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1.
J Hepatol ; 80(2): 352-361, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37890721

RESUMO

Gene therapy has garnered increasing interest over recent decades. Several therapies employing gene transfer mechanisms have been developed, and, of these, adeno-associated virus (AAV) vectors have demonstrated viability for use with in vivo gene therapy. Several AAV-based therapeutics have received regulatory approval in the last few years including those for retinal disease, spinal muscular atrophy or aromatic L-amino acid decarboxylase deficiency. Lately, with the introduction of novel liver-directed AAV vector-based therapeutics for the treatment of haemophilia A and B, gene therapy has attracted significant attention in the hepatology community, with the liver increasingly recognised as a target for gene therapy. However, the introduction of foreign DNA into hepatocytes is associated with a risk of hepatic reactions, with raised ALT (alanine aminotransferase) and AST (aspartate aminotransferase) being - so far - the most commonly reported side effects. The complete mechanisms underlying the ALT flairs remain to be determined and the long-term risks associated with these new treatments is not yet known. The liver community is increasingly being asked to support liver-directed gene therapy to mitigate potential liver associated harm. In this review, we focus on AAV vector-based gene therapy, shedding light on this promising technique and its remarkable success in haemophilia, with a special focus on hepatic complications and their management in daily clinical practice.


Assuntos
Gastroenterologistas , Técnicas de Transferência de Genes , Humanos , Dependovirus/genética , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Fígado , Vetores Genéticos/genética
2.
J Viral Hepat ; 31 Suppl 1: 14-20, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38606951

RESUMO

Hepatitis is a common adverse event following gene therapy for haemophilia, often associated with a loss of transgene expression. Investigating the potential causes and implications of this is crucial for the overall success of treatment. Gene therapy trials using adeno-associated virus (AAV) vectors have demonstrated promising results marked by increases in factor FVIII and FIX levels and reductions in episodes of bleeding. However, hepatocellular injury characterised by elevations in alanine aminotransferases (ALT) has been noted. This liver injury is typically transient and asymptomatic, posing challenges in determining its clinical significance. Proposed causes encompass immune-mediated responses, notably T cell cytotoxicity in response to the AAV vector, direct liver injury from the viral capsid or transcribed protein via the unfolded protein response and pre-existing liver conditions. Liver biopsy data conducted years post-gene therapy infusion has shown sinusoidal infiltration without significant inflammation. The overall safety profile of gene therapy remains favourable with no evidence drug-induced liver injury (DILI) based on Hy's Law criteria. Essential pre-therapy monitoring and identifying patients at high risk of liver injury should involve liver function tests and non-invasive fibroscans, while novel blood-based biomarkers are under exploration. Further research is required to comprehend the mechanisms underlying transaminitis, loss of transgene expression and long-term effects on the liver, providing insights for optimising gene therapy for haemophilia.


Assuntos
Hemofilia A , Hepatite A , Hepatite , Humanos , Hemofilia A/genética , Hemofilia A/terapia , Testes de Função Hepática , Terapia Genética/efeitos adversos , Terapia Genética/métodos
3.
J Viral Hepat ; 31 Suppl 1: 21-25, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38606938

RESUMO

Attempts to achieve a functional cure or amelioration of the severe X linked bleeding disorders haemophilia A (factor VIII deficiency) and haemophilia B (factor IX deficiency) using AAV-based vectors have been frustrated by immune responses that limit efficacy and durability. The immune responses include adaptive and innate pathways as well as cytokine mediated inflammation, especially of the target organ cells-hepatocytes. Immune suppression has only been partly effective in clinical trials at ameliorating the immune response and the lack of good animal models has delayed progress in identifying mechanisms and developing more effective approaches to controlling these effects of AAV gene transfer. Here we discuss the arguments for and against more potent immunosuppression to improve factor expression after AAV-mediated gene therapy.


Assuntos
Hemofilia A , Hemofilia B , Animais , Hemofilia A/genética , Hemofilia A/terapia , Hemofilia B/genética , Hemofilia B/terapia , Terapia Genética , Terapia de Imunossupressão , Imunidade
4.
J Viral Hepat ; 31(11): 645-656, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39056891

RESUMO

Pakistan harbours a large burden of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. We utilised repeat sero-surveys to assess progress achieved towards hepatitis elimination in Pakistan. Multilevel logistic regression evaluated the change in HBV infection (HBV surface antigen (HBsAg)-positive) prevalence and HCV exposure (HCV antibody (HCV-Ab)-positive) prevalence between two sero-surveys from 2007 and 2019 for Sindh province and associated risk factors. Adjusted odds ratios (aORs) were estimated and population-attributable fractions (PAF) for modifiable risk factors for HCV exposure. The 2007 and 2019 surveys included 8855 and 6672 individuals. HBsAg prevalence decreased from 2.6% (95% confidence intervals (95% CI): 2.2-2.9) in 2007 to 1.1% (95% CI: 0.8-1.3) in 2019, while HCV-Ab prevalence increased from 5.1% (95% CI: 4.6%-5.5%) to 6.2% (95% CI: 5.6%-6.8%). The age and gender-adjusted HBsAg prevalence decreased by 80% (aOR = 0.2, 95% CI: 0.1-0.4) among children and 60% (aOR = 0.4, 95% CI: 0.3-0.6) among adults over 2007-2019, while HCV-Ab prevalence decreased by 60% (aOR = 0.4, 95%CI:0.2-0.7) in children and increased by 40% (aOR = 1.4, 95% CI: 1.2-1.7) in adults. HCV-Ab prevalence was lower in adults with secondary (aOR = 0.6, 95% CI: 0.5-0.8) and higher (aOR = 0.5, 95%CI:0.3-0.8) education compared to illiterates and higher among adults reporting blood transfusion (aOR = 1.7, 95% CI: 1.2-2.4), family history of hepatitis (aOR = 2.5, 95% CI: 1.9-3.3), past year medical injection (aOR = 2.1, 95% CI: 1.6-2.7), being tattooed (aOR = 1.4, 95% CI: 1.0-1.9) and shaved by traditional barber (aOR = 1.2, 95% CI: 1.0-1.5). Modifiable risk factors accounted for 45% of HCV exposure, with medical injection(s) accounting for 38% (95%CI,25.7-48.4%). Overall HCV has increased over 2007-2019 in Sindh province, while HBV prevalence has decreased. Medical injections should be an important focus of prevention activities.


Assuntos
Antígenos de Superfície da Hepatite B , Hepatite B , Anticorpos Anti-Hepatite C , Hepatite C , Humanos , Paquistão/epidemiologia , Feminino , Masculino , Adulto , Hepatite B/epidemiologia , Hepatite C/epidemiologia , Adolescente , Pessoa de Meia-Idade , Estudos Soroepidemiológicos , Adulto Jovem , Prevalência , Fatores de Risco , Criança , Antígenos de Superfície da Hepatite B/sangue , Anticorpos Anti-Hepatite C/sangue , Pré-Escolar , Idoso , Lactente , Hepacivirus/imunologia , Hepacivirus/genética , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/genética
5.
BMC Public Health ; 24(1): 2427, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39243047

RESUMO

BACKGROUND: Direct acting antivirals (DAAs) for the Hepatitis C virus (HCV) have shifted the World Health Organisation global strategic focus to the elimination of HCV by 2030. In England, the UK Health Security Agency (UKHSA) led a national 'patient re-engagement exercise', using routine surveillance data, which was delivered through the HCV Operational Delivery Networks (ODNs) with support from National Health Service England (NHSE), to help find and support people with a positive HCV PCR test result to access treatment. We report a quantitative evaluation of outcomes of this exercise. METHODS: Individuals with a recorded positive HCV antibody or PCR result between 1996 and 2017 were identified using UKHSA's records of HCV laboratory diagnosis. Linkage with established health-care datasets helped to enhance patient identification and minimise attempts to contact deceased or previously treated individuals. From September to November 2018 each ODN was provided with a local list of diagnosed individuals. ODNs were asked to perform further data quality checks through local systems and then write to each individual's GP to inform them that the individual would be contacted by the ODN to offer confirmatory HCV PCR testing, assessment and treatment unless the GP advised otherwise. Outcomes of interest were receipt of treatment, a negative PCR result, and death. Data were collected in 2022. RESULTS: Of 176,555 individuals with a positive HCV laboratory report, 55,329 individuals were included in the exercise following linkage to healthcare datasets and data reconciliation. Participants in the study had a median age of 51 years (IQR: 43, 59), 36,779 (66.5%) were males, 47,668 (86.2%) were diagnosed before 2016 and 11,148 (20.2%) lived in London. Of the study population, 7,442 (13.4%) had evidence of treatment after the re-engagement exercise commenced, 6,435 (11.6%) were reported as PCR negative (96% had no previous treatment records), 4,195 (7.6%) had prescription data indicating treatment before the exercise commenced or were reported to have been treated previously by their ODN, and 2,990 (5.4%) had died. The status of 32,802 (59.3%) people remains unknown. CONCLUSIONS: A substantial number of those included had treatment recorded after the exercise commenced, however, many more remain unengaged. Evaluation of the exercise highlighted areas that could be streamlined to improve future exercises.


Assuntos
Antivirais , Humanos , Masculino , Antivirais/uso terapêutico , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto , Inglaterra/epidemiologia , Hepatite C/tratamento farmacológico , Hepatite C/diagnóstico , Idoso , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Hepacivirus/isolamento & purificação
6.
J Hepatol ; 79(2): 576-580, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37030400

RESUMO

Hepatitis D virus (HDV) infection occurs as a coinfection with hepatitis B and increases the risk of hepatocellular carcinoma, decompensated cirrhosis, and mortality compared to hepatitis B virus (HBV) monoinfection. Reliable estimates of the prevalence of HDV infection and disease burden are essential to formulate strategies to find coinfected individuals more effectively and efficiently. The global prevalence of HBV infections was estimated to be 262,240,000 in 2021. Only 1,994,000 of the HBV infections were newly diagnosed in 2021, with more than half of the new diagnoses made in China. Our initial estimates indicated a much lower prevalence of HDV antibody (anti-HDV) and HDV RNA positivity than previously reported in published studies. Accurate estimates of HDV prevalence are needed. The most effective method to generate estimates of the prevalence of anti-HDV and HDV RNA positivity and to find undiagnosed individuals at the national level is to implement double reflex testing. This requires anti-HDV testing of all hepatitis B surface antigen-positive individuals and HDV RNA testing of all anti-HDV-positive individuals. This strategy is manageable for healthcare systems since the number of newly diagnosed HBV cases is low. At the global level, a comprehensive HDV screening strategy would require only 1,994,000 HDV antibody tests and less than 89,000 HDV PCR tests. Double reflex testing is the preferred strategy in countries with a low prevalence of HBV and those with a high prevalence of both HBV and HDV. For example, in the European Union and North America only 35,000 and 22,000 cases, respectively, will require anti-HDV testing annually.


Assuntos
Coinfecção , Hepatite B , Hepatite D , Neoplasias Hepáticas , Humanos , Vírus da Hepatite B/genética , Prevalência , Hepatite D/diagnóstico , Hepatite D/epidemiologia , Hepatite B/diagnóstico , Hepatite B/epidemiologia , Vírus Delta da Hepatite/genética , Antígenos de Superfície da Hepatite B , Anticorpos Anti-Hepatite , Reflexo , RNA , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia
7.
J Viral Hepat ; 30(5): 448-454, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36740893

RESUMO

To evaluate the safety and tolerability of the fixed-dose, single-tablet regimen sofosbuvir/velpatasvir (SOF/VEL) for the treatment of hepatitis C virus (HCV) infection in three Phase 3 studies in patients with and without compensated cirrhosis. Data from three registrational trials (ASTRAL-1, NCT02201940; ASTRAL-2, NCT02220998; ASTRAL-3, NCT02201953) were pooled by treatment regimen. Researchers assessed treatment-emergent adverse events (TEAEs) and laboratory abnormalities in patients randomized to SOF/VEL or placebo for 12 weeks in ASTRAL-1 and SOF/VEL for 12 weeks in ASTRAL-2 and ASTRAL-3. Overall, 1035 patients were treated with SOF/VEL, and 116 patients received placebo. Rates of any TEAE were generally similar between patients receiving SOF/VEL (79.4%) and those receiving placebo (76.7%). The majority of TEAEs were mild to moderate, with 23 (2.2%) treatment-emergent serious AEs in patients treated with SOF/VEL. Of these treatment-emergent serious AEs, none led to premature study discontinuation, nor were they considered related to treatment. Presence of compensated cirrhosis, greater age and mild renal impairment did not impact incidence or severity of TEAEs with SOF/VEL treatment. The most common TEAEs (incidence ≥10%) were headache, fatigue, nausea and nasopharyngitis in patients receiving SOF/VEL; similar rates were observed in placebo-treated patients. Three deaths (<1%) were reported in patients treated with SOF/VEL, all posttreatment and none assessed as related to study treatment. Similar to that of placebo, SOF/VEL treatment of HCV infection had a safety/tolerability profile that was not affected by baseline factors, such as the presence of compensated cirrhosis, mild renal impairment or advanced age.


Assuntos
Hepatite C Crônica , Hepatite C , Humanos , Sofosbuvir/efeitos adversos , Antivirais/efeitos adversos , Hepatite C Crônica/tratamento farmacológico , Resultado do Tratamento , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Hepatite C/tratamento farmacológico , Hepacivirus/genética , Cirrose Hepática , Genótipo
8.
BMC Public Health ; 23(1): 2529, 2023 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-38110885

RESUMO

BACKGROUND: Pakistan has one of the highest burdens of Hepatitis C virus (HCV) infection globally. To achieve the World Health Organization's goals for HCV elimination, there is a need for substantial scale-up in testing, treatment, and a reduction in new infections. Data on the population impact of scaling up treatment is not available in Pakistan, nor is there reliable data on the incidence of infection/reinfection. This project will fill this gap by providing important empirical data on the incidence of infection (primary and reinfection) in Pakistan. Then, by using this data in epidemic models, the study will determine whether response rates achieved with affordable therapies (sofosbuvir plus daclatasvir) will be sufficient to eliminate HCV in Pakistan. METHODS: This prospective multi-centre cohort study will screen 25,000 individuals for HCV antibody (Ab) and RNA (if Ab-positive) at various centers in Pakistan- Karachi (Sindh) and Punjab, providing estimates of the disease prevalence. HCV positive patients will be treated with sofosbuvir and daclatasvir for 12-weeks, (extended to 24-weeks in those with cirrhosis) and the proportion responding to this first-line treatment estimated. Patients who test HCV Ab negative will be recalled 12 months later to test for new HCV infections, providing estimates of the incidence rate. Patients diagnosed with HCV (~ 4,000) will be treated and tested for Sustained Virological Response (SVR). Questionnaires to assess risk factors, productivity, health care usage and quality of life will be completed at both the initial screening and at 12-month follow-up, allowing mathematical modelling and economic analysis to assess the current treatment strategies. Viral resistance will be analysed and patients who have successfully completed treatment will be retested 12 months later to estimate the rate of re-infection. CONCLUSION: The HepFREEPak study will provide evidence on the efficacy of available and widely used treatment options in Pakistan. It will also provide data on the incidence rate of primary infections and re-infections. Data on incidence risk factors will allow us to model and incorporate heterogeneity of risk and how that affects screening and treatment strategies. These data will identify any gaps in current test-and-treat programs to achieve HCV elimination in Pakistan. STUDY REGISTRATION: This study was registered on clinicaltrials.gov (NCT04943588) on June 29, 2021.


Assuntos
Hepatite C Crônica , Hepatite C , Humanos , Antivirais/uso terapêutico , Estudos de Coortes , Hepacivirus/genética , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Hepatite C/epidemiologia , Hepatite C Crônica/tratamento farmacológico , Estudos Multicêntricos como Assunto , Estudos Observacionais como Assunto , Paquistão/epidemiologia , Estudos Prospectivos , Qualidade de Vida , Reinfecção/tratamento farmacológico , Sofosbuvir/uso terapêutico
9.
J Hepatol ; 77(5): 1444-1447, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35907517

RESUMO

Advances in diagnostics and therapeutics have brought the elimination of chronic viral hepatitis into focus. The World Health Organization has defined the targets for elimination, but it is unclear how these can be achieved and how they should be measured. The goal of this special conference was to examine current efforts and metrics to assess progress towards elimination.


Assuntos
Hepatite A , Hepatite Viral Humana , Antivirais/uso terapêutico , Erradicação de Doenças , Hepatite Viral Humana/diagnóstico , Hepatite Viral Humana/epidemiologia , Hepatite Viral Humana/prevenção & controle , Humanos , Organização Mundial da Saúde
10.
J Transl Med ; 20(1): 2, 2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34980174

RESUMO

BACKGROUND: People with liver disease are at increased risk of developing cardiovascular disease (CVD), however, there has yet been an investigation of incidence burden, risk, and premature mortality across a wide range of liver conditions and cardiovascular outcomes. METHODS: We employed population-wide electronic health records (EHRs; from 1998 to 2020) consisting of almost 4 million adults to assess regional variations in disease burden of five liver conditions, alcoholic liver disease (ALD), autoimmune liver disease, chronic hepatitis B infection (HBV), chronic hepatitis C infection (HCV) and NAFLD, in England. We analysed regional differences in incidence rates for 17 manifestations of CVD in people with or without liver disease. The associations between biomarkers and comorbidities and risk of CVD in patients with liver disease were estimated using Cox models. For each liver condition, we estimated excess years of life lost (YLL) attributable to CVD (i.e., difference in YLL between people with or without CVD). RESULTS: The age-standardised incidence rate for any liver disease was 114.5 per 100,000 person years. The highest incidence was observed in NAFLD (85.5), followed by ALD (24.7), HCV (6.0), HBV (4.1) and autoimmune liver disease (3.7). Regionally, the North West and North East regions consistently exhibited high incidence burden. Age-specific incidence rate analyses revealed that the peak incidence for liver disease of non-viral aetiology is reached in individuals aged 50-59 years. Patients with liver disease had a two-fold higher incidence burden of CVD (2634.6 per 100,000 persons) compared to individuals without liver disease (1339.7 per 100,000 persons). When comparing across liver diseases, atrial fibrillation was the most common initial CVD presentation while hypertrophic cardiomyopathy was the least common. We noted strong positive associations between body mass index and current smoking and risk of CVD. Patients who also had diabetes, hypertension, proteinuric kidney disease, chronic kidney disease, diverticular disease and gastro-oesophageal reflex disorders had a higher risk of CVD, as do patients with low albumin, raised C-reactive protein and raised International Normalized Ratio levels. All types of CVD were associated with shorter life expectancies. When evaluating excess YLLs by age of CVD onset and by liver disease type, differences in YLLs, when comparing across CVD types, were more pronounced at younger ages. CONCLUSIONS: We developed a public online app ( https://lailab.shinyapps.io/cvd_in_liver_disease/ ) to showcase results interactively. We provide a blueprint that revealed previously underappreciated clinical factors related to the risk of CVD, which differed in the magnitude of effects across liver diseases. We found significant geographical variations in the burden of liver disease and CVD, highlighting the need to devise local solutions. Targeted policies and regional initiatives addressing underserved communities might help improve equity of access to CVD screening and treatment.


Assuntos
Doenças Cardiovasculares , Hepatite C , Adulto , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/epidemiologia , Carga Global da Doença , Hepatite C/complicações , Hepatite C/epidemiologia , Humanos , Pessoa de Meia-Idade , Anos de Vida Ajustados por Qualidade de Vida , Fatores de Risco
11.
J Viral Hepat ; 29(1): 43-51, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34664352

RESUMO

Many people with chronic hepatitis C infection don't engage in treatment. To eliminate hepatitis C and avoid health inequalities therapy must be provided to everyone. In other diseases peers with lived experience of the condition have improved care but, for hepatitis C, studies have not shown unequivocal benefit. We completed a retrospective analysis of the English National Health Service treatment registry comparing treatment networks with and without peers using Bayesian Poisson (for count outcomes) or Bayesian Binomial (for proportion outcomes) mixed effects models with time fixed effects. For each outcome, we estimated relative ratio (RR-Poisson model) or odds ratio (Odds Ratio (OR)-Binomial model) between peer and non-peer networks. We analysed 30,729 patients within 20 operational delivery networks. In networks with peers there was an increase in the number of people initiating therapy (RR 1.12 95%, credible interval 1.02-1.21) and an increase in the proportion completing therapy (OR 2.45 95%, credible interval 1.49-3.84). However, we saw no change in proportions of people using drugs who initiated therapy nor any significant change in virological response (OR 1.14 95% credible interval 0.979-1.36). We repeated the analysis looking at the impact of peers two months after they had been introduced, when they had established networks of contacts, and saw an increase in the proportion of people treated in addiction services. In treating patients with chronic hepatitis C infection the inclusion of peer supporters may increase the number of people who initiate and complete antiviral therapy.


Assuntos
Hepatite C Crônica , Hepatite C , Antivirais/uso terapêutico , Teorema de Bayes , Hepatite C/tratamento farmacológico , Hepatite C/epidemiologia , Hepatite C Crônica/tratamento farmacológico , Humanos , Estudos Retrospectivos , Medicina Estatal
12.
J Viral Hepat ; 29(6): 474-486, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35278339

RESUMO

Achieving global elimination of hepatitis C virus requires a substantial scale-up of testing. Point-of-care HCV viral load assays are available as an alternative to laboratory-based assays to promote access in hard to reach or marginalized populations. The diagnostic performance and lower limit of detection are important attributes of these new assays for both diagnosis and test of cure. Therefore, our objective was to determine an acceptable LLoD for detectable HCV viraemia as a test for cure, 12 weeks post-treatment (SVR12). We assembled a global data set of patients with detectable viraemia at SVR12 from observational databases from 9 countries (Egypt, the United States, United Kingdom, Georgia, Ukraine, Myanmar, Cambodia, Pakistan, Mozambique) and two pharmaceutical-sponsored clinical trial registries. We examined the distribution of HCV viral load at SVR12 and presented the 90th, 95th, 97th and 99th percentiles. We used logistic regression to assess characteristics associated with low-level virological treatment failure (defined as <1000 IU/mL). There were 5973 cases of detectable viraemia at SVR12 from the combined data set. Median detectable HCV RNA at SVR12 was 287,986 IU/mL. The level of detection for the 95th percentile was 227 IU/mL (95% CI 170-276). Females and those with minimal fibrosis were more likely to experience low-level viraemia at SVR12 compared to men (adjusted odds ratio AOR = 1.60 95% confidence interval [CI] 1.30-1.97 and those with cirrhosis (AOR = 1.49 95% CI 1.15-1.93). In conclusion, an assay with a level of detection of 1000 IU/mL or greater may miss a proportion of those with low-level treatment failure.


Assuntos
Hepatite C Crônica , Hepatite C , Antivirais/uso terapêutico , Feminino , Genótipo , Hepacivirus/genética , Hepatite C/complicações , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/tratamento farmacológico , Humanos , Limite de Detecção , Masculino , RNA Viral , Resposta Viral Sustentada , Resultado do Tratamento , Carga Viral , Viremia/diagnóstico , Viremia/tratamento farmacológico
13.
N Engl J Med ; 378(4): 354-369, 2018 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-29365309

RESUMO

BACKGROUND: Glecaprevir and pibrentasvir are direct-acting antiviral agents with pangenotypic activity and a high barrier to resistance. We evaluated the efficacy and safety of 8-week and 12-week courses of treatment with 300 mg of glecaprevir plus 120 mg of pibrentasvir in patients without cirrhosis who had hepatitis C virus (HCV) genotype 1 or 3 infection. METHODS: We conducted two phase 3, randomized, open-label, multicenter trials. Patients with genotype 1 infection were randomly assigned in a 1:1 ratio to receive once-daily glecaprevir-pibrentasvir for either 8 or 12 weeks. Patients with genotype 3 infection were randomly assigned in a 2:1 ratio to receive 12 weeks of treatment with either glecaprevir-pibrentasvir or sofosbuvir-daclatasvir. Additional patients with genotype 3 infection were subsequently enrolled and nonrandomly assigned to receive 8 weeks of treatment with glecaprevir-pibrentasvir. The primary end point was the rate of sustained virologic response 12 weeks after the end of treatment. RESULTS: In total, 1208 patients were treated. The rate of sustained virologic response at 12 weeks among genotype 1-infected patients was 99.1% (95% confidence interval [CI], 98 to 100) in the 8-week group and 99.7% (95% CI, 99 to 100) in the 12-week group. Genotype 3-infected patients who were treated for 12 weeks had a rate of sustained virologic response at 12 weeks of 95% (95% CI, 93 to 98; 222 of 233 patients) with glecaprevir-pibrentasvir and 97% (95% CI, 93 to 99.9; 111 of 115) with sofosbuvir-daclatasvir; 8 weeks of treatment with glecaprevir-pibrentasvir yielded a rate of 95% (95% CI, 91 to 98; 149 of 157 patients). Adverse events led to discontinuation of treatment in no more than 1% of patients in any treatment group. CONCLUSIONS: Once-daily treatment with glecaprevir-pibrentasvir for either 8 weeks or 12 weeks achieved high rates of sustained virologic response among patients with HCV genotype 1 or 3 infection who did not have cirrhosis. (Funded by AbbVie; ENDURANCE-1 and ENDURANCE-3 ClinicalTrials.gov numbers, NCT02604017 and NCT02640157 .).


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Ácidos Aminoisobutíricos , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Carbamatos , Ciclopropanos , Esquema de Medicação , Combinação de Medicamentos , Feminino , Genótipo , Hepatite C Crônica/virologia , Humanos , Imidazóis/efeitos adversos , Imidazóis/uso terapêutico , Lactamas Macrocíclicas , Leucina/análogos & derivados , Masculino , Pessoa de Meia-Idade , Prolina/análogos & derivados , Pirrolidinas , Quinoxalinas/efeitos adversos , RNA Viral/sangue , Sofosbuvir/efeitos adversos , Sofosbuvir/uso terapêutico , Sulfonamidas/efeitos adversos , Valina/análogos & derivados , Carga Viral
14.
J Pathol ; 252(1): 41-52, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32506441

RESUMO

The severity of sterile inflammation, as seen in acute pancreatitis, is determined by damage-sensing receptors, signalling cascades and cytokine production. Stat2 is a type I interferon signalling mediator that also has interferon-independent roles in murine lipopolysaccharide-induced NF-κB-mediated sepsis. However, its role in sterile inflammation is unknown. We hypothesised that Stat2 determines the severity of non-infective inflammation in the pancreas. Wild type (WT) and Stat2-/- mice were injected i.p. with caerulein or l-arginine. Specific cytokine-blocking antibodies were used in some experiments. Pancreata and blood were harvested 1 and 24 h after the final dose of caerulein and up to 96 h post l-arginine. Whole-tissue phosphoproteomic changes were assessed using label-free mass spectrometry. Tissue-specific Stat2 effects were studied in WT/Stat2-/- bone marrow chimera and using Cre-lox recombination to delete Stat2 in pancreatic and duodenal homeobox 1 (Pdx1)-expressing cells. Stat2-/- mice were protected from caerulein- and l-arginine-induced pancreatitis. Protection was independent of type I interferon signalling. Stat2-/- mice had lower cytokine levels, including TNF-α and IL-10, and reduced NF-κB nuclear localisation in pancreatic tissue compared with WT. Inhibition of TNF-α improved (inhibition of IL-10 worsened) caerulein-induced pancreatitis in WT but not Stat2-/- mice. Phosphoproteomics showed downregulation of MAPK mediators but accumulation of Ser412-phosphorylated Tak1. Stat2 deletion in Pdx1-expressing acinar cells (Stat2flox/Pdx1-cre ) reduced pancreatic TNF-α expression, but not histological injury or serum amylase. WT/Stat2-/- bone marrow chimera mice were protected from pancreatitis irrespective of host or recipient genotype. Stat2 loss results in disrupted signalling in pancreatitis, upstream of NF-κB in non-acinar and/or bone marrow-derived cells. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Inflamação/genética , Pâncreas/metabolismo , Pancreatite/genética , Fator de Transcrição STAT2/genética , Doença Aguda , Animais , Arginina , Ceruletídeo , Citocinas/sangue , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Camundongos , Camundongos Knockout , Pâncreas/patologia , Pancreatite/induzido quimicamente , Pancreatite/metabolismo , Pancreatite/patologia , Fosforilação , Fator de Transcrição STAT2/metabolismo , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/metabolismo
15.
BMC Med Inform Decis Mak ; 21(1): 281, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34641870

RESUMO

BACKGROUND: An Informatics Consult has been proposed in which clinicians request novel evidence from large scale health data resources, tailored to the treatment of a specific patient. However, the availability of such consultations is lacking. We seek to provide an Informatics Consult for a situation where a treatment indication and contraindication coexist in the same patient, i.e., anti-coagulation use for stroke prevention in a patient with both atrial fibrillation (AF) and liver cirrhosis. METHODS: We examined four sources of evidence for the effect of warfarin on stroke risk or all-cause mortality from: (1) randomised controlled trials (RCTs), (2) meta-analysis of prior observational studies, (3) trial emulation (using population electronic health records (N = 3,854,710) and (4) genetic evidence (Mendelian randomisation). We developed prototype forms to request an Informatics Consult and return of results in electronic health record systems. RESULTS: We found 0 RCT reports and 0 trials recruiting for patients with AF and cirrhosis. We found broad concordance across the three new sources of evidence we generated. Meta-analysis of prior observational studies showed that warfarin use was associated with lower stroke risk (hazard ratio [HR] = 0.71, CI 0.39-1.29). In a target trial emulation, warfarin was associated with lower all-cause mortality (HR = 0.61, CI 0.49-0.76) and ischaemic stroke (HR = 0.27, CI 0.08-0.91). Mendelian randomisation served as a drug target validation where we found that lower levels of vitamin K1 (warfarin is a vitamin K1 antagonist) are associated with lower stroke risk. A pilot survey with an independent sample of 34 clinicians revealed that 85% of clinicians found information on prognosis useful and that 79% thought that they should have access to the Informatics Consult as a service within their healthcare systems. We identified candidate steps for automation to scale evidence generation and to accelerate the return of results. CONCLUSION: We performed a proof-of-concept Informatics Consult for evidence generation, which may inform treatment decisions in situations where there is dearth of randomised trials. Patients are surprised to know that their clinicians are currently not able to learn in clinic from data on 'patients like me'. We identify the key challenges in offering such an Informatics Consult as a service.


Assuntos
Fibrilação Atrial , Acidente Vascular Cerebral , Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Humanos , Informática , Encaminhamento e Consulta , Acidente Vascular Cerebral/tratamento farmacológico , Resultado do Tratamento , Varfarina/uso terapêutico
16.
Gastroenterology ; 157(3): 692-704.e9, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31078622

RESUMO

BACKGROUND & AIMS: Sofosbuvir is a frequently used pan-genotype inhibitor of hepatitis C virus (HCV) polymerase. This drug eliminates most chronic HCV infections, and resistance-associated substitutions in the polymerase are rare. However, HCV genotype 3 responds slightly less well to sofosbuvir-based therapies than other genotypes. We collected data from England's National Health Service Early Access Program to search for virus factors associated with sofosbuvir treatment failure. METHODS: We collected patient serum samples and used the capture-fusion assay to assess viral sensitivity to sofosbuvir in 14 HCV genotype 3 samples. We identified polymorphisms associated with reduced response and created modified forms of HCV and replicons containing the substitutions of interest and tested their sensitivity to sofosbuvir and ribavirin. We examined the effects of these polymorphisms by performing logistic regression multivariate analysis on their association with sustained virologic response in a separate cohort of 411 patients with chronic HCV genotype 3 infection who had been treated with sofosbuvir and ribavirin, with or without pegylated interferon. RESULTS: We identified a substitution in the HCV genotype 3a NS5b polymerase at amino acid 150 (alanine [A] to valine [V]), V at position 150 was observed in 42% of patients) with a reduced response to sofosbuvir in virus replication assays. In patients treated with sofosbuvir-containing regimens, the A150V variant was associated with a reduced response to treatment with sofosbuvir and ribavirin, with or without pegylated interferon. In 326 patients with V at position 150, 71% achieved an sustained virologic response compared to 88% with A at position 150. In cells, V at position 150 reduced the response to sofosbuvir 7-fold. We found that another rare substitution, glutamic acid (E) at position 206, significantly reduced the response to sofosbuvir (8.34-fold reduction); the combinations of V at position 150 and E at position 206 reduced the virus response to sofosbuvir 35.77-fold. Additionally, in a single patient, we identified 5 rare polymorphisms that reduced sensitivity to sofosbuvir our cell system. CONCLUSIONS: A common polymorphism, V at position 150 in the HCV genotype 3a NS5b polymerase, combined with other variants, reduces the virus response to sofosbuvir. Clinically, infection with HCV genotype 3 containing this variant reduces odds of sustained virologic response. In addition, we identified rare combinations of variants in HCV genotype 3 that reduce response to sofosbuvir.


Assuntos
Antivirais/uso terapêutico , Farmacorresistência Viral , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Mutação , Polimorfismo Genético , Sofosbuvir/uso terapêutico , Proteínas não Estruturais Virais/antagonistas & inibidores , Substituição de Aminoácidos , Antivirais/efeitos adversos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Farmacorresistência Viral/genética , Quimioterapia Combinada , Genótipo , Hepacivirus/enzimologia , Hepacivirus/genética , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/virologia , Humanos , Fenótipo , Sofosbuvir/efeitos adversos , Resposta Viral Sustentada , Fatores de Tempo , Resultado do Tratamento , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
17.
Lancet ; 392(10162): 2398-2412, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30473364

RESUMO

This report presents further evidence on the escalating alcohol consumption in the UK and the burden of liver disease associated with this major risk factor, as well as the effects on hospital and primary care. We reiterate the need for fiscal regulation by the UK Government if overall alcohol consumption is to be reduced sufficiently to improve health outcomes. We also draw attention to the effects of drastic cuts in public services for alcohol treatment, the repeated failures of voluntary agreements with the drinks industry, and the influence of the industry through its lobbying activities. We continue to press for reintroduction of the alcohol duty escalator, which was highly effective during the 5 years it was in place, and the introduction of minimum unit pricing in England, targeted at the heaviest drinkers. Results from the introduction of minimum unit pricing in Scotland, with results from Wales to follow, are likely to seriously expose the weakness of England's position. The increasing prevalence of obesity-related liver disease, the rising number of people diagnosed with type 2 diabetes and its complications, and increasing number of cases of end-stage liver disease and primary liver cancers from non-alcoholic fatty liver disease make apparent the need for an obesity strategy for adults. We also discuss the important effects of obesity and alcohol on disease progression, and the increased risk of the ten most common cancers (including breast and colon cancers). A new in-depth analysis of the UK National Health Service (NHS) and total societal costs shows the extraordinarily large expenditures that could be saved or redeployed elsewhere in the NHS. Excellent results have been reported for new antiviral drugs for hepatitis C virus infection, making elimination of chronic infection a real possibility ahead of the WHO 2030 target. However, the extent of unidentified cases remains a problem, and will also apply when new curative drugs for hepatitis B virus become available. We also describe efforts to improve standards of hospital care for liver disease with better understanding of current service deficiencies and a new accreditation process for hospitals providing liver services. New commissioning arrangements for primary and community care represent progress, in terms of effective screening of high-risk subjects and the early detection of liver disease.


Assuntos
Política de Saúde , Hepatopatias/epidemiologia , Hepatopatias/prevenção & controle , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/prevenção & controle , Bebidas Alcoólicas/economia , Comorbidade , Custos e Análise de Custo , Erradicação de Doenças , Progressão da Doença , Feminino , Indústria Alimentícia , Hepatite B Crônica/epidemiologia , Hepatite B Crônica/prevenção & controle , Hepatite C Crônica/epidemiologia , Hepatite C Crônica/prevenção & controle , Mortalidade Hospitalar , Humanos , Hepatopatias/mortalidade , Hepatopatias Alcoólicas/epidemiologia , Hepatopatias Alcoólicas/prevenção & controle , Manobras Políticas , Masculino , Neoplasias/epidemiologia , Obesidade/epidemiologia , Obesidade/prevenção & controle , Prevalência , Reino Unido/epidemiologia
18.
BMC Med ; 17(1): 71, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30929642

RESUMO

BACKGROUND: Peer support can enable patient engagement with healthcare services, particularly for marginalised populations. In this randomised controlled trial, the efficacy of a peer support intervention at promoting successful engagement with clinical services for chronic hepatitis C was assessed. METHODS: In London, UK, potential participants were approached through outreach services for problematic drug use and homelessness. Individuals positive for hepatitis C virus (HCV) after confirmatory testing were randomised using an online service to the intervention (peer support) or standard of care. The primary outcome of interest was successful engagement with clinical hepatitis services. The study was non-blinded. Absolute differences were calculated using a generalised linear model and the results compared to logistic regression. RESULTS: Three hundred sixty-four individuals consented to participate. One hundred one had chronic hepatitis C and were randomised, 63 to receive the intervention (peer support). A successful outcome was achieved by 23 individuals in this arm (36.5%) and seven (18.4%) receiving the standard of care, giving an absolute increase of 18.1% (95% confidence interval 1.0-35.2%, p value = 0.04). This was mirrored in the logistic regression (odds ratio 2.55 (0.97-6.70), p = 0.06). No serious adverse events were reported. CONCLUSIONS: Peer support can improve the engagement of patients with chronic HCV with healthcare services. TRIAL REGISTRATION: ISRCTN24707359 . Registered 19th October 2012.


Assuntos
Hepatite C/terapia , Aceitação pelo Paciente de Cuidados de Saúde , Defesa do Paciente , Participação do Paciente/métodos , Grupo Associado , Sistemas de Apoio Psicossocial , Adulto , Aconselhamento , Feminino , Hepatite C/epidemiologia , Hepatite C/psicologia , Pessoas Mal Alojadas/psicologia , Pessoas Mal Alojadas/estatística & dados numéricos , Humanos , Londres/epidemiologia , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Defesa do Paciente/psicologia , Defesa do Paciente/normas , Participação do Paciente/estatística & dados numéricos , Grupos de Autoajuda/organização & administração , Grupos de Autoajuda/normas , Padrão de Cuidado/estatística & dados numéricos , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/terapia
19.
J Viral Hepat ; 26(9): 1127-1138, 2019 09.
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.


Assuntos
Antivirais/administração & dosagem , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Pirrolidinas/administração & dosagem , Resposta Viral Sustentada , Tiazóis/administração & dosagem , Uridina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/uso terapêutico , Esquema de Medicação , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Interferons/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pirrolidinas/uso terapêutico , RNA Viral/sangue , Ribavirina/uso terapêutico , Tiazóis/uso terapêutico , Uridina/administração & dosagem , Uridina/uso terapêutico , Adulto Jovem
20.
J Viral Hepat ; 26(9): 1040-1049, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30972912

RESUMO

In a multicentre, genome-wide association study to identify host genetic factors associated with treatment response in adult chronic hepatitis B patients, genotype data were obtained by microarray analysis from 1669 patients who received peginterferon alfa-2a for ≥ 24 weeks with/without a nucleos(t)ide analog. Treatment response was assessed at least 24 weeks post-treatment, using serological and/or virological endpoints. Thirty-six single-marker analyses and a gene-by-gene analysis were conducted. No single nucleotide polymorphisms (SNPs) achieved genome-wide significance (P < 5 × 10-8 ) in single-marker analyses, but suggestive associations (P < 1 × 10-5 ) were identified for 116 SNPs. In gene-by-gene analyses, one gene, FCER1A (rs7549785), reached genome-wide significance (P = 2.65 × 10-8 ) in East Asian patients for hepatitis B surface antigen (HBsAg) clearance, with a moderate effect size (odds ratio = 4.74). Eleven of 44 carriers (25%) of the A allele at rs7549785 achieved HBsAg clearance compared with 69/1051 (7%) noncarriers. FCER1A encodes the alpha subunit of the immunoglobulin E receptor. In a post hoc analysis of a homogenous patient subset, the strongest intragenic association was for rs7712322 (POLR3G, P = 7.21 × 10-7 ). POLR3G encodes the G subunit of the polymerase (RNA) III enzyme, involved in sensing and limiting infection by intracellular bacteria and DNA viruses, and as a DNA sensor in innate immune responses. FCER1A (rs7549785) and possibly POLR3G (rs7712322) are shown to be associated with peginterferon alfa-2a response in adult patients with chronic hepatitis B. Independent confirmation of these findings is warranted (clinicaltrials.gov number NCT01855997).


Assuntos
Antivirais/uso terapêutico , Antígenos de Superfície da Hepatite B/imunologia , Hepatite B Crônica/etnologia , Hepatite B Crônica/genética , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Receptores de IgE/genética , Adulto , Alelos , Povo Asiático , Quimioterapia Combinada , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Hepatite B Crônica/tratamento farmacológico , Humanos , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RNA Polimerase III/genética , Receptores de IgE/imunologia , Proteínas Recombinantes/uso terapêutico
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