Hepatocellular carcinoma risk decreases as time accrues following hepatitis C virus eradication.

BACKGROUND: It is unclear whether the risk of hepatocellular carcinoma (HCC) decreases over time following hepatitis C virus (HCV) eradication. AIM: To determine if patients who have accrued longer time since sustained virologic response (SVR) have a lower risk of HCC than those with less time since SVR METHODS: We conducted a retrospective cohort study of all HCV-infected Veterans Affairs patients who achieved SVR before 1 January 2018 and remained alive without a diagnosis of HCC as of 1 January 2019 (n = 75,965). We ascertained their baseline characteristics as of 1 January 2019 (time zero), including time accrued since SVR and followed them for the subsequent 12 months for incident HCC. We used multivariable Cox proportional hazards regression to determine the association between time since SVR and HCC risk after adjusting for age, race/ethnicity, sex, diabetes, hypertension, body mass index, alcohol use, Charlson Comorbidity Index, Fibrosis-4 score, HCV genotype, hepatitis B virus co-infection and HIV co-infection. RESULTS: 96.0% were male; mean age was 64.6 years. Among those with cirrhosis (n = 19,678, 25.9%), compared to patients who had accrued only ≥1 to 2 years since SVR (HCC incidence 2.71/100 person-years), those who had accrued >2 to 4 years (2.11/100 person-years, aHR 0.80, 95% CI 0.63-1.01) and >4 to 6 years (1.65/100 person-years, aHR 0.61, 95% CI 0.41-0.90) had progressively lower HCC risk. However, HCC risk appeared to plateau for those with >6 years since SVR (1.68/100 person-years, aHR 0.70, 95% CI 0.46-1.07). Among those without cirrhosis, HCC risk was 0.23-0.27/100 person-years without a significant association between time since SVR and HCC risk. CONCLUSIONS: Among patients with cirrhosis and cured HCV infection, HCC risk declined progressively up to 6 years post-SVR-although it remained well above thresholds that warrant screening. This suggests that time since SVR can inform HCC surveillance strategies in patients with cured HCV infection and can be incorporated into HCC risk prediction models.

Combining FIB-4 and Liver Stiffness Into the FIB-5, a Single Model that Accurately Predicts Complications of Portal Hypertension.

INTRODUCTION: We aimed to combine the fibrosis (FIB)-4 score and fibroscan-derived liver stiffness (LS) into a single score (FIB-5) that predicts incident complications of portal hypertension (PH) in persons with compensated liver disease. METHODS: In this retrospective cohort study, we identified 5849 US veterans who underwent LS measurement from May 01, 2014 to June 30, 2019, and laboratory tests enabling FIB-4 calculation within 6 months of LS measurement. Patients were followed up from the LS measurement date until February 05, 2020, for incident complications of PH. We combined LS values and the individual components of the FIB-4 score (i.e. age, aspartate aminotransferase, alanine aminotransferase, and platelet count) using multivariable Cox proportional hazards modeling and the machine learning algorithm eXtreme gradient boosting to develop the C-FIB-5 and X-FIB-5 models, respectively. Models were internally validated using optimism-corrected measures. RESULTS: Among 5,849 patients, the mean age was 62.8 years, 95.9% were men, and the mean follow-up time was 2.14 ± 1.21 years. Within 3 years after LS measurement date, 116 (2.0%) patients developed complications of PH. The X-FIB-5 (area under the receiver operating characteristic [AUROC] 0.845) and C-FIB-5 scores (AUROC 0.868) demonstrated superior discrimination over LS (AUROC 0.688) and FIB-4 (AUROC 0.672) for predicting incident complications of PH. Both the X-FIB-5 and C-FIB-5 models demonstrated higher classification accuracy across all sensitivity cutoffs when compared with LS or FIB-4 alone. DISCUSSION: We combined LS and the individual components of the FIB-4 into a single scoring system (FIB-5, www.fib5.net ), which can help identify patients with compensated liver disease at risk of developing complications of PH.

Comparison of Moderna versus Pfizer-BioNTech COVID-19 vaccine outcomes: A target trial emulation study in the U.S. Veterans Affairs healthcare system.

Background: mRNA COVID-19 vaccines manufactured by Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) have been shown to be efficacious but have not been compared in head-to-head clinical trials. Methods: We designed this observational study to emulate a target trial of COVID-19 vaccination by BNT162b2 versus mRNA-1273 among persons who underwent vaccination in the national U.S. Veterans Affairs (VA) healthcare system from 11/12/2020 to 25/03/2021 using combined VA and Medicare electronic health records. We identified the best matching mRNA-1273 recipient(s) for each BNT162b2 recipient, using exact/coarsened-exact matching (calendar week, VA integrated service network, age buckets and Charlson comorbidity index buckets) followed by propensity score matching. Vaccine recipients were followed from the date of first vaccine dose until 25/08/2021 for the development of SARS-CoV-2 infection, SARS-CoV-2-related hospitalization or SARS-CoV-2-related death. Findings: Each group included 902,235 well-matched vaccine recipients, followed for a mean of 192 days, during which 16,890 SARS-CoV-2 infections, 3591 SARS-CoV-2-related hospitalizations and 381 SARS-CoV-2-related deaths were documented. Compared to BNT162b2, mRNA-1273 recipients had significantly lower risk of SARS-CoV-2 infection (adjusted hazard ratio [aHR] 0.736, 95% CI 0.696-0.779) and SARS-CoV-2-related hospitalization (aHR 0.633, 95% CI 0.562-0.713), which persisted across all age groups, comorbidity burden categories and black/white race. The differences between mRNA-1273 and BNT162b2 in risk of infection or hospitalization were progressively greater when the follow-up period was longer, i.e. extending to March 31, June 30 or August 25, 2021. These differences were more pronounced when we analyzed separately the outcomes that occurred during the follow-up period from July 1 to August 25, 2021 when the Delta variant became predominant in the U.S. (aHR for infection 0.584, 95% CI 0.533-0.639 and aHR for hospitalization 0.387, 95% 0.311-0.482). SARS-CoV-2-related deaths were less common in mRNA-1273 versus BNT162b2 recipients (168 versus 213) but this difference was not statistically significant (aHR 0.808, 95% CI 0.592-1.103). Interpretation: In conclusion, although absolute rates of infection, hospitalization and death in both vaccine groups were low regardless of the vaccine received, our data suggests that compared to BNT162b2, vaccination with mRNA-1273 resulted in significantly lower rates of SARS-CoV-2-infection and SARS-CoV-2-related hospitalization. These differences were greater with longer follow-up time since vaccination and even more pronounced in the Delta variant era. Funding: U.S. Department of Veterans Affairs, grant numbers COVID19-8900-11 and C19 21-278.

Risk factors for adverse outcomes in emergency versus nonemergency open umbilical hernia repair and opportunities for elective repair in a national cohort of patients with cirrhosis.

BACKGROUND: Whether to perform umbilical hernia repair in patients with cirrhosis is a common dilemma for surgeons. We aimed to determine the incidence, morbidity, and mortality associated with emergency and nonemergency umbilical hernia repair in patients with and without cirrhosis, and to explore opportunities for nonemergency repair. METHODS: Veterans diagnosed with cirrhosis between 2001 and 2014 and a frequency-matched sample of veterans without cirrhosis were followed through September 2017. Veterans Affairs Surgical Quality Improvement Program data provided outcomes and risk factors for mortality after umbilical hernia repair. We performed chart review of a random sample of patients undergoing emergency umbilical hernia repair. RESULTS: Among 119,605 veterans with cirrhosis and 118,125 matched veterans without cirrhosis, the Veterans Affairs Surgical Quality Improvement Program database included 1,475 and 552 open umbilical hernia repairs, respectively. In patients with cirrhosis, 30-day mortality was 1.2% after nonemergency umbilical hernia repair and 12.2% after emergency umbilical hernia repair, contrasting with zero deaths in patients without cirrhosis undergoing these repairs. In patients with cirrhosis but no ascites in the prior month, 30-day mortality after nonemergency umbilical hernia repair was 0.7%, compared to 2.2% in those with ascites. Chart review of patients requiring emergency umbilical hernia repair revealed that elective umbilical hernia repair may have been feasible in 30% of these patients in the prior year; fewer than half of those undergoing emergency umbilical hernia repair had received a general surgery consultation in the prior 2 years. CONCLUSIONS: Nonemergency open umbilical hernia repair was associated with relatively low perioperative mortality in patients with cirrhosis and no recent ascites. About 30% of patients undergoing emergency umbilical hernia repair may have been candidates for nonemergency repair in the prior year.

Associations Between Alcohol Use and Liver-Related Outcomes in a Large National Cohort of Patients With Cirrhosis.

Alcohol use can cause hepatic necroinflammation and worsening portal hypertension in patients with cirrhosis. We aimed to evaluate the associations between degree of alcohol use and clinical liver-related outcomes according to etiology of cirrhosis. In this retrospective cohort analysis, 44,349 U.S. veterans with cirrhosis from alcohol-associated liver disease (ALD), chronic hepatitis C virus (HCV) infection, or nonalcoholic fatty liver disease were identified who completed the Alcohol Use Disorders Identification Test Consumption questionnaire in 2012. Based on this score, level of alcohol use was categorized as none, low level, or unhealthy. Multivariable Cox proportional hazards regression was used to assess for associations between alcohol use and mortality, cirrhosis decompensation (new ascites, encephalopathy, or variceal bleeding), and hepatocellular carcinoma (HCC). At baseline, 36.4% of patients endorsed alcohol use and 17.1% had unhealthy alcohol use. During a mean 4.9 years of follow-up, 25,806 (57.9%) patients died, 9,409 (21.4%) developed a new decompensation, and 4,733 (11.1%) developed HCC. In patients with ALD-cirrhosis and HCV-cirrhosis, unhealthy alcohol use, compared with no alcohol use, was associated with higher risks of mortality (adjusted hazard ratio [aHR] = 1.13, 95% confidence interval [CI] = 1.07-1.19 and aHR = 1.14, 95% CI = 1.08-1.20, respectively) and decompensation (aHR = 1.18, 95% CI = 1.07-1.30 and aHR = 1.08, 95% CI = 1.00-1.16, respectively). Alcohol use was not associated with HCC, regardless of cirrhosis etiology. Conclusion: Unhealthy alcohol use was common in patients with cirrhosis and was associated with higher risks of mortality and cirrhosis decompensation in patients with HCV-cirrhosis and ALD-cirrhosis. Therefore, health care providers should make every effort to help patients achieve abstinence. The lack of association between alcohol use and HCC merits further investigation.

Incidence and Risk Factors of Postoperative Mortality and Morbidity After Elective Versus Emergent Abdominal Surgery in a National Sample of 8193 Patients With Cirrhosis.

OBJECTIVE: To describe the incidence and risk factors for mortality and morbidity in patients with cirrhosis undergoing elective or emergent abdominal surgeries. BACKGROUND: Postoperative morbidity and mortality are higher in patients with cirrhosis; variation by surgical procedure type and cirrhosis severity remain unclear. METHODS: We analyzed prospectively-collected data from the Veterans Affairs (VA) Surgical Quality Improvement Program for 8193 patients with cirrhosis, 864 noncirrhotic controls with chronic hepatitis B infection, and 5468 noncirrhotic controls without chronic liver disease, who underwent abdominal surgery from 2001 to 2017. Data were analyzed using random-effects models controlling for potential confounders. RESULTS: Patients with cirrhosis had significantly higher 30-day mortality than noncirrhotic patients with chronic hepatitis B [4.4% vs 1.3%, adjusted odds ratio (aOR) 2.80, 95% confidence interval (CI) 1.57-4.98] or with no chronic liver disease (0.8%, aOR 4.68, 95% CI 3.27-6.69); mortality difference was highest in patients with Model for End-stage Liver Disease (MELD) score ≥10. Among patients with cirrhosis, postoperative mortality was almost 6 times higher after emergent rather than elective surgery (17.2% vs. 2.1%, aOR 5.82, 95% CI 4.66-7.27). For elective surgeries, 30-day mortality was highest after colorectal resection (7.0%) and lowest after inguinal hernia repair (0.6%). Predictors of postoperative mortality included cirrhosis-related characteristics (high MELD score, low serum albumin, ascites, encephalopathy), surgery-related characteristics (emergent vs elective, type of surgery, intraoperative blood transfusion), comorbidities (chronic obstructive pulmonary disease, cancer, sepsis, ventilator dependence, functional status), and age. CONCLUSIONS: Accurate preoperative risk assessments in patients with cirrhosis should account for cirrhosis severity, comorbidities, type of procedure, and whether the procedure is emergent versus elective.

Alcohol Use and Long-Term Outcomes Among U.S. Veterans Who Received Direct-Acting Antivirals for Hepatitis C Treatment.

Outcomes related to alcohol use after hepatitis C virus (HCV) treatment are unknown in the direct-acting antiviral (DAA) era. We assessed levels of alcohol use before and after HCV treatment and their association with long-term outcomes in a cohort of U.S. veterans. In this retrospective cohort analysis, 29,037 patients who initiated DAA regimens between 2013 and 2015 were followed for a mean of 3.04 years. We categorized alcohol use into three categories (nondrinking, low-level drinking, and unhealthy drinking) using Alcohol Use Disorders Identification Test-Consumption questionnaires administered within 1 year before (baseline) and after treatment. Multivariable Cox proportional hazards regression was used to determine the associations between alcohol use and mortality or liver-related outcomes. Before DAA treatment, 68% of veterans reported nondrinking, 22.9% reported low-level drinking, and 9.1% reported unhealthy drinking. Compared to patients with baseline non-drinking, those with unhealthy drinking had a higher risk of mortality (adjusted hazard ratio [HR] 1.53, 95% confidence interval [CI]: 1.34-1.75) and decompensated cirrhosis (adjusted HR 1.30, 95% CI: 1.06-1.59) and lower likelihood of liver transplantation (adjusted HR 0.24, 95% CI: 0.06-0.92). These associations were greater in patients without sustained virologic response than in those with sustained virologic response. When alcohol use before and after treatment was modeled as a time-varying covariate, similar associations were observed. Survival analysis also found that unhealthy drinking was significantly associated with a lower probability of survival compared with nondrinking. Low-level alcohol use was not associated with increased risk of adverse outcomes. Conclusion: In this large cohort of U.S. veterans with HCV who received DAAs, unhealthy drinking was common and associated with a higher risk of posttreatment mortality. Interventions to achieve alcohol cessation before and during antiviral treatment should be encouraged.

Reduced Incidence of Hepatic Encephalopathy and Higher Odds of Resolution Associated With Eradication of HCV Infection.

BACKGROUND & AIMS: It is unclear whether a sustained virologic response (SVR) to direct-acting antiviral (DAA) therapy reduces the risk of incident hepatic encephalopathy (HE) in patients with hepatitis C virus (HCV) infection or whether it leads to resolution of pre-existent HE. METHODS: We identified 71,457 patients who initiated antiviral treatments in the Veterans Affairs Healthcare System from January 1, 1999 through December 31, 2015; 35,871 patients (58%) received only interferon, 4535 patients (7.2%) received DAAs plus interferon, and 21,948 patients (35%) received DAA-only regimens. We collected data from patients through October 31, 2018, for an average of 6.6 years. We evaluated the association between SVR and the development of incident HE or the resolution of pre-existent HE (defined by cessation of pharmacotherapy) as well as the risk of hospitalization with HE after adjusting for potential confounders. RESULTS: Compared to no SVR, SVR after DAA therapy was associated with a significantly lower risk of developing HE (0.28 vs 1.39 per 100 person-years; adjusted hazard ratio [AHR] 0.41; 95% CI, 0.32-0.51). This association persisted among patients with co-morbid alcohol use disorder and diabetes as well as patients with cirrhosis (AHR, 0.36; 95% CI, 0.31-0.43) and model for end-stage liver disease (MELD) scores of 9 or more (AHR, 0.36; 95% CI, 0.30-0.44). SVR was also associated with reduced risk of hospitalization with HE (AHR, 0.59; 95% CI, 0.43-0.81). Among 2396 patients who were receiving pharmacotherapy for HE at the time of antiviral treatment, SVR was associated with a significantly increased likelihood of HE resolution for those with MELD scores below 9 (AHR, 2.26; 95% CI, 1.74-2.93) but not those with MELD scores of 9 or more. CONCLUSIONS: In a retrospective study of veterans, we found DAA eradication of HCV infection to be associated with a 59% reduction in risk of development of HE and a > 2-fold increased likelihood of resolution of pre-existing HE in all subgroups except patients with MELD scores of 9 or more.

Hepatitis C eradication with direct-acting anti-virals reduces the risk of variceal bleeding.

BACKGROUND: The real-world, long-term benefits of sustained virologic response (SVR) on the risk of variceal bleeding remain unclear. AIM: To assess the association between DAA-induced SVR and post-treatment variceal bleeding METHODS: We identified patients who initiated DAA-only anti-viral treatments in the United States Veterans Affairs healthcare system from 2013 to 2015. We followed patients until 1 January 2019 for the development of gastro-oesophageal variceal bleeding defined by diagnostic codes. We used multivariable Cox proportional hazards regression to assess the association between SVR and development of variceal bleeding, adjusting for potential confounders. RESULTS: Among 33 582 DAA-treated patients, 549 (1.6%) developed variceal bleeding after treatment (mean follow-up 3.1 years). Compared to no SVR, SVR was associated with a significantly lower incidence of variceal bleeding among all patients (0.46 vs 1.26 per 100 patient-years, adjusted hazard ratio [AHR] 0.66, 95% CI 0.52-0.83), among patients with pre-treatment cirrhosis (1.55 vs 2.96 per 100 patient-years, AHR 0.73, 95% CI 0.57-0.93) and among patients without pre-treatment cirrhosis (0.07 vs 0.29 per 100 patient-years, AHR 0.33, 95% CI 0.17-0.65). The risk of variceal bleeding after treatment was lower in those who achieved SVR vs no SVR among patients who had non-bleeding varices (3.5 vs 4.9 per 100 patient-years) or bleeding varices (12.9 vs 16.4 per 100 patient-years) diagnosed before treatment, but these differences were not statistically significant in adjusted analyses. CONCLUSION: DAA-induced SVR is independently associated with a lower risk of variceal bleeding during long-term follow-up in patients with and without pre-treatment cirrhosis. These findings demonstrate an important real-world benefit of DAA treatment.

Eradication of Hepatitis C Virus Is Associated With Reduction in Hematologic Malignancies: Major Differences Between Interferon and Direct-Acting Antivirals.

It is unclear whether eradication of hepatitis C virus (HCV) leads to a reduction in the risk of hematologic malignancies. We aimed to determine the impact of sustained virologic response (SVR) induced by either direct-acting antivirals (DAAs) or interferon (IFN) on the risk of hematologic malignancies. We identified 69,581 patients who initiated antiviral treatment in the Veterans Affairs national health care system from January 1, 1999, to December 31, 2015, including 40,410 (58%) IFN-only regimens, 4,546 (6.5%) DAA + IFN regimens, and 24,625 (35%) DAA-only regimens. We retrospectively followed patients to identify incident cases of hematologic malignancies or monoclonal gammopathy of unknown significance (MGUS), a premalignant precursor of multiple myeloma. Among patients treated with IFN, SVR was significantly associated with a reduction in the risk of lymphoma (adjusted hazard ratio [AHR], 0.70; 95% confidence interval [CI], 0.51-0.97), multiple myeloma (AHR, 0.40; 95% CI, 0.20-0.77), MGUS (AHR, 0.65; 95% CI, 0.42-0.99), or all hematologic malignancies and MGUS combined (AHR, 0.67; 95% CI, 0.53-0.84) over a mean follow-up of 10.6 years. In contrast, among patients treated with DAA, SVR was not associated with the risk of lymphoma, multiple myeloma, MGUS, or all hematologic malignancies and MGUS combined (AHR, 1.08; 95% CI, 0.66-1.78) during a mean follow-up of 2.9 years. Neither IFN-induced SVR nor DAA-induced SVR was associated with risk of colon cancer or prostate cancer, which were chosen a priori as comparison/control malignancies. Conclusion: We describe novel strong associations between IFN-induced SVR and lymphoma, multiple myeloma, MGUS, and all hematologic malignancies combined. Surprisingly, these associations were not observed with DAA-induced SVR.

Increased Risk for Hepatocellular Carcinoma Persists Up to 10 Years After HCV Eradication in Patients With Baseline Cirrhosis or High FIB-4 Scores.

BACKGROUND & AIMS: It is unclear if hepatocellular carcinoma (HCC) risk declines over time after hepatitis C virus (HCV) eradication. We analyzed changes in HCC annual incidence over time following HCV eradication and identified dynamic markers of HCC risk. METHODS: We identified 48,135 patients who initiated HCV antiviral treatment from 2000 through 2015 and achieved a sustained virologic response (SVR) in the Veterans Health Administration (29,033 treated with direct-acting antiviral [DAA] agents and 19,102 treated with interferon-based regimens). Patients were followed after treatment until February 14, 2019 (average 5.4 years), during which 1509 incident HCCs were identified. RESULTS: Among patients with cirrhosis before treatment with DAAs (n = 9784), those with pre-SVR fibrosis-4 (FIB-4) scores ≥3.25 had a higher annual incidence of HCC (3.66%/year) than those with FIB-4 scores <3.25 (1.16%/year) (adjusted hazard ratio 2.14; 95% confidence interval 1.66-2.75). In DAA-treated patients with cirrhosis and FIB-4 scores ≥3.25, annual HCC risk decreased from 3.8%/year in the first year after SVR to 2.4%/year by the fourth year (P=.01). In interferon-treated patients with FIB-4 scores ≥3.25, annual HCC risk remained above 2%/year, even 10 years after SVR. A decrease in FIB-4 scores from ≥3.25 pre-SVR to <3.25 post-SVR was associated with an approximately 50% lower risk of HCC, but the absolute annual risk remained above 2%/year. Patients without cirrhosis before treatment (n = 38,351) had a low risk of HCC, except for those with pre-SVR FIB-4 scores ≥3.25 (HCC risk 1.22%/year) and post-SVR FIB-4 scores ≥3.25 (HCC risk 2.39%/year); risk remained high for many years after SVR. CONCLUSIONS: Patients with cirrhosis before an SVR to treatment for HCV infection continue to have a high risk for HCC (>2%/year) for many years, even if their FIB-4 score decreases, and should continue surveillance. Patients without cirrhosis but with FIB-4 scores ≥3.25 have a high enough risk to merit HCC surveillance, especially if FIB-4 remains ≥3.25 post-SVR.

Development of models estimating the risk of hepatocellular carcinoma after antiviral treatment for hepatitis C.

BACKGROUND & AIMS: Most patients with hepatitis C virus (HCV) infection will undergo antiviral treatment with direct-acting antivirals (DAAs) and achieve sustained virologic response (SVR). We aimed to develop models estimating hepatocellular carcinoma (HCC) risk after antiviral treatment. METHODS: We identified 45,810 patients who initiated antiviral treatment in the Veterans Affairs (VA) national healthcare system from 1/1/2009 to 12/31/2015, including 29,309 (64%) DAA-only regimens and 16,501 (36%) interferon ±â€¯DAA regimens. We retrospectively followed patients until 6/15/2017 to identify incident cases of HCC. We used Cox proportional hazards regression to develop and internally validate models predicting HCC risk using baseline characteristics at the time of antiviral treatment. RESULTS: We identified 1,412 incident cases of HCC diagnosed at least 180 days after initiation of antiviral treatment during a mean follow-up of 2.5 years (range 1.0-7.5 years). Models predicting HCC risk after antiviral treatment were developed and validated separately for four subgroups of patients: cirrhosis/SVR, cirrhosis/no SVR, no cirrhosis/SVR, no cirrhosis/no SVR. Four predictors (age, platelet count, serum aspartate aminotransferase/√alanine aminotransferase ratio and albumin) accounted for most of the models' predictive value, with smaller contributions from sex, race-ethnicity, HCV genotype, body mass index, hemoglobin and serum alpha-fetoprotein. Fitted models were well-calibrated with very good measures of discrimination. Decision curves demonstrated higher net benefit of using model-based HCC risk estimates to determine whether to recommend screening or not compared to the screen-all or screen-none strategies. CONCLUSIONS: We developed and internally validated models that estimate HCC risk following antiviral treatment. These models are available as web-based tools that can be used to inform risk-based HCC surveillance strategies in individual patients. LAY SUMMARY: Most patients with hepatitis C virus have been treated or will be treated with direct-acting antivirals. It is important that we can model the risk of hepatocellular carcinoma in these patients, so that we develop the optimum screening strategy that avoids unnecessary screening, while adequately screening those at increased risk. Herein, we have developed and validated models that are available as web-based tools that can be used to guide screening strategies.

End-of-Life Care for Patients With Advanced Kidney Disease in the US Veterans Affairs Health Care System, 2000-2011.

BACKGROUND: Little is known about patterns of end-of-life care for patients with advanced kidney disease not treated with maintenance dialysis. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: A sample of 14,071 patients with sustained estimated glomerular filtration rates < 15mL/min/1.73m2 treated in the US Veterans Affairs health care system who died during 2000 to 2011. Before death, 12,756 of these patients had been treated with dialysis, 503 had been discussing and/or preparing for dialysis therapy, and for 812, there had been a decision not to pursue dialysis therapy. OUTCOMES: Hospitalization and receipt of an intensive procedure during the final month of life, in-hospital death, and palliative care consultation and hospice enrollment before death. RESULTS: Compared with decedents treated with dialysis, those for whom a decision not to pursue dialysis therapy had been made were less often hospitalized (57.3% vs 76.8%; OR, 0.40 [95% CI, 0.34-0.46]), less often the recipient of an intensive procedure (3.5% vs 24.6%; OR, 0.15 [95% CI, 0.10-0.22]), more often the recipient of a palliative care consultation (52.6% vs 21.6%; OR, 4.19 [95% CI, 3.58-4.90]), more often used hospice services (38.7% vs 18.2%; OR, 3.32 [95% CI, 2.83-3.89]), and died less frequently in a hospital (41.4% vs 57.3%; OR, 0.78 [95% CI, 0.74-0.82]). Hospitalization (55.5%; OR, 0.39 [95% CI, 0.32-0.46]), receipt of an intensive procedure (13.7%; OR, 0.60 [95% CI, 0.46-0.77]), and in-hospital death (39.0%; OR, 0.47 [95% CI, 0.39-0.56]) were also less common among decedents who had been discussing and/or preparing for dialysis therapy, but their use of palliative care and hospice services was similar. LIMITATIONS: Findings may not be generalizable to groups not well represented in the Veterans Affairs health care system. CONCLUSIONS: Among decedents, patients not treated with dialysis before death received less intensive patterns of end-of-life care than those treated with dialysis. Decedents for whom there had been a decision not to pursue dialysis therapy before death were more likely to receive palliative care and hospice.

HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma.

BACKGROUND & AIMS: It is unclear whether direct-acting antiviral (DAA) treatment-induced sustained virologic response (SVR) reduces the risk of hepatocellular carcinoma (HCC) in patients with HCV infection. Therefore, in the current study, our aim was to determine the impact of DAA-induced SVR on HCC risk. METHODS: We identified 62,354 patients who initiated antiviral treatment in the Veterans Affairs (VA) national healthcare system from 1 January 1999 to 31 December 2015, including 35,871 (58%) interferon (IFN)-only regimens, 4,535 (7.2%) DAA + IFN regimens, and 21,948 (35%) DAA-only regimens. We retrospectively followed patients until 15 June 2017 to identify incident cases of HCC. We used Cox proportional hazards regression to determine the association between SVR and HCC risk or between type of antiviral regimen (DAA-only vs. DAA + IFN vs. IFN-only) and HCC risk. RESULTS: We identified 3,271 incident cases of HCC diagnosed at least 180 days after initiation of antiviral treatment during a mean follow-up of 6.1 years. The incidence of HCC was highest in patients with cirrhosis and treatment failure (3.25 per 100 patient-years), followed by cirrhosis and SVR (1.97), no cirrhosis and treatment failure (0.87), and no cirrhosis and SVR (0.24). SVR was associated with a significantly decreased risk of HCC in multivariable models irrespective of whether the antiviral treatment was DAA-only (adjusted hazard ratio [AHR] 0.29; 95% CI 0.23-0.37), DAA + IFN (AHR 0.48; 95% CI 0.32-0.73) or IFN-only (AHR 0.32; 95% CI 0.28-0.37). Receipt of a DAA-only or DAA + IFN regimen was not associated with increased HCC risk compared with receipt of an IFN-only regimen. CONCLUSIONS: DAA-induced SVR is associated with a 71% reduction in HCC risk. Treatment with DAAs is not associated with increased HCC risk compared with treatment with IFN. LAY SUMMARY: It was unclear whether direct-acting antiviral treatment-induced sustained virologic response reduces the risk of liver cancer in patients with HCV infection. We demonstrated that eradication of HCV infection with direct-acting antiviral agents reduces the risk of liver cancer by 71%.

Improvement in Glycemic Control of Type 2 Diabetes After Successful Treatment of Hepatitis C Virus.

OBJECTIVE: Hepatitis C virus (HCV) infection is associated with diabetes and may worsen glycemic control in patients with diabetes. We aimed to investigate whether eradication of HCV infection with direct-acting antiviral (DAA) agents is associated with improved glycemic control in patients with diabetes. RESEARCH DESIGN AND METHODS: We identified 2,435 patients with diabetes who underwent interferon-free and ribavirin-free DAA-based antiviral treatment for HCV in the national Veterans Affairs health care system. Changes in average hemoglobin A1c (HbA1c) level and use of antidiabetic medications 1 year before and after antiviral treatment were compared between patients who achieved sustained virologic response (SVR) and those who did not. RESULTS: Among patients with elevated baseline HbA1c, the drop in HbA1c associated with antiviral treatment was greater in those who achieved SVR (0.98%) than in those who sustained treatment failure (0.65%) (adjusted mean difference 0.34, P = 0.02). Use of antidiabetic medications decreased more in patients who achieved SVR than in those who sustained treatment failure, especially for the use of insulin, which dropped significantly from 41.3% to 38% in patients achieving SVR compared with a slight increase from 49.8% to 51% in those who sustained treatment failure. CONCLUSIONS: DAA-based eradication of HCV is associated with improved glycemic control in patients with diabetes as evidenced by decreased mean HbA1c and decreased insulin use. These endocrine benefits of SVR provide additional justification for considering antiviral treatment in all patients with diabetes.

Effectiveness of hepatitis C antiviral treatment in a USA cohort of veteran patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatitis C virus (HCV) treatment for patients with hepatocellular carcinoma (HCC) was uncommon before direct-acting antiviral (DAA) medications. Real-world effectiveness of DAAs for HCV in patients with HCC is unclear. We describe rates of sustained virologic response (SVR) with DAA regimens by HCV genotype in patients with a history of HCC. METHODS: We identified patients who initiated antiviral treatment between January 1, 2014 and June 30, 2015 in the national Veterans Affairs health care system. Regimens included sofosobuvir, ledipasvir/sofosbuvir, and paritaprevir/ritonavir/ombitasvir and dasabuvir with or without ribavirin. HCC patients were divided into those who were treated with liver transplantation after HCC diagnosis ("HCC/LT" group) and those treated with other modalities prior to antiviral therapy ("HCC" group). RESULTS: Of 17,487 HCV treatment recipients, 624 (3.6%) had prior HCC, including 142 with HCC/LT and 482 with HCC. Overall SVR was 91.1% in non-HCC, 74.4% in HCC, and 94.0% in HCC/LT. Among HCC patients, genotype 1 had the highest SVR overall (79.1% in HCC and 96.4% in HCC/LT), and genotype 3 the lowest (47.0% in HCC and 88.9% in HCC/LT). After adjustment for confounders, the presence of HCC was associated with lower likelihood of SVR overall (AOR 0.38 [95% CI 0.29, 0.48], p<0.001). CONCLUSION: HCV can be cured with DAAs in the majority of patients with prior HCC, and in virtually all HCC patients post-liver transplant. Deferral of HCV treatment until the post-transplant setting may be considered among HCC patients listed for transplantation. LAY SUMMARY: Over three-quarters of patients with hepatocellular carcinoma who have hepatitis C can achieve viral cure with direct-acting antiviral drugs. Among patients with hepatocellular carcinoma who subsequently received liver transplantation, over 90% of patients can achieve viral cure.

Direct-acting antivirals are effective for chronic hepatitis C treatment in elderly patients: a real-world study of 17 487 patients.

BACKGROUND: The mean age of patients with chronic hepatitis C virus (HCV) infection in the USA has been increasing. Despite the increasing proportion of HCV-infected elderly patients, this group is under-represented in clinical trials of HCV treatment. AIM: We aimed to describe the real-world effectiveness of direct-acting antivirals (DAAs) among elderly patients. PATIENTS AND METHODS: We retrospectively identified 17 487 HCV-infected patients who were started on treatment with sofosbuvir, ledipasvir/sofosbuvir, or paritaprevir/ombitasvir/ritonavir/dasabuvir-based regimens in the Veterans Affairs Healthcare System between 1 January 2014 and 30 June 2015. We ascertained sustained virologic response (SVR) rates in patients aged below 55, 55-59, 60-64, 65-69, 70-74, and 75 years or older and performed multivariable logistic regression to determine whether age predicted SVR. RESULTS: Overall unadjusted SVR rates were 91.2% [95% confidence interval (CI): 89.7-92.4], 89.8% (95% CI: 88.8-90.7), 90.8% (95% CI: 90.1-91.6), 91.1% (95% CI: 90.1-91.9), 90.0% (95% CI: 86.9-92.4), and 93.8% (95% CI: 88.8-96.7) in patients aged below 55, 55-59, 60-64, 65-69, 70-74, and 75 years or older. Unadjusted SVR rates were similar in all age groups after stratifying by genotype, treatment regimen, stage of liver disease, and treatment experience. In multivariate models, age was not predictive of SVR after adjusting for confounders. CONCLUSION: DAAs produce high rates of SVR in all age groups, including patients in our oldest age category (≥75 years). Advanced age in and of itself should not be considered a barrier to initiating DAA treatment.

The association between race/ethnicity and the effectiveness of direct antiviral agents for hepatitis C virus infection.

Black race and Hispanic ethnicity were associated with lower rates of sustained virologic response (SVR) to interferon-based treatments for chronic hepatitis C virus infection, whereas Asian race was associated with higher SVR rates compared to white patients. We aimed to describe the association between race/ethnicity and effectiveness of new direct-acting antiviral regimens in the Veterans Affairs health care system nationally. We identified 21,095 hepatitis C virus-infected patients (11,029 [52%] white, 6,171 [29%] black, 1,187 [6%] Hispanic, 348 [2%] Asian/Pacific Islander/American Indian/Alaska Native, and 2,360 [11%] declined/missing race or ethnicity) who initiated antiviral treatment with regimens containing sofosbuvir, simeprevir + sofosbuvir, ledipasvir/sofosbuvir, or paritaprevir/ombitasvir/ritonavir/dasabuvir during the 18-month period from January 1, 2014, to June 30, 2015. Overall SVR rates were 89.8% (95% confidence interval [CI] 89.2-90.4) in white, 89.8% (95% CI 89.0-90.6) in black, 86.0% (95% CI 83.7-88.0) in Hispanic, and 90.7% (95% CI 87.0-93.5) in Asian/Pacific Islander/American Indian/Alaska Native patients. However, after adjustment for baseline characteristics, black (adjusted odds ratio = 0.77, P < 0.001) and Hispanic (adjusted odds ratio = 0.76, P = 0.007) patients were less likely to achieve SVR than white patients, a difference that was not explained by early treatment discontinuations. Among genotype 1-infected patients treated with ledipasvir/sofosbuvir monotherapy, black patients had significantly lower SVR than white patients when treated for 8 weeks but not when treated for 12 weeks. CONCLUSION: Direct-acting antivirals produce high SVR rates in white, black, Hispanic, and Asian/Pacific Islander/American Indian/Alaska Native patients; but after adjusting for baseline characteristics, black race and Hispanic ethnicity remain independent predictors of treatment failure. Short 8-week ledipasvir/sofosbuvir monotherapy regimens should perhaps be avoided in black patients with genotype 1 hepatitis C virus. (Hepatology 2017;65:426-438).