Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B.

Current therapies for chronic hepatitis B (CHB) have a number of limitations, and better treatment options are needed. Peginterferon alpha-2a (40 kDa) is superior to conventional interferon alpha-2a in the treatment of chronic hepatitis C. This is the first report on peginterferon alpha-2a (40 kDa) in the treatment of CHB. In this phase II study, 194 patients with CHB not previously treated with conventional interferon-alpha were randomized to receive weekly subcutaneous doses of peginterferon alpha-2a (40 kDa) 90, 180 or 270 microg, or conventional interferon alpha-2a 4.5 MIU three times weekly. Twenty-four weeks of therapy were followed by 24 weeks of treatment-free follow-up. All subjects were assessed for loss of hepatitis B e antigen (HBeAg), presence of hepatitis B antibody (anti-HBe), suppression of hepatitis B virus (HBV) DNA, and normalization of serum alanine transaminase (ALT) after follow-up. At the end of follow-up, HBeAg was cleared in 37, 35 and 29% of patients receiving peginterferon alpha-2a (40 kDa) 90, 180 and 270 microg, respectively, compared with 25% of patients on conventional interferon alpha-2a. The combined response (HBeAg loss, HBV DNA suppression, and ALT normalization) of all peginterferon alpha-2a (40 kDa) doses combined was twice that achieved with conventional interferon alpha-2a (24%vs 12%; P = 0.036). All treatment groups were similar with respect to frequency and severity of adverse events. These results indicate that peginterferon alpha-2a (40 kDa) is superior in efficacy to conventional interferon alpha-2a in chronic hepatitis B based on clearance of HBeAg, suppression of HBV DNA, and normalization of ALT.

Sustained response to interferon-alpha2a monotherapy of young blood donors with minimal-to-mild chronic hepatitis C. The Donor Surveillance Study Group.

Subjects with minimal-to-mild chronic hepatitis C may suffer long-term consequences of hepatitis C virus (HCV) infection. Nonetheless, they are not candidates for antiviral treatment, mainly because little data are available concerning the efficacy and safety of therapy. Thirty-two HCV RNA positive individuals aged 18-45 years, who had a histological activity index score < or = 8 and alanine aminotransferase (ALT) levels < or = 1.5 times lower than the normal limit for at least 1 year, were prospectively enrolled among a cohort of 35358 candidate blood donors, and treated with 4.5 mega units (MU) of recombinant interferon-alpha2a (IFN-alpha2a) thrice weekly for 6 months, and for an additional 6 months if a virological response was observed. Twelve months after the completion of treatment, 13 of 31 evaluable patients were HCV RNA negative, accounting for a sustained response rate of 42%. Patients without fibrosis had a lower response rate than those with mild fibrosis (two of 14 vs 11 of 17; P=0.012). In responders, median aminotransferase levels were significantly lower after therapy than before (11.04 +/- 3.98 vs 27.3 +/- 12.32 U l-1, respectively; P < 0. 005). When the analysis was limited to the six responders whose pretreatment aminotransferase levels were consistently normal, this difference was still significant (9.33 +/- 4.12 vs 20.58 +/- 6.73 U l-1; P=0.002). In conclusion, a durable suppression of viraemia can be obtained by IFN monotherapy in a relatively high proportion of young subjects with minimal-to-mild chronic hepatitis C, especially when portal fibrosis is found on liver biopsy. The disappearance of viraemia always leads to a reduction in the degree of hepatocellular necrosis.

Chronic hepatitis C: interferon retreatment of relapsers. A meta-analysis of individual patient data. European Concerted Action on Viral Hepatitis (EUROHEP).

Relapse after interferon (IFN) therapy for chronic hepatitis C virus (HCV) infection occurs in 50% of patients after the initial response. The benefit of retreatment with IFN alone has not been assessed in large controlled studies. To assess the effectiveness and the tolerability of IFN retreatment and to identify the optimal second course regimen, we performed a meta-analysis of individual patient's data on a set of 549 patients (mean age 43.8 years; 12.2 SD, men: 65%) who had an end-of-treatment biochemical response to a first IFN course and then relapsed. Retreatment was started within 24 months after the end of the first course. Biochemical end-of-treatment responses (ETR) and sustained responses (SR) were observed in 405 of 549 (73.8%; 95% confidence interval [CI] 70.1-77.5) and in 124 of 549 (22.6%; CI 19.1-26.1) patients, respectively. One hundred seventy-five of 404 patients (43.3%; CI 38.6-48.2) developed an end-of-treatment, biochemical, and virological response when retreated. A biochemical and virological SR to retreatment occurred in 73 of 494 (14.8%; CI 11.7-18) patients. Thirty-two patients (5. 8%; CI 3.5-7.8) stopped retreatment for adverse effects. Biochemical and virological SR was predicted independently by logistic regression analysis using a negative HCV RNA at the end of the first cycle of IFN (P =.01) and by retreatment with a high IFN dose (P =. 03). Age, cirrhosis, genotype, and gamma-glutamyl transferase levels before retreatment were not significant by multivariate analysis. The excellent tolerability of IFN monotherapy retreatment makes it an option for patients who transiently cleared HCV-RNA during their first IFN course. Patients should be retreated with a high IFN dose regardless of the strength of the dose received during the previous course of treatment.

Retreatment of chronic hepatitis B e antigen-positive patients with recombinant interferon alfa-2a. The European Concerted Action on Viral Hepatitis (EUROHEP).

Fifty-seven patients with chronic hepatitis B, hepatitis B virus (HBV) e antigen (HBeAg) and HBV DNA positivity, and aminotransferase elevation despite a previous course of any type of adequate interferon alfa (IFN-alpha) therapy were included in a multicenter prospective randomized controlled trial. The objective of the study was to compare a second course of IFN-alpha therapy (9 million units [MU] of IFN-alpha-2a, Roferon-A, thrice weekly for 6 months) versus no therapy in terms of loss of HBV DNA and HBeAg. At the end of the study, a sustained clearance of HBV DNA and HBeAg was observed in 9 of the 27 (33.3%) patients who had received retreatment with IFN-alpha compared with 3/30 (10%) patients who spontaneously cleared these markers in the untreated control group (chi2 = 4.66, P =.031; odds ratio: 4.5, 95%; confidence interval: 1.1-18.9). None of the responders lost HBsAg. Patients retreated with IFN-alpha were more likely to have biochemical remission in association with HBV clearance (5/27, 18.5%) compared with untreated patients (1/30, 3. 3%; Fisher's exact test P =.09 ). Histological improvement in the liver necroinflammatory activity was observed among sustained responders to IFN-alpha retreatment, consisting of regression of the portal and periportal inflammation and of the piecemeal necrosis; there was no change in the degree of liver fibrosis. Side effects were similar to those previously reported during IFN-alpha treatment; these were mild and reversible on IFN-alpha discontinuation. None of the baseline features were associated with response by Cox's regression analysis. In summary, viremic patients with chronic HBeAg-positive hepatitis may experience disease remission following retreatment with IFN-alpha. Thus, retreatment with IFN-alpha may be considered a therapeutic option.

In vitro effect of amantadine and interferon alpha-2a on hepatitis C virus markers in cultured peripheral blood mononuclear cells from hepatitis C virus-infected patients.

The effects of amantadine (1-5 microM) and interferon alpha (IFNalpha)-2a alone (1000 IU/ml) and combined, have been studied in cultured peripheral blood mononuclear cells (PBMC) from 15 chronic hepatitis C patients and ten healthy donors. Amantadine itself did not affect cell viability and had minor effects on the response to mitogens by PBMC. Four patients (27%), but no donors, had hepatitis C virus (HCV) core and NS3-specific proliferative responses. Amantadine suppressed these responses in all cases and its antiproliferative effect was greater than that of IFNalpha (Mann-Whitney's U-test: P < 0.05 in both cases). All PBMC cultures from patients, but none from donors, were HCV RNA positive. Amantadine alone or combined with IFNalpha dose-dependently reduced HCV RNA content in individual PBMC (Wilcoxon's signed rank test: 1 microM, P < 0.05; 2 microM, P < 0.02; and 5 microM, P = 0.16) with respect to untreated cultures. In addition, 7, 13 and 20% of PBMC cultures became HCV RNA negative with 2 microM amantadine alone, IFNalpha alone and their combination, respectively. Finally, in contrast to IFNalpha, amantadine did not modify expression of 2',5'-oligoadenylate synthetase activity or the spontaneous or mitogen-stimulated IFNgamma and interleukin 10 production. In conclusion, these effects in PBMC from HCV patients suggest that the amantadine/IFNalpha combination might be considered a therapeutic option for treating chronic hepatitis C patients.

Antiviral activity of ganciclovir, 9-(1,3-dihydroxy-2-propoxymethyl) guanine against woodchuck hepatitis virus: quantitative measurement of woodchuck hepatitis virus DNA using storage phosphor technology.

BACKGROUND & AIMS: Ganciclovir is a nucleoside analogue active against cytomegalovirus. The compound has also shown in vitro and in vivo activity against duck hepatitis B virus. We investigated the ability of ganciclovir to inhibit another Hepadnaviridae, the woodchuck hepatitis virus, which is the most closely related with hepatitis B virus. We compared two different quantification methods of woodchuck hepatitis virus DNA. METHODS: We treated seven chronic woodchuck hepatitis virus carriers by daily intravenous injections of 5 mg/kg body weight of ganciclovir for seven consecutive days, and followed the animals for 3 weeks post therapy. In addition to traditional X-ray autoradiography, which is a semi-quantitative method, we evaluated woodchuck hepatitis virus DNA levels with storage phosphor technology. RESULTS: A reduction in serum woodchuck hepatitis virus DNA was observed during treatment in all animals regardless of pre-treatment viraemia levels when using x-ray films and phosphor storage technology. The latter method allowed calculation of mean values of average phosphor imager signals. When comparing the mean values (+/- 95% confidence intervals) before and during therapy, a significant decrease in woodchuck hepatitis virus DNA (80 to 100%) could be shown. After stopping therapy, virus DNA rebounded in all animals. CONCLUSIONS: Our results show that ganciclovir inhibits viral replication in woodchucks chronically infected with woodchuck hepatitis virus. No signs of toxicity were observed. After dot-blot hybridization, storage phosphor imaging was proven superior to X-ray autoradiography for measuring viral DNA. Storage phosphor technology is highly sensitive, quantitative and easy to handle. By comparing mean values and confidence intervals before and during therapy, treatment effects can be distinguished from natural fluctuations.

Treatment of woodchuck hepatitis virus infection in vivo with 2', -3'-dideoxycytidine (ddC) and 2',-3'-dideoxycytidine monophosphate coupled to lactosaminated human serum albumin (L-HSA ddCMP).

Dideoxycytidine (ddC) is a nucleoside analogue active against human immunodeficiency virus and with in vitro activity against human hepatitis B virus. We investigated the ability of ddC to inhibit one of the Hepadnaviridae, the woodchuck hepatitis virus and compared the results with the effect obtained by a conjugate of lactosaminated human serum albumin 2',-3'-dideoxycytidine monophosphate (L-HSA ddCMP). This compound specifically enters the hepatocyte via the asialoglycoprotein receptor. We treated five chronic woodchuck hepatitis virus carriers with intravenous injections of 0.5 mg/kg body weight of ddC for 5 consecutive days, and under the same protocol five woodchucks with 10.4 mg/ kg L-HSA ddCMP, a dose equivalent to 0.25 mg/kg of free ddC. A reduction of serum woodchuck hepatitis virus DNA (5-125 fold) was observed during therapy in three out of five animals receiving ddC and in two of the five animals treated with L-HSA ddCMP. In responding woodchucks, virus DNA levels rebounded immediately after stopping therapy. No signs of toxicity were observed during or after the course of therapy. These preliminary results of short-term treatment indicate that ddC has anti-viral activity against woodchuck hepatitis virus. When the dose was reduced by 50%, L-HSA ddCMP showed anti-viral activity to an even lesser degree.

Long-term titrated recombinant interferon-alpha 2a in chronic hepatitis C: a randomized controlled trial.

The efficacy and tolerability of 12-month treatment with titrated doses of recombinant interferon-alpha 2a (IFN-alpha 2a) in chronic hepatitis C were studied in 67 consecutively recruited patients randomly assigned either to a starting dose of IFN-alpha 2a 6 MU, subsequently adjusted to the serum alanine aminotransferase (ALT) response (n = 35), or to no therapy (n = 32; controls). End-of-treatment ALT levels were normal and hepatitis C virus (HCV) RNA was negative by nested polymerase chain reaction (PCR) in 17 (49%) treated patients compared to none of the controls (P < 0.001). During the 12 months after stopping treatment the number of patients who remained in remission was eight (23%) and one respectively (4%) (P = 0.031). Follow-up liver biopsy showed reduced hepatic inflammation in 80% of treated patients and in 29% of controls (P < 0.001). The eight sustained responders and 27 non-responders or relapsers received similar mean total doses of IFN (565 MU vs 545 MU) and had a similar incidence of anti-IFN neutralizing antibodys (13% vs 19%). Absence of cirrhosis was the only independent pretreatment parameter that predicted a sustained response. In conclusion, a mean cumulative dose of IFN 549 MU, titrated over 12 months, was well tolerated, and resulted in the long-term clearance of HCV RNA and normal ALT levels in 23% of patients.

Continuous versus intermittent therapy for chronic hepatitis C with recombinant interferon alfa-2a.

BACKGROUND/AIMS: Prolonged interferon administration to patients with chronic hepatitis C, although increasing the sustained response rate, is poorly accepted and may favor drug resistance. A pulse-treatment schedule would be preferred for compliance and costs. METHODS: One hundred thirty-five patients with chronic hepatitis C received 6 MU units of interferon alfa-2a, three times weekly, continuously for 9 months (group 1: 66 patients) or for two 3-month cycles, separated by 6 months pause (group 2: 69 patients). RESULTS: At the end of therapy, 25 of 54 patients of group 1 (46.3%) and 28 of 60 of group 2 (46.7%) had normal serum aminotransferase levels. Six months after the end of treatment, sustained responders were still similar in the two groups (11 or 16.7% vs. 7 or 10.1%; NS). A loss of response before the end of therapy was seen in 10 patients of group 1 and 6 of group 2; interferon-neutralizing antibodies developed in 1 of 7 and 6 of 6 of such patients, respectively. CONCLUSIONS: The intermittent administration of interferon alfa-2a to patients with chronic hepatitis C shows a sustained response rate comparable with that achieved with continuous treatment at the same dosage. Hepatitis breakthroughs during pulse therapy appeared to be limited to interferon neutralizing antibodies, whereas a prolonged, continuous treatment is more likely to induce other forms of interferon resistance.

In vitro studies of fleroxacin (Ro 23-6240), a new trifluorinated quinolone derivative.

The in vitro activity of fleroxacin (Ro 23-6240) against 441 bacterial isolates was compared with those of ciprofloxacin, ofloxacin, amoxycillin, cefadroxil, cefuroxime and tobramycin. An agar dilution method was used for the determination of minimal inhibitory concentrations (MICs). Ciprofloxacin showed the highest activity against the Enterobacteriaceae, 95% of the isolates were inhibited by 0.06 mg/l, but fleroxacin and ofloxacin were also highly active (MIC 90% = 0.5 and 0.25 mg/l, respectively). Ciprofloxacin was the most active agent against Pseudomonas aeruginosa (MIC 90% = 0.12 mg/l), whereas the activities of fleroxacin and ofloxacin were more variable. Tobramycin was highly active against P. aeruginosa, 75% of the isolates were inhibited by 0.5 mg/l or less. The quinolones and tobramycin exhibited high activity against Acinetobacter calcoaceticus, the great majority of the isolates being susceptible to 0.5 mg/l or less of any agent. All the quinolones showed high activity against Staphylococcus aureus, but fleroxacin was less active against Staphylococcus epidermidis and Staphylococcus saprophyticus than were the other derivatives. The pneumococcal and streptococcal isolates were markedly less susceptible to fleroxacin than to the other quinolones tested (MIC range 4-32 mg/l). All isolates of Haemophilus influenzae and Neisseria gonorrhoeae were inhibited by the lowest concentration of the quinolones employed in the study (0.03 mg/l). Cefuroxime was also highly active against N. gonorrhoeae, whether the strains were beta-lactamase-producing or not, but was somewhat less active against H. influenzae. The quinolones displayed moderate and similar activity against Bacteroides fragilis isolates (MIC range 1-16 mg/l). The MICs of fleroxacin against gram-negative rods were generally 4-16 times higher at pH 8.8 than those obtained at pH 5.8 and 7.3. The activity against gram-positive cocci was not markedly influenced by changes in pH.