Opportunities to treat infection with hepatitis C virus (HCV) are evolving rapidly. From the introduction of interferon‐α monotherapy in 1992 to the approval of telaprevir‐ and boceprevir‐based ...triple therapies with pegylated interferon‐α and ribavirin in 2011, the chances of curing patients infected with HCV genotype 1 have improved from <10% to approximately 70%. Significant further improvements are on the horizon, which may well cure virtually all hepatitis C patients with an all‐oral, interferon‐free regimen in the very near future. These exciting developments are reviewed in the present article.
Normal and cancer breast stem cell in vivo self‐renewal, chemoresistance and tumor growth is regulated by the prolyl‐isomerase Pin1 by promoting Notch1 and Notch4 escape from major ubiquitin‐ligase Fbxw7alphamediated proteasomal degradation.
Nonalcoholic steatohepatitis (NASH)-related cirrhosis and cryptogenic cirrhosis (CC) have become leading indications for liver transplantation (LT) in the US. Our aim was to compare the trends, ...clinical presentation, and outcomes for transplant candidates with NASH and CC.The Scientific Registry of Transplant Recipients (1994-2016) was used to select adult LT candidates and recipients with primary diagnoses of NASH and CC without hepatocellular carcinoma.Two lakh twenty-three thousand three hundred ninety-one LT candidates were listed between 1994 and 2016. Of these, 16,214 (7.3%) were listed for CC and 11,598 (5.2%) for NASH. Before 2004, NASH was seldom coded for an indication for LT, but became more common after 2009. Averaged across the study period, CC candidates compared with NASH candidates were younger and had fewer conditions of metabolic syndrome (MS). CC patients were more likely to have MS components in comparison to candidates with other chronic liver diseases (CLDs) (all P < .0001). For most of the study period, patients with CC or NASH were similarly more likely to be taken off the list due to deterioration or death, with to patients with other CLDs. Post-LT data were available for 14,052 transplant recipients with NASH or CC. With the exception of post-transplant diabetes, the outcomes of patients transplanted for CC and NASH were similar to those of other CLD patients.Number of LT due to CC and NASH cirrhosis is increasing. In the past decade, there is a shift from LT listing diagnosis from CC to NASH potentially related to increased awareness about NASH in transplant centers in the US.
Background. Telaprevir (TVR), a hepatitis C virus (HCV) NS3/4A protease inhibitor, has been approved to treat genotype 1 HCV. To understand the clinical impact of TVR-resistant variants, we analyzed ...samples from patients in phase 3 clinical trials to determine the frequency and retention of TVR-resistant variants in patients who did not achieve sustained virologic response (SVR). Methods. A total of 1797 patients were treated with TVR. Resistant variants (V36A/G/I/L/M, T54A/S, I132V subtype 1a only, R155G/K/T/M, A156F/N/S/T/V, and D168N) were identified after treatment failure and at visits thereafter, by direct (population) sequencing of the NS3/4A region. Kaplan-Meier analysis was used to determine median time to loss of these variants. Results. Resistant variants were observed in 77% (299/388) of patients who did not achieve SVR. Resistance occurred more commonly in subtype 1a (86%; 232/269) than subtype 1b infections (56%; 67/119). After treatment failure, 355 patients had at least 1 follow-up visit (median follow-up period: 9.6 months). Of patients with resistance at time of failure and at least 1 follow-up visit, 60% (153/254) lost resistance. Kaplan-Meier analysis, including all patients with any sequence data after treatment failure, indicated that median time to wild type was 10.6 months (95% confidence interval CI, 9.47–12.20) in subtype 1a and 0.9 months (95% CI, 0.00–2.07) in subtype 1b infections. Conclusions. After failure to achieve SVR with TVR-based treatment, resistant variants are observed in most patients. However, presumably due to the lower fitness of those variants, they tend to be replaced with wild-type virus over time.
Background & Aims Treatment for CH-C contains interferon with substantial associated side effects and health-related quality of life (HRQL) impairment. Currently, there is no published data assessing ...the impact of interferon-free regimens on HRQL. The aim is to report the HRQL of patients who participated in clinical trials of sofosbuvir (SOF) for CH-C. Methods CH-C patients were treated with sofosbuvir (SOF), pegylated interferon (PegIFN), ribavirin (RBV), or placebo in different combinations and duration (POSITRON, FISSION, FUSION, and NEUTRINO phase III trials). HRQL was assessed using SF-36 at baseline, during treatment, at the end of treatment, and at follow-up, and compared between treatment arms. Results HRQL scores decreased over the course of treatment for all treatment arms in all studies; however, patients returned to their baseline score by the end of follow-up. Compared to placebo, SOF and RBV was not associated with HRQL impairment (POSITRON). Compared to SOF and RBV, HRQL was significantly more impaired in the PegIFN and RBV arm (FISSION). For those treated with SOF and RBV, there was no difference in HRQL between 12 weeks or 16 weeks of treatment (FUSION). Multivariate analysis demonstrated that depression, fatigue, and insomnia were important predictors of patients’ HRQL prior, during or after treatment. Additionally, anemia and receiving interferon were predictors of HRQL impairment during treatment. Achieving sustained virologic response after 12 weeks of follow-up (SVR-12) with SOF and RBV was associated with improvement in HRQL scores from baseline. Conclusions Treatment-related HRQL impairment during SOF and RBV regimen is mild, and does not increase with longer treatment duration. Achieving SVR-12 with SOF and RBV is associated with an improvement in HRQL.
Background & Aims Peginterferon lambda-1a (Lambda) is a type-III interferon with similar antiviral activity to alfa interferons but with a diminished extrahepatic receptor distribution, reducing the ...risk for extrahepatic adverse events. Methods This was a randomized, blinded, actively-controlled, multicentre phase 2b dose-ranging study in patients chronically infected with HCV genotypes 1–4. Treatment-naive patients received Lambda (120/180/240 μg) or peginterferon alfa-2a (alfa; 180 μg) once-weekly with ribavirin for 24 (genotypes GT 2,3) or 48 (GT1,4) weeks. Results Rates of undetectable HCV-RNA at week 12 (complete early virologic response cEVR; primary end point) were significantly higher in GT1,4 patients receiving Lambda vs. alfa (170/304, 56% vs. 38/103, 37%); with similar cEVR rates for GT2,3 (80/88, 91% vs. 26/30, 87%). Rates of undetectable HCV-RNA at week 4 were significantly higher on 180 μg (15/102, 15% GT1,4; 22/29, 76% GT2,3) and 240 μg (17/104, 16% GT1,4; 20/30, 67% GT2,3) Lambda than alfa (6/103, 6% GT1,4; 9/30, 30% GT2,3). Sustained virologic responses (post-treatment week 24) were comparable between Lambda and alfa for GT1,4 (37–46% Lambda; 37% alfa) and GT2,3 (60–76% Lambda; 53% alfa). Aminotransferase and/or bilirubin elevations were the primary dose-limiting abnormalities for Lambda; a sponsor-mandated 240 to 180 μg dose reduction was therefore implemented. Serious adverse events were comparable (3–13% Lambda; 3–7% alfa). Grade 3–4 haemoglobin, neutrophil, and platelet reductions were lower on Lambda than alfa. Among alfa patients, 28/133 (21%) had peginterferon and 31/133 (23%) had ribavirin dose reductions for haematologic abnormalities vs. 0/392 and 8/392 (2%) on Lambda. Lambda demonstrated fewer musculoskeletal (16–28% vs. 47–63%) and influenza-like events (8–23% vs. 40–46%) than alfa. Conclusion Lambda was associated with improved or similar rates of virologic response with fewer extrahepatic adverse events than alfa in chronic HCV infection.
Whether the presence of cirrhosis influences patient‐reported outcomes (PROs), including health‐related quality of life, during treatment with newly available anti‐HCV (hepatitis C virus) regimens is ...unclear. Our aim was to assess the association of cirrhosis with PROs in patients treated with sofosbuvir (SOF)‐containing regimens. Four PRO questionnaires (Short Form‐36 SF‐36, Functional Assessment of Chronic Illness Therapy‐Fatigue FACIT‐F, Chronic Liver Disease Questionnaire‐HCV (CLDQ‐HCV), and the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem WPAI‐SHP) were administered to subjects receiving SOF and ribavirin (RBV; FUSION trial, N = 201, 34% cirrhosis; VALENCE trial: N = 333, 21% cirrhosis) and SOF, RBV, and pegylated interferon (Peg‐IFN; NEUTRINO trial: N = 327, 17% cirrhosis). HCV patients with cirrhosis showed significant impairment of PROs before initiation of treatment. During treatment, patients with cirrhosis treated with the IFN‐free regimen experienced moderate decline in their PRO scores (0.6%‐5.2% on a normalized scale of the summary scores; all P > 0.02). In contrast, patients with cirrhosis treated with IFN‐containing regimen showed decline in PRO scores that ranged from 3.4% to 16.0% (all P < 0.005). Nevertheless, by follow‐up week 12, no PRO decrement from baseline was observed in patients with cirrhosis regardless of the treatment regimen. Furthermore, in patients with cirrhosis with HCV who achieved sustained virological response at 12 weeks (SVR‐12), some improvement in PROs from baseline was observed. During treatment, changes in PRO scores were similar between patients with and without cirrhosis for both treatment regimens (all P > 0.05). Independent predictors of lower PROs in patients with cirrhosis included baseline depression, anxiety, fatigue, high HCV viral load, female gender, and receiving IFN‐containing treatment. Conclusions: Treatment with SOF+RBV with or without Peg‐IFN is tolerated by HCV patients with and without cirrhosis in terms of their PRO scores. After achieving SVR‐12 with the IFN‐free regimen, patients with cirrhosis showed improvement in some aspects of their PROs. (Hepatology 2014;59:2161–2169)
Hepatitis C-A clinical review Wang, Lan S.; D'Souza, Lionel S.; Jacobson, Ira M.
Journal of medical virology,
11/2016, Letnik:
88, Številka:
11
Journal Article
HDV leads to the most severe form of viral hepatitis; however, the prevalence of HDV is not well understood. Using real-world data from the All-Payer Claims Database, this study estimates the ...prevalence of HBV/HDV infection among the chronic HBV population and describes patient/clinical characteristics for adults with HBV/HDV infection in the United States.
Adults (≥18 years) with ≥1 inpatient claim or ≥2 outpatient claims for HDV infection or HBV in the All-Payer Claims Database from January 1, 2014, to December 31, 2020, were identified. HDV prevalence was calculated as the proportion of patients with HBV/HDV infection among total patients with HBV infection. Patient characteristics, socioeconomic status, advanced liver complications (eg, cirrhosis, HCC), and comorbidities were assessed. A total of 6719 patients were diagnosed with HBV/HDV among 144,975 with HBV and 12 months of continuous data, for a prevalence of 4.6%. At diagnosis, 31.7% of patients with HBV/HDV had advanced liver complications, including compensated cirrhosis (16.3%) and decompensated cirrhosis (10.4%). Diabetes (50.5%), hypertension (49.8%), and HIV infection (30.9%) were the top 3 comorbidities.
In a large database capturing approximately 80% of the US-insured population, HBV/HDV infection prevalence was 4.6% among adults infected with HBV. Patients infected with HDV had high rates of baseline liver complications and other comorbidities at the time of diagnosis, suggesting potentially delayed diagnosis and/or treatment. Earlier identification of HBV/HDV infection among the population with HBV may provide opportunities to improve linkage to care and treatment, thereby reducing the risk of liver-related morbidity and mortality.
Hepatocellular carcinoma (HCC) has long been recognized as a complication in people with chronic liver disease, particularly those with cirrhosis. Two gene therapies for haemophilia A and B recently ...approved in Europe and the US utilize adeno-associated virus (AAV) vectors designed to target hepatocytes. A number of other AAV gene therapies are undergoing clinical investigation for both liver and extrahepatic diseases, many of which likely transduce hepatocytes as well. Although AAV vectors predominantly persist in episomal forms, concerns about insertional mutagenesis have arisen due to findings in pre-clinical models and in a small subset of human HCC cases featuring wild-type AAV integrations in proximity to potential oncogenes. Despite the absence of any causative link between AAV vector therapy and HCC in approved extrahepatic gene therapies or haemophilia gene therapy trials, the package inserts for the recently approved haemophilia gene therapies advise HCC screening in subsets of individuals with additional risk factors. In this review, we discuss HCC risk factors, compare various screening modalities, discuss optimal screening intervals, and consider when to initiate and possibly discontinue screening. At this early point in the evolution of gene therapy, we lack sufficient data to make evidence-based recommendations on HCC screening. While AAV vectors may eventually be shown to be unassociated with risk of HCC, we presently favour a cautious approach that entails regular surveillance until such time as it is hopefully proven to be unnecessary.
Background & Aims Interferon-based treatment of chronic hepatitis C virus (HCV) infection can negatively affect patient-reported outcomes (PROs) and work productivity (WP). We assessed these factors ...in patients with chronic hepatitis C treated with sofosbuvir and ribavirin, with or without pegylated interferon. Methods The HCV-specific Quality of Life (Chronic Liver Disease Questionnaire-HCV version CLDQ-HCV), Functional Assessment of Chronic Illness Therapy-Fatigue, and Work Productivity and Activity Index: Specific Health Problem questionnaires were completed before, during, and after treatment of patients infected with HCV genotypes 2 or 3 who received sofosbuvir and ribavirin for 16 or 12 weeks (the FUSION study, n = 201) or patients infected with HCV genotype 1 who received pegylated interferon, sofosbuvir, and ribavirin for 12 weeks (the NEUTRINO study, n = 327). Results Patients in each group of the FUSION study had similar PRO and WP scores at each time point (all comparisons, P > .05). Compared with baseline, patients had modest reductions in fatigue, HCV-specific quality of life, and WP and Activity Index scores during treatment ( P = .02 to <.0001). However, by 4 weeks after treatment, all scores returned to baseline levels or higher. Subjects in the NEUTRINO study had greater reductions in these scores during treatment; most remained significant through 4 weeks after treatment ( P < .05). Significant improvements in PROs were observed among patients with sustained virologic responses 12 weeks after treatment in the FUSION and NEUTRINO studies (all P < .05). In multivariate analyses after adjustment for confounders, interferon therapy was independently associated with worse PROs after 12 weeks of treatment. Conclusions On the basis of an analysis of 2 large clinical trials (FUSION and NEUTRINO), patient outcome and productivity are more negatively affected by the inclusion of pegylated interferon in treatment than by interferon-free regimens. Patients with sustained virologic responses 12 weeks after treatment had significant improvements in PROs in both studies.
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