G. Grossi

Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B

Hepatitis B virus (HBV)-specific CD8 T cells are functionally exhausted in chronic hepatitis B infection, and this condition can be corrected only partially through the modulation of inhibitory pathways, which suggests that a more complex molecular interplay underlies T cell exhaustion. To gain broader insight into this process and identify additional targets for the restoration of T cell function, we compared the transcriptome profiles of HBV-specific CD8 T cells from patients with acute and chronic disease with those of HBV-specific CD8 T cells from patients able to resolve HBV infection spontaneously and influenza (FLU)-specific CD8 T cells from healthy participants. The results indicate that exhausted HBV-specific CD8 T cells are markedly impaired at multiple levels and show substantial downregulation of various cellular processes centered on extensive mitochondrial alterations. A notable improvement of mitochondrial and antiviral CD8 functions was elicited by mitochondrion-targeted antioxidants, which suggests a central role for reactive oxygen species (ROS) in T cell exhaustion. Thus, mitochondria represent promising targets for novel reconstitution therapies to treat chronic hepatitis B infection.

The prognosis and management of inactive HBV carriers.

Patients with chronic hepatitis B virus (HBV) infection lacking the serum hepatitis B e antigen (HBeAg) and with antibodies against HBeAg (anti‐HBe), are the prevalent subgroup of HBV carriers worldwide. The prognosis of these patients is different from inactive carriers (ICs), who are characterized by persistently normal serum alanine aminotransferase (ALT) and low (<2000 IU/ml) serum HBV DNA levels, a serological profile that may also be intermittently observed in patients with HBeAg‐negative chronic hepatitis. This is why a confirmed diagnosis of IC requires quarterly ALT and HBV DNA measurements for at least 1 year, while a single‐point detection of combined HBsAg <1000 IU/ml and HBV DNA <2000 IU/ml has a robust predictive value for the diagnosis of IC. Characteristically, ICs have minimal or no histological lesions of the liver corresponding to liver stiffness values on Fibroscan of <5 kPa. Antiviral treatment is not indicated in ICs since the prognosis for the progression of liver disease is favourable if there are no cofactors of liver damage such as alcohol abuse, excess weight or co‐infection with the hepatitis C virus or delta virus. Moreover, spontaneous HBsAg loss frequently occurs (1–1.9% per year) in these patients while the development of hepatocellular carcinoma (HCC) is rare, at least in Caucasian patients. However, an emerging issue reinforcing the need for clinical surveillance of ICs is the risk of HBV reactivation in patients who undergo immunosuppressive therapy without receiving appropriate antiviral prophylaxis. After diagnosis, management of ICs includes monitoring of ALT and HBV DNA every 12 months with periodic measurement of serum HBsAg levels to identify viral clearance.

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.

Reactivation of hepatitis B virus during targeted therapies for cancer and immune-mediated disorders

ABSTRACT Introduction: Targeted therapies have gained popularity in the treatment of several oncologic and immune-mediated diseases. Immunosuppression caused by these drugs has been associated to reactivation of hepatitis B virus (HBV) in both hepatitis B surface antigen (HBsAg) positive patients (overt infection) and HBsAg negative/anti-hepatitis B core antigen (anti-HBc) positive carriers (resolved infection), leading to premature discontinuation of therapy and potentially fatal hepatitis. Areas covered: This review summarizes the evidence of HBV reactivation in patients with overt or resolved HBV infection undergoing targeted therapies for cancer or immune-mediated disorders, providing recommendations for the management of these patients. Expert opinion: The risk of HBV reactivation relies on the immunosuppressive potency and duration of these therapies, the underlying disease and the virological patient’s profile. However, HBV reactivation is preventable by screening for HBV markers in all patients scheduled to receive targeted therapies, assessing the virological profile and patient’s clinical state, followed by appropriate antiviral treatment or prophylaxis in those patients at high risk of HBV reactivation. Close monitoring of HBV carriers at low risk of reactivation is warranted with the aim to start antiviral therapy as soon as HBV reactivates.

Review article: the potential of interferon and nucleos(t)ide analogue combination therapy in chronic hepatitis B infection.

A short‐term course of pegylated‐interferon (Peg‐IFN), or a long‐term treatment with a third generation nucleot(s)ide analogue (NUC), of chronic hepatitis B (CHB) infection achieves viral suppression and may prevent disease progression. Owing to different mechanisms of action of the two regimens, a Peg‐IFN and NUC combination treatment may be an attractive approach to enhance the off‐treatment rates of virological and serological response.

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.

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