Division of Viral Hepatitis, CDC Performance of Algorithms Using Serial Hepatitis C RNA Tests to Predict Treatment and Cure Among Patients Infected with Chronic Hepatitis C Ademola Osinubi, MS Division of Viral Hepatitis, CDC MAY 19, 2018

Background ~3 million with chronic hepatitis C virus (HCV) infection HCV is a leading cause of liver related deaths Liver cirrhosis Liver cancer End stage liver disease Chronic HCV infection is curable Interferon-based therapy (1991-2013) –> 50% cure rates Direct Acting Antivirals (2013-present) – > 90% cure rates Highly effective across all HCV genotypes Minimal adverse effects High cost of treatment is a barrier to access Allison.2015.J Hepatol

Electronic Medical Record (EMR) EMR has been used to monitor HCV patients from diagnosis to cure, but required manual chart review We created a HCV registry from EMR data abstraction to assess HCV treatment and cure rates * Friedman.2013.Am J Pub Health

Grady Health System Grady Memorial Hospital is public safety net hospital for the city of Atlanta and the largest hospital in the state of Georgia

Objectives Using HCV RNA test results to assess the sensitivity and positive predictive value for various algorithms to determine: Treatment initiation with direct acting antivirals Cure measured by sustained virologic response

Methods: Data source HCV-related treatment information included: Patient-level data was extracted from Grady’s EMR Data used to create HCV registry of HCV-infected patients HCV-related laboratory data included: Anti-HCV antibody results HCV RNA test results Genotype test results HCV antiviral treatment regimens HCV-related treatment information included: Direct acting antiviral regimen Date of treatment initiation/completion

Analytic methods Included patients with HCV RNA test date or treatment start date after 1 Dec 2013 Developed 5 algorithms as a proxy: Treatment with direct acting antivirals (DAA) Cure measured by sustained virologic response (SVR) Calculated sensitivity and positive predictive value for each algorithm

Sensitivity and Positive Predictive Value Definitions treated/cured not treated/cured algorithm true Sensitivity=a/a + c PPV = a/a + b false Gold standards to compare serial HCV RNA algorithms Treatment: DAA regimen with start date or completion date SVR (cure): HCV RNA undetectable >24 weeks after treatment start date or >12 weeks after treatment completion date True positives a False positives b False negatives c True negatives d

Treatment Path for a Typical Patient with Chronic HCV-infection Receiving Care at Grady Time 4 weeks 12 weeks 24 weeks 36 weeks HCV RNA+ RX START RVR RX ENDS SVR 24 SVR 12 1ST HCVRNA TESTING 2ND HCV RNA TESTING 3RD HCV RNA TESTING 4TH HCVRNA TESTING 5TH HCV RNA TESTING The registry was designed to capture five most recent HCV RNA test results in order to capture all these HCV RNA testing events * Rx: Prescription; RVR: Rapid Virologic Response; SVR: sustained virologic resonse=cure

Algorithms as a proxy to determine Treatment

Any one of these 4 results reported Treatment Algorithm 1 An initial detectable HCV RNA test result followed by one sequential HCV RNA test result Time 4 weeks 12 weeks 24 weeks 36 weeks HCV RNA+ RX START RVR RX ENDS SVR 24 SVR 12 1ST HCV RNA TESTING 2ND HCV RNA TESTING 3RD HCV RNA TESTING 4TH HCVRNA TESTING 5TH HCV RNA TESTING HCV RNA + * Rx: Prescription; RVR: Rapid Virologic Response; SVR: sustained virologic resonse=cure Any one of these 4 results reported

Results: Treatment Algorithm 1 (N=1807) outcome treated not treated Sens % PPV % 1 Yes 667 475 96 58 No 31 634 2 Y 644 278 92 70 N 54 831 3 608 154 87 80 90 955 4 596 134 85 82 102 975 5 515 50 74 91 183 1059 Total treated with DAA in HCV registry by gold standard: 698

Any one of these test results is 10-fold less Treatment Algorithm 2 An initial detectable HCV RNA test result followed by one sequential HCV RNA test result that indicated at least 10–fold decrease in viral load compared to the initial test Time 4 weeks 12 weeks 24 weeks 36 weeks HCV RNA+ RX START RVR RX ENDS SVR 24 SVR 12 1ST HCVRNA TESTING 2ND HCV RNA TESTING 3RD HCV RNA TESTING 4TH HCVRNA TESTING 5TH HCV RNA TESTING HCV RNA+ * Rx: Prescription; RVR: Rapid Virologic Response; SVR: sustained virologic resonse=cure Any one of these test results is 10-fold less

Results: Treatment Algorithm 2 (N=1807) outcome treated not treated Sens % PPV % 1 Y 667 475 96 58 N 31 634 2 Yes 644 278 92 70 No 54 831 3 608 154 87 80 90 955 4 596 134 85 82 102 975 5 515 50 74 91 183 1059 Total treated with DAA in HCV registry by gold standard: 698

Any two of these test results reported Treatment Algorithm 3 An initial detectable HCV RNA test result followed by two sequential HCV RNA test results Time 4 weeks 12 weeks 24 weeks 36 weeks HCV RNA+ RX START RVR RX ENDS SVR 24 SVR 12 1ST HCVRNA TESTING 2ND HCV RNA TESTING 3RD HCV RNA TESTING 4TH HCVRNA TESTING 5TH HCV RNA TESTING HCV RNA+ * Rx: Prescription; RVR: Rapid Virologic Response; SVR: sustained virologic resonse=cure Any two of these test results reported

Results: Treatment Algorithm 3 (N=1807) outcome treated not treated Sens % PPV % 1 Y 667 475 96 58 N 31 634 2 644 278 92 70 54 831 3 Yes 608 154 87 80 No 90 955 4 596 134 85 82 102 975 5 515 50 74 91 183 1059 Total treated with DAA in HCV registry by gold standard: 698

Any two of these test results > 6 weeks apart Treatment Algorithm 4 An initial detectable HCV RNA test result followed by two sequential HCV RNA test results > 6 weeks apart from each other Time 4 weeks 12 weeks 24 weeks 36 weeks HCV RNA+ RX START RVR RX ENDS SVR 24 SVR 12 1ST HCVRNA TESTING 2ND HCV RNA TESTING 3RD HCV RNA TESTING 4TH HCVRNA TESTING 5TH HCV RNA TESTING Treatment Algorithm 4 An initial detectable HCV RNA test result followed by two sequential HCV RNA test results > 6 weeks apart from each other HCV RNA + * Rx: Prescription; RVR: Rapid Virologic Response; SVR: sustained virologic resonse=cure Any two of these test results > 6 weeks apart

Results: Treatment Algorithm 4 (N=1807) treated not treated Sens % PPV % 1 Y 667 475 96 58 N 31 634 2 644 278 92 70 54 831 3 608 154 87 80 90 955 4 Yes 596 134 85 82 No 102 975 5 515 50 74 91 183 1059 Total treated with DAA in HCV registry by gold standard: 698

Any three of these test result reported Treatment Algorithm 5 An initial detectable HCV RNA test result followed by three sequential HCV RNA test results Time 4 weeks 12 weeks 24 weeks 36 weeks HCV RNA+ RX START RVR RX ENDS SVR 24 SVR 12 1ST HCVRNA TESTING 2ND HCV RNA TESTING 3RD HCV RNA TESTING 4TH HCVRNA TESTING 5TH HCV RNA TESTING HCV RNA + * Rx: Prescription; RVR: Rapid Virologic Response; SVR: sustained virologic resonse=cure Any three of these test result reported

Results: Treatment Algorithm 5 (N=1807) outcome treated not treated Sens % PPV % 1 Y 667 475 96 58 N 31 634 2 644 278 92 70 54 831 3 608 154 87 80 90 955 4 596 134 85 82 102 975 5 Yes 515 50 74 91 No 183 1059 Total treated with DAA in HCV registry by gold standard: 698

Algorithms as a proxy to determine cure

One of these two test results Undetectable SVR Algorithm 1 An Undetectable HCV RNA test result ≥ 6 months (24 weeks) after the first detectable HCV RNA test result Time 4 weeks 12 weeks 24 weeks 36 weeks HCV RNA+ RX START RVR RX ENDS SVR 24 SVR 12 1ST HCVRNA TESTING 2ND HCV RNA TESTING 3RD HCV RNA TESTING 4TH HCV RNA TESTING 5TH HCVRNA TESTING One of these two test results Undetectable * Rx: Prescription; RVR: Rapid Virologic Response; SVR: sustained virologic resonse=cure Detectable

Results: SVR Algorithm 1 (N=442) outcome cured not cured Sens % PPV % 1 Yes 261 46 83 85 No 53 82 2 Y 249 23 79 92 N 65 105 3 4 247 19 93 67 109 5 Total Cured in the HCV registry by gold standard :314

One of these two test results Undetectable SVR Algorithm 2 Treated initiation algorithm 1 and an undetectable HCV RNA test result ≥ 12 weeks after the last HCV RNA test result Time 4 weeks 12 weeks 24 weeks 36 weeks HCV RNA+ RX START RVR RX ENDS SVR 24 SVR 12 1ST HCVRNA TESTING 2ND HCV RNA TESTING 3RD HCV RNA TESTING 4TH HCV RNA TESTING 5TH HCV RNA TESTING One of these two test results Undetectable * Rx: Prescription; RVR: Rapid Virologic Response; SVR: sustained virologic resonse=cure HCV RNA test reported

Results: SVR Algorithm 2 (N=442) outcome cured not cured Sens % PPV % 1 Y 261 46 83 85 N 53 82 2 Yes 249 23 79 92 No 65 105 3 4 247 19 93 67 109 5 Total Cured in the HCV registry by gold standard :314

One of these two test results Undetectable SVR Algorithm 3 Treated initiation algorithm 2 and an undetectable HCV RNA test result ≥12 weeks after the last HCV RNA test result Time 4 weeks 12 weeks 24 weeks 36 weeks HCV RNA+ RX START RVR RX ENDS SVR 12 SVR 24 1ST HCVRNA TESTING 2ND HCV RNA TESTING 3RD HCV RNA TESTING 4TH HCV RNA TESTING 5TH HCV RNA TESTING * Rx: Prescription; RVR: Rapid Virologic Response; SVR: sustained virologic resonse=cure One of these two test results Undetectable HCV RNA test reported

Results: SVR Algorithm 3 (N=442) outcome cured not cured Sens % PPV % 1 Y 261 46 83 85 N 53 82 2 249 23 79 92 65 105 3 Yes No 4 247 19 93 67 109 5 Total Cured in the HCV registry by gold standard :314

One of these two test results Undetectable SVR Algorithm 4 Treated initiation algorithm 3 and an undetectable HCV RNA test result ≥ 12 weeks after the last HCV RNA test result Time 4 weeks 12 weeks 24 weeks 36 weeks HCV RNA+ RX START RVR RX ENDS SVR 24 SVR 12 1ST HCVRNA TESTING 2ND HCV RNA TESTING 3RD HCV RNA TESTING 4TH HCV RNA TESTING 5TH HCV RNA TESTING One of these two test results Undetectable * Rx: Prescription; RVR: Rapid Virologic Response; SVR: sustained virologic resonse=cure HCV RNA test reported

Results: SVR Algorithm 4 (N=442) outcome cured not cured Sens % PPV % 1 Y 261 46 83 85 N 53 82 2 249 23 79 92 65 105 3 4 Yes 247 19 93 No 67 109 5 Total Cured in the HCV registry by gold standard :314

One of these two test results Undetectable SVR Algorithm 5 Treated initiation algorithm 4 and an undetectable HCV RNA test result ≥ 12 weeks after the last HCV RNA test result Time 4 weeks 12 weeks 24 weeks 36 weeks HCV RNA+ RX START RVR RX ENDS SVR 12 SVR 24 1ST HCVRNA TESTING 2ND HCV RNA TESTING 3RD HCV RNA TESTING 4TH HCV RNA TESTING 5TH HCV RNA TESTING One of these two test results Undetectable * Rx: Prescription; RVR: Rapid Virologic Response; SVR: sustained virologic resonse=cure HCV RNA test reported

Results: SVR Algorithm 5 (N=442) outcome cured not cured Sens % PPV % 1 Y 261 46 83 85 N 53 82 2 249 23 79 92 65 105 3 4 247 19 93 67 109 5 Yes No Total Cured in the HCV registry by gold standard :314

Summary of Key Results for Treatment Algorithm Sensitivities ranged from 74-96% and PPV ranged from 58-91% Algorithms 3 and 4 had the best combination of sensitivity (87% and 85% respectively) and PPV (80% and 82% respectively) Likely because it follows a typical patient treatment path: sequential HCV RNA measurements after a detectable HCV RNA indicating that a patient is being monitored

Summary of Key Results for SVR algorithm Sensitivities ranged from 79–83% and PPV ranged from 85–93% Algorithms all had similar performance A high PPV (92-93%) was found for each SVR algorithm based on the presence of undetectable HCV RNA test result 12 weeks after the last HCV RNA test result regardless which treatment algorithm was applied to the SVR algorithm

Limitations Missing treatment starts and end dates on a subset of patients HCV registry abstracted only up to five HCV RNA test results May have misclassify patients with > 12 weeks regimen May not be generalizable because limited to one health system Algorithms were not validated on external cohort

Conclusions & Recommendations Algorithms relying Serial HCV RNA tests can be used as a proxy for determining DAA treatment initiation and achievement of SVR on longitudinal data from an HCV registry where treatment data are unavailable Algorithms have the potential to be a powerful tool in monitoring trends in HCV treatment and cure in large data sets when treatment information is unavailable, though additional validation is needed

Acknowledgement Special Thanks to : Alexander J Millman, MDa Aaron M. Harris, MD, MPHa Claudia Vellozzi, MD, MPHa Lesley Miller, MDb Jennifer Lom, MDb a. Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta ,GA USA b. Emory University School of Medicine, Department of medicine, Division of General Medicine and Geriatrics, Atlanta, GA

Thank you! For more information please contact Centers for Disease Control and Prevention 1600 Clifton Road NE, Atlanta, GA 30333 Telephone: 1-800-CDC-INFO (232-4636)/TTY: 1-888-232-6348 E-mail: cdcinfo@cdc.gov Web: http://www.cdc.gov The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Office of the Director Place Office Title Here