[Show abstract][Hide abstract] ABSTRACT: Background & Aims: Hepatocellular carcinoma (HCC) has become a major cause of liver related death and indication to liver transplantation (LT) in patients with chronic hepatitis B virus (HBV) infection following the widespread adoption of antiviral therapy with nucleos(t)ide analogs (NUCs). Yet, the long-term outcome of patients undergoing liver transplantation for an HCC developed during effective NUC treatment is unknown. Methods: We evaluated 101 patients with persistently compensated cirrhosis who were consecutively transplanted for HCC in two centers in Milan. At LT, 91 (90%) patients had undetectable serum HBV DNA (<12 IU/mL) and 90 (89%) were within Milan criteria(MC).All patients received post transplant HBV prophylaxis with specific immunoglobulins (HBIgs) and NUCs. End-points were long-term patient survival and recurrence of HCC and HBV. Results: During 106 (range 3-165) months following LT, HCC recurred in 11
(11%) patients (9 beyond MC at explant, 2 within MC with HBV recurrence). Age (HR 1.1, 95%CI 1.0-1.2, p=0.04) and exceeding MC (HR 9.6, 95%CI 2.9-32, p<0.0001) were the only independent pretransplant predictors of tumor recurrence. The 10-year cumulative rate of HCC recurrence was 7% among patients transplanted within MC compared to 45% among those beyond MC al LT (p=0.004). Overall, 18 patients (18%, 9 HCC, 9 non liver-related events) died with a 10-year cumulative probability of overall and liver-related survival of 79% and 89%, respectively.
Conclusions: Extended survival of HBV cirrhotics transplanted for HCC can be achieved by
coupling MC at listing with persistent pharmacological suppression of HBV.
Liver international: official journal of the International Association for the Study of the Liver 05/2015; DOI:10.1111/liv.12835 · 4.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and Aims: Hepatitis B surface antigen (HBsAg)- negative/anti-hepatitis B core antigen (anti-HBc)-positive patients undergoing Rituximab (RTX)-based chemotherapy (R-CT) for non-Hodgkin’s B cell lymphoma (NHL) face up to 27% risk of hepatitis B virus (HBV) reactivation. Aim of the study was to assess the efficacy and safety of lamivudine (LMV) prophylaxis in these patients.
Methods: Sixty-seven consecutive HBsAg-negative/anti-HBc- positive patients (median age 70yrs, 61% males, 13% HCV seropositive, 100% serum HBV DNA negative by sensitive PCR assay, 75% anti-HBs positive, 100% with ALT <ULN) undergoing different R-CT protocols (48% R-CHOP) in two hematological centres were retrospectively enrolled. LMV prophylaxis was started before the first R-CT dose and planned to last for 18 months after the end of R-CT. R-CT was administered for 6 cycles (range: 1–15) during 5 (range: 1–38) months, while LMV was administered for 20 (range: 3–54) months. Serum ALT, HBsAg and HBV DNA levels by PCR assay were assessed every 3–4 months.
Results: All patients remained HBV DNA and HBsAg negative during a median of 20 months (range: 2–60), including both the LMV prophylaxis and the subsequent off treatment follow-up. Anti-HBs titers declined in 18% of patients but none lost serum reactivity for anti-HBs. Overall, 2 patients had an increase of ALT (>ULN) but this event was unrelated to HBV reactivation and 7 patients died of liver unrelated causes. No safety issues related to LMV were recorded.
Conclusions: LMV monotherapy is an inexpensive, safe and effective prophylaxis regimen to prevent HBV reactivation in such a high-risk population as HBsAg-negative/anti-HBc-positive patients receiving RTX-based chemotherapy for non-Hodgkin’s B cell lymphoma.
Journal of Hepatology 04/2015; 62(Supplement 2):S566. · 11.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hepatitis B surface antigen (HBsAg)-negative/anti-hepatitis B core antigen (anti-HBc)-positive patients undergoing Rituximab (RTX)-based chemotherapy (R-CT) for non–Hodgkin's B cell lymphoma (NHL) face up to 27% risk of hepatitis B virus (HBV) reactivation. Aim of the study was to assess the efficacy and safety of lamivudine (LMV) prophylaxis in these patients
[Show abstract][Hide abstract] ABSTRACT: HBeAg negative chronic hepatitis B (CHB) is a frequent, progressive and difficult-to-cure phase of CHB. The end-point of therapy is to persistently suppress viral replication to halt progression of liver disease. Two different treatment strategies are currently available: a short-term course of pegylated interferon alpha (PEG-IFN) or long-term therapy with nucleot(s)ide analogues (NA), i.e. entecavir or tenofovir. Young patients with mild-to-moderate stages of liver disease can benefit from a 48-week course of PEG-IFN, while NA may be preferred in patients with more severe liver disease, in older patients, and in those who do not respond, are unwilling or have contraindications to PEG-IFN. Nucleot(s)ide analogues provide persistent viral suppression and biochemical normalization in almost all patients, together with the regression of fibrosis and the prevention of decompensation, but the effect on hepatocellular carcinoma rates is limited. Thus, NAs have become the most popular treatment strategy worldwide but lifelong administration is associated with high cost, unknown safety and adherence issues and an unknown risk of drug-resistance over time as well as limited rates of HBsAg seroclearance. On the other hand, PEG-IFN treatment may achieve a SVR in nearly a quarter of patients ultimately leading to HBsAg loss in almost 30–50%. Interestingly, response rates to PEG-IFN may further increase with more careful patient selection based on age, ALT and HBV DNA levels at baseline and by applying early on-treatment stopping rules based on HBV DNA and HBsAg kinetics. The combination of NA and PEG-IFN is not currently recommended but numerous studies are ongoing.
Liver international: official journal of the International Association for the Study of the Liver 01/2015; 35(s1). DOI:10.1111/liv.12717 · 4.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor widely used to treat patients with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infection. Despite the excellent safety records of this regimen, a few cases of acute renal failure and Fanconi syndrome have been reported among HIV patients exposed to TDF. In the HBV monoinfection scenario, only two cases of TDF-associated Fanconi syndrome have been reported thus far. Here, we describe two additional patients with chronic hepatitis B (CHB) who developed a TDF-induced Fanconi syndrome that reverted after TDF withdrawal and had viral replication fully suppressed upon switching to entecavir (ETV). Though the overall risk of TDF associated severe renal toxicity in HBV patients appears to be negligible, both glomerular and tubular function should be monitored in patients exposed to TDF, especially when other renal risk factors or a history of previous exposure to adefovir dipivoxil (ADV) are present.
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Rituximab (RTX), a chimeric mouse anti-human CD20 monoclonal antibody, is indicated for the treatment of patients with non-Hodgkin's lymphoma, chronic lymphocytic leukemia, granulomatosis with polyangiitis and microscopic polyangiitis, and rheumatoid arthritis, but nowadays it is increasingly used for the treatment of many other immune-mediated disorders. Hepatitis B virus (HBV) reactivation in RTX-treated patients, eventually leading to fatal liver failure, has been reported more often among hepatitis B surface antigen (HBsAg)-positive patients (overt infection) than in HBsAg-negative, antibody to hepatitis B core antigen (anti-HBc) seropositive patients (resolved infection).
This paper reviews the safety of RTX in patients with overt or resolved HBV infection, providing recommendations for its safe use in such patients.
Prior to starting RTX treatment, all patients should be screened for HBV infection. While HBsAg-positive active carriers should receive long-term antiviral treatment with entecavir (ETV) or tenofovir, inactive carriers are candidates for universal prophylaxis with lamivudine, or ETV or tenofovir in selected cases, to prevent hepatitis reactivation. Conversely, for HBsAg-negative anti-HBc positive carriers, that is, those with resolved HBV infection, universal prophylaxis with lamivudine is recommended for those with onco-hematological diseases, whereas watchful monitoring of HBsAg/HBV DNA levels is advisable for all the other indications.
[Show abstract][Hide abstract] ABSTRACT: Background/aims:
Cryoglobulinemic vasculitis remains an uncommon complication of hepatitis B virus infection.
We report the case of a 40-years old female Chinese patient with chronic hepatitis B developing cryoglobulinemic vasculitis with multiple organ involvement (liver, kidney, and skin) coupled with weakness, arthralgias, haemolytic anaemia, and autoimmune thyroiditis. She received entecavir mono-therapy at dose adjusted for estimated glomerular filtration rate.
Within five months of entecavir treatment, hepatitis B viraemia decreased below the limit of detection with normal serum amino-transferase levels, HBeAg clearance occurred, vasculitis regressed with disappearance of purpura and ascites; in addition, renal function normalized and nephritic syndrome remitted. After a five-year follow-up, the patient is asymptomatic with intact kidney function, proteinuria in the normal range, and normal liver biochemistry, despite the antiviral treatment was withdrawn and the patient remained HBsAg positive.
This is the second case of hepatitis B virus-related cryoglobulinemic vasculitis successfully treated with entecavir suggesting that effective antiviral therapy may counteract both the hepatic and extra-hepatic manifestations of infection by hepatitis B virus.
Kidney and Blood Pressure Research 06/2014; 39(1):65-73. DOI:10.1159/000355778 · 2.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of chronic hepatitis B (CHB) antiviral therapy is to persistently suppress HBV and improve survival by preventing the progression of liver damage to cirrhosis, end-stage liver disease or hepatocellular carcinoma (HCC), thus preventing early liver-related death. In HBeAg-negative patients who do not or will not respond to or be treated with pegylated interferon (PEG-IFN), the administration of third generation nucleot(s)ide analogues (NAs), i.e. entecavir (ETV) and tenofovir disoproxil fumarate (TDF), is the treatment of choice. Long-term administration of ETV or TDF suppresses HBV replication in >95% of patients after 5 years of treatment with high rates of biochemical normalization, regression of fibrosis and cirrhosis at histology as well as preventing clinical decompensation but not HCC, in compensated cirrhosis and improving survival. No major safety issues have been recorded with either drug. The need for long-term, perhaps indefinite, treatment is the main limitation of NA therapy with possible associated costs, unknown long-term safety and the low rates of HBsAg seroclearance. The latter is important since HBsAg seroclearance is still the best stopping rule for HBeAg-negative NA-treated patients, including those with cirrhosis. For this reason new trials based upon a combination of PEG-IFN and third generation NAs in both naïve and NA-responder HBeAg-negative patients are ongoing.
Liver international: official journal of the International Association for the Study of the Liver 02/2014; 34 Suppl 1(s1):120-6. DOI:10.1111/liv.12401 · 4.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Rituximab (RTX), an anti-CD20 monoclonal antibody, is an effective treatment for Rheumatoid arthritis (RA), targeting B cells. However, the safety of this drug in hepatitis B surface antigen (HBsAg) negative/anti-hepatitis B core antigen (anti-HBc) positive carriers is still unknown. The purpose of our study is to evaluate the risk of HBsAg seroreversion in this kind of patients.
Objectives The purpose of our study is to evaluate the risk of HBsAg seroreversion in this kind of patients.
Methods We retrospectively reviewed 310 RA patients treated in 5 italian outpatient rheumatologic Clinics with RTX from August 2006 to December 2011. 35 (11,2%) were HBsAg negative/anti-HBc positive patients and they did not undergo antiviral prophylaxis. Complete serological panel for HBV status before starting RTX infusions and adequate post-treatment follow-up were available. All patients (75% female, median age 60 years, median disease duration 8 yrs, 100% serum HBV DNA negative by sensitive PCR assay, 87% anti-HBs positive) has been treated with one or more disease-modifying anti-rheumatic drugs (83% MTX, 26% CYS, 80% PDN, 8% LEF, 6% AZA) and were eligible for RTX therapy according to international guidelines. The median period of RTX administration was 3 cycles (range: 1-8) and the therapy was ongoing at the end of observational period in 76% of cases. All patients were laboratory and clinically evaluated every three months. Serum HBsAg and serum HBV DNA were assessed in all patients every 6 months or in case of alanine aminotransferase (ALT) elevation and at the end of the follow-up period.
Results The median follow-up time was 45 months (range: 12-80). In this period 27% of patients had anti-HBs titer decrease (2 patient with a complete lost of anti-HBs levels). Only one patient (3%) had an increase of serum HBV DNA (from undetectable to 24 and 44 IU/mL, 1 week apart) without either HBsAg seroreversion or ALT increase. This virological breakthrough occurred 5 months after the first cycle of RTX and required Lamivudine treatment which successfully suppressed viral replication in 4 weeks. One patient (3%) had an ALT flare, not related to HBV reactivation.
Conclusions The retrospective review of our multicentre experience suggest that an adequate monitoring of HBsAg and HBV DNA levels in RA patients HBsAg negative/anti-HBc positive, as recommended by international guidelines, allows us to avoid the antiviral prophylaxis during RTX treatment.
Disclosure of Interest None declared
[Show abstract][Hide abstract] ABSTRACT: Interferon lambda 3 (IFN-λ3) polymorphisms are the strongest genetic predictor of outcome of hepatitis C virus infection and of response to Pegylated interferon (PegIFN)-based therapy. Whether this holds true for hepatitis B virus (HBV) infection is matter of controversy.
To review the association between host genomics and spontaneous or interferon-induced clearance of HBV with specific reference to the recently identified interleukin 28B gene now renamed IFN-λ3.
A literature search was performed on MEDLINE, EMBASE and Web of Science for English articles and abstracts using free text words and combinations of the following terms 'IL28B', 'IFN lambda', 'genomics', 'hepatitis B virus', 'interferon' 'GWAS', 'treatment', 'SNPs', 'HLA', 'polymorphisms'.
Genome-wide association studies convincingly demonstrated an association between SNPs in the HLA locus and spontaneous resolution of HBV infection in subgroups of Asian patients, yet no information is available for Caucasians. The preliminary observations of an association between IFN-λ3 SNP and virological and serological responses to IFN in both HBeAg-positive and -negative patients could not be replicated by subsequent studies. Yet, majority of studies performed so far suffer several limitations in terms of sample size, selection of the patients, endpoints of therapy, treatment strategies and duration of follow-up.
While host genetics is associated with an increased likelihood of spontaneous clearance of HBV among genotype B/C patients, the relationship between IFN-λ3 polymorphisms and response to IFN has not been confirmed. Further studies in large cohorts of homogeneous patients are required, before this genetic test can be recommended in clinical practice.
[Show abstract][Hide abstract] ABSTRACT: Unlabelled:
Steatosis is a common histopathological feature of chronic hepatitis B (CHB) and has been associated with severity of liver disease. Recently, the rs738409 I148M patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism has been demonstrated to influence steatosis susceptibility and fibrosis progression in patients with different liver diseases, but no data are yet available for CHB. The aim of this study was to evaluate whether PNPLA3 I148M influences steatosis susceptibility in a large series of patients with CHB. We enrolled 235 treatment-naïve CHB patients consecutively examined by percutaneous liver biopsy. In ≥2-cm-long liver tissue cores, steatosis and fibrosis were staged by Kleiner and METAVIR scores, respectively. The I148M polymorphism was determined by Taqman assays. Steatosis was present in 146 (62%) patients, of whom 24 (10%) had severe (>33% of hepatocytes) steatosis. Steatosis was independently associated with age (odds ratio [OR]: 2.67; confidence interval [CI]: 1.50-4.92; for age ≥50 years), body mass index (BMI; OR, 2.84; CI, 1.30-6.76; for BMI ≥27.5 kg/m(2) ), diabetes or impaired fasting glucose (OR, 4.45; CI, 1.10-30.0), and PNPLA3 148M allele (OR, 1.62; CI, 1.00-7.00; for each 148M allele). Independent predictors of severe steatosis were BMI (OR, 3.60; CI, 1.39-9.22; for BMI ≥27.5 kg/m(2) ) and PNPLA3 148M allele (OR, 6.03; CI, 1.23-5.0; for each 148M allele). PNPLA3 148M alleles were associated with a progressive increase in severe steatosis in patients with acquired cofactors, such severe overweight and a history of alcohol intake (P = 0.005).
In CHB patients, the PNPLA3 I148M polymorphism influences susceptibility to steatosis and, in particular, when associated with severe overweight and alcohol intake, severe steatosis.