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1.
Sci Rep ; 9(1): 10529, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324819

RESUMO

Despite the high global prevalence of chronic hepatitis B (CHB) infection, datasets covering the whole hepatitis B viral genome from large patient cohorts are lacking, greatly limiting our understanding of the viral genetic factors involved in this deadly disease. We performed deep sequencing of viral samples from patients chronically infected with HBV to investigate the association between viral genome variation and patients' clinical characteristics. We discovered novel viral variants strongly associated with viral load and HBeAg status. Patients with viral variants C1817T and A1838G had viral loads nearly three orders of magnitude lower than patients without those variants. These patients consequently experienced earlier viral suppression while on treatment. Furthermore, we identified novel variants that either independently or in combination with precore mutation G1896A were associated with the transition from HBeAg positive to the negative phase of infection. These observations are consistent with the hypothesis that mutation of the HBeAg open reading frame is an important factor driving CHB patient's HBeAg status. This analysis provides a detailed picture of HBV genetic variation in the largest patient cohort to date and highlights the diversity of plausible molecular mechanisms through which viral variation affects clinical phenotype.

3.
J Hepatol ; 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31203153

RESUMO

BACKGROUND & AIMS: Around 5% of patients with chronic hepatitis C virus (HCV) infection treated with direct-acting antiviral (DAA) agents do not achieve sustained virological response (SVR). The currently approved retreatment regimen for prior DAA failure is a combination of sofosbuvir, velpatasvir, and voxilaprevir (SOF/VEL/VOX), although there is little data on its use in clinical practice. The aim of this study was to analyse the effectiveness and safety of SOF/VEL/VOX in the real-world setting. METHODS: This was a prospective multicentre study assessing the efficacy of retreatment with SOF/VEL/VOX in patients who had experienced a prior DAA treatment failure. The primary endpoint was SVR 12 weeks after the completion of treatment (SVR12). Data on safety and tolerability were also recorded. RESULTS: A total of 137 patients were included: 75% men, 35% with liver cirrhosis. Most were infected with HCV genotype (GT) 1 or 3. The most common prior DAA combinations were sofosbuvir plus an NS5A inhibitor or ombitasvir/paritaprevir/r+dasabuvir. A total of 136 (99%) patients achieved undetectable HCV RNA at the end of treatment. Overall SVR12 was 95% in the 135 patients reaching this point. SVR12 was lower in patients with cirrhosis (89%, p = 0.05) and those with GT3 infection (80%, p <0.001). Patients with GT3 infection and cirrhosis had the lowest SVR12 rate (69%). Of the patients who did not achieve SVR12, 1 was reinfected and 7 experienced treatment failure (6 GT3, 1 GT1a). The presence of resistance-associated substitutions did not impact SVR12. Adverse effects were mild and non-specific. CONCLUSION: Real-world data show that SOF/VEL/VOX is an effective, safe rescue therapy for patients with prior DAA treatment failure despite the presence of resistance-associated substitutions. However, patients with liver cirrhosis infected by GT3 remain the most-difficult-to-treat group. LAY SUMMARY: Treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) for 12 weeks is the current recommendation for the 5% of patients infected with HCV who do not achieve eradication of the virus under treatment with direct-acting antivirals. In a Spanish cohort of 137 patients who failed a previous combination of direct-acting antivirals, a cure rate of 95% was achieved with SOF/VEL/VOX. Genotypic characteristics of the virus (genotype 3) and the presence of cirrhosis were factors that decreased the rate of cure. Treatment with SOF/VEL/VOX is an effective and safe rescue therapy due to its high efficacy and very good safety profile.

4.
J Viral Hepat ; 26(9): 1127-1138, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31108015

RESUMO

Ruzasvir (MK-8408, an NS5A inhibitor) and uprifosbuvir (MK-3682, a nonstructural protein 5B nucleotide inhibitor) are highly potent direct-acting antiviral agents for the treatment of hepatitis C virus (HCV) infection. A phase III clinical trial evaluating the two-drug combination of ruzasvir 60 mg plus uprifosbuvir 450 mg suggested suboptimal efficacy in certain HCV genotypes (C-BREEZE 1; NCT02759315). The aim of the present study was to evaluate the efficacy and safety of ruzasvir in combination with uprifosbuvir administered at a higher dose than that assessed in the earlier study (C-BREEZE 2: NCT02956629/Merck protocol PN041). Treatment-naïve or interferon (with or without ribavirin)-experienced participants with or without compensated cirrhosis were enrolled. All participants received ruzasvir 180 mg plus uprifosbuvir 450 mg once daily for 12 weeks. The primary objectives were the proportion of participants with HCV RNA <15 lU/mL at 12 weeks after the end of study therapy (SVR12), and safety and tolerability of the study drug. Overall, 282 participants were enrolled. SVR12 (n/N) was 91.3% (42/46) in participants infected with HCV genotype (GT) 1a; GT1b, 96.7% (29/30); GT2, 91.5% (43/47); GT3, 73.8% (45/61); GT4, 98.2% (55/56); GT5, 100.0% (18/18); and GT6, 90.9% (20/22). Adverse events (AEs) were reported by 61.3% of participants; drug-related AEs were reported by 33.3%. The most frequent (≥5% of participants) drug-related AEs in all participants were fatigue (7.8%) and headache (7.4%). In conclusion, the two-drug combination of ruzasvir 180 mg plus uprifosbuvir 450 mg for 12 weeks was highly effective and well tolerated in participants infected with HCV GT1, GT2, GT4, GT5 and GT6, with a lower efficacy in GT3-infected persons.

5.
Liver Int ; 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31136052

RESUMO

BACKGROUND & AIMS: Tenofovir disoproxil fumarate (TDF) is a first-line treatment for chronic hepatitis B (CHB). We aimed to describe the efficacy and safety profiles of TDF treatment for up to 10 years in a well-described cohort of CHB patients. METHODS: Hepatitis B e antigen (HBeAg)-negative and HBeAg-positive patients from two randomised, double-blind trials (ClinicalTrials.gov: NCT00117676 and NCT00116805) completed 48 weeks of randomised treatment with TDF or adefovir dipivoxil. A subset of these patients was then eligible to receive open-label TDF treatment for up to 10 years. At Year 10, patients were assessed for virological suppression, alanine aminotransferase (ALT) normalisation, serological response, safety and tolerability. RESULTS: Of 641 randomised and treated patients, 585 (91%) entered the open-label extension phase with 203 (32%) patients completing Year 10 of the study. At Year 10, 118/118 (100%) of HBeAg-negative patients and 78/80 (98%) of HBeAg-positive patients with available data achieved hepatitis B virus (HBV) DNA < 69 IU/mL, while 88/106 (83%) and 60/77 (78%) patients achieved ALT normalisation, respectively. Of the 23 patients with HBeAg status available at Year 10, 12 (52%) and six (27%) experienced HBeAg loss and seroconversion, respectively. No resistance to TDF was documented up to Year 10. In the period between Year 8 and Year 10, the safety profile of TDF was similar to previous reports, with few patients experiencing renal- or bone-related adverse events. CONCLUSIONS: Over 10 years, TDF had a favourable safety profile, was well tolerated, and resulted in continued maintenance of virological suppression with no documented resistance.

6.
Ann Hepatol ; 18(1): 215-219, 2019 Jan - Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31113593

RESUMO

IgG4-related disease is a recently-described fibro-inflammatory condition with characteristic histopathological findings in the organs involved. The most commonly affected organs are pancreas, lymph nodes, and retroperitoneum. Liver disease usually involves bile structures and therefore IgG4-related disease is considered a cause of secondary sclerosing cholangitis. One out of three patients with IgG4 sclerosing cholangitis also presents autoimmune pancreatitis, although it can be associated with manifestations in other organs. One of the main features of IgG4-related disease is its good prognosis due to the great response to glucocorticoid therapy. However, relapse of the disease is not uncommon, especially when steroid therapy is decreased or stopped. Rituximab seems to be an effective treatment to achieve remission of the disease. We report the case of a 74 year-old man diagnosed with IgG4-related disease based on increase of serum IgG4 levels, imaging and histopathological findings, with systemic involvement including sclerosing cholangitis. Despite the absence of liver fibrosis at onset, the early use of glucocorticoids and rituximab therapy, the patient presented clinical and analytical deterioration, leading to secondary biliary cirrhosis. In conclusion, this clinical case highlights the importance of prompt diagnosis and therapeutics for sclerosing cholangitis secondary to IgG4-related disease in order to avoid progression of the disease and development of liver cirrhosis, as well as the refractory, aggressive nature of the disease in some cases as this one.

7.
Lancet Gastroenterol Hepatol ; 4(7): 538-544, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30975477

RESUMO

BACKGROUND: Ruling out the presence of cirrhosis is important for the management of chronic hepatitis B. We aimed to study and optimise the performance of two non-invasive indices for ruling out cirrhosis: the aspartate aminotransferase-platelet ratio index (APRI) and fibrosis score based on four factors (FIB-4). METHODS: We applied established cutoffs to rule in (APRI >2·00; FIB-4 >3·25) or rule out (APRI <1·00; FIB-4 <1·45) cirrhosis to data from eight global randomised trials that required baseline biopsy, and identified new cutoffs aiming for a sensitivity for detection of cirrhosis greater than 90% and a negative predictive value (NPV) of greater than 95% in the same dataset. We externally validated the new cutoffs using data from all consecutive biopsied patients from two tertiary referral hospitals in the Netherlands and Canada. FINDINGS: In the derivation dataset (n=2926; of whom 1750 were Asian); 340 (12%) individuals had cirrhosis. The validation cohort consisted of 1034 individuals (of whom 575 were Asian), with 155 (15%) individuals with cirrhosis. Application of conventional cutoffs for FIB-4 in the derivation dataset yielded unclassifiable results in 686 (23%) individuals, and 139 (41%) of the 340 patients with cirrhosis were misclassified as having no cirrhosis. Similarly, conventional cutoffs for APRI in the derivation dataset yielded unclassifiable results in 706 (24%) individuals, and 153 (45%) were misclassified as having no cirrhosis. An APRI of 0·45 or less had sensitivity of 91·5%, an NPV of 95·4%, and misclassified 29 (9%) of 340 individuals with cirrhosis in the derivation dataset, but performance was reduced in the validation set (22 [14%] of 155 individuals with cirrhosis misclassified). A FIB-4 score of 0·70 had a sensitivity of 90·9%, an NPV of 96·6%, and misclassified 31 (9%) of individuals with cirrhosis in the derivation dataset. In the validation cohort, the same score gave a sensitivity of 94·2%, an NPV of 97·3%, and misclassified nine (6%) of the individuals with cirrhosis. Subgroup analysis indicated that the new FIB-4 cutoff performed acceptably in all subgroups except for individuals aged 30 years or younger. INTERPRETATION: Conventional cutoffs for APRI and FIB-4 should not be used to guide management of patients with chronic hepatitis B due to high rates of misclassification. A newly identified and externally validated cutoff for FIB-4 (≤0·70) can be used to exclude cirrhosis in patients over 30 years of age. FUNDING: Foundation for Liver and Gastrointestinal Research, Rotterdam, Netherlands.

8.
World J Gastroenterol ; 25(13): 1566-1579, 2019 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-30983817

RESUMO

BACKGROUND: Hepatitis delta virus (HDV) seems to strongly suppress hepatitis B virus (HBV) replication, although little is known about the mechanism of this interaction. Both these viruses show a dynamic distribution of mutants, resulting in viral quasispecies. Next-generation sequencing is a viable approach for analyzing the composition of these mutant spectra. As the regulatory hepatitis B X protein (HBx) is essential for HBV replication, determination of HBV X gene (HBX) quasispecies complexity in HBV/HDV infection compared to HBV mono-infection may provide information on the interactions between these two viruses. AIM: To compare HBV quasispecies complexity in the HBX 5' region between chronic hepatitis delta (CHD) and chronic HBV mono-infected patients. METHODS: Twenty-four untreated patients were included: 7/24 (29.2%) with HBeAg-negative chronic HBV infection (CI, previously termed inactive carriers), 8/24 (33.3%) with HBeAg-negative chronic hepatitis B (CHB) and 9/24 (37.5%) with CHD. A serum sample from each patient was first tested for HBV DNA levels. The HBX 5' region [nucleotides (nt) 1255-1611] was then PCR-amplified for subsequent next-generation sequencing (MiSeq, Illumina, United States). HBV quasispecies complexity in the region analyzed was evaluated using incidence-based indices (number of haplotypes and number of mutations), abundance-based indices (Hill numbers of order 1 and 2), and functional indices (mutation frequency and nucleotide diversity). We also evaluated the pattern of nucleotide changes to investigate which of them could be the cause of the quasispecies complexity. RESULTS: CHB patients showed higher median HBV-DNA levels [5.4 logIU/mL, interquartile range (IQR) 3.5-7.9] than CHD (3.4 logIU/mL, IQR 3-7.6) (P = n.s.) or CI (3.2 logIU/mL, IQR 2.3-3.5) (P < 0.01) patients. The incidence and abundance indices indicated that HBV quasispecies complexity was significantly greater in CI than CHB. A similar trend was observed in CHD patients, although only Hill numbers of order 2 showed statistically significant differences (CHB 2.81, IQR 1.11-4.57 vs CHD 8.87, 6.56-11.18, P = 0.038). There were no significant differences in the functional indices, but CI and CHD patients also showed a trend towards greater complexity than CHB. No differences were found for any HBV quasispecies complexity indices between CHD and CI patients. G-to-A and C-to-T nucleotide changes, characteristic of APOBEC3G, were higher in CHD and CI than in CHB in genotype A haplotypes, but not in genotype D. The proportion of nt G-to-A vs A-to-G changes and C-to-T vs T-to-C changes in genotype A and D haplotypes in CHD patients showed no significant differences. In CHB and CI the results of these comparisons were dependent on HBV genotype. CONCLUSION: The lower-replication CHD and CI groups show a trend to higher quasispecies complexity than the higher-replication CHB group. The mechanisms associated with this greater complexity require elucidation.


Assuntos
Hepatite B Crônica/virologia , Hepatite D Crônica/virologia , Quase-Espécies/genética , Superinfecção/virologia , Transativadores/genética , Adulto , Feminino , Haplótipos/genética , Vírus da Hepatite B/isolamento & purificação , Vírus da Hepatite B/fisiologia , Vírus Delta da Hepatite/isolamento & purificação , Vírus Delta da Hepatite/fisiologia , Humanos , Masculino , Replicação Viral/genética
9.
J Hepatol ; 70(5): 1008-1015, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30982526

RESUMO

Chronic hepatitis delta represents the most severe form of chronic viral hepatitis. The current treatment of hepatitis delta virus (HDV) infection consists of the use of interferons and is largely unsatisfactory. Several new compounds are currently in development for the treatment of HDV infection. However, surrogate markers that can be used to develop clinical endpoints in HDV infection are not well defined. In the current manuscript, we aimed to evaluate the existing data on treatment of HDV infection and to suggest treatment goals (possible "trial endpoints") that could be used across different clinical trials.

10.
Gastroenterology ; 156(6): 1820-1833, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30768983

RESUMO

BACKGROUND & AIMS: Hepatitis D virus (HDV) superinfection in patients with hepatitis B virus (HBV) is associated with rapid progression to liver cirrhosis and hepatocellular carcinoma. Treatment options are limited, and no vaccine is available. Although HDV-specific CD8+ T cells are thought to control the virus, little is known about which HDV epitopes are targeted by virus-specific CD8+ T cells or why these cells ultimately fail to control the infection. We aimed to define how HDV escapes the CD8+ T-cell-mediated response. METHODS: We collected plasma and DNA samples from 104 patients with chronic HDV and HBV infection at medical centers in Europe and the Middle East, sequenced HDV, typed human leukocyte antigen (HLA) class I alleles from patients, and searched for polymorphisms in HDV RNA associated with specific HLA class I alleles. We predicted epitopes in HDV that would be recognized by CD8+ T cells and corresponded with the identified virus polymorphisms in patients with resolved (n = 12) or chronic (n = 13) HDV infection. RESULTS: We identified 21 polymorphisms in HDV that were significantly associated with specific HLA class I alleles (P < .005). Five of these polymorphisms were found to correspond to epitopes in HDV that are recognized by CD8+ T cells; we confirmed that CD8+ T cells in culture targeted these HDV epitopes. HDV variant peptides were only partially cross-recognized by CD8+ T cells isolated from patients, indicating that the virus had escaped detection by these cells. These newly identified HDV epitopes were restricted by relatively infrequent HLA class I alleles, and they bound most frequently to HLA-B. In contrast, frequent HLA class I alleles were not associated with HDV sequence polymorphisms. CONCLUSIONS: We analyzed sequences of HDV RNA and HLA class I alleles that present epitope peptides to CD8+ T cells in patients with persistent HDV infection. We identified polymorphisms in the HDV proteome that associate with HLA class I alleles. Some variant peptides in epitopes from HDV were only partially recognized by CD8+ T cells isolated from patients; these could be mutations that allow HDV to escape the immune response, resulting in persistent infection. HDV escape from the immune response was associated with uncommon HLA class I alleles, indicating that HDV evolves, at the population level, to evade recognition by common HLA class I alleles.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Hepatite B Crônica/genética , Hepatite D Crônica/genética , Vírus Delta da Hepatite/genética , Vírus Delta da Hepatite/imunologia , Vigilância Imunológica/imunologia , Superinfecção/genética , Alelos , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular , Epitopos de Linfócito T/imunologia , Evolução Molecular , Antígenos HLA-A/imunologia , Antígenos HLA-B/imunologia , Humanos , Tolerância Imunológica , Interferon gama/metabolismo , Mutação , Polimorfismo Genético
11.
Lancet Gastroenterol Hepatol ; 4(4): 296-304, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30795958

RESUMO

BACKGROUND: Effective and well tolerated nucleos(t)ide analogue treatment exists for patients with chronic hepatitis B, although treatment is generally anticipated to be life-long, with concomitant costs and treatment-related side-effects. We aimed to characterise the outcomes of patients with persistent viral suppression who discontinued nucleotide analogue use after extended treatment. METHODS: The primary objective of this prespecified analysis was to evaluate the safety of stopping long-term tenofovir disoproxil fumarate therapy in patients enrolled in two (completed) randomised controlled studies, GS-US-174-0102 (ClinicalTrials.gov, number NCT00117676) and GS-US-174-0103 (ClinicalTrials.gov, number NCT00116805). In those studies, patients who had completed 8 years or more of nucleotide analogue treatment, were hepatitis B surface antigen (HBsAg)-positive with hepatitis B virus (HBV) DNA concentration of less than 29 IU/mL, and were unwilling or unable to continue therapy were required by protocol to enter a 24-week treatment-free follow-up (TFFU) phase. We present data for patients in the TFFU phase who were assessed at baseline and monitored every 4 weeks for changes in qualitative serum HBsAg, HBV DNA, and alanine aminotransferase (ALT) concentrations in addition to standard safety assessments. FINDINGS: Of 124 patients who entered the TFFU phase, 54 (44%) patients did not complete 24 weeks of follow-up (median 12 weeks; IQR 0-20). Overall, 32 (26%) patients reported an adverse event. Serious adverse events occurred in five (4%) patients, including elevated ALT concentrations in two patients, hepatic flare in two patients, and increased lipase in one patient. 38 (31%) of patients had grade 3 or higher laboratory abnormalities, the majority of which were ALT elevations (36 patients). Of the 106 hepatitis B e antigen (HBeAg)-negative patients who entered the TFFU phase, 63 (59%) were followed for 24 weeks. HBsAg loss was observed in five (5%) of the 106 HBeAg-negative patients who entered the TFFU phase, and 37 (35%) had both HBV DNA concentrations of less than 2000 IU/mL and ALT concentrations less than the ULN at TFFU week 24. 18 HBeAg-positive patients entered the TFFU phase, of whom seven (39%) were followed up for 24 weeks. Of these seven patients, none had HBsAg loss or HBV DNA of less than 2000 IU/mL and one (14%) had an ALT less than the ULN at week 24. INTERPRETATION: Within 24 weeks of stopping 8 years or more of nucleotide analogue therapy almost a third of patients experienced a grade 3 or higher laboratory abnormality. Although few patients achieved HBsAg loss, a subgroup of HBeAg-negative patients can achieve a low-replicative state within a short duration of follow-up. FUNDING: Gilead Sciences, Inc.

12.
Hepatology ; 69(6): 2349-2363, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30693573

RESUMO

The combination of three direct-acting antiviral agents (AL-335, odalasvir, and simeprevir: JNJ-4178 regimen) for 6 or 8 weeks demonstrated good efficacy and safety in a phase IIa study in chronic hepatitis C virus (HCV) genotype (GT)-1-infected patients without cirrhosis and has now been evaluated in a larger phase IIb study, OMEGA-1. This multicenter, randomized, open-label study (NCT02765490) enrolled treatment-naïve and interferon (±ribavirin) treatment-experienced patients with HCV GT1, 2, 4, 5, or 6 infection. Patients with HCV GT3 infection and/or liver cirrhosis were excluded. Patients received AL-335 800 mg, odalasvir 25 mg, and simeprevir 75 mg once daily for 6 or 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). In total, 365 patients (GT1a, 29.3%; GT1b, 42.5%; GT2, 12.3%; GT4, 14.2%; GT5, 1.4%; GT6, 0%) were randomized to receive 6 weeks (n = 183) or 8 weeks (n = 182) of treatment. SVR12 rates after 6 weeks (98.9%) or 8 weeks (97.8%) of treatment were noninferior to a historical control (98%). Viral relapse occurred in 5 patients (1.4%; 4 with HCV GT2c; 1 with GT1a). With the exception of 4 patients in the 8-week group, including 3 patients with missing data at the SVR24 timepoint, all patients who achieved SVR12 also achieved SVR24. One GT1a-infected patient experienced late viral relapse after achieving SVR18. Most adverse events (AEs) were mild with no treatment-related serious AEs. All randomized patients completed treatment. Conclusion: In HCV-infected patients, 6 and 8 weeks of treatment with JNJ-4178 resulted in SVR12 rates of 98.9% and 97.8%, respectively, and was well tolerated.

14.
Eur J Gastroenterol Hepatol ; 31(2): 267-271, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30576297

RESUMO

OBJECTIVE: The objective of this study was to determine the long-term clinical outcome and persistence of hepatitis B surface antigen (HBsAg) loss after discontinuation of treatment. BACKGROUND: The prognosis of patients with chronic hepatitis B (CHB) treated with nucleos(t)ide analogues (NAs) who discontinue treatment after loss of HBsAg remains largely unknown, particularly in White patients. PATIENTS AND METHODS: We analysed a cohort of patients with CHB who discontinued NA treatment after loss of HBsAg. A total of 69 patients with hepatitis-B-e antigen-positive or hepatitis-B-e antigen-negative CHB with undetectable HBsAg during NA treatment were included after discontinuation of treatment, and followed up for a median period of 37.8 months (interquartile range: 23.8-54.6 months). RESULTS: At the end of follow-up, none of the patients showed spontaneous reappearance of HBsAg and only one patient had detectable hepatitis B virus DNA (22 IU/ml). Another patient negative for HBsAg and anti-HBs developed hepatitis B virus reactivation without elevated transaminases after treatment with corticosteroids and vincristine for dendritic cell neoplasm, 38 months after withdrawal of the antiviral treatment. Regarding clinical outcome, a patient with cirrhosis developed hepatocellular carcinoma, 6.6 years after discontinuing treatment. None of the patients had hepatic decompensation or underwent liver transplantation. CONCLUSION: HBsAg clearance after discontinuing NAs in patients with CHB is persistent and associated with good prognosis. The risk for developing hepatocellular carcinoma persists among patients with cirrhosis.


Assuntos
Antivirais/administração & dosagem , Grupo com Ancestrais do Continente Europeu , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Nucleosídeos/administração & dosagem , Nucleotídeos/administração & dosagem , Adulto , Antivirais/efeitos adversos , Biomarcadores/sangue , Esquema de Medicação , Feminino , Vírus da Hepatite B/imunologia , Hepatite B Crônica/sangue , Hepatite B Crônica/etnologia , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Nucleosídeos/efeitos adversos , Nucleotídeos/efeitos adversos , Recidiva , Indução de Remissão , Estudos Retrospectivos , Fatores de Risco , Espanha/epidemiologia , Fatores de Tempo , Resultado do Tratamento
16.
Infect Drug Resist ; 11: 2207-2210, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30519058

RESUMO

Background: Controversy is ongoing about whether a minority mutant present at frequencies below 15% may be clinically relevant and should be considered to guide treatment. Methods: Resistance-associated substitution (RAS) studies were performed in patients before and at failure of antiviral treatments using Next-generation hepatitis C virus (HCV) sequencing (NGS). Results: We have found two patients with genotype 1a infection having RAS in 3.5%-7.1% of the viral population at baseline that were selected during ledipasvir + sofosbuvir treatment. Co-selection of RAS located in a region not directly affected by the antiviral treatment also occurred. This observation calls into question, the recommendations to guide RAS-based direct-acting antiviral (DAA) treatment only when RAS are present in >15% of the sequences generated. Conclusion: Our results suggests that RAS study should include all three HCV DAA target proteins and minority mutants should be considered as clinically relevant.

17.
Curr Opin Virol ; 32: 100-107, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30415162

RESUMO

Hepatitis D virus (HDV) is a hepatotropic subviral infectious agent, obligate satellite of the Hepatitis B virus (HBV) and is highly related to viroids. HDV affects around 5% of the 257 million chronic HBV-carriers worldwide, leading to the most severe form of chronic viral hepatitis. Interferon alpha is the only approved treatment for chronic hepatitis D, albeit with low response rates (around 20%-30%). New antiviral strategies are currently under study. Due to the high viral evolution rates (10-3 to 10-4 substitutions/site/year) HDV forms an extremely complex viral population (quasispecies) that can be studied by Next-Generation Sequencing. Therefore, although specific viral resistance in HDV infection has not been reported, it cannot be completely discarded.

18.
PLoS One ; 13(11): e0208036, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30485377

RESUMO

BACKGROUND: Elimination of hepatitis C virus (HCV) infection requires high diagnostic rates and universal access to treatment. Around 40% of infected individuals are unaware of their infection, which indicates that effective screening strategies are needed. We analyzed the efficiency (incremental cost-utility ratio, ICUR) of 3 HCV screening strategies: a) general population of adults, b) high-risk groups, and c) population with the highest anti-HCV prevalence plus high-risk groups. METHODS: An analytical decision model, projecting progression of the disease over a lifetime, was used to establish the candidate population for HCV screening. HCV data were obtained from the literature: anti-HCV prevalence (0.56%-1.54%), viremic patients (31.5%), and percentage of undiagnosed persons among those with viremia (35%). It was assumed that most patients would be treated and have HCV therapy response (98% SVR); transition probabilities, utilities, and disease management annual costs were obtained from the literature. Efficiency over the life of patients under the National Health System perspective was measured as quality-adjusted life years (QALY) and total cost (screening, diagnosis, pharmacological and disease management). A discount rate of 3% was applied to costs and outcomes. RESULTS: Screening of the adult population would identify a larger number of additional chronic hepatitis C cases (N = 52,694) than screening the highest anti-HCV prevalence population plus high-risk groups (N = 42,027) or screening high-risk groups (N = 26,128). ICUR for the general population vs. high-risk groups was €8914/QALY gained per patient (€18,157 incremental cost and 2.037 QALY). ICUR for the general population vs. population with highest anti-HCV prevalence plus high-risk groups was €7,448/QALY gained per patient (€7,733 incremental cost and 1.038 QALY). These ICUR values are below the accepted efficiency threshold (€22,000-€30,000). CONCLUSION: HCV screening and treatment of the general adult population is cost-effective compared to screening of high-risk groups or the population with the highest anti-HCV prevalence plus high-risk groups.

20.
Gastroenterology ; 2018 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-30342034

RESUMO

BACKGROUND & AIMS: Seroclearance of hepatitis B surface antigen (HBsAg) is a marker for clearance of chronic hepatitis B virus (HBV) infection but reported annual incidence rates of HBsAg seroclearance vary. We performed a systematic review and meta-analysis to provide more precise estimates of HBsAg seroclearance rates among subgroups and populations. METHODS: We searched PubMed, Embase, and Cochrane library for cohort studies that reported HBsAg seroclearance in adults with chronic HBV infection with more than 1 year of follow up and at least 1 repeat test for HBsAg. Annual and 5-, 10-, and 15-year cumulative incidence rates were pooled using a random effects model. RESULTS: We analyzed 34 published studies (with 42,588 patients; 303,754 person-years of follow-up; and 3194 HBsAg seroclearance events), including additional and updated aggregated data from 19 studies. The pooled annual rate of HBsAg seroclearance was 1.02% (95% CI, 0.79-1.27). Cumulative incidence rates were 4.03% at 5 years (95% CI, 2.49-5.93), 8.16% at 10 years (95% CI, 5.24-11.72), and 17.99% at 15 years (95% CI, 6.18-23.24). There were no significant differences between sexes. A higher proportion of patients negative for HBeAg at baseline had seroclearance (1.33%; 95% CI, 0.76-2.05) than patients positive for HBeAg (0.40%; 95% CI, 0.25-0.59) (P<.01). HBsAg seroclearance was also associated with a lower baseline HBV DNA (6.61 log10IU/mL; 95% CI, 5.94-7.27) than in patients without HBsAg seroclearance (7.71 log10IU/mL; 95% CI, 7.41-8.02) (P<.01) and lower level of HBsAg at baseline (2.74 log10IU/mL; 95% CI, 1.88-3.60) than in patients without HBsAg seroclearance (3.90 log10IU/mL, 95% CI, 3.73-4.06) (P<.01). HBsAg seroclearance was not associated with HBV genotype or treatment history. Heterogeneity was substantial across the studies (I2=97.49%). CONCLUSION: In a systematic review and meta-analysis, we found a low rate of HBsAg seroclearance in untreated and treated patients (pooled annual rate approximately 1%). Seroclearance occurred mainly in patients with less active disease. Patients with chronic HBV infection should therefore be counseled on the need for lifelong treatment, and curative therapies are needed.

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