On-treatment prediction of sustained response to peginterferon alfa-2a for HBeAg-negative chronic hepatitis B patients.

BACKGROUND & AIMS: We assessed predictors of response in HBeAg-negative chronic hepatitis B patients treated with peginterferon alfa-2a in routine clinical practice. METHODS: Ninety-five HBeAg-negative patients received peginterferonalfa-2a for 48 weeks and were followed-up for 48 weeks post-treatment. Serum HBsAg and HBV DNA levels were monitored during and after therapy with valid commercial assays. Sustained response (SR) was defined as HBV DNA <2000 IU/ml at study week 96. RESULTS: Twenty-two patients (23%) achieved SR and nine (9.5%) lost HBsAg. HBsAg decline was more profound in patients with SR. HBsAg decline ≥10% from baseline to week 24 was significantly associated with SR [81% (17/21) vs 37% (21/57); Odds ratio: 7.286 (2.162-24.552), P = 0.001]. The PARC rule (no decrease in HBsAg and <2 log drop in HBV DNA at week 12) was evaluated in a subset of 47 patients. Among eight patients who fulfilled the PARC rule, none achieved SR. Of the 39 patients who did not fulfil the PARC rule, 24 (62%) had HBsAg decline of ≥10% at week 24 (12 achieved SR) and 15 (38%) had HBsAg decline of <10% (1 achieved SR; negative predictive value: 93%). CONCLUSIONS: In HBeAg-negative chronic hepatitis B patients treated with peginterferon alfa-2a, HBsAg decline >10% at 24 weeks is significantly associated with SR. The combination of the PARC rule and week 24 decline in HBsAg can identify almost two-thirds of patients who are unlikely to achieve SR. Clinicaltrials.gov identifier: NCT01283074.

Efficacy and safety of entecavir versus adefovir in chronic hepatitis B patients with hepatic decompensation: a randomized, open-label study.

A randomized, open-label comparative study of entecavir versus adefovir therapy was performed in subjects with chronic hepatitis B who had hepatic decompensation (Child-Turcotte-Pugh score ≥7). Adult subjects were randomized and treated (n = 191) with entecavir 1.0 mg or adefovir 10 mg daily for up to 96 weeks from the date of last subject randomization. Subjects were positive or negative for hepatitis B e antigen and experienced or naive for treatment with nucleos(t)ide analogues. The primary efficacy endpoint was the mean reduction in serum hepatitis B virus (HBV) DNA, as determined by polymerase chain reaction, at week 24, adjusted for baseline HBV DNA and lamivudine resistance status by linear regression analysis. Entecavir demonstrated superiority to adefovir for this endpoint (treatment difference 1.74 log(10) copies/mL [95% confidence interval -2.30, -1.18]; P < 0.0001). The entecavir group showed a greater change from baseline in HBV DNA at all time points through week 48 and a higher proportion of subjects who achieved HBV DNA < 300 copies/mL at weeks 24 (entecavir 49%; adefovir 16%; P < 0.0001) and 48 (entecavir 57%; adefovir 20%; P < 0.0001). Approximately two-thirds of subjects in both groups showed improvement/stabilization in Child-Turcotte-Pugh status. Model for End-Stage Liver Disease score change at week 48 was -2.6 for entecavir and -1.7 for adefovir. Adverse event rates were comparable between groups. Cumulative hepatocellular carcinoma rates were 12% for entecavir and 20% for adefovir. Cumulative death rates were 23% for entecavir and 33% for adefovir. Week 24 mortality rates were 12% for both groups. conclusion: Entecavir demonstrated superior virologic efficacy to adefovir in a population of patients with chronic hepatitis B who had hepatic decompensation. Biochemical and clinical benefits were also demonstrated. Entecavir was well tolerated, and early mortality rates were consistent with rates observed in similar populations treated with lamivudine.

Virological suppression does not prevent the development of hepatocellular carcinoma in HBeAg-negative chronic hepatitis B patients with cirrhosis receiving oral antiviral(s) starting with lamivudine monotherapy: results of the nationwide HEPNET. Greece cohort study.

OBJECTIVE: To evaluate the risk and predictors of hepatocellular carcinoma (HCC) in HBeAg-negative chronic hepatitis B patients of the large HEPNET.Greece cohort study who received long-term oral antivirals starting with lamivudine monotherapy. DESIGN: Retrospective analysis of HCC incidence in HBeAg-negative chronic hepatitis B patients from a retrospective-prospective cohort who were treated with nucleos(t)ide analogue(s) starting with lamivudine monotherapy for ≥12 months. SETTING: A nationwide network of liver centres. PATIENTS: 818 patients were included: 517 with chronic hepatitis B only; 160 with compensated cirrhosis; 56 with decompensated cirrhosis; 85 with unclassified disease severity. INTERVENTIONS: All patients were treated with nucleos(t)ide analogue(s) starting with lamivudine monotherapy. MAIN OUTCOME MEASURES: Development of HCC. RESULTS: During a median follow-up of 4.7 years, HCC developed in 49 (6.0%) patients. The 5-year cumulative incidence of HCC was higher in patients with cirrhosis than in those with chronic hepatitis B only (11.5% vs 3.2%, respectively; p<0.001). HCC developed in 0.7%, 6.7% and 11.7% of patients <50, 50-60 and >60 years old, respectively (p<0.001). Virological on-therapy remission did not significantly affect the incidence of HCC in all patients or those with cirrhosis, but it showed a trend for lower HCC incidence in patients with chronic hepatitis B only (p=0.076). In multivariate analysis, age, gender and cirrhosis were independently associated with HCC risk regardless of virological remission. CONCLUSIONS: Long-term therapy with nucleos(t)ide analogue(s) starting with lamivudine monotherapy does not eliminate HCC risk in HBeAg-negative chronic hepatitis B. The risk of HCC is particularly high in patients with cirrhosis, who should remain under HCC surveillance even during effective therapy. Older age and male gender remain independent risk factors for HCC, while virological on-therapy remission does not seem to significantly reduce the overall incidence of HCC.

A randomized trial of peginterferon alpha-2a with or without ribavirin for HBeAg-negative chronic hepatitis B.

OBJECTIVES: Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B patients are at high risk of treatment relapse after any antiviral therapy. Combining peginterferon alpha-2a with ribavirin might improve sustained response rates. METHODS: Overall, 138 HBeAg-negative chronic hepatitis B patients were randomized to receive monotherapy (peginterferon alpha-2a 180 microg weekly plus placebo) or combination therapy (peginterferon alpha-2a weekly plus ribavirin 1,000 or 1,200 mg daily, depending on body weight) for 48 weeks. Post-treatment follow-up lasted 24 weeks. Analyses were based on the modified intention-to-treat population after exclusion of five patients. RESULTS: At the end of follow-up, 14 (20%) of 69 patients assigned to monotherapy and 10 (16%) of 64 assigned to combination therapy had a combined response (hepatitis B virus (HBV) DNA <10,000 copies/ml (<1,714 IU/ml) and a normal alanine aminotransferase level, P=0.49). At the end of treatment, more patients had a combined response (25 (36%) vs. 26 (41%) in the monotherapy and combination therapy group, respectively, P=0.60), but subsequently relapsed during follow-up. Serum HBV DNA and hepatitis B surface antigen (HBsAg) levels decreased during treatment (mean change at week 48 compared with baseline -3.9 vs. -2.6 log copies/ml, P<0.001 and -0.56 vs. -0.34 log IU/ml, P=0.23, respectively). HBV DNA levels relapsed after treatment discontinuation; HBsAg remained at end-of-treatment levels. In general, combination therapy was well tolerated, although it was associated with a higher risk of anemia and neutropenia. CONCLUSIONS: Treatment with peginterferon alpha-2a resulted in a limited sustained response rate in HBeAg-negative chronic hepatitis B patients. Addition of ribavirin did not improve response to therapy.

Brucellar spondylodiscitis: noncontiguous multifocal involvement of the cervical, thoracic, and lumbar spine.

Brucellosis is a zoonosis of worldwide distribution presenting with a wide clinical spectrum. Brucellosis can involve any organ or system. The axial skeleton is the most common site of involvement with a frequency ranging from 2% to 53%. Multiple-level spinal involvements are rare. This report describes the first case of noncontiguous synchronous multifocal involvement of all cervical, thoracic, and lumbar regions in a patient with brucellar spondylodiscitis.

Epidemiology, clinical data, and treatment of viral hepatitis in a large cohort of intravenous drug users.

OBJECTIVES: The aim of this study was to evaluate retrospectively the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, epidemiological parameters, and the clinical data from the antiviral treatment of hepatitis C in a large cohort of intravenous drug users (IDUs) followed-up from 1994 until 2008. PATIENTS AND METHODS: A total of 1179 former IDUs followed up either in the liver unit or in the context of a substitution program organization were included in this study. A retrospective chart review was prepared to retrieve data on the patients' demographic characteristics, the prevalence of viral hepatitis, and information on HCV treatment. RESULTS: The prevalence of HBsAg positive was 5%. A substantial number of patients were anti-HCV positive (847/1170, 73%), 189 were lost to follow-up, 526 (80%) were HCV RNA positive and 132 (20%) had a self-limited disease. The most prevalent genotype was 3 (59.7%). Twenty-five percent of the study population received antiviral treatment against HCV infection. Patients seen in the Liver Unit were more likely to receive antiviral treatment. The sustained virological response (SVR) was 80% with patients treated with pegylated interferon and ribavirin having a significantly higher SVR rate. CONCLUSIONS: Our results show that (a) the majority of IDUs in Greece have chronic hepatitis C and the prevalent genotype is 3 (b) patients who complete therapy have SVR rates similar to those without drug-dependence, and (c) since IDUs constitute the core of the hepatitis C epidemic and the main route of HCV transmission, efforts to treat these patients should be made.

Long-term follow-up of hepatitis B e antigen-negative patients treated with peginterferon α-2a: progressive decrease in hepatitis B surface antigen in responders.

OBJECTIVE: Peginterferon (PEG-IFN) is considered as a first-line treatment option for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. We aimed to evaluate the long-term response to PEG-IFN in HBeAg-negative patients. METHODS: All patients enrolled in the PARC study who completed the treatment phase were eligible for this long-term follow-up (LTFU) study. Patients received PEG-IFN α-2a (180 µg weekly) ± ribavirin (1000-1200 mg daily) for 48 weeks and had at least one additional LTFU visit after the initial follow-up period of 24 weeks (mean duration 2.1 ± 0.2 years). Retreated patients were considered nonresponders. RESULTS: Of 117 patients who completed the treatment phase, 79 (68%) were included in this LTFU study. Among 19 patients with a combined response at 24 weeks after treatment [initial responders; hepatitis B virus DNA<10 000 copies/ml (<1714 IU/ml) and normal alanine aminotransferase], 12 (63%) sustained this response through LTFU. Three additional patients showed such a response at LTFU, resulting in a total of 15 (19%) combined responders at LTFU. A marked decrease in the serum hepatitis B surface antigen (HBsAg) levels was observed in initial responders, resulting in HBsAg clearance in 26% of the patients (6% of all LTFU participants). CONCLUSION: About one-third of HBeAg-negative patients with a response to PEG-IFN at 24 weeks after treatment subsequently had a relapse during 2 years of follow-up. Despite the limited overall efficacy of PEG-IFN, patients responding to PEG-IFN treatment showed a marked decrease in serum HBsAg, resulting in a high rate of HBsAg clearance, which indicates the need for predictors of response to PEG-IFN in HBeAg-negative disease.

Diminished percentage of CD4+ T-lymphocytes expressing interleukine-2 receptor alpha in chronic brucellosis.

OBJECTIVES AND METHODS: Despite the treatment, a considerable proportion of brucellosis patients develop chronic disease, characterized by atypical clinical picture and/or relapses. Th1 cytokines are critical for the clearance of Brucella infection and diminished production of IL-2 in response to PHA, has been described in chronic brucellosis. In order to investigate the role of IL-2R alpha (CD25) in disease outcome, we evaluated the ex vivo and PHA-induced percentage of peripheral CD4+ T-lymphocytes expressing CD25 in 13 acute brucellosis patients (AB), 22 chronic brucellosis patients (CB), 11 "clinically cured" subjects and 15 healthy volunteers (controls). Simultaneously, CD3+, CD4+ and CD8+ T-lymphocytes subsets were measured. RESULTS: The ex vivo percentage of CD4+/CD25+ T-cells was significantly higher in AB patients compared to "clinically cured" subjects (p=0.005) and controls (p=0.006). By contrast, CD4+/CD25+ T-cells were significantly lower in CB patients (p=0.001). T-lymphocytes subsets did not significantly differ between the groups. After PHA stimulation, CD4+/CD25+ T-cells remained significantly lower in CB and specifically in the relapsing form of chronic disease compared to AB (p=0.044, 0.023). Additionally, CD8+ T-lymphocytes were found to be significantly increased in CB and mainly in the relapsing subgroup of CB patients compared to AB (p=0.044, 0.011). CONCLUSION: Diminished percentage of peripheral CD4+ T-lymphocytes expressing IL-2R alpha is associated with chronic relapsing brucellosis.

Long term follow-up of a large cohort of inactive HBsAg (+)/ HBeAg (-)/ anti-HBe (+) carriers in Greece.

AIM: To investigate the long-term outcome and the risk of progression to chronic hepatitis B in inactive hepatitis B surface antigen carriers. MATERIAL AND METHODS: A total of 307 HBsAg (+)/HBeAg (-)/antiHBe (+) subjects with initially normal alanine aminotransferase (ALT) levels and undetectable/ low serum HBVDNA with hybridization assay and later with PCR (10(5) copies/ml), were followed-up every 6 months for a period of 3 to 21 years (7.45 +/- 3.75 years). RESULTS: 234 out of the 307 HBsAg (+) patients (76.2%) had persistently normal ALT and undetectable / low (10(5) copies/ml) HBVDNA during follow-up. In 73 patients (23.8%), a reactivation of the disease with elevated ALT and positive HBVDNA (> (10(5)copies/ml) was recorded during the follow up. Thirty-five out of 73 patients underwent liver biopsy, while 22 of them received treatment. Twenty-four patients (7.8%) lost HBsAg after a mean of 7.4 +/- 3.6 years. Regarding the complications of chronic hepatitis B, only one patient developed compensated cirrhosis and no one developed HCC. CONCLUSIONS: Our results show that in almost 24% of inactive chronic hepatitis B carriers reactivation of the disease may occur even after many years. However the risk of liver-related complications is very low in these subjects.