Current Pharmaceutical Design - Volume 8, Issue 11, 2002

Infection with the hepatitis B virus has switched over the last 20 years from the classical HBeAg positive serologic pattern to a HBeAg negative form that is linked, in the Mediterranean basin, with the epidemiologic replacement of the causative wild-type of virus B with mutant variants, whereby mutations in the core-promoter and in the pre-core region prevent the secretion of HBeAg. The wild-type pattern of infection (characterized by relatively high steady level ALT, high HBV-DNA levels and clinically overt liver disease) responds relatively well to Interferon: 3 to 5 mega units daily or 10 mega units every other day for 16 weeks induce anti-HBe seroconv ersion, normalize the ALT and possibly also eliminate the HBsAg in some 40% of the adults with a minimal (7%) risk of relapse. However, the mutant type infection (anti-HBe positive / HBe Ag negative) is less responsive to Interferon; this has led to the search for novel nucleoside analogues which has currently culminated in the advent of Lamivudine. This competitor of cytidine is 80% bioavailable and devoid of side-effects at the oral dose of 100 mg daily; tolerance continues for therapies up to 3 years. Lamivudine therapy shares with Interferon a rapid decline of ALT accompanied by improvement of histology; at variance with Interferon there is a delayed accumulating seronconversion to anti-HBe and the switch to anti-HBs is rare. Over the long term its activity is abolished by the emergence of specific viral mutations (YMDD mutants) that rekindle the disease. The indications to Lamivudine therapy in HBeAg negative chronic hepatitis B are currently under investigation. Lamivudine is highly efficacious in preventing HBV reinfection in liver transplants.

Treatment of chronic hepatitis C (HCV) was based on Interferon alpha IFNa administration three times a week (tiw), but the efficacy of this schedule (evaluated as virological sustained response) was limited to less than 20% of patients. The combination of Ribavirin and IFN is known to be significantly more effective than IFN monotherapy in naive and relapser patients but it induces a sustained response only in 41% of patients and in less than 30% of patients infected with genotype 1. Several studies on IFN and viral kinetics suggested that daily administration of IFN may increase the sustained response rate. The development of pegylated IFNs, characterized by a long half life and weekly administrability, seems to induce a significant improvement in the treatment of chronic hepatitis particularly in combination with Ribavirin. In order to further improve the efficacy of treatment in chronic hepatitis C (HCV) many controlled clinical trials evaluating Amantadine, Micophenolate, a1 Thymosin, Maxamine (in combination with IFN or pegylated IFN), Protease, Helicase, Polymerase inhibitors, Ribozymes and anti-sense olygonucleotides, and Interleukin 10 are in progress. Finally anti-HCV vaccine development seems to be very promising.

Approximately 60% of all patients with chronic hepatitis C (C-HCV) treated with standard interferon (IFN) treatment, i.e. combination of recombinant a IFN and ribavirin (RBV), are refractory to treatment. Many factors should be responsible for HCV persistence after antiviral treatment. Beside the well-known importance of some factors such as viral heterogeneity, co-infections with Hepatitis B Virus (HBV) or Human Immunodeficiency Virus (HIV), presence or absence of fibrosis, age, sex, iron overload, a greater attention is being paid to the study of viral kinetics. Observing the trend of the slope of viral decline, already after a few hours antiviral administration, it is possibile to predict the sustained virologic response and therefore to optimize therapy.As for alternative therapeutics, re-treatment with IFN alone was excluded considering the very disappointing results, whereas it seemed that the combination IFN plus RBV could recover up to 30% of the patients.Later both randomized trials and two metanalyses have demonstrated that this option is disadvantageous from the cost-effectiveness point of view since 14 patients need to be treated to obtain one responsive.The treatment combining IFN plus RBV and amantadine seems more promising.Recently trials with pegylated IFN have started with the aim to increase the therapeutical response in this category of HCV-positive patients.

Background: Alpha interferon (IFN) alone or in combination with Ribavirin (RBV) is the treatment of choice for HCV related chronic liver disease. There are many types of alpha IFN and to date only few reports are available comparing different types of alpha interferon. We run a randomised controlled trial with the aim to compare tolerability and efficacy of two different types of IFN: recombinant alpha 2b interferon (IFN-R) and leukocyte alpha n-3 interferon (IFN-L) at the same dosage of 3 MU subcutaneously thrice weekly for one year. Methods: one hundred sixty eight consecutive anti-HCV positive naive patients, 34 mild chronic active hepatitis (MCH), 81 moderate-severe hepatitis (MSCR) and 53 active cirrhosis (CIRR) that met the inclusion criteria were enrolled into the study. The diagnosis of HCV chronic liver disease was established by liver biopsy performed on patients with abnormal serum alanine aminotransferase (ALT) value for at least one year. HCV serology: all patients were tested for confirmatory test RIBA II, HCV-RNA, and identification of viral genotype. Patients were randomised to receive either IFN-R or IFN-L. Follow-up continued for at least two years after stopping treatment. Results: no significant differences were observed between the two groups of treatment as far as the incidence of side effects is concerned. Tolerability was good: only 11 in IFN-R and 8 patients IFN-L group respectively had to stop therapy due to side effects. The two types of IFN showed a comparable efficacy: an end of therapy response was observed in 34% of IFN-R and 30% of IFN-L patients; a sustained response was seen in 16% of IFN-R and in 19% of IFN-L patients. Conclusion: in the treatment of patients with chronic hepatitis C there was no statistically significant difference in tolerability and efficacy between the two IFNs tested.

The balance between T helper (h)1 and Th2 responsiveness seems to represent a key event in the evolution of hepatitis C virus (HCV) infection. In particular, Th1 cytokines [interleukin (IL-2) and interferon (IFN-γ)] have been demonstrated to mediate the antiviral immune response.Serum levels of Th1 cytokines (IL-2 and IFN-γ) as well as of Th2 products (IL-4 and IL-10) were determined in a group of HCV-positive patients before and after treatment with IFN-α and Ribavirin (RIB).Results indicate that responder patients exhibited increased levels of IFN-γ and IL-10, while this enhancement was not observed in non-responder patients. In this respect, the major effect exerted by the combined therapy with IFN-α / RIB could be represented by the attainment of a re-equilibrium between inflammatory (Th1) and antiinflammatory (Th2) mechanisms.In this framework, according to current literature, novel therapeutical approaches to treat HCV infection are represented by administration of recombinant IL-2 and IL-10.

Endotoxins or lipopolysaccharides (LPS), major components of the cell wall of Gram-negative bacteria, once released from the bacterial outer membrane bind to specific receptors and, in particular, to a membrane-bound receptor, the CD14 (mCD14) and the toll-like receptor 4 present on monocytes / macrophages. In turn, LPS-activated monocytes / macrophages release in the host tissue an array of so-called proinflammatory cytokines and, among them, Tumor Necrosis Factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8 and IL-12 are the major mediators.Before therapy (To) and at the end of 6-month interferon (IFN)-α / Ribavirin (RIB) treatment (T6), circulating endotoxin levels were measured in responder and non responder HCV+ patients.At T0, 57% of the non responders were endotoxin-positive and had, on average, 54 pg / ml of plasma LPS while in 50% of the responder patients endotoxin were found with an average of 29 pg / ml. At T6, in responders LPS were no longer detectable, while in 42% of the non responders LPS were found (average levels 45 pg / ml).In terms of serum cytokine concentration, at T6 IFN-γ levels when compared to those detected at T0 were increased in both endotoxin-positive and endotoxin-negative patients. However, at T6 IL-10 concentration was significantly increased only in the group of endotoxin-negative subjects (responder patients), in comparison to T0 values.The origin of endotoxemia in HCV+ patients seems to be multifactorial, likely depending on impaired phagocytic functions and reduced T-cell mediated antibacterial activity . In these patients, however, one cannot exclude the passage of LPS from the gut flora to the blood stream, owing a condition of altered intestinal permeability. At the same time, a less efficient detoxification of enteric bacterial antigens at the hepatic level should be taken into consideration.Finally, novel therapeutic attempts aimed to neutralize LPS in the host are discussed.

Between 1995 and 1997 we studied 100 patients with hepatocarcinoma (HCC) and cirrhosis. Of these 74 were males and 26 females with a mean age of 66 years. 13% patients were only HbsAg positive, 75% only anti-HCV positive, 6% HbsAg and anti-HCV and the etiology in 6% of cases was alcoholic. Alpha-foetoprotein was >400ng / ml in only 18% of cases and portal thrombosis was present in 12%. Mononodular HCC was observed in 63% of cases (small HCC in only 38%) and in 79% was localized to the right lobe. Of the mononodular types, 70% were shown by echography to be hypoechoic, 6% hysoechoic, 6% hyperechoic and 17% mixed patterns. Histologically, 49% were well-differentiated, 45% moderately-differentiated and 6%poorly-differentiated. No correlation was found between histologic pattern and number of nodules. Welldifferentiated HCC was found in 51% of mononodular types and in 46% of multinodular types. Moderatelydifferentiated HCC was detected in 46% and 43% respectively and poorly-differentiated HCC in 3% and 11%respectively. No correlation was found between number of nodules and the degree of Edmonson.

Background: In 1998, when data of a meta-analysis on tamoxifen in the treatment of hepatocellular carcinoma (HCC) had suggested a little advantage for this treatment, we published the results of a multicenter randomised controlled trial, that showed no survival benefit for tamoxifen vs. control. Here we report an updated analysis of the study results 4.5 years after the closure of enrollment.Methods: The study had a planned sample size of 480 patients. Patients with any stage HCC were eligible, irrespective of locoregional treatment. Tamoxifen was given orally, 40 mg/die, from randomisation until death.Results: 496 patients were randomised by 30 Institutions from January 1995 to January 1997. Information was available for 477 patients. As of July 2001, 374 deaths (78%) were recorded, and median survival times were 16 and 15 months (p=0.54), in the control and tamoxifen arm. Data were further analysed separately for advanced patients and for those eligible to potentially curative locoregional treatments: relative hazard of death for patients receiving tamoxifen was equal to 0.98 (95% CI 0.76-1.25) for the former group and 1.38 (95% CI 0.95- 2.01) for the latter. The prognostic score recently devised by our group (CLIP score) was, as expected, strictly correlated (p<0.0001) to the locoregional treatment received and strongly correlated with prognosis.Conclusions: the update of the present study confirms that tamoxifen is not effective in prolonging survivals, both in advanced patients and in those potentially curable and that the CLIP score is able to predict prognosis.