1. 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

2. 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 ( ) –> 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. Algorithms as a proxy to determine Treatment

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. Algorithms as a proxy to determine cure

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

37. Thank you!
For more information please contact Centers for Disease Control and Prevention
1600 Clifton Road NE, Atlanta, GA
Telephone: CDC-INFO ( )/TTY:
Web:
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.
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