RESUMO
AIMS: As previous reports show an association of chronic hepatitis C (HCV) with hepatocellular carcinoma (HCC) and non-liver cancers, we examine the association of HCV with liver cancer and non-liver cancers. METHODS: Retrospective cross-sectional study at Kaiser Permanente Southern California (KPSC) evaluating HCV and non-HCV patients from 1 January 2008 to 12 December 2012. Cancer diagnoses were obtained from the KPSC-SEER-affiliated registry. Logistic regression analyses were used for rate ratios and time-to-event analyses were performed using Cox proportional hazards models, adjusted for age, gender, race, smoking and cirrhosis. Cancer rate ratios were stratified by tobacco, alcohol abuse, diabetes and body mass index (BMI). RESULTS: The initial population and final population of multivariable analysis were N = 5 332 903 and N = 2 080 335 respectively. Cancer burden (all sites) was significantly higher in HCV than in non-HCV patients and HCV patients had a high rate of liver cancer. When liver cancer was excluded, cancer rates remained significantly increased in HCV. Unadjusted cancer rates were significantly higher in HCV compared to non-HCV for oesophageal, stomach, colorectal, pancreas, myeloma, non-Hodgkin's lymphoma, head/neck, lung, renal and prostate cancer. After stratification for alcohol abuse, tobacco, diabetes and BMI, increased cancer rates remained significant for all cancer sites, liver cancer and non-Hodgkin's lymphoma. Multivariable analyses demonstrated a strong correlation between cirrhosis and cancer. Tobacco use and diabetes were also associated with cancer. In the absence of cirrhosis, HCV, tobacco use and diabetes significantly increased the cancer risk. Mediation analyses showed that cirrhosis was responsible for a large proportion on the effect of HCV on cancer risk. CONCLUSION: This study supports the concept of HCV as a systemic illness and treating HCV regardless of disease severity and prior to progression to cirrhosis.
Assuntos
Carcinoma Hepatocelular , Hepatite C Crônica , Hepatite C , Neoplasias Hepáticas , Estudos Transversais , Hepatite C Crônica/complicações , Hepatite C Crônica/epidemiologia , Humanos , Cirrose Hepática/epidemiologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Masculino , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: A care pathway for nonalcoholic fatty liver disease (NAFLD) in Kaiser Permanente San Diego, California was instituted in August 2017 to improve efficiency of disease staging and promote lifestyle modification. METHODS: The NAFLD Care Pathway includes: (1) patient education (2) vibration controlled transient elastography (VCTE) examination (3) hepatology consultation for VCTE ≥ 8 kPa and (4) referral to weight management (WM). Patients referred to the pathway during the first 6 months of its implementation were studied for adherence to its components and impact on weight change and ALT values in the 12 months following referral. Retrospective assessment of WM participation, change in weight, and change in ALT were evaluated in the 12-months following referral and compared to changes 12-months prior. Student's t-test or Wilcoxon signed rank test were used as appropriate (p < 0.05). RESULTS: 632 patients were included. 575 (91.0%) completed VCTE examination with mean liver stiffness 8.5 kPa (SD 9.2). 52 patients had mean liver stiffness ≥ 15 kPa. 180/632 (28.5%) attended NAFLD education. 153/632 (24.2%) were offered hepatology clinic and 136/153 (88.9%) completed at least 1 appointment. Participation in WM was 24/632 (3.8%) prior to referral and 67/632 (10.6%) after referral and increased among patients who attended NAFLD education. Mean weight change following referral was - 0.69 kg (SD 6.58 kg) among patients without WM and - 7.78 kg (SD 13.43 kg) with WM. Overall, 44.2% of participants experienced weight gain after referral, 40.8% had weight loss < 5% and 15% had weight loss ≥ 5%. Variables associated with weight loss included WM (p < 0.0001) and higher liver stiffness (p = 0.0066). Mean ALT change was - 15.2 (SD 38.5) U/L without WM and - 28.8 (SD 29.6) U/L with WM. CONCLUSIONS: A care pathway for NAFLD within a large, integrated healthcare system provides non-invasive disease staging and minimizes hepatology clinic utilization to those with more advanced disease. Referral was associated with increased enrollment in WM, weight loss, and decreased ALT. Given its impact on healthcare resources, strategies to improve NAFLD identification, staging, and promotion of lifestyle modification are imperative.
Assuntos
Técnicas de Imagem por Elasticidade , Hepatopatia Gordurosa não Alcoólica , Atenção à Saúde , Humanos , Hepatopatia Gordurosa não Alcoólica/terapia , Estudos Retrospectivos , Redução de PesoRESUMO
BACKGROUND: Myelosuppression due to pegylated interferon (peg-IFN) is common during treatment for hepatitis C virus. The relationship between infection risk and decreases in leukocyte lines, however, is not well established. The objective of this analysis was to determine the incidence of and risk factors for infections during peg-IFN/ribavirin (RBV) therapy. METHODS: A total of 3070 treatment-naive, chronic hepatitis C genotype 1-infected patients were treated for up to 48 weeks with peg-IFN alfa-2b 1.5 µg/kg/week or 1 µg/kg/week, or peg-IFN alfa-2a 180 µg/week plus RBV. On-treatment leukocyte counts were obtained every 2-6 weeks. Dose reduction was required for a neutrophil count <0.75 × 10(9) cells/L, and treatment discontinuation was required for a neutrophil count <0.5 × 10(9) cells/L. Granulocyte colony-stimulating factor was prohibited. Data on infections were captured at each study visit and categorized according to MedDRA version 13.0. RESULTS: A total of 581 (19%) patients experienced moderate, severe, or life-threatening infections as assessed by the investigator; 648 (21%) patients had at least 1 neutrophil count <0.75 × 10(9) cells/L, but only 242 (8%) sustained an infection and had a neutrophil count <0.75 × 10(9) cells/L at any time while on treatment. Twelve patients had severe or life-threatening infection and grade 3/4 neutropenia, but only 4 had temporally related infections. In a multivariate logistic regression model, nadir lymphocyte count, history of depression, and female sex, but not nadir neutrophil count, were associated with moderate, severe, or life-threatening infection. CONCLUSIONS: Nadir lymphocyte count, not nadir neutrophil count, was independently associated with moderate, severe, or life-threatening infections in the IDEAL study. Clinicians should be aware of their patients' absolute lymphocyte counts during peg-IFN/RBV therapy; peg-IFN dose reductions may be a consideration in patients with significant lymphocytopenia (<0.5 × 10(9) cells/L).
Assuntos
Hepatite C/tratamento farmacológico , Infecções/epidemiologia , Interferon-alfa/efeitos adversos , Polietilenoglicóis/efeitos adversos , Ribavirina/efeitos adversos , Adolescente , Adulto , Idoso , Feminino , Hepatite C/complicações , Humanos , Incidência , Infecções/complicações , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Contagem de Linfócitos , Linfopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neutrófilos/efeitos dos fármacos , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico , Medição de Risco , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND & AIMS: We assessed the safety and efficacy of boceprevir (BOC) plus peginterferon-ribavirin (PR) in patients with HCV-G1 infection and advanced fibrosis/cirrhosis (Metavir F3/F4). METHODS: In two randomized controlled studies of previously untreated and previous treatment failures, patients received a 4-week lead-in of PR followed by PR plus placebo for 44 weeks (PR48); PR plus BOC using response guided therapy (BOC/RGT); or PR plus BOC for 44 weeks (BOC/PR48). RESULTS: The trials enrolled 178 patients with F3/4. HCV RNA levels at week 4 and 8 were highly predictive of response. No patient with F3/4 in the PR48 arm with a <1 log(10) decline in HCV RNA at week 4 achieved SVR, whereas those randomized to BOC/RGT or BOC/PR48 had SVR rates of 11-33% (F3) and 10-14% (F4). In these latter groups, patients with high baseline viral load (>2 × 10(6)IU/ml) had an overall SVR rate of 6% (2/33). For patients with a ≥1 log(10) decline at week 4, SVR rates in the BOC/PR48 arm of SPRINT-2 and RESPOND-2, respectively, were 77% and 87% vs. 18% and 50% for PR48; SVR rates in early responders (undetectable HCV RNA at week 8) were 90-93% in the BOC/PR48 arm. Neutropenia and thrombocytopenia were more common in cirrhotics than non-cirrhotics. CONCLUSIONS: BOC improves SVR rates in patients with F3/4, and longer treatment duration provides the most benefit. With triple therapy, SVR rates are modest in F4 patients with a <1 log(10) decline at week 4, thus the 4-week PR lead-in aids in the assessment of early futility.
Assuntos
Antivirais/administração & dosagem , Hepacivirus/classificação , Hepatite C/tratamento farmacológico , Interferon-alfa/administração & dosagem , Cirrose Hepática/virologia , Polietilenoglicóis/administração & dosagem , Prolina/análogos & derivados , Ribavirina/administração & dosagem , Adulto , Método Duplo-Cego , Farmacorresistência Viral , Quimioterapia Combinada , Feminino , Hepatite C/virologia , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Prolina/administração & dosagem , Prolina/efeitos adversos , RNA Viral/sangue , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Ribavirina/efeitos adversosRESUMO
OBJECTIVES: Direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) lead to cure in more than 95% of recipients; however, payers may limit access to these lifesaving drugs due to high initial cost. Here, the cost-effectiveness of treating HCV with DAAs vs no treatment over a lifetime horizon is evaluated from the perspective of Kaiser Permanente Southern California (KPSC). STUDY DESIGN: A hybrid decision-tree Markov model. METHODS: The model simulated the health and economic outcomes for a real cohort of patients with HCV treated with either ledipasvir-sofosbuvir or sofosbuvir-velpatasvir between November 1, 2014, and October 31, 2019, at KPSC. Patients entered the model at different stages of liver disease and received either active treatment with DAAs or no treatment. Patients who did not achieve sustained virological response experienced disease progression; those who achieved sustained virological response experienced either significantly slower or no disease progression depending on the stage of fibrosis at model start. Demographics, treatment experience, genotype, baseline fibrosis stage, treatment rates, and treatment efficacy were sourced from KPSC real-world data. Costs and utilities were sourced from published literature. RESULTS: A total of 7255 patients with a mean age of 59 years were treated during the study period. Over a lifetime horizon, DAAs resulted in significant reduction in advanced liver disease events and a total cost savings of $1 billion compared with no treatment based on a hybrid decision-tree Markov state-transition model. Cost savings were achieved after only 3 years. DAA intervention dominated no treatment on a per-patient and cohort basis. CONCLUSIONS: DAA treatment at KPSC is predicted to significantly reduce HCV-related morbidity and mortality, providing an anticipated return on investment in drug costs after 3 years of treatment.
Assuntos
Hepatite C Crônica , Sofosbuvir , Humanos , Pessoa de Meia-Idade , Sofosbuvir/uso terapêutico , Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Hepacivirus , Quimioterapia Combinada , California , Fibrose , GenótipoRESUMO
BACKGROUND: Treatment guidelines recommend the use of peginterferon alfa-2b or peginterferon alfa-2a in combination with ribavirin for chronic hepatitis C virus (HCV) infection. However, these regimens have not been adequately compared. METHODS: At 118 sites, patients who had HCV genotype 1 infection and who had not previously been treated were randomly assigned to undergo 48 weeks of treatment with one of three regimens: peginterferon alfa-2b at a standard dose of 1.5 microg per kilogram of body weight per week or a low dose of 1.0 microg per kilogram per week, plus ribavirin at a dose of 800 to 1400 mg per day, or peginterferon alfa-2a at a dose of 180 microg per week plus ribavirin at a dose of 1000 to 1200 mg per day. We compared the rate of sustained virologic response and the safety and adverse-event profiles between the peginterferon alfa-2b regimens and between the standard-dose peginterferon alfa-2b regimen and the peginterferon alfa-2a regimen. RESULTS: Among 3070 patients, rates of sustained virologic response were similar among the regimens: 39.8% with standard-dose peginterferon alfa-2b, 38.0% with low-dose peginterferon alfa-2b, and 40.9% with peginterferon alfa-2a (P=0.20 for standard-dose vs. low-dose peginterferon alfa-2b; P=0.57 for standard-dose peginterferon alfa-2b vs. peginterferon alfa-2a). Estimated differences in response rates were 1.8% (95% confidence interval [CI], -2.3 to 6.0) between standard-dose and low-dose peginterferon alfa-2b and -1.1% (95% CI, -5.3 to 3.0) between standard-dose peginterferon alfa-2b and peginterferon alfa-2a. Relapse rates were 23.5% (95% CI, 19.9 to 27.2) for standard-dose peginterferon alfa-2b, 20.0% (95% CI, 16.4 to 23.6) for low-dose peginterferon alfa-2b, and 31.5% (95% CI, 27.9 to 35.2) for peginterferon alfa-2a. The safety profile was similar among the three groups; serious adverse events were observed in 8.6 to 11.7% of patients. Among the patients with undetectable HCV RNA levels at treatment weeks 4 and 12, a sustained virologic response was achieved in 86.2% and 78.7%, respectively. CONCLUSIONS: In patients infected with HCV genotype 1, the rates of sustained virologic response and tolerability did not differ significantly between the two available peginterferon-ribavirin regimens or between the two doses of peginterferon alfa-2b. (ClinicalTrials.gov number, NCT00081770.)
Assuntos
Antivirais/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Ribavirina/administração & dosagem , Antivirais/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Proteínas Recombinantes , Ribavirina/efeitos adversosRESUMO
BACKGROUND & AIMS: We recently identified a polymorphism upstream of interleukin (IL)-28B to be associated with a 2-fold difference in sustained virologic response (SVR) rates to pegylated interferon-alfa and ribavirin therapy in a large cohort of treatment-naive, adherent patients with chronic hepatitis C virus genotype 1 (HCV-1) infection. We sought to confirm the polymorphism's clinical relevance by intention-to-treat analysis evaluating on-treatment virologic response and SVR. METHODS: HCV-1 patients were genotyped as CC, CT, or TT at the polymorphic site, rs12979860. Viral kinetics and rates of rapid virologic response (RVR, week 4), complete early virologic response (week 12), and SVR were compared by IL-28B type in 3 self-reported ethnic groups: Caucasians (n = 1171), African Americans (n = 300), and Hispanics (n = 116). RESULTS: In Caucasians, the CC IL-28B type was associated with improved early viral kinetics and greater likelihood of RVR (28% vs 5% and 5%; P < .0001), complete early virologic response (87% vs 38% and 28%; P < .0001), and SVR (69% vs 33% and 27%; P < .0001) compared with CT and TT. A similar association occurred within African Americans and Hispanics. In a multivariable regression model, CC IL-28B type was the strongest pretreatment predictor of SVR (odds ratio, 5.2; 95% confidence interval, 4.1-6.7). RVR was a strong predictor of SVR regardless of IL-28B type. In non-RVR patients, the CC IL-28B type was associated with a higher rate of SVR (Caucasians, 66% vs 31% and 24%; P < .0001). CONCLUSIONS: In treatment-naive HCV-1 patients treated with pegylated interferon and ribavirin, a polymorphism upstream of IL-28B is associated with increased on-treatment and sustained virologic response and effectively predicts treatment outcome.
Assuntos
Hepacivirus/classificação , Hepatite C/genética , Interleucinas/genética , Polimorfismo de Nucleotídeo Único , Adulto , Feminino , Genótipo , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Interferons , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Carga ViralRESUMO
Nonalcoholic fatty liver disease (NAFLD) is a global public health problem. However, the natural history of NAFLD is incomplete. This is a retrospective cohort study of patients identified with NAFLD by diagnosis codes in a large, community-based health care delivery system. The objectives were (1) to follow patients from initial NAFLD presentation through progression to cirrhosis and/or decompensated cirrhosis to liver cancer, liver transplant, and death for up to 10 years; and (2) to conduct disease progression analysis restricted to patients with NAFLD identified as having diabetes at baseline. A total of 98,164 patients with full NAFLD and 26,488 with diabetes were divided into three baseline prevalent states: (1) no cirrhosis, (2) compensated cirrhosis, and (3) decompensated cirrhosis. In baseline patients without cirrhosis, annual rates of compensated cirrhosis, decompensated cirrhosis, and death were 0.28%, 0.31%, and 0.63% per year, respectively. With baseline compensated cirrhosis, the annual rates of decompensation and death were 2.4% and 6.7% per year. Finally, in those with decompensated cirrhosis at baseline, the death rate was 8.0% per year. In those without cirrhosis and with cirrhosis at baseline, the rates of liver cancer and death were increased approximately 2-fold in the diabetic subpopulation compared with the full NAFLD cohort. Age and comorbidities increased with increasing disease severity. Cox proportional hazards regression analysis showed that cirrhosis was strongly associated with death and liver cancer, and that diabetes was associated with a significant increase in the hazard of both liver cancer and death (2.56 [2.04-3.20] and 1.43 [1.35-1.52]), respectively. Conclusion: The findings of this community-based study further our understanding of the natural history of NAFLD and demonstrate that diabetes is a major factor in the progression of this disease.
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Diabetes Mellitus/epidemiologia , Cirrose Hepática/epidemiologia , Neoplasias Hepáticas/epidemiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Adulto , Idoso , Comorbidade , Diabetes Mellitus/mortalidade , Progressão da Doença , Feminino , Humanos , Cirrose Hepática/mortalidade , Neoplasias Hepáticas/mortalidade , Transplante de Fígado/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/mortalidade , Análise de Regressão , Estudos Retrospectivos , Índice de Gravidade de Doença , Estados Unidos/epidemiologiaRESUMO
UNLABELLED: Treatment response remains suboptimal for many patients with chronic hepatitis C, particularly those with genotype 1 and high levels of viremia. The efficacy of high-dose regimens of peginterferon alfa-2a and ribavirin was compared with conventional dose regimens in patients with features predicting poor treatment responses. Eligible treatment-naïve adults with genotype 1 infection, hepatitis C virus (HCV) RNA >800,000 IU/mL and body weight >85 kg were randomized to double-blind treatment with peginterferon alfa-2a at 180 or 270 microg/week plus ribavirin at 1200 or 1600 mg/day for 48 weeks (four regimens were evaluated). The primary endpoint was viral kinetics during the first 24 weeks of therapy. Among patients receiving peginterferon alfa-2a (270 microg/week) the magnitude of HCV RNA reduction was significantly greater than for patients randomized to the conventional dose of peginterferon alfa-2a (180 microg/week) for the pairwise comparison for ribavirin at 1600 mg/day (P = 0.036) and numerically greater for the pairwise comparison for ribavirin at 1200 mg/day (P = 0.060). Patients randomized to the highest doses of peginterferon alfa-2a (270 microg/week) and ribavirin (1600 mg/day) experienced the numerically highest rates of sustained virologic response (HCV RNA < 50 IU/mL) and the lowest relapse rate (47% and 19%, respectively). The arm with the higher doses of both drugs was less well-tolerated than the other regimens. CONCLUSION: Higher fixed doses of peginterferon alfa-2a (270 microg/week) and ribavirin (1600 mg/day) may increase sustained virologic response rates compared with lower doses of both drugs in patients with a cluster of difficult-to-treat characteristics.
Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Antivirais/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Hepacivirus/genética , Hepatite C/sangue , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Pessoa de Meia-Idade , Projetos Piloto , Polietilenoglicóis/efeitos adversos , RNA Viral/sangue , Proteínas Recombinantes , Ribavirina/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Radiographic study following inversion ankle sprain commonly is used to determine the presence of anatomic laxity across the talocrural joint. PURPOSE: To compare the degree of talar tilt derived from a radiographic ankle stress exam under 2 conditions: self-stress vs manual stress applied by the clinician. METHODS: Twenty-four subjects seeking medical care following ankle sprain underwent talar tilt stress exams of both ankles. The involved ankle was imaged with self-stress by use of a strap and with the clinician providing manual stress during the imaging exam. Mean talar tilt for the self-stress method was 2.2 degrees, compared with 5.9 degrees for the manual stress method (P < .001). RESULTS: Significantly greater and clinically meaningful differences in talar tilt angle were found when manual stress was provided by the clinician. To avoid false negative findings of anatomic laxity in stress talar tilt studies at the ankle, a standardized procedure in which the clinician provides manual stress may be necessary.
Assuntos
Traumatismos do Tornozelo/diagnóstico por imagem , Entorses e Distensões/diagnóstico por imagem , Estresse Mecânico , Tálus/diagnóstico por imagem , Tálus/lesões , Adolescente , Adulto , Análise de Variância , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RadiografiaRESUMO
OBJECTIVE: Hepatitis C virus (HCV) infection has been associated with the production of autoantibodies and the development of several autoimmune disorders. Immune thrombocytopenic purpura (ITP) is an immune-mediated syndrome of unknown etiology characterized by the presence of autoantibodies against platelet membrane proteins. METHODS: Retrospective chart review. RESULTS: Seven patients with chronic HCV infection (five with cirrhosis and two with chronic active hepatitis) developed thrombocytopenia, out of proportion to their liver disease, and were diagnosed with ITP based on the presence of anti-platelet antibodies and their response to treatment. The number of patients with ITP which occurred in a population of 3440 HCV patients seen over this time interval is much greater than would be expected by chance (p < 0.00001). Six patients required treatment and four required hospitalization. Four of the six responded to corticosteroids alone. Both of the patients who failed to respond to corticosteroids responded to cyclophosphamide. No mortality occurred from complications of thrombocytopenia. CONCLUSIONS: ITP occurs more commonly in patients with chronic HCV infection than would be expected by chance. This should be considered in patients with liver disease and unexplained thrombocytopenia, as well as in patients with newly diagnosed ITP. Evaluation of antiplatelet antibodies, using an antigen-specific assay, was useful in supporting this diagnosis. Therapy with either corticosteroids or cyclophosphamide was successful in the six patients who required treatment.