Treatment of chronic hepatitis C

Chronic hepatitis C entails a life-long risk of developing cirrhosis and hepatocellular carcinoma and eradication of the hepatitis C virus (HCV) is the only realistic approach for lowering the risk of disease progression. Treatment is indicated for patients with high transaminases and histologic signs of chronic hepatitis: 6-12 month therapy with 3-6MU interferon alfa thrice weekly combined with 1-1.2 grams ribavirin yielded up to 30% sustained virological responses (SVR). SVR raised up to 50% with pegylated interferons combined with ribavirin. Favourable predictors of response to the former treatment are genotype 2 or 3, less than 2 million copies of HCV, no or portal fibrosis at biopsy, age less than 40 yr and female gender. The same was true for the latter treatment, however, with body weight less than 82 kg replacing female gender. Six month treatment is enough for treating genotype 2 or 3 patients whereas 12-month therapy is indicated for the more resistant patients with genotype 1 or 4.98% cure of community-acquired acute hepatitis C was achieved with early treatment with daily doses of 5MU interferon, compared to a calculated 30% virus clearance occurring in untreated patients. Cost-effective stopping rules based upon early clearance of serum HCV-RNA, are under investigation. A cut-off equal or more than 2 log decrease in serum HCV-RNA at week 12, has 97% negative predictive value and 60% positive predictive value. Treatment could be optimized also by retreatment with combination therapy of relapsers and non-responders to monotherapy, with SVR rates of 50% and 25%, respectively. Difficult-to-treat patients include patients who have high genotype 1 and 4 viremia or coinfection with HIV or hepatitis B virus as well as patients who carry an organ graft. Extended treatment of virological non responders with pegylated interferons might slow down progression of hepatic fibrosis and prevent hepatocellular carcinoma.     

慢性病毒性肝炎研究进展

近年,慢性病毒性肝炎研究领域有较大进展,慢性乙型肝炎病毒（HBV）感染,虽然有了应用广泛、历史较久、且效果较好的疫苗,但迄今仍是世界范围肝硬化和肝癌的主要诱因。传染途径可经产道、性接触和非肠道途径（包括静脉吸毒、血制品等）。成年病人有少有变慢性,但一岁以下患儿90％变成慢性肝炎。慢性肝损伤的临床表现可以是轻微的炎症重到晚期肝硬化,程度不等。α干扰素（IFNα）是治疗活动性肝炎的产宰药物,单核苷酸类药物（lamivudine和adefovir）也具有同样的疗效。晚期肝病和肝癌患者可进行移植,但异常伴发移植物的感染。乙型肝炎免疫球蛋白和新型抗病毒药物联合应用,可降低移植物感染的严重性。丙型肝炎病毒（HCV）在20世纪后期感染了大约1％的世界人口。这中RNA病毒非经口传播,绝大多数病人变成慢性肝炎,约20％逐渐演变成肝硬化或肝癌。用IFNα和病毒唑（Ribavirin）联合治疗,约40％病人的病理表现有所改善。肝移植对某些病例是适宜的,但移植物感染仍是悬而未决的问题,新发现的庚型肝炎病毒（HGV）和TT病毒目前认为并不引起严重的肝损害。     

Interferon alfa with or without ribavirin for chronic hepatitis C: systematic review of randomised trials

ObjectiveTo assess the efficacy and safety of interferon alfa with or without ribavirin for treatment of chronic hepatitis C.DesignSystematic review of randomised trials on interferon alfa plus ribavirin combination therapy versus interferon alfa. Patients were naive (not previously treated with interferon), relapsers (transient response to previous interferon therapy), or non-responders (no response to previous interferon therapy).ResultsCompared with interferon, combination therapy reduced the risk of not having a sustained virological response for 6 months by 26% in naive patients (relative risk 0.74, 95% confidence interval 0.70 to 0.78), 33% in relapsers (0.67, 0.57 to 0.78), and 11% in non-responders (0.89, 0.83 to 0.96). Morbidity and mortality showed a non-significant trend in favour of combination therapy (Peto odds ratio 0.45, 0.19 to 1.06). Combination therapy significantly reduced the risk of not having improvement in results of histology by 17% in naive patients (0.83, 0.74 to 0.93) and by 27% in relapsers and non-responders (0.73, 0.66 to 0.82). The risk of treatment discontinuations was significantly higher after combination therapy (1.28, 1.07 to 1.52).ConclusionTreatment with interferon alfa plus ribavirin has a significant beneficial effect on the virological and histological responses of patients with chronic hepatitis C, irrespective of previous treatment. Combination therapy may therefore also be considered appropriate for relapsers and non-responders.

What is already known on this subject

Interferon alfa was the recommended treatment for chronic hepatitis C until the late 1990sCombination therapy is recommended for previously untreated patients with chronic hepatitis C, but the benefit of treating relapsers and non-responders to previous treatment with interferon remains controversialThe effect of treatment on liver related morbidity and mortality has not been established

What this study adds

Combination therapy is more effective in treating hepatitis C than interferon alfa alone in naive patients, relapsers, and non-respondersCombination therapy significantly reduced the risk of not having a sustained virological or histological response irrespective of previous treatment and may therefore also be considered in relapsers and non-responders to previous treatmentThe data indicate a non-significant trend towards a beneficial effect on morbidity plus mortality rates     

Randomised controlled trial of lymphoblastoid interferon alfa in Europid men with chronic hepatitis B virus infection.

OBJECTIVE--To confirm the findings of pilot studies that interferon alfa is an effective treatment of Europid men with chronic hepatitis B virus infection. DESIGN--Randomised controlled trial of three months treatment with interferon alfa followed by 12 months of observation. SETTING--Outpatient clinic of a tertiary referral centre. PATIENTS--37 Treated men (six anti-HIV positive) and 34 untreated men (nine anti-HIV positive) who met the criteria for the trial. Four controls failed to complete follow up. INTERVENTIONS--The treated group received subcutaneous injections of 5-10 MU interferon alfa/m2 daily for five days, then 10 MU/m2 thrice weekly for 11 weeks. Follow up continued at monthly intervals for 12 months. Untreated controls were monitored over the same period. MAIN OUTCOME MEASURE--Hepatitis B e antigen and hepatitis B virus DNA state after 15 months of observation. RESULTS--12 Of the 37 treated patients cleared hepatitis B e antigen and hepatitis B virus DNA, whereas only one of 30 untreated controls seroconverted over the same period--an increased response rate of 29% (95% confidence interval 13% to 45%). The life table estimate of response at 15 months was 35% in treated patients, an increase of 32% above controls (95% confidence interval 16% to 48%). The response rates in groups by predictive pretreatment variables were 12 of 31 anti-HIV negative patients (excess response 34%; 95% confidence interval 14% to 54%), 12 of 26 with chronic active hepatitis before treatment (excess response 46%; 27% to 65%), and 12 of 21 with a pretreatment serum aspartate aminotransferase activity greater than 70 IU/l (excess response 46%; 16% to 76%). The combination of these factors predicted response with a sensitivity of 100% and a specificity of 80%. Four of the 12 responders, who had all been infected for less than two years, also lost hepatitis B surface antigen. Treatment was well tolerated. CONCLUSIONS--Interferon alfa is effective in the treatment of a proportion of Europid men with chronic hepatitis B virus infection, who might be identified before treatment. Additional strategies are required to improve the rate of response.     

Randomised controlled trial of interferon alfa (lymphoblastoid interferon) in chronic non-A non-B hepatitis.

OBJECTIVE--To determine the effect of low dose interferon alfa (human lymphoblastoid interferon) on aminotransferase activities in chronic non-A non-B hepatitis. DESIGN--Prospective randomised controlled parallel group study of active treatment versus no treatment carried out over 16 weeks and preceded by baseline measurements at weeks 8 and 4 and time zero. SETTING--HEPATOLOGY outpatient clinics in secondary referral centres. PATIENTS--Fourteen adults with histologically proved chronic hepatitis and persistently raised aminotransferase activities for six months or more. INTERVENTIONS--Seven patients randomised to receive interferon alfa 5 megaunits (MU) daily for one week, reducing to 5 MU thrice weekly for seven weeks, then 3 MU thrice weekly for eight weeks. Controls not treated. END POINT--Control of hepatic enzyme activity in chronic non-A non-B hepatitis. MEASUREMENTS AND MAIN RESULTS--Serum aspartate aminotransferase activity remained raised in controls (mean increase in study period 23.4 U/l) but fell rapidly to normal in the treated group (mean decrease 106.4 U/l). In four cases values were normal by eight weeks and in five cases by 16 weeks. Only minor side effects were recorded (fever, myalgia), which became less common as treatment progressed. CONCLUSIONS--Continuous low dose interferon alfa reduces aspartate aminotransferase activity to normal in most patients with chronic non-A non-B hepatitis and may prevent progression to cirrhosis.     

Interferon therapy in chronic hepatitis C virus infection

Abstract: Antiviral treatment of chronic hepatitis C with interferon is reviewed. Alpha-interferon, both recombinant alpha-2a, -2b and human lymphoblastoid interferon given at a dose of ≥3MU t.i.w. for 6–12 months will result in normalisation of ALT levels complete response) in some 50–60% of treated patients with chronic hepatitis C virus (HCV) infection. Approximately half of the complete responders to interferon will relapse within 6 months once treatment is withdrawn (non-sustained response). Longer treatment schedules (6 vs. 12 months) seem to diminish the relapse rate and increase the percentage of sustained response. In patients with sustained response to interferon treatment with continuously normal ALT levels ≥6 months after treatment stop a concomitant eradication of the viraemia is usually seen, whereas a non-sustained or non-response to interferon usually will indicate a continuous viraemia. Factors predictive of a favourable response are low pretreatment HCV RNA levels in serum, genotypes other than type II according to Okamoto, short disease duration, female gender and less pronounced liver damage, whereas high serum HCV RNA levels, having genotype II and cirrhosis, are predictive of a less favourable response. Patients with a sustained response and eradication of the viraemia will also improve their liver inflammation with diminishing scores for portal inflammation, piecemeal necrosis, lobular inflammation and also fibrosis after treatment. For non-responders and non-sustained responders to interferon, ribavirin especially in combination with interferon will offer some hope for the future.     

Predictive value of early virological response to treatment with different interferon-based regimens plus ribavirin in patients with chronic hepatitis C

Early virological response (EVR) to different interferon-based regimens plus ribavirin and its ability to predict the outcome of therapy in patients with chronic hepatitis C were investigated. The study design was as follows: 64 naive patients were considered, 32/64 received pegylated interferon alpha-2b (Peg-IFN-alpha2b) plus ribavirin and the remaining 32 received leucocyte interferon alpha (IFN-alpha) plus ribavirin. At week 4 of treatment, EVR was present in 68.7% and 37.5% of patients treated with Peg-IFN-alpha2b plus ribavirin, and with leucocyte interferon alpha (IFN-alpha) plus ribavirin, respectively (p = 0.024). At week 12, the cumulative EVR rates did not differ between the two groups (71.9% vs 56.2%, p >0.05) because a higher proportion of patients achieved EVR for the first time after more than 4 weeks of therapy in the standard IFN-alpha group. Sustained virological response (SVR) rates, however, resulted significantly higher in the Peg-IFN-alpha2b group (65.6% vs 37.5%; p = 0.045) since a higher proportion of patients who received standard IFN-alpha relapsed during the follow-up. In the standard IFN-alpha group, HCV genotype 1 (p = 0.035), high baseline viral load (p = 0.035) and the presence of bridging fibrosis/cirrhosis (p = 0.011) were closely associated with significantly lower SVR rates. In the Peg-IFN-alpha2b group, only bridging fibrosis/cirrhosis (p = 0.02) negatively influenced the outcome of treatment. Overall, 33/41 (80.5%) patients with EVR at week 12 were sustained responders, yielding a positive predictive value (PPV) of 0.80. However, when SVR was related to the time taken to reach EVR, 32/34 (94.1%) patients with EVR at week 4 of therapy (PPV = 0.94) versus 1/7 (14.3%) patients who had EVR after more than 4 weeks of therapy (PPV = 0.14) resulted sustained responders (p = 0.000057). In conclusion, EVR at week 4 of treatment is strongly associated with the likelihood of achieving SVR, regardless of the therapeutic regimen. However, when compared with standard IFN-alpha plus ribavirin, treatment with Peg-IFN-alpha2b plus ribavirin significantly increases the probability of viral clearance within the first 4 weeks of treatment. Finally, patients who do not clear the virus within the first 12 weeks of treatment have no chance of achieving SVR, justifying discontinuation of therapy in these patients.     

Treatment of Na?ve Patients with Chronic Hepatitis C Genotypes 2 and 3 with Pegylated Interferon Alpha and Ribavirin in a Real World Setting: Relevance for the New Era of DAA

Evidence based clinical guidelines are implemented to treat patients efficiently that include efficacy, tolerability but also health economic considerations. This is of particular relevance to the new direct acting antiviral agents that have revolutionized treatment of chronic hepatitis C. For hepatitis C genotypes 2/3 interferon free treatment is already available with sofosbuvir plus ribavirin. However, treatment with sofosbuvir-based regimens is 10–20 times more expensive compared to pegylated interferon alfa and ribavirin (PegIFN/RBV). It has to be discussed if PegIFN/RBV is still an option for easy to treat patients. We assessed the treatment of patients with chronic hepatitis C genotypes 2/3 with PegIFN/RBV in a real world setting according to the latest German guidelines. Overall, 1006 patients were recruited into a prospective patient registry with 959 having started treatment. The intention-to-treat analysis showed poor SVR (GT2 61%, GT3 47%) while patients with adherence had excellent SVR in the per protocol analysis (GT2 96%, GT3 90%). According to guidelines, 283 patients were candidates for shorter treatment duration, namely a treatment of 16 weeks (baseline HCV-RNA <800.000 IU/mL, no cirrhosis and RVR). However, 65% of these easy to treat patients have been treated longer than recommended that resulted in higher costs but not higher SVR rates. In conclusion, treatment with PegIFN/RBV in a real world setting can be highly effective yet similar effective than PegIFN± sofosbuvir/RBV in well-selected naïve G2/3 patients. Full adherence to guidelines could be further improved, because it would be important in the new era with DAA, especially to safe resources.     

Chronic viral hepatitis C: management update

The management of chronic viral hepatitis C is evolving rapidly. Monotherapy with interferon, the accepted standard of treatment until recently, achieves only a modest sustained virological response rate of 15%. Combination treatment with alpha-2b interferon and ribavirin has been shown to increase sustained response rates to 40% in patients who have never been treated with interferon and to 50% in those who have relapsed following monotherapy with interferon. However, side effects, which have led to the discontinuation of combination treatment in a significant proportion of patients, must be carefully monitored. Treatment with interferon alpha-2b and ribavirin has now been approved in Canada, but the selection and monitoring of patients suitable for combination treatment requires special expertise. Although improvements in current therapeutic options may be possible with more frequent, higher doses or long-acting forms of interferon together with ribavirin, low sustained response rates (i.e., below 30%) for patients with hepatitis C virus genotype 1 emphasize the need for novel antiviral medications that will target the functional sites of the HCV genome.     

Production of profibrotic cytokines by invariant NKT cells characterizes cirrhosis progression in chronic viral hepatitis

Invariant (inv)NKT cells are a subset of autoreactive lymphocytes that recognize endogenous lipid ligands presented by CD1d, and are suspected to regulate the host response to cell stress and tissue damage via the prompt production of cytokines. We investigated invNKT cell response during the progression of chronic viral hepatitis caused by hepatitis B or C virus infection, a major human disease characterized by a diffused hepatic necroinflammation with scarring fibrotic reaction, which can progress toward cirrhosis and cancer. Ex vivo frequency and cytokine production were determined in circulating and intrahepatic invNKT cells from controls (healthy subjects or patients with nonviral benign or malignant focal liver damage and minimal inflammatory response) or chronic viral hepatitis patients without cirrhosis, with cirrhosis, or with cirrhosis and hepatocellular carcinoma. invNKT cells increase in chronically infected livers and undergo a substantial modification in their effector functions, consisting in the production of the type 2 profibrotic IL-4 and IL-13 cytokines, which characterizes the progression of hepatic fibrosis to cirrhosis. CD1d, nearly undetectable in noncirrhotic and control livers, is strongly expressed by APCs in cirrhotic ones. Furthermore, in vitro CD1d-dependent activation of invNKT cells from healthy donors elicits IL-4 and IL-13. Together, these findings show that invNKT cells respond to the progressive liver damage caused by chronic hepatitis virus infection, and suggest that these cells, possibly triggered by the recognition of CD1d associated with viral- or stress-induced lipid ligands, contribute to the pathogenesis of cirrhosis by expressing a set of cytokines involved in the progression of fibrosis.     

Therapy for chronic hepatitis C.

BACKGROUND/AIMS: in Hungary, over the past 5 years more than 900 patients with chronic hepatitis C have been examined for treatment with interferon at 16 major hepatology centres, using unified diagnostic and therapeutical criteria. Authors give an account of their experiences on the clinical features of patients with chronic hepatitis C and report the results of the interferon therapy. METHODS: a total of 993 patients--virtually the entire Hungarian hepatitis C patient population who had been referred for interferon treatment--were included in the program. Actually, the sustained efficacy of the therapy was evaluated in 724 cases. Treatment protocols (dose of interferon and duration of therapy) have changed with time from a weekly dose of 3x3 MU IFN for 6 months in the first period, to 3x3-5 MU for 12 months in the second period, and finally in the third period a combination therapy with ribavirin has also been introduced. RESULTS: in the first period, the end-of-treatment response (ETR) was 35%, sustained response (SR) 13%, the second phase schedule resulted in 42% ETR and 22% SR, while in the third period, ETR was 49% and SR 36%, respectively. Fibrosis in histology and baseline pretreatment HCV-RNA level appeared as predictors of response. The duration of treatment and the total dose of interferon exerted a moderate effect on therapeutic efficacy. Neither age nor gender influenced the outcome. CONCLUSIONS: our results-obtained in a Central East European country-are in accordance with findings of suboptimal efficacy of traditional interferon monotherapy for chronic hepatitis C reported in the West, and suggest the benefit of the combination treatment of interferon with ribavirin.     

Interferon-based treatment of chronic hepatitis C

The treatment of patients with chronic hepatitis C has rapidly evolved in the past 10 years centered on the use of interferon alpha 2 as an antiviral and immunomodulatory agent against hepatitis C virus. Firstly used as a monotherapy associated with a deceiving long-term efficacy, interferon alpha was then combined with ribavirin, a nucleoside analog with large antiviral properties. Combination of both drugs dramatically improved the efficacy of treatment with 50% of patients reaching a sustained viral response, characterized by the final eradication of the virus from the infected individual. Surprisingly, this synergistic effect remains greatly unexplained. The third step consisted in the use of pegylated interferon in order to adapt its pharmacokinetics and to allow a better efficacy with a more tolerable dosing schedule: once weekly subcutaneous injection instead of thrice weekly. Pegylated interferon combined with ribavirin during 24-48 weeks of treatment is the current standard of care with nearly 60% of sustained virologic response, overall. Development of new forms of interferon alpha are on the way with promising preliminary results.     

Chronic hepatitis B--who should be treated?

Hepatitis B virus (HBV) can cause both acute and chronic infection and is an important human pathogen, with an estimated 350 million individuals chronically infected worldwide. HBV carriers are at risk for the development of cirrhosis and hepatocellular carcinoma (HCC), and patients with chronic infection require life-long monitoring. Effective hepatitis B antiviral treatment is important given the significant associated global morbidity and mortality from liver-related complications. The goals of treatment are to achieve sustained suppression of HBV replication and remission of liver disease. In the past decade, great progress has been made in the treatment of chronic HBV infection. Interferon alfa, longer-acting pegylated interferon, and nucleos(t)ide analogs such as lamivudine, adefovir dipivoxil, and entecavir are currently available for treatment of HBV infection. Effective treatment decisions require an understanding of the natural history of hepatitis B and the range of treatment options. This review includes criteria for determining when and how to most effectively intervene with antiviral therapy for chronically infected patients.     

Treatment of genotype 1b HCV-related chronic hepatitis: efficacy and toxicity of three different interferon alfa-2b/ribavirin combined regimens in naive patients

This prospective open-label randomized trial of chronic hepatitis C genotype-1b patients compared compared the efficacy and safety of peg-interferon alfa-2b administered once-weekly versus interferon alfa-2b thrice-weekly or daily, both in combination with ribavirin. Seventy-eight previously untreated patients, with biopsy-documented genotype 1 chronic HCV and persistently elevated ALT levels and detectable HCV RNA, were randomized (26 subjects each) to receive: interferon alfa-2b at 6MIUs.c./three-times-weekly (group A) or interferon alfa-2b, 3MIUs.c./daily (group B) or peg-interferon alfa-2b 1.5mcg/Kg s.c./once-weekly (group C). All regimens included standard weight-based doses of ribavirin (800, 1,000 or 1,200 mg/day) administered for 52-weeks. Patients in the three groups were comparable for age, sex, viral load, ALT value and histological-activity-index (HAI). Therapy was completed by 22, 20 and 23 patients in groups A, B and C, respectively. At the end of treatment, a complete (biochemical and virological) response was observed in 50.0% patients of group A, 57.7% of group B and 65.4% of group C. After an additional 24-weeks of follow-up, a sustained response was observed in 26.9%, 46.1% and 50.0% of patients in groups A, B or C, respectively. Therapy was discontinued by 4, 6 and 2 patients because of adverse events in the above three groups. In naive patients with chronic genotype-lb hepatitis C, a 48 week therapy with peg-interferon or interferon at daily doses combined with ribavirin were both more effective than treatment with thrice-weekly interferon in inducing end of treatment and sustained response. Peg-interferon treatment was better tolerated and provoked significantly fewer therapy discontinuations.     

Advances in therapy for hepatitis C infection

The first approved therapy for chronic hepatitis C virus (HCV) infection was recombinant interferon. Subsequently, controlled studies demonstrated that the combination of interferon-alpha and ribavirin leads to significantly higher virologic sustained responses in patients with chronic hepatitis C. A novel modification of the interferon molecule resulted in the formulation of pegylated interferons, which have a longer half-life than standard interferon. Two recent trials have established the superiority of pegylated interferons compared with interferon-alpha in inducing sustained virologic responses in patients with chronic HCV infection, with or without cirrhosis. Presumably, pegylated interferons will replace standard interferon in treating HCV infection. Phase 3 trials of pegylated interferons in combination with ribavirin are currently under way. Noninterferon-based therapies for the treatment of HCV infection are also in the developmental and experimental phases. Our aims in this review are to present the currently available therapeutic options for HCV infection and the evidence supporting their use in typical patients with chronic hepatitis C or in patients with special circumstances. We also briefly review novel therapeutic approaches, including noninterferon-based therapies.     

Assessment of the treatment of chronic hepatitis C in the state of Mato Grosso, central Brazil

In Brazil, the treatment of hepatitis C virus (HCV) infection is funded by the national public health system (SUS). To evaluate treatment results in the state of Mato Grosso, central Brazil, we have consulted the files of the office of the State Department of Health responsible for supplying such medications. We obtained information on 232 treatments of 201 patients who underwent treatment in or prior to 2008. The study was conducted by reviewing medical records, making telephone calls and interviewing the assistant physicians. Thirty-nine patients (19.4%) had cirrhosis and HCV genotype 1 predominated (64.3%). Excluding patients with comorbidities or treatment without ribavirin we analysed 175 treatments (sustained virologic response occurred in 32.6% of cases). Twenty-six of these 175 were retreatments and the sustained virological response (SVR) rate among them was 30.8%; the SVR rate was 32.9% among those receiving treatment for the first time. The SVR rate of genotype 1 patients was 27.8%, whereas it was 37.5% in non-1 genotype patients. The adjusted multivariate analysis showed association of SVR with the absence of cirrhosis [odds ratio (OR): 7.7; confidence interval (CI) 95%: 2.5, 33.3], the use of pegylated interferon (OR: 5.8; CI 95%: 1.5, 21.4), non-1 genotype (OR: 5.3; CI 95%: 1.7, 16.7) and uninterrupted treatment (OR: 9.0; CI 95%: 3.3, 45.4). The SVR rates were similar to those found in other Brazilian studies about HCV, but lower than those found in national and international clinical trials. These data suggest that the treatments of chronic hepatitis C that are made available by SUS does not, under normal conditions, work as well as the original controlled studies indicated.     

Cell adhesion molecules and hyaluronic acid as markers of inflammation, fibrosis and response to antiviral therapy in chronic hepatitis C patients.

OBJECTIVE: Cell adhesion molecules (intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1)) and hyaluronic acid, markers of inflammation and fibrosis were monitored in hepatitis C patients to determine whether changes in plasma levels, during antiviral treatment, can predict long-term response to therapy. METHODS: In 55 patients with chronic hepatitis C virus (HCV), 33 treated with interferon (IFN) and 22 treated with IFN + ribavirin, sera was collected prior to treatment, at 3 + 6 months of therapy and 6 months post-treatment. Levels of ICAM-1, VCAM-1 and hyaluronic acid were correlated with alanine aminotransferase levels, HCV-RNA-polymerase chain reaction status and histological fibrosis scoring. RESULTS: A decrease in ICAM-1 levels at 3 and 6 months of therapy, compared with pretreatment levels, was observed in responders to IFN + ribavirin therapy but this decrease in ICAM-1 levels was not evident following cessation of treatment. Hyaluronic acid levels, in both treatment groups, did not differ significantly between responders and non-responders. Hyaluronic acid levels did correlate, significantly, with degree of fibrosis whereas VCAM-1 levels were marginally increased only in patients with moderate (grade III) fibrosis. CONCLUSIONS: Monitoring of VCAM-1 and hyaluronic acid, during antiviral therapy, does not differentiate between responders and non-responders. A decrease in ICAM-1 levels during IFN + ribavirin treatment is associated with response to therapy, and its efficacy in predicting long-term response should be further substantiated.     

Effect of interferon-alpha on experimental septal fibrosis of the liver - study with a new model

Interferon-alpha is used in antiviral therapy in humans, mainly for viral hepatitis B and C. An anti-fibrotic effect of interferon has been postulated even in the absence of anti-viral response, which suggests that interferon directly inhibits fibrogenesis. Rats infected with the helminth Capillaria hepatica regularly develop diffuse septal fibrosis of the liver, which terminates in cirrhosis 40 days after inoculation. The aim of this study was to test the anti-fibrotic effect of interferon in this experimental model. Evaluation of fibrosis was made by three separate methods: semi-quantitative histology, computerized morphometry and hydroxyproline measurements. Treatment with interferon-alpha proved to inhibit the development of fibrosis in this model, especially when doses of 500,000 and 800,000 IU were used for 60 days. Besides confirming the anti-fibrotic potential of interferon-alpha on a non-viral new experimental model of hepatic fibrosis, a clear-cut dose-dependent effect was observed.     

Serum zinc as a factor predicting response to interferon-alpha2b therapy in children with chronic hepatitis B

Although it has been unclear why more than 50% of children with chronic hepatitis B virus infection do not respond to interferon therapy, in some instances resistance to interferon probably is caused by an inability to stimulate appropriately cellular immune responses to hepatitis B virus. It is known that immune integrity is tightly linked to zinc status. We examined the relationship between serum zinc levels and response to interferon (INF)-α therapy in children with chronic hepatitis B. Twenty-five children with chronic hepatitis B infection were injected with 5 × 10⁶ units/m² recombinant IFN-α 2b subcutaneously three times weekly for 9 mo. Children were followed for at least 9 mo after the end of therapy. Sustained response was obtained in eight (32%) patients. Although initial serum zinc and alanine aminotransferase levels were significantly higher; initial hepatitis B Virus (HBV)-DNA values, hepatic activity index, periportal necrosis, and fibrosis scores were significantly lower in sustained responders than in nonresponders. Mean baseline serum zinc, alanine aminotransferase and HBV-DNA values, histologic activity index, periportal necrosis, and fibrosis scores were predictive of response to IFN-α 2b therapy. These findings suggest that serum zinc levels might be used as a factor predicting response to interferon-α 2b therapy, and so may help in identifying those children with a better chance of response.     

Subversion of innate host antiviral strategies by the hepatitis C virus

Since its discovery in 1989, Hepatitis C Virus (HCV) has been recognized as a major cause of chronic hepatitis, end-stage cirrhosis and hepatocellular carcinoma affecting world wide more than 210 million people. The fact that 80% of newly infected patients fail to control infection, the slow development of overt disease and immune-response as well as the unsatisfying results of current IFN/ribavirin combination therapy suggests that the hepatitis C virus developed powerful strategies to evade and to antagonize the immune response of the host and to resist the antiviral actions of interferons. During the last 10 years several viral strategies have been uncovered for control and evasion from cellular antiviral host response initiated by the pathogen-associated molecular pattern recognizing receptors RIG1 and TLR3 and mediated by the release of type I interferon and subsequent induction of interferon stimulated genes. This review highlights recent results providing an idea of how the hepatitis C virus interferes with the different steps of initial antiviral host-response and establishes persistent infection.