus Interferon-α2b for Therapy of Chronic Hepatitis C: Results of a Controlled, Randomized Trial

Compared to either drug alone, therapy with the combination of ribavirin and interferon- leads to improved rates of response in patients with chronic hepatitis C. Side effects often mandate downward dose adjustment or cessation of therapy, and the optimal dose of ribavirin has not been established. The aim of this study was to learn whether 600 mg ribavirin per day would prove as efficacious as 1000–1200 mg/day when combined with interferon (3 million units thrice weekly) for therapy of patients previously treated with standard interferon who had failed to respond or who had relapsed. We enrolled 69 patients with chronic hepatitis C and compensated liver disease: 45 were men, 65 were Caucasian, 48 were infected with genotype 1 hepatitis C virus. By random assignment, 35 received 600 mg ribavirin/day (group A), whereas the other 34 received 1000 mg (75 kg body wt) or 1200 mg/day (>75 kg body wt) (group B). At baseline, the two groups were well matched for demographic and laboratory features. In both groups, mean serum levels of alanine aminotransferase (ALT) and hepatitis C viral (HCV) RNA levels fell promptly and remained significantly lower than baseline throughout 24 weeks of therapy. There was no significant difference in mean levels of ALT or HCV RNA during therapy or at the end of follow-up (24 weeks after cessation of therapy). At the end of 24 weeks of posttherapy follow-up, 12 patients in each group had undetectable HCV RNA in serum, whereas 11 (31%) in group A and 9 (26.5%) in group B had normal serum ALT levels. The lower doses of ribavirin (group A) were tolerated better. %In conclusion, in previous nonresponders or relapsers to interferon done, combination therapy with interferon-_2b (3 MU thrice weekly) + 600 mg ribavirin/day is tolerated better and is as effective as interferon plus higher (standard) doses of ribavirin (1000–1200 mg/day).     

Tolerance and Antiviral Effects of High-Dose Interferon-α B/D in Patients with Chronic Hepatitis B

A novel recombinant interferon- B/Dhybrid was applied to assess tolerability, antiviraleffect, and biological activity in chronic hepatitis B.The study was designed as an open nonrandomized trial. Treatment comprised a two-week run-in phasewith 16 MU three times a week followed by 14 weeks with64 MU three times a week (or 48 MU if toxicity occurredwith 64 MU). Total follow-up was 36 weeks. Nineteen patients were included; three discontinuedtreatment during the run-in with 16 MU. Fourteen of 16patients had 14 weeks of treatment with 32 MU threetimes a week. Fourteen dose reductions were necessary in nine patients. The adverse experienceprofile was similar to other interferon-s.HBV-DNA decreased using all doses studied. HBV-DNAbecame undetectable in five patients, two of whom hadHBeAg seroconversion. No HBsAg seroconversion was observed. It isconcluded that interferon- B/D is well toleratedin high doses. The anti-viral effect starts at at least16 MU three times a week.     

A Randomized, Controlled Study of Thymosin-α1 Therapy in Patients with Anti-HBe, HBV-DNA-Positive Chronic Hepatitis B

No consistently effective therapy is yet available for the treatment of chronic HBsAg, anti-HBe, HBV-DNA-positive hepatitis. A multicenter trial has shown that the response rates are not significantly different when patients with anti-HBe-positive hepatitis are treated with six-month course of thymosin-₁ or of interferon-. However, since among these patients, interferon's real efficacy is still debated, with sustained biochemical response achieved in only a few of the treated patients, we conducted this controlled study to investigate the safety and efficacy of thymosin-₁ as compared with no treatment. Forty-four chronic hepatitis B virus (HBV) carriers, who were anti-HBe- and HBV-DNA-positive, were randomized, with stratification for the presence of cirrhosis at baseline liver biopsy, to receive either thymosin-₁ at a dose of 900 g/m² twice a week for six months or no treatment. At entry, both groups of patients were comparable for sex, age, liver histology, ALT, IgM anti-HBc, and HBV-DNA levels. Forty-two patients were followed-up for 20 months (median; range 12–32 months) after completion of therapy: one dropped out, and one developed hepatocellular carcinoma at six months. Thymosin-₁ treatment had no side effects. Six months after the end of the therapy, HBV-DNA was negative and ALT had normalized in 14% of treated cases and in 4.5% of control group, while IgM anti-HBc was negative (<0.200) in 14% of the treated patients and in 4.5% of the controls. Among the treated patients, the median ALT levels stayed significantly lower compared to the pretreatment values during the treatment period and six months of follow-up. During the first year, there were six flares of hepatitis in the control group and five among the treated patients (P = NS), yielding a per year average of 0.3 and 0.23 flares per patient, respectively. Among the treated patients, median IgM anti-HBc levels were low with respect to baseline values 4–10 months after treatment started. None became HBsAg negative. In conclusion, these results indicate that, in anti-HBe, HBV-DNA-positive chronic hepatitis B, thymosin-₁ therapy alone does not increase the response rate, but may contribute to reduce the immune-mediated liver cell necrosis as indirectly assessed by ALT and IgM anti-HBc levels.     

Effect of Combined Interferon-α Induction Therapy and Ribavirin on Chronic Hepatitis C Virus Infection: a Randomized Multicentre Study

Background: The efficacy of interferon- α (IFN) induction in combination with ribavirin for chronic hepatitis C virus (HCV) infection is not known. Methods: A total of 256 treatment-naive HCV RNA-positive patients with biopsy-confirmed chronic hepatitis were enrolled in a randomized multicentre study. The patients received either standard combination therapy with 3 MIU interferon- α 2b thrice weekly for 26 weeks or 6 MIU interferon- α 2b daily for 4 weeks and 3 MIU 3/7 days for 22 weeks. All patients received ribavirin 1000 mg or 1200 mg (weight dependent) daily during the 26-week treatment period. Patients were monitored for HCV RNA during and following treatment. Results: The sustained virological response rates (26 weeks after end of treatment) were 54% and 47% for patients receiving IFN induction/ribavirin and standard IFN/ribavirin, respectively ( P = 0.35). Among patients infected with genotype 1a/1b, the sustained response rates were 32% and 35%. In patients infected with genotype 2b/3a IFN induction/ribavirin led to a sustained response rate of 80% as compared to 65% in the standard combination therapy group ( P = 0.073). Steatosis was more frequently seen in liver biopsies from patients infected with genotype 3a as compared to genotypes 1a/1b. Among genotype 1a/1b infected patients, steatosis was a highly significant predictor of failure to achieve sustained virological response. Logistic regression analysis (multivariate analysis) showed that independent predictors of sustained virological response were low age, female gender, genotype 2b/3a and HCV RNA negativity at 2 weeks. Conclusions: IFN induction in combination with ribavirin does not increase the sustained virological response rate among patients infected with HCV. Absence of steatosis is an independent predictor of sustained virological response in patients infected with genotypes 1a/1b.     

Endogenous Interferon-α Concentration and Outcome of Interferon Treatment in Patients with Chronic Hepatitis C

To verify its value with regard to the outcomeof therapy in chronic hepatitis C, seruminterferon- (IFN) was measured by ELISA in 70patients (43 male, 27 female) with chronic hepatitis C,treated with IFN 9 MU/week subcutaneously for up to oneyear. Serum IFN was detectable in 49/70 patients, 16 ofwhom had IFN values >125 pg/ml. Only 1/22 patientswho maintained a sustained response six months after the end of treatment had pretreatment serum IFN> 125 pg/ml, in comparison to 15/48 patients who didnot respond or who relapsed ( 6.1, P < 0.02). Atmultivariate analysis the predictive value of serum IFN was independent of age, sex, presence ofcirrhosis, infection by genotype 1b (improvement 7.1, P < 0.01). In patients with chronic hepatitis C,measurement of serum IFN at baseline might be useful for the selection of patients with higherprobability of long-term response.     

Extracorporeal Photopheresis Alone and with Interferon-α2a in Chronic Hepatitis C Patients Who Failed Previous Interferon Therapy

Extracorporeal photopheresis (ECP) is approvedfor treatment of cutaneous, T-cell lymphoma. Evidencesuggests that ECP can induce an immune response againsttumor antigens expressed by malignant T lymphocytes. We theorized that if HCV-infected PBMCs expressviral antigens, ECP could demonstrate antiviral activityby eliciting an immune response against these antigens.Fifteen cirrhotic patients with genotype-1 HCV, who had previously relapsed or notresponded to interferon- (IFN-) therapywere stratified by their HCV RNA titer into one of threetreatment groups: (1) ECP alone, (2) ECP + 3 MIUIFN-_2a subcutaneously three times a week and (3) ECP+ 6 MIU IFN-_2a subcutaneously threetimes a week. All patients received treatment for 24weeks. Group 1 had no significant decrease in HCV RNA.Two patients in group 2 had undetectable HCV RNA at the endof treatment. One patient in group 3 had undetectableHCV RNA at the end of treatment. However, HCV RNA wasdetected in all three patients during follow-up. ECP alone or with IFN- was welltolerated. ECP alone demonstrated no clear antiviralactivity. The combination of ECP and IFN-resulted in an end-of-treatment response (ETR) in threeof 10 patients. All responders had elimination of serum HCV RNAby three months, although no patient had a sustainedresponse. More intensive therapy for a longer durationmay result in sustained responses. A multicenter trial is now underway.     

Pegylated Interferon α Therapy in Chronic Delta Hepatitis: A One-Center Experience

Background:

The only established therapy for chronic viral delta hepatitis, the most severe form of viral hepatitis is treatment with pegylated-interferon α (Peg IFN α).

Objectives:

In this study, we aimed to determine the efficacy of pegylated-interferon α 2a (Peg-IFN α 2a) and 2b (Peg IFN α 2b) in the treatment of patients infected with chronic delta hepatitis virus.

Patients and Methods:

The sample size was based on available patients potentially to be recruited. Data of 63 patients receiving either Peg IFN alpha 2a or Peg IFN alpha 2b were retrospectively assessed in the present cohort study performed in Turkey. Of 56 patients completed the study, 41 received Peg IFN α 2a and 15 received Peg IFN α 2b for 12 months. Patients were evaluated for biochemical and virological responses at the end of given treatment and six months after the treatment.

Results:

Stage of fibrosis was found high in both groups (85.4% vs. 86.7%), while cirrhosis was higher in the group of Peg IFN α 2b (53.3% vs. 34.1%). At the end of treatment, either hepatitis delta virus RNA (HDV RNA) alone or both HDV RNA and hepatitis b virus DNA (HBV DNA) had negative results in 32% of patients. Although HDV RNA negativity was sustained in 30.3% of patients, negativity of both HDV RNA and HBV DNA was decreased to 19.6% six months after completion of the treatment. HBV DNA became positive in one third of patients with response at six months after completion of the treatment (10.7% of all patients). HDV RNA negativity at month six was found as a predictor of positive response. No significant difference was found between Peg IFN α 2a and Peg IFN α 2b for virological response rate.

Conclusions:

Treatment with Peg IFN α achieved a sustained negativity of HDV RNA in about one third of patients. Duration of Peg IFN α therapy might be prolonged to at least 24 months or more to prevent the occurrence of Hepatitis B virus (HBV) relapse encountered six months after completion of the treatment.     

Activation of Tumor Necrosis Factor-α System in Chronic Hepatitis C Virus Infection

Tumor necrosis factor- (TNF-)plays a central role in the host's immunomodulatoryresponse to infective agents. To evaluate theTNF- system in patients with chronic hepatitis Cvirus (HCV) infection, plasma, serum, and peripheral bloodmononuclear cells (PBMC) were prospectively collectedfrom 53 patients and 33 healthy control subjects.Circulating TNF- and TNF receptors were assayed by their respective enzyme immunoassays. Inaddition, TNF- mRNA was quantitated in PBMC usinga branched DNA assay, and production of TNF- byPBMC with and without lipopolysaccharide was also assessed. Patients with chronic HCV infectionhad a higher level of circulating TNF- comparedto healthy control subjects (9.62 ± 6.01 vs 3.66± 1.23 pg/ml, P < 0.001). They also had highercirculating levels of TNF receptors compared to control(CD120a: 3323 ± 1267, pg/ml, N = 49 vs 1855± 422 pg/ml, N = 33, P < 0.001; CD120b: 1290± 650 pg/ml, N = 51, vs 863 ± 207 pg/ml,N = 33, P < 0.001). Plasma TNF- level correlated with circulatingCD120a (r = 0.52, N = 49, P < 0.001) and weakly withCD120b (r = 0.32, N = 51, P = 0.02). Plasma TNF-also correlated with markers of hepatocellular injury, including ALT (r = 0.34, N = 53, P = 0.01) and-GST (r = 0.31, N = 43, P = 0.042), but not withserum HCV RNA levels. There was no difference in theTNF- mRNA levels in PBMC between patients with chronic HCV infection (1.4 ± 1.9units/106 cells, N = 8) and healthy control subjects(2.1 ± 1.4 units/106 cells, N = 8, P = NS). Therewas also no difference in the spontaneous production ofTNF- by PBMC (1 × 10⁶ cells/ml)between patients with chronic HCV infection (14.2± 36.5 pg/ml, N = 11) and healthy subjects (11.9± 14.0 pg/ml, N = 14, P = NS). However, patientswith chronic HCV infection produced more TNF- upon stimulation withlipopolysaccharide compared to healthy control subjects(1278 ± 693 pg/ml, N = 11, vs 629 ± 689pg/ml, N = 14, P < 0.05). These data indicate thatthe TNF- system is activated in patients with chronicHCV infection.     

Effectiveness of Leukocyte Interferon-α Treatment in Patients with Chronic Hepatitis C Not Responsive to Recombinant Interferon

Twenty-four patients with chronic active HCVinfection, nonresponders to a previous treatment cyclewith recombinant interferon- (r-IFNA), underwentretreatment with leukocyte (LE-) IFN-. This was administered at the dose of 3 MU threetimes a week, for either six months (group A) or 12months (group B). All patients were followed-up for afurther 12 months. ALT levels significantly (P <0.05) decreased in group A, with complete response inthree cases and a partial response in a further three atthe end of treatment. During follow-up all patientsagain showed increases in ALT values. In group B also ALT significantly (P < 0.05)decreased, with two complete and five partial responses.During follow-up, apart from two patients with partialresponses who relapsed, all maintained their initial response. At the end of treatment HCV RNA wasno longer detectable in complete responders of bothgroups, while it was found reduced in those partialresponders who maintained their response duringfollow-up. Partially responding subjects treated for sixmonths evidenced higher levels than those treated for 12months. IFN- retreatment could therefore beeffective in previously nonresponding patients, with a change in the type of interferon administeredand the use of higher dosages and/or longer treatmentperiods.     

Acetyl-L-Carnitine Supplementation During HCV Therapy With Pegylated Interferon-α 2b Plus Ribavirin: Effect on Work Performance; A Randomized Clinical Trial

Background:

The health status of employees with chronic hepatitis C has major implications for organizations and labour market.

Objectives:

To assess the effects of Acetyl-L-Carnitine administration on work productivity, daily activity, and fatigue in subjects with chronic hepatitis C treated with Pegylated-Interferon-α2b and Ribavirin.

Patients and Methods:

In this prospective, randomized, placebo controlled, double blind clinical trial, 30 subjects (Group A) with chronic hepatitis, received Pegylated-Interferon-α2b (1.5 mg/kg per week) plus Ribavirin and placebo, while 32 subjects (Group B) received the same dosage of Pegylated-Interferon-α2b plus Ribavirin plus 2g Acetyl-L-Carnitine twice per day, for 12 months. Work productivity loss, impairment in daily activities, presenteeism, absenteeism, have been assessed using the Work Productivity and Activity Impairment questionnaire. We also evaluated severity of fatigue, mental fatigue and physical fatigue.

Results:

Significant difference were observed in physical fatigue, mental fatigue and severity of fatigue, aspartate aminotransferase, alanine aminotransferase, and viremia after 12 months treatment. In Group B we observed a significant decrease of presenteeism and daily activity impairment after 6 months, 12 months and at follow up. A significant increase of work productivity was observed after 12 months and at follow up.

Conclusions:

Office workers with chronic hepatitis C, treated with Pegylated-Interferon-α2b plus Ribavirin, had work performance loss. In subjects treated with Acetyl-L-Carnitine supplementation we observed increased daily activity and reduced presenteeism and fatigue. Acetyl-L-Carnitinegroup had a smaller reduction of productivity comparing to placebo group.     

Pegylated Interferon-α Plus Ribavirin Therapy Improves Left Ventricular Diastolic Dysfunction in Patients With Chronic Hepatitis C Attaining Sustained Virological Response

Background

Pegylated interferon (pegIFN) in combination with ribavirin (RBV) has successfully improved the rate of sustained virological response (SVR) in chronic hepatitis C virus (HCV) infected individuals, which reduces the progression of the chronic liver disease. However, the influence of combination therapy (pegIFN/RBV) on cardiac function has yielded ambiguous results. The present study aimed to evaluate the effects of combination therapy with pegIFN/RBV on cardiac function of HCV-infected individuals with SVR.