Background: Chronic hepatitis B infection can lead to liver failure, hepatocellular carcinoma, and death. Purpose: To evaluate the effectiveness of antiviral therapy for adults with chronic hepatitis B infection. Data Sources: Randomized, controlled trials (RCTs) of interferon (α2b and pegylated α2a), lamivudine, adefovir, entecavir, and telbivudine published from 1990 to 2008. Study Selection: Randomized, controlled clinical trials of adults with chronic hepatitis B published in English after 1989 that reported death; incidence of hepatocellular carcinoma or liver failure; prevalence and incidence of cirrhosis; presence or seroconversion of hepatitis B e antigen (HBeAg) or surface antigen (HBsAg), viral load of hepatitis B virus DNA; aspartate aminotransferase and alanine aminotransferase (ALT) levels; or fibrosis scores after therapy with interferon-α2b, pegylated interferon-α2a, lamivudine, adefovir, entecavir, and telbivudine. Data Extraction: Data extracted with standard protocols to calculate risk difference for clinical outcomes, viral load, HBeAg and HBsAg, ALT, histologic scores, and adverse events. Data Synthesis: In 16 RCTs (4431 patients), drug treatment did not improve clinical outcomes of chronic hepatitis B infection, but the trials were underpowered. In 60 RCTs that examined intermediate outcomes, no single treatment improved all intermediate outcomes. Low-quality evidence suggested HBsAg clearance after interferon-α2b (2 RCTs; 211 patients). Moderate-quality evidence suggested ALT normalization at follow-up after treatment with adefovir (2 RCTs; 600 patients) and HBeAg loss with lamivudine (2 RCTs; 318 patients). With interferon-α2b, moderate-quality evidence suggested HBeAg loss (3 RCTs; 351 patients), seroconversion (2 RCTs; 304 patients), and ALT normalization (2 RCTs; 131 patients). Pegylated interferon-α2a versus lamivudine improved HBeAg seroconversion (1 RCT; 814 patients) and ALT normalization (2 RCTs; 905 patients) off treatment. Pegylated interferon-α2a combined with lamivudine versus lamivudine improved HBeAg loss (1 RCT; 543 patients) and ALT normalization (2 RCTs; 905 patients). Adverse events during antiretroviral therapy occurred in more than 50% of patients but were not associated with increased treatment discontinuation. However, most studies excluded patients with hepatic or renal insufficiency or other serious comorbid conditions. Limitation: Marked heterogeneity in study samples, interventions, and measured outcomes preclude definitive conclusions. Conclusion: Evidence was insufficient to assess treatment effect on clinical outcomes or determine whether inconsistent improvements in selected intermediate measures are reliable surrogates. Future research is needed to provide evidence-based recommendations about optimal antiviral therapy in adults with chronic hepatitis B infection. © 2009 American College of Physicians.

BACKGROUND & AIMS:

Therapy of chronic hepatitis B with HBV-polymerase inhibitors, in particular tenofovir or adefovir, may affect renal function. To assess renal function more accurately in the normal range, we used the recently validated, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula to calculate the estimated glomerular filtration rate (eGFR).

METHODS:

Patient subgroups included: patients with HBV-monoinfection treated with lamivudine (n=36), adefovir (n=32), entecavir (n=32), or tenofovir (n=37). HBsAg-positive untreated patients (n=60) served as control. For comparison HIV-monoinfected patients treated with tenofovir (n=120) or zidovudine (n=52) based antiretroviral therapy and antiretroviral naive patients (n=109) were assessed. CKD-EPI equation was used to calculate eGFR. In a more sensitive approach, we modeled the individual change in eGFR over time with linear mixed effects models (LME).

RESULTS:

Yearly predicted median changes in individual eGFR according to the LME model were: HBV untreated -2.05 ml/min, HBV lamivudine -0.92 ml/min, HBV adefovir -1.02 ml/min, HBV entecavir -1.00 ml/min, and HBV tenofovir -0.92 ml/min (p<0.01 for HBV untreated vs. HBV treated). In HIV-monoinfected patients: HIV untreated -0.62 ml/min, HIV treated with tenofovir -2.64 ml/min, HIV treated with zidovudine -1.0 ml/min (p=0.017 for tenofovir vs. no treatment, p<0.001 for tenofovir vs. zidovudine).

CONCLUSIONS:

Therapy of HBV infection irrespective of medication seems to result in a milder decrease of renal function. In contrast tenofovir as part of HIV combination therapy seems to impair renal function in this Caucasian population.

Background The optimal oral anti-viral agent to use in patients with decompensated HBV cirrhosis remains unclear. Aim We performed a meta-analysis of the oral nucleos(t)ide analogues in patients with decompensated HBV cirrhosis. Methods One year efficacy and safety outcomes in 22 studies published in English between95 and 2010 were analysed. Results Substantial heterogeneity was noted in the inclusion/exclusion criteria, controls, and sensitivity of the HBV DNA assay used. Pooled 1-year data showed benefit favouring lamivudine (LAM) vs. untreated controls for Child-Turcotte-Pugh (CTP) score improvement by ≥2 (OR: 117 (15 921), P ≤ 0.0001) and transplant-free survival (OR: 3.2 (1.2, 9), P = 0.022). Adefovir (ADV) led to undetectable HBV DNA at 1-year in 41% compared to 83% with LAM and 80% with entecavir (ETV). Overall, 1-year transplant-free survival rates varied from 78% with LAM to 95% and 94% with Tenofovir (TDF) and Telbivudine (TBV), respectively. The 1-year incidence of drug resistant HBV was 0% with ADV, ETV and TDF and 11% with LAM although TBV was associated with a 29% incidence at 2 years. Drug-related adverse events were infrequently reported. Conclusions All the oral anti-viral agents were associated with improved virological, biochemical and clinical parameters at 1-year. However, the efficacy of lamivudine and telbivudine is limited by drug resistance, and adefovir is limited by its potency and slower onset of action. Additional studies of tenofovir and entecavir are needed to determine the optimal agent(s) for treatment nave patients and in those with drug-resistant decompensated HBV cirrhosis. © 2012 Blackwell Publishing Ltd.

Se analizó la evidencia disponible sobre la eficacia y la tolerabilidad de una vez al día la terapia antirretroviral altamente activa (HAART), bases de datos de búsqueda, actas de congresos y revistas. Dos revisores seleccionaron de forma independiente no controlada 6 y 2 ensayos clínicos aleatorios de al menos 24 semanas de duración y con un 80% el seguimiento de los participantes. Los regímenes incluyen didanosina (ddI), emtricitabina (FTC) y efavirenz (EFV) (2 estudios, 326 pacientes); ddI, lamivudina (3TC) y efavirenz (3 estudios, 147 pacientes); ddI, 3TC, EFV, y adefovir dipivoxil (1 estudio, 11 pacientes); ddI, nevirapina y efavirenz (1 estudio, 15 pacientes) y ddI, 3TC, indinavir y ritonavir (un estudio, 10 pacientes). Eficacia virológica osciló entre 70% y el 91%. Los ensayos clínicos preliminares aleatorios mostraron que una vez al día los regímenes (ddI, 3TC y EFV o ddI, FTC y EFV) tuvo una eficacia virológica, al menos similar a la de la terapia HAART convencional. El aumento de CD4 general celda era por lo menos 114 linfocitos / microL. La tolerabilidad fue buena, con una tasa de abandono baja.

OBJECTIVES:

Synthesize evidence of the natural history of chronic hepatitis B (CHB) and effects and harms of antiviral drugs on clinical, virological, histological, and biochemical outcomes.

DATA SOURCES:

MEDLINE, electronic databases, and manual searches of systematic reviews.

REVIEW METHODS:

We included original observational studies to assess natural history and randomized controlled trials (RCTs) of adults with CHB published in English to assess treatment effects and harms if they reported mortality, incidence of hepato-cellular carcinoma (HCC), cirrhosis or failure, HBeAg or HBsAg, viral load (HBV DNA), alanine aminotransferase (ALT) levels, histological necroinflammatory and fibrosis scores, and adverse events after interferon alfa-2b, pegylated interferon alfa 2-a, lamivudine, adefovir, entecavir, tenovir or telbivudine. We excluded pregnant women, transplant patients, and individuals undergoing cancer chemotherapy. We calculated relative risk or absolute risk differences at end of treatment and post-treatment.

RESULTS:

Observational studies (41 publications) suggested that male gender, coinfection with hepatitis C, D, or HIV, increased HBV DNA, and cirrhosis were associated with increased risk of HCC and death. Drugs did not reduce death, liver failure, or HCC in 16 RCTs not designed to test long-term clinical outcomes. Evidence from 93 publications of 60 RCTs suggested drug effects on viral load or replication, liver enzymes, and histology at end of treatment and lasting from 3 to 6 months off treatment. No one treatment improved all outcomes and there was limited evidence on comparative effects. Two RCTs suggested interferon alfa-2b increased CHB solution versus placebo. Interferon alfa-2b or lamivudine improved off treatment HBV DNA and HBeAg clearance and seroconversion and ALT normalization. Adefovir improved off treatment ALT normalization and HBV DNA clearance. Pegylated interferon alfa 2-a versus lamivudine improved off-treatment HBV DNA and HBeAg clearance and seroconversion, ALT normalization and liver histology. Lamivudine combined with interferon alfa-2b versus lamivudine improved off treatment HBV DNA clearance and HBeAg seroconversion and reduced HBV DNA mutations. Pegylated interferon alfa 2-a plus lamivudine improved off treatment HBV DNA and HBeAg clearance and seroconversion and ALT normalization compared to lamivudine but not pegylated interferon alfa 2-a monotherapy. Adverse events were common but generally mild and did not result in increased treatment discontinuation. Longer hepatitis duration, male gender, baseline viral load and genotype, HBeAg, and histological status may modify treatment effect on intermediate outcomes. Adefovir and pegylated interferon alfa 2-a with lamivudine improved off treatment viral clearance in HBeAg negative patients. There was insufficient evidence to determine if biochemical, viral, or histological measures are valid surrogates of treatment effect on mortality, liver failure, or cancer.

CONCLUSION:

Adults with CHB have an increased risk of death, hepatic decompensation, and HCC. Mono or combined drug therapy improves selected virological, biochemical, and histological markers with no consistent effects on all examined outcomes. Patient and disease characteristics may modify treatment-induced intermediate outcomes. Evidence was insufficient to assess treatment effect on clinical outcomes, predict individualized patient response, or determine if intermediate measures are reliable surrogates. Future research should assess long-term drug effects on clinical outcomes and among patient subpopulations.

BACKGROUND:

Antiviral treatment has improved the short-term outcome of kidney transplant recipients with chronic hepatitis B infection, but its long-term impact, especially in patients who have developed drug resistance, remains uncertain.

METHODS:

Sixty-three hepatitis B surface antigen positive (HBsAg+) and 63 HBsAg- patients who have undergone kidney transplantation from 1985 to 2008 were retrospectively reviewed and their clinical outcomes were compared.

RESULTS:

With lamivudine as initial treatment, 62% of patients developed drug resistance after 4 years. Lamivudine resistance was associated with a higher incidence of chronic hepatitis but had no significant impact on liver stiffness score or patient survival during follow-up. Salvage treatment with adefovir or entecavir was well tolerated, and resulted in a three-log decrease in hepatitis B deoxynucleic acid after 6 months and normalization of alanine aminotransferase in 75% of patients. The survival rate of HBsAg+ patients transplanted in the recent era of antiviral treatment was 81% at 10 years. Treatment of hepatitis B with nucleoside/nucleotide analogues resulted in significantly improved patient survival (83% vs. 34% at 20 years, P=0.006). Although antiviral treatment was associated with reduced mortality because of liver complications (P=0.036), liver-related deaths still accounted for 40% of mortalities in HBsAg+ patients in the era of antiviral therapies and 22.2% of all deaths that occurred in patients who had received antiviral treatment.

CONCLUSION:

Treatment of HBsAg+ renal transplant recipients with nucleoside/nucleotide analogues confers long-term survival benefit, and that rescue therapy with adefovir or entecavir is effective and well tolerated in patients who had developed resistance to lamivudine.

OBJECTIVE:

To investigate the prevention and treatment of hepatitis B virus (HBV) reinfection and recurrence after orthotopic liver transplantation (OLT) for HBV related end-stage liver disease.

METHODS:

The clinical data of 316 patients undergoing allograft orthotopic liver transplantation who lived more than 6 months and had HBV infection preoperative with complete data from March 2001 to March 2007 at the First Affiliated Hospital of Sun Yat-sen University. According to the HBV prevention strategy, these patients were divided into two groups: group with pure lamivudine (LAM) (n = 106) and group with lamivudine plus intramuscular injection of low dose anti-hepatis B immunoglobulin (HBIG) (n = 210).

RESULTS:

Mean follow-up was 33.6 months. The rate of HBsAg negative conversion 1 week after OLT of the LAM group was 82.1% (87/106), significantly lower than that of LAM + HBIG group [91.0% (191/210), P < 0.05]. The rates of HBV reinfection, HBV recurrence, and YMDD mutation of the lamivudine group was 17.0% (18/106), 11.3% (12/106) and 8.5% (9/106) respectively, all significantly higher than those of LAM + HBIG group [6.2% (13/210), 3.8% (8/210) and 2.4% (5/210) respectively, P < 0.05 respectively]. All patients with HBV reinfection or HBV recurrence were treated with Adefovir, Entecavir or increased dose of HBIG and achieved better curative effect.

CONCLUSIONS:

The therapy with high dose of HBIG combining with adefovir or entecavir is better for patients who have HBV reinfection. Patients with HBV recurrence after OLT should be administrated reasonable liver aid, immunity regulation and anti-hepatic fibrosis to obtain better transplant liver histological results and normal transplant liver function.

Aim: To investigate whether adjuvant antiviral treatment could improve prognosis and entecavir is the optimal nucleoside/nucleotide analog (NA) regimen after curative therapy of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Methods: A comprehensive electronic search was performed. All controlled trials comparing antiviral treatment with placebo or no treatment for HBV-related HCC after curative treatment were included. The pooled hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Stata 12.0 software. An indirect treatment comparison method was used to compare the relative efficacy of different NA strategies. Results: Twenty-one studies containing 8072 patients were included. NA was found to significantly improve recurrence-free survival (RFS) and overall survival (OS). Alternatively, for interferon, a non-significant benefit was found. By adjusted indirect comparisons among entecavir, lamivudine and adefovir, entecavir were found to display almost but not significant superiority to the other NA in improving RFS. No tendency favoring a specific NA regimen was found for OS. Conclusion: In HBV-HCC patient after curative treatment, NA improve the prognosis significantly but the role of interferon remains to be elucidated; entecavir was not found to be superior to other NA based on available data. © 2016 John Wiley & Sons, Ltd.

Objective. To evaluate the efficacy and safety of Kushenin (KS) combined with nucleoside analogues (NAs) for chronic hepatitis B (CHB). Methods. Randomized controlled trials (RCTs) of KS combined with NAs for CHB were identified through 7 databases. Frequencies of loss of serum HBeAg, HBeAg seroconversion, undetectable serum HBV-DNA, ALT normalization, and adverse events at 48 weeks were abstracted by two reviewers. The Cochrane software was performed to assess the risk of bias in the included trials. Data were analyzed with Review Manager 5.3 software. Results. 18 RCTs involving 1684 subjects with CHB were included in the analysis. KS combined with NAs including lamivudine (LAM), entecavir (ETV), adefovir dipivoxil (ADV), and telbivudine (TLV) showed different degree of improvement in CHB indices. KS combined with NAs increased the frequency of loss of serum HBeAg, HBeAg seroconversion, undetectable HBV-DNA levels, and ALT normalization compared with single agents. It also decreased serum ALT and AST level after one-year treatment. However, KS combined with TLV did not show a significant difference in CHB indices. The side-effects of KS combined with NAs were light and of low frequency. Conclusion. KS combined with NAs improves the efficacy of NAs in CHB.

INTRODUCTION:

The aim of this study was to ascertain the outcomes of chronic hepatitis B (CHB) infection following immunosuppressive therapy in 38 consecutive oriental patients with systemic rheumatic diseases.

MATERIALS AND METHODS:

This is a retrospective consecutive, non-comparative study.

RESULTS:

The majority of patients were female (26, 68.4%), predominantly Chinese (92.1%), with a mean age 54 +/- 14 years (range, 16 to 87). The mean duration of rheumatic disease was 9 +/- 11 years (range, 0.1 to 48), with rheumatoid arthritis (52.6%) and systemic lupus erythematosus (23.7%) being the most common. The mean duration of CHB infection was 6 +/- 5 years (range, 0.1 to 17), with the majority diagnosed during pre-methotrexate screening (50.0%) and asymptomatic transaminitis following initiation of immunosuppressive therapy (23.7%). Upon diagnosis of rheumatic disease, all patients had normal alanine aminotransferase (ALT). Of these, 18.2% were positive for hepatitis B e antigen (HBeAg) and 78.1% were positive for anti- HBe antibody. Twenty (52.6%) developed ALT elevation, which was more than twice the upper limit of normal in 12 patients. ALT normalised spontaneously in 12 patients without hepatic decompensation or change in therapy. Seven (18.4%) patients received lamivudine for 18 +/- 22 months (range, 2 to 61). Two patients developed YMDD mutation subsequently treated with adefovir (1) and adefovir/lamivudine (1). There were 3 (7.9%) hepatitis B virus (HBV)-unrelated deaths [infection (2), genitourinary malignancy (1)], and 1 from HBV-reactivation complicated by septicaemia. None have developed hepatocellular carcinoma.

CONCLUSION:

Elevated ALT occurred in 52.6% of patients, with only 18.4% requiring anti-viral therapy for HBV reactivation. HBV-related mortality was low. With the appropriate precautionary measures, prednisolone and immunosuppressants (except methotrexate and leflunomide) may be used safely in patients where clinically indicated.