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ObjectiveThe benefit of direct-acting antivirals (DAAs) against HCV following successful treatment of hepatocellular carcinoma (HCC) remains controversial. This meta-analysis of individual patient data assessed HCC recurrence risk following DAA administration.DesignWe pooled the data of 977 consecutive patients from 21 studies of HCV-related cirrhosis and HCC, who achieved complete radiological response after surgical/locoregional treatments and received DAAs (DAA group). Recurrence or death risk was expressed as HCC recurrence or death per 100 person-years (100PY). Propensity score-matched patients from the ITA.LI.CA. cohort (n=328) served as DAA-unexposed controls (no-DAA group). Risk factors for HCC recurrence were identified using random-effects Poisson.ResultsRecurrence rate and death risk per 100PY in DAA-treated patients were 20 (95% CI 13.9 to 29.8, I2=74.6%) and 5.7 (2.5 to 15.3, I2=54.3), respectively. Predictive factors for recurrence were alpha-fetoprotein logarithm (relative risk (RR)=1.11, 95% CI 1.03 to 1.19; p=0.01, per 1 log of ng/mL), HCC recurrence history pre-DAA initiation (RR=1.11, 95% CI 1.07 to 1.16; p<0.001), performance status (2 vs 0, RR=4.35, 95% CI 1.54 to 11.11; 2 vs 1, RR=3.7, 95% CI 1.3 to 11.11; p=0.01) and tumour burden pre-HCC treatment (multifocal vs solitary nodule, RR=1.75, 95% CI 1.25 to 2.43; p<0.001). No significant difference was observed in RR between the DAA-exposed and DAA-unexposed groups in propensity score-matched patients (RR=0.64, 95% CI 0.37 to 1.1; p=0.1).ConclusionEffects of DAA exposure on HCC recurrence risk remain inconclusive. Active clinical and radiological follow-up of patients with HCC after HCV eradication with DAA is justified.

In the last decade, a big European effort has been made in terms of research, strategies and initiatives to boost new forms of sustainable urban mobility to replace individual transport. Among the other instruments identified to achieve this goal the European Commission emphasises integrated planning at all mobility levels, to be realised through the writing of the PUMS, and its management and through Intelligent Transport Systems (ITS). Under these two conditions, car sharing is expected to become an efficient sustainable transport service, able to limit the use of private cars and to facilitate multi-modality for public transport.

Antiviral therapy is generally indicated in patients who have histologic evidence of chronic hepatitis and ongoing viral replication. The aim of treatment is to normalize alanine aminotransferase levels and to eliminate virus replication. Interferon-alfa (IFN-α) is the most used agent. The standard treatment regimen for hepatitis B e antigen (HBeAg)-positive cirrhosis is based on IFN-α given alone, but the efficacy of new antivirals (famciclovir, lamivudine) with or without IFN-α is currently under investigation. Conversely, the therapy of antiHBe-positive cirrhosis is far from being satisfactory. The results of treatment of patients affected by type C cirrhosis with IFN-α alone have been disappointing, as 10-15% of treated patients shows a sustained virologic response. Although current evidence suggests that the combination of ribavirin and IFN-α might be more efficacious than IFN alone in increasing the response rate in patients in the advanced fibrotic stage, the efficacy of this regimen for patients with well-compensated HCV-related cirrhosis is still unknown and prospective well-designed studies are urgently needed. Patients with decompensated cirrhosis are not generally treated unless they are included in liver transplantation programs. Prospective long-term trials with large sample sizes are needed to determine if responders to IFN-α have a low incidence of liver-related complications and hepatocellular carcinoma.

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-α1or of interferon-α. 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-α1as 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-α1at a dose of 900 μg/m2twice 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-α1treatment 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-α1therapy 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.

Background: α interferon has proven of limited efficacy in the treatment of chronic hepatitis C. Ribavirin has also been used to treat chronic hepatitis C, but nearly all patients show relapse of hepatitis after the drug is discontinued. Therefore, new therapeutic strategies based on the use of both of these drugs are currently under evaluation. Methods: Patients, 16, with chronic hepatitis C resistant to a previous 6 months course of lymphoblastoid α-interferon (eight interferon non-responders and eight interferon relapsers) received a 4 month course of ribavirin, 1000 mg/day, followed by a second course of the same schedule of lymphoblastoid α-interferon. Results: During the course of ribavirin, alanine aminotransferase levels decreased in all patients (range 12.7–83.9%, median 61.8%) and normalized in five earlier relapsers and in three earlier non-responders to α-interferon. In spite of the biochemical response to ribavirin, HCV-RNA remained detectable in the serum of all patients. At the end of α-interferon treatment, transaminase levels were abnormal in all earlier non-responders and normal in five earlier relapsers to α-interferon. HCV-RNA was cleared from serum in three of them. Six months, after the complete course of ribavirin and α-interferon, sustained normalization of aminotransferase levels associated with persistent clearance of HCV-RNA from serum was obtained in one of these patients. Another patient showed sustained biochemical response without clearance of HCV-RNA. In earlier relapsers to α-interferon, serum HCV-RNA levels decreased during treatment but returned to the pre-treatment values during the follow-up. The treatment could be carried out in all patients but one, who developed thrombocytopenia. Conclusions: This sequential treatment with ribavirin followed by α-interferon does not induce sustained response in previous non-responders to α-interferon alone and does not appear to significantly improve the results of retreatment with α-interferon alone in previous relapsers to treatment.

Background: α interferon has proven of limited efficacy in the treatment of chronic hepatitis C. Ribavirin has also been used to treat chronic hepatitis C, but nearly all patients show relapse of hepatitis after the drug is discontinued. Therefore, new therapeutic strategies based on the use of both of these drugs are currently under evaluation. Methods: Patients, 16, with chronic hepatitis C resistant to a previous 6 months course of lymphoblastoid α-interferon (eight interferon non-responders and eight interferon relapsers) received a 4 month course of ribavirin, 1000 mg/day, followed by a second course of the same schedule of lymphoblastoid α-interferon. Results: During the course of ribavirin, alanine aminotransferase levels decreased in all patients (range 12.7–83.9%, median 61.8%) and normalized in five earlier relapsers and in three earlier non-responders to α-interferon. In spite of the biochemical response to ribavirin, HCV-RNA remained detectable in the serum of all patients. At the end of α-interferon treatment, transaminase levels were abnormal in all earlier non-responders and normal in five earlier relapsers to α-interferon. HCV-RNA was cleared from serum in three of them. Six months, after the complete course of ribavirin and α-interferon, sustained normalization of aminotransferase levels associated with persistent clearance of HCV-RNA from serum was obtained in one of these patients. Another patient showed sustained biochemical response without clearance of HCV-RNA. In earlier relapsers to α-interferon, serum HCV-RNA levels decreased during treatment but returned to the pre-treatment values during the follow-up. The treatment could be carried out in all patients but one, who developed thrombocytopenia. Conclusions: This sequential treatment with ribavirin followed by α-interferon does not induce sustained response in previous non-responders to α-interferon alone and does not appear to significantly improve the results of retreatment with α-interferon alone in previous relapsers to treatment.