Nucleos(t)ide analogues entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are recommended as first-line monotherapies for chronic hepatitis B (CHB). Multiple HBV genotypes/subgenotypes have been described, but their impact on treatment response remains largely elusive. We investigated the effectiveness of ETV/TDF on HBV/D-subgenotypes, D1/D2/D3/D5, studied the structural/functional differences in subgenotype-specific reverse transcriptase (RT) domains of viral polymerase, and identified novel molecules with robust inhibitory activity on various D-subgenotypes. Transfection of Huh7 cells with full-length D1/D2/D3/D5 and in vitro TDF/ETV susceptibility assays demonstrated that D1/D2 had greater susceptibility to TDF/ETV while D3/D5 exhibited poorer response. Additionally, HBV load was substantially reduced in TDF-treated CHB patients carrying D1/D2 but minimally reduced in D3/D5-infected patients. Comparison of RT sequences of D-subgenotypes led to identification of unique subgenotype-specific residues, and molecular modeling/docking/simulation studies depicted differential bindings of TDF/ETV to the active site of their respective RTs. Replacement of signature residues in D3/D5 HBV clones with corresponding amino acids seen in D1/D2 improved their susceptibility to TDF/ETV. Using high throughput virtual screening, we identified N(9)-[3-fluoro-2-(phosphonomethoxy)propyl] (FPMP) derivatives of purine bases, including N6-substituted (S)-FPMP derivative of 2,6-diaminopurine (DAP) (OB-123-VK), as potential binders of RT of different D-subgenotypes. We synthesized (S)-FPMPG prodrugs (FK-381-FEE/FK-381-SEE/FK-382) and tested their effectiveness along with OB-123-VK. Both OB-123-VK and FK-381-FEE exerted similar antiviral activities against all D-subgenotypes, although FK-381-FEE was more potent. Our study highlighted the natural variation in therapeutic response of D1/D2/D3/D5 and emphasized the need for HBV subgenotype determination before treatment. Novel molecules described here could benefit future design/discovery of pan-D-subgenotypic inhibitors. IMPORTANCE Current treatment of chronic hepatitis B relies heavily on nucleotide/nucleoside analogs in particular, tenofovir disoproxil fumarate (TDF) and entecavir (ETV) to keep HBV replication under control and prevent end-stage liver diseases. However, it was unclear whether the therapeutic effects of TDF/ETV differ among patients infected with different HBV genotypes and subgenotypes. HBV genotype D is the most widespread of all HBV genotypes and multiple D-subgenotypes have been described. We here report that different subgenotypes of HBV genotype-D exhibit variable response toward TDF and ETV and this could be attributed to naturally occurring amino acid changes in the reverse transcriptase domain of the subgenotype-specific polymerase. Further, we identified novel molecules and also synthesized prodrugs that are equally effective on different D-subgenotypes and could facilitate management of HBV/D-infected patients irrespective of D-subgenotype.
- MeSH
- antivirové látky chemie farmakologie terapeutické užití MeSH
- chronická hepatitida B farmakoterapie virologie MeSH
- genotyp MeSH
- guanin analogy a deriváty chemie farmakologie terapeutické užití MeSH
- inhibitory reverzní transkriptasy chemie farmakologie terapeutické užití MeSH
- lidé MeSH
- mutace MeSH
- organofosfonáty chemie farmakologie MeSH
- prekurzory léčiv MeSH
- proteinové domény MeSH
- racionální návrh léčiv * MeSH
- reverzní transkriptasa chemie genetika MeSH
- tenofovir chemie farmakologie terapeutické užití MeSH
- virová léková rezistence účinky léků genetika MeSH
- virová nálož účinky léků MeSH
- virus hepatitidy B účinky léků enzymologie genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The management of chronic hepatitis B virus (CHB) infection is an area of massive unmet clinical need worldwide. In spite of the development of powerful nucleoside/nucleotide analogue (NUC) drugs, and the widespread use of immune stimulators such as interferon-alpha (IFNα) or PEGylated interferon-alpha (PEG-IFNα), substantial improvements in CHB standards of care are still required. We believe that the future for CHB treatment now rests with advanced therapeutics, vaccination, and precision medicine, if all are to bring under control this most resilient of virus infections. In spite of a plethora of active drug treatments, anti-viral vaccinations and diagnostic techniques, the management of CHB infection remains unresolved. The reason for this is the very complexity of the virus replication cycle itself, giving rise to multiple potential targets for therapeutic intervention some of which remain very intractable indeed. Our review is focused on discussing the potential impact that advanced therapeutics, vaccinations and precision medicine could have on the future management of CHB infection. We demonstrate that advanced therapeutic approaches for the treatment of CHB, in the form of gene and immune therapies, together with modern vaccination strategies, are now emerging rapidly to tackle the limitations of current therapeutic approaches to CHB treatment in clinic. In addition, precision medicine approaches are now gathering pace too, starting with personalized medicine. On the basis of this, we argue that the time has now come to accelerate the design and creation of precision therapeutic approaches (PTAs) for CHB treatment that are based on advanced diagnostic tools and nanomedicine, and which could maximize CHB disease detection, treatment, and monitoring in ways that could genuinely eliminate CHB infection altogether.
- MeSH
- antivirové látky aplikace a dávkování MeSH
- chronická hepatitida B farmakoterapie prevence a kontrola virologie MeSH
- individualizovaná medicína trendy MeSH
- lidé MeSH
- vakcína proti hepatitidě B aplikace a dávkování MeSH
- vakcinace MeSH
- virus hepatitidy B účinky léků genetika fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Recombinant interferon-α (IFN-α) treatment functionally cures chronic hepatitis B virus (HBV) infection in some individuals and suppresses virus replication in hepatocytes infected in vitro. We studied the antiviral effect of conditioned media (CM) from peripheral blood mononuclear cells (PBMCs) stimulated with agonists of Toll-like receptors (TLRs) 2, 7, 8 and 9. We found that CM from PBMCs stimulated with dual-acting TLR7/8 (R848) and TLR2/7 (CL413) agonists were more potent drivers of inhibition of HBe and HBs antigen secretion from HBV-infected primary human hepatocytes (PHH) than CM from PBMCs stimulated with single-acting TLR7 (CL264) or TLR9 (CpG-B) agonists. Inhibition of HBV in PHH did not correlate with the quantity of PBMC-produced IFN-α, but it was a complex function of multiple secreted cytokines. More importantly, we found that the CM that efficiently inhibited HBV production in freshly isolated PHH via various cytokine repertoires and mechanisms did not reduce covalently closed circular (ccc)DNA levels. We confirmed our data with a cell culture model based on HepG2-NTCP cells and the plasmacytoid dendritic cell line GEN2.2. Collectively, our data show the importance of dual-acting TLR agonists inducing broad cytokine repertoires. The development of poly-specific TLR agonists provides novel opportunities towards functional HBV cure.
- MeSH
- buňky Hep G2 MeSH
- chronická hepatitida B virologie MeSH
- cytokiny metabolismus MeSH
- hepatocyty virologie MeSH
- interferon alfa metabolismus MeSH
- kruhová DNA metabolismus MeSH
- kultivační média speciální farmakologie MeSH
- leukocyty mononukleární metabolismus MeSH
- lidé MeSH
- přirozená imunita účinky léků MeSH
- replikace viru účinky léků MeSH
- systémy cílené aplikace léků MeSH
- toll-like receptory agonisté metabolismus MeSH
- virus hepatitidy B fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND & AIMS: Long-term treatment with tenofovir disoproxil fumarate (TDF) alone, or in combination with emtricitabine (FTC) is associated with sustained viral suppression in patients with lamivudine resistant (LAM-R) chronic hepatitis B (CHB). METHODS: LAM-R CHB patients were randomised 1:1 to receive TDF 300mg or FTC 200mg and TDF 300mg once daily in a prospective, double blind, study. The proportion of patients with plasma hepatitis B virus (HBV) DNA<69IU/ml (<400copies/ml) at week 96 (primary efficacy endpoint) was reported previously. Here we present week 240 follow-up data. RESULTS: Overall, 280 patients were randomised to receive TDF (n=141) or FTC/TDF (n=139), and 85.4% completed 240weeks of treatment. At week 240, 83.0% of patients in the TDF arm, and 82.7% of patients in the FTC/TDF treatment arm had HBV DNA<69IU/ml (p=0.96). Rates of normal alanine aminotransferase (ALT) and normalised ALT were similar between groups (p=0.41 and p=0.97 respectively). Hepatitis B e antigen loss and seroconversion at week 240 were similar between groups, (p=0.41 and p=0.67 respectively). Overall, six patients achieved hepatitis B surface antigen (HBsAg) loss and one patient (FTC/TDF arm) had HBsAg seroconversion by week 240. No TDF resistance was observed up to week 240. Treatment was generally well tolerated, and renal events were mild and infrequent (∼8.6%). The mean change in bone mineral density at week 240 was -0.98% and -2.54% at the spine and hip, respectively. CONCLUSIONS: TDF monotherapy was effective and well tolerated in LAM-R CHB patients for up to 240weeks. LAY SUMMARY: The goal of oral antiviral treatment for chronic hepatitis B (CHB) is to achieve and maintain undetectable HBV DNA levels. Treatment options with enhanced potency, and low risk of resistance development for patients infected with lamivudine resistant (LAM-R) HBV are required. Tenofovir disoproxil fumarate (TDF) monotherapy was effective and well tolerated without TDF resistance development in CHB patients with LAM-R, for up to 240weeks. Clinical trial number: NCT00737568.
- MeSH
- antivirové látky aplikace a dávkování škodlivé účinky MeSH
- chronická hepatitida B * farmakoterapie virologie MeSH
- DNA virů krev MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- emtricitabin * aplikace a dávkování škodlivé účinky MeSH
- hepatitida B - antigeny e krev MeSH
- hepatitida B - antigeny povrchové krev MeSH
- kombinovaná farmakoterapie metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- monitorování léčiv MeSH
- tenofovir * aplikace a dávkování škodlivé účinky MeSH
- virová léková rezistence MeSH
- virová nálož účinky léků MeSH
- virus hepatitidy B * účinky léků izolace a purifikace fyziologie MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
- MeSH
- antivirové látky terapeutické užití MeSH
- biologické markery * krev MeSH
- chronická hepatitida B * farmakoterapie krev virologie MeSH
- DNA virů krev MeSH
- dospělí MeSH
- hepatitida B - antigeny povrchové * krev MeSH
- interferon alfa terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- monitorování léčiv MeSH
- pilotní projekty MeSH
- polyethylenglykoly terapeutické užití MeSH
- rekombinantní proteiny terapeutické užití MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- virová nálož MeSH
- virus hepatitidy B genetika imunologie účinky léků MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- MeSH
- adenin analogy a deriváty terapeutické užití MeSH
- antivirové látky * terapeutické užití MeSH
- chronická hepatitida B * farmakoterapie přenos virologie MeSH
- chronická hepatitida C * farmakoterapie virologie MeSH
- Hepacivirus genetika účinky léků MeSH
- hepatitida E * diagnóza farmakoterapie přenos virologie MeSH
- inhibitory serinových proteinas terapeutické užití MeSH
- interferon alfa terapeutické užití MeSH
- jaterní cirhóza epidemiologie farmakoterapie virologie MeSH
- kombinovaná farmakoterapie metody normy MeSH
- kyseliny fosforité terapeutické užití MeSH
- lamivudin terapeutické užití MeSH
- lidé MeSH
- polyethylenglykoly terapeutické užití MeSH
- progrese nemoci MeSH
- uridinmonofosfát aplikace a dávkování MeSH
- virová léková rezistence MeSH
- virus hepatitidy B imunologie účinky léků MeSH
- Check Tag
- lidé MeSH
BACKGROUND: The presence of hepatitis B infection (HBI) and metabolic syndrome (MS) at the same time constitutes a high risk for liver cirrhosis and potentially hepatocellular carcinoma. AIM: In this study we aim to explore the relationship between MS and HBI. METHODS: We used data from the cross-sectional HepaMeta study conducted in 2011 in Slovakia. Patients were tested for presence of MS, while lipid levels (total cholesterol, HDL, LDL, TG, apolipoprotein B100 and HBI (HBsAg and antiHBcIgG)) were also monitored. Viral load was measured in HBsAg positive patients. RESULTS: Altogether 855 patients were screened, MS was diagnosed in 25.1% of patients and 7.9% of patients presented with HBI. AntiHBcIgG antibodies were present in 34.6% patients. HBI patients had lower levels of total and LDL cholesterol along with a decreased apolipoprotein B100 (4.54 ± 0.84 vs. 5.0 ± 0.99 mmol/l, P=0.001; 2.29 ± 0.58 vs. 2.6 ± 0.68 mmol/l, P=0.001 and 0.71 ± 0.21 vs. 0.77 ± 0.23 mmol/l, P=0.013 respectively). Patients diagnosed with MS had higher HBV DNA load than patients without MS - 1300.2 (95% CI 506.06-3440.41) vs. 7661.3 (95% CI 2008.17-29,228.06) IU/ml; P=0.011. HBI patients with TC and apolipoprotein B100 in the reference range had lower HBV DNA load than patients with high or low values of TC or apolipoprotein B100. CONCLUSION: Hepatitis B patients had lower levels of total and LDL cholesterol along with a decreased apolipoprotein B100. Viral load of chronic hepatitis B patients with MS was higher than that in patients without MS.
- MeSH
- chronická hepatitida B komplikace virologie MeSH
- dospělí MeSH
- lidé MeSH
- metabolický syndrom komplikace epidemiologie virologie MeSH
- průřezové studie MeSH
- virová nálož MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- adenin analogy a deriváty aplikace a dávkování MeSH
- antivirové látky aplikace a dávkování MeSH
- chronická hepatitida B * farmakoterapie imunologie virologie MeSH
- DNA virů analýza diagnostické užití MeSH
- dospělí MeSH
- guanin analogy a deriváty aplikace a dávkování MeSH
- hepatitida B - antigeny jádrové * diagnostické užití imunologie MeSH
- hepatitida B - antigeny povrchové * diagnostické užití imunologie MeSH
- kombinovaná farmakoterapie MeSH
- kyseliny fosfinové aplikace a dávkování MeSH
- lamivudin aplikace a dávkování MeSH
- lidé MeSH
- polymerázová řetězová reakce metody MeSH
- sérologické testy metody MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- Klíčová slova
- peginterferon alfa - 2a,
- MeSH
- antivirové látky terapeutické užití MeSH
- chronická hepatitida B diagnóza terapie virologie MeSH
- chronická hepatitida C diagnóza terapie virologie MeSH
- interferon alfa účinky léků MeSH
- interferony účinky léků MeSH
- lidé MeSH
- ribavirin terapeutické užití MeSH
- tenofovir MeSH
- Check Tag
- lidé MeSH
Cíle léčby chronické hepatitidy B jsou v současné době jasné a nepochybné – zabránit progresi choroby k cirhóze a zabránit vzniku závažných komplikací. Riziko komplikací koreluje s hladinou virémie a dobou trvání choroby. Účinná léčba musí proto vést k co možná nejhlubší a pokud možno trvalé supresi virémie. Tohoto cíle lze u omezeného počtu pacientů dosáhnout léčbou peginterferonem α. Zbývající pacienti potřebují dlouhodobou či spíše trvalou léčbu syntetickými antivirotiky, jejichž největší nevýhodou je ztráta účinnosti selekcí rezistentních mutací. Současným standardem stále zůstává sekvenční léčba různými antivirotiky, jejichž záměna má být prováděna po průkazu rezistence. Kombinovaná léčba není účinnější z hlediska suprese virémie, ale snižuje frekvenci vzniku rezistentních mutací. Za odůvodněné lze považovat pouze přidání adefoviru k lamivudinu u pacientů s rezistencí na lamivudin. Ostatní kombinovaná léčba by zatím měla zůstat vyhrazena skupinám pacientů, kteří jsou zvlášť ohroženi vznikem rezistence (cirhotici, transplantovaní pacienti), nebo by se měla provádět v rámci klinických studií.
The objectives of the treatment of chronic hepatitis B are currently clear and unquestionable: to prevent progression of the disease to cirrhosis and development of serious complications. It means to achieve as extensive and stable suppression of viremia as possible. In a limited number of patients, stable suppression of viremia can be induced by peginterferon α . The remaining patients need long-term or rather in definite treatment with synthetic antivirotics that have the major disadvantage of becoming ineffective due to the selection of resistant mutants. Sequential treatment with various antivirotics, to be replaced by effective alternatives after detection of resistance, remains the current standard. Combined treatment is not superior in viremia suppression but reduces the frequency of resistant mutants. Adding adefovir to lamivudine can be considered as justified in lamivudine resistant patients only. Other combination treatments should be reserved to groups of patients at particular risk of developing resistance (cirrhotic patients and transplant recipients) or should be tested in clinical trials.
