Hepatocellular carcinoma surveillance may be associated with potential psychological harms in patients with cirrhosis.

BACKGROUND AND AIMS: The value of HCC surveillance is determined by the balance between benefits and harms; however, no studies have enumerated psychological harms. APPROACH AND RESULTS: We fielded surveys measuring psychological harms to patients with cirrhosis in a multicenter randomized trial of HCC surveillance outreach. All patients with positive or indeterminate surveillance results and matched patients with negative results were invited to complete surveys measuring (1) depression through the Patient Health Questionnaire-ninth version, (2) anxiety through State-Trait Anxiety Inventory, (3) HCC-specific worry through Psychological Consequences Questionnaire, and (4) decisional regret. Patients were classified into 4 groups: true positive (TP), false positive (FP), indeterminate, and true negative (TN). Multivariable longitudinal regression analysis using the generalized estimating equation method was performed to compare the means of measures across groups. We conducted 89 semistructured interviews in a subset of patients stratified by health system and test results. Of 2872 patients in the trial, 311 completed 1+ follow-up survey (63 FP, 77 indeterminate, 38 TP, and 133 TN). Moderate depression decreased in TN patients, increased in TP, and had intermittent but mild increases in those with FP and indeterminate results. High anxiety temporarily increased in patients with TP results but resolved over time and was stable in those with FP and indeterminate results. Decisional regret was low and did not differ across groups. In semistructured interviews, patients reported apprehension, anxiety, emotional distress, and coping related to HCC surveillance. CONCLUSIONS: Psychological harms of HCC surveillance appear mild but differ by test result. Future research should determine the impact of psychological harms on the value of HCC surveillance programs.

Defining and Understanding Diagnostic Delays Among Pancreatic Cancer Patients: A Retrospective Cohort Study.

BACKGROUND AND AIMS: Pancreatic cancer is a lethal cancer of increasing incidence, presenting with several clinically detectable signals allowing for earlier diagnosis. However, there are limited data related to diagnostic process, including prevalence of diagnostic delays and their contributing factors. We aimed to develop a standardized definition of diagnostic delay, evaluate its prevalence, and identify its contributing factors among pancreatic cancer patients. METHODS: We convened an expert panel who defined diagnostic delay among pancreatic cancer patients. We then conducted a retrospective cohort study among pancreatic adenocarcinoma patients consecutively diagnosed from 2007 to 2019 at a tertiary care Veterans Affairs medical center. We manually reviewed diagnostic delay instances for contributing factors. Secondary analyses, using multivariate logistic regression and Cox proportional hazards models, explored associations between diagnostic delays and cancer outcomes. RESULTS: Diagnostic delay was defined as cancer diagnosis made ≥60 days after first clinical presence of predefined red flag(s). Among 197 pancreatic adenocarcinoma patients, 38.6% experienced a diagnostic delay. Among delay cases, the most common primary contributing factor was related to the patient-provider encounter (44.7% with lack of recognition of objective weight loss). Patients with delays were more likely to be diagnosed at advanced stage disease (adjusted odds ratio, 1.62; 95% confidence interval, 0.79-3.30) and less likely to receive potentially curative treatment (adjusted odds ratio, 0.72; 95% confidence interval, 0.28-1.84), although these trends did not reach statistical significance. CONCLUSIONS: Over one-third of pancreatic cancer patients experienced a diagnostic delay, mostly due to inadequate recognition of red flag findings. Results can inform targeted interventions to reduce preventable diagnostic delays among pancreatic cancer patients.

Financial Burden of Hepatocellular Carcinoma Screening in Patients With Cirrhosis.

BACKGROUND: The overall value of hepatocellular carcinoma screening is defined by the balance of benefits and harms. Studies have only reported physical harms with none describing financial harms. METHODS: We conducted a multicenter pragmatic randomized clinical trial of hepatocellular carcinoma screening outreach among 2872 patients with cirrhosis from March 2018 to April 2021. Patients with positive or indeterminate results and matched patients with negative results completed surveys at baseline and at follow-up measuring financial harms via Cancer Self-Administered Questionnaire and financial burden via Comprehensive Score for Financial Toxicity Functional Assessment of Chronic Illness Therapy. Univariable and multivariable longitudinal regression analyses were performed to compare changes in financial harms across groups: true positive, true negative, false positive, and indeterminate. Semistructured interviews were conducted in a subset of patients, sampled by center and test result. RESULTS: Of 311 patients who completed at least 1 follow-up survey (75% response rate), 37 had true positive, 133 true negative, 64 false positive, and 77 indeterminate results. Financial harms increased in true positive and false positive patients with no significant changes noted among those with true negative or indeterminate results. At follow-up, 21.8% of patients reported moderate-severe financial burden, which was not significantly associated with test results. Semistructured interviews revealed variation in the frequency and severity of financial harms based on test results, with increased harm in those with false positive results. CONCLUSIONS: Financial harms of hepatocellular carcinoma screening vary by test result and can pose a barrier that must be considered when determining the optimal screening program.

Emergency Presentations Predict Worse Outcomes Among Patients with Pancreatic Cancer.

BACKGROUND: Emergency presentation (EP) of cancer, a new cancer diagnosis made following an emergency department (ED) visit, is associated with worse patient outcomes and greater organizational stress on healthcare systems. Pancreatic cancer has the highest rate of EPs among European studies but remains understudied in the U.S. AIMS: To evaluate the association between pancreatic cancer EPs and cancer stage, treatment, and survival. METHODS: We conducted a retrospective cohort study among patients with pancreatic adenocarcinoma diagnosed from 2007 to 2019 at a tertiary-care Veterans Affairs medical center. Electronic health records were reviewed to identify EP cases, defined as a new pancreatic cancer diagnosis made within 30 days of an ED visit where cancer was suspected. We used multivariate logistic regression models and Cox proportional hazards models to examine the associations between EPs and cancer stage, treatment, and survival. RESULTS: Of 243 pancreatic cancer patients, 66.7% had EPs. There was no difference in stage by EP status. However, patients diagnosed through EPs were 72% less likely to receive cancer treatment compared to non-emergency presenters (adjusted OR 0.28; 95% CI 0.13-0.57). Patients with EPs also had a 73% higher mortality risk (adjusted HR 1.73; 95% CI 1.29-2.34). This difference in mortality remained statistically significant after adjusting for cancer stage and receipt of cancer treatment (adjusted HR 1.47; 95% CI 1.09-1.99). CONCLUSIONS: Pancreatic cancer EPs are common and independently associated with lower treatment rates and survival. Enhanced understanding of process breakdowns that lead to EPs can help identify care gaps and inform future quality improvement efforts.

Longitudinal changes in fibrosis markers are associated with risk of cirrhosis and hepatocellular carcinoma in non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Currently, there is no consistent information on the course of fibrosis-4 (FIB-4) score changes in non-alcoholic fatty liver disease (NAFLD) or their association with subsequent risk of cirrhosis and/or hepatocellular carcinoma (HCC). Thus, we aimed to evaluate the association between longitudinal changes in FIB-4 and subsequent risk of HCC and a composite endpoint of cirrhosis and HCC in patients with NAFLD. METHODS: We conducted a retrospective cohort study of patients with NAFLD seen in 130 Veterans Administration hospitals between 1/1/2004-12/31/2008, with follow-up through to 12/31/2018. We calculated FIB-4 longitudinally and categorized patients based on risk of advanced fibrosis (low-risk FIB-4 <1.45, indeterminate-risk FIB-4 1.45-2.67, and high-risk FIB-4 >2.67). We used landmark Fine-Gray competing risks models to determine the effects of change in FIB-4 between NAFLD diagnosis date and 3-year landmark time on the subsequent risk of HCC and a composite endpoint. RESULTS: Among the 202,319 patients with NAFLD in the 3-year landmark analysis, 473 progressed to HCC at an incidence rate of 0.28 per 1,000 person years (PY) (95% CI 0.26-0.30). The incidence rate of the composite endpoint was 1.31 per 1,000 PY (95% CI 1.25-1.37). At baseline, 74.7%, 21.4%, and 3.8% of patients had a low, indeterminate, and high FIB-4, respectively. Compared to patients who were at stable low FIB-4 at both time points, the risk of HCC and that of the composite endpoint was higher for all other subgroups with the highest risk in patients with persistently high FIB-4 (HCC adjusted sub-distribution hazard ratio 57.7, 95% CI 40.5-82.2 and composite endpoint hazard ratio 28.6, 95% CI 24.6-33.2). CONCLUSION: Longitudinal changes in FIB-4 were strongly associated with progression to cirrhosis and HCC. IMPACT AND IMPLICATIONS: Tools to stratify the risk of HCC development in patients with NAFLD are currently lacking. The fibrosis-4 (FIB-4) score is a widely available non-invasive test for liver fibrosis, a primary determinant of the development of cirrhosis and HCC. In a large retrospective cohort of patients with NAFLD, we found that serial changes in FIB-4 over time were strongly associated with progression to cirrhosis and HCC. Integrating serial measurements of non-invasive tests for fibrosis into the care pathway for patients with NAFLD could help tailor HCC risk prevention.

The Risk of Hepatocellular Carcinoma in Entecavir Versus Tenofovir Treated US Cohort With Chronic Hepatitis B Virus.

The comparative effectiveness of tenofovir (TDF) vs entecavir (ETV) in reducing the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) remains unclear. Data from a retrospective Korean cohort study published by Choi et al1 initially suggested a lower-than-expected incidence of HCC in patients on long-term TDF. However, additional studies from Korea did not show a statistically significant difference in HCC incidence rate between TDF and ETV groups,2,3 and subsequent studies reported mixed results ranging from no association or a slight advantage for TDF.4 Most of these studies examined Asian patients from Korea, Taiwan, and China.

Risk Stratification Model for Hepatocellular Cancer in Patients With Cirrhosis.

BACKGROUND & AIMS: The available risk stratification indices for hepatocellular cancer (HCC) have limited applicability. We developed and externally validated an HCC risk stratification index in U.S. cohorts of patients with cirrhosis. METHODS: We used data from 2 prospective U.S. cohorts to develop the risk index. Patients with cirrhosis were enrolled from 8 centers and followed until development of HCC, death, or December 31, 2021. We identified an optimal set of predictors with the highest discriminatory ability (C-index) for HCC. The predictors were refit using competing risk regression and its predictive performance was evaluated using the area under the receiver-operating characteristic curve (AUROC). External validation was performed in a cohort of 21,550 patients with cirrhosis seen in the U.S Veterans Affairs system between 2018 and 2019 with follow-up through 2021. RESULTS: We developed the model in 2431 patients (mean age 60 years, 31% women, 24% cured hepatitis C, 16% alcoholic liver disease, and 29% nonalcoholic fatty liver disease). The selected model had a C-index of 0.77 (95% confidence interval [CI], 0.73-0.81), and the predictors were age, sex, smoking, alcohol use, body mass index, etiology, α-fetoprotein, albumin, alanine aminotransferase, and platelet levels. The AUROCs were 0.75 (95% CI, 0.65-0.85) at 1 year and 0.77 (95% CI, 0.71-0.83) at 2 years, and the model was well calibrated. In the external validation cohort, the AUROC at 2 years was 0.70 with excellent calibration. CONCLUSION: The risk index, including objective and routinely available risk factors, can differentiate patients with cirrhosis who will develop HCC and help guide discussions regarding HCC surveillance and prevention. Future studies are needed for additional external validation and refinement of risk stratification.

Cost of Care for Patients With Cirrhosis.

INTRODUCTION: There are limited longitudinal data on the cost of treating patients with cirrhosis, which hampers value-based improvement initiatives. METHODS: We conducted a retrospective cohort study of patients with cirrhosis seen in the Veterans Affairs health care system from 2011 to 2015. Patients were followed up through 2019. We identified a sex-matched and age-matched control cohort without cirrhosis. We estimated incremental annual health care costs attributable to cirrhosis for 4 years overall and in subgroups based on severity (compensated, decompensated), cirrhosis complications (ascites, encephalopathy, varices, hepatocellular cancer, acute kidney injury), and comorbidity (Deyo index). RESULTS: We compared 39,361 patients with cirrhosis with 138,964 controls. The incremental adjusted costs for caring of patients with cirrhosis were $35,029 (95% confidence interval $32,473-$37,585) during the first year and ranged from $14,216 to $17,629 in the subsequent 3 years. Cirrhosis complications accounted for most of these costs. Costs of managing patients with hepatic encephalopathy (year 1 cost, $50,080) or ascites ($50,364) were higher than the costs of managing patients with varices ($20,488) or hepatocellular cancer ($37,639) in the first year. Patients with acute kidney injury or those who had multimorbidity were the most costly at $64,413 and $66,653 in the first year, respectively. DISCUSSION: Patients with cirrhosis had substantially higher health care costs than matched controls and multimorbid patients had even higher costs. Cirrhosis complications accounted for most of the excess cost, so preventing complications has the largest potential for cost saving and could serve as targets for improvement.

Effect of HIV and antiretroviral therapy use on body weight changes in a cohort of U.S. veterans living with and without HIV.

OBJECTIVE: People living with HIV have high rates of obesity and obesity-related comorbidities. Our study sought to evaluate weight trajectory in a retrospective cohort of people living with HIV and matched HIV-negative veterans (controls) and to evaluate risk factors for weight gain. METHODS: This was a retrospective database analysis of data extracted from the VA Corporate Data Warehouse that included people living with HIV (n = 22 421) and age-matched HIV-negative controls (n = 63 072). The main outcomes were baseline body weight and weight change from baseline at 1, 2, and 5 years after diagnosis (baseline visit for controls). RESULTS: Body weight at baseline was lower in people living with HIV than in controls. People living with HIV on antiretroviral therapy (ART) gained more weight than did controls. In a sub-analysis of ART-exposed people living with HIV, age >50 years, African American race, body mass index (BMI) <25, CD4 ≤200, and HIV diagnosis year after 2000 were associated with more weight gain at year 1. Nucleoside reverse transcriptase inhibitors (NRTI) plus non-NRTIs (NNRTIs) were associated with less weight gain than NRTIs plus protease inhibitors, NRTIs plus integrase inhibitors, or NRTIs plus other agents at year 1. CONCLUSIONS: Among US veterans, those living with HIV had lower rates of obesity than age-matched HIV-negative controls; however, primarily in the first 2 years after starting ART, people living with HIV gained more weight than did controls.

Effect of diabetes medications and glycemic control on risk of hepatocellular cancer in patients with nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: In patients with NAFLD, those with type 2 diabetes mellitus (DM) have a high risk of progression to HCC. However, the determinants of HCC risk in these patients remain unclear. APPROACH AND RESULTS: We assembled a retrospective cohort of patients with NAFLD and DM diagnosed at 130 facilities in the Veterans Administration between 1/1/2004 and 12/31/2008. We followed patients from the date of NAFLD diagnosis to HCC, death, or 12/31/2018. We used landmark Cox proportional hazards models to determine the effects of anti-DM medications (metformin, insulin, sulfonylureas) and glycemic control (percent of follow-up time with hemoglobin A1c < 7%) on the risk of HCC while adjusting for demographics and other metabolic traits (hypertension, obesity, dyslipidemia). We identified 85,963 patients with NAFLD and DM. In total, 524 patients developed HCC during a mean of 10.3 years of follow-up. Most common treatments were metformin monotherapy (19.7%), metformin-sulfonylureas (19.6%), insulin (9.3%), and sulfonylureas monotherapy (13.6%). Compared with no medication, metformin was associated with 20% lower risk of HCC (HR, 0.80; 95% CI, 0.93-0.98). Insulin had no effect on HCC risk (HR, 1.02; 95% CI, 0.85-1.22; p = 0.85). Insulin in combination with other oral medications was associated with a 1.6 to 1.7-fold higher risk of HCC. Adequate glycemic control was associated with a 31% lower risk of HCC (HR, 0.69; 95% CI, 0.62-0.78). CONCLUSIONS: In this large cohort of patients with NAFLD and DM, use of metformin was associated with a reduced risk of HCC, whereas use of combination therapy was associated with increased risk. Glycemic control can serve as a biomarker for HCC risk stratification in patients with NAFLD and diabetes.

Effectiveness of elbasvir/grazoprevir plus ribavirin for hepatitis C virus genotype 1a infection and baseline NS5A resistance.

INTRODUCTION AND OBJECTIVES: In clinical trials, patients with hepatitis C virus (HCV) genotype (GT)1a infection and baseline resistance-associated substitutions (RASs) at amino acid positions 28, 30, 31, or 93 receiving elbasvir/grazoprevir for 12 weeks achieved lower rates of sustained virologic response (SVR) than those without baseline RASs. SVR rates in patients with RASs were improved when elbasvir/grazoprevir treatment duration was extended from 12 to 16 weeks and administered concomitantly with ribavirin. MATERIALS AND METHODS: This was a retrospective, observational analysis using electronic health record abstraction. Patients with HCV GT1a infection and RASs at positions 28, 30, 31, or 93 who were prescribed 16 weeks of elbasvir/grazoprevir and ≥ 1 prescription for ribavirin were included. SVR was defined as HCV RNA below the lower limit of quantification ≥ 70 days after end of treatment. RESULTS: The primary analysis included patients with baseline RASs at positions 30, 31, or 93 (n = 76); a secondary analysis included patients with RASs at positions 28, 30, 31, or 93 (n = 93). SVR was achieved by 77.6% (59/76) of patients in the primary analysis and 80.6% (75/93) of those in the secondary analysis. Of the 18 (19.4%) patients in the secondary cohort who failed to achieve SVR, 8 relapsed (4 with treatment-emergent NS5A substitutions) and 10 did not have viral sequencing to distinguish relapse from reinfection. CONCLUSIONS: This analysis highlights the opportunities in leveraging real-world data to further understand treatment outcomes in smaller, discrete subgroups of patients with HCV infection who cannot be thoroughly evaluated in clinical trials.

Risk and incidence of head and neck cancers in veterans living with HIV and matched HIV-negative veterans.

BACKGROUND: Persons living with HIV/AIDS have a higher incidence of virus-related and tobacco/alcohol-related cancers. This study is the first to estimate the effect of HIV versus HIV-negative veterans on the risk of head and neck squamous cell carcinoma incidence in a large retrospective cohort study. METHODS: The authors constructed a retrospective cohort study using patient data from 1999 to 2016 from the National Veterans Administration Corporate Data Warehouse and the VA Central Cancer Registry. This cohort study included 45,052 veterans living with HIV/AIDS and 162,486 HIV-negative patients matched by age, sex, and index visit (i.e., HIV diagnosis date or clinic visit date). The age-standardized incidence rates and estimated adjusted hazard ratios were calculated with a Cox proportional hazards regression for oropharyngeal and nonoropharyngeal head and neck cancer squamous cell carcinoma (HNSCC). The authors also abstracted human papillomavirus (HPV) status from oropharyngeal HNSCC diagnosed after 2010. RESULTS: Veterans living with HIV/AIDS (VLWH) have 1.71 (95% confidence interval [CI], 1.36, 2.14) times the risk of oropharyngeal cancer and 2.06 (95% CI, 1.76, 2.42) times the hazard of nonoropharyngeal cancer compared with HIV-negative veterans. VLWH with oropharyngeal squamous cell carcinoma (OPSCC) were more likely to be HPV-positive (N = 30 [81.1%]) than the HIV-negative veterans with OPSCC (N = 50 [67.6%]), although this difference was not significant (p = .135). For nonoropharyngeal cancer, the increased risk of oral cavity cancer among VLWH drove the increased risk. CONCLUSIONS: The study results suggest that HIV may play a role in virally mediated and nonvirally mediated HNSCC. As the HIV prevalence rises in the United States due to better survival and the incidence of HPV-positive oropharyngeal HNSCC increases, the interaction between HPV and HIV becomes increasingly relevant.

Multicenter Randomized Clinical Trial of a Mailed Outreach Strategy for Hepatocellular Carcinoma Surveillance.

BACKGROUND: The effectiveness of hepatocellular carcinoma (HCC) surveillance is mitigated by underuse in clinical practice, highlighting a need for interventions. We evaluated the effectiveness of mailed HCC surveillance outreach to promote HCC surveillance in patients with cirrhosis. METHODS: We conducted a multicenter pragmatic randomized clinical trial comparing mailed outreach for surveillance ultrasound (n = 1436) and usual care with visit-based surveillance (n = 1436) among patients with cirrhosis at 3 health systems (tertiary care referral center, safety net health system, and Veterans Affairs medical center) from April 2018 to December 2019. The primary outcome of this interim analysis was guideline concordant semiannual HCC surveillance over a 12-month period and a secondary outcome was proportion time covered by surveillance. All patients were included in intention-to-screen analyses. RESULTS: Compared with usual care, the outreach arm had significantly higher semiannual surveillance (35.1% vs 21.9%) and lower no-surveillance (29.8% vs 43.5%) (P < .001), resulting in significant increases in the proportion of time covered by surveillance (41.3% vs 31.0%; P < .001). The intervention increased HCC surveillance across most predefined subgroups; however, there were site-level differences in the intervention effect, with significant increases in semiannual surveillance at the Veterans Affairs and safety net health systems but not at the tertiary care referral center. CONCLUSIONS: Mailed outreach significantly increased semiannual HCC surveillance vs usual care in patients with cirrhosis, with a consistent intervention effect across most examined subgroups. Continued follow-up is ongoing to determine if these increases in surveillance translate into improved downstream outcomes includi.ng early HCC detection and curative treatment receipt. (ClinicalTrials.gov, Numbers: NCT02582918 and NCT03756051).

Depression and Anxiety Are Common Among Patients With Cirrhosis.

BACKGROUND & AIMS: Depression and anxiety can have negative effects on patients and are important to treat. There have been few studies of their prevalence among patients with cirrhosis. We aimed to characterize the prevalence and risk factors for depression and anxiety in a large multi-center cohort of patients with cirrhosis. METHODS: We conducted a telephone-based survey of patients with cirrhosis at 3 health systems in the United States (a tertiary-care referral center, a safety net system, and a Veterans hospital) from April through December 2018. Of 2871 patients approached, 1021 (35.6%) completed the survey. Depression and anxiety were assessed using the PHQ-9 (range 0-25) and STAI (range 20-80) instruments, with clinically significant values defined as PHQ-9 ≥15 and STAI ≥40. We performed multivariate logistic regression analysis to identify factors associated with significant depression and anxiety. RESULTS: The median PHQ-9 score was 7 (25th percentile-75th percentile, 3-12) and the median STAI score was 33 (25th percentile-75th percentile, 23-47); 15.6% of patients had moderately severe to severe depression and 42.6% of patients had high anxiety. In multivariable analyses, self-reported poor health (odds ratio [OR], 4.08; 95% CI, 1.79-9.28), being widowed (OR, 2.08; 95% CI, 1.07-4.05), fear of hepatocellular carcinoma (OR, 1.89; 95% CI, 1.04-3.42), higher household income (OR, 0.30; 95% CI, 0.10-0.95), and Hispanic ethnicity (OR, 0.57; 95% CI, 0.33-0.97) were associated with moderately severe to severe depression. Male sex (OR, 0.71; 95% CI, 0.51-0.98), self-reported poor health (OR, 2.73; 95% CI, 1.73-4.32), and fear of hepatocellular carcinoma (OR, 2.24; 95% CI, 1.33-3.78) were associated with high anxiety. CONCLUSIONS: Nearly 1 in 6 patients with cirrhosis have moderately severe to severe depression and nearly half have moderate-severe anxiety. Patients with cirrhosis should be evaluated for both of these disorders.

Longitudinal Associations of Risk Factors and Hepatocellular Carcinoma in Patients With Cured Hepatitis C Virus Infection.

INTRODUCTION: There are limited data on the effect and evolution of risk factors for hepatocellular carcinoma (HCC) in patients with virologically cured hepatitis C virus (HCV) infection. METHODS: We conducted a retrospective cohort study of patients with HCV who achieved sustained virological response with direct-acting antivirals from 130 Veterans Administration hospitals during 2014-2018, followed through 2021. Cox proportional hazards models were constructed at 3 landmark times (baseline and 12 and 24 months after sustained virological response) to examine associations between demographic, clinical, and behavioral factors and HCC risk, stratified by cirrhosis status. RESULTS: Among 92,567 patients (32% cirrhosis), 3,247 cases of HCC were diagnosed during a mean follow-up of 2.5 years. In patients with cirrhosis, male sex (hazard ratios [HR]: 1.89, 1.93, and 1.99), cirrhosis duration ≥5 years (HR: 1.71, 1.79, and 1.34), varices (HR: 1.73, 1.60, and 1.56), baseline albumin (HR: 0.48, 0.47, and 0.49), and change in albumin (HR: 0.82 and 0.90) predicted HCC risk at each landmark time. HCV genotype 3, previous treatment, bilirubin, smoking, and race influenced HCC risk at baseline, but their effects attenuated over time. In patients without cirrhosis, diabetes (HR: 1.54, 1.42, and 1.47) and hypertension (HR: 1.59, 1.65, and 1.74) were associated with HCC risk at all landmark times. Changes in fibrosis-4 scores over time were associated with HCC risk both in patients with and without cirrhosis. DISCUSSION: Risk factors for HCC were different in patients with and without cirrhosis and some also evolved during follow-up. These factors can help with risk stratification and HCC surveillance decisions in patients with cured HCV.

Treatment of hepatitis C virus infection in people with opioid use disorder: a real-world study of elbasvir/grazoprevir in a US Department of Veterans Affairs population.

Background: Hepatitis C virus (HCV) infections in the United States have increased in recent years, with the most rapid rise among people who inject drugs (PWIDs). Historically, there have been concerns regarding treatment adherence among PWIDs with HCV infection, leading to undertreatment of this population and increased HCV transmission. Elbasvir (EBR)/grazoprevir (GZR) has demonstrated high rates of virologic cure (sustained virologic response [SVR]) in clinical trials enrolling PWIDs with HCV infection. Objective: To evaluate the real-world effectiveness of EBR/GZR in HCV genotype (GT) 1-infected patients with a diagnosis of opioid use disorder. Methods: A retrospective analysis of electronic medical records from the US Department of Veterans Affairs Corporate Data Warehouse. Adults with chronic HCV GT1 infection, ≥1 prescription for EBR/GZR, and ≥1 clinic visit were included. All patients had ≥1 ICD-9/10 code of opioid use disorder. SVR was the primary outcome. Results: 419 patients were included; 97.1% had a history of any illicit drug use and 40.8% were receiving medication for opioid use disorder (MOUD). SVR was achieved by 96.9% (406/419) of all patients, 97.0% (350/361) of those receiving EBR/GZR for 12 weeks, and 95.3% (163/171) of those receiving MOUD. SVR in patients receiving psychiatric medications ranged from 96.1% (221/230) in those taking antidepressant medications to 98.5% (128/130) in those taking mood stabilizers. Conclusion: In this real-world setting, high rates of virologic cure were achieved in patients with HCV GT1 infection on MOUD receiving EBR/GZR for 12 weeks, including patients with multiple comorbidities and high rate of psychiatric medication use.

Veteran Women Living With Human Immunodeficiency Virus Have Increased Risk of Human Papillomavirus (HPV)-Associated Genital Tract Cancers.

BACKGROUND: Disparities in access to screening often confound observed differences in human papillomavirus (HPV)-associated female genital tract cancer (FGTC) incidence between women living with human immunodeficiency virus (HIV; WLWH) and their HIV-negative counterparts. We aimed to determine if there have been changes in cancer risk among WLWH during the antiretroviral era in a single-payer health system. METHODS: We retrospectively selected WLWH and HIV-negative controls receiving care between 1999 and 2016 at the US Department of Veterans Affairs (VA) and identified FGTC diagnoses via Cancer Registry and International Classification of Diseases-9/10 codes. We extracted demographic and clinical variables from the VA's Corporate Data Warehouse; evaluated incidence rates (IRs), incidence rate ratios, hazard ratios, and 95% confidence intervals (CIs) for cancer risk; and conducted survival analyses. RESULTS: We identified 1454 WLWH and compared them with 5816 matched HIV-negative controls. More WLWH developed HPV-associated FGTCs (total n = 28 [2.0%]; cervical = 22, vulvovaginal = 4, and anal/rectal = 2) than HIV-negative women (total n = 32 [0.6%]; cervical = 24, vulvovaginal = 5, and anal/rectal = 5) (log rank P < .0001). Cervical cancer IR was >6-fold higher for WLWH (204.2 per 100 000 person-years [py] [95% CI, 83.8-324.7]) than HIV-negative women (IR = 31.2 per 100 000 py [95% CI, 17.9-44.5]). The IRs for vulvovaginal and anal cancers were also higher in WLWH. Overall, WLWH were more likely to develop HPV-associated FGTCs compared with their HIV-negative counterparts (all log rank P values < .0001). CONCLUSIONS: Veteran WLWH are more likely to develop HPV-associated FGTCs despite equal access to health care. Even in single-payer health systems, WLWH continue to require special attention to ensure guideline-based high-risk HPV screening for prevention of FGTCs.

Patient-Reported Barriers Are Associated With Receipt of Hepatocellular Carcinoma Surveillance in a Multicenter Cohort of Patients With Cirrhosis.

BACKGROUND: More than 20% of patients with cirrhosis do not receive semi-annual hepatocellular carcinoma (HCC) surveillance as recommended. Few studies have evaluated the effects of patient-level factors on surveillance receipt. METHODS: We administered a telephone survey to a large cohort of patients with cirrhosis from 3 health systems (a tertiary care referral center, a safety-net health system, and Veterans Affairs) to characterize patient knowledge, attitudes, and perceived barriers of HCC surveillance. Multinomial logistic regression was performed to identify factors associated with HCC surveillance receipt (semi-annual and annual vs none) during the 12-month period preceding survey administration. RESULTS: Of 2871 patients approached, 1020 (35.5%) completed the survey. Patients had high levels of concern about developing HCC and high levels of knowledge about HCC. However, patients had knowledge deficits, including believing surveillance was unnecessary when physical examination and laboratory results were normal. Nearly half of patients reported barriers to surveillance, including costs (28.9%), difficulty scheduling (24.1%), and transportation (17.8%). In the year before the survey, 745 patients (73.1%) received 1 or more surveillance examination; 281 received on-schedule, semi-annual surveillance and 464 received annual surveillance. Semi-annual HCC surveillance (vs none) was significantly associated with receipt of hepatology subspecialty care (odds ratio, 30.1; 95% CI, 17.5-51.8) and inversely associated with patient-reported barriers (odds ratio, 0.62; 95% CI, 0.41-0.94). Patterns of associations comparing annual vs no surveillance were similar although the magnitude of effects were reduced. CONCLUSIONS: Patient-reported barriers such as knowledge deficits, costs, difficulty scheduling, and transportation are significantly associated with less frequent receipt of HCC surveillance, indicating a need for patient-centered interventions, such as patient navigation.

Long-Term Risk of Hepatocellular Carcinoma in HCV Patients Treated With Direct Acting Antiviral Agents.

Sustained virologic response (SVR) after direct acting antiviral agents (DAAs) holds promise for reducing hepatocellular cancer (HCC). DAAs have recently been available long enough to estimate the long-term risk. We conducted a retrospective cohort study of hepatitis C virus (HCV) patients who achieved SVR with DAAs from 129 Veterans Health Administration hospitals between January 1, 2015, and December 31, 2015, with follow-up through September 30, 2018. We calculated the overall and quarterly HCC incidence rates. We examined the effect of demographic, clinical, and behavioral factors and the decline or increase of FIB-4 and aspartate aminotransferase to platelet ratio index (APRI) on HCC risk. Among the 18,076 patients with SVR, 544 incident cases of HCC were diagnosed during the mean 2.9 years of follow-up. The cumulative 1, 2, and 3-year risks of HCC were 1.1%, 1.9% and 2.8%, respectively. Cirrhosis was strongly associated with HCC risk (adjusted hazard ratio = 4.13, 95% confidence interval = 3.34-5.11). The quarterly incidence rate of HCC remained stable between 1.00 and 1.23/100 person-years (PY) and 1.5 to 2.3/100 PY in patients with cirrhosis. The risk of HCC was the highest in patients who had persistently high FIB-4/APRI and both with and without cirrhosis. HCC risk fell in patients with cirrhosis who experienced a decrease of FIB-4/APRI scores yet remained higher than the accepted threshold for HCC surveillance. HCC risk was also higher in patients with alcohol use, older age, and infection with HCV genotype 3. Most patients treated at an early stage of liver fibrosis had a stable low risk. Conclusion: Patients successfully treated with DAAs and at risk of HCC did not regress after 3.6 years of follow-up. HCC risk remained above the accepted thresholds for surveillance in patients with cirrhosis. These data have important implications for HCC surveillance in cured HCV patients.

Risk of Cirrhosis and Hepatocellular Cancer in Patients With NAFLD and Normal Liver Enzymes.

BACKGROUND AND AIMS: The long-term risk of disease for patients with nonalcoholic fatty liver disease (NAFLD) in the absence of elevated enzymes is unclear. We conducted a retrospective cohort study using the Corporate Data Warehouse of the Veterans Health Administration. APPROACH AND RESULTS: We classified patients into three groups: patients with steatosis/normal alanine aminotransferase (ALT), steatosis/elevated ALT, and no steatosis/normal ALT. We examined incidence rates for cirrhosis and hepatocellular carcinoma (HCC) and conducted cause-specific hazard models to evaluate the risk of cirrhosis and HCC. We identified 3,522 patients with steatosis/normal ALT, 15,419 patients with steatosis/elevated ALT, and 9,267 patients with no steatosis/normal ALT. The mean age in each group was 58.9, 54.7 and 59.3 years, respectively; over 90% were men. Compared to patients with hepatic steatosis/normal ALT, those with steatosis/elevated ALT were younger and more likely to be obese (both P < 0.01). In patients with steatosis/normal ALT, the incidence rates of cirrhosis and HCC were 1.22 (95% confidence interval [CI]: 0.83-1.74) and 0.20 (95% CI: 0.06-0.46) per 1,000 person-years, respectively; this was lower than in patients with steatosis/elevated ALT (cirrhosis: 3.85; 95% CI: 3.50-4.23, and HCC: 0.37; 95% CI: 0.26-0.49). Patients with steatosis/elevated ALT had a higher risk of developing cirrhosis (adjusted hazard ratio: 3.37; 95% CI:  2.34-4.86; P < 0.01) than patients with steatosis/normal ALT; they also had a higher risk of HCC, although it did not reach statistical significance (hazard ratio: 2.07; 95% CI: 0.82-5.28; P = 0.13). The risk of cirrhosis and HCC in patients with steatosis/normal ALT and those without steatosis was not significantly different. CONCLUSIONS: Patients with hepatic steatosis with persistently normal ALT are at lower risk for cirrhosis compared to those with steatosis and elevated ALT and not different from the risk in a clinical cohort without hepatic steatosis.