Mihály Makara

Performance of two HCV RNA assays during protease inhibitor-based triple therapy in patients with advanced liver fibrosis and cirrhosis.

Introduction On-treatment HCV RNA measurements are crucial for the prediction of a sustained virological response (SVR) and to determine treatment futility during protease inhibitor-based triple therapies. In patients with advanced liver disease an accurate risk/benefit calculation based on reliable HCV RNA results can reduce the number of adverse events. However, the different available HCV RNA assays vary in their diagnostic performance. Aim To investigate the clinical relevance of concordant and discordant results of two HCV RNA assays during triple therapy with boceprevir and telaprevir in patients with advanced liver fibrosis/cirrhosis. Methods We collected on-treatment samples of 191 patients with advanced liver fibrosis/cirrhosis treated at four European centers for testing with the Abbott RealTime (ART) and COBAS AmpliPrep/COBAS TaqMan HCV v2.0 (CTM) assays. Results Discordant test results for HCV RNA detectability were observed in 23% at week 4, 17% at week 8/12 and 9% at week 24 on-treatment. The ART detected HCV RNA in 41% of week 4 samples tested negative by the CTM. However, the positive predictive value of an undetectable week 4 result for SVR was similar for both assays (80% and 82%). Discordance was also found for application of stopping rules. In 27% of patients who met stopping rules by CTM the ART measured levels below the respective cut-offs of 100 and 1000 IU/ml, respectively, which would have resulted in treatment continuation. In contrast, in nine patients with negative HCV RNA by CTM at week 24 treatment would have been discontinued due to detectable residual HCV RNA by the ART assay. Importantly, only 4 of these patients failed to achieve SVR. Conclusion Application of stopping rules determined in approval studies by one assay to other HCV RNA assays in clinical practice may lead to over and undertreatment in a significant number of patients undergoing protease inhibitor-based triple therapy.

Non-Hodgkin Lymphoma and Hepatitis C: Where We are and What Next?

The association between hepatitis C virus and certain B-cell non-Hodgkin lymphomas, such as marginal zone lymphomas, is supported by epidemiological studies. The exact pathogenetic mechanism is still unknown but both chronic antigenic stimulation and viral lymphotropism may contribute to the evolution of the malignant clone. Furthermore, the hematologic response following hepatitis C antiviral treatment suggests that the virus may have an etiologic role. Interferon and ribavirin based treatment proved to be successful in small case series of hepatitis C virus associated splenic lymphoma with villous lymphocytes, therefore, it is suggested that antiviral treatment could be an alternative to chemo-immunotherapy. In the near future new more potent direct acting antivirals will make interferon free treatments possible. It is still an open question whether these new short-course regimens are also effective in the treatment of associated lymphomas and what is the importance of the lymphoid reservoir in eliminating HCV.

Hepatic steatosis in individuals living with HIV measured by controlled attenuation parameter: a cross-sectional study.

Objectives Available data on the prevalence of hepatic steatosis in an unselected HIV-infected population are limited. The aim of this study was to determine the prevalence of hepatic steatosis and assess the associated factors in HIV-infected individuals. Patients and methods One hundred and thirty-six HIV-infected individuals were enrolled in this cross-sectional study. Patients underwent transient elastography and controlled attenuation parameter (CAP) measurements. We analyzed the associations between the CAP value and demographic, metabolic, and immunologic parameters. For the first time, in HIV-infected individuals, we used a continuous scale of CAP values to identify significant covariates of hepatic fat accumulation. As a result and compared with other methods, one of the main advantages of CAP was that the quantitative measurement of liver steatosis could be used for analysis. Results Using univariate analysis, CAP was significantly correlated with the following continuous variables: CD4 percentage (P=0.035), CD8 percentage (P=0.016), age (P<0.001), CD4/8 ratio (P=0.002), BMI (P<0.001), serum triglyceride (P<0.001), and serum cholesterol (P=0.004) levels, the length of known HIV positivity (P<0.001), and liver stiffness (P=0.041). With respect to categorical variables, a significant association was found for the presence of diabetes (P=0.006), hypertension (P<0.001), facial lipodystrophy (P=0.031), and the use of lopinavir (P=0.042). In multivariate analysis using linear regression, BMI (P<0.001), presence of diabetes (P=0.026), and hypertension (P=0.040) were identified as independent significant correlates. Darunavir therapy was associated negatively with the CAP value (P=0.032). Conclusion Our findings reflect the importance of metabolic factors in hepatic steatosis. The strongest independent covariate was BMI.

Predictive value of psychosocial assessment for the mortality of patients waiting for liver transplantation

Abstract Selecting suitable candidates for liver transplantation is the most challenging task of pre-transplant evaluation. In addition to somatic assessment, psychosocial evaluation has been proven important in identifying patients at high risk of potential failure. The Transplant Evaluation Rating Scale (TERS) is a widely used rating instrument for the assessment of psychosocial risk factors before liver transplantation. The aim of this study was to explore the predictive value of TERS for mortality in liver transplant patients before and after transplantation. The medical records of patients referred for psychiatric evaluation before liver transplantation between 2003 –2013 were analysed. Administering TERS was part of the pre-transplant evaluation. The TERS scores of patients who died before and after transplantation were compared with those who survived following transplantation. One hundred and sixteen patients were referred for pre-transplant psychiatric evaluation. Patients with successful liver transplants scored significantly lower on TERS than those who died before transplantation (30.65 ± 6.06 vs. 34.75 ± 8.25, p = .031). Patients who died after transplantation scored significantly better on TERS than those who died before transplantation (28.79 ± 2.81 vs. 34.75 ± 8.25, p = .003). There was no significant difference between the deceased and surviving transplanted patients’ TERS scores (28.79 ± 2.81 vs. 31.19 ± 6.66, p = .365). TERS appears to be a suitable rating instrument to help select candidates who have higher chance to survive prior to transplantation but it could not predict post-transplant mortality.

New therapeutic options for HCV in Central Europe

New therapeutic options became available in 2015 in the European Union. We present the availability of interferon-free regimens with direct acting antivirals (DAA) in four Central European countries – the Czech Republic, Hungary, Poland and Slovakia – which despite similar historical, geographical and economic situations demonstrate different systems for access to anti-HCV (hepatitis C virus) medication. Treatment of patients in the Czech Republic was based in 2015 on an exceptional individual reimbursement procedure, but regular reimbursement procedures are expected in 2016. In Hungary the decision for treatment is balanced against budget limitations and the national Priority Index system reflecting stage of liver disease, activity of the disease and predictive factors. A reimbursed interferon (IFN)-free therapeutic program for all genotypes, without restrictions related to hepatic fibrosis and treatment history, is already available in Poland. In Slovakia patients with advanced fibrosis are currently selected for possible IFN-free therapy in 2016.

Diagnosis and treatment of chronic hepatitis B and D. Hungarian national consensus guideline

Diagnosis and treatment of hepatitis B and D virus infections mean that the patient is able to maintain working capacity, increase quality of life, prevent cancer, and prolong life expectancy, while the society benefits from eliminating the chances of further transmission of the viruses, and decreasing the overall costs of serious complications. The guideline delineates the treatment algorithms for 2014, which is agreed on a consensus meeting of specialists involved in the treatment of the above diseases. The prevalence of hepatitis B virus infection in the Hungarian general population is 0.5-0.7%. The indications of treatment is based upon viral examinations (including viral nucleic acid determination), determinations of disease activity and stage (including biochemical, pathologic, and/or non-invasive methods), and excluding contraindications. To avoid unnecessary side effects and for cost-effective approach the guideline emphasizes the importance of quick and detailed virologic evaluations, the applicability of transient elastography as an acceptable alternative of liver biopsy in this regard, as well as the relevance of appropriate consistent follow up schedule for viral response during therapy. The first choice of therapy in chronic hepatitis B infection can be pegylated interferon for 48 weeks or continuous entecavir or tenofovir therapy. The latter two must be continued for at least 12 months after hepatitis B surface antigen seroconversion. Adefovir dipivoxil is recommended mainly in combination therapy. Lamivudine is no longer a first choice; patients currently taking lamivudine must switch if response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection.

[Diagnosis, treatment, and follow-up of hepatitis C-virus related liver disease. Hungarian national consensus guideline].

Approximately 70 000 people are infected with hepatitis C virus in Hungary, more than half of whom are not aware of their infection. Early recognition and effective treatment of related liver injury may prevent consequent advanced liver diseases (liver cirrhosis and liver cancer) and its complications. In addition, it may increase work productivity and life expectancy of infected individual, and can prevent further viral transmission. Early recognition can substantially reduce the long term financial burden of related morbidity from socioeconomic point of view. Pegylated interferon + ribavirin dual therapy, which is available in Hungary since 2003, can kill the virus in 40-45% of previously not treated (naïve), and in 5-21% of previous treatment-failure patients. Addition of two direct acting first generation protease inhibitor drugs (boceprevir and telaprevir) to the dual therapy increased the chance of sustained clearance of virus to 63-75% and 59-66%, respectively. These two protease inhibitor drugs are available and financed for a segment of Hungarian patients since May 2013. Indication of therapy includes exclusion of contraindications to the drugs and demonstration of viral replication with consequent liver injury, i.e., inflammation and/or fibrosis in the liver. For initiation of treatment as well as for on-treatment decisions accurate and timely molecular biology tests are mandatory. Staging of liver damage (fibrosis) non-invasive methods (transient elastography and biochemical methods) are acceptable to avoid concerns of patients related to liver biopsy. Professional decision for treatment is balanced against budget limitations in Hungary, and priority is given to those with urgent need using a national Priority Index system reflecting stage of liver disease as well as additional factors (activity and progression of liver disease, predictive factors and other special circumstances). All naïve patients are given a first chance with dual therapy. Those with genotype 1 infection and with on-treatment or historic failure to dual therapy are eligible to receive protease inhibitor based triple therapy provided, they reach financial cutoff eligibility based on Priority Index. Duration of therapy is usually 48 weeks in genotype 1 with a response-guided potential to reduce duration for non-cirrhotic patients. Patients with non-1 genotypes are treated with dual therapy (without protease inhibitors) for a genotype and response driven duration of 16, 24, 48, or 72 week. Careful monitoring for early recognition and management of side-effects as well as viral response and potential breakthrough during protease-inhibitor therapy are recommended.

Ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin in HCV genotype 1 infected patients who failed previous protease inhibitor therapy

Aim of the study Combination of ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin (3DDA±RBV) therapy is shown to be effective in HCV genotype 1 (GT1) infected patients. However, sparse data exist in patients who failed previous boceprevir or telaprevir based therapies. Real life efficacy and safety of this combination were evaluated in HCV GT1b infected patients (mostly cirrhotics) with compensated liver disease who failed previous boceprevir or telaprevir based therapies more than a year before. Material and methods Data of previous protease inhibitor failure patients, treated with 3DAA+RBV for 12 weeks (GT1b and/or non-cirrhotics) or 24 weeks (non-GT1b cirrhotics), were retrospectively collected. Results Population characteristics: boceprevir/telaprevir-failure: 82/45, GT1b: 117, cirrhotic: 111 (87.4%). SVR12/24 was observed in 103/105 patients (98.1%) of those who reached either time point. Four SAEs reported: one death due to myocardial infarction, another due to recurrent hepatocellular carcinoma after achieving SVR12, two hospitalizations (elevation of transaminases, pneumonia). Grade ≥ 3 AEs or laboratory abnormalities were reported in < 10% of patients; they were transient in all patients. No early discontinuation of drugs due to SAE has been reported. Conclusions One year after previous failure of boceprevir or telaprevir based therapy, 12 weeks of 3DAA+RBV combination in HCV GT1b infected patients is similarly effective and safe as in those with no previous HCV therapy, even in the presence of cirrhosis. These findings might be of particular interest in settings where alternative therapies for such patients are not available or not affordable.

Hepatic fibrosis and factors associated with liver stiffness in HIV mono-infected individuals

Background Liver disease has become an important cause of morbidity and mortality even in those HIV-infected individuals who are devoid of hepatitis virus co-infection. The aim of this study was to evaluate the degree of hepatic fibrosis and the role of associated factors using liver stiffness measurement in HIV mono-infected patients without significant alcohol intake. Methods We performed a cross-sectional study of 101 HIV mono-infected patients recruited prospectively from March 1, 2014 to October 30, 2014 at the Center for HIV, St István and St László Hospital, Budapest, Hungary. To determine hepatic fibrosis, liver stiffness was measured with transient elastography. Demographic, immunologic and other clinical parameters were collected to establish a multivariate model. Bayesian Model Averaging (BMA) was performed to identify predictors of liver stiffness. Results Liver stiffness ranged from 3.0–34.3 kPa, with a median value of 5.1 kPa (IQR 1.7). BMA provided a very high support for age (Posterior Effect Probability-PEP: 84.5%), moderate for BMI (PEP: 49.3%), CD4/8 ratio (PEP: 44.2%) and lipodystrophy (PEP: 44.0%). For all remaining variables, the model rather provides evidence against their effect. These results overall suggest that age and BMI have a positive association with LS, while CD4/8 ratio and lipodystrophy are negatively associated. Discussion Our findings shed light on the possible importance of ageing, overweight and HIV-induced immune dysregulation in the development of liver fibrosis in the HIV-infected population. Nonetheless, further controlled studies are warranted to clarify causal relations.

A hepatitis B- és D-vírus-fertőzés diagnosztikája, antivirális kezelése. Magyar konszenzusajánlás. Érvényes: 2017. szeptember 22-től

1Budai Hepatológiai Centrum, Budapest, Szent János Kórház és Észak-budai Egyesített Kórházak, Hepatológiai Szakambulancia, Budapest Semmelweis Egyetem, Általános Orvostudományi Kar, 2Transzplantációs és Sebészeti Klinika, 3II. Belgyógyászati Klinika, 4I. Belgyógyászati Klinika, Budapest 5Szent György Egyetemi Oktató Kórház, I. Belgyógyászat és Molekuláris Diagnosztikai Laboratórium, Székesfehérvár 6Egyesített Szent István és Szent László Kórház, Budapest 7Pécsi Tudományegyetem, Általános Orvostudományi Kar, I. Belgyógyászati Klinika, Pécs 8MH Egészségügyi Központ Honvédkórház, I. Belgyógyászati Osztály, Budapest 9Debreceni Egyetem, Általános Orvostudományi Kar, Orvosés Egészségtudományi Centrum, Belgyógyászati Intézet, Debrecen 10Somogy Megyei Kaposi Mór Oktató Kórház, Belgyógyászati Osztály, KaposvárDiagnosis and treatment of hepatitis B virus (HBV) and hepatitis D virus infection mean for the patient to be able to maintain working capacity, to increase quality of life, to prevent cancer, and to prolong life expectancy, while the society benefits from eliminating the chances of further transmission of the viruses, and decreasing the overall costs of serious complications. The guideline delineates the treatment algorithms from 22 September 2017 set by a consensus meeting of physicians involved in the treatment of these diseases. The prevalence of HBV infection in the Hungarian general population is 0,5-0,7%. The indications of treatment are based upon viral examinations (including viral nucleic acid determination), determinations of disease activity and stage (including biochemical, pathologic, and/or non-invasive methods), and excluding contraindications. To avoid unnecessary side effects and for a cost-effective approach, the guideline stresses the importance of quick and detailed virologic evaluations, the applicability of transient elastography as an acceptable alternative of liver biopsy in this regard as well as the relevance of appropriate consistent follow-up schedule for viral response during therapy. The first choice of therapy in chronic HBV infection can be pegylated interferon for 48 weeks or continuous entecavir or tenofovir therapy. The latter two must be continued for at least 12 months after hepatitis B surface antigen seroconversion. Lamivudine is no longer the first choice; patients currently taking lamivudine must switch if the response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection. Orv Hetil. 2018; 159(Suppl 1): 24-37.