Real-world effectiveness of elbasvir/grazoprevir In HCV-infected patients in the US veterans affairs healthcare system.

Elbasvir/grazoprevir (EBR/GZR) is an all-oral direct-acting antiviral agent (DAA) with high sustained virologic response (SVR) in clinical trials. This study's primary objective was to evaluate effectiveness of EBR/GZR among HCV-infected patients in a real-world clinical setting. We conducted a nationwide retrospective observational cohort study of HCV-infected patients in the US Department of Veterans Affairs (VA) using the VA Corporate Data Warehouse. The study population included patients with positive HCV RNA who initiated EBR/GZR from February 1 to August 1, 2016. We calculated the 95% confidence interval for binomial proportions for SVR overall and by demographic subgroups. Clinical and demographic characteristics were also evaluated. We included 2436 patients in the study cohort. Most were male (96.5%), African American (57.5%), with mean age of 63.5 (SD = 5.9) and 95.4% infected with genotype (GT) 1 [GT1a (34.7%), GT1b (58.6%)]. Other comorbidities included diabetes (53.2%), depression (57.2%) and HIV (3.0%). More than 50% had history of drug or alcohol abuse (53.9% and 60.5%, respectively). 33.2% of the cohort had cirrhosis. A total of 95.6% (2,328/2,436; 95% CI: 94.7%-96.4%) achieved SVR. The SVR rates by subgroups were: male, 95.5% (2245/2350); female, 96.5% (83/86); GT1a, 93.4%, GT1b, 96.6%, GT4, 96.9%, African American, 95.9% (1,342/1,400); treatment-experienced, 96.3% (310/322); cirrhosis, 95.6% (732/766); stage 4-5 CKD, 96.3% (392/407); and HIV, 98.6% (73/74). SVR rates were high overall and across patient subgroups regardless of gender, race/ethnicity, cirrhosis, renal impairment or HIV. This study provided important data regarding the effectiveness of EBR/GZR in a large clinical setting.

Hepatitis C virus re-treatment in the era of direct-acting antivirals: projections in the USA.

BACKGROUND: The introduction of oral direct-acting antivirals (DAAs) has dramatically changed the landscape of HCV treatment. However, a small percentage of patients fail to achieve sustained virologic response (SVR). Understanding the number of people who fail on DAAs and require re-treatment is important for budget impact and disease burden projections. AIM: To quantify the number of HCV patients who fail to achieve SVR on oral DAAs (NS5A vs. non-NS5A) and require re-treatment. METHODS: We used a mathematical model to simulate clinical management of HCV in the USA, which included the implementation of HCV screening, treatment, and disease progression. We simulated different waves of DAA treatment and used real-world data to extract SVR rates and market shares of available therapies. RESULTS: Our model projected that the number of people living without viraemia (i.e. cured) would increase from 0.70 million in 2014 to 1.78 million by 2020. Between 2014 and 2020, 1.50 million people would receive treatment with DAAs, of whom 124 000 (8.3%) are projected to fail to achieve SVR. Among those treatment failures, 66 600 (53.7%) patients would fail treatment with NS5A inhibitors and 69 600 (56.1%) would have cirrhosis. During the same period, 34 200 people would progress to decompensated cirrhosis and 27 300 would develop hepatocellular carcinoma after failing to achieve SVR. CONCLUSIONS: Even in the era of highly effective DAAs, a significant number of patients will fail to achieve SVR and will require re-treatment options. Timely and effective re-treatment is essential to prevent the long-term sequelae of HCV.

Barriers to hepatitis C treatment in the era of direct-acting anti-viral agents.

BACKGROUND: Direct-acting anti-virals (DAA) are safe, effective treatment of hepatitis C virus (HCV). Suboptimal linkage to specialists and access to DAAs are the leading barriers to treatment; however, data are limited. AIM: To determine predictors of follow-up, receipt of DAAs, and reasons for the lack thereof. METHODS: We used clinical data from retrospective cohort of HCV-infected patients with previously established HCV care in the US Department of Veterans Affairs to examine predictors of follow-up in HCV clinics and DAA treatment (during 12/1/2013-4/30/2015). We then conducted a structured review of medical charts of HCV patients to determine reasons for lack of follow-up and treatment. RESULTS: We identified 84 221 veterans who were previously seen in HCV clinics during the pre-DAA era. Of these, 47 165 (56.0%) followed-up in HCV specialty clinics, 13 532 (28.7%) of whom received DAAs. Older age, prior treatment, presence of cirrhosis or HCC, HIV/HBV co-infection and psychiatric illness were predictors of follow-up. Alcohol/drug abuse and medical co-morbidity were predictors of lack of treatment. Of the 905 prospectively recruited patients, 56.2% patients had a specialist visit and 28% received DAAs. Common reasons for lack of follow-up were relocation (n = 148, 37.4%) and missed/cancelled appointments (n = 63, 15.9%). Reasons for lack of treatment included waiting for newer therapy (n = 99, 38.8%), co-morbidities (n = 66, 25.9%) and alcohol/drug abuse (n = 63, 24.7%). CONCLUSIONS: Half of patients with established HCV care were followed-up in the DAA era and only 29% received DAAs. Targeted efforts focusing on patient and system-levels may improve the reach of treatment with the new DAAs.

Hepatitis C virus-related complications are increasing in women veterans: A national cohort study.

There are gender-specific variations in the epidemiology and clinical course of hepatitis C virus (HCV) infection. However, few long-term longitudinal studies have examined trends in the incidence and prevalence of serious liver complications among women compared with men with HCV infection. We used the Veterans Administration Corporate Data Warehouse to identify all veterans with positive HCV viraemia from January 2000 to December 2013. We calculated gender-specific annual incidence and prevalence rates of cirrhosis, decompensated cirrhosis and hepatocellular cancer (HCC) adjusting for age, diabetes, HIV and alcohol use. We also calculated the average annual per cent change (AAPC) for each outcome by gender using piecewise linear regression in the Joinpoint software. We identified 264 409 HCV-infected veterans during 2000-2013, of whom 7162 (2.7%) were women. There were statistically significant increases over time in the incidence rates of cirrhosis, decompensated cirrhosis and HCC for both men and women. The annual-adjusted incidence rates of cirrhosis, decompensated cirrhosis and HCC were higher in men than women for all study years. However, these complications increased at a similar rate in both groups. Specifically, the AAPC for cirrhosis was 13.1 and 15.2, while it was 15.6 and 16.9 for decompensated cirrhosis and 21.0 and 25.3 for HCC in men and women, respectively (all test of parallelism not significant). The results were similar in the prevalence analyses, although AAPCs were slightly smaller for each outcome. In conclusion, we found an ongoing upward trend in the incidence and prevalence of HCV complications in this cohort of HCV-infected women. This increase in cirrhosis complications in women with active HCV infection is similar to those in men. With cure from HCV now becoming a reality, most of the projected burden of HCV is potentially preventable. However, benefits of HCV treatment will need to extend to all patients in order to stem the rising tide of HCV complications.

Palliative Care Quality Indicators for Patients with End-Stage Liver Disease Due to Cirrhosis.

BACKGROUND AND AIMS: There are guidelines for the medical management of cirrhosis and associated quality indicators (QIs), but QIs focusing on standards for palliative aspects of care are needed. METHODS: We convened a 9-member, multidisciplinary expert panel and used RAND/UCLA modified Delphi methods to develop palliative care quality indicators for patients with cirrhosis. Experts were provided with a report based on a systematic review of the literature that contained evidence concerning the proposed candidate QIs. Panelists rated QIs prior to a planned meeting using a standard 9-point RAND appropriateness scale. These ratings guided discussion during a day-long phone conference meeting, and final ratings were then provided by panel members. Final QI scores were computed and QIs with a final median score of greater than or equal to 7, and no disagreement was included in the final set. RESULTS: Among 28 candidate QIs, the panel rated 19 as valid measures of quality care. These 19 quality indicators cover care related to information and care planning (13) and supportive care (6). CONCLUSIONS: These QIs are evidence-based process measures of care that may be useful to improve the quality of palliative care. Research is needed to better understand the quality of palliative care provided to patients with cirrhosis.

Epidemiology and outcomes of hepatitis C infection in elderly US Veterans.

The chronic hepatitis C (CHC) cohort in the United States is getting older. Elderly patients with CHC may be at a high risk of cirrhosis and hepatocellular carcinoma (HCC), but also other nonhepatic comorbidities that negatively impact their likelihood of receiving or responding to antiviral treatment. There is little information on the clinical epidemiology or outcomes of CHC and its treatment in the elderly. We conducted a retrospective cohort study of 1 61 744 patients with a positive Hepatitis C virus RNA in the Veterans Health Administration Hepatitis C Clinical Case Registry to examine the association between age subgroups (20-49, 50-64, 65-85 years) and risk of cirrhosis, HCC or death using Cox proportional hazards models. We also examined the effect of treatment with a sustained viral response (SVR) on these outcomes in each age subgroup. The age distribution was 36.8% 20- to 49-year-olds, 57.6% 50- to 64-year-olds and 5.6% 65- to 85-year-olds (i.e. elderly). Risk of cirrhosis, HCC and death was significantly elevated in elderly patients [HR cirrhosis = 1.14 (1.00-1.29), HR HCC = 2.44 (1.99-2.99); HR death 2.09 (1.98-2.22)] compared with younger patients. The incidence of HCC was than 8.4 per 1000 PY in the elderly compared with 2.6 per 1000 PY and 5.7 per 1000 PY, among the 20-49 and 50-64 age groups, respectively. Elderly patients were significantly less likely to receive antiviral treatment (3.8% vs 14.8% and 19.1%, P < 0.0001), but among those who received treatment SVR was not different among the age groups (33.5% vs 33.2% and 32.1%). In an analysis limited to those who received treatment, SVR compared to treatment receipt with no SVR was associated with a reduction in risk of developing cirrhosis (HR = 0.34; 0.18-0.66) and HCC (HR = 0.60; 0.22-1.61) and all-cause mortality risk (HR = 0.52, 0.33-0.82). Elderly patients with CHC are more likely to develop HCC than younger patients but have traditionally received less antiviral treatment than younger patients. However, receipt of curative treatment is associated with a benefit in reducing cirrhosis, HCC and overall mortality, irrespective of age.

Cirrhosis is under-recognised in patients subsequently diagnosed with hepatocellular cancer.

BACKGROUND: Most clinical practice guidelines recommend screening for HCC in patients with cirrhosis. However, patients with compensated cirrhosis are often asymptomatic and may remain unrecognised for years. AIMS: To determine the extent to which cirrhosis is unrecognised in a US Veteran population with HCC, and to evaluate the association between lack of cirrhosis recognition and stage of HCC at diagnosis. METHODS: We reviewed the electronic medical records of a random sample of HCC cases diagnosed in the national Veterans Affairs system between 2005 and 2011. We conducted multivariable analyses adjusting for patients' demographics, comorbidity, aetiology of underlying disease and healthcare utilisation including HCC surveillance. RESULTS: Of 1201 patients with HCC and cirrhosis, 24.6% had unrecognised cirrhosis prior to HCC diagnosis. Older patients [>65 years, odds ratio (OR) 2.32], African Americans (OR 1.93), patients with alcoholic or NAFLD liver disease (OR 1.69 and 4.77 respectively), HIV (OR 3.02), and fewer comorbidities (Deyo 0 vs. 3, OR 2.42) had significantly higher odds of having unrecognised cirrhosis than comparison groups. Furthermore, patients with unrecognised cirrhosis were 6.5 times more likely to have advanced stage HCC at diagnosis. The effect of cirrhosis recognition on HCC stage remained significant after adjusting for pre-specified covariates (OR 3.37). CONCLUSIONS: In one quarter of patients, cirrhosis was unrecognised prior to HCC diagnosis, and this group was significantly more likely to have advanced stage HCC. These findings emphasise the importance of timely evaluation for cirrhosis in at-risk populations as a critical step to improving outcomes for patients with HCC.

Nonalcoholic fatty liver disease (NAFLD) in the Veterans Administration population: development and validation of an algorithm for NAFLD using automated data.

BACKGROUND: In practice, nonalcoholic fatty liver disease (NAFLD) is diagnosed based on elevated liver enzymes and confirmatory liver biopsy or abdominal imaging. Neither method is feasible in identifying individuals with NAFLD in a large-scale healthcare system. AIM: To develop and validate an algorithm to identify patients with NAFLD using automated data. METHODS: Using the Veterans Administration Corporate Data Warehouse, we identified patients who had persistent ALT elevation (≥2 values ≥40 IU/mL ≥6 months apart) and did not have evidence of hepatitis B, hepatitis C or excessive alcohol use. We conducted a structured chart review of 450 patients classified as NAFLD and 150 patients who were classified as non-NAFLD by the database algorithm, and subsequently refined the database algorithm. RESULTS: The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) for the initial database definition of NAFLD were 78.4% (95% CI: 70.0-86.8%), 74.5% (95% CI: 68.1-80.9%), 64.1% (95% CI: 56.4-71.7%) and 85.6% (95% CI: 79.4-91.8%), respectively. Reclassifying patients as having NAFLD if they had two elevated ALTs that were at least 6 months apart but within 2 years of each other, increased the specificity and PPV of the algorithm to 92.4% (95% CI: 88.8-96.0%) and 80.8% (95% CI: 72.5-89.0%), respectively. However, the sensitivity and NPV decreased to 55.0% (95% CI: 46.1-63.9%) and 78.0% (95% CI: 72.1-83.8%), respectively. CONCLUSIONS: Predictive algorithms using automated data can be used to identify patients with NAFLD, determine prevalence of NAFLD at the system-wide level, and may help select a target population for future clinical studies in veterans with NAFLD.

The impact of hepatitis C burden: an evidence-based approach.

BACKGROUND: Infection with the hepatitis C virus (HCV) has been considered a major cause of mortality, morbidity and resource utilisation in the US. In addition, HCV is the main cause of hepatocellular cancer (HCC) in the US. Recent developments in the diagnosis and treatment of HCV, including new recommendations pertaining to screening for HCV by the Centers for Disease Control and Prevention and newer treatment regimens with high efficacy, short duration and the potential for interferon-free therapies, have energised the health care practitioners regarding HCV management. AIM: To assess the full impact of HCV burden on clinical, economic and patient-reported outcomes. METHODS: An expert panel was convened to assess the full impact of HCV burden on a number of important outcomes using an evidence-based approach predicated on Grading of Recommendations Assessment, Development and Evaluation methodology. The literature was summarised, graded using an evidence-based approach and presented during the workshop. Workshop presentations were intended to review recent, relevant evidence-based literature and provide graded summary statements pertaining to HCV burden on topics including the relationships between HCV and the development of important outcomes. RESULTS: The associations of HCV with cirrhosis, HCC, liver-related mortality, type 2 diabetes mellitus, rheumatological diseases and quality of life impairments are supported by strong evidence. Also, there is strong evidence that sustained viral eradication of HCV can improve important outcomes such as mortality and quality of life. CONCLUSIONS: The current evidence suggests that HCV has been associated with tremendous clinical, economic and quality of life burden.

The association between serological and dietary vitamin D levels and hepatitis C-related liver disease risk differs in African American and white males.

BACKGROUND: Vitamin D may affect the severity of HCV-related liver disease. AIM: To examine the association between serum vitamin D levels and advanced liver disease in a multiethnic US cohort of HCV patients, and account for dietary and supplemental intake. METHODS: We measured serum 25-hydroxyvitamin D levels and used FibroSURE-ActiTest to assess hepatic pathology in a cohort of HCV-infected male veterans. We estimated and adjusted for daily intake of vitamin D from diet using a Dietary History Questionnaire, and dispensed prescriptions prior to study enrolment. We used race-stratified logistic regression analyses to evaluate the relationship between serum vitamin D levels and risk of advanced fibrosis (F3/F4-F4) and advanced inflammation (A2/A3-A3). RESULTS: A total of 163 African American (AA) and 126 White non-Hispanics were studied. Overall, ~44% of AAs and 15% of Whites were vitamin D deficient (<12 ng/mL) or insufficient (12-19 ng/mL); 4% of AAs and 9% of White patients had an elevated level (>50 ng/mL). Among AAs, patients with elevated serum vitamin D levels had significantly higher odds of advanced fibrosis (OR = 12.91, P = 0.03) than those with normal levels. In contrast, AAs with insufficient or deficient levels had > two-fold excess risk of advanced inflammation (P = 0.06). Among White males there was no association between vitamin D levels and advanced fibrosis (F3/F4-F4) or inflammation (A2/A3-A3) risk. CONCLUSIONS: We observed potential differences in the association between vitamin D levels and degree of HCV-related hepatic fibrosis between White and African American males. Additional research is necessary to confirm that high serum vitamin D levels may be associated with advanced fibrosis risk in African American males, and to evaluate whether racial differences exist in HCV-infected females.

Potentially curative treatment in patients with hepatocellular cancer--results from the liver cancer research network.

BACKGROUND: The extent to which potentially curative therapies are used in patients with hepatocellular cancer (HCC) and their related outcomes are unknown in the US. AIM: To determine the rate and outcomes of potentially curative treatment in patients with HCC. METHODS: Eleven US centers followed patients with HCC between 2001 and 2007. We determined rates of liver transplantation, surgical resection, or tumour ablation during follow-up, examined differences in adjusted survival of patients receiving these treatments, and determined the factors associated with receipt of potentially curative treatment. RESULTS: Of the 267 patients, 76 (28%) patients had early HCC, defined as Child A or B cirrhosis, with a solitary HCC or ≤ 3 nodules, each ≤ 3 cm. Of these, 53 (69.7%) received curative treatment. Thirty six percent of patients with non-early HCC received curative treatment. Compared to patients with non-early HCC who did not receive curative treatment, patients with early HCC and curative treatment had the best survival [hazard ratio, HR = 0.19 (95% CI, 0.08-0.42)] followed by patients with advanced HCC who received curative treatment [HR = 0.37 (95% CI, 0.22-0.64)]. Baseline performance status was significantly associated with receipt of curative treatment as well as survival after adjusting for demographics, clinical characteristics, and HCC stage. CONCLUSIONS: In this multicenter database, most of the patients with early HCC received potentially curative treatment. However, only 28% of patients had early HCC. One-third of patients with non-early HCC also underwent curative therapy. Potentially curative treatment improved survival and this effect was seen in patients with early as well as non-early HCC.

Hepatitis vaccination in patients with hepatitis C: practice and validation of codes at a large Veterans Administration Medical Centre.

BACKGROUND: Hepatitis vaccination is recommended in patients with chronic liver disease. AIM: To validate Current Procedural Terminology (CPT) codes and drug codes for hepatitis vaccination in administrative databases and determine vaccination rates in hepatitis C virus (HCV)-infected patients in a single large Veterans Administration Medical Center. METHODS: We calculated predictive values for hepatitis vaccination codes in a validation set of 168 patients. We then conducted a retrospective cohort study of 243 HCV-infected patients to determine rates of hepatitis vaccination and serological testing. RESULTS: The presence of CPT or drug codes for hepatitis A vaccine yielded a positive predictive value (PPV) and negative predictive value (NPV) of 93.2% and 94.0%. The presence of hepatitis B vaccine codes yielded a PPV of 98.0% and an NPV of 94.0%. Among patients diagnosed with HCV between 2000 and 2005, receipt of hepatitis vaccination was documented in approximately 8% overall and 7% in patients with cirrhosis. Half of the patients without hepatitis vaccinations were either not tested for immunity or had negative serology. CONCLUSIONS: Current Procedural Terminology or drug codes for hepatitis vaccinations in administrative data are highly predictive of the presence of vaccinations in medical records. Our data suggest that there is significant under-utilization of vaccination in patients with HCV.

Prospective validation of the short form liver disease quality of life instrument.

BACKGROUND: Despite the realization that health-related quality of life (HRQOL) is an important outcome in patients with liver disease, there is scarcity of disease-targeted HRQOL measures that have undergone prospective evaluation. AIM: To validate prospectively the short form of liver disease quality of life instrument (the SF-LDQOL) in patients with advanced liver disease. METHODS: The SF-LDQOL includes 36 disease-targeted items representing nine domains: symptoms of liver disease, effects of liver disease, memory/concentration, sleep, hopelessness, distress, loneliness, stigma of liver disease and sexual problems. We administered the SF-LDQOL to 156 advanced liver disease patients at baseline and at 6-month follow-up. We estimated internal consistency reliability for multi-item scales, item discrimination across scale and evaluated construct validity by estimating the associations of SF-LDQOL scores with SF-36 scores, symptom severity and disability days. To evaluate the SF-LDQOL's responsiveness, we compared HRQOL changes for patients who received with those who did not receive liver transplantation (LT). RESULTS: The internal consistency reliability coefficients were > or = 0.70 for seven of nine scales in baseline and for all scales in follow-up administration. The SF-LDQOL correlated highly with SF-36 scores, symptom severity, disability days and global health. Patients undergoing LT reported improved HRQOL compared with patients without LT and the responsiveness indices were excellent. CONCLUSIONS: This study provides support for the reliability and validity of the SF-LDQOL in patients with advanced chronic liver disease. This instrument may be useful in everyday clinical practice and in future clinical trials.

HBsAg seropositive status and survival after renal transplantation: meta-analysis of observational studies.

The natural history of hepatitis B virus (HBV) infection after renal transplantation (RT) remains unclear. We conducted a systematic review of the published medical literature on the impact of HBV surface antigen (HBsAg) seropositivity on survival of RT recipients. We used the random effects model of DerSimonian and Laird to generate a summary estimate of the relative risk for mortality and graft loss in HBsAg positive RT recipients across the published studies. We identified six observational studies (6050 unique patients); all of them being cohort, retrospective studies. Pooling of study results demonstrated that HBsAg in serum was an independent and significant risk factor for death after RT; the summary estimate for relative risk was 2.49 with a 95% confidence interval (95% CI) of 1.64-3.78. A test for homogeneity of the relative risk across the studies gave a p-value of <0.0001. HBsAg seropositivity was an independent and significant risk factor for graft failure after RT; the summary estimate was 1.44 with a 95% CI of 1.02-2.04 (homogeneity test, p <0.0001). This meta-analysis shows that HBsAg positive RT recipients have an increased risk for mortality and graft failure compared to seronegative patients.

A comparison of liver transplantation outcomes in the pre- vs. post-MELD eras.

BACKGROUND: The model for end stage liver disease (MELD)-based organ allocation system is designed to prioritize orthotopic liver transplantation (OLT) for patients with the most severe liver disease. However, there are no published data to confirm whether this goal has been achieved or whether the policy has affected long-term post-OLT survival. AIM: To compare pre-OLT liver disease severity and long-term (1 year) post-OLT survival between the pre- and post-MELD eras. METHODS: Using the United Network of Organ Sharing database, we compared two cohorts of adult patients undergoing cadaveric liver transplant in the pre-MELD (n = 3857) and post-MELD (n = 4245) eras. We created multivariable models to determine differences in: (i) pre-OLT liver disease severity as measured by MELD; and (ii) 1-year post-OLT outcomes. RESULTS: Patients undergoing OLT in the post-MELD era had more severe liver disease at the time of transplantation (mean MELD = 20.5) vs. those in the pre-MELD era (mean MELD = 17.0). There were no differences in the unadjusted patient or graft survival at 1 year post-OLT. This difference remained insignificant after adjusting for a range of prespecified recipient, donor, and transplant centre-related factors in multivariable survival analysis. CONCLUSIONS: Although liver disease severity is higher in the post- vs. pre-MELD era, there has been no change in long-term post-OLT patient or graft survival. These results indicate that the MELD era has achieved its primary goals by allocating cadaveric livers to the sickest patients without compromising post-OLT survival.

Uvular necrosis after upper endoscopy: a case report and review of the literature.

Uvular necrosis after endotracheal intubation or upper endoscopy is rare. We report here on a case of uvular necrosis and ulceration after endoscopy. The combination of ulceration and necrosis suggests uvular ischemia during endoscopy. The uvula may have been sandwiched between the shaft of the endoscope and the gum or hard palate, or may have been pressed against the posterior pharynx, leading to prolonged ischemia and resultant ulceration and necrosis. Uvular trauma can also be caused by oral pharyngeal suction. We recommend that post-endoscopy uvular necrosis should be managed conservatively based on the patient's symptoms. In all reported cases, and in the present case as well, the uvula healed and the symptoms resolved within 2 weeks (5 - 14 days) after the procedure. The uvula regained its normal appearance. Overall, these patients should have a good clinical outcome.