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BACKGROUND & AIMS: Nucleo(s)tide analogue (NUC) cessation can lead to HBsAg clearance but also a high rate of virological relapse. However, the effect of pegylated interferon alpha-2a (PegIFN-α-2a) on virological relapse after NUC cessation is unknown. Therefore, this study aimed to evaluate the effect of switching from NUC to PegIFN-α-2a treatment for 48 weeks on virological relapse until week 96. METHODS: In this multicentre randomized controlled clinical trial, 180 non-cirrhotic HBeAg-negative chronic hepatitis B patients on continuous NUC therapy for ≥ 2.5 years with HBV DNA levels < 60 IU/mL were randomized to discontinue NUC (n=90) or receive 48 weeks of PegIFN-α-2a treatment (n=90) and followed up till 96 weeks. The primary endpoint was the virological relapse rate until week 96. RESULTS: Intention-to-treat analysis revealed patients in the interferon monotherapy group had significantly lower cumulative virological relapse rates than the NUC cessation group until week 96 (20.8% vs. 53.6%, P < 0.0001). Consistently, a significantly lower proportion of patients in the interferon monotherapy group had virological relapse than those in the NUC cessation group at 48 weeks off treatment (17.8% vs. 36.7%, P = 0.007). The virological relapse rate positively correlated with HBsAg levels in the NUC cessation group. The interferon monotherapy group had a lower cumulative clinical relapse rate (7.8% vs. 20.9%, P = 0.008) and a higher HBsAg loss rate (21.5% vs. 9.0%, P = 0.03) than the NUC cessation group. CONCLUSIONS: Switching from NUC to PegIFN-α-2a treatment for 48 weeks significantly reduces virological relapse rates and achieves higher HBsAg loss rates than NUC treatment cessation alone in HBeAg-negative chronic hepatitis B patients. IMPACT AND IMPLICATIONS: Nucleo(s)tide analogue (NUC) cessation can lead to HBsAg clearance but also a high rate of virological relapse, but an optimised scheme to reduce the virological relapse rate after NUC withdrawal is yet to be reported. This randomized controlled trial investigated the effect of switching from NUC to PegIFN-α-2a treatment for 48 weeks on virological relapse until week 96 in HBeAg-negative chronic hepatitis B patients. The interferon monotherapy group had a significantly lower cumulative virological relapse rate (20.8% vs. 53.6%, P < 0.0001) and higher HBsAg loss rate (21.5% vs. 9.0%, P= 0.03) than the NUC cessation group until week 96. This provides an optimized strategy for NUC cessation in HBeAg-negative patients. TRIAL REGISTRATION NUMBER: NCT02594293.
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BACKGROUND: Nucleos(t)ide analogues (NUCs) rarely cure chronic hepatitis B (CHB) because they do not eliminate covalently closed circular deoxyribonucleic acid, the stable replication template. In hepatitis B e antigen (HBeAg)-positive CHB during NUCs, HBV-infected cells decline slowly and are transcriptionally silenced. Whether these occur in HBeAg-negative CHB is unknown. METHODS: Using paired liver biopsies separated by 2.7-3.7 years in 4 males with HIV and HBeAg-negative CHB at both biopsies and 1 male with HIV who underwent HBeAg seroconversion between biopsies, we quantified amounts of viral nucleic acids in hundreds of individual hepatocytes. RESULTS: In the 4 persistently HBeAg-negative participants, HBV-infected hepatocytes ranged from 6.2% to 17.7% (biopsy 1) and significantly declined in 3 of 4 by biopsy 2. In the HBeAg seroconverter, the proportion was 97.4% (biopsy 1) and declined to 81.9% at biopsy 2 (P < .05). We extrapolated that HBV eradication with NUCs would take >100 years. At biopsy 1 in the persistently HBeAg-negative participants, 23%-56.8% of infected hepatocytes were transcriptionally inactive-higher than we observed in HBeAg-positive CHB-and significantly declined in 1 of 4 at biopsy 2. CONCLUSIONS: In HBeAg-negative CHB on NUCs, the negligible decline in infected hepatocytes is similar to HBeAg-positive CHB, supporting the need for more potent therapeutics to achieve functional cure.
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Infecções por HIV , Hepatite B Crônica , Humanos , Masculino , Antígenos E da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Vírus da Hepatite B/genética , Antivirais/uso terapêutico , DNA Viral , Hepatócitos , Infecções por HIV/tratamento farmacológicoRESUMO
BACKGROUND & AIMS: This study aimed to establish multivariate prediction models according to a response-guided therapy (RGT) based strategy at baseline and week 12 and 24 of follow-up to predict the functional cure for HBeAg-negative patients with chronic hepatitis B (CHB) treated with pegylated interferonα (PEG-IFNα). METHODS: A total of 242 HBeAg-negative patients with CHB were treated with PEG-IFNα for 52 weeks and followed up for 24 weeks. Responses at the end of follow-up (EOF) were defined as hepatitis B surface antigen (HBsAg) loss, and patients were defined as either responders or non-responders. RESULTS: The three most meaningful predictors were an age ≤ 40 years, alanine aminotransferase (ALT) levels ≤ 40 U/L, and HBsAg levels ≤ 100 IU/mL at baseline; ALT levels ≥ 80 U/L, anti-HBc levels ≤ 8.42 S/CO, and HBsAg levels ≤ 50 IU/mL at week 12; and ALT levels ≥ 40 U/L, anti-HBc levels ≤ 8.46 S/CO, and HBsAg levels ≤ 0.2 IU/mL at week 24. The response rates of patients with a score of 0-1 and 4-5 at baseline, week 12, and 24 were 13.5%, 7.8%, and 11.7%; and 63.6%, 68.1%, and 98.1%, respectively. At week 12, the cumulative scores were 0-2, 3-4, 5-7, and 8-10 (response rates 5.0%, 18.9%, 41.3%, and 71.4%, respectively). At week 24, the cumulative scores were 0-3, 4-6, 7-10, and 11-15 (response rates: 1.3%, 12.3%, 37.0%, and 92.5%, respectively). At baseline, patients with scores of 0-1 were slightly recommended; at week 12, patients with 0-1 or 0-2 cumulative scores were recommended to stop treatment. At week 24, patients with a score of 0-1 or a cumulative score of 0-6 were recommended to stop treatment. CONCLUSION: We established a multi-parameter prediction model for the functional cure of HBeAg-negative patients with CHB treated with PEG-IFNα.
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Antígenos E da Hepatite B , Hepatite B Crônica , Humanos , Adulto , Antígenos de Superfície da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Alanina Transaminase , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêuticoRESUMO
BACKGROUND: Serum hepatitis B virus (HBV) RNA is a surrogate biomarker for intrahepatic covalently closed circular DNA (cccDNA) transcriptional activity and persistence. In this retrospective study, we investigated its presence, levels and composition in ab initio Hepatitis B e antigen (HBeAg) negative chronically infected patients and examined possible associations with disease activity and the outcome of nucleos(t)ide analogue (NA) discontinuation. METHODS: We developed a sensitive real time polymerase chain reaction (RT-PCR) for the specific detection of HBV pregenomic RNA (pgRNA) and precore (preC) mRNA and analyzed 220 serum specimens, 160 under NA treatment, from 116 Greek patients initially negative for HBeAg. RESULTS: HBV pgRNA was detected in 31% and preC mRNA in 15% of samples, at lower levels representing a small fraction (3.4%) of total core promoter produced transcripts. In the absence of NAs, pgRNA was detected in 57% of samples with median value of 5.19 (2.61-8.35) log10 cp/mL, at lower levels than HBV DNA and correlated significantly with ALT (r = 0.764) and serum HBV DNA (r = 0.906). A wide range of HBV DNA/pgRNA ratio was observed with significant inter- and intra-patient variation. During NA treatment, pgRNA displayed low detectability (22%) and variable levels, median 3.97 (2.30- 8.13) log10 cp/mL, as well as, a significant inverse correlation with the duration of treatment (r = - 0.346, p < 0.01). In 74 events of NA discontinuation, end-of-treatment pgRNA-positive compared to pgRNA-negative cases, experienced more frequently virological (p = 0.016) and clinical (p = 0.011) relapse. CONCLUSIONS: In genotype D ab initio HBeAg negative patients, serum HBV RNA is primarily composed of pgRNA plus a minor fraction of preC mRNA transcripts. Serum pgRNA is associated with disease activity, suggesting lysis of infected hepatocytes as a possible source of serum HBV RNA in untreated patients and in the early phase of NA treatment. During long term NA treatment, detectable serum pgRNA predicts viral rebound and clinical relapse following treatment discontinuation and may thus serve as a marker for the decision of cessation of therapy.
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Vírus da Hepatite B , Hepatite B Crônica , Antivirais/uso terapêutico , DNA Viral/genética , Antígenos E da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Humanos , RNA , Estudos RetrospectivosRESUMO
AIM: Hepatitis B flare has been interpreted as result of immune response against upsurging hepatitis B virus (HBV) and its antigen(s) that may lead to HBV decline/clearance spontaneously. It has been speculated that antiviral therapy could halt the effective immune response with viral persistent as a consequence. A proof-of-concept study was conducted to investigate this issue. METHODS: Serial biochemical, quantitative hepatitis B surface antigen (HBsAg), interferon-γ (IFN-γ) and tumor-necrosis factor-α (TNF-α) assays were performed in four patients with severe hepatitis flare who had achieved precipitous HBsAg decline within 4 weeks of antiviral therapy. RESULTS: TNF-α and IFN-γ were found to be elevated in parallel to upsurging HBV DNA and HBsAg levels in all patients. Higher levels of TNF-α and IFN-γ and levels relative to qHBsAg were observed during and after early termination of therapy within 4 weeks in two patients and were followed by further HBsAg decline to <5 IU/ml and even achieved HBsAg loss in one patient. The patient who had stopped therapy on day 44 showed minimal HBsAg decline afterward and the patient who continued therapy showed a 10-fold rebound of qHBsAg from its nadir. The subsequent IFN-γ and TNF-α activity of these two patients was minimal. CONCLUSIONS: The results suggest that patients with severe hepatitis flare who achieved precipitous HBsAg decline may have robust immune response to clear the virus, and early termination of antiviral therapy may allow the protective immune response to continue and accelerate HBV decline toward HBsAg loss.
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The distinction between chronic HBeAg-negative hepatitis (CHB) and chronic HBeAg-negative infection (CIB) can be challenging and important for providing advice on prognosis, as well as determining need for treatment. The aim of the present study was to evaluate pgRNA levels in treatment-naïve HBeAg-negative chronic HBV-infected patients. In addition, pgRNA levels were compared to traditional markers in order to assess their clinical utility. A retrospective study was carried out, including 85 cases of CHBs and 74 CIBs. Globally, when the virological markers (pgRNA, qHBsAg, and HBV DNA) were analyzed, significant differences were found between the CHB and CIB groups (P<0.001). Overall, positive correlations were demonstrated, as follows: between pgRNA levels and qHBsAg (Spearman r=0.30, P<0.001), between pgRNA and HBV DNA (Spearman r=0.73, P<0.001), and between pgRNA and ALT (Spearman r=0.67, P<0.001). Out of the 85 CHB patients, 82 (96.5%) agreed to start treatment. At baseline, 38/82 patients, as well as the 3 untreated CHB patients, had undetectable pgRNA levels. The 74 CIB carriers also had undetectable pgRNA levels. During the follow-up period, no patients experienced viral reactivation or progression of liver disease. These results suggest that the addition of plasmatic HBV-pgRNA levels to the traditional diagnostic flowchart of HBeAg-negative patients may improve the correct identification of cases at risk, especially patients with occasional increases in HBV viremia.
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Antígenos E da Hepatite B , Vírus da Hepatite B , Biomarcadores , DNA Viral/genética , Vírus da Hepatite B/genética , Humanos , RNA , Estudos RetrospectivosRESUMO
Background and Objective: The study aims to investigate the correlation between Hepatitis B 'e' antigen (HBeAg) and HBV DNA levels, and to find a convenient tool to estimate the HBV DNA level for clinicians. Materials and Methods: We enrolled 1020 patients in this cross-sectional study and divided them into four groups: an HbeAg-positive and -negative group, and high and low HBV DNA levels groups. Results: Alanine aminotransferase (ALT), Albumin (ALB) and HBeAg are independent risk factors for CHB patients. When the level of HBeAg is higher than 16.15 S/CO, it is four times more likely that the patients will have high levels of HBV DNA than those who do not. The ALT and TB are independent risk factors in HBeAg-negative patients with a high HBV DNA level. We have drawn three predictive models to estimate the HBV DNA levels for those with the chronic hepatitis B virus (CHB), and those that are HBeAg-positive and HBeAg-negative (Y1 = 0.004 × ALT(IU/L) + 1.412 × HBeAg (S/CO) - 0.029 × ALB (g/L) + 0.779, the AUC is 0.672, and the cutoff value is -0.072, there the sensitivity is 0.615, the specificity is 0.648, PPV is 65.182% and NPV is 60.837%; Y2 = 0.007 × HBeAg (S/CO) - 0.016 × HGB (g/L) + 3.070, the AUC is 0.724, and the cutoff value is 1.216, where the sensitivity is 0.626, the specificity is 0.897, PPV is 94.118% and NPV is 34.437%; Y3 = -0.005 × ALT(IU/L) + 0.006 × TB (umol/L) + 0.385, the AUC is 0.661, and the cutoff value is 0.263, where the sensitivity is 0.677, the specificity is 0.587, PPV is 66.820% and NPV is 40.774%, respectively). We propose that HBeAg is the most important risk factor for the patient with a high HBV DNA level, however, it is not as important in the HBeAg-positive group. Conclusions: HBeAg is an independent risk factor that reflects the level of HBV DNA with a strong correlation. Patient with HBeAg (-) should combine TB and ALT to estimate the level of HBV DNA.
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Antígenos E da Hepatite B , Hepatite B Crônica , Alanina Transaminase , Albuminas , Estudos Transversais , DNA Viral , Vírus da Hepatite B/genética , Hepatite B Crônica/diagnóstico , HumanosRESUMO
Although discontinuation of nucleos(t)ide analogue (NA) treatment before HBsAg loss is part of all current HBV treatment guidelines for HBeAg-positive patients who achieve HBeAg seroconversion, a treatment endpoint known to be associated with silencing of HBV transcriptional activity and restoration of HBV-specific immune control, whether it is even appropriate to consider NA discontinuation before HBsAg loss in the HBeAg-negative phase remains highly controversial. Despite the growing evidence that a relevant, albeit small, proportion of patients with HBeAg-negative disease can be cured by stopping NA treatment, the fear of discontinuation-associated relapse and the uncertainty of how to predict off-therapy response and monitor patients after discontinuation have generated scepticism and subsequently led to low implementation of this concept in the clinic. In this article, we propose a concept in which NA discontinuation-associated relapse is an integral part of the stop-to-cure approach and ultimately the trigger for achieving HBsAg loss. However, the relapse in this sense becomes functionally effective only if HBV-specific immune reinvigoration and silencing of HBV transcriptional activity have been achieved during the NA treatment period. The probability of functional cure and the severity of post-discontinuation flares depend on the underlying baseline transcriptional activity of HBV when NA therapy was started, as well as the duration of NA treatment, both factors that should be considered as we move towards individualised approaches to HBV cure.
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Vírus da Hepatite B/efeitos dos fármacos , Nucleosídeos/administração & dosagem , Vírus da Hepatite B/metabolismo , Humanos , Nucleosídeos/uso terapêutico , Soroconversão/efeitos dos fármacos , Resultado do TratamentoRESUMO
Sensitive polymerase chain reaction assays to measure hepatitis B virus (HBV) DNA became only available the last decade. Hence, the long-term outcome of Caucasian patients in Western Europe with hepatitis B e antigen (HBeAg)-negative chronic infection, especially with a baseline HBV DNA level ⩾2000 IU/mL, is still unclear. Out of a cohort of 1936 chronic HBV patients, 413 Caucasian individuals were identified with HBeAg-negative chronic infection, defined as persistently normal alanine aminotransferase (ALT) levels and HBV DNA levels <20 000 IU/mL. During a mean follow-up of 12 years, 366 (88.6%) maintained an HBeAg-negative chronic infection status, whereas 25 (6.1%) developed chronic active hepatitis (CAH). In total, Nine of these 25 CAH cases were related to immunosuppression. In total, 22 (5.3%) individuals had ALT > 2 × upper limit of normal due to non-HBV-related causes. The cumulative probability of spontaneously developing CAH after 10 years was almost exclusively seen in patients with baseline HBV DNA level ⩾2000 IU/mL (11.7% vs 1.2%; P < .001). Advanced liver disease developed significantly more in patients with baseline HBV DNA level ⩾2000 IU/mL (5.2% vs 1.5%; P = .018) and occurred especially in patients with obesity (16.7% vs 4.2%; P = .049). The incidence of hepatocellular carcinoma was 0.0%. Caucasian patients with HBeAg-negative chronic infection and baseline HBV DNA level <2000 IU/mL have an excellent long-term prognosis in the absence of immunosuppressive therapy. However, patients with baseline HBV DNA level ⩾2000 IU/mL are at risk to develop advanced liver disease.
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OBJECTIVE: Although most patients with chronic hepatitis B (CHB) reach effective virological suppression with long-term nucleos(t)ide analogues (NA) therapy, some might not need to continue treatment for life. In this randomised, controlled, phase IV trial, we evaluated off-therapy outcomes in patients after discontinuing long-term NA therapy. DESIGN: Patients who had received NA therapy for ≥1 year and achieved virological suppression (hepatitis B e antigen (HBeAg) seroconversion combined with undetectable hepatitis B virus (HBV) DNA ≥12 months in HBeAg-positive patients or undetectable HBV DNA ≥36 months in HBeAg-negative patients) were randomised 2:1 to stop or continue NA therapy for 72 weeks. Sustained disease remission (HBeAg negative, HBV DNA <2000 IU/mL and normal alanine aminotransferase (ALT)) was evaluated at 72 weeks after stopping NA therapy. RESULTS: Among 67 enrolled patients, sustained disease remission was observed in 13/45 (29%) stop versus 18/22 (82%) continue patients. Hepatitis B surface antigen (HBsAg) loss occurred in two patients (one in each group). The median HBsAg decline from randomisation to week 72 was similar in both groups (0.2 (0.0-0.4) vs 0.1 (0.0-0.2) log IU/mL in stop vs continue patients). Among patients who stopped, 15/45 (33%) had virological or biochemical relapse and 17/45 (38%) were retreated according to predefined criteria. A total of 11/18 (61%) pretreatment HBeAg-positive versus 6/27 (22%) HBeAg-negative patients required retreatment (p=0.01). Fourteen (31%) patients developed ALT >10× upper limit of normal (ULN) and another 7 (16%) had ALT >5× ULN. No patients experienced liver decompensation or died. CONCLUSION: The findings of this prospective study suggest limited benefit of stopping NA therapy in chronic hepatitis B. TRIAL REGISTRATION NUMBER: NCT01911156.
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Hepatite B Crônica/tratamento farmacológico , Nucleosídeos/análogos & derivados , DNA Viral/análise , Feminino , Seguimentos , Antígenos de Superfície da Hepatite B/análise , Antígenos E da Hepatite B/análise , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Nucleosídeos/uso terapêutico , Estudos Prospectivos , Resultado do TratamentoRESUMO
Liver necroinflammation is the indicator for treating patients with chronic hepatitis B (CHB) infection. However, there is no suitable non-invasive index for diagnosing liver necroinflammation. This study aimed to create a non-invasive index to predict liver necroinflammation in patients who lack clear-cut clinical inflammation parameters. Patients who were hepatitis B e antigen (HBeAg)-negative and underwent liver histological diagnosis, had a normal or minimally increased alanine aminotransferase (ALT) level were enrolled. Liver necroinflammation was defined as histological active index ≥4. A logistic regression model (LRM) was established based on the parameters independently associated with liver necroinflammation. Of all 550 patients, 36.73% had necroinflammation. In patients with an abnormal ALT level, the rate of necroinflammation was 52.49%. The area under the curve (AUC) of the ALT level for predicting necroinflammation was 0.655 (95% confidence interval [CI], 0.609-0.702), and that of the HBV DNA level ≥2000 IU/mL combined with an abnormal ALT level was 0.618. By using the LRM, the AUC improved to 0.769 (95% CI, 0.723-0.815) with a Youden index of 0.519 and diagnostic accuracy of 75.3%. The cutoff value ≥0.7 in the LRM had a specificity of 97.4% and positive predictive value of 85.0% for predicting necroinflammation. By using the cutoff value <0.15 in the LRM, the presence of necroinflammation could be excluded with a negative predictive value of 90.8%. This study indicated that the LRM can be used to effectively diagnose liver necroinflammation in HBeAg-negative patients with CHB who have normal or minimally elevated ALT levels.
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Alanina Transaminase/sangue , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B , Hepatite B Crônica/sangue , Hepatite B Crônica/patologia , Necrose/patologia , Adolescente , Adulto , Idoso , Biomarcadores , Biópsia , Estudos Transversais , DNA Viral , Feminino , Antígenos E da Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Humanos , Testes de Função Hepática , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Carga Viral , Adulto JovemRESUMO
The discrimination between active chronic hepatitis B (CHB) and the clinically quiescent infection (CIB) is not always easy, as a significant portion of patients falls in a "grey" zone. Hepatitis B core-related antigen (HBcrAg) is a now quantifiable serological marker with potential applications in diagnosis and therapy monitoring. The aim of the present study was to evaluate the HBcrAg serum levels in HBeAg-negative HBV infection, and its ability in identifying the clinical profile, in comparison with HBsAg serum levels. HBcrAg was retrospectively assessed on serum samples from a population of treatment-naive HBeAg-negative patients by ChemiLuminescent Enzyme Immunoassay (CLEIA). HBsAg and HBV-DNA data were collected. Serological data were associated to clinical profile, defined in the subsequent follow-up of at least 1 year. In the overall population of 160 HBeAg-negative patients, HBcrAg results weakly correlated with qHBsAg levels (Spearman r = 0.471, P < 0.0001) and correlated closely with HBV-DNA (Spearman r = 0.746, P < 0.0001). HBcrAg levels were significantly higher in 85 CHB patients relative to 75 CIB carriers. A value of 2.5 logU/mL produced the optimal cut-off to identify CIB patients, with diagnostic accuracy comparable to HBsAg levels. In long-term clinical evaluation, a single measurement of HBcrAg at the established cut-off was optimally consistent with clinical outcome. Conversely, the HBsAg cut-off performed well in the true quiescent phase and less in more difficult-to-categorize patients. In conclusion, single-point use of HBcrAg serum levels provides an accurate identification of CIB and represents a useful tool for patient classification.
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Testes Diagnósticos de Rotina/métodos , Antígenos do Núcleo do Vírus da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , DNA Viral/sangue , Feminino , Antígenos de Superfície da Hepatite B/sangue , Hepatite B Crônica/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Soro/química , Adulto JovemRESUMO
Nucleos(t)ide analogues (NAs) and peginterferon have complementary effects in chronic hepatitis B, but it is unclear whether combination therapy improves responses in genotype D-infected patients. We conducted an open-label study of peginterferon alfa-2a 180 µg/wk added to ongoing NA therapy in hepatitis B e antigen (HBeAg)-negative, genotype D-infected patients with hepatitis B virus DNA <20 IU/mL. The primary endpoint was proportion of patients with ≥50% decline in serum HBsAg by the end of the 48-week add-on phase. Seventy patients received treatment, 11 were withdrawn at week 24 for no decrease in HBsAg, and 14 withdrew for other reasons. Response rate (per-protocol population) was 67.4% (29/43) at week 48 (95% confidence interval [CI]: 51, 81) and 50.9% (28/55) at week 96 (95% CI: 38, 66). Median serum HBsAg decreased throughout peginterferon alfa-2a treatment and was significantly lower than baseline at weeks 48, 72 and 96 (P < 0.001). Decreases in HBsAg of ≥0.5-log10 and ≥1-log10 were documented in 19 (44.2%) and 6 (14.0%) patients at week 48 and 6 (10.9%) and 17 (30.9%) patients at week 96. The proportion of patients with HBsAg <1000, <500, <100 and <10 IU/mL at ≥1 timepoint during treatment was 78.6% (n = 44), 57.1% (n = 32), 21.4% (n = 12) and 7.1% (n = 4). Interferon gamma-induced protein 10 increased from baseline up to week 48, with week 12 levels significantly associated with response at week 48. Addition of peginterferon alfa-2a to ongoing NA therapy significantly decreased HBsAg levels in HBeAg-negative patients with genotype D infection (ClinicalTrials.gov NCT01706575).
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Antivirais/administração & dosagem , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Nucleosídeos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adulto , Esquema de Medicação , Quimioterapia Combinada , Feminino , Genótipo , Vírus da Hepatite B/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Resultado do TratamentoRESUMO
Migration from sub-Saharan Africa is contributing to the rising incidence of chronic hepatitis B (CHB) infection and its complications in Australia. African CHB is associated with unique genotypes, such as E and A1, which are associated with reduced vaccine efficacy and early-onset hepatocellular carcinoma, respectively, although the prevalence of these genotypes outside Africa is poorly described. Treatment-naïve children of African origin with CHB were recruited at the Royal Children's Hospital Melbourne. Population-based sequencing of the complete HBV genome, or the clinically relevant basal core promoter (BCP)/precore (PC) region, was performed, and the HBV genotype/subgenotype assigned by phylogenetic analysis. HBV was characterized in serum from 67 children, median age 12.5 years. HBV genotype E was most frequent (70â%), with genotype D [25â%; subgenotypes D6 (formerly D7)/D3/D2)] and subgenotype A1 (5â%) also being identified. Despite their young age, over 50â% of the children were HBeAg-negative and had seroconverted to anti-HBe, with this being associated with canonical BCP/PC mutations in the majority of cases. The profile of HBV in African children living in Australia was characterized by early HBeAg seroconversion and infection with HBV variants associated with poor clinical outcome, as well as genotypes previously associated with reduced vaccine efficacy or rapid progression to liver cancer. These findings have important ramifications for patient monitoring and treatment guidelines in the Australian paediatric setting.
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Vírus da Hepatite B/genética , Hepatite B/epidemiologia , Hepatite B/virologia , Adolescente , África/epidemiologia , Austrália/epidemiologia , Criança , Pré-Escolar , Feminino , Genoma Viral , Humanos , Masculino , Mutação , Filogenia , Regiões Promotoras Genéticas/genética , SorogrupoRESUMO
Infection with hepatitis B virus (HBV) e-antigen (HBeAg)-negative strains is increasingly prevalent. Currently, detailed information of the obtained natural HBV strain is not available except for the B genotype and HBeAg-negative. The aim of the present study was to characterize the natural genetic variation of the HBeAg-negative strain and investigate its function. The genic sequence was determined using Sanger sequencing, and compared to related sequences using alignment and phylogenetic analysis. In vivo, virus-specific serum markers were investigated in CBA/CaJ mice. The sequence had a full genome length of 3215 nucleotides. Sites 122, 125, 127, and 160 in S regions were identified as lysine, threonine, proline, and lysine respectively. The main four point variants including A1762T, G1764A, G1896A, and G1899A were detected in the full-length genome. The genotype of the sequence was B, with sub-genotype B2 and serological subtype adw2. The characterize of the natural genetic variation strain showed no reported drug-resistant variant in P region and no reported immune escape site in S region. The strain will increase viral replication and infection for mutations A1762T and G1764A in the basal core promoter region, and mutations G1896A and G1899A in the pre-core region. The G1896A variant resulted in a premature stop codon and abolished HBeAg expression. HBsAg persisted for 26 weeks and HBeAg was still negative in CBA/CaJ mice. The present sequence is representative of the HBeAg-negative genome and may serve as a valuable reference for studying HBeAg-negative strains. The present findings were successfully verified in CBA/CaJ mice, demonstrating good applicability of the sequence.
Assuntos
DNA Viral/genética , Genoma Viral , Antígenos E da Hepatite B/genética , Vírus da Hepatite B/genética , Hepatite B/virologia , Animais , DNA Circular/genética , DNA Circular/imunologia , DNA Viral/imunologia , Modelos Animais de Doenças , Variação Genética , Genótipo , Hepatite B/imunologia , Antígenos E da Hepatite B/imunologia , Vírus da Hepatite B/crescimento & desenvolvimento , Vírus da Hepatite B/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos CBA , Mutação , Regiões Promotoras Genéticas , Padrões de Referência , Análise de Sequência de DNA , Replicação ViralRESUMO
Seroclearance of hepatitis B surface antigen (HBsAg) has been widely studied; however, seroconversion of HBsAg and characteristics of viral load among hepatitis B e antigen (HBeAg)-negative chronic infection patients after HBsAg lost is not clear. We performed a large-scale study in a HBeAg-negative chronic infection cohort to evaluate spontaneous HBsAg seroclearance incidence from October 2012 to April 2017 in Jiangsu province, China. We also elucidated the characteristics of HBsAg seroconversion and hepatitis B virus (HBV) DNA detectability among patients who cleared HBsAg. A total of 2997 HBeAg-negative chronic infection patients (mean age 52.3 ± 12.9 years at baseline) were included. With 10 519 person-years of follow-up, 348 patients successfully spontaneously cleared HBsAg, with an incidence rate of 3.31 per 100 person-years. Patients with HBV DNA detectable ~1999 IU/mL at baseline had a lower probability of HBsAg seroclearance relative to those with undetectable HBV DNA, with a hazard ratio of 0.31 (95% CI = 0.23, 0.41). HBsAg seroconversion occurred in 37.3% of those patients who cleared HBsAg. The geometric mean of anti-HBs among those with HBsAg conversion was 79.4 mIU/mL. Female had a higher HBsAg seroconversion rate (P = 0.011). Among those with HBsAg seroclearance, 11.2% still had HBV DNA levels of higher than 100 IU/mL. Patients with higher HBV DNA at baseline had a higher risk of detectable HBV DNA levels even after HBsAg seroclearance (P < 0.001). This study reveals HBsAg seroconversion rates and HBV DNA undetectability epidemiological characteristics of patients with HBsAg seroclearance and suggests that monitoring HBV DNA is needed when managing HBeAg-negative chronic patients, even after clearing HBsAg.
Assuntos
Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/imunologia , Hepatite B Crônica/epidemiologia , Remissão Espontânea , Soroconversão , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Carga Viral , Adulto JovemRESUMO
An alternative approach in the treatment of chronic hepatitis B (CHB) with pegylated (PEG)-interferon (IFN) is the prolonged course to 96 weeks of therapy, with higher sustained response (SR) than patients treated for 48 weeks. This result was confirmed in patients with CHB and D genotype, while no data are currently available about the prolonged course of PEG-IFN in E genotype. This retrospective analysis reported the role of different treatment duration of PEG-IFN on the SR in patients affected by CHB and E genotype. A total of 86 subjects with CHB and E genotype were considered in this analysis; different treatment durations were: 48 weeks (control group, 41 patients), 72 weeks (25 patients), and 96 weeks (19 patients). Treatment effectiveness was evaluated with sustained response (SR) and serological response. SR was significantly higher in patients who underwent PEG-IFN for 96 weeks in comparison to 48 weeks: 14.6% versus 26.3% (P = 0.016). HBsAg loss rate was 5.3% in patients treated for 96 weeks and 2.4% in the control group. In the multivariate analysis only the 72 and 96 weeks of therapy (OR 2.335, 95% CI 1.550-4.578; P = 0.020 and (OR 3.890, 95% CI 1.991-10.961; P = 0003) were predictive of SR. The extended duration of PEG-IFN course in patients with CHB and genotype E is a promising approach to increase the SR and HBsAg clearance.
Assuntos
Antivirais/administração & dosagem , Genótipo , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adulto , Feminino , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/classificação , Humanos , Masculino , Proteínas Recombinantes/administração & dosagem , Estudos Retrospectivos , Resposta Viral Sustentada , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND & AIM: Robust baseline predictors of interferon (IFN) response in HBeAg-negative chronic hepatitis B (CHB) patients are not currently available. The recently described rs368234815 TT/ΔG dinucleotide and rs117648444 nonsynonymous P70S polymorphisms in IFN lambda 4 (IFNL4) gene, which are strongly associated with response to IFN in hepatitis C virus (HCV) infection, could be also useful in IFN-treated CHB patients. Here we assessed whether IFNL4 rs368234815 and rs117648444 polymorphisms predict IFN-induced HBsAg clearance in CHB patients. METHODS: We sequenced the IFNL4 gene on genomic DNA collected from 126 HBeAg-negative CHB patients treated with IFN and followed up for a median of 11 (1-23) years. RESULTS: The 15-year cumulative probability of HBsAg loss in the 62 carriers of the rs368234815 TT/TT genotype, which abolishes the IFNλ4 protein production, was comparable to that of 19 patients carrying the rs117648444 T allele predicted to produce an impaired IFNλ4-S70 protein (39% vs 42%, P = .827). In contrast, these 81 patients, either not producing IFNλ4 or producing an impaired IFNλ4-S70 protein, had a significantly higher 15-year probability of HBsAg loss compared to the 45 subjects predicted to encode only the fully functional IFNλ4-P70 (42% vs 11% P = .003). At multivariate analysis, combination of the rs368234815 and rs117648444 genotypes strongly predicted HBsAg clearance (HR 5.90, 95% CI 1.70-20.9, P = .006) together with pretreatment serum HBV DNA levels (HR 0.57, 95% CI 0.39-0.83, P = .003). CONCLUSION: IFNL4 rs368234815 and rs117648444 functional variants are worth to be investigated as pretreatment combined predictors of IFN response in HBeAg-negative CHB patients.
Assuntos
Antivirais/uso terapêutico , Antígenos de Superfície da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/genética , Interferon-alfa/uso terapêutico , Interleucinas/genética , Polietilenoglicóis/uso terapêutico , Adulto , DNA Viral/sangue , Feminino , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Proteínas Recombinantes/uso terapêuticoRESUMO
Di-Wu-Yang-Gan Granules is a Traditional Chinese Medicine prescription used for the treatment of HBeAg-negative chronic hepatitis B patients in China. It consists of five commonly used Chinese herbs. However, the chemical constituents of the whole prescription had not been clarified yet. Hence, in this study, the chemical profiling of Di-Wu-Yang-Gan Granules was explored by ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry, which can provide accurate molecular weight within 5-ppm error and sufficient MS/MS fragment ions without the need for precursor ion selection. As a result, 116 compounds were identified, including lignans, triterpenesaponins, flavonoids, coumarins, iridoids, nortriterpenoids, phenolic acids, and sesquiterpenes. All compounds were further assigned to the individual herbs. In conclusion, this established method was reliable and effective for the separation and identification of the constituents in Di-Wu-Yang-Gan Granules. The findings are beneficial for quality control of the prescription during production and provide helpful chemical information for exploring its efficacy and the mechanism of action. The fragmentation regularity summarized in this study also provided important information for the rapid identification of the chemical composition in herbal medicines or their prescription.
Assuntos
Cromatografia Líquida/métodos , Medicamentos de Ervas Chinesas/química , Espectrometria de Massas/métodos , Cumarínicos/análise , Flavonoides/análise , Iridoides/análise , Lignanas/análise , Fenóis/análise , Sesquiterpenos/análiseRESUMO
BACKGROUND & AIMS: There is currently no virological cure for chronic hepatitis B but successful nucleos(t)ide analogue (NA) therapy can suppress hepatitis B virus (HBV) DNA replication and, in some cases, result in HBsAg loss. Stopping NA therapy often leads to viral relapse and therefore life-long therapy is usually required. This study investigated the potential to discontinue tenofovir disoproxil fumarate (TDF) therapy in HBeAg-negative patients. METHODS: Non-cirrhotic HBeAg-negative patients who had received TDF for ≥4years, with suppressed HBV DNA for ≥3.5years, were randomly assigned to either stop (n=21) or continue (n=21) TDF monotherapy. Standard laboratory tests including HBV DNA viral load, HBsAg and alanine aminotransferase (ALT) measurements, and adverse event reporting were carried out during treatment and post-treatment follow-up for 144weeks. RESULTS: Of the patients who stopped TDF therapy, 62% (n=13) remained off-therapy to Week 144. Median HBsAg change in this group was -0.59log10IU/ml (range -4.49 to 0.02log10IU/ml) vs. 0.21log10IU/ml in patients who continued TDF therapy. Four patients (19%) achieved HBsAg loss. Patients stopping therapy had initial fluctuations in viral load and ALT; however, at Week 144, 43% (n=9) had either achieved HBsAg loss or had HBV DNA <2,000IU/ml. There were no unexpected safety issues identified with stopping TDF therapy. CONCLUSIONS: This controlled study demonstrated the potential for HBsAg loss and/or sustained virological response in non-cirrhotic HBeAg-negative patients stopping long-term TDF therapy. Lay summary: Nucleos(t)ide analogue (NA) is usually a life-long therapy for HBV patients. This randomised controlled study investigated the discontinuation of tenofovir disoproxil fumarate (TDF) therapy in HBeAg-negative patients. Of the patients who stopped TDF therapy, 62% remained off-therapy to Week 144, of which 43% of patients had achieved either HBsAg loss or HBV DNA <2,000IU/ml. This offers a potential for long-term HBV-suppressed patients without cirrhosis to stop NA therapy under strict surveillance. Clinical trial number: NCT01320943.