A. Loglio

The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B

Whether there is a change of hepatocellular carcinoma (HCC) incidence in chronic hepatitis B patients under long‐term therapy with potent nucleos(t)ide analogues is currently unclear. We therefore assessed the HCC incidence beyond year 5 of entecavir/tenofovir (ETV/TDF) therapy and tried to determine possible factors associated with late HCC occurrence. This European, 10‐center, cohort study included 1,951 adult Caucasian chronic hepatitis B patients without HCC at baseline who received ETV/TDF for ≥1 year. Of them, 1,205 (62%) patients without HCC within the first 5 years of therapy have been followed for 5‐10 (median, 6.8) years. HCCs have been diagnosed in 101/1,951 (5.2%) patients within the first 5 years and 17/1,205 (1.4%) patients within 5‐10 years. The yearly HCC incidence rate was 1.22% within and 0.73% after the first 5 years (P = 0.050). The yearly HCC incidence rate did not differ within and after the first 5 years in patients without cirrhosis (0.49% versus 0.47%, P = 0.931), but it significantly declined in patients with cirrhosis (3.22% versus 1.57%, P = 0.039). All HCCs beyond year 5 developed in patients older than 50 years at ETV/TDF onset. Older age, lower platelets at baseline and year 5, and liver stiffness ≥12 kPa at year 5 were independently associated with more frequent HCC development beyond year 5 in multivariable analysis. No patient with low Platelets, Age, Gender‐Hepatitis B score at baseline or year 5 developed HCC. Conclusion: The HCC risk decreases beyond year 5 of ETV/TDF therapy in Caucasian chronic hepatitis B patients, particularly in those with compensated cirrhosis; older age (especially ≥50 years), lower platelets, and liver stiffness ≥12 kPa at year 5 represent the main risk factors for late HCC development. (Hepatology 2017;66:1444–1453).

The long-term benefits of nucleos(t)ide analogs in compensated HBV cirrhotic patients with no or small esophageal varices: A 12-year prospective cohort study.

BACKGROUND & AIMS Esophageal varices (EV) are a marker of disease severity in compensated cirrhosis due to hepatitis B virus (HBV) which predicts also the risk of hepatocellular carcinoma (HCC), clinical decompensation and anticipated liver related death. The dynamics and prognostic significance of EV in patients under long-term HBV suppression by nucleos(t)ide analogs (NUC), are poorly known. METHODS A standardized protocol (Baveno) including 414 upper gastrointestinal (GI) endoscopies was applied to 107 HBeAg-negative compensated cirrhotic patients (93% Child-Pugh A) during a median of 12 (range 2 to 17) years of NUC therapy. Patients who initially started on lamivudine (LMV) and then developed resistance (LMV-R), were rescued by early administration of adefovir, or were switched to tenofovir. Surveillance included serum HBV DNA every three months and abdominal ultrasound every six months. RESULTS Twenty-seven patients had baseline F1 EV which regressed in 18, remained unchanged in eight and progressed in one patient; the 12-year cumulative incidence of EV regression was 83% (95% CI: 52-92%). De novo F1/F2 EV developed in 6/80 patients with a 12-year cumulative incidence of 10% (95% CI: 5-20%). Six of seven patients with de novo varices or progression of pre-existing varices had either a clinical breakthrough due to LMV-R and/or developed a HCC. No bleedings from ruptured EV occurred, 12 patients died (9 HCC) and 15 were transplanted (13 HCC): the 12-year cumulative incidence of HCC and overall survival was 33% (95% CI: 24-42%) and 76% (95% CI: 67-83%), respectively. CONCLUSIONS Long-term pharmacological suppression of HBV in HBeAg-seronegative patients with compensated cirrhosis leads to a significant regression of pre-existing EV accompanied by a negligible risk of developing de novo EV.

Hepatitis B virus long-term impact of antiviral therapy nucleot(s)ide analogues (NUCs)

The goal of antiviral therapy is to improve the quality of life and survival of patients with chronic hepatitis B (CHB) by halting the progression to cirrhosis, end‐stage liver disease or hepatocellular carcinoma (HCC), thus preventing anticipated liver‐related death. Oral administration of potent and less resistance‐prone nucleot(s)ide analogues (NUCs), such as entecavir (ETV) and tenofovir disoproxil fumarate (TDF) has become the most popular treatment strategy worldwide because of their excellent efficacy and safety profile as well as easy management confirmed in both registration trials and in clinical practice studies. Long‐term administration of ETV or TDF suppresses HBV replication in >95% of patients, resulting in biochemical remission, histological improvement including the regression of cirrhosis and prevention or reversal of clinical decompensation but not the development of HCC, particularly in patients with cirrhosis. Moreover, NUCs can be administered to all patients including those with severe liver disease, the elderly and in those who do not respond, are unwilling to take or have contraindications to interferon. The need for long‐term, perhaps indefinite, treatment is the main limitation of NUCs therapy with the associated costs, unknown long‐term safety and the low rates of hepatitis B surface antigen (HBsAg) seroclearance, which is still the best stopping rule for NUCs‐treated patients with cirrhosis.

Treatment of hepatitis B: Is there still a role for interferon?

The treatment of chronic hepatitis B (CHB) patients is based on monotherapy with pegylated‐interferon (Peg‐IFN) or with one of the three most potent nucleot(s)ide analogues (NUCs) with the best resistance profiles, i.e. entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). Long‐term NUCs treatment can achieve virological suppression in almost all patients. However, this requires lifelong therapy, is costly and the rate of hepatitis B surface antigen (HBsAg) seroclearance is low. A one‐year course of Peg‐IFN has the advantage of providing immune‐mediated control of the hepatitis B virus (HBV) infection, the possibility of achieving a sustained off‐treatment response in nearly 30% of the patients and ultimately, HBsAg loss in approximately 30%‐50% of the latter patients during long‐term off treatment follow‐up. However, the major limitations to the extensive use of this treatment are the need for parenteral therapy and clinical and laboratory monitoring, the side‐effects profile and contraindications in certain patients and the limited effectiveness in a large proportion of patients. Nevertheless, the cost‐effectiveness of Peg‐IFN can be significantly increased by careful patient selection based upon baseline alanine aminotransferase (ALT), HBV DNA levels, viral genotype, host genetic variants and especially by applying early on‐treatment stopping rules based upon HBsAg kinetics. Recently, because of the different mechanisms of action of Peg‐IFN and NUCs, the strategy of “adding‐on” or “switching to” Peg‐IFN in patients being treated with NUCs to accelerate the decline in HBsAg and enhance HBsAg seroclearance rates, has provided interesting results.

Eight-year survival in chronic hepatitis B patients under long-term entecavir or tenofovir therapy is similar to the general population

BACKGROUND & AIMS The effects of long-term antiviral therapy on survival have not been adequately assessed in chronic hepatitis B (CHB). In this 10-centre, ongoing cohort study, we evaluated the probability of survival and factors affecting survival in Caucasian CHB patients who received long-term entecavir/tenofovir therapy. METHODS We included 1,951 adult Caucasians with CHB, with or without compensated cirrhosis and without hepatocellular carcinoma (HCC) at baseline, who received entecavir/tenofovir for ≥12 months (median, six years). Kaplan-Meier estimates of cumulative survival over time were obtained. Standardized mortality ratios (SMRs) were calculated by comparing death rates with those in the Human Mortality Database. RESULTS The one-, five-, and eight-year cumulative probabilities were 99.7, 95.9, and 94.1% for overall survival, 99.9, 98.3, and 97.4% for liver-related survival, and 99.9, 97.8, and 95.8% for transplantation-free liver-related survival, respectively. Overall mortality was independently associated with older age and HCC development, liver-related mortality was associated with HCC development only, and transplantation-free liver-related mortality was independently associated with HCC development and lower platelet levels at baseline. Baseline cirrhosis was not independently associated with any type of mortality. Compared with the general population, in all CHB patients mortality was not significantly different (SMR 0.82), whereas it was lower in patients without HCC regardless of baseline cirrhosis (SMR 0.58) and was higher in patients who developed HCC (SMR 3.09). CONCLUSION Caucasian patients with CHB and compensated liver disease who receive long-term entecavir/tenofovir therapy have excellent overall and liver-related eight-year survival, which is similar to that of the general population. HCC is the main factor affecting their overall mortality, and is the only factor affecting their liver-related mortality. LAY SUMMARY Caucasian patients with chronic hepatitis B with or without compensated cirrhosis who receive long-term entecavir or tenofovir therapy have excellent overall eight-year survival, which is similar to that of the general population. Hepatocellular carcinoma is the main factor affecting their overall mortality, and is the only factor affecting liver-related mortality in this setting.

A STAT4 variant increases liver fibrosis risk in Caucasian patients with chronic hepatitis B

Host genetic modifiers of the natural history of chronic hepatitis B (CHB) remain poorly understood. Recently, a genome‐wide association study (GWAS)‐identified polymorphism in the STAT4 gene that contributes to the risk for hepatocellular carcinoma (HCC) was shown to be associated with the full spectrum of hepatitis B virus (HBV) outcomes in Asian patients. However, the functional mechanisms for this effect are unknown and the role of the variant in modulating HBV disease in Caucasians has not been investigated.

IFNL4 rs368234815 and rs117648444 variants predict off-treatment HBsAg seroclearance in IFN-treated HBeAg-negative chronic hepatitis B patients

Robust baseline predictors of interferon (IFN) response in HBeAg‐negative chronic hepatitis B (CHB) patients are not currently available. The recently described rs368234815 TT/ΔG dinucleotide and rs117648444 nonsynonymous P70S polymorphisms in IFN lambda 4 (IFNL4) gene, which are strongly associated with response to IFN in hepatitis C virus (HCV) infection, could be also useful in IFN‐treated CHB patients. Here we assessed whether IFNL4 rs368234815 and rs117648444 polymorphisms predict IFN‐induced HBsAg clearance in CHB patients.

Tenofovir alafenamide as a rescue therapy in a patient with HBV-cirrhosis with a history of Fanconi syndrome and multidrug resistance

Tenofovir disoproxil fumarate (TDF) is a recommended first-line therapy for both naïve and experienced patients with chronic hepatitis B (CHB), although reduced estimated glomerular filtration rate (eGFR), hypophosphatemia, hyperphosphaturia and Fanconi syndrome have been reported in some patients. Entecavir (ETV) could be considered as a rescue therapy for TDF-treated patients developing renal dysfunction, though patients with prior history of treatment with lamivudine (LAM) can develop ETV resistance strains, which can lead to potentially severe hepatitis flares. Tenofovir alafenamide (TAF), a new prodrug of tenofovir, has recently been developed to improve the renal and bone safety profile compared to TDF, while maintaining the same virologic efficacy. The recently published 48-week phase III TAF registration studies confirmed the superior safety profile. Here we describe a case of a 75-year-old woman with HBV mono-infection and compensated cirrhosis who developed ETV resistant strains and grade 3 chronic kidney disease after many years of LAM and adefovir (ADV) treatment and a TDF-induced Fanconi syndrome. The administration of 25mg/day of TAF, granted as part of a compassionate use program, rapidly suppressed viral replication to undetectable levels without worsening renal function or side effects.

Clinical features and outcomes of hepatocellular carcinoma in Caucasian cirrhotic patients on long-term analogue therapy for hepatitis B

Long‐term oral nucleos(t)ide analogue (NUC) therapy in hepatitis B virus (HBV)‐related compensated cirrhotics prevents clinical decompensation but not hepatocellular carcinoma (HCC) development.

Failure of long-term lamivudine prophylaxis in patients with resolved hepatitis B infection undergoing chemotherapy and allogenic hematopoietic stem cell transplantation for hematological malignancies: Two case reports

Hepatitis B virus (HBV) reactivation is a well known complication in patients with resolved HBV infection, i.e., HBsAg negative, hepatitis B core antibody (anti-HBc) positive ± antibodies against HBsAg (anti-HBs), undergoing chemotherapy (CT) and/or allogenic hematopoietic stem cell transplantation (HSCT) for onco-hematological diseases. In these patients, this risk can be prevented by either “pre-emptive anti-HBV therapy”, based on the monitoring of HBV DNA and/or HBsAg, followed by rescue therapy with anti-HBV regimens, or by “anti-HBV prophylaxis” based on the administration of nucleos(t)ides analogs (NUCs) during immunosuppression and for a consolidation time after the end of immunosuppressive drugs. As per standard procedure in our centre, all patients with hematological malignancies and a resolved HBV infection receive lamivudine (LMV) prophylaxis at the time of CT or HSCT to be maintained for at least 18 months after the discontinuation of immunosuppressive drugs. Herein, we describe two patients with resolved HBV infection who, following allogenic HSCT and repeated cycles of CT for hematological malignancies, developed HBsAg seroreversion due to the late emergence of LMVresistance (R) during long-term LMV prophylaxis. Case A. A 56-year-old Italian male was diagnosed with micromolecular IgG kappa multiple myeloma (MM) on June 2008. Since the virological profile was consistent with a resolved HBV infection with positive anti-HBe and anti-HBs (240 IU/L) and undetectable serum HBV DNA (<12 IU/mL), LMV prophylaxis was started concomitantly with CT initiation. Between January 2009 and December 2010, several cycles of CT were administered (Table 1 and Figure 1). In December 2010, a matched unrelated donor (MUD) HSCT was carried out (donor HBV profile: HBsAg negative, anti-HBs 715 IU/L, antiHBc negative) and cysclosporin (CSA) as a prophylaxis and treatment of graft versus host disease (GvHD) was started to be progressively reduced and withdrawn in May 2012. However, in April 2012, MM relapsed requiring further cycles of CT without, nevertheless, achieving complete disease remission. In November 2015, the patient was enrolled in a phase I/II trial based on the coadminstration of carfilzomib+pomalidomide+dexamethasone. Between 2008 and November 2015, the patient remained persistently negative for HBsAg, HBeAg