Liver Fibrosis Regression and Associated Factors in HCV Patients Treated with Direct-Acting Antiviral Agents.

There is accumulating evidence that treatment of chronic hepatitis C (HCV) leads to improvements in liver fibrosis. We aimed to investigate the improvement in fibrosis stage following treatment with direct-acting antivirals (DAAs) and factors associated with fibrosis regression. Fibroscan® was performed for patients treated with DAAs, at least 3 years post-HCV eradication. The fibrosis stage at the onset of treatment was compared with the current fibrosis stage. A total of 209 patients were enrolled in this study (56% males; age 58.8 ± 13.3 years; age at treatment 54 ± 10.9 years). Genotype subgrouping was as follows: 1a (16%), 1b (58%), 2a (4%), 3 (18%), and 4a (2%). Overall, 71% of patients were considered treatment-naïve, with a mean follow-up time of 4.5 ± 1.3 years. Fibrosis improvement was observed among 57% of patients; fibrosis progression was seen among 7% of patients and no change was seen in 36% of patients. Moreover, 28% of these patients regressed from F3/F4 to F2 or less. In our multivariable analysis, the age at treatment and advanced fibrosis stage were found to be factors significantly associated with fibrosis regression. In conclusion, fibrosis improvement was observed among 57% of HCV patients after treatment with DAAs. Age and advanced fibrosis at baseline were found to be factors associated with fibrosis regression.

Response guided therapy for reducing duration of direct acting antivirals in chronic hepatitis C infected patients: a Pilot study.

The advent of direct-acting antivirals (DAAs) has transformed the landscape of hepatitis C virus (HCV) management. We aimed to prospectively (real-time) evaluate the feasibility of using a response-guided therapy approach, based on mathematical modeling of early viral kinetics, to reduce the duration of DAAs therapy. Patients were treated with DAAs according to the physicians' preference. HCV was measured at baseline and at day 2 and weeks 1, 2 and 4 after treatment initiation. The primary endpoint was the proportion of patients with sustained-virological response (SVR) at 12 and/or 24 weeks post-treatment. Twenty-nine patients (mean age 54 ± 16, 44% females, 73% with HCV genotype 1), were enrolled and all completed therapy. Treatment duration was shortened in 11 of the 29 patients (38%). SVR was achieved in 28 of the 29 patients (97%). Relapse occurred post treatment in a single case of a non-cirrhotic male with genotype 3, who was treated with sofosbuvir/velpatasvir for 6 weeks. Virus sequencing did not identify baseline or treatment emergent resistance associated substitutions. Real-time mathematical modeling of early HCV kinetics can be utilized for shortening DAAs duration in approximately 40% of patients without compromising treatment efficacy.Clinical trial registration: ClinicalTrials.gov Identifier: NCT03603327.

Effectiveness of dasabuvir/ombitasvir/paritaprevir/ritonavir for hepatitis C virus in clinical practice: A population-based observational study.

BACKGROUND: Direct acting antivirals for hepatitis C virus have shown dramatic results in clinical trials. However, their effectiveness has yet to be demonstrated within observational cohorts which lack exclusion criteria found in randomized control trials. AIM: To determine the effectiveness of dasabuvir/ombitasvir/paritaprevir/ritonavir in achieving sustained virological response. METHODS: Retrospective observational cohort study of all Clalit Health Services members with hepatitis C virus genotype 1 who were dispensed dasabuvir/ombitasvir/paritaprevir/ritonavir from January 1, 2015 to-November 31, 2015. RESULTS: There were 564 participants during the study period. The average age was 61.9 years, 52.0% were male, and 61.5% were born Eastern/Central Europe or Central Asia. The prevalence of diabetes was 31.7% and 70.3% were overweight/obese. Cirrhosis was present in 41.0% of participants, of whom 52.8% had stage 4 fibrosis. Of the cohort, 416 (74.8%) had follow-up viral load testing at 10 or more weeks after the end of treatment. We report a sustained virological response of 98.8% among those tested. CONCLUSIONS: Treatment with dasabuvir/ombitasvir/paritaprevir/ritonavir demonstrated a near universal effectiveness in achieving a sustained virological response among HCV patients in a large cohort.

[Vertical HBV transmission in Jerusalem in the vaccine era].

UNLABELLED: We evaluated the vertical transmission of hepatitis B virus (HBV) in the vaccine era after 1992. METHODS: A cross-sectional descriptive study was conducted in the year 2005-2006 at Clalit Health Services, Jerusalem. Children at age > or = 1 year born after 1992, with HBsAg positive mothers, were evaluated. RESULTS: A total of 22,683 HBsAg tests were performed for 20,415 patients (11,186 Jewish and 9,229 Arabs). The prevalence of positive HBsAg was 2.64% (95% CI, 2.43-2.87] among the general Jerusalem population. It was 3.9% among the Arab population (95% CI, 3.34-4.34), compared to 1.59% [95% CI, 1.37-1.84) among the Jewish population. Data from fertile women aged 18-44 years, showed a prevalence of HBV carrier state of 1.7% (total); 2.84% (95%CI, 2.43-3.3) in Arab women as compared to 0.66% [95% CI, 0.48-0.9) among Jewish women. Of 164 Arab positive HBsAg women, we identified 157 mothers for 409 children at age > or = 1 year born after 1992. Data for 188 children of 70 mothers was collected. The prevalence of vertical infection among the child cohort (positive anti-HBc) as well as the prevalence of chronic infection [positive HBsAg) were 8.4% (95% CI, 4.71-13.1) and 4.4% (95% CI, 1.8-7.6], respectively; 37.1% of these children had negative anti-HBs titters, compared to 41.4% with antiHBs 11-100 mlU/ml and only 21.5% with titters above antiHBs 100 mLU/mL; 48% (23/48) children received passive-active vaccine combination; 35% (17/48) children received only active vaccination; 12.5% (6/48) were born to mothers prior to HBV infection diagnosis and received only the active vaccine; 4.5% (2/48) received no vaccination at all. CONCLUSION: HBV vertical transmission is highly prevalent in our tested Arab cohort, in spite of the universal vaccination program, suggesting its failure. Improvement of physician awareness and double vaccination of infants of carrier mothers will likely reduce the vertical transmission.

Clinical evaluation (Phase I) of a human monoclonal antibody against hepatitis C virus: safety and antiviral activity.

BACKGROUND/AIMS: HCV-AB68, a human monoclonal antibody against the envelope protein of hepatitis C virus (HCV), neutralizes HCV in cell-culture and in the HCV-Trimera mouse model. A Phase 1 clinical trial was designed to test safety, tolerability, and antiviral activity of HCV-AB68 in patients with chronic HCV-infection. METHODS/RESULTS: Single doses of HCV-AB68, 0.25-40 mg, administered to 15 patients were well tolerated with no moderate or serious adverse events (SAEs) reported. In six patients, HCV-RNA levels transiently decreased by 2- to 100-fold immediately following infusion and rebound to baseline in 24-48 h. Multiple doses of HCV-AB68, 10-120 mg, were administered to 25 patients. Doses were given weekly for 3 weeks, then 3x a week during the fourth week, after which patients were followed for 3 months. No drug-related SAEs were reported and no specific pattern of adverse events was evident. Eight out of 25 patients had at least a 1-log reduction and 17 had at least a 0.75-log reduction in HCV-RNA levels from baseline at one or more time points following HCV-AB68 infusion. CONCLUSIONS: These data support the investigation of HCV-AB68 in the prevention of recurrent HCV-infection in patients who had received hepatic allografts for end-stage liver disease.

Incidence of hepatitis A in Israel following universal immunization of toddlers.

CONTEXT: In Israel, the mean annual incidence of hepatitis A disease was 50.4 per 100 000 during 1993-1998. A 2-dose universal hepatitis A immunization program aimed at children aged 18 and 24 months (without a catch-up campaign) was started in 1999. OBJECTIVE: To observe the impact of toddlers-only universal vaccination on hepatitis A virus disease in Israel. DESIGN AND SETTING: Ongoing passive national surveillance of hepatitis A cases in Israel has been conducted since 1993 by the Ministry of Health. An active surveillance program in the Jerusalem district in 1999-2003 provided validation for the passive program. MAIN OUTCOME MEASURE: Incidence of reported hepatitis A disease, 1993-2004. RESULTS: Overall vaccine coverage in Israel in 2001-2002 was 90% for the first dose and 85% for the second dose. A decline in disease rates was observed before 1999 among the Jewish but not the non-Jewish population. After initiation of the program, a sharp decrease in disease rates was observed in both populations. The annual incidence of 2.2 to 2.5 per 100 000 during 2002-2004 represents a 95% or greater reduction for each year with respect to the mean incidence during 1993-1998 (P<.001). For children aged 1 through 4 years, a 98.2% reduction in disease was observed in 2002-2004, compared with the prevaccination period (P<.001). However, a sharp decline was also observed in all other age groups (84.3% [<1 year], 96.5% [5-9 years], 95.2% [10-14 years], 91.3% [15-44 years], 90.6% [45-64 years], and 77.3% [>or=65 years]). Among the Jewish population in the Jerusalem district, in whom the active surveillance program was successfully conducted, a more than 90% reduction of disease was demonstrated. Of the 433 cases reported nationwide in 2002-2004 in whom vaccination status could be ascertained, 424 (97.9%) received no vaccine and none received 2 doses. CONCLUSION: This universal toddlers-only immunization program in Israel demonstrated not only high effectiveness of hepatitis A vaccination but also marked herd protection, challenging the need for catch-up hepatitis A vaccination programs.

Genotype prevalence, viral load and outcome of hepatitis B virus precore mutant infection in stable patients and in patients after liver transplantation.

OBJECTIVE: The precore mutant is detectable in most Israeli patients with persistent hepatitis B virus (HBV) infection. The aim of this study was to determine the prevalence of HBV genotypes, viral load and outcome of precore mutant infection in stable patients and in patients after liver transplantation. METHODS: The prevalence of HBV genotype and viral load were investigated in 81 patients with HBV precore mutant infection. Of these, 50 patients (40 males, 10 females; mean age 43.4 +/- 11.0 yr) underwent liver transplantation and were serum HBV DNA-negative by hybridization at the time of transplantation. Patients received long-term HBV immunoprophylaxis and immunosuppression, and lamivudine in cases of graft HBV recurrence. The remaining 31 patients were stable, with serum anti-HBe-positivity. Genotypes were tested by restriction fragment length polymorphism of an S gene amplicon. Precore mutations were studied with an INNO-LiPA probe assay. RESULTS: Follow-up was 46.6 +/- 37.7 months. Most of the transplanted group was of Middle Eastern origin (53.6%); the remainder were from Eastern Europe (21.4%), Western Europe and the USA (10.8%), Africa (7.1%), and Asia (7.1%). In the transplanted group, the pre-transplant HBV genotype D was the most prevalent (96%), while genotype A was found in only 4%. Eleven patients (22%) developed recurrent HBV infection post-transplantation. There were no differences in genotype distribution between patients with graft reinfection or lamivudine resistance and patients without recurrence. Mean viral load at recurrence was 148.4 x 10(6) +/- 60.4 x 10(6) copies/mL. The stable group had a similar origin and HBV genotype prevalence, but a lower mean viral load of 12.4 x 10(6) +/- 29.4 x 10(6) copies/mL (p = 0.007). The prevalence of mutations at the precore region and codon 28 was similar in both groups. CONCLUSIONS: The chronic precore mutant HBV-infected patients were characterized as follows: (i) genotype D was the most frequent genotype, (ii) the HBV genotype distribution was similar in patients with stable infection and after liver transplantation, (iii) viral load at recurrence was significantly higher than in stable infection, and (iv) HBV genotype was unrelated to the development of recurrence or lamivudine resistance in the tested population.

Reduced incidence of hyperuricemia, gout, and renal failure following liver transplantation in comparison to heart transplantation: a long-term follow-up study.

BACKGROUND: Hyperuricemia and gout are common complications of heart transplantation, reaching a prevalence of 84% and 30%, respectively, in heart transplant recipients. In contrast, they are seldom reported following orthotopic liver transplantation (OLT). METHODS: We retrospectively evaluated 75 consecutive liver transplant recipients and 47 consecutive heart transplant recipients, followed for at least 3 years after transplantation in a single transplantation center in Jerusalem, Israel. Data was collected on demographic and clinical variables, levels of uric acid, the occurrence of gout, renal function, and variables effecting hyperuricemia, such as weight and medications. RESULTS: Clinical gout was significantly more prevalent in heart recipients than in liver recipients (25.5% and 2.6%, respectively). Hyperuricemia was present in 100% of heart recipients, with an average uric acid level of 451 micromol/l, as compared with 85.7% and 403 micromol/l for liver recipients (P < 0.001 for both variables). Univariate analysis identified several parameters which significantly influenced the difference in hyperuricemia and gout among the two groups including age, gender, rejection episodes, hypertension, diabetes mellitus, the level of uric acid prior to transplantation, and the use of cyclosporine A, diuretics, steroids, and aspirin. Use of tacrolimus and azathioprine were associated with decreased incidence of hyperuricemia and gout. Multivariate analysis identified the type of transplantation as the only independent risk factor predicting the development of hyperuricemia and gout. CONCLUSION: Clinical gout and hyperuricemia were significantly more prevalent in heart recipients than in liver recipients. The disparity can be explained by differences in age, gender and renal function among the groups, as well as by the use of different medication regimens.

Late cytomegalovirus disease following liver transplantation.

The widespread use of antiviral prophylaxis or preemptive therapy among orthotopic liver transplantation (OLT) recipients has reduced the occurrence of early cytomegalovirus (CMV) disease. Late disease is increasingly reported. Little is known about CMV disease occurring beyond the first year after transplantation. The aim of this study was to evaluate the occurrence of CMV disease two or more years after OLT and to determine its risk factors and clinical features. Eighty-one consecutive OLT recipients followed for 2 years or longer after transplantation were included in the study. Data were collected on demographic and clinical variables, clinical presentation, treatment, and outcome of late CMV disease. Late CMV disease occurred in 7/81 liver recipients (8.5%) at a mean time of 5.9 years after OLT (range: 3.5--9.3, median: 6.3 years). All seven patients were women, with a mean age of 47.7 years (range: 26--60, median: 59 years). There was no association between the development of late CMV disease and the occurrence of rejection episodes, treatment with corticosteroids, or the early use of antiviral prophylaxis. Clinical presentation included fever and disturbed liver functions in all patients, one patient had concurrent CMV pneumonitis and one CMV retinitis. Though all patients responded to ganciclovir, two had recurrent disease episodes and one patient died of secondary bacterial sepsis. Late-onset CMV disease can occur several years after OLT. Although it manifests classic clinical features of early disease, it is not associated with traditional risk factors and its pathogenesis may differ from that of early disease.

Malignancy after liver transplantation in patients with premalignant conditions.

GOALS: Liver transplant recipients are at increased risk of developing nonhepatic malignant tumors. The aim of the current study was to evaluate the role of premalignant states, not associated with the liver disease prior to transplantation, in the development of posttransplantation malignancy. STUDY: One hundred seventy-five patients who had undergone liver transplantation were retrospectively evaluated for the development of malignant conditions. Each of the patients who developed malignancy following transplantation was evaluated for the presence of premalignant conditions before transplantation. RESULTS: Post-liver transplantation malignancy was identified in 13 patients (7.4%). Five patients developed non-Hodgkin lymphoma: four had posttransplantation lymphoproliferative diseases, and one had B cell lymphoma of the stomach. Eight patients developed solid tumors. In five of these patients, evidence of a premalignant state was identified: ulcerative colitis was diagnosed in 1 patient with carcinoma of the colon; colonic polyp, 1 patient with carcinoma of the colon; Barrett esophagus, 1 patient with esophageal carcinoma; Caroli disease, 1 patient with anaplastic cholangiocarcinoma; and cervical atypia, 1 patient with carcinoma of the cervix. CONCLUSIONS: Premalignant conditions existing before transplantation, which are not associated with the primary liver disease, are major risk factors for posttransplantation malignancy. Screening for premalignant conditions should be included in pretransplantation evaluation. Liver transplant patients with evidence of a premalignant state should be followed after transplantation for detection of malignancy.

Exacerbation of pulmonary sarcoidosis after liver transplantation.

Patients with hepatic sarcoidosis rarely require orthotopic liver transplantation (OLT). Progression of granulomatous activity involving other organs after OLT has rarely been described. We describe a 32-year-old woman who underwent liver transplantation for sarcoidosis-associated end-stage liver disease. She presented 4 years later with shortness of breath, hilar lymphadenopathy, and interstitial lung abnormalities. Liver functions were normal. Open lung biopsy results revealed granulomata compatible with sarcoidosis. The patient made a complete recovery after corticosteroid treatment. To the best of our knowledge, this is a first description of severe exacerbation of pulmonary sarcoidosis in an immunosuppressed patient who underwent liver transplantation for sarcoidosis-associated liver disease.

Prognosis of symptomatic versus asymptomatic autoimmune hepatitis: a study of 68 patients.

BACKGROUND: Autoimmune hepatitis (AIH) is a chronic liver disorder of unknown etiology. Disease presentation ranges from asymptomatic to symptomatic onset, fulminant, acute, or chronic. GOALS: To evaluate the prognosis of patients with asymptomatic versus symptomatic AIH and to determine the role of early treatment and prognostic factors in this subgroup of patients. METHODS: Sixty-eight patients with AIH were retrospectively evaluated for clinical presentation, liver function tests, autoantibody profile, liver biopsy, treatment, and long-term prognosis. RESULTS: Twenty-three patients were classified as having asymptomatic AIH. They were compared with the 45 AIH patients with symptomatic onset. Patients with symptomatic and asymptomatic presentations were indistinguishable by age, but there was a relative male predominance in the asymptomatic group. Aminotransferase and immunoglobulin levels were lower in the asymptomatic group. In contrast, the histopathologic picture was indistinguishable between the two groups. Lobular hepatitis of a moderate to severe degree, portal fibrosis, and bridging fibrosis were detected in similar frequencies in both groups. Asymptomatic onset led to a delay in diagnosis and, consequently, in the initiation of treatment and was associated with use of relatively lower doses of corticosteroids. Response to treatment and long-term prognosis of asymptomatic patients was better than that observed in the symptomatic group. CONCLUSIONS: Asymptomatic onset of AIH is relatively common. The clinical presentation appears in correlation with liver functions tests but not with liver histology. This subgroup of AIH carries a better response to treatment and a favorable prognosis.

[Neurologic complications following liver transplantation].

Neurologic complications are very common following liver transplantation and appear in 30%-90% of the patients. These complications represent a wide array of etiologies, often presenting complicated diagnostic options. The primary liver disease for which the patient underwent the transplantation can cause neurologic complications, or they can be a presentation of a metabolic or vascular derangement. The medications given to liver transplanted patients can cause neurologic complication either directly via drug side effects or indirectly via immune-suppression and secondary opportunistic infections of the nervous system. We present two cases of liver transplanted patients, one suffering from a complex neurologic syndrome attributed to her primary Wilsons disease and the second with recurrent encephalopathy following transplantation attributed to a porto-systemic shunt. We review the current literature on the subject.