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We evaluated the cost-effectiveness of two alternative direct-acting antiviral (DAA) treatment policies in a real-life cohort of hepatitis C virus–infected patients: policy 1, “universal,” treat all patients, regardless of fibrosis stage; policy 2, treat only “prioritized” patients, delay treatment of the remaining patients until reaching stage F3. A liver disease progression Markov model, which used a lifetime horizon and health care system perspective, was applied to the PITER cohort (representative of Italian hepatitis C virus–infected patients in care). Specifically, 8,125 patients naive to DAA treatment, without clinical, sociodemographic, or insurance restrictions, were used to evaluate the policies’ cost-effectiveness. The patients’ age and fibrosis stage, assumed DAA treatment cost of €15,000/patient, and the Italian liver disease costs were used to evaluate quality-adjusted life-years (QALY) and incremental cost-effectiveness ratios (ICER) of policy 1 versus policy 2. To generalize the results, a European scenario analysis was performed, resampling the study population, using the mean European country-specific health states costs and mean treatment cost of €30,000. For the Italian base-case analysis, the cost-effective ICER obtained using policy 1 was €8,775/QALY. ICERs remained cost-effective in 94%-97% of the 10,000 probabilistic simulations. For the European treatment scenario the ICER obtained using policy 1 was €19,541.75/QALY. ICER was sensitive to variations in DAA costs, in the utility value of patients in fibrosis stages F0-F3 post–sustained virological response, and in the transition probabilities from F0 to F3. The ICERs decrease with decreasing DAA prices, becoming cost-saving for the base price (€15,000) discounts of at least 75% applied in patients with F0-F2 fibrosis. Conclusion: Extending hepatitis C virus treatment to patients in any fibrosis stage improves health outcomes and is cost-effective; cost-effectiveness significantly increases when lowering treatment prices in early fibrosis stages. (Hepatology 2017;66:1814–1825).

Background/Aims Interferon and ribavirin combination therapy for chronic hepatitis C induces a low response rate in human immunodeficiency virus (HIV) infected patients. To assess the impact of intensification of interferon administration and of the addition of amantadine on the efficacy and safety of standard anti-hepatitis C virus (HCV) treatment in HIV-infected patients. Methods Multicentre, prospective, open-label, randomized, phase III clinical trial. Eighty co-infected patients were randomized to receive ribavirin 800-1000 mg/day in combination with, group A: interferon alpha2a 3MIU thrice weekly; group B: IFNα2a 3MIU daily, plus amantadine 200 mg/day; treatment duration was 24-48 weeks according to HCV genotype. Results Forty-one patients were randomized in group A and 39 in group B. Intention-to-treat analysis showed a sustained virological response, defined as HCV-RNA negativization, 6 months after stopping treatment in 22% of patients from group A and 13% from group B (P>0.05). The lack of a 2-log drop in HCV-RNA levels after 12 weeks of treatment showed a 100% predictive value of lack of sustained response. Conclusions Amantadine addition and interferon intensification do not improve the low efficacy of combination of interferon alfa plus ribavirin in HIV/HCV co-infected patients. Patients with no early virologic response did not have any probability of sustained response. © 2004 European Association for the Study of the Liver

In 2012, we conducted a retrospective cross-sectional study to assess the number of people living with HIV linked to care and, among these, the number of people on antiretroviral therapy. The health authority in each of the 20 Italian Regions provided the list of Public Infectious Diseases Clinics providing antiretroviral therapy and monitoring people with HIV infection. We asked every Public Infectious Diseases Clinic to report the number of HIV-positive people diagnosed and linked to care and the number of those on antiretroviral therapy during 2012. In 2012, 94,146 people diagnosed with HIV and linked to care were reported. The majority were males (70.1%), Italians (84.4%), and aged between 25 and 49 years (63.4%); the probable route of transmission was heterosexual contact in 37.5% of cases, injecting drug use in 28.1%, and male-to-male contact in 27.9%. Among people in care, 20.1% had less than 350 CD4 cells/μl, 87.6% received antiretroviral therapy, and among these, 62.4% had a CD4 cell count higher than 350 cells/μl. The overall estimated prevalence of individuals diagnosed and linked to care in 2012 in Italy was 0.16 per 100 residents (all ages). Adding the estimated proportion of undiagnosed people, the estimated HIV prevalence would range between 0.19 and 0.26 per 100 residents. In Italy, the majority of people diagnosed and linked to care receive antiretroviral therapy. A higher prevalence of individuals diagnosed and linked to care was observed in Northern Italy and among males. More information for developing the HIV care continuum is necessary to improve the entire engagement in care, focusing on test-and-treat strategies to substantially reduce the proportion of people still undiagnosed or with a detectable viral load.

To develop recommendations for the management of acute hepatitis B by the Italian Society for the Study of Infectious and Tropical Diseases.Development of the recommendations divided into three levels of evidence according to the GRADE system: A (high), B (medium) and C (low experts opinion), together with three recommendation levels: 1 (strong), 2 (medium), 3 (weak).The treatment with antivirals is in selected cases the mainstay of management of severe acute hepatitis, and should be started as a matter of urgency in order to prevent death.These recommendations are meant to provide the rationale and practical indications for the management of acute hepatitis B (AHB).

Background The continuing migration of individuals from geographic areas with high/medium endemicity has determined the arrival of new chronic hepatitis B virus (HBV) carriers in Italy. The magnitude of this phenomenon and clinical/virological features of HBsAg-positive migrants remain not very well defined. Aims To evaluate the proportion of HBsAg-positive immigrants enrolled in this multicenter Societa` Italiana di Malattie Infettive e Tropicali (SIMIT) cross-sectional study and to compare the characteristics of chronic hepatitis B infection in migrants to those of Italian carriers. Methods From February 1 to July 31 2008, anonymous data were obtained from all HBsAg-positive patients aged C18 years observed at 74 Italian centers of infectious diseases. Results Of the 3,760 HBsAg-positive subjects enrolled, 932 (24.8 %) were immigrants, with a prevalent distribution in central to northern Italy. The areas of origin were: Far East (37.1 %), Eastern Europe (35.4 %), Sub- Saharan Africa (17.5 %), North Africa (5.5 %), and 4.5 % from various other sites. Compared to Italian carriers, migrants were significantly younger (median age 34 vs. 52 years), predominantly female (57.5 vs. 31 %), and most often at first observation (incident cases 34.2 vs. 13.3 %). HBeAg-positives were more frequent among migrants (27.5 vs. 14 %). Genotype D, found in 87.8 % of Italian carriers, was present in only 40 % of migrants, who were more frequently inactive HBV carriers, with a lower prevalence of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Only 27.1 % of migrants received antiviral treatment compared to 50.3 % of Italians. Conclusions Twenty-five percent of all HBV carriers examined at Italian centers was composed of immigrants with demographic, serological, and virological characteristics that differed from those of natives and appeared to have an inferior access to treatment

Background & Aims In long-term responder patients, it is unclear whether lamivudine (LAM) monotherapy should be continued or switched to a high-genetic-barrier analogue. This study aims at assessing LAM efficacy over a 5-year period and the residual risk of drug resistance. The rate of HBsAg clearance and LAM long-term safety profile were also evaluated. Methods One hundred and ninety-one patients with chronic HBeAg-negative hepatitis B successfully treated with LAM monotherapy for at least 5years were included. Biochemical and virological tests were assessed every 3months in all patients and HBsAg quantification was performed in 45/191. Reverse-transcriptase (RT) region was directly sequenced in virological breakthrough patients. Results One hundred and ninety-one patients (148 males, median age 53years, 72 with compensated cirrhosis) responding to 60-month LAM monotherapy continued to receive LAM monotherapy beyond the initial 5years and were followed for an additional 36-month median period (range 1–108). Virological response was maintained in 128/191 patients (67%) and HBsAg clearance was observed in 15/128 (11.7%) after a 32-month median period (range 1–65). The 63 remaining patients (33%) showed virological breakthrough after a 15-month median treatment (range 1–78). RT region analysis was performed in 38/63 breakthrough patients and LAM resistant mutations were found in 37/38. No significant side effects were observed. Conclusions In long-term responder patients, continuation of LAM monotherapy resulted in persistent viral suppression in most cases with undetectable HBV DNA by real-time PCR; moreover, 11.7% of these patients cleared HBsAg. Selection of LAM resistance, however, can still occur even after successful long-term therapy, thus emphasising the importance of a careful virological monitoring.

The Italian recommendations for the therapy of hepatitis B virus (HBV)-related disease were issued in 2008. Subsequently in 2008 the nucleotide analogue (NA) Tenofovir was approved for antiviral treatment. The introduction of this important new drug has called for the current guidelines update, which includes some additional revisions: (a) the indication for therapy is extended to mild liver fibrosis and the indication for treatment is graded as “possible”, “optional” or “mandatory” according to the fibrosis stage; (b) two different treatment strategies are described: first line definite duration treatment with interferon, long-term treatment of indefinite duration with NA; (c) the indication to follow either strategy is also based on the stage of liver fibrosis; (d) virological monitoring is modified to include the definitions of failure and of sustained virological response to interferon therapy; (e) the recommendation to use HBV DNA assays with high sensitivity and wide linear ranges is underlined (f) guidelines on post-treatment follow-up after finite treatment with NA, potential side effects of therapy and non-virological monitoring are defined; (g) definitions and treatment of patients without optimal response to NA are reported; (f) treatment and monitoring of compensated or decompensated cirrhosis and hepatocellular carcinoma are updated.

Hepatitis B virus (HBV) and hepatitis delta virus (HDV) interplay was investigated by examining liver and serum samples from 21 coinfected and 22 HBV-monoinfected patients with chronic liver disease. Different real-time PCR assays were applied to evaluate intrahepatic amounts of HBV DNA, covalently closed circular DNA (cccDNA), pregenomic RNA (pgRNA), pre-S/S RNAs, and HDV RNA. Besides HBV DNA and HDV RNA levels, HBsAg concentrations in the sera were also determined. HDV-coinfected cases showed significantly lower median levels of serum HBV DNA (−5 log), intrahepatic relaxed-circular DNA (−2 log), and cccDNA (−2 log) than those of HBV-monoinfected cases. Interestingly, pgRNA and pre-S/S RNA amounts were significantly lower (both −1 log) in HDV-positive patients, whereas serum HBsAg concentrations were comparable between the two patient groups. Pre-S/S RNA and HBsAg amounts per cccDNA molecule were higher in HDV-positive patients (3-fold and 1 log, respectively), showing that HBV replication was reduced, whereas synthesis of envelope proteins was not specifically decreased. The ratios of cccDNA to intracellular total HBV DNA showed a larger proportion of cccDNA molecules in HDV-positive cases. For these patients, both intrahepatic and serum HDV RNA amounts were associated with cccDNA but not with HBsAg or HBV DNA levels. Finally, HBV genomes with large deletions in the basal core promoter/precore region were detected in 5/21 HDV-positive patients but in no HDV-negative patients and were associated with lower viremia levels. These findings provide significant information about the interference exerted by HDV on HBV replication and transcription activities in the human liver.

Few data are available on histological features of chronic hepatitis B (HBV) and C (HCV) virus coinfection. We enrolled 142 consecutive patients with viral chronic hepatitis on their first liver biopsy: 27 HBsAg and anti-HCV positive (case BC group), 57 HBsAg positive and anti-HCV negative (control B group) and 58 anti-HCV positive, HBsAg/anti-HBs/anti-HBc negative (control C group). Patients in the case BC group showed serum HBVDNA (37% vs 71.9%, p < 0.005) and ground-glass hepatocytes (37% vs 66.7%, p < 0.01) less frequently than those in the control B group. The case BC group showed a lower prevalence of patients with detectable HCV-RNA than the control C group (60% vs 92.3%, p < 0.001) and a significantly higher fibrosis score (2.1 ± 1.2 vs 1.5 ± 1.1, p < 0.05). Of the 27 patients in the case BC group, 10 lacked serum HCV-RNA and showed significantly higher histological activity index (HAI) and fibrosis scores than those found in the 17 HCV-RNA positive (8.5 ± 4.4 vs 5.4 ± 2.4 for HAI, p < 0.05; 3.0 ± 1.3 vs 1.69 ± 1.0, p < 0.05 for fibrosis). Liver histology seems to be more severe in chronic coinfection with HBV and HCV than in single infection, particularly when HCV replication is impaired.

We studied 648 hepatitis B surface antigen (HBsAg)- and/or anti-hepatitis C virus (HCV)-positive patients to evaluate the virologic and clinical characteristics of multiple hepatitis viral infection. We defined as Case B-C an HBsAg/anti-HCV positive patient and as Case b-C an anti-HCV/anti-HBc-positive, HBsAg/anti-HBs-negative patient. For each Case B-C we scheduled as Control-B an HBsAg positive and anti-HCV negative patient and as Control-C an HBsAg/anti-HBs/anti-hepatitis B core antigen (HBc)-negative and anti-HCV-positive patient. Control group C was used as the control also for Case group b-C. Serum HBV DNA by molecular hybridization was found more frequently in Control group B (54% of 161 patients) than in Case group B-C (35.7% of 84, P

Background/Aims: Nucleoside analogues such as lamivudine and famciclovir are potent drugs for treatment of chronic hepatitis B virus infection. Breakthrough infections during lamivudine therapy are associated with mutations in the YMDD motif and putative B region of the HBV polymerase. This study investigated whether failure of famciclovir therapy is also associated with presence or emergence of particular mutations in the HBV polymerase. Methods: We analyzed longitudinally the sequence of the priming and polymerase domain in seven patients with primary non-response to therapy and two patients with a breakthrough during therapy. Two patients who responded to therapy served as a control. Results: The YMDD motif and the B region were conserved in all isolates. V→I changes at position 555 just downstream of the YMDD motif were observed before and during therapy in a virus subpopulation of two patients with a primary non-response. In patients with a breakthrough, 378-V→I and 424-N→D mutations emerged in the N terminal part of the polymerase domain during follow-up. Lamivudine rescue therapy initiated in four patients, including a patient infected with YMDD(555-V→I) variants, efficiently reduced viremia. Conclusions: These data indicate that failure of famciclovir therapy can occur independently of mutations in the YMDD motif or B region of the HBV polymerase and provide a rationale for rescue therapy with lamivudine.

The efficacy data obtained with boceprevir and telaprevir for persons with hepatitis C virus (HCV) genotype 1 infection raise the question of whether HCV protease inhibitors should be used in human immunodeficiency virus (HIV)/HCV co-infected persons. The Italian Association for the Study of Infectious and Tropical Diseases has made these recommendations to provide the rationale and practical indications for the use of triple anti-HCV therapy in persons living with HIV (PLWHIV). A Writing Committee of experts indicated by the President of the Association and a Consulting Committee con- tributed to the document. The final draft was submitted to the evaluation of external experts and the text modified according to their suggestions and comments. Treatment of HCV co-infection should be considered for all HCV RNA positive PLWHIV. Response-guided therapy with pegylated interferon and ribavirin is the standard treatment of PLWHIV with infection by HCV genotype 2, 3, 4, 5 and 6. Boceprevir and telaprevir should be used to treat HCV genotype 1 infection in HIV/HCV co-infected patients for 48 weeks on an individual basis, with close monitoring of their efficacy and tolerability with concur- rent antiretroviral therapy, taking into account potential drug-drug interactions. The decision to treat a patient or to wait for better treatment options, or to discontinue treatment should be made on an individual basis taking into account pre-treatment variables and the on-treatment HCV RNA kinetics.