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1.
Gastroenterology ; 166(1): 168-177.e8, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37769952

RESUMO

BACKGROUND & AIMS: Patients who discontinue nucleo(s)tide analogue therapy are at risk of viral rebound and severe hepatitis flares, necessitating intensive off-treatment follow-up. METHODS: We studied the association between hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA levels at off-treatment follow-up week 24 (FU W24), with subsequent clinical relapse, and HBsAg loss in a multicenter cohort of hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B who discontinued nucleo(s)tide analogue therapy. RESULTS: We studied 475 patients, 82% Asian, and 55% treated with entecavir. Patients with higher HBV DNA levels at FU W24 had a higher risk of clinical relapse (hazard ratio [HR], 1.576; P < .001) and a lower chance of HBsAg loss (HR, 0.454; P < .001). Similarly, patients with higher HBsAg levels at FU W24 had a higher risk of clinical relapse (HR, 1.579; P < .001) and a lower chance of HBsAg loss (HR, 0.263; P < .001). A combination of both HBsAg <100 IU/mL and HBV DNA <100 IU/mL at FU W24 identified patients with excellent outcomes (9.9% clinical relapse and 58% HBsAg loss at 216 weeks of follow-up). Conversely, relapse rates were high and HBsAg loss rates negligible among patients with both HBsAg >100 IU/mL and HBV DNA >100 IU/mL (P < .001). CONCLUSIONS: Among HBeAg-negative patients with chronic hepatitis B who discontinued antiviral therapy and who did not experience clinical relapse before FU W24, serum levels of HBV DNA and HBsAg at FU W24 can be used to predict subsequent clinical relapse and HBsAg clearance. A combination of HBsAg <100 IU/mL with HBV DNA <100 IU/mL identifies patients with a low risk of relapse and excellent chances of HBsAg loss and could potentially be used as an early surrogate end point for studies aiming at finite therapy in HBV.


Assuntos
Antígenos de Superfície da Hepatite B , Hepatite B Crônica , Humanos , Antígenos E da Hepatite B , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/tratamento farmacológico , DNA Viral , Antivirais/uso terapêutico , Seguimentos , Vírus da Hepatite B/genética , Recidiva , Resultado do Tratamento
2.
Am J Gastroenterol ; 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38483300

RESUMO

INTRODUCTION: Complete viral suppression with nucleos(t)ide analogs (NAs) has led to a profound reduction in hepatocellular carcinoma and mortality among patients with chronic hepatitis B. Finite therapy yields higher rates of functional cure; however, initial hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) elevations are almost certain after treatment interruption. We aimed to analyze off-treatment outcomes beyond 12 months after NA cessation. METHODS: Patients with well-suppressed chronic hepatitis B who were hepatitis B e antigen-negative at NA cessation and remained off treatment without hepatitis B surface antigen (HBsAg) loss at 12 months were included (n = 945). HBV DNA and ALT fluctuations were allowed within the first 12 months. We used Kaplan-Meier methods to analyze outcomes beyond 12 months. Sustained remission was defined as HBV DNA <2,000 IU/mL and ALT <2× upper limit of normal (ULN) and an ALT flare as ALT ≥5× ULN. RESULTS: Cumulative probability of sustained remission was 29.7%, virological relapse was 65.2% with a mean peak HBV DNA of 5.0 ± 1.5 log 10 IU/mL, an ALT flare was 15.6% with a median peak ALT × ULN of 8.3 (5.7-11.3), HBsAg loss was 9.9% and retreatment was 34.9% at 48 months after NA cessation. A single occurrence of virological relapse or an ALT flare within the first 12 months off-treatment were associated with significantly lower rates of sustained remission beyond 12 months. DISCUSSION: Despite allowing for HBV DNA and ALT fluctuations within the first 12 months off-treatment, most patients without HBsAg loss did not maintain a sustained response thereafter. The best candidates for NA withdrawal are patients with low HBsAg levels at NA cessation, and those without profound or recurrent virological and biochemical relapses in the first off-treatment year.

3.
Liver Int ; 44(1): 52-60, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37718515

RESUMO

BACKGROUND AND AIMS: The path to hepatitis C virus (HCV) elimination is complicated by individuals who become lost to follow-up (LTFU) during care, particularly before receiving effective HCV treatment. We aimed to determine factors contributing to LTFU and whether LTFU is associated with mortality. METHODS: In this secondary analysis, we constructed a database including individuals with HCV who were either LTFU (data from the nationwide HCV retrieval project, CELINE) or treated with directly acting antivirals (DAA) (data from Statistics Netherlands) between 2012 and 2019. This database was linked to mortality data from Statistics Netherlands. Determinants associated with being LTFU versus DAA-treated were assessed using logistic regression, and mortality rates were compared between groups using exponential survival models. These analyses were additionally stratified on calendar periods: 2012-2014, 2015-2017 and 2018-2019. RESULTS: About 254 individuals, LTFU and 5547 DAA-treated were included. Being institutionalized (OR = 5.02, 95% confidence interval (CI) = 3.29-7.65), household income below the social minimum (OR = 1.96, 95% CI = 1.25-3.06), receiving benefits (OR = 1.74, 95% CI = 1.20-2.52) and psychiatric comorbidity (OR = 1.51, 95% CI = 1.09-2.10) were associated with LTFU. Mortality rates were significantly higher in individuals LTFU compared to those DAA-treated (2.99 vs. 1.15/100 person-years (PY), p < .0001), while in those DAA-treated, mortality rates slowly increased between 2012-2014 (.22/100PY) and 2018-2019 (2.25/100PY). CONCLUSION: In the Netherlands, individuals who are incarcerated/institutionalized, with low household income, or with psychiatric comorbidities are prone to being LTFU, which is associated with higher mortality. HCV care needs to be adapted for these vulnerable individuals.


Assuntos
Hepatite C Crônica , Hepatite C , Humanos , Antivirais/uso terapêutico , Estudos Transversais , Seguimentos , Hepacivirus , Hepatite C/tratamento farmacológico , Hepatite C/epidemiologia , Hepatite C/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/epidemiologia , Hepatite C Crônica/complicações , Fatores Socioeconômicos
4.
BMC Med Inform Decis Mak ; 24(1): 227, 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39138441

RESUMO

BACKGROUND AND AIMS: Systematic reviews and medical guidelines are widely used in clinical practice. However, these are often not up-to-date and focussed on the average patient. We therefore aimed to evaluate a guideline add-on, TherapySelector (TS), which is based on monthly updated data of all available high-quality studies, classified in specific patient profiles. METHODS: We evaluated the TS for the treatment of hepatitis C (HCV) in an international cohort of patients treated with direct-acting antivirals between 2015 and 2020. The primary outcome was the number of patients receiving one of the two preferred treatment options of the HCV TS, based on the highest level of evidence, cure rate, absence of ribavirin-associated adverse effects, and treatment duration. RESULTS: We enrolled 567 patients. The number of patients treated with one of the two preferred treatment options according to the HCV TS ranged between 27% (2015) and 60% (2020; p < 0.001). Most of the patients received a regimen with a longer treatment-duration (up to 34%) and/or addition of ribavirin (up to 14%). The effect on the expected cure-rate was minimal (1-6% higher) when the first preferred TherapySelector option was given compared to the actual treatment. CONCLUSIONS: Medical decision-making can be optimised by a guideline add-on; in HCV its use appears to minimise adverse effects and cost. The use of such an add-on might have a greater impact in diseases with suboptimal cure-rates, high costs or adverse effects, for which treatment options rely on specific patient characteristics.


Assuntos
Antivirais , Guias de Prática Clínica como Assunto , Humanos , Antivirais/uso terapêutico , Guias de Prática Clínica como Assunto/normas , Feminino , Pessoa de Meia-Idade , Masculino , Hepatite C/tratamento farmacológico , Tomada de Decisão Clínica , Adulto , Idoso , Ribavirina/uso terapêutico , Hepatite C Crônica/tratamento farmacológico
5.
Clin Gastroenterol Hepatol ; 21(6): 1513-1522.e4, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-35863683

RESUMO

BACKGROUND AND AIMS: Whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) differentially affect relapse and outcomes following treatment discontinuation across different patient subpopulations remains unclear. We aimed to compare rates of off-therapy hepatitis B surface antigen (HBsAg) loss, virological and clinical relapse, and retreatment between chronic hepatitis B (CHB) patients who discontinued TDF or ETV therapy. METHODS: This study included 1402 virally suppressed CHB patients who stopped either ETV (n = 981) or TDF (n = 421) therapy between 2001 and 2020 from 13 participating centers across North America, Europe, and Asia. All patients were hepatitis B e antigen-negative at treatment discontinuation. Inverse probability of treatment weighting was used to balance the treatment groups. Outcomes were analyzed using survival methods. RESULTS: During a median off-treatment follow-up of 18 months, HBsAg loss occurred in 96 (6.8%) patients overall. Compared with ETV, TDF was associated with a higher rate of HBsAg loss (P = .03); however, the association was no longer significant after statistical adjustment (P = .61). Virological relapse occurred earlier among TDF-treated patients (P < .01); nonetheless, rates became comparable after the first year off therapy (P = .49). TDF was significantly associated with a higher clinical relapse rate than ETV throughout follow-up (P < .01). The development of a virological or clinical relapse did not affect the rate of HBsAg loss. Retreatment rates were not significantly different between the treatment groups. CONCLUSIONS: TDF and ETV have differential relapse patterns but are associated with similar rates of HBsAg loss and retreatment following discontinuation. Finite therapy can be considered for CHB patients on either TDF or ETV therapy.


Assuntos
Hepatite B Crônica , Humanos , Tenofovir , Hepatite B Crônica/tratamento farmacológico , Antivirais , Antígenos de Superfície da Hepatite B , Resultado do Tratamento , Recidiva , Vírus da Hepatite B , DNA Viral
6.
Gastroenterology ; 162(3): 757-771.e4, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34762906

RESUMO

BACKGROUND & AIMS: Functional cure, defined based on hepatitis B surface antigen (HBsAg) loss, is rare during nucleos(t)ide analogue (NA) therapy and guidelines on finite NA therapy have not been well established. We aim to analyze off-therapy outcomes after NA cessation in a large, international, multicenter, multiethnic cohort of patients with chronic hepatitis B (CHB). METHODS: This cohort study included patients with virally suppressed CHB who were hepatitis B e antigen (HBeAg)-negative and stopped NA therapy. Primary outcome was HBsAg loss after NA cessation, and secondary outcomes included virologic, biochemical, and clinical relapse, alanine aminotransferase flare, retreatment, and liver-related events after NA cessation. RESULTS: Among 1552 patients with CHB, cumulative probability of HBsAg loss was 3.2% at 12 months and 13.0% at 48 months of follow-up. HBsAg loss was higher among Whites (vs Asians: subdistribution hazard ratio, 6.8; 95% confidence interval, 2.7-16.8; P < .001) and among patients with HBsAg levels <100 IU/mL at end of therapy (vs ≥100 IU/mL: subdistribution hazard ratio, 22.5; 95% confidence interval, 13.1-38.7; P < .001). At 48 months of follow-up, Whites with HBsAg levels <1000 IU/mL and Asians with HBsAg levels <100 IU/mL at end of therapy had a high predicted probability of HBsAg loss (>30%). Incidence rate of hepatic decompensation and hepatocellular carcinoma was 0.48 per 1000 person-years and 0.29 per 1000 person-years, respectively. Death occurred in 7/19 decompensated patients and 2/14 patients with hepatocellular carcinoma. CONCLUSIONS: The best candidates for NA withdrawal are virally suppressed, HBeAg- negative, noncirrhotic patients with CHB with low HBsAg levels, particularly Whites with <1000 IU/mL and Asians with <100 IU/mL. However, strict surveillance is recommended to prevent deterioration.


Assuntos
Antivirais/uso terapêutico , Povo Asiático/estatística & dados numéricos , Hepatite B Crônica/sangue , Hepatite B Crônica/tratamento farmacológico , Nucleosídeos/uso terapêutico , População Branca/estatística & dados numéricos , Adulto , Fatores Etários , Estudos de Coortes , DNA Viral/sangue , Feminino , Seguimentos , Guanina/análogos & derivados , Guanina/uso terapêutico , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B , Hepatite B Crônica/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Nucleosídeos/análogos & derivados , Fatores Raciais , Recidiva , Retratamento , Tenofovir/uso terapêutico
7.
Am J Gastroenterol ; 118(9): 1601-1608, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36719174

RESUMO

INTRODUCTION: Despite improvements in the management of chronic hepatitis B (CHB), risk of cirrhosis and hepatocellular carcinoma remains. While hepatitis B surface antigen loss is the optimal end point, safe discontinuation of nucleos(t)ide analog (NA) therapy is controversial because of the possibility of severe or fatal reactivation flares. METHODS: This is a multicenter cohort study of virally suppressed, end-of-therapy (EOT) hepatitis B e antigen (HBeAg)-negative CHB patients who stopped NA therapy (n = 1,557). Survival analysis techniques were used to analyze off-therapy rates of hepatic decompensation and differences by patient characteristics. We also examined a subgroup of noncirrhotic patients with consolidation therapy of ≥12 months before cessation (n = 1,289). Hepatic decompensation was considered related to therapy cessation if diagnosed off therapy or within 6 months of starting retreatment. RESULTS: Among the total cohort (11.8% diagnosed with cirrhosis, 84.2% start-of-therapy HBeAg-negative), 20 developed hepatic decompensation after NA cessation; 10 events were among the subgroup. The cumulative incidence of hepatic decompensation at 60 months off therapy among the total cohort and subgroup was 1.8% and 1.1%, respectively. The hepatic decompensation rate was higher among patients with cirrhosis (hazard ratio [HR] 5.08, P < 0.001) and start-of-therapy HBeAg-positive patients (HR 5.23, P < 0.001). This association between start-of-therapy HBeAg status and hepatic decompensation remained significant even among the subgroup (HR 10.5, P < 0.001). DISCUSSION: Patients with cirrhosis and start-of-therapy HBeAg-positive patients should be carefully assessed before stopping NAs to prevent hepatic decompensation. Frequent monitoring of viral and host kinetics after cessation is crucial to determine patient outcome.


Assuntos
Hepatite B Crônica , Neoplasias Hepáticas , Humanos , Antígenos E da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/epidemiologia , Hepatite B Crônica/diagnóstico , Incidência , Estudos de Coortes , Antivirais/uso terapêutico , Recidiva Local de Neoplasia , Antígenos de Superfície da Hepatite B , Resultado do Tratamento , Cirrose Hepática/epidemiologia , Cirrose Hepática/tratamento farmacológico , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/tratamento farmacológico , Vírus da Hepatite B , DNA Viral
8.
Fam Pract ; 40(1): 83-90, 2023 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-35869658

RESUMO

BACKGROUND: The Dutch guideline for general practitioners (GPs) advises biannual surveillance of hepatitis B (HBV) patients and referral of every hepatitis C (HCV) patient. We aimed to study the prevalence, incidence, and the management of hepatitis B and C in primary care. METHODS: This is a retrospective cohort study using the Rijnmond Primary Care database (RPCD), including health care data of medical records of GPs of approximately 200,000 patients in the area of Rotterdam, the Netherlands. Patient records were selected based on laboratory results, International Classification of Primary Care (ICPC) codes, and free-text words. RESULTS: In total, 977 patients were included: 717 HBV, 252 HCV, and 8 HBV/HCV coinfected patients. Between 2013 and 2019, the prevalence of HBV and HCV declined from 5.21 to 2.99/1,000 person-years (PYs) and 1.50 to 0.70/1,000 PYs, respectively. We observed that the majority of the patients had been referred to a medical specialist at least once (71% HBV and 89% HCV patients). However, among chronic patients, we observed that 36.2% of the HBV patients did not receive adequate surveillance by their GP (≥2 alanine aminotransferase checks within 3 years) or a medical specialist. In addition, 44.4% of the HCV patients had no record about successful antiviral treatment. CONCLUSIONS: This study demonstrated a declining prevalence in viral hepatitis B and C in primary care in the Netherlands. However, a substantial part of the patients did not receive adequate surveillance or antiviral therapy. It is therefore crucial to involve GPs in case finding and in follow-up after treatment.


Assuntos
Hepatite B , Hepatite C , Humanos , Estudos Retrospectivos , Países Baixos/epidemiologia , Hepatite B/tratamento farmacológico , Hepatite B/epidemiologia , Hepatite C/tratamento farmacológico , Hepatite C/epidemiologia , Antivirais/uso terapêutico , Atenção Primária à Saúde
9.
J Infect Dis ; 227(1): 113-122, 2022 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-35599306

RESUMO

BACKGROUND: Emerging evidence suggests a pivotal role for B-cell responses in the natural history of chronic hepatitis B. Serum levels of antibodies to hepatitis B core antigen (anti-HBc) vary across infection stages, but their role in predicting response to antiviral therapy is uncertain. METHODS: Anti-HBc levels were assessed before peginterferon (PEG-IFN) therapy in patients with chronic hepatitis B who either started de novo PEG-IFN (n = 299; 195 hepatitis B e antigen [HBeAg] positive) or started PEG-IFN as add-on to an existing nucleo(s)tide analogue backbone (n = 91; all HBeAg-positive). Associations were explored between anti-HBc and (1) serum biomarkers, (2) liver histological findings, and (3) treatment response. RESULTS: We studied 390 patients. The hepatitis B virus (HBV) genotype were A, B, C, and D in 24%, 9%, 16%, and 49%, respectively; 72% of patients were Caucasian. Among currently untreated HBeAg-positive patients, anti-HBc was correlated with HBV DNA, hepatitis B core-related antigen (HBcrAg), hepatitis B surface antigen (HBsAg), and HBV RNA, but not with alanine aminotransferase (ALT). Higher anti-HBc was associated with more severe histological inflammatory activity (P < .001), irrespective of HBeAg status. After de novo PEG-IFN, higher anti-HBc levels were associated with HBeAg loss, sustained response, HBsAg decline, and HBsAg clearance (P < .050). Among patients treated with add-on PEG-IFN, higher anti-HBc was associated with HBeAg loss (P = .01). CONCLUSIONS: Serum anti-HBc levels correlate with histological inflammatory activity. Higher anti-HBc levels were associated with favorable treatment outcomes. These findings suggest that anti-HBc could be used to select patients most likely to respond to immunomodulatory therapy. CLINICAL TRIALS REGISTRATION: NCT00114361, NCT00146705, NCT00877760, and NCT01532843.


Assuntos
Hepatite B Crônica , Humanos , Antivirais/uso terapêutico , DNA Viral , Anticorpos Anti-Hepatite B , Antígenos do Núcleo do Vírus da Hepatite B , Antígenos E da Hepatite B , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B , Inflamação/tratamento farmacológico , Ensaios Clínicos como Assunto
10.
J Hepatol ; 76(5): 1042-1050, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35092743

RESUMO

BACKGROUND & AIMS: Nucleo(s)tide analogue (NUC) withdrawal may result in HBsAg clearance in a subset of patients. However, predictors of HBsAg loss after NUC withdrawal remain ill-defined. METHODS: We studied predictors of HBsAg loss in a global cohort of HBeAg-negative patients with undetectable HBV DNA who discontinued long-term NUC therapy. Patients requiring retreatment after treatment cessation were considered non-responders. RESULTS: We enrolled 1,216 patients (991 with genotype data); 98 (8.1%) achieved HBsAg loss. The probability of HBsAg loss was higher in non-Asian patients (adjusted hazard ratio [aHR] 8.26, p <0.001), and in patients with lower HBsAg (aHR 0.243, p <0.001) and HBV core-related antigen (HBcrAg) (aHR 0.718, p = 0.001) levels. Combining HBsAg (<10, 10-100 or >100 IU/ml) and HBcrAg (<2log vs. ≥2 log) levels improved prediction of HBsAg loss, with extremely low rates observed in patients with HBsAg >100 IU/ml with detectable HBcrAg. HBsAg loss rates also varied with HBV genotype; the highest rates were observed for genotypes A and D, and none of the patients with HBV genotype E experienced HBsAg loss (p <0.001 for the overall comparison across genotypes; p <0.001 for genotypes A/D vs. genotypes B/C). HBV genotype C was independently associated with a higher probability of HBsAg loss when compared to genotype B among Asian patients (aHR 2.494; 95% CI 1.490-4.174, p = 0.001). CONCLUSIONS: The probability of HBsAg loss after NUC cessation varies according to patient ethnicity, HBV genotype and end-of-treatment viral antigen levels. Patients with low HBsAg (<100 IU/ml) and/or undetectable HBcrAg levels, particularly if non-Asian or infected with HBV genotype C, appear to be the best candidates for treatment withdrawal. LAY SUMMARY: A subset of patients may achieve clearance of hepatitis B surface antigen (HBsAg) - so-called functional cure - after withdrawal of nucleo(s)tide analogue therapy. In this multicentre study of 1,216 patients who discontinued antiviral therapy, we identified non-Asian ethnicity, HBV genotype C, and low hepatitis B surface antigen and hepatitis B core-related antigen levels as factors associated with an increased chance of HBsAg loss.


Assuntos
Antígenos de Superfície da Hepatite B , Hepatite B Crônica , Antivirais/uso terapêutico , DNA Viral , Genótipo , Antígenos do Núcleo do Vírus da Hepatite B , Antígenos E da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Humanos , Probabilidade
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