Dorota Kozielewicz

Association of IL28B Polymorphisms With the Response to Peginterferon Plus Ribavirin Combined Therapy in Polish Patients Infected With HCV Genotype 1 and 4

Background Three single nucleotide polymorphisms (SNPs) near interleukin-28B (IL-28B) gene were shown to be highly associated with treatment response (SVR) in patients with chronic hepatitis C virus (HCV) infection. There is limited data about the role of single and combined IL-28B polymorphisms in HCV-infected Polish population. Objectives This studys aim was to determine predictability of three IL-28B gene polymorphisms and other known prognostic factors on the treatment response in HCV genotype 1 and 4 infected Polish patients. The effect of IL-28B polymorphisms on therapy was also compared with other known prognostic factors. Patients and Methods We genotyped IL-28B polymorphisms (rs12979860, rs12980275 and rs8099917) by polymerase chain reaction-based restriction fragment length polymorphism assay in a group of 293 patients from which a selected cohort of 174 treatment-naiev patients underwent treatment. Results We showed that rs12979860 CC [odds ratio (OR) = 4.6, P < 0.001], rs12980275 AA (OR = 2.9, P = 0.002) and rs8099917 TT (OR = 2.2, P = 0.016) genotypes were associated with successful treatment compared to the rs12979860 CT-TT, rs12980275 AG-GG and rs8099917 TG-GG, respectively. Patients bearing of IL-28B profile including the three favourable genotypes do not have much chance of a recovery (OR = 3.4, P = 0.002). Except for IL-28B polymorphisms, there was no association of SVR with any other pretreatment clinical data in analyzed group. The correlation of SNPs with other host and viral factors revealed association of favorable genotypes of IL-28B markers with high levels of alanine aminotransferase and baseline HCV viral load. Conclusions IL-28B polymorphisms were the strongest pretreatment predictors of response to pegylated interferon and ribavirin in Polish patients chronically infected with HCV genotype 1 and 4. This study confirm the strongest impact of IL-28B rs12979860 on SVR, nevertheless rs12980275 AA seems to be more important than rs8099917 TT in predicting positive treatment response.

Can pegylated interferon α 2a cause development of thyroid disorders in patients with chronic hepatitis B

Introduction: Hepatitis B virus infection is treated with pegylated (Peg) IFNα and nucleos(t)ide analogues. The disadvantages of PegIFNα include thyroid disorders. In this single-center study, the type, incidence and consequences of thyroid dysfunction in patients receiving PegIFNα due to chronic hepatitis B (CHB) were analyzed. Patients and methods: The analysis included 106 patients (80 males) with CHB, aged 20 – 58 years, treated with PegIFNα-2a at a dose of 180 μg/week subcutaneously for 48 weeks. The levels of thyroid-stimulating hormone (TSH) and thyroid antibodies (TAbs) that is anti-thyroid peroxidase antibodies (TPOAb) and thyroglobulin antibodies were measured in all patients at baseline. Furthermore, TSH was measured every 3 months during treatment and for 12 months after completion of treatment. If the TSH level was abnormal, free thyroxine 4 levels and TAbs were measured. Results: All patients started the therapy with normal TSH and TAb levels. In 99 patients, TSH levels remained normal throughout the therapy. Thyroid disorder occurred in seven patients (6.6%), six of whom developed hypothyroidism and one who developed hyperthyroidism. Thyroid dysfunction was diagnosed in six women and one man. TAbs (only TPOAbs) were found in two patients (1.88%). Conclusions: Thyroid disorder is a rare, though possible not transient, complication of IFN therapy in CHB patients.

Effectiveness and safety of ledipasvir/sofosbuvir ± ribavirin in the treatment of HCV infection: The real-world HARVEST study

BACKGROUND To evaluate the effectiveness and safety of ledipasvir/sofosbuvir (LDV/SOF)±ribavirin (RBV) regimen in a real-world setting. METHODS Patients received a fixed-dose combination tablet containing LDV and SOF with or without RBV, for 8, 12 or 24 weeks. Patients were assessed at baseline, end of treatment, and 12 weeks after the end of treatment. The primary effectiveness endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). RESULTS Of the 86 patients, aged 20-80 years, 82.6% were HCV genotype 1b-infected and 50.0% were cirrhotic. More than half (52.3%) had previously followed pegylated interferon-containing (PEG-IFN) treatment regimens, and 38.5% were null-responders. SVR12 was achieved by 94.2% of patients. All non-responders were cirrhotic: two demonstrated virologic breakthrough and the remaining three relapsed. All patients treated with an 8-week regimen achieved SVR12 despite having high viral load at baseline (HCV RNA of >1 million IU/mL in 8/10 patients, including one with a viral load of >6 million IU/mL). Adverse events were generally mild and transient. Most frequently, fatigue (22.1%), headache (15.1%), and arthralgia (7.0%) were observed. Laboratory abnormalities included anemia and hyperbilirubinemia. CONCLUSIONS Treatment with LDV/SOF±RBV is an effective and safe option for patients with HCV, including those with advanced liver disease or a history of non-response to PEG-IFN-based therapy.

The Impact of IL28B Genotype and Liver Fibrosis on the Hepatic Expression of IP10, IFI27, ISG15, and MX1 and Their Association with Treatment Outcomes in Patients with Chronic Hepatitis C.

The strong impact of interleukin 28B (IL28B) polymorphisms on sustained virological response (SVR) after peginterferon and ribavirin treatment in patients with chronic hepatitis C (CHC) is well-known. We investigated IL28B variability and hepatic expression of IP10, IFI27, ISG15, and MX1 in CHC patients, the relation of each with their clinical characteristics, and how they associated with responses to combined therapy. Genotyping and gene expression analysis were conducted in a selected cohort of treatment-naïve patients who underwent interferon and ribavirin treatment. Differential expression of IP10, IFI27, ISG15, and MX1 genes was assessed from pretreatment liver biopsies using quantitative PCR. Histopathological evaluation of liver specimens was performed on the basis of the Scheuer’s modified scale. We showed that hepatic IFI27, ISG15, and MX1 expression was lower in the IL28B CC 12979860 and TT rs8099917 groups than in the CT-TT rs12979860 and TG-GG rs8099917 groups (P < 0.001). We found no differences in IP10 expression between the IL28B genotypes (P > 0.05); in contrast, IP10 expression was significantly affected by the progression of fibrosis (P = 0.007). We showed that the rs12979860 CC genotype was associated with successful treatment when compared to the rs12979860 CT-TT genotype (P = 0.004). Additionally, the expression levels of IP10, IFI27 and ISG15, but not MX1, were significantly higher in non-SVR patients than in SVR patients. The effect of variation in IL28B on the results of IFN-based treatment may be associated with changes in IFI27 and ISG15, but not with IP10. Silencing of IP10 is positive and independent from IL28B prediction of SVR, which is strongly associated with liver fibrosis in CHC patients.

Acute liver failure and liver transplantation in a patient with multiple sclerosis treated with interferon beta

In the treatment of multiple sclerosis (MS), interferon beta (IFNβ) applies. It rarely can lead to acute liver failure (ALF). A 42-year-old female with MS was admitted to the Department because of jaundice, general weakness, drowsiness and nausea. Four weeks earlier, she had started therapy with IFNβ-1a. Liver tests made prior to initiation of IFNβ-1a were normal but on admission to the Department exceed several times the upper limit. ALF was recognized and IFNβ-1a was immediately stopped. In the fourth day of hospitalization, symptoms of hepatic encephalopathy have progressed. The patient was transferred to the Department of Transplantation, where hepatic coma developed and three days later the orthotopic liver transplantation was performed. In histopathological picture of the removed liver extensive necrosis and fibrosis dominated. Immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil and tapering prednisone. Within five years after surgery, there was no recurrence of symptoms of MS and the transplanted organ is functioning properly. ALF is a rare complication of IFNβ therapy but it can occur. The appearance of symptoms suggestive of liver injury should prompt extension of diagnosis and, if necessary, discontinuation of therapy.

Effect of Peginterferon or Ribavirin Dosing on Efficacy of Therapy With Telaprevir in Treatment-Experienced Patients With Chronic Hepatitis C and Advanced Liver Fibrosis: A Multicenter Cohort Study.

AbstractWe investigated the safety, efficacy, and impact of ribavirin and peginterferon dose reduction on complete early virologic response and sustained virologic response (SVR) to triple therapy with telaprevir in treatment-experienced patients with advanced liver fibrosis.Treatment was initiated for 211 patients who failed treatment with peginterferon and ribavirin, with bridging fibrosis (F3, n = 68) or cirrhosis (F4, n = 143), including 103 (49%) null-responders (NR), 30 (14%) partial responders (PR), and 78 (37%) relapsers (REL). Impaired liver function (ILF) platelets <100,000/mm3 or albumin <35 g/L were present in 40 patients. The distribution of hepatitis C virus subtypes was: 1a, 1b, or 1, with undetermined subtype for 10 (5%), 187 (89%), and 14 (6%) patients, respectively. Treatment was started with peginterferon alpha-2a or alpha-2b, ribavirin, and telaprevir at standard doses.The overall SVR24 rate was 56% and was lower in cirrhotic patients (NR: 35%, PR: 40%, and REL: 63%, respectively) than in patients with bridging fibrosis (NR: 50%, PR: 75%, and REL: 75%, respectively). The lowest probability of SVR24 was in NRs with ILF (26%). The SVR24 rate significantly decreased in NRs receiving <60% vs >60% of the total ribavirin dose (23% vs 44%, respectively) or <80% vs >80% of the total ribavirin dose (33% vs 48%, respectively). A significant SVR24 decrease was noted subsequent to a total peginterferon dose reduction, both when comparing patients who received <60% vs >60% of the total dose (NR: 0% vs 44%; REL: 33% vs 68%) and patients who received <80% vs >80% of the total dose (NR: 17% vs 50%; REL: 46% vs 71%).Serious adverse events were observed in 31 patients (15%). Deaths occurred in 4 patients. All of the deceased subjects were cirrhotic members of the ILF (baseline serum albumin level <35 g/L and/or platelet count <100,000/mm3) group.Ribavirin dose reduction did not affect efficacy in REL but did in NR. Peginterferon dose reduction decreased the SVR24 rate for all groups, particularly in prior NR. ILF increased the risk of fatal complications with a low probability to achieve SVR24. One solution might be to provide wide and early access to novel, efficient, and safe interferon-free combinations to treatment-experienced patients, particularly those with liver cirrhosis.

Renal impairment in patients with chronic hepatitis C treated with first generation protease inhibitors

Background: The incidence, course and risk factors associated with renal impairment (RI) in patients treated with triple therapy (TT) with pegylated interferon, ribavirin and telaprevir/boceprevir (PR/TVR/BOC) vs. dual therapy (DT) with PR were analyzed in this study. The association between RI and the decline of hemoglobin (Hb) was also examined. Methods: Retrospective analysis included 110 patients with genotype 1b chronic HCV infection, aged 18 – 80 years, who underwent TT (48TVR/14BOC) or DT (48 patients). The estimated glomerular filtration rate (eGFR), serum creatinine concentration (SCr) and Hb were measured at baseline, at weeks 4, 12, 24, 48 of treatment, and post-treatment week 24. Results: RI occurred in 9/62 (14.5%) patients who underwent TT, eight of whom were treated with TVR, one with BOC, and none treated with DT. The risk factors associated with RI were the following: TT (p = 0.0078), usage of nephrotoxic drugs (p = 0.0288), and older age (p < 0.0001). RI was reversible. A drop of Hb was associated with RI, older age and TT. Conclusions: RI is not a rare but a reversible complication of TT. It is necessary to monitor SCr and eGFR, especially in patients with a potential risk factor of RI occurrence. The Hb drop is more severe in patients with RI than in those without it.

Prophylaxis of vertical HBV infection

ABSTRACT Introduction: An appropriate management of HBV infection is the best strategy to finally reduce the total burden of HBV infection. Mother-to-child transmission (MTCT) is responsible for more than one third of chronic HBV infections worldwide. Because HBV infection in infancy or early childhood often leads to chronic infection, appropriate prophylaxis and management of HBV in pregnancy is crucial to prevent MTCT. Areas covered: The prevention of HBV vertical transmission is a complex task and includes: universal HBV screening of pregnant women, administration of antivirals in the third trimester of pregnancy in women with high viral load and passive-active HBV immunoprophylaxis with hepatitis B vaccine and hepatitis B immune globulin in newborns of all HBV infected women. Expert opinion: Universal screening of pregnant women for HBV infection, early identification of HBV DNA level in HBV-infected mothers, maternal treatment with class B according to FDA antivirals and passive/active anti-HBV immunoprophylaxis to newborns of HBV-positive mothers are crucial strategies for reducing vertical HBV transmission rates. Consideration of caesarean section in order to reduce the risk of vertical HBV transmission should be recommend in HBV infected pregnant women with high viral load despite antiviral therapy or when the therapy in the third trimester of pregnancy is not available.

Efficacy and safety of pegylated interferon α and ribavirin in patients monoinfected with HCV genotype 4

Introduction Dual therapy (PegIFN and ribavirin) (DT) was the standard of care in patients infected with HCV genotype 4 (HCV-4) until 2014. Nowadays, new treatment options are available including interferon (IFN)-based and other IFN-free regimens. Aim To assess the efficacy (SVR24) and safety of DT and the selected predictor factors of SVR in HCV-4 infected patients. Material and methods One hundred and twelve patients (62 men) of median age 23 years were treated with DT for 48/72 weeks (107/5) in the years 2006–2014. Most of them were treatment naïve (80.4%) and with fibrosis F ≤ 2 (83.1%). To select a subset of independent predictors of SVR Logistic Regression Analysis was applied. Results SVR24 was achieved in 46/112 (41.1%) patients. The mean viral load was 5.55 log10 IU/ml. Lack of therapy experience increases the odds of achieving SVR (OR = 4.17; 1.04–16.67), whereas more advanced fibrosis and higher baseline viral load tend to decrease the probability of SVR (OR = 0.05; 0.01–0.52 and OR = 0.44; 0.17–1.13, respectively). In contrast, the weight loss is associated with higher probability of virological response (OR = 4.31; 1.37–13.60). Two hundred and seventy-nine adverse events (AEs) were reported in 96 individuals. The rates and types of AEs were similar in patients treated with PegIFN-α2a/RBV and PegIFN-α2b/RBV. Overall, 3 (2.7%) patients discontinued therapy prematurely because of serious AEs. Conclusions SVR24 was low. Loss of weight was a new positive predictive factor of SVR found in our study. Most of the AEs were typical of those previously reported for DT.