Identification of hepatic steatosis among persons with and without HIV using natural language processing.

BACKGROUND: Steatotic liver disease (SLD) is a growing phenomenon, and our understanding of its determinants has been limited by our ability to identify it clinically. Natural language processing (NLP) can potentially identify hepatic steatosis systematically within large clinical repositories of imaging reports. We validated the performance of an NLP algorithm for the identification of SLD in clinical imaging reports and applied this tool to a large population of people with and without HIV. METHODS: Patients were included in the analysis if they enrolled in the Veterans Aging Cohort Study between 2001 and 2017, had an imaging report inclusive of the liver, and had ≥2 years of observation before the imaging study. SLD was considered present when reports contained the terms "fatty," "steatosis," "steatotic," or "steatohepatitis." The performance of the SLD NLP algorithm was compared to a clinical review of 800 reports. We then applied the NLP algorithm to the first eligible imaging study and compared patient characteristics by SLD and HIV status. RESULTS: NLP achieved 100% sensitivity and 88.5% positive predictive value for the identification of SLD. When applied to 26,706 eligible Veterans Aging Cohort Study patient imaging reports, SLD was identified in 72.2% and did not significantly differ by HIV status. SLD was associated with a higher prevalence of metabolic comorbidities, alcohol use disorder, and hepatitis B and C, but not HIV infection. CONCLUSIONS: While limited to those undergoing radiologic study, the NLP algorithm accurately identified SLD in people with and without HIV and offers a valuable tool to evaluate the determinants and consequences of hepatic steatosis.

Severe Acute Liver Injury After Hepatotoxic Medication Initiation in Real-World Data.

Importance: Current approaches to classify the hepatotoxic potential of medications are based on cumulative case reports of acute liver injury (ALI), which do not consider the size of the exposed population. There is little evidence from real-world data (data relating to patient health status and/or the delivery of health care routinely collected from sources outside of a research setting) on incidence rates of severe ALI after initiation of medications, accounting for duration of exposure. Objective: To identify the most potentially hepatotoxic medications based on real-world incidence rates of severe ALI and to examine how these rates compare with categorization based on case reports. Design, Setting, and Participants: This series of cohort studies obtained data from the US Department of Veterans Affairs on persons without preexisting liver or biliary disease who initiated a suspected hepatotoxic medication in the outpatient setting between October 1, 2000, and September 30, 2021. Data were analyzed from June 2020 to November 2023. Exposures: Outpatient initiation of any one of 194 medications with 4 or more published reports of hepatotoxicity. Main Outcomes and Measures: Hospitalization for severe ALI, defined by either inpatient: (1) alanine aminotransferase level greater than 120 U/L plus total bilirubin level greater than 2.0 mg/dL or (2) international normalized ratio of 1.5 or higher plus total bilirubin level greater than 2.0 mg/dL recorded within the first 2 days of admission. Acute or chronic liver or biliary disease diagnosis recorded during follow-up or as a discharge diagnosis of a hospitalization for severe ALI resulted in censoring. This study calculated age- and sex-adjusted incidence rates of severe ALI and compared observed rates with hepatotoxicity categories based on cumulative published case reports. Results: The study included 7 899 888 patients across 194 medication cohorts (mean [SD] age, 64.4 [16.4] years, 7 305 558 males [92.5%], 4 354 136 individuals [55.1%] had polypharmacy). Incidence rates of severe ALI ranged from 0 events per 10 000 person-years (candesartan, minocycline) to 86.4 events per 10 000 person-years (stavudine). Seven medications (stavudine, erlotinib, lenalidomide or thalidomide, chlorpromazine, metronidazole, prochlorperazine, and isoniazid) exhibited rates of 10.0 or more events per 10 000 person-years, and 10 (moxifloxacin, azathioprine, levofloxacin, clarithromycin, ketoconazole, fluconazole, captopril, amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and ciprofloxacin) had rates between 5.0 and 9.9 events per 10 000 person-years. Of these 17 medications with the highest observed rates of severe ALI, 11 (64%) were not included in the highest hepatotoxicity category when based on case reports. Conclusions and Relevance: In this study, incidence rates of severe ALI using real-world data identified the most potentially hepatotoxic medications and can serve as a tool to investigate hepatotoxicity safety signals obtained from case reports. Case report counts did not accurately reflect the observed rates of severe ALI after medication initiation.

Risk of Arterial and Venous Thrombotic Events Among Patients with COVID-19: A Multi-National Collaboration of Regulatory Agencies from Canada, Europe, and United States.

Purpose: Few studies have examined how the absolute risk of thromboembolism with COVID-19 has evolved over time across different countries. Researchers from the European Medicines Agency, Health Canada, and the United States (US) Food and Drug Administration established a collaboration to evaluate the absolute risk of arterial (ATE) and venous thromboembolism (VTE) in the 90 days after diagnosis of COVID-19 in the ambulatory (eg, outpatient, emergency department, nursing facility) setting from seven countries across North America (Canada, US) and Europe (England, Germany, Italy, Netherlands, and Spain) within periods before and during COVID-19 vaccine availability. Patients and Methods: We conducted cohort studies of patients initially diagnosed with COVID-19 in the ambulatory setting from the seven specified countries. Patients were followed for 90 days after COVID-19 diagnosis. The primary outcomes were ATE and VTE over 90 days from diagnosis date. We measured country-level estimates of 90-day absolute risk (with 95% confidence intervals) of ATE and VTE. Results: The seven cohorts included 1,061,565 patients initially diagnosed with COVID-19 in the ambulatory setting before COVID-19 vaccines were available (through November 2020). The 90-day absolute risk of ATE during this period ranged from 0.11% (0.09-0.13%) in Canada to 1.01% (0.97-1.05%) in the US, and the 90-day absolute risk of VTE ranged from 0.23% (0.21-0.26%) in Canada to 0.84% (0.80-0.89%) in England. The seven cohorts included 3,544,062 patients with COVID-19 during vaccine availability (beginning December 2020). The 90-day absolute risk of ATE during this period ranged from 0.06% (0.06-0.07%) in England to 1.04% (1.01-1.06%) in the US, and the 90-day absolute risk of VTE ranged from 0.25% (0.24-0.26%) in England to 1.02% (0.99-1.04%) in the US. Conclusion: There was heterogeneity by country in 90-day absolute risk of ATE and VTE after ambulatory COVID-19 diagnosis both before and during COVID-19 vaccine availability.

Hepatitis B care cascade among people with HIV/HBV coinfection in the North American AIDS Cohort Collaboration on Research and Design, 2012-2016.

A care cascade is a critical tool for evaluating delivery of care for chronic infections across sequential stages, starting with diagnosis and ending with viral suppression. However, there have been few data describing the hepatitis B virus (HBV) care cascade among people living with HIV infection who have HBV coinfection. We conducted a cross-sectional study among people living with HIV and HBV coinfection receiving care between January 1, 2012 and December 31, 2016 within 13 United States and Canadian clinical cohorts contributing data to the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). We evaluated each of the steps in this cascade, including: 1) laboratory-confirmed HBV infection, 2) tenofovir-based or entecavir-based HBV therapy prescribed, 3) HBV DNA measured during treatment, and 4) viral suppression achieved via undetectable HBV DNA. Among 3,953 persons with laboratory-confirmed HBV (median age, 50 years; 6.5% female; 43.8% were Black; 7.1% were Hispanic), 3,592 (90.9%; 95% confidence interval, 90.0-91.8%) were prescribed tenofovir-based antiretroviral therapy or entecavir along with their antiretroviral therapy regimen, 2,281 (57.7%; 95% confidence interval, 56.2-59.2%) had HBV DNA measured while on therapy, and 1,624 (41.1%; 95% confidence interval, 39.5-42.6) achieved an undetectable HBV DNA during HBV treatment. Our study identified significant gaps in measurement of HBV DNA and suppression of HBV viremia among people living with HIV and HBV coinfection in the United States and Canada. Periodic evaluation of the HBV care cascade among persons with HIV/HBV will be critical to monitoring success in completion of each step.

Risk of admission to hospital with arterial or venous thromboembolism among patients diagnosed in the ambulatory setting with covid-19 compared with influenza: retrospective cohort study.

Objective: To measure the 90 day risk of arterial thromboembolism and venous thromboembolism among patients diagnosed with covid-19 in the ambulatory (ie, outpatient, emergency department, or institutional) setting during periods before and during covid-19 vaccine availability and compare results to patients with ambulatory diagnosed influenza. Design: Retrospective cohort study. Setting: Four integrated health systems and two national health insurers in the US Food and Drug Administration's Sentinel System. Participants: Patients with ambulatory diagnosed covid-19 when vaccines were unavailable in the US (period 1, 1 April-30 November 2020; n=272 065) and when vaccines were available in the US (period 2, 1 December 2020-31 May 2021; n=342 103), and patients with ambulatory diagnosed influenza (1 October 2018-30 April 2019; n=118 618). Main outcome measures: Arterial thromboembolism (hospital diagnosis of acute myocardial infarction or ischemic stroke) and venous thromboembolism (hospital diagnosis of acute deep venous thrombosis or pulmonary embolism) within 90 days after ambulatory covid-19 or influenza diagnosis. We developed propensity scores to account for differences between the cohorts and used weighted Cox regression to estimate adjusted hazard ratios of outcomes with 95% confidence intervals for covid-19 during periods 1 and 2 versus influenza. Results: 90 day absolute risk of arterial thromboembolism with covid-19 was 1.01% (95% confidence interval 0.97% to 1.05%) during period 1, 1.06% (1.03% to 1.10%) during period 2, and with influenza was 0.45% (0.41% to 0.49%). The risk of arterial thromboembolism was higher for patients with covid-19 during period 1 (adjusted hazard ratio 1.53 (95% confidence interval 1.38 to 1.69)) and period 2 (1.69 (1.53 to 1.86)) than for patients with influenza. 90 day absolute risk of venous thromboembolism with covid-19 was 0.73% (0.70% to 0.77%) during period 1, 0.88% (0.84 to 0.91%) during period 2, and with influenza was 0.18% (0.16% to 0.21%). Risk of venous thromboembolism was higher with covid-19 during period 1 (adjusted hazard ratio 2.86 (2.46 to 3.32)) and period 2 (3.56 (3.08 to 4.12)) than with influenza. Conclusions: Patients diagnosed with covid-19 in the ambulatory setting had a higher 90 day risk of admission to hospital with arterial thromboembolism and venous thromboembolism both before and after covid-19 vaccine availability compared with patients with influenza.

Association of COVID-19 vs Influenza With Risk of Arterial and Venous Thrombotic Events Among Hospitalized Patients.

Importance: The incidence of arterial thromboembolism and venous thromboembolism in persons with COVID-19 remains unclear. Objective: To measure the 90-day risk of arterial thromboembolism and venous thromboembolism in patients hospitalized with COVID-19 before or during COVID-19 vaccine availability vs patients hospitalized with influenza. Design, Setting, and Participants: Retrospective cohort study of 41 443 patients hospitalized with COVID-19 before vaccine availability (April-November 2020), 44 194 patients hospitalized with COVID-19 during vaccine availability (December 2020-May 2021), and 8269 patients hospitalized with influenza (October 2018-April 2019) in the US Food and Drug Administration Sentinel System (data from 2 national health insurers and 4 regional integrated health systems). Exposures: COVID-19 or influenza (identified by hospital diagnosis or nucleic acid test). Main Outcomes and Measures: Hospital diagnosis of arterial thromboembolism (acute myocardial infarction or ischemic stroke) and venous thromboembolism (deep vein thrombosis or pulmonary embolism) within 90 days. Outcomes were ascertained through July 2019 for patients with influenza and through August 2021 for patients with COVID-19. Propensity scores with fine stratification were developed to account for differences between the influenza and COVID-19 cohorts. Weighted Cox regression was used to estimate the adjusted hazard ratios (HRs) for outcomes during each COVID-19 vaccine availability period vs the influenza period. Results: A total of 85 637 patients with COVID-19 (mean age, 72 [SD, 13.0] years; 50.5% were male) and 8269 with influenza (mean age, 72 [SD, 13.3] years; 45.0% were male) were included. The 90-day absolute risk of arterial thromboembolism was 14.4% (95% CI, 13.6%-15.2%) in patients with influenza vs 15.8% (95% CI, 15.5%-16.2%) in patients with COVID-19 before vaccine availability (risk difference, 1.4% [95% CI, 1.0%-2.3%]) and 16.3% (95% CI, 16.0%-16.6%) in patients with COVID-19 during vaccine availability (risk difference, 1.9% [95% CI, 1.1%-2.7%]). Compared with patients with influenza, the risk of arterial thromboembolism was not significantly higher among patients with COVID-19 before vaccine availability (adjusted HR, 1.04 [95% CI, 0.97-1.11]) or during vaccine availability (adjusted HR, 1.07 [95% CI, 1.00-1.14]). The 90-day absolute risk of venous thromboembolism was 5.3% (95% CI, 4.9%-5.8%) in patients with influenza vs 9.5% (95% CI, 9.2%-9.7%) in patients with COVID-19 before vaccine availability (risk difference, 4.1% [95% CI, 3.6%-4.7%]) and 10.9% (95% CI, 10.6%-11.1%) in patients with COVID-19 during vaccine availability (risk difference, 5.5% [95% CI, 5.0%-6.1%]). Compared with patients with influenza, the risk of venous thromboembolism was significantly higher among patients with COVID-19 before vaccine availability (adjusted HR, 1.60 [95% CI, 1.43-1.79]) and during vaccine availability (adjusted HR, 1.89 [95% CI, 1.68-2.12]). Conclusions and Relevance: Based on data from a US public health surveillance system, hospitalization with COVID-19 before and during vaccine availability, vs hospitalization with influenza in 2018-2019, was significantly associated with a higher risk of venous thromboembolism within 90 days, but there was no significant difference in the risk of arterial thromboembolism within 90 days.

Protease inhibitor-based direct-acting antivirals are associated with increased risk of aminotransferase elevations but not hepatic dysfunction or decompensation.

BACKGROUND & AIMS: Cases of acute liver injury (ALI) have been reported among chronic HCV-infected patients receiving protease inhibitor (PI)-based direct-acting antiviral (DAA) regimens, but no analyses have compared the risk of ALI in patients receiving PI- vs. non-PI-based DAAs. Thus, we compared the risk of 3 ALI outcomes between patients (by baseline Fibrosis-4 [FIB-4] group) receiving PI-based or non-PI-based DAAs. METHODS: We conducted a cohort study of 18,498 patients receiving PI-based DAA therapy (paritaprevir/ritonavir/ombitasvir±dasabuvir, elbasvir/grazoprevir, glecaprevir/pibrentasvir) matched 1:1 on propensity score to those receiving non-PI-based DAAs (sofosbuvir/ledipasvir, sofosbuvir/velpatasvir) in the 1945-1965 Veterans Birth Cohort (2014-2019). During exposure to DAA therapy, we determined development of: i) alanine aminotransferase (ALT) >200 U/L, ii) severe hepatic dysfunction (coagulopathy with hyperbilirubinemia), and iii) hepatic decompensation. We used Cox regression to determine hazard ratios (HRs) with 95% CIs for each ALI outcome within groups defined by baseline FIB-4 (≤3.25; >3.25). RESULTS: Among patients with baseline FIB-4 ≤3.25, those receiving PIs had a higher risk of ALT >200 U/L (HR 3.98; 95% CI 2.37-6.68), but not severe hepatic dysfunction (HR 0.67; 95% CI 0.19-2.39) or hepatic decompensation (HR 1.01; 95% CI 0.29-3.49), compared to those receiving non-PI-based regimens. For those with baseline FIB-4 >3.25, those receiving PIs had a higher risk of ALT >200 U/L (HR, 2.15; 95% CI 1.09-4.26), but not severe hepatic dysfunction (HR, 1.23 [0.64-2.38]) or hepatic decompensation (HR, 0.87; 95% CI 0.41-1.87), compared to those receiving non-PI-based regimens CONCLUSION: While risk of incident ALT elevations was increased in those receiving PI-based DAAs in both FIB-4 groups, the risk of severe hepatic dysfunction and hepatic decompensation did not differ between patients receiving PI- or non-PI-based DAAs in either FIB-4 group. LAY SUMMARY: Cases of liver injury have been reported among patients treated with protease inhibitor-based direct-acting antivirals for hepatitis C infection, but it is not clear if the risk of liver injury among people starting these drugs is increased compared to those starting non-protease inhibitor-based therapy. In this study, patients receiving protease inhibitor-based treatment had a higher risk of liver inflammation than those receiving a non-protease inhibitor-based treatment, regardless of the presence of pre-treatment advanced liver fibrosis/cirrhosis. However, the risk of severe liver dysfunction and decompensation were not higher for patients treated with protease inhibitor-based regimens.

Validity of ICD-10-CM diagnoses to identify hospitalizations for serious infections among patients treated with biologic therapies.

PURPOSE: Identifying hospitalizations for serious infections among patients dispensed biologic therapies within healthcare databases is important for post-marketing surveillance of these drugs. We determined the positive predictive value (PPV) of an ICD-10-CM-based diagnostic coding algorithm to identify hospitalization for serious infection among patients dispensed biologic therapy within the FDA's Sentinel Distributed Database. METHODS: We identified health plan members who met the following algorithm criteria: (1) hospital ICD-10-CM discharge diagnosis of serious infection between July 1, 2016 and August 31, 2018; (2) either outpatient/emergency department infection diagnosis or outpatient antimicrobial treatment within 7 days prior to hospitalization; (3) inflammatory bowel disease, psoriasis, or rheumatological diagnosis within 1 year prior to hospitalization, and (4) were dispensed outpatient biologic therapy within 90 days prior to admission. Medical records were reviewed by infectious disease clinicians to adjudicate hospitalizations for serious infection. The PPV (95% confidence interval [CI]) for confirmed events was determined after further weighting by the prevalence of the type of serious infection in the database. RESULTS: Among 223 selected health plan members who met the algorithm, 209 (93.7% [95% CI, 90.1%-96.9%]) were confirmed to have a hospitalization for serious infection. After weighting by the prevalence of the type of serious infection, the PPV of the ICD-10-CM algorithm identifying a hospitalization for serious infection was 80.2% (95% CI, 75.3%-84.7%). CONCLUSIONS: The ICD-10-CM-based algorithm for hospitalization for serious infection among patients dispensed biologic therapies within the Sentinel Distributed Database had 80% PPV for confirmed events and could be considered for use within pharmacoepidemiologic studies.

Risk of HCC With Hepatitis B Viremia Among HIV/HBV-Coinfected Persons in North America.

BACKGROUND AND AIMS: Chronic HBV is the predominant cause of HCC worldwide. Although HBV coinfection is common in HIV, the determinants of HCC in HIV/HBV coinfection are poorly characterized. We examined the predictors of HCC in a multicohort study of individuals coinfected with HIV/HBV. APPROACH AND RESULTS: We included persons coinfected with HIV/HBV within 22 cohorts of the North American AIDS Cohort Collaboration on Research and Design (1995-2016). First occurrence of HCC was verified by medical record review and/or cancer registry. We used multivariable Cox regression to determine adjusted HRs (aHRs [95% CIs]) of factors assessed at cohort entry (age, sex, race, body mass index), ever during observation (heavy alcohol use, HCV), or time-updated (HIV RNA, CD4+ percentage, diabetes mellitus, HBV DNA). Among 8,354 individuals coinfected with HIV/HBV (median age, 43 years; 93% male; 52.4% non-White), 115 HCC cases were diagnosed over 65,392 person-years (incidence rate, 1.8 [95% CI, 1.5-2.1] events/1,000 person-years). Risk factors for HCC included age 40-49 years (aHR, 1.97 [1.22-3.17]), age ≥50 years (aHR, 2.55 [1.49-4.35]), HCV coinfection (aHR, 1.61 [1.07-2.40]), and heavy alcohol use (aHR, 1.52 [1.04-2.23]), while time-updated HIV RNA >500 copies/mL (aHR, 0.90 [0.56-1.43]) and time-updated CD4+ percentage <14% (aHR, 1.03 [0.56-1.90]) were not. The risk of HCC was increased with time-updated HBV DNA >200 IU/mL (aHR, 2.22 [1.42-3.47]) and was higher with each 1.0 log10 IU/mL increase in time-updated HBV DNA (aHR, 1.18 [1.05-1.34]). HBV suppression with HBV-active antiretroviral therapy (ART) for ≥1 year significantly reduced HCC risk (aHR, 0.42 [0.24-0.73]). CONCLUSION: Individuals coinfected with HIV/HBV on ART with detectable HBV viremia remain at risk for HCC. To gain maximal benefit from ART for HCC prevention, sustained HBV suppression is necessary.

Brief Report: Accuracy of FIB-4 for Cirrhosis in People Living With HIV and Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) may develop in the absence of cirrhosis in HIV, and determining how often this occurs can provide insights into mechanisms of carcinogenesis. Studies evaluating the prevalence of cirrhosis in the setting of HCC among people living with HIV (PLWH) often rely on noninvasive markers, such as the Fibrosis-4 Index for Hepatic Fibrosis (FIB-4). However, the accuracy of FIB-4 for cirrhosis in the setting of HCC has not been determined among PLWH. METHODS: We conducted a cross-sectional study among PLWH in the Veterans Aging Cohort Study with VA cancer registry-confirmed HCC diagnosed between 1999 and 2015. FIB-4 was calculated using the age, alanine aminotransferase, aspartate aminotransferase, and platelet count obtained closest to, but within 1 year before, HCC diagnosis. Medical records were reviewed within 1 year before HCC diagnosis to determine the cirrhosis status. We evaluated the area under the receiver-operating characteristic curve and performance characteristics of FIB-4 for confirmed cirrhosis. RESULTS: Incident HCC was diagnosed in 302 PLWH. After medical record review, 203 (67.2%, 95% confidence interval: 61.6% to 72.5%) had evidence of cirrhosis. FIB-4 identified patients with cirrhosis with an area under the receiver-operating characteristic curve of 0.67 (95% confidence interval: 0.60 to 0.73). FIB-4 scores >5.0 had a positive predictive value >80% and specificity of >77%, negative predictive value of <41%, and sensitivity of <45%. CONCLUSION: The accuracy of FIB-4 for cirrhosis in the setting of HIV and HCC is modest and may result in misclassification of cirrhosis in this population.

HIV RNA, CD4+ Percentage, and Risk of Hepatocellular Carcinoma by Cirrhosis Status.

BACKGROUND: Despite increasing incidence of hepatocellular carcinoma (HCC) among HIV-infected patients, it remains unclear if HIV-related factors contribute to development of HCC. We examined if higher or prolonged HIV viremia and lower CD4+ cell percentage were associated with HCC. METHODS: We conducted a cohort study of HIV-infected individuals who had HIV RNA, CD4+, and CD8+ cell counts and percentages assessed in the Veterans Aging Cohort Study (1999-2015). HCC was ascertained using Veterans Health Administration cancer registries and electronic records. Cox regression was used to determine hazard ratios (HR, 95% confidence interval [CI]) of HCC associated with higher current HIV RNA, longer duration of detectable HIV viremia (≥500 copies/mL), and current CD4+ cell percentage less than 14%, adjusting for traditional HCC risk factors. Analyses were stratified by previously validated diagnoses of cirrhosis prior to start of follow-up. RESULTS: Among 35 659 HIV-infected patients, 302 (0.8%) developed HCC over 281 441 person-years (incidence rate = 107.3 per 100 000 person-years). Among patients without baseline cirrhosis, higher HIV RNA (HR = 1.25, 95% CI = 1.12 to 1.40, per 1.0 log10 copies/mL) and 12 or more months of detectable HIV (HR = 1.47, 95% CI = 1.02 to 2.11) were independently associated with higher risk of HCC. CD4+ percentage less than 14% was not associated with HCC in any model. Hepatitis C coinfection was a statistically significant predictor of HCC regardless of baseline cirrhosis status. CONCLUSION: Among HIV-infected patients without baseline cirrhosis, higher HIV RNA and longer duration of HIV viremia increased risk of HCC, independent of traditional HCC risk factors. This is the strongest evidence to date that HIV viremia contributes to risk of HCC in this group.

Differences in Pathology, Staging, and Treatment between HIV+ and Uninfected Patients with Microscopically Confirmed Hepatocellular Carcinoma.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) is substantially higher among HIV-infected (HIV+) than uninfected persons. It remains unclear if HCC in the setting of HIV infection is morphologically distinct or more aggressive. METHODS: We evaluated differences in tumor pathology in a cohort of HIV+ and uninfected patients with microscopically confirmed HCC in the Veterans Aging Cohort Study from 2000 to 2015. We reviewed pathology reports and medical records to determine Barcelona Clinic Liver Cancer stage (BCLC), HCC treatment, and survival by HIV status. Multivariable Cox regression was used to determine the hazard ratio [HR; 95% confidence interval (CI)] of death associated with HIV infection after microscopic confirmation. RESULTS: Among 873 patients with HCC (399 HIV+), 140 HIV+ and 178 uninfected persons underwent liver tissue sampling and had microscopically confirmed HCC. There were no differences in histologic features of the tumor between HIV+ and uninfected patients, including tumor differentiation (well differentiated, 19% vs. 28%, P = 0.16) and lymphovascular invasion (6% vs. 7%, P = 0.17) or presence of advanced hepatic fibrosis (40% vs. 39%, P = 0.90). There were no differences in BCLC stage (P = 0.06) or treatment (P = 0.29) by HIV status. After adjustment for risk factors, risk of death was higher among HIV-infected than uninfected patients (HR = 1.37; 95% CI, 1.02-1.85). CONCLUSIONS: We found no differences in HCC tumor characteristics or background hepatic parenchyma by HIV status, yet HIV was associated with poorer survival. Of note, pathology reports often omitted these characteristics. IMPACT: Systematic evaluation of HCC pathology by HIV status is needed to understand tumor characteristics associated with improved survival.

Concordance of hospitalizations between Clinical Practice Research Datalink and linked Hospital Episode Statistics among patients treated with oral antidiabetic therapies.

PURPOSE: The ability of the Clinical Practice Research Datalink (CPRD) to ascertain all-cause hospitalizations remains unknown. We determined the proportion of hospitalizations in CPRD that were also recorded in Hospital Episode Statistics (HES), and vice versa, among patients initiating oral antidiabetic (OAD) therapy. METHODS: We conducted a retrospective cohort study from October 2009 to September 2012 among OAD-treated patients registered with general practitioners who contribute to CPRD and consent to HES linkage. In CPRD, we identified initial hospitalizations for each calendar year by an Inpatient Referral, Consultation Type code, or Read code indicating an inpatient episode and determined if an admission date was recorded in HES within ±30 days. We then identified initial HES admission dates and determined if a hospitalization was documented in CPRD within ±30 days. Sensitivity analyses were conducted utilizing HES discharge, rather than admission, dates. RESULTS: Among 8574 OAD-treated HES-linked patients in CPRD, 6574 initial hospitalizations across the study period were identified in CPRD, and 5188 (78.9% [95% CI, 77.9%-79.9%]) were confirmed by a HES admission date within ±30 days (median difference, ±3 days [IQR, 1-7 days]). Among 8609 initial hospital admissions in HES, 4803 (55.7% [95% CI, 54.7%-56.8%]) hospitalizations were recorded in CPRD within ±30 days (median difference, ±4 days [IQR, 1-9 days]). Similar results were observed using HES discharge dates. CONCLUSION: A substantial minority of patient-level hospitalization data are nonconcordant between HES and CPRD. Pharmacoepidemiologic studies within CPRD that seek to identify hospitalizations should consider linkage with HES to ensure adequate ascertainment of inpatient events.

Determinants of Liver Complications Among HIV/Hepatitis B Virus-Coinfected Patients.

BACKGROUND: Hepatitis B virus (HBV) infection is a leading cause of end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC) in HIV. Factors contributing to the high rates of liver complications among HIV/HBV-coinfected individuals remain unknown. SETTING: North American AIDS Cohort Collaboration on Research and Design. METHODS: We performed a retrospective cohort study among HIV/HBV-coinfected patients in 10 US and Canadian cohorts of the North American AIDS Cohort Collaboration on Research and Design that validated ESLD (ascites, spontaneous bacterial peritonitis, variceal hemorrhage, and/or hepatic encephalopathy) and HCC diagnoses from 1996 to 2010. Multivariable Cox regression was used to examine adjusted hazard ratios [aHRs with 95% confidence interval (CIs)] of liver complications (first occurrence of ESLD or HCC) associated with hypothesized determinants and with increasing durations of HIV suppression (≤500 copies/mL). RESULTS: Among 3573 HIV/HBV patients with 13,790 person-years of follow-up, 111 liver complications occurred (incidence rate = 8.0 [95% CI: 6.6 to 9.7] events/1000 person-years). Rates of liver complication were increased with non-black/non-Hispanic race [aHR = 1.76 (1.13-2.74)], diabetes mellitus [aHR = 2.07 (1.20-3.57)], lower time-updated CD4 cell count [<200 cells/mm: aHR = 2.59 (1.36-4.91); 201-499 cells/mm: aHR = 1.75 (1.01-3.06) versus ≥500 cells/mm], heavy alcohol use [aHR = 1.58 (1.04-2.39)], and higher FIB-4 at start of follow-up [>3.25: aHR = 9.79 (5.73-16.74); 1.45-3.25: aHR = 3.20 (1.87-5.47) versus FIB-4 <1.45]. HIV suppression for ≥6 months was associated with lower liver complication rates compared with those with unsuppressed HIV [aHR = 0.56 (0.35-0.91)]. CONCLUSIONS: Non-black/non-Hispanic race, diabetes, lower CD4 cell count, heavy alcohol use, and advanced liver fibrosis were determinants of liver complications among HIV/HBV patients. Sustained HIV suppression should be a focus for HIV/HBV-coinfected patients to reduce the risks of ESLD/HCC.

Absolute Insurer Denial of Direct-Acting Antiviral Therapy for Hepatitis C: A National Specialty Pharmacy Cohort Study.

BACKGROUND: Despite the availability of new direct-acting antiviral (DAA) regimens, changes in DAA reimbursement criteria, and a public health focus on hepatitis C virus (HCV) elimination, it remains unclear if public and private insurers have increased access to these therapies over time. We evaluated changes in the incidence of absolute denial of DAA therapy over time and by insurance type. METHODS: We conducted a prospective cohort study among patients who had a DAA prescription submitted from January 2016 to April 2017 to Diplomat Pharmacy, Inc., which provides HCV pharmacy services across the United States. The main outcome was absolute denial of DAA prescription, defined as lack of fill approval by the insurer. We calculated the incidence of absolute denial, overall and by insurance type (Medicaid, Medicare, commercial), for the 16-month study period and each quarter. RESULTS: Among 9025 patients from 45 states prescribed a DAA regimen (4702 covered by Medicaid, 1821 Medicare, 2502 commercial insurance), 3200 (35.5%; 95% confidence interval, 34.5%-36.5%) were absolutely denied treatment. Absolute denial was more common among patients covered by commercial insurance (52.4%) than Medicaid (34.5%, P < .001) or Medicare (14.7%, P < .001). The incidence of absolute denial increased across each quarter of the study period, overall (27.7% in first quarter to 43.8% in last quarter; test for trend, P < .001) and for each insurance type (test for trend, P < .001 for each type). CONCLUSIONS: Despite the availability of new DAA regimens and changes in restrictions of these therapies, absolute denials of DAA regimens by insurers have remained high and increased over time, regardless of insurance type.

Validity of diagnostic codes to identify hospitalizations for infections among patients treated with oral anti-diabetic drugs.

PURPOSE: Identification of hospitalizations for infection is important for post-marketing surveillance of drugs, but the validity of using diagnosis codes to identify these events is unknown. Differentiating between hospitalization for and with infection is important, as the latter is common and less likely to arise from pre-admission exposure to drugs. We determined positive predictive values (PPVs) of diagnostic coding-based algorithms to identify hospitalization for infection among patients prescribed oral anti-diabetic drugs (OADs). METHODS: We identified patients initiating OADs within 2 United States claims databases (Medicare, HealthCore Integrated Research DatabaseSM [HIRDSM ]) and 2 United Kingdom electronic medical record databases (Clinical Practice Research Datalink [CPRD], The Health Improvement Network [THIN]) from 2009 to 2014. To identify potential hospitalizations for infection, we selected patients with a hospital diagnosis of infection and, within 7 days prior to hospitalization, either an outpatient/emergency department visit with an infection diagnosis or outpatient antimicrobial treatment. Hospital records were reviewed by infectious disease specialists to adjudicate hospital admissions for infection. PPVs for confirmed outcomes were determined for each database. RESULTS: Code-based algorithms to identify hospitalization for infection had PPVs exceeding 80% within Medicare (PPV, 83% [90/109]; 95% CI, 74-89%), HIRDSM (PPV, 89% [73/82]; 95% CI, 80-95%), and THIN (PPV, 86% [12/14]; 95% CI, 57-98%) but not within CPRD (PPV, 67% [14/21]; 95% CI, 43-85%). CONCLUSIONS: Algorithms identifying hospitalization for infection utilizing hospital diagnoses along with antecedent outpatient/emergency infection diagnoses or antimicrobial therapy had sufficiently high PPVs for confirmed events within Medicare, HIRDSM , and THIN to enable their use for pharmacoepidemiologic research.

Postauthorization safety study of the DPP-4 inhibitor saxagliptin: a large-scale multinational family of cohort studies of five outcomes.

OBJECTIVE: To evaluate the risk of serious adverse events among patients with type 2 diabetes mellitus initiating saxagliptin compared with oral antidiabetic drugs (OADs) in classes other than dipeptidyl peptidase-4 (DPP-4) inhibitors. RESEARCH DESIGN AND METHODS: Cohort studies using 2009-2014 data from two UK medical record data sources (Clinical Practice Research Datalink, The Health Improvement Network) and two USA claims-based data sources (HealthCore Integrated Research Database, Medicare). All eligible adult patients newly prescribed saxagliptin (n=110 740) and random samples of up to 10 matched initiators of non-DPP-4 inhibitor OADs within each data source were selected (n=913 384). Outcomes were hospitalized major adverse cardiovascular events (MACE), acute kidney injury (AKI), acute liver failure (ALF), infections, and severe hypersensitivity events, evaluated using diagnostic coding algorithms and medical records. Cox regression was used to determine HRs with 95% CIs for each outcome. Meta-analyses across data sources were performed for each outcome as feasible. RESULTS: There were no increased incidence rates or risk of MACE, AKI, ALF, infection, or severe hypersensitivity reactions among saxagliptin initiators compared with other OAD initiators within any data source. Meta-analyses demonstrated a reduced risk of hospitalization/death from MACE (HR 0.91, 95% CI 0.85 to 0.97) and no increased risk of hospitalization for infection (HR 0.97, 95% CI 0.93 to 1.02) or AKI (HR 0.99, 95% CI 0.88 to 1.11) associated with saxagliptin initiation. ALF and hypersensitivity events were too rare to permit meta-analysis. CONCLUSIONS: Saxagliptin initiation was not associated with increased risk of MACE, infection, AKI, ALF, or severe hypersensitivity reactions in clinical practice settings. TRIAL REGISTRATION NUMBER: NCT01086280, NCT01086293, NCT01086319, NCT01086306, and NCT01377935; Results.

Risk of liver decompensation with cumulative use of mitochondrial toxic nucleoside analogues in HIV/hepatitis C virus coinfection.

PURPOSE: Among patients dually infected with human immunodeficiency virus (HIV) and chronic hepatitis C virus (HCV), use of antiretroviral therapy (ART) containing mitochondrial toxic nucleoside reverse transcriptase inhibitors (mtNRTIs) might induce chronic hepatic injury, which could accelerate HCV-associated liver fibrosis and increase the risk of hepatic decompensation and death. METHODS: We conducted a cohort study among 1747 HIV/HCV patients initiating NRTI-containing ART within the Veterans Aging Cohort Study (2002-2009) to determine if cumulative mtNRTI use increased the risk of hepatic decompensation and death among HIV-/HCV-coinfected patients. Separate marginal structural models were used to estimate hazard ratios (HRs) of each outcome associated with cumulative exposure to ART regimens that contain mtNRTIs versus regimens that contain other NRTIs. RESULTS: Over 7033 person-years, we observed 97 (5.6%) decompensation events (incidence rate, 13.8/1000 person-years) and 125 (7.2%) deaths (incidence rate, 17.8 events/1000 person-years). The risk of hepatic decompensation increased with cumulative mtNRTI use (1-11 mo: HR, 1.79 [95% confidence interval (CI), 0.74-4.31]; 12-35 mo: HR, 1.39 [95% CI, 0.68-2.87]; 36-71 mo: HR, 2.27 [95% CI, 0.92-5.60]; >71 mo: HR, 4.66 [95% CI, 1.04-20.83]; P = .045) versus nonuse. Cumulative mtNRTI use also increased risk of death (1-11 mo: HR, 2.24 [95% CI, 1.04-4.81]; 12-35 mo: HR, 2.05 [95% CI, 0.68-6.20]; 36-71 mo: HR, 3.04 [95% CI, 1.12-8.26]; >71 mo: HR, 3.93 [95% CI, 0.75-20.50]; P = .030). CONCLUSIONS: These findings suggest that cumulative mtNRTI use may increase the risk of hepatic decompensation and death in HIV/HCV coinfection. These drugs should be avoided when alternatives exist for HIV/HCV patients.

Risk of Acute Liver Injury With Antiretroviral Therapy by Viral Hepatitis Status.

BACKGROUND: The risk of hepatotoxicity with antiretroviral therapy (ART) remains unknown. We determined the comparative risk of acute liver injury (ALI) for antiretroviral drugs, classes, and regimens, by viral hepatitis status. METHODS: We followed a cohort of 10 083 human immunodeficiency virus (HIV)-infected persons in Kaiser Permanente Northern California (n = 2099) from 2004 to 2010 and the Veterans Aging Cohort Study (n = 7984) from 2004 to 2012. Within the first year of ART, we determined occurrence of (1) liver aminotransferases >200 U/L and (2) severe ALI (coagulopathy with hyperbilirubinemia). We used Cox regression to determine hazard ratios (HRs) with 95% confidence intervals (CIs) of endpoints among initiators of nucleos(t)ide analogue combinations, antiretroviral classes, and ART regimens, all stratified by viral hepatitis status. RESULTS: Liver aminotransferases >200 U/L developed in 206 (2%) persons and occurred more frequently among HIV/viral hepatitis-coinfected than HIV-monoinfected persons (116.1 vs 20.7 events/1000 person-years; P < .001). No evidence of differential risk was found between initiators of abacavir/lamivudine versus tenofovir/emtricitabine among coinfected (HR, 0.68; 95% CI, .29-1.57) or HIV-monoinfected (HR, 1.19; 95% CI, .47-2.97) groups. Coinfected patients had a higher risk of aminotransferases >200 U/L after initiation with a protease inhibitor than nonnucleoside reverse-transcriptase inhibitor (HR, 2.01; 95% CI, 1.36-2.96). Severe ALI (30 events; 0.3%) occurred more frequently in coinfected persons (15.9 vs 3.1 events/1000 person-years; P < .001) but was too uncommon to evaluate in adjusted analyses. CONCLUSIONS: Within the year after ART initiation, aminotransferase elevations were infrequently observed and rarely led to severe ALI. Protease inhibitor use was associated with a higher risk of aminotransferase elevations among viral hepatitis-coinfected patients.