Search

HBV nucleos(t)ide reverse transcriptase inhibitors (NrtIs) do not completely suppress HBV replication. Previous reports indicate persistent viremia during NrtI treatment despite HBV DNA being undetectable. HBV core inhibitors may enhance viral suppression when combined with NrtIs. This phase II trial (NCT03576066) evaluated the efficacy and safety of the investigational core inhibitor, vebicorvir (VBR), in virologically- suppressed patients on NrtIs.Non-cirrhotic, NrtI-suppressed patients with chronic HBV were randomised to VBR 300 mg once daily or matching placebo (PBO) for 24 weeks. Treatment was stratified by hepatitis B e antigen (HBeAg) status. The primary endpoint was change from Baseline in serum HBeAg or hepatitis B surface antigen (HBsAg) after 24 weeks.Of 73 patients enrolled, 47 were HBeAg positive and 26 were HBeAg negative. In HBeAg-positive and -negative patients, there were no differences in the change from Baseline at Week 24 for HBsAg or HBeAg. Using a novel, high-sensitivity assay to detect HBV DNA, a greater proportion of patients with detectable HBV DNA at Baseline achieved undetectable HBV DNA at Week 24 in the VBR+NrtI vs. PBO+NrtI group. In HBeAg-positive patients, a greater change from Baseline in HBV pregenomic (pg)RNA was observed at Week 24 with VBR+NrtI vs. PBO+NrtI. Treatment-emergent adverse events (TEAEs) in VBR+NrtI patients included upper respiratory tract infection, nausea, and pruritus. No serious adverse events, Grade 4 TEAEs, or deaths were reported.In this 24-week study, VBR+NrtI demonstrated a favourable safety and tolerability profile. While there were no significant changes in viral antigen levels, enhanced viral suppression was demonstrated by greater changes in DNA and pgRNA with the addition of VBR compared to NrtI alone.NCT03576066.Core inhibitors represent a novel approach for the treatment of chronic hepatitis B virus (HBV) infection, with mechanisms of action distinct from existing treatments. In this study, vebicorvir added to existing therapy reduced HBV replication to a greater extent than existing treatment and was generally safe and well tolerated.

Nucleos(t)ide reverse transcriptase inhibitors do not completely suppress HBV DNA in chronic HBV infection (cHBV). Vebicorvir (VBR) is an investigational core inhibitor that interferes with multiple aspects of HBV replication. This phase II trial evaluated the safety and efficacy of VBR in combination with entecavir (ETV) in treatment-naïve patients with cHBV.HBeAg-positive, treatment-naïve patients without cirrhosis were randomised 1:1 in a double-blind manner to once-daily VBR 300 mg+ETV 0.5 mg or placebo (PBO)+ETV 0.5 mg for 24 weeks. The primary endpoint was change in mean logAll patients in both treatment groups (PBO+ETV: 12/12; VBR+ETV: 13/13) completed the study. At Week 12, VBR+ETV led to a greater mean (SD) reduction from Baseline in logIn this 24-week study, VBR+ETV provided additive antiviral activity over PBO+ETV in treatment-naïve patients with cHBV, with a favourable safety and tolerability profile.NCT03577171 LAY SUMMARY: Hepatitis B is a long-lasting viral infection of the liver. Current treatments can suppress hepatitis B virus but do not offer the opportunity of cure, hence, new treatment approaches are required. Herein, we show that the combination of the novel core inhibitor vebicorvir with an existing antiviral (entecavir) in treatment-naïve patients chronically infected with hepatitis B virus demonstrated greater antiviral activity than entecavir alone. Additionally, vebicorvir was safe and well tolerated. Thus, further studies evaluating its potential role in the treatment of chronic hepatitis B are warranted.

Chronic hepatitis B infection continues to be a major public health concern worldwide. The natural history of the disease can be divided into 4 different phases: immune tolerance, immune clearance, inactive carrier, and reactivation. The goals of treatment are sustained viral suppression, normalization of ALT, and improvement in liver histology. Antiviral agents in current use include standard interferon-alpha, lamivudine, and adefovir. With an improved understanding of the natural history of the disease and a growing repertoire of antiviral drugs, the important questions are: who should receive treatment, what is the best agent to use, and what is the optimal duration of therapy? Treatment is indicated for patients in the immune clearance and reactivation phases. Patients with high pretreatment ALT level, detectable HBV DNA in the serum, and active inflammation on liver biopsy are predicted to have the highest chance of response to treatment. The choice of a particular agent must balance long-term benefits such as the likelihood of a sustained response against long-term risks such as drug resistance. Interferon treatment leads to a more durable response but is associated with unpleasant side effects. Lamivudine is effective and well tolerated but requires long-term therapy and is associated with drug resistance. Adefovir has proven efficacy and a very low rate of drug resistance but is associated with a small risk of reversible nephrotoxicity. For HBeAG-positive chronic hepatitis B and HBeAG-negative chronic hepatitis B, the duration of interferon therapy is 4-6 months and 12 months, respectively. Duration of treatment is at least 1 year with lamivudine and adefovir; longer duration of treatment is needed in most patients, but the optimal duration of treatment and the criteria for stopping treatment have not been established.

OBJECTIVE: To describe the microbiology and potential virulence factors ofBurkholderia cepacia; to discuss the studies that have investigated its mode of transmission among cystic fibrosis patients; and to identify the major risk factors associated with acquisition of this pathogen inside and outside of the hospital environment.DATA SOURCES: MEDLINE search of the literature published between 1986 and 1997 using the key words/subject wordsPseudomonas cepacia,Burkholderia cepacia, cystic fibrosis, infection control and transmissibility, and the bibliography of selected papers.DATA EXTRACTION: Selected studies examining epidemiology, microbiology, virulence factors and mode of transmission ofB cepaciain cystic fibrosis.DATA SYNTHESIS AND CONCLUSIONS:B cepaciais a multidrug-resistant Gram-negative bacillus that has recently been recognized as a major respiratory pathogen in patients with cystic fibrosis. Colonization by this organism can lead to rapid pulmonary deterioration and premature death. Recent studies based on genomic subtyping techniques have suggested that it can be transmitted from person to person. Close social contact and hospitalization have been identified as risk factors for cross-infection. With the implementation of strict infection control policies such as segregation according to colonization status, the rate of new colonization has substantially decreased in most cystic fibrosis treatment centres.

Accurate quantification of hepatitis B virus (HBV) DNA levels is important for monitoring patients with chronic HBV infection and for assessing their responses to antiviral therapy. This study aimed to develop a real-time PCR assay that is sensitive and can accurately quantify a wide range of HBV DNA levels across the known HBV genotypes. An “in-house” real-time PCR assay using primers and a TaqMan probe in a highly conserved region of the HBV surface gene was designed. The assay was standardized against a WHO standard and validated against plasmids of HBV genotypes A through H. The linear quantification range was approximately 5 × 10 0 to 2.0 × 10 9 IU/ml. Results of samples from patients infected with HBV genotypes A through H tested using our real-time “in-house” PCR assay showed an excellent correlation with those of the Cobas Amplicor HBV Monitor ( R 2 = 0.9435) and the Cobas TaqMan HBV ( R 2 = 0.9873) tests. We have established a real-time PCR assay that is genotype independent and can accurately quantify a wide range of HBV DNA levels. Further studies of additional samples are ongoing to validate the genotype independence of our assay.

Multi-drug resistant hepatitis B virus (HBV) has been reported in hepatitis B patients who received sequential antiviral therapy. In vitro studies showed that HBV constructs with mutations resistant to lamivudine and adefovir have marked reduction in sensitivity to combination of lamivudine and adefovir, whereas constructs with mutations resistant to either drug remain sensitive to the other drug. We conducted this study to determine whether mutations conferring resistance to multiple antiviral agents co-locate on the same HBV genome in vivo and to describe the evolution of these mutations. Sera from six patients who had been found to have multi-drug resistant HBV mutations to lamivudine + adefovir, lamivudine + hepatitis B immunoglobulin (HBIG), or lamivudine + entecavir on direct sequencing were cloned after nested polymerase chain reaction (PCR). Analysis of 215 clones from 11 samples with multi-drug resistant mutations on direct sequencing showed that 183 (85%) clones had mutations to both therapies on the same genome; 31 clones had lamivudine-resistant mutants only. Clonal analysis of serial samples from three patients showed progressive evolution from all clones with lamivudine-resistant HBV mutations only to mixtures of clones that have multi-drug resistant mutations and clones that have lamivudine-resistant HBV mutations only, and ultimately all clones having multi-drug resistant HBV mutations. In conclusion, mutations conferring resistance to multiple antiviral agents co-locate on the same viral genome, suggesting that combination therapy directed against mutants resistant to each treatment may not be adequate in suppressing multi-drug resistant HBV. De novo combination therapy may prevent the emergence of multi-drug resistant mutants. (HEPATOLOGY 2006;44:703–712.)

The INNO-LiPA HBV DR v2 assay is designed to detect hepatitis B virus mutations conveying resistance to lamivudine and adefovir. Our study confirms that this assay can simultaneously detect the presence of lamivudine and adefovir resistance mutations in clinical samples, has a high degree of concordance with sequencing, and can detect mutants earlier.

Background/Aims The susceptibility of adefovir-resistant hepatitis B virus (HBV) mutants is only reduced by 3–10-fold in in vitro studies, suggesting that virologic breakthrough and clinical deterioration are unlikely. The aim of this study was to describe the clinical course of patients with adefovir-resistant HBV infection. Methods Testing for adefovir-resistant mutations was performed on patients who had a suboptimal response or virologic breakthrough on adefovir. Adefovir-resistant mutations were detected using a line probe assay and direct sequencing of the HBV P-gene. Results Eight male patients with pre-existing lamivudine resistance or breakthrough (mean age 47±13 years) were found to have adefovir-resistant mutations rtA181V/T or rtN236T. Baseline median ALT was 66 IU/L (range, 27–1161) and median HBV DNA 7.9 log 10 copies/ml (range, 6–8.3). At the time of adefovir resistance (mean of 20±9 months), HBV DNA increased to ≥5 log 10 copies/ml in 7 patients. After detection of adefovir resistance, hepatic decompensation occurred in 2 patients, 1 of whom died. Salvage therapy with lamivudine, entecavir or tenofovir was given to 7 patients and a reduction in HBV DNA by ≥3 log 10 was seen in 3 patients. Conclusions In conclusion, adefovir resistance can be associated with significant viral rebound and hepatic decompensation which may be fatal.

SUMMARY. Lamivudine has demonstrated efficacy for the treatment of hepatitis B e antigen-negative chronic hepatitis B (e-CHB). However, treatment withdrawal after 1 year has been associated with a high rate of relapse while long-term treatment is associated with increasing risks of drug resistance. We report our treatment experience of 50 ChineseCanadian patients with e-CHB. All patients received lamivudine for 2 years. Treatment was withdrawn at month 24 in patients who had undetectable hepatitis B virus (HBV) DNA by PCR and normal aminotransferases during the second year of therapy. All patients had HBV genotype B or C. Biochemical response at months 6, 12 and 24 was 74%, 71% and 66%, respectively. HBV DNA was undetectable at months 6, 12 and 24 by hybrid capture and PCR assays in 100%, 92% and 86%; and 94%, 88% and 74% patients, respectively. The cumulative rates of genotypic resistance (GR) after 1 and 2 years were 15% and 25%, respectively. Four (44%) patients with GR experienced a hepatitis flare. The probability of clinical and virological relapse 6, 12, and 18 months after treatment withdrawal were 12% and 30%, 18% and 50%, and 30% and 50%, respectively. Reinstitution of lamivudine resulted in prompt virological and biochemical responses. Our study demonstrates that a sustained response can be achieved after a 2-year course of lamivudine in a subset of patients with e-CHB.