Pamela S. Belperio

Clinical Case Registries: Simultaneous Local and National Disease Registries for Population Quality Management

The Department of Veterans Affairs (VA) has a system-wide, patient-centric electronic medical record system (EMR) within which the authors developed the Clinical Case Registries (CCR) to support population-centric delivery and evaluation of VA medical care. To date, the authors have applied the CCR to populations with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Local components use diagnosis codes and laboratory test results to identify patients who may have HIV or HCV and support queries on local care delivery with customizable reports. For each patient in a local registry, key EMR data are transferred via HL7 messaging to a single national registry. From 128 local registry systems, over 60,000 and 320,000 veterans in VA care have been identified as having HIV and HCV, respectively, and entered in the national database. Local and national reports covering demographics, resource usage, quality of care metrics and medication safety issues have been generated.

Real‐world effectiveness of ledipasvir/sofosbuvir in 4,365 treatment‐naive, genotype 1 hepatitis C‐infected patients

Real‐world effectiveness data are needed to inform hepatitis C virus (HCV) treatment decisions. The uptake of ledipasvir/sofosbuvir (LDV/SOF) regimens across health care settings has been rapid, but variations often occur in clinical practice. The aim of this study was to assess sustained virologic response (SVR) of LDV/SOF±ribavirin (RBV) in routine medical practice. This observational, intent‐to‐treat cohort was comprised of 4,365 genotype 1, treatment‐naive, HCV‐infected veterans treated with LDV/SOF±RBV. SVR rates were 91.3% (3,191/3,495) for LDV/SOF and 92.0% (527/573) for LDV/SOF+RBV (P = 0.65). African American race (odds ratio 0.70, 95% confidence interval 0.54‐0.90, P  = 0.004) and FIB‐4 >3.25 (odds ratio 0.56, 95% confidence interval 0.43‐0.71, P < 0.001) were independently associated with decreased likelihood of SVR; age, sex, body mass index, decompensated liver disease, diabetes, genotype 1 subtype, and regimen did not predict SVR. In models limited to those who completed 12 weeks of treatment, African American race was no longer a significant predictor of SVR but FIB‐4 >3.25 (odds ratio 0.35, 95% confidence interval 0.24‐0.50, P < 0.001) remained. Among those without cirrhosis (defined by FIB‐4 ≤3.25) and with baseline HCV RNA<6,000,000 IU/mL, SVR rates were 93.2% (1,020/1,094) for those who completed 8 weeks of therapy and 96.6% (875/906) for those who completed 12 weeks of therapy (P = 0.001). Conclusions: In this real‐world cohort, SVR rates with LDV/SOF±RBV nearly matched the rates reported in clinical trials and were consistently high across all subgroups; those without cirrhosis but with HCV RNA<6,000,000 IU/mL were less likely to achieve SVR with 8 weeks compared to 12 weeks of therapy, although the numeric difference in SVR rates was small. (Hepatology 2016;64:405‐414)

Evaluation of hepatitis B reactivation among 62,920 veterans treated with oral hepatitis C antivirals

Reactivation of hepatitis B virus (HBV) has been reported in hepatitis C virus–infected individuals receiving direct‐acting antiviral (DAA) therapy. The overall risk among patients with current or prior HBV infection in the context of DAA treatment is unknown. The aim of this evaluation was to identify and characterize HBV reactivation among veterans treated with oral DAA therapy. This retrospective evaluation included 62,290 hepatitis C virus–infected veterans completing oral DAA treatment. Baseline HBV infection status for each veteran was identified from HBV laboratory data performed prior to DAA initiation. To assess for HBV reactivation and hepatitis we identified all hepatitis B surface antigen (HBsAg), HBV DNA, and alanine aminotransferase results obtained while on DAA treatment or 7 days after. HBV reactivation was defined as a >1000 IU/mL increase in HBV DNA or HBsAg detection in a person who was previously negative. Prior to DAA treatment 85.5% (53,784/62,920) had HBsAg testing and 0.70% (377/53,784) were positive; 84.6% (53,237/62,920) had a hepatitis B surface antibody test, of which 42.2% (22,479/53,237) were positive. In all, 9 of 62,290 patients treated with DAAs had evidence of HBV reactivation occurring while on DAA treatment. Eight occurred in patients known to be HBsAg‐positive, and 1 occurred in a patient known to be isolated hepatitis B core antibody–positive. Seventeen other patients had small increases in HBV DNA levels that did not qualify as HBV reactivation. Only 3 of the 9 patients identified with HBV reactivation in this cohort exhibited peak alanine aminotransferase elevations >2 times the upper limit of normal. Conclusion: HBV reactivation of varying severity, even in the setting of isolated hepatitis B core antibody, with or without accompanying hepatitis can occur—though the occurrence of accompanying severe hepatitis was rare. (Hepatology 2017;66:27–36).

National quality forum performance measures for HIV/AIDS care: the Department of Veterans Affairs' experience.

BACKGROUND Information technology promises to improve health care through reporting of standardized quality-of-care measures. In 2008, the National Quality Forum (NQF) first endorsed performance measures for human immunodeficiency virus (HIV)/AIDS care. Little is known about performance on these measures in routine medical practice. We assessed performance using available electronic data for the large, diverse population with HIV in the Department of Veterans Affairs (VA) and evaluated the influence of patient and resource factors. METHODS In a retrospective analysis of observational data for 21 564 patients with HIV receiving VA medical care in 2008, we determined performance rates for 10 NQF measures for HIV/AIDS care for the VA nationwide and for 73 facilities with caseloads of 100 or more patients with HIV. RESULTS National rates for 6 measures were greater than 80%; the remaining measures and their rates were as follows: annual syphilis screening (54%), tuberculosis screening (65%), Pneumocystis pneumonia prophylaxis (72%), and HIV RNA control (73%). For all measures, rates varied across facilities. In multivariate logistic regression models, African Americans and hard drug users were less likely to access care and less likely to receive HIV-specific care but more likely to receive indicated general medical care. Resource factors (number of primary care/infectious disease outpatient visits, duration of care, and larger facility caseload) were associated with increased likelihood of receipt of indicated general and HIV-specific care. CONCLUSIONS National performance rates were generally high, but variation in rates across facilities revealed room for improvement. Both patient and resource factors had an impact on the likelihood of receipt of indicated care.

Impact of Race/Ethnicity and Gender on HCV Screening and Prevalence Among US Veterans in Department of Veterans Affairs Care

OBJECTIVES We assessed HCV screening and prevalence among veterans and estimated the potential impact of complete birth cohort screening, accounting for the disparate HCV disease burden by race/ethnicity and gender. METHODS We used the Department of Veterans Affairs (VA) Corporate Data Warehouse to identify birth dates, gender, race/ethnicity, and laboratory tests for veterans with at least 1 VA outpatient visit in 2012. We calculated HCV screening rates, prevalence, and HCV infection incident diagnosis. RESULTS Among 5,499,743 veterans, 54.7% had HCV screening through the VA. In more than 2.9 million veterans screened, HCV prevalence was 6.1% overall and highest among Blacks (11.8%), particularly Black men born in 1945 to 1965 (17.7%). HCV infection incident diagnosis in 2012 was 5.9% for men and 2.3% for women. An estimated additional 48,928 male veterans, including 12,291 Black men, and 1484 female veterans would potentially be identified as HCV infected with full birth cohort screening. CONCLUSIONS HCV prevalence was markedly elevated among veterans born in 1945 to 1965, with substantial variation by race/ethnicity and gender. Full adoption of birth cohort screening may reveal substantial numbers of veterans with previously unknown HCV infection.

Effectiveness of All-Oral Antiviral Regimens in 996 Human Immunodeficiency Virus/Hepatitis C Virus Genotype 1-Coinfected Patients Treated in Routine Practice

Background. Large cohorts are needed to assess human immunodeficiency virus (HIV)/hepatitis C virus (HCV) real-world treatment outcomes. We examined the effectiveness of ledipasvir/sofosbuvir with or without ribavirin (LDV/SOF ± RBV) and ombitasvir/ paritaprevir/ritonavir plus dasabuvir (OPrD) ± RBV in HIV/HCV genotype 1 (GT1)-coinfected patients initiating HCV therapy in clinical practice. Methods. Observational intent-to-treat cohort analysis using the Veterans Affairs Clinical Case Registry to identify HIV/HCV GT1-coinfected veterans initiating 12 weeks of LDV/SOF ± RBV or OPrD ± RBV. Multivariate models of sustained virologic response (SVR) included age, race, cirrhosis, proton pump inhibitor (PPI) prescription, prior HCV treatment, body mass index, genotype subtype, and HCV treatment regimen. Results. Nine hundred ninety-six HIV/HCV GT1-coinfected veterans initiated therapy: 757 LDV/SOF, 138 LDV/SOF + RBV, 28 OPrD, and 73 OPrD + RBV. Overall SVR was 90.9% (823/905); LDV/SOF 92.1% (631/685), LDV/SOF + RBV 86.3% (113/131), OPrD 88.9% (24/27), and OPrD + RBV 88.7% (55/62). SVR was 85.9% (176/205) and 92.4% (647/700) in those with and without cirrhosis (P = .006). SVR was similar between African Americans (90.5% [546/603]) and all others (91.7% [277/302]). PPI use with LDV/SOF ± RBV did not affect SVR (89.7% [131/146] with PPI and 91.5% [613/670] without PPI). Cirrhosis was predictive of reduced SVR (0.51 [95% confidence interval {CI}, .31-.87]; P = .01). Median creatinine change did not differ among patients receiving LDV/SOF and tenofovir disoproxil fumarate (TDF) without a protease inhibitor (PI) (0.18 [interquartile range {IQR}, 0.08-0.30]; n = 372), LDV/SOF and TDF/PI (0.17 [IQR, 0.04-0.30]; n = 100), and LDV/SOF without TDF (0.15 [IQR, 0.00-0.30]; n = 423). Conclusions. SVR rates in HIV/HCV GT1-coinfected patients were high. African American race or PPI use with LDV/SOF ± RBV was not associated with lower SVR rates, but cirrhosis was. Renal function did not worsen on LDV/SOF regimens with TDF.

Real-world effectiveness and predictors of sustained virological response with all-oral therapy in 21,242 hepatitis C genotype-1 patients.

BACKGROUND Predictors of sustained virological response (SVR) to all-oral HCV regimens can inform nuanced treatment decisions. We evaluated effectiveness and identified predictors of SVR for ledipasvir/sofosbuvir ± ribavirin (LDV/SOF ±RBV) and ombitasvir/paritaprevir/ritonavir + dasabuvir (OPrD) ±RBV in patients treated in routine practice. METHODS Observational, intent-to-treat cohort of 21,142 genotype-1 patients initiating 8 or 12 weeks of LDV/SOF ±RBV or 12 weeks of OPrD ±RBV at any Veterans Affairs facility. Multivariate logistic regression models were constructed to model SVR and identify predictors. RESULTS SVR was 91.2% (9,781/10,720) for LDV/SOF, 89.6% (3,266/3,646) for LDV/SOF+RBV, 91.7% (1,197/1,306) for OPrD and 87.8% (3,365/3,832) for OPrD+RBV. For LDV/SOF ±RBV, reduced odds of SVR occurred in African-Americans (0.80, 95% CI 0.70, 0.92, P<0.001), body mass index (BMI)<25 (0.77, 95% CI 0.66, 0.90, P<0.001), BMI≥30 (0.77, 95% CI 0.67, 0.89, P<0.001), proton pump inhibitors (PPIs; 0.81, 95% CI 0.71, 0.92, P<0.001), decompensated liver disease (0.58, 95% CI 0.45, 0.74, P<0.001) and FIB4>3.25 (0.60, 95% CI 0.53, 0.69, P<0.001). For OPrD ±RBV, FIB-4>3.25 negatively predicted SVR (0.72, 95% CI 0.59, 0.88, P<0.001). Detectable 4-week on-treatment HCV RNA≥15 IU/ml reduced SVR odds for both regimens (LDV/SOF ±RBV OR 0.49, 95% CI 0.41, 0.58, P<0.001; OPrD ±RBV OR 0.38, 95% CI 0.29, 0.50, P<0.001). Receipt of OPrD+RBV compared to LDV/SOF reduced odds of SVR (OR 0.70, 95% CI 0.62, 0.80, P<0.001). Mental health diagnosis did not impact likelihood of SVR. CONCLUSIONS The diversity and size of this cohort allowed for extensive examination of regimen-specific predictors of SVR. FIB-4>3.25 and detectable 4-week on-treatment HCV RNA had the greatest negative impact. African-American race, low or high BMI, and PPIs negatively impacted odds of SVR for LDV/SOF ±RBV. Mental health diagnoses did not.

Cascade of Care for Hepatitis C Virus Infection Within the US Veterans Health Administration

OBJECTIVES We measured the quality of HCV care using a cascade of HCV care model. METHODS We estimated the number of patients diagnosed with chronic HCV, linked to HCV care, treated with HCV antivirals, and having achieved a sustained virologic response (SVR) in the electronic medical record data from the Veterans Health Administrations Corporate Data Warehouse and the HCV Clinical Case Registry in 2013. RESULTS Of the estimated 233,898 patients with chronic HCV, 77% (181,168) were diagnosed, 69% (160,794) were linked to HCV care, 17% (39,388) were treated with HCV antivirals, and 7% (15,983) had achieved SVR. CONCLUSIONS This Cascade of HCV Care provides a clinically relevant model to measure the quality of HCV care within a health care system and to compare HCV care across health systems.

Impact of Sustained Virologic Response with Direct-Acting Antiviral Treatment on Mortality in Patients with Advanced Liver Disease

The impact of sustained virologic response (SVR) on mortality after direct‐acting antiviral treatment is not well documented. This study evaluated the impact of direct‐acting antiviral–induced SVR on all‐cause mortality and on incident hepatocellular carcinoma (HCC) in 15,059 hepatitis C virus–infected patients with advanced liver disease defined by a FIB‐4 >3.25. Overall, 1,067 patients did not achieve SVR (no SVR) and 13,992 patients achieved SVR. In a mean follow‐up period of approximately 1.6 years, 195 no SVR patients and 598 SVR patients died. Mortality rates were 12.3 deaths/100 patient years of follow‐up for no SVR patients and 2.6 deaths/100 patient years for SVR patients, a 78.9% reduction (P < 0.001). Among patients without a prior diagnosis of HCC, 140 no SVR patients and 397 SVR patients were diagnosed with incident HCC. HCC rates were 11.5 HCCs/100 patient years for no SVR patients and 1.9 HCCs/100 patient years for SVR patients, an 83.5% reduction (P < 0.001). In multivariable Cox proportional hazard models controlling for baseline demographics, clinical characteristics, and comorbidities, SVR was independently associated with reduced risk of death compared to no SVR (hazard ratio, 0.26; 95% confidence interval, 0.22‐0.31; P < 0.001). A history of decompensated liver disease (hazard ratio, 1.57; 95% confidence interval, 1.34‐1.83; P < 0.001) and decreased albumin (hazard ratio, 2.70 per 1 g/dL decrease; 95% confidence interval, 2.38‐3.12; P < 0.001) were independently associated with increased risk of death. Conclusion: Those achieving SVR after direct‐acting antiviral treatment had significantly lower all‐cause mortality and lower incident HCC rates than those who did not achieve SVR.

Curing Hepatitis C Virus Infection: Best Practices From the U.S. Department of Veterans Affairs

Since the introduction of direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection, the U.S. Department of Veterans Affairs (VA) has made extensive progress in advancing HCV care and curing substantial numbers of infected veterans. As the nations largest provider of care to patients with HCV infection, the VA is uniquely suited to inform the recent National Strategy for the Elimination of Viral Hepatitis, produced by the National Academies of Sciences, Engineering, and Medicine (1). The national strategy emphasizes prevention, screening, and universal treatmentareas in which the VA has become a recognized leader (13). The strategy presents specific actions to reduce the burden of HCV infection, with 5 distinct areas outlined: information, interventions, service delivery, financing, and research (1, 2). The VAs best practices and successes, informed by extensive population health data analysis, national guidance, and policies, may inform other health care organizations and providers in reducing the national burden of HCV infection. The VAs commitment to prioritizing HCV care is reflected in dedicated funding for HCV treatment, unrestricted access to DAAs, detailed guidance on individualizing care, and the establishment of Veterans Integrated Service Network Hepatitis C Innovation Teams (HITs) (4). This work, in collaboration with other key VA offices, is supported by the VAs National Viral Hepatitis Program, which develops national guidance, policy, and patient and provider resources (5). The resources and efforts that the VA and its HCV providers have dedicated to prioritizing this disease at every level of the organization are being tangibly realized. Between January 2014 and June 2017, a total of 92000 HCV-infected veterans initiated DAA treatment, achieving cure rates exceeding 90% (6, 7) (U.S. Department of Veterans Affairs. Unpublished data). As of July 2017, a total of 51000 veterans remain potentially eligible for treatment, compared with more than 168000 three years ago (8) (U.S. Department of Veterans Affairs. Unpublished data). The Table shows the characteristics of the HCV-infected veteran population before all-oral DAA treatment became available (U.S. Department of Veterans Affairs. Unpublished data). Table. Demographic and Clinical Characteristics of the HCV-Infected Veteran Population Before All-Oral Direct-Acting Antiviral Treatment Became Available in 2014 Although elimination seems attainable, the VA recognizes the reality of the HCV epidemic and populationnamely, many of those in care who remain to be treated have complex substance use, mental health, and medical comorbidities, and many are challenged by homelessness, lack of transportation, and rurality, which have been considerable barriers to engagement in care and treatment. Epidemiologic control of HCV in the VA includes a long tail of persistence driven by system, patient, and care delivery determinants (Figure 1). Figure 1. Number of veterans with HCV infection in VA care requiring HCV antiviral treatment over time. On 1 October 2013, a total of 168708 veterans in VA care were identified as having chronic HCV infection requiring treatment; by 1 July 2017, the number had decreased to 50986. The trend line indicates the projected number of veterans requiring treatment through 30 September 2021. HCV= hepatitis C virus; VA= U.S. Department of Veterans Affairs. Information: Population Health Management Using national databases and analytics, the VA employs population health management strategies to measure, monitor, and identify trends in HCV care, gaining insight into patterns of access and tailoring care provision accordingly. Veterans in VA care who are diagnosed with HCV infection are followed in the VAs National Hepatitis C Clinical Case Registry, developed in part to ensure that veterans with chronic HCV infection are linked to care (9). This registry, which is used for both local and national population reporting, provides administrative data on the number of known HCV-infected patients together with clinical information, including patient and disease characteristics, care delivery site, treatment, and clinical outcomes. The VAs Corporate Data Warehouse, a repository of electronic medical record data, has spurred the creation of local and regional HCV dashboards, which provide access to patient-specific data reports for real-time intervention and tracking. These sources allow for comprehensive monitoring of incidence, prevalence, and disease course; national, regional, and individual-facility data are posted, enabling providers, teams, and leadership to assess progress and goals. This leveraging of health systems data transforms numbers into knowledge and guides providers and the VA toward more informed and effective delivery of care for each veteran. Essential Interventions Improved Case Identification A critical first step in improving HCV care is identifying infected persons. In 2012, the Centers for Disease Control and Prevention and the U.S. Preventive Services Task Force each developed recommendations for testing persons born between 1945 and 1965, a cohort determined to have the highest prevalence of HCV infection (10, 11). Before 2014, VA guidance recommended risk-based testing and testing of Vietnam-era veterans, a group that largely overlaps with the 19451965 birth cohort (3). Using information systems to track screening, the VA has identified and targeted additional populations at risk for HCV infection, including African American males, in whom prevalence is more than double that in white males (17.7% vs. 8.3%); homeless persons, who have a prevalence more than triple that in nonhomeless persons (13.4% vs. 3.5%); and persons who inject drugs (12, 13). To date, the VA has screened 79.5% of the 2.7 million veterans in the 19451965 birth cohort and 89.6% of its homeless population (13). Using updated calculations of annual prevalence, the VA estimates that only about 15000 additional veterans in VA care would test positive for HCV if the entire population were screened. Testing Initiatives The most important initiatives the VA has undertaken to increase HCV testing include national electronic point-of-care clinical reminders for HCV risk assessment and testing, automated letters recommending HCV testing (which also serve as laboratory orders when presented to VA laboratories), and weekly primary care panel reviews identifying patients with upcoming appointments who require testing. To emphasize this as a priority, the VA added birth cohort testing as a national performance measure in 2015 and reports quarterly screening rates by facility and region. To ensure complete testing and an efficient patient-centered approach, the VA recommends automatic reflex confirmatory HCV RNA testing with the same laboratory sample for all patients with a positive antibody test result; greater than 97% adherence was achieved in 2015. These factors have resulted in a 3% to 4% annual increase in the proportion of veterans screened for HCV infection, substantially higher than in other large health care systems (14). Hepatitis C Innovative Team Collaborative Recognizing that care is not delivered the same way in all settings, regional HITs, comprising a multidisciplinary group of 15 to 30 health care providers, administrators, and information technology and system redesign specialists, have implemented Lean Process Improvement methods to maximize clinical expertise and redesign the process of HCV testing, treatment, and management to provide the most efficient and effective care possible for the populations they serve (15, 16). The HIT Collaborative has enabled a clinically focused foundation to share and implement best practices across and within teams, supported by local and regional administrators (17). The development of the HIT infrastructure, which has leveraged and supported the work of dedicated VA providers, has been a critical implementation arm that has allowed the VA to respond to challenges in funding variability and other access issues that have arisen since the introduction of DAAs. Service Delivery: Improving Linkage and Access Population health data, the HIT infrastructure, and legions of dedicated providers have been instrumental in enhancing the VAs outreach and engagement. Efforts have focused on raising provider and staff awareness about HCV testing and treatment availability, promoting direct outreach to at-risk veterans, utilizing mobile phone applications and secure messaging, and broadening veteran community outreach through national and local social media and advertising campaigns. Expanding Capacity Telemedicine and Electronic Technologies The VA has focused on increasing specialist capacity through telemedicine and real-time clinical video teleconferencing, whereby HCV clinicians provide care to patients and/or consultation to providers at other locations. Largely modeled on Project ECHO (Extension for Community Healthcare Outcomes) (18), the expanded HCV VA-ECHO model includes urban, rural, and homeless clinics and incorporates pharmacist-led provider programs and mental health and substance use programs to aid providers in treating HCV infection in patients with these comorbidities. The HCV VA-ECHO program was associated with a 20% higher HCV treatment initiation rate than sites without this program (19). By leveraging electronic databases, HCV teams can identify treatment candidates, notify primary care providers through the electronic medical record, and provide immediate HCV management recommendations. Similarly, primary care providers can efficiently consult HCV specialists on management and treatment via interprovider electronic consults, eliminating the need for specialty visits. Nonphysician Advanced Practice Providers The VA has emphasized the expansion of HCV care beyond specialty providers. A substantial portion of HCV treatment has shifted from liver and infectious disease specialty cli