Subject(s)
Antiviral Agents/adverse effects , Hepatitis C, Chronic/drug therapy , Photosensitivity Disorders/chemically induced , Porphyrins/metabolism , Simeprevir/adverse effects , Antiviral Agents/therapeutic use , Carcinoma, Hepatocellular/complications , Carcinoma, Hepatocellular/surgery , Cytochrome P-450 Enzyme System/metabolism , Drug Therapy, Combination , Graft Rejection/prevention & control , Hepatitis C, Chronic/complications , Humans , Immunosuppressive Agents/therapeutic use , Liver Cirrhosis/complications , Liver Cirrhosis/surgery , Liver Neoplasms/complications , Liver Neoplasms/surgery , Liver Transplantation , Male , Middle Aged , Photosensitivity Disorders/metabolism , Recurrence , Ribavirin/therapeutic use , Sofosbuvir/therapeutic useABSTRACT
There are reports of pretransplant sofosbuvir (SOF) plus ribavirin being effective in preventing recurrent hepatitis C virus (HCV) infection after liver transplantation (LT). The aim of this study was to assess the cost-effectiveness of this strategy in the area served by the North Italy Transplant program. We retrospectively assessed the impact of HCV infection on post-LT survival in 2376 consecutive adult patients (MELD ≤ 25, unknown genotype, period 2004-2009) and the prevalence costs of conventional standard of care (SOC) antiviral therapy (pegylated interferon plus ribavirin) after LT. A Markov model was developed to compare two strategies: 12-24 weeks of SOF+ ribavirin for pre-LT anti-HCV treatment versus on-demand post-LT SOC antiviral therapy. Among the 1794 patients undergoing LT, 860 (48%) were HCV+ and 50% of them were given SOC therapy after LT (mean cost of drugs and adverse effect management = 14,421 per patient). HCV etiology had a strong impact on post-LT survival (hazard ratio = 1.59, 95% CI = 1.22-2.09, P = 0.0007). After Monte Carlo simulation, pre-LT SOF therapy showed a median survival benefit of 1.5 quality-adjusted life years and an Incremental cost-effectiveness ratio (ICER) of 30,663/QALY, proving cost-effective in our particular Italian scenario. The costs of SOF therapy, sustained viral response rate 12 weeks after LT, and recipient's age were the main ICER predictors at multivariate analysis. This study proposes a dynamic model based on real-life data from northern Italy for adjusting the costs of pre-LT direct-acting antiviral therapies to the actual sustained virological response reached after LT.
Subject(s)
Antiviral Agents/administration & dosage , Hepatitis C, Chronic/prevention & control , Liver Failure/surgery , Liver Transplantation/economics , Sofosbuvir/administration & dosage , Antiviral Agents/economics , Chronic Disease , Cost-Benefit Analysis , End Stage Liver Disease/surgery , Female , Hepacivirus , Hepatitis C, Chronic/complications , Humans , Italy , Kaplan-Meier Estimate , Liver Failure/complications , Liver Transplantation/adverse effects , Male , Markov Chains , Middle Aged , Preoperative Period , Probability , Recurrence , Research Design , Retrospective Studies , Sofosbuvir/economics , Treatment Outcome , Waiting ListsABSTRACT
BACKGROUND: Triple therapy including Telaprevir or Boceprevir still represents in many European countries the standard of care for patients with Hepatitis C Virus genotype 1 infection. The number of patients who received this treatment resulted generally lower than expected. We investigated, among naïve patients, number and characteristics of treatment candidates who were started on triple or dual therapy in comparison to those who were deferred. PATIENTS AND METHODS: 621 naïve treatment candidates were prospectively evaluated at each center. Factors associated with decision to defer or treat with dual or triple therapy were investigated by univariate and multivariate analyses. Rates of Sustained Virological Response and safety profile were analysed. RESULTS: Of candidates to treatment, 33% did not received it. It was mostly due to high risk of Interferon-induced decompensation. Of 397 patients who were started on treatment, 266 (67%) received triple, 131 dual. Among patient receiving treatment, unfavorable IL28B, severe liver damage and higher albumin were independently associated with the physician decision to administer triple therapy. Sustained Virological Response after dual therapy was 66.4%, after triple 73.7% (pâ=â0.14). 142 patients received Telaprevir. The choice of Telaprevir-based therapy was associated with higher Body Mass Index and advanced liver disease. Sustained Virological Response rates were 71.1% after Telaprevir and 76.6% after Boceprevir. CONCLUSIONS: Individualizing treatment with available regimens allows to maximize Sustained Virological Response and to reduce the number of patients who remain untreated. High proportion of patients with severe liver damage urgently need Interferon free treatment.
Subject(s)
Hepacivirus/genetics , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/genetics , Precision Medicine , Decision Making , Drug Therapy, Combination , Female , Genetic Association Studies , Genotype , Hepatitis C, Chronic/virology , Humans , Interferons , Interleukins/genetics , Italy , Male , Middle Aged , Oligopeptides/therapeutic use , Proline/analogs & derivatives , Proline/therapeutic use , Treatment OutcomeABSTRACT
OBJECTIVES: To evaluate whether, in chronic hepatitis C-positive naive patients recruited in the routine clinical setting and treated with pegylated-interferon-α2b (Peg-IFN) and ribavirin (RBV), the sustained virologic response (SVR) is durable over the long term and whether it is associated with a decrease in liver complications and incidence of glucose abnormalities. PATIENTS AND METHODS: This was a prospective long-term follow-up study of 182 naive patients enrolled in 2001-2002 and treated with Peg-IFN and RBV and followed up to December 2010, with clinical, biochemical, and virological evaluations every 6-12 months. RESULTS: None of the 115 (63.2%) sustained responders showed late viremic relapse during the follow-up. SVR was better defined at 24 weeks (16/16 relapsers, 100%) than at 12 weeks after the end of therapy (14/16 relapsers, 87.5%). On multivariable analysis, viral genotype (odds ratio 0.16, 95% confidence interval 0.07-0.36, P=0.0001) and a greater than 20% RBV reduction (odds ratio 5.21, 95% confidence interval 1.54-17.67, P=0.008) predicted long-term response (LTR) independently. The incidence of cirrhosis was significantly higher among nonresponders (21.3%) compared with long-term responders (0.9%, P≤0.0001), but the risk of developing glucose abnormalities was not significantly reduced in long-term responders (hazard ratio 1.36, P=0.363). Hepatocellular carcinoma occurred only in three cases. CONCLUSION: SVR achieved in patients treated in the routine clinical setting with Peg-IFN and RBV is durable over the long term and LTR significantly reduces the risk of progression to cirrhosis; however, in a population with mild liver fibrosis, the clinical impact of LTR on the risk of glucose abnormalities seems negligible.
Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C, Chronic/drug therapy , Interferon-alpha/therapeutic use , Polyethylene Glycols/therapeutic use , Ribavirin/therapeutic use , Adult , Antiviral Agents/adverse effects , Disease Progression , Drug Therapy, Combination , Female , Follow-Up Studies , Glucose Metabolism Disorders/prevention & control , Glucose Metabolism Disorders/virology , Hepacivirus/drug effects , Hepacivirus/genetics , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/diagnosis , Humans , Interferon-alpha/adverse effects , Kaplan-Meier Estimate , Liver Cirrhosis/prevention & control , Liver Cirrhosis/virology , Logistic Models , Male , Middle Aged , Multivariate Analysis , Odds Ratio , Polyethylene Glycols/adverse effects , Proportional Hazards Models , Prospective Studies , RNA, Viral/blood , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic use , Recurrence , Ribavirin/adverse effects , Risk Factors , Time Factors , Treatment Outcome , Viral LoadABSTRACT
Hepatitis C virus (HCV) readily establishes high-level lifelong persistent infection in the majority of immunocompetent adults with failure of HCV-specific CD8+ CTL to clear viral replication. Virus-induced conditioning of innate immune responses is a possible mechanism that may contribute to the impairment of virus-specific CD8+ CTL responses. Here, we analyzed whether triggering of NK cell receptor expression and function is affected during chronic viremic HCV infection. Flow cytometric analysis of purified resting peripheral NK cells showed no evidence of NK cell activation, while analysis of natural cytotoxicity receptors (NCR) showed that NK cells from HCV-infected patients had selective increased expression of NKp30 and NKp46. NK cells had corresponding conserved cytotoxic activity against all targets with the exception of HepG2 hepatoma cells. Freshly separated NK cells from HCV patients showed significant production of IL-10 and normal concentrations of IFN-gamma upon cell-mediated triggering. Thus, increased expression of NKp30 during HCV infection with increased IL-10 production could contribute, once NK cells localize in the liver, to a NK-DC crosstalk leading to skewing of subsequent adaptive immune responses and lack of virus control.
Subject(s)
Hepatitis C, Chronic/immunology , Interleukin-10/biosynthesis , Killer Cells, Natural/immunology , Membrane Glycoproteins/biosynthesis , Receptors, Immunologic/biosynthesis , Cytotoxicity, Immunologic , Flow Cytometry , Fluorescent Antibody Technique , Humans , Interferon-gamma/biosynthesis , Membrane Glycoproteins/immunology , Natural Cytotoxicity Triggering Receptor 1 , Natural Cytotoxicity Triggering Receptor 3 , Receptors, Immunologic/immunology , ViremiaABSTRACT
BACKGROUND: Hepatitis C virus (HCV) is believed to exert a suppressive effect on hepatitis B virus (HBV) in most HBV/HCV-coinfected patients; once HCV is cured by interferon-based therapy, these patients may show HBV reactivation. However, recent evidence revealed that the virological status in HBV/HCV-untreated individuals may vary over time and may show fluctuating profiles. METHODS: To evaluate the behaviour of apparently inactive HBV infection in patients under treatment for a concurrent HCV infection, we performed a prospective study that evaluated nine consecutive patients (eight males with a median age of 45.9 years, and one female aged 62 years) longitudinally followed-up with bi-monthly evaluation of HBV/HCV viraemia levels and liver biochemistry during a 1-year treatment with interferon plus ribavirin. RESULTS: In seven cases the HBV infection maintained its inactive status independently of the HCV response to therapy. By contrast, two non-responder cases with persistently high HCV RNA levels showed HBV DNA flairs during the follow-up, indicating a status of active HBV infection with fluctuating virological profiles. CONCLUSIONS: This study suggests that the HBV behaviour may be independent of the HCV activity during anti-HCV therapy in HBV/HCV-coinfected patients, and that the HBV virological profile should be monitored to recognize possible reactivations that might lead to more proper therapeutic choices or adjustments.
Subject(s)
Antiviral Agents/therapeutic use , Hepacivirus/isolation & purification , Hepatitis B virus/isolation & purification , Hepatitis B, Chronic/virology , Hepatitis C, Chronic/drug therapy , Interferon Type I/therapeutic use , Interferon-alpha/therapeutic use , Ribavirin/therapeutic use , Adult , DNA, Viral/blood , Drug Therapy, Combination , Female , Hepacivirus/genetics , Hepatitis B virus/physiology , Hepatitis B, Chronic/complications , Hepatitis C, Chronic/complications , Humans , Interferon alpha-2 , Italy , Male , Middle Aged , Polyethylene Glycols , RNA, Viral/blood , Recombinant Proteins , Viral Load , Virus ActivationABSTRACT
OBJECTIVES: The virological profiles of hepatitis B and C viruses (HBV and HCV) and their interplay in cases of coinfection are undefined. A suppressed and occult HBV infection may occur in hepatitis B surface antigen (HBsAg) negative patients with chronic hepatitis C. The HCV core protein is able to inhibit HBV "in vitro," and serines at positions 99 and 116 are essential for such inhibition. We aimed to assess the HBV and HCV virological profiles in cases of coinfection and to evaluate the relationship between HCV core gene variability and HBV activity. METHODS: Eighty-two anti-HCV positive patients were examined: 35 cases were HBsAg positive, 24 were HBsAg negative with "occult" HBV infection, and 23 were HBV negative. HBV and HCV viremia levels were evaluated in all cases. HCV genomic region coding for the aminoacid sequence 99-116 of core protein was amplified and sequenced in all HCV RNA positive cases. The entire core gene was amplified and sequenced in three randomly selected cases. RESULTS: Serum HCV RNA was detected in all cases but 13, all HBsAg positive individuals; HCV viremia levels of the other 22 HBsAg positive subjects were similar to those detected in HBsAg negative patients with or without occult HBV infection. Among the 35 HBsAg positive patients both HBV DNA and HCV RNA were detected in five cases, HCV RNA alone in 17, and HBV DNA alone in six, whereas seven cases had undetectable levels of both viruses. Sequencing analyses showed that the HCV core gene was highly preserved in all patients. CONCLUSION: A wide spectrum of HCV and HBV virological patterns may occur in a case of coinfection. HCV core variability is not related to HBV activity "in vivo."