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Biomedicines Jan 2022Hepatitis B virus (HBV) is known to cause severe liver diseases such as acute or chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Chronic hepatitis B...
Hepatitis B virus (HBV) is known to cause severe liver diseases such as acute or chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Chronic hepatitis B (CHB) infection is a major health problem with nearly 300 million individuals infected worldwide. Currently, nucleos(t)ide analogs (NAs) and interferon alpha are clinically approved treatments for HBV infection. NAs are potent antiviral agents that bind to HBV polymerase and block viral reverse transcription and replication. Besifovir dipivoxil maleate (BSV) is a newly developed NA against HBV in the form of acyclic nucleotide phosphonate that is available for oral administration similar to adefovir and tenofovir. Until now, resistance to BSV treatment has not been reported. In this study, we found a CHB patient who showed viral breakthrough after long-term treatment with BSV. The isolated HBV DNA from patient's serum were cloned into the replication-competent HBV 1.2 mer and the sequence of reverse transcriptase (RT) domain of HBV polymerase were analyzed. We also examined the drug susceptibility of generated clones in vitro. Several mutations were identified in HBV RT domain. A particular mutant harboring ten RT mutations showed resistance to BSV treatment in vitro. The ten mutations include rtV23I (I), rtH55R (R), rtY124H (H), rtD134E (E), rtN139K (K), rtL180M (M), rtM204V (V), rtQ267L (L), rtL269I (I) and rtL336M (M). To further identify the responsible mutations for BSV resistance, we performed in vitro drug susceptibility assay on several artificial clones. As a result, our study revealed that rtL180M (M) and rtM204V (V) mutations, already known as lamivudine-resistant mutations, confer resistance to BSV in the CHB patient.
PubMed: 35203489
DOI: 10.3390/biomedicines10020282 -
Clinical Drug Investigation Sep 2019Oral nucleoside/nucleotide analogues (NAs) have been advocated for chronic hepatitis B (CHB) treatment with good efficacy. However, less attention has been put on their... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND OBJECTIVE
Oral nucleoside/nucleotide analogues (NAs) have been advocated for chronic hepatitis B (CHB) treatment with good efficacy. However, less attention has been put on their adverse events. Therefore, a Bayesian network meta-analysis (NMA) was performed to evaluate the relative safety of five NAs (lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate) in CHB treatment among adults.
METHODS
Eligible randomized clinical trials (RCTs) and prospective cohort studies were systematically and thoroughly searched until May 1, 2019. Poisson-prior-based Bayesian NMA was performed to synthesize both direct and indirect evidence with reporting hazard ratios (HRs) and 95% credible intervals (CrIs) for serious adverse events (SAEs) and hepatic/renal impairments.
RESULTS
Thirty-three RCTs and 11 prospective cohort studies were identified. As to SAEs, no statistically significant difference was found of any comparison among five NAs. In terms of hepatotoxicity, lamivudine was safer than telbivudine (HR 0.45; 95% CrI 0.21, 0.85), and entecavir increased the risk by 102% (entecavir vs lamivudine: HR 2.02; 95% CrI 1.19, 3.27).
CONCLUSIONS
The findings from this large NMA could influence clinical practice, and the methodological framework of this study could provide evidence-based support to analyze sparse safety data in the field.
Topics: Adenine; Antiviral Agents; Bayes Theorem; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Network Meta-Analysis; Organophosphonates; Prospective Studies; Telbivudine; Tenofovir
PubMed: 31228017
DOI: 10.1007/s40261-019-00802-8 -
Journal of Clinical and Experimental... 2022Currently available treatment options for chronic hepatitis B (CHB) are not recommended for HBeAg-negative patients with a low viral load. These patients may however...
BACKGROUND
Currently available treatment options for chronic hepatitis B (CHB) are not recommended for HBeAg-negative patients with a low viral load. These patients may however benefit from treatment by achieving a functional cure, defined by HBsAg-loss and undetectable HBV DNA. This study evaluated the long-term effect of combination treatment with peg-interferon-alpha-2a (peg-IFN) and adefovir or tenofovir compared to no treatment in these patients.
METHODS
HBeAg-negative CHB patients with HBV-DNA levels < 20,000 IU/mL ( = 151) were previously randomised 1:1:1 for peg-IFN 180 μg/week plus either adefovir 10 mg/day or tenofovir 245 mg/day, or no treatment and treated for 48 weeks in an open-label study. In this prospective long-term follow-up study, patients were monitored yearly up to five years after end of treatment (week 308). The primary outcome was sustained HBsAg-loss and secondary outcome the dynamics of HBsAg and HBV-DNA levels over time.
RESULTS
Of the 131 followed patients, the HBsAg-status was known for 118 patients after five-year follow-up. HBsAg-loss occurred similarly ( = 0.703) in all arms: 8/43 (18.6%) peg-IFN + adefovir, 4/34 (11.7%) peg-IFN + tenofovir, and 6/41 (14.6%) among the untreated patients. The time to HBsAg-loss did not differ between groups ( = 0.641). Low baseline HBsAg levels and genotype A were independently associated with HBsAg-loss irrespective of allocation. HBsAg and HBV-DNA levels declined similarly during follow-up in all patient groups.
CONCLUSIONS
This prospective randomised controlled study showed that HBsAg-loss overtime was not influenced by treatment with a combination of nucleotide analogue and Peg-IFN. Low baseline HBsAg levels can predict HBsAg-loss irrespective of treatment allocation.
PubMed: 35677522
DOI: 10.1016/j.jceh.2021.12.011 -
Systematic Reviews Aug 2019Chronic hepatitis B (CHB) infection poses a significant burden to public health worldwide. Most cases are clinically silent until late in the disease course. The main... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Chronic hepatitis B (CHB) infection poses a significant burden to public health worldwide. Most cases are clinically silent until late in the disease course. The main goal of current therapy is to improve survival and quality of life by preventing disease progression to cirrhosis and liver failure, and consequently hepatocellular carcinoma development. The objective of this review is to provide a contemporary and comprehensive evaluation of the effectiveness of treatment options.
METHODS
We performed a systematic review of peer-reviewed literature for randomized controlled trials involving treatment-naïve CHB adult population who received antiviral therapy. The endpoints were virologic response (VR), normalization of alanine aminotransferase (ALT norm), HBeAg loss, HBeAg seroconversion, and HBsAg loss for the HBeAg-positive population; and VR and ALT norm for the HBeAg-negative population. Network meta-analysis (NMA) was performed to synthesize evidence on the efficacy of treatment.
RESULTS
Forty-two publications were selected. Twenty-three evaluated HBeAg-positive population, 13 evaluated HBeAg-negative population, and six evaluated both. We applied NMA to the efficacy outcomes of the two populations separately. Treatment strategies were ranked by the probability of achieving outcomes, and pairwise comparisons calculated from NMA were reported in odds ratios (OR). For HBeAg-positive population, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) were the best for VR; OR vs adefovir = 14.29, 95% CI 7.69-25 and 12.5, 95% CI 4.35-33.33 respectively. TAF was the best for achieving ALT norm (OR vs placebo = 12.5, 95% CI 4.55-33.33), HBeAg loss, and seroconversion (OR vs entecavir/TDF combination = 3.03, 95% CI 1.04-8.84 and 3.33, 95% CI 1.16-10 respectively). In the HBeAg-negative population, TDF and TAF were the best for VR (OR vs adefovir = 9.79, 95% CI 2.38-42.7 and 11.71, 95% CI 1.03-150.48 respectively). Telbivudine and TAF were the best for ALT norm. Certain nucleos(t)ide combinations also had high probability of achieving positive outcomes.
CONCLUSIONS
Our results are consonant with current clinical guidelines and other evidence reviews. For both HBeAg-positive and HBeAg-negative populations, TDF and TAF are the most effective agents for virologic suppression, and TAF is effective across all outcomes.
Topics: Antiviral Agents; Hepatitis B, Chronic; Humans; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 31426837
DOI: 10.1186/s13643-019-1126-1 -
Journal of Clinical Pharmacy and... Aug 2020To explore the clinical characteristics of adefovir dipivoxil-induced Fanconi's syndrome in the Chinese population and provide a reference for rational drug use in the...
WHAT IS KNOWN AND OBJECTIVE
To explore the clinical characteristics of adefovir dipivoxil-induced Fanconi's syndrome in the Chinese population and provide a reference for rational drug use in the clinic.
METHODS
By searching the CNKI, Wanfang, Chinese VIP, PubMed/MEDLINE, Web of Knowledge, Ovid, Elsevier and SpringerLink databases during 1 January 2008 to 31 December 2019, 78 studies of ADV-induced Fanconi's syndrome involving a total of 110 patients were collected and analysed retrospectively.
RESULTS AND DISCUSSION
Prolonged usage of adefovir dipivoxil at low doses to treat hepatitis B might cause Fanconi's syndrome as the first symptom, especially for use over 12 months.The main clinical manifestation was bone pain accompanied by hypophosphataemia, elevated alkaline phosphatase (ALP), urine glycosuria and urine protein. X-rays and bone mineral density (BMD) examinations were mainly used to characterized osteoporosis. The patients had pain relief within 1 week to 1 month, and the biochemical indicators returned to normal within from 2 to 4 months.
WHAT IS NEW AND CONCLUSION
Sufficient attention is required before and during exposure to long-term ADV therapy. The clinical picture, laboratory and radiograph alterations are important clues for ADV-induced Fanconi's syndrome.
Topics: Adenine; Adult; Aged; Alkaline Phosphatase; Asian People; Bone Density; Fanconi Syndrome; Female; Glycosuria; Humans; Hypophosphatemia; Male; Middle Aged; Organophosphonates; Osteoporosis; Retrospective Studies; Young Adult
PubMed: 32406123
DOI: 10.1111/jcpt.13154 -
Annals of Hepatology Dec 2021Covalently closed circular (ccc)DNA acts as a viral reservoir in the liver of patients with a chronic hepatitis B (CHB) infection and can only be quantified in liver...
INTRODUCTION AND OBJECTIVES
Covalently closed circular (ccc)DNA acts as a viral reservoir in the liver of patients with a chronic hepatitis B (CHB) infection and can only be quantified in liver biopsies. Hepatitis B core-related antigen (HBcrAg) levels in plasma/serum have been proposed to reflect intrahepatic cccDNA-levels and may therefore monitor treatment efficacy. This study aimed to validate the relationship between HBcrAg and other intrahepatic and circulating viral markers in CHB patients with high viral load, before and after combination treatment.
MATERIALS AND METHODS
Plasma/serum levels of HBcrAg, HBsAg, HBV-DNA, and HBV pregenomic RNA (HBV-pgRNA), and intrahepatic cccDNA and HBV-DNA levels and fibrosis scores were measured in 89 CHB patients with HBV-DNA levels of >100,000 copies/mL (17,182 IU/mL). Measurements were done before and after a 48-week treatment with pegylated interferon alfa-2a and adefovir in a prospective study (ISRCTN77073364).
RESULTS
Baseline HBcrAg-values correlated strongly with intrahepatic cccDNA (ρ 0.77, p < 0.001), intrahepatic HBV-DNA (ρ 0.73, p < 0.001) and plasma/serum HBV-DNA (ρ 0.80, p < 0.001), HBV-pgRNA (ρ 0.80, p < 0.001), and to lesser extend HBsAg (ρ 0.56, p < 0.001). Baseline HBcrAg-levels could not predict functional cure (FC) but HBcrAg-levels declined more strongly in patients who developed FC or HBeAg-loss. Furthermore, most correlations persisted at the end of treatment and follow-up.
CONCLUSIONS
HBcrAg reflects cccDNA transcription activity more accurately than HBsAg and may replace HBV-DNA as a marker during future treatment regimens, especially when cccDNA transcription is targeted or nucleot(s)ide analogues are included in the treatment regime.
Topics: Adult; Antiviral Agents; Biomarkers; DNA, Viral; Female; Follow-Up Studies; Hepatitis B Core Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver; Male; Prospective Studies; Viral Load
PubMed: 34583061
DOI: 10.1016/j.aohep.2021.100540 -
The Journal of International Medical... Oct 2020More than 150 cases of Fanconi syndrome (FS) or hypophosphatemia osteomalacia induced by low-dose adefovir dipivoxil (ADV) have been reported since 2002, when ADV was... (Review)
Review
More than 150 cases of Fanconi syndrome (FS) or hypophosphatemia osteomalacia induced by low-dose adefovir dipivoxil (ADV) have been reported since 2002, when ADV was introduced for the long-term treatment of hepatitis B virus (HBV) infection. Because the life expectancy of HBV-infected individuals has increased, the adverse effects of long-term treatment with antiviral therapies are increasingly observed, and nephrotoxicity is one of the most severe adverse effects of ADV. Therefore, the number of cases may be far higher than reported. Moreover, ADV-induced FS is often misdiagnosed or diagnosed long after it first develops. ADV-induced FS may seriously decrease patient quality of life and lead to bone fractures and even disability. Although progress has been made in the identification of biomarkers and treatments, few systematic clinical guidelines or clinical reviews for FS induced by ADV have been reported. In this study, we highlighted the recent progress toward understanding of FS induced by ADV, described a clinical case, and summarized the primary characteristics and laboratory findings of this disease.
Topics: Adenine; Antiviral Agents; Fanconi Syndrome; Hepatitis B virus; Hepatitis B, Chronic; Humans; Organophosphonates; Quality of Life
PubMed: 33100076
DOI: 10.1177/0300060520954713 -
World Journal of Clinical Cases Nov 2023Osteomalacia (OM) is frequently confused with various musculoskeletal or other rheumatic diseases, especially in patients with adult-onset widespread musculoskeletal...
BACKGROUND
Osteomalacia (OM) is frequently confused with various musculoskeletal or other rheumatic diseases, especially in patients with adult-onset widespread musculoskeletal pain because of its low prevalence and non-specific manifestations.
AIM
To facilitate the early diagnosis and etiology-specific treatment of adult-onset hypophosphatemic OM.
METHODS
A retrospective review of medical records was performed to screen adult patients who visited a physiatry locomotive medicine clinic (spine and musculoskeletal pain clinic) primarily presenting with widespread musculoskeletal pain at a single tertiary hospital between January 2011 and December 2019. We enrolled patients with hypophosphatemia, high serum bone-specific alkaline phosphatase levels, and at least one imaging finding suggestive of OM.
RESULTS
Eight patients with adult-onset hypophosphatemic OM were included. The back was the most common site of pain. Proximal dominant symmetric muscle weakness was observed in more than half of the patients. Bone scintigraphy was the most useful imaging modality for diagnosing OM because radiotracer uptake in OM showed characteristic patterns. Six patients were diagnosed with adefovir (ADV)-induced Fanconi syndrome, and the other two patients were diagnosed with tumor-induced OM and light-chain nephropathy, respectively. After phosphorus and vitamin D supplementation and treatment for the underlying etiologies, improvements in pain, muscle strength, and gait were observed in all patients.
CONCLUSION
Mechanical pain characteristics, hypophosphatemia, and distinctive bone scintigraphy patterns are the initial diagnostic indicators of adult-onset hypophosphatemic OM. ADV-induced Fanconi syndrome is the most common etiology of hypophosphatemic OM in hepatitis B virus-endemic countries.
PubMed: 38073682
DOI: 10.12998/wjcc.v11.i32.7785 -
Antiviral Research Feb 2020Pradefovir is a liver targeted novel prodrug of adefovir (PMEA) developed to provide higher antiviral activity with reduced systemic toxicities. This study evaluated the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIMS
Pradefovir is a liver targeted novel prodrug of adefovir (PMEA) developed to provide higher antiviral activity with reduced systemic toxicities. This study evaluated the tolerability, pharmacokinetics, and antiviral activity of pradefovir in patients with chronic hepatitis B (CHB) virus infection.
METHODS
Non-cirrhotic, treatment-naïve subjects with CHB were divided into five groups (10 patients each) and randomized within each group in a ratio of 6:2:2 to receive an ascending dose of 30, 60, 75, 90, or 120 mg pradefovir, 10 mg adefovir dipivoxil (ADV), or 300 mg tenofovir disoproxil fumarate (TDF) once a day for 28 days.
RESULTS
A total of 51 subjects were randomized and 49 subjects completed the study. The groups were well matched and included 39 males, of whom 71% were hepatitis B e-antigen-negative with a mean hepatitis B virus (HBV) DNA level of 6.4-7.16 log10 IU/mL. No subject experienced a serious adverse event or nephrotoxicity. The most frequently reported adverse event was asymptomatic reduction in blood cholinesterase levels in the pradefovir group which recovered without any treatment about 13 ± 7 days after drug discontinuation. This adverse event was not observed in the ADV and TDF groups. The mean changes in serum HBV DNA were -2.78, -2.77, -3.08, -3.18, -3.44, -2.34, and -3.07 log10 IU/mL at 30, 60, 75, 90, and 120 mg pradefovir, 10 mg ADV and 300 mg TDF, respectively, with plateau levels reached with 60 mg pradefovir. Pradefovir and its metabolite PMEA showed linear pharmacokinetics proportional to the dose. The half-life of PMEA in the pradefovir group was 11.47-17.63 h.
CONCLUSIONS
Short-term use of pradefovir was well tolerated. A decline in HBV DNA levels was superior to TDF at higher doses of pradefovir. 30-60 mg pradefovir is recommended for CHB treatment.
CLINICAL TRIAL NUMBER
CTR20150224.
Topics: Adenine; Adult; Antiviral Agents; DNA, Viral; Drug Therapy, Combination; Female; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Organophosphonates; Organophosphorus Compounds; Prodrugs; Tenofovir; Treatment Outcome; Viral Load
PubMed: 31838002
DOI: 10.1016/j.antiviral.2019.104693 -
International Journal of Molecular... Feb 2021Seroclearance of hepatitis B surface antigen (HBsAg) ("functional cure") is the optimal endpoint of antiviral therapy for chronic hepatitis B virus (HBV) infection.... (Review)
Review
Combination of Entecavir or Tenofovir with Pegylated Interferon-α for Long-Term Reduction in Hepatitis B Surface Antigen Levels: Simultaneous, Sequential, or Add-on Combination Therapy.
Seroclearance of hepatitis B surface antigen (HBsAg) ("functional cure") is the optimal endpoint of antiviral therapy for chronic hepatitis B virus (HBV) infection. Currently available anti-HBV therapy includes nucleoside/nucleotide analogs (NAs) and peginterferon-α (Peg-IFNα). Combination of NAs and Peg-IFNα, each with different mechanisms of action, is an attractive approach for treating chronic HBV infection. In earlier studies, compared with monotherapy using IFNα, combination therapy showed greater on-treatment HBV DNA suppression but no difference in the sustained response. However, responses to the combination of non-pegylated IFNα with lamivudine or adefovir were not assessed based on HBsAg quantification but were defined by normal alanine aminotransferase levels, testing negative for hepatitis B e-antigen, and low HBV DNA load over a short term. Here, we reviewed previous reports regarding the effects of combination therapy of entecavir or tenofovir with Peg-IFNα, focusing on long-term reduction in HBsAg levels. Regimens of combination therapy were classified into "simultaneous" combination ("de novo" strategy); "sequential" combination, which involved starting with one therapy followed by the other ("switch-to" strategy); "add-on" combination, which involved adding Peg-IFNα to an ongoing NAs. Some studies have shown promising results, but there is no robust evidence that combination therapy is superior to monotherapy. Large studies are needed to assess the safety and efficacy of combination therapies to increase the rates of HBsAg seroclearance over the long term.
Topics: Adenine; Antiviral Agents; DNA, Viral; Drug Therapy, Combination; Genotype; Guanine; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B e Antigens; Hepatitis B virus; Humans; Interferon-alpha; Lamivudine; Organophosphonates; Randomized Controlled Trials as Topic; Reproducibility of Results; Tenofovir; Treatment Outcome; Viral Load
PubMed: 33535672
DOI: 10.3390/ijms22031456