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Backgound: A significant proportion of hepatitis B surface antigen (HBsAg) negative/anti-hepatitis B core antigen (anti-HBc) positive patients with non-Hodgkin lymphoma (NHL) undergoing rituximab-based chemotherapy (R-CT) may suffer hepatitis B virus (HBV) reactivation., Aims: We wanted to assess efficacy and safety of lamivudine (LMV) prophylaxis to prevent this complication., Methods: Eighty-five consecutive HBsAg negative/anti-HBc positive NHL patients (71 years, 100% serum HBV DNA undetectable, 74% anti-HBs positive) received LMV coadministered with R-CT and for 18 months after the end of R-CT. Serum ALT, HBsAg, anti-HBs and HBV DNA were assessed every 4 months during and after end of LMV., Results: During 39 (2-108) months of study period, including 21 months of LMV and 27 additional months after LMV discontinuation, one patient (2%) had HBV reactivation, 31 months after stopping LMV and during administration of new immunosuppressive regimens, without LMV prophylaxis, owing to incomplete oncological response. A 50% decline of anti-HBs titers occurred in 22/63 (35%) patients, including 12 who became anti-HBs seronegative. Five (6%) patients had ALT increase during R-CT but none required R-CT discontinuation. Seventeen (20%) patients died, all for tumour progression., Conclusion: LMV prophylaxis is safe and effective in preventing HBV reactivation in HBsAg negative/anti-HBc positive NHL patients receiving R-CT., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Reactivation of the hepatitis B virus (HBV) has been reported in patients with occult infection (OBI), i.e. HBV surface antigen (HBsAg) negative, HBV core antibody (anti-HBc) positive ± antibodies against HBsAg (anti-HBs) and detectable HBV DNA in serum or liver, receiving immunosuppressive or cytotoxic therapies. Recently, concerns have been raised regarding the risk of HBV reactivation in OBI patients treated with direct acting antiviral agents (DAAs) for chronic hepatitis C (CHC). Here we describe a case of HBV reactivation in a 72-year-old woman with OBI as a possible consequence of effective treatment with sofosbuvir (SOF) and ribavirin (Rbv) for genotype 2a/2c CHC.

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 (nine beyond MC at explant, two 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 tumour recurrence. The 10-year cumulative rate of HCC recurrence was 7% among patients transplanted within MC compared with 45% among those beyond MC at LT (P = 0.004). Overall, 18 patients (18%, nine HCC, nine 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., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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)., Areas Covered: This paper reviews the safety of RTX in patients with overt or resolved HBV infection, providing recommendations for its safe use in such patients., Expert Opinion: 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.

Introduction: Drugs targeting TNF-α biological activity are increasingly used for the treatment of immune-mediated diseases, like rheumatoid arthritis, inflammatory bowel diseases and psoriasis. Since TNF-α is a mediator of the immune response against viral infections, use of TNF-α inhibitors in patients with concurrent HBV or HCV infection can promote viral reactivation and potentially fatal liver failure., Areas Covered: This paper reviews TNF mechanisms of action in viral hepatitis B and C, recommendations for managing HBV and HCV-infected patients receiving treatment with anti-TNF drugs, safety and anti-TNF hepatotoxicity., Expert Opinion: In hepatitis B surface antigen (HBsAg) carriers undergoing anti-TNF therapy, either anti-HBV treatment or prophylaxis is mandatory to prevent hepatitis reactivation, whereas HBsAg-negative antibody to hepatitis B core antigen (anti-HBc) seropositive patients require watchful monitoring, only. Conversely, in HCV-infected patients, TNF-α inhibition by specific drugs is safe and could be even beneficial, as TNF-α pathways are involved in perpetuating liver inflammation and fibrosis progression in HCV. HBV- or HCV-infected patients should be referred to a hepatologist for expert clinical management whenever antiviral therapy is deemed necessary or hepatitis reactivation occurs.

Hepatitis B virus (HBV) infection persists among patients with renal insufficiency in the industrialized world. A variety of therapeutic options are now available for the treatment of chronic hepatitis B infection, including potent new nucleos(t)ide analogs, along with standard and pegylated interferon. We report on a patient with aggressive hepatitis B and renal insufficiency who was successfully treated with nucleoside analogs (mostly entecavir monotherapy) for two years. He received intense immunosuppression for severe myopathy of lower limbs, probably related to vasculitis. HBV DNA (at the beginning, > 1 x 10(8) IU/mL) was no longer detectable in serum after a few months of antiviral therapy, while HBeAg and HBsAg seroconversion occurred with ALT normalization. Clinical signs of vasculitis disappeared. Five months after discontinuation of entecavir therapy, he remained HBsAg negative with detectable anti-HBs antibody in serum. We conclude that nucleos(t)ide analogs can offer excellent response in selected patients with renal insufficiency and hepatitis B-related liver disease. Prospective, controlled clinical trials are needed to confirm these encouraging results.

Background and Aims: The diagnostic accuracy of transient elastography (TE) for assessment of hepatic fibrosis is hampered by several factors, including acute parenchymal injury. Evaluation of liver stiffness (LS) using TE during acute hepatitis B may help to assess chronic hepatitis B patients with flares., Patients and Methods: Twelve patients consecutively referred for acute hepatitis B, underwent sequential examinations with TE and laboratory examinations for 24 weeks., Results: On admission, aminotransferase ranged from 487 to 6067 IU/l (median=2590 IU/l) and LS ranged from 7.1 to 57 kPa (median=15.6 kPa) with nine (75%) patients showing LS greater than 11.9 kPa, that is, the predictive cutoff for cirrhosis. LS levels correlated significantly with bilirubin, only (r=0.58, P<0.05). During follow-up, LS declined from 15.6 to 5.2 kPa at week 24, with a significant reduction being observed at week 2 for aminotransferase (from 2590 to 452 IU/l, P<0.0001) and at week 6 for both LS (from 15.6 to 6.0 kPa, P=0.008) and bilirubin (from 10.7 to 0.95 mg/dl, P<0.01). Median decline of LS significantly correlated with bilirubin decline (rs=0.70, P<0.05). At week 24, 10 (83%) patients showed LS of less than 7.9 kPa and two (17%) patients had LS values between 7.9 and 11.9 kPa, including the only patient who developed chronic hepatitis B., Conclusion: In patients with acute hepatitis B, the initial high values of LS mimicking LS cutoff of cirrhosis, likely reflect the liver cell inflammation, oedema and swelling as they progressively taper down during hepatitis resolution.

Background: Interferon (IFN) combined with ribavirin (RBV) is an effective therapy for hepatitis C virus (HCV)-infected patients. Those who are coinfected with hepatitis B virus (HBV), however, might suffer from HBV reactivation. The aim of this study was to assess HBV reactivation in HCV-coinfected inactive HBV carriers following IFN/RBV., Methods: A total of 32 HBV carriers with 4 log(10) copies/ml (range 5.2-6.5 log(10) copies/ml); however, these patients had no ALT flare either on treatment (n=2) or off treatment (n=1). During follow-up, 8 (36%) treated patients and 4 controls lost serum hepatitis B surface antigen (HBsAg; annual rate 6.5% versus 6.9%; P-value non-significant), whereas 4 and 2 patients seroconverted to antibodies against HBsAg, respectively. Hepatocellular carcinoma developed in 1 patient with SVR and 1 non-responder under nucleoside therapy for HBV, both with cirrhosis. No patient clinically decompensated., Conclusions: Inactive HBV carriers coinfected with HCV might achieve an SVR following IFN/RBV. Combination therapy carries a low risk of on- and off-treatment HBV reactivation and does not prevent HBsAg seroclearance.

Background & Aims: Adefovir monotherapy is an established treatment modality for lamivudine-experienced patients with chronic hepatitis B, but it carries a significant risk of resistance in the long term. We assessed whether this risk could be overcome by adefovir-lamivudine combination therapy., Methods: A total of 145 lamivudine-resistant patients with chronic hepatitis B (73% cirrhotics, 86% hepatitis B e antigen negative, 92% genotype D) were treated with adefovir 10 mg in addition to lamivudine 100 mg. Liver function tests and hepatitis B virus (HBV) DNA (Versant 3.0) were assessed bimonthly, whereas adefovir-related mutations were searched by INNO-LiPA assay at baseline and at yearly intervals., Results: During 42 months (range, 12-74), 116 patients (80%) cleared serum HBV DNA, 67 (84%) had normalized alanine aminotransferase levels, and 145 (100%) remained free of virologic and clinical breakthroughs, independently of the degree of HBV suppression. The rtA181V/T was the only adefovir-related mutation detected, which occurred in 6 patients at baseline (4%; 1 rtA181V and 5 rtA181T) and in an additional 3 patients (2%; all rtA181T) during treatment. In all these 9 patients, HBV DNA levels progressively declined during therapy to become undetectable in 7 (78%). The 1-, 2-, 3-, and 4-year cumulative rates of de novo rtA181T were 1%, 2%, 4%, and 4%, respectively. None of the cirrhotic patients clinically decompensated, but 11 (12%) developed hepatocellular carcinoma., Conclusions: Under prolonged adefovir-lamivudine therapy, patients with lamivudine-resistant hepatitis B were unlikely to develop genotypic resistance to adefovir and had durable prevention of virologic and clinical breakthrough.

We describe a case of severe reactivation of occult hepatitis B virus infection in a 49-year-old man, who was treated with high doses of chlorambucil for a Binet stage A B-cell chronic lymphocytic leukemia (B-CLL). The patient was initially treated with lamivudine and subsequently with lamivudine and adefovir dipivoxil combination therapy to control viral replication and allow for long-term anti-cancer chemotherapy with alemtuzumab (Campath-1H), which was introduced to rescue for a B-CLL relapse. During 20 months of anti-HBV therapy, ALT and HBV-DNA levels progressively declined and B-CLL was successfully kept under control by long-term alemtuzumab administration.

Progression of hepatitis B in patients with lamivudine-resistant strains is slowed down by adefovir dipivoxil (ADV). Whether the time point of ADV administration (genotypic vs. phenotypic resistance) influences the outcome of therapy is unknown. We compared the outcome of ADV therapy in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B patients with genotypic and phenotypic resistance to lamivudine. Ten milligrams of ADV was administered daily for 2 years to 46 HBeAg-negative patients at the time of phenotypic resistance (group A, >6 log(10) copies/mL of hepatitis B virus [HBV] DNA and high alanine aminotransferase [ALT] levels) and 28 patients at the time of genotypic resistance (group B, 3-6 log(10) copies/mL of HBV-DNA and normal ALT). HBV DNA was assessed every 2 months using Versant 3.0 assay, and lamivudine resistance was confirmed via INNO-LiPA assay in all patients. By month 3, HBV DNA tested negative in all patients from group B compared with only 20 (46%) in group A (P < .0001). The 2-year rates of virological response were 100% in the former patients and 78% in the latter ones (P < .0001). ALT levels remained persistently normal in all group B patients, whereas in group A patients they normalized at rates of 50% at month 6 (P < .0001), 72% at month 12 (P < .01), and 93% at month 24. None of the patients developed ADV resistance or ADV-related side effects. In conclusion, to optimize antiviral treatment in HBeAg-negative patients selecting resistant strains to lamivudine, ADV should be added to lamivudine as soon as genotypic resistance is detected.

Background & Aims: Protein induced by vitamin K absence or antagonist‐II (PIVKA‐II) has been suggested as a serum biomarker for hepatocellular carcinoma (HCC) in Asian hepatitis B virus (HBV)‐treated subjects but no studies tested it in Caucasian cirrhotics long‐term nucleos(t)ide analogues (NUCs)‐treated. We assessed the detection accuracy of PIVKA‐II alone or in combination with alpha‐foetoprotein (AFP) in patients under surveillance. Methods: This cross‐sectional, single centre case‐control study was conducted in 212 NUC‐treated cirrhotics: 64 HCC and 148 HCC‐free controls for 84 (60‐107) months. PIVKA‐II was determined by a CMIA immunoassay (Abbott; limit of quantification: 8.2 mAU/mL). Results: Protein induced by vitamin K absence or agonist II (PIVKA‐II) and AFP levels were significantly higher in HCC patients [Barcelona Clinic Liver Cancer staging system stage 0/A in 91%, diameter 20 (6‐50) mm] compared to controls: 109 (17‐12 157) vs 31 (13‐82) mAU/mL and 5 (1‐1163) vs 2 (1‐7) ng/mL (P <.001 for both markers), with a cut‐off of 48 mAU/mL and 4.2 ng/mL by AUROC analysis. The PIVKA‐II 82 mAU/mL and AFP 7 ng/mL cut‐offs showed 100% specificity, with the former more sensitive (54% vs 42%), accurate (86% vs 83%), with higher negative predictive value (80% vs 76%) compared to AFP for HCC detection. PIVKA‐II more frequently than AFP levels exceeded the cut‐off 6‐18 months before HCC diagnosis. Combining PIVKA‐II with AFP increased sensitivity, accuracy and negative predictive values to 67%, 90% and 85%, preserving 100% specificity. PIVKA‐II was associated with lesions >20 mm or neoplastic thrombosis. Conclusions: Combination of PIVKA‐II and AFP increases the detection rate for HCC in NUC‐treated HBV Caucasian cirrhotics, a potential new approach for surveillance. [ABSTRACT FROM AUTHOR]

Background & Aims: In Caucasian patients with compensated cirrhosis caused by hepatitis B virus (HBV), the risk of hepatocellular carcinoma (HCC) developing persist despite long‐term nucleos(t)ide analogs (NUC) treatment. In the surveillance of this population with persistently normal transaminases because of NUCs, the added value of serum alpha‐foetoprotein (AFP) monitoring is poorly defined. Methods: Two hundred and fifty‐eight Caucasian HCC‐free patients with HBV‐compensated cirrhosis who started tenofovir or entecavir while having normal serum AFP levels (≤7 ng/mL) at baseline or within the first year of treatment underwent HCC surveillance by semiannual ultrasound evaluation and serum AFP determination. Results: During 96 (18‐120) months of antiviral therapy, 3947 AFP values were collected, median AFP level was 2 ng/mL. Thirty‐five patients developed an HCC at an overall 8‐year crude cumulative incidence of 14% (annual incidence of 2%). HCC incidence increased in parallel with increasing AFP thresholds: 24%, 36%, 64% and 92% for AFP levels after exceeding 2, 4, 6 and 7 ng/mL for the first‐time. Of the 12 patients who experienced an AFP rise > 7 ng/mL, 11 developed an HCC and one had liver metastases of lung cancer. Overall, an AFP > 7 ng/mL had 99.6% specificity, 31.4% sensitivity, 91.7% PPV, 90.2% NPV, LR+ 70.1 and LR− 0.69 for HCC; this excellent specificity was maintained up to 18 months before HCC detection. Conclusions: In Caucasian patients with HBV‐compensated cirrhosis on long‐term NUC, an increase in AFP over 7 ng/mL shows excellent specificity, heralding HCC development within 1 year. [ABSTRACT FROM AUTHOR]

Background and Aims: Tenofovir disoproxil fumarate (TDF) is recommended for chronic hepatitis B (CHB) treatment, but it may induce kidney dysfunction whose management is not yet known. This Italian, multicentre, retrospective study aimed to assess the efficacy and safety of switching to entecavir (ETV) patients who developed TDF‐associated glomerular and/or tubular dysfunction. Methods: A total of 103 TDF‐treated patients were included as follows: age 64 years, 83% male, 49% cirrhotics, 98% with undetectable HBV DNA, 47% with previous lamivudine resistance (LMV‐R) and 71% previously treated with adefovir. Twenty‐nine (28%) were switched to ETV because estimated glomerular filtration rate (eGFRMDRD) was <60 mL/min, 37 (36%) because blood phosphate (P) levels were <2.5 mg/dL and 37 (36%) for both reasons. Kidney, liver and virological parameters were recorded every 4 months thereafter. Results: During 46 (4‐115) months of ETV treatment, all patients' renal parameters significantly improved as follows: creatinine from 1.30 to 1.10 mg/dL (P < 0.0001), eGFRMDRD from 54 to 65 mL/min (P = 0.002), P from 2.2 to 2.6 mg/dL (P < 0.0001) and maximal tubule phosphate reabsorption (TmPO4/eGFR) from 0.47 to 0.62 mmol/L (P < 0.0001). Thirteen patients (52%) improved their eGFRMDRD class, P levels were normalised in 13 (35%), and eight (22%) showed improvements in both parameters. Viral suppression was maintained in all but five patients (5%), all of whom had been LMV‐R. The 5‐year cumulative probability of ETV‐R was 0% in LMV‐naïve patients, and 11% in LMV‐R patients (P = 0.018). Conclusions: Entecavir is an effective and safe rescue strategy for CHB patients who develop renal dysfunction during long‐term TDF treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Quantification of serum hepatitis B surface antigen (HBsAg) helps the management of patients with chronic hepatitis B virus (HBV) infection. Median HBsAg levels differ significantly during the natural history of HBV infection, progressively declining from immune tolerance to inactive phase. The combination of an HBsAg <1000 IU/mL and HBV DNA <2000 IU/mL at a single time point accurately identifies true inactive carriers. During antiviral treatment, HBsAg levels decline more rapidly in patients under peg-interferon (Peg-IFN) than in those under nucleos(t)ide analogues (NUC), and in responders to peg-IFN compared to non responders suggesting that a response-guided therapy in both HBeAg-positive and -negative patients treated with Peg-IFN could improve to cost-effectiveness of this therapeutic approach. Given the low rates of HBsAg clearance on NUC therapy, new studies to test whether Peg-IFN and NUC combination fosters HBsAg decline in long-term responders to NUC, are being explored. [ABSTRACT FROM AUTHOR]

Background. To assess the long-term effectiveness and safety of adefovir (ADV) plus lamivudine (LMV) in LMV-resistant (R) kidney transplants with chronic hepatitis B, 11 such patients were treated with add-on ADV.Methods. Serum alanine aminotransferase, renal function and serum hepatitis B virus (HBV) DNA levels were assessed every 3 months; ADV mutations were searched for by INNO-LiPA HBV DR v2 assay.Results. During 36 months (12–48), nine patients cleared serum HBV DNA with a 3-year cumulative virological response rate of 88%, without the emergence of ADV mutations. ADV dose was reduced in six patients (55%) showing a decline of creatinine clearance, in the absence of proximal tubulopathy.Conclusions. In LMV-R kidney graft recipients, long-term add-on therapy with ADV is efficacious and safe with timely adaptation of ADV dose. [ABSTRACT FROM AUTHOR]

Serum HBeAg-negative chronic hepatitis B, which is usually a late stage of chronic hepatitis B virus infection, is difficult to treat, because it is characterized by fluctuating alanine transaminase values resulting in hepatitis flares, accelerated progression to cirrhosis and liver cancer. Antiviral treatment, either long-term nucleot(s)ide therapy or 1-year administration of pegylated interferon (PEG-IFN), is therefore necessary to limit the course of the disease. A sustained virological response to PEG-IFN is achieved in approximately 1/4 of the patients, with significant rates of HBsAg seroclearance. While waiting for the results of several studies whose goal is to improve the long-term efficacy of PEG-IFN, the treatment strategy can be optimized by a careful selection of patients, discontinuation of PEG-IFN as early as possible in primary non-responders and extended therapy (up to 96 weeks) in responders. [ABSTRACT FROM AUTHOR]

Background & Aims: Adefovir monotherapy is an established treatment modality for lamivudine-experienced patients with chronic hepatitis B, but it carries a significant risk of resistance in the long term. We assessed whether this risk could be overcome by adefovir-lamivudine combination therapy. Methods: A total of 145 lamivudine-resistant patients with chronic hepatitis B (73% cirrhotics, 86% hepatitis B e antigen negative, 92% genotype D) were treated with adefovir 10 mg in addition to lamivudine 100 mg. Liver function tests and hepatitis B virus (HBV) DNA (Versant 3.0) were assessed bimonthly, whereas adefovir-related mutations were searched by INNO-LiPA assay at baseline and at yearly intervals. Results: During 42 months (range, 12–74), 116 patients (80%) cleared serum HBV DNA, 67 (84%) had normalized alanine aminotransferase levels, and 145 (100%) remained free of virologic and clinical breakthroughs, independently of the degree of HBV suppression. The rtA181V/T was the only adefovir-related mutation detected, which occurred in 6 patients at baseline (4%; 1 rtA181V and 5 rtA181T) and in an additional 3 patients (2%; all rtA181T) during treatment. In all these 9 patients, HBV DNA levels progressively declined during therapy to become undetectable in 7 (78%). The 1-, 2-, 3-, and 4-year cumulative rates of de novo rtA181T were 1%, 2%, 4%, and 4%, respectively. None of the cirrhotic patients clinically decompensated, but 11 (12%) developed hepatocellular carcinoma. Conclusions:: Under prolonged adefovir-lamivudine therapy, patients with lamivudine-resistant hepatitis B were unlikely to develop genotypic resistance to adefovir and had durable prevention of virologic and clinical breakthrough. [Copyright &y& Elsevier]