1. Adherence to HCV Therapy: Relation with Virologic Outcomes and Changes in Adherence Over Time Vincent Lo Re, MD, MSCE V. Teal, R. Localio, V. Amorosa, D. Kaplan, R. Gross Division of Infectious Diseases Center for Clinical Epidemiology and Biostatistics University of Pennsylvania School of Medicine CCEB

2. Hepatitis C Virus (HCV) Therapy Pegylated interferon (PEG-IFN) + ribavirin o Complex treatment regimen o Frequent monitoring of laboratory results o Office visits to evaluate for adverse effects Suboptimal adherence response

3. Adherence to HCV Therapy Prior data: o drug exposure from dosage reductions: SVR o Few data: drug exposure from missed doses o 85% adherence: wk 12 HCV RNA declines* Unanswered questions: o Differences between PEG-IFN, ribavirin o Levels of adherence for virologic response o Changes in antiviral adherence over time * Lo Re V et al. Clin Infect Dis 2009;48:186-93.

4. Specific Aims Aim 1: Evaluate relation between adherence to PEG-IFN, ribavirin and virologic response o Hypothesis: adherence HCV response Aim 2: Assess changes in adherence over course of HCV treatment o Hypothesis: Adherence with time

5. Study Design / Setting Retrospective cohort study Setting: U.S. VA Hepatitis C Case Registry o Extract of VA records from HCV+ veterans o Demographic, administrative, lab data o Dispensing data on meds o Advantages: Majority receive meds through VA * Initiate contact for refills (not automatic) Dispensing of antivirals not linked * Steiner JF et al. Med Care 1988;26:814-23.

6. Study Subjects Inclusion criteria: o HCV RNA+, HCV genotype 1 – 4 o PEG-IFN + ribavirin rx: Jan 2003 Dec 2006 o HCV viral load prior to, after treatment start Exclusion criteria: o Clinical trial, switched IFN formulation, HIV Selection: first treatment course

7. Adherence: Pharmacy Refills Calculated over 12-wk intervals: o 0 – 12 wks o 13 – 24 wks o 25 – 36 wks o 37 – 48 wks Initial fills: closest to wks 13, 25, 37 Included in analyses: fill during interval

8. Data Analysis: Calculation of Adherence Time Fill #: 1 st Fill 2 nd Fill 3 rd Fill 4 th Fill Days: (Day 0) (Day 32) (Day 64) (Day 98) Days Supply % Adherence = ------------------------------------------ x 100 Days Between 1 st & Final Fills % Adherence = 90 days / 98 days = 92% Days Supply: 30 days 30 days 30 days

9. Study Outcomes Early virologic response (EVR) o 2 log in HCV RNA copies/ml at 12 wks o Defined wk 12 HCV RNA: wks 9 – 15 Sustained virologic response (SVR) o Undetectable HCV RNA in all follow-up viral load tests 24 wks after treatment end date o Collected HCV viral loads Dec. 2008

10. Data Analysis Calculated adherence separately Adherence categorized into 4 strata o Examined virologic response in each stratum o Chi-square tests for trend Mixed effects regression models o Changes in adherence (each med) over time

11. Results: Subject Selection 9,450 HCV genotype 1 - 4 Prescribed PEG-IFN + Ribavirin 5,706 Patients Included 3,744 Excluded: 3,416 No HCV RNA prior, after start of therapy 48 Received antivirals in clinical trial 75 Switched IFN formulation 205 HIV 3,992 Available for EVR Analyses

12. Results: Patient Characteristics CharacteristicAll Subjects (n=5,706) Mean age (yrs, SD)52 (6) Male sex (no., %)5,482 (96%) Race (no., %) African-American Caucasian 1,080 (19%) 3,397 (60%) HCV genotype 1 or 4 (no., %)4,207 (74%) HCV viral load >400,000 IU/mL (no., %)3,158 (55%)

13. Ribavirin Adherence and EVR: Genotypes 1 / 4 Chi-square test for trend, p<0.001. <70% 70%-79% 80%-89% 90%-100% n=296 n=232 n=299 n=2187 Adherence (%)

14. Ribavirin Adherence and EVR: Genotypes 2 / 3 Chi-square test for trend, p<0.001. <70% 70%-79% 80%-89% 90%-100% n=103 n=76 n=86 n=713 Adherence (%)

15. Ribavirin Adherence and SVR: Genotypes 1 / 4, EVR+ (n=1,911) (n=1,580) (n=1,261) Test for trend: p=0.012 p=0.008 p=0.065 % Adherence to Ribavirin 13 – 24 wks 25 – 36 wks 37 – 48 wks

16. Adherence Over Time Mean PEG-Interferon Adherence (%, SD) Mean Ribavirin Adherence (%, SD) P-Value Adherence Interval (Weeks)NAdherenceN 0-125,706100% (23%)5,70697% (38%)<0.001 13-243,54295% (23%)3,49786% (38%)<0.001 25-362,50194% (24%)2,45384% (38%)<0.001 37-4890489% (30%)86076% (40%)<0.001 P-values via paired t-tests Mean : 3.5% / 12 wks p<0.001 Mean : 6.8% / 12 wks p<0.001

17. Potential Limitations Overestimate actual adherence o Patients may not take meds after refill Assoc. with biological surrogate that only responds to antiviral therapy Retrospective design o No standardized HCV RNA testing Generalizability

18. Conclusions EVR and SVR with higher levels of adherence to PEG-IFN and ribavirin PEG-IFN adherence higher than ribavirin Adherence to both anti-HCV drugs over time o Greater decline in ribavirin adherence

19. Implications / Future Directions Addition of direct acting antivirals: o Increase complexity o adherence antiviral resistance Methods to measure adherence in real time o Identify non-adherence as soon as it occurs Future research emphasis: o Identify risk factors for non-adherence o Develop interventions

20. Acknowledgements Center for Clinical Epi: o Robert Gross, MD, MSCE o Russell Localio, PhD o Valerie Teal, MS Infectious Diseases: o Valerianna Amorosa, MD Gastroenterology: o David E. Kaplan, MD Funding Sources: o K01 AI07001 o Penn CERT o VA Pilot Project Grant Patients in VA Hepatitis C Case Registry CCEB

22. Results: Virologic Response Virologic Response (no., %) HCV Genotype Early (n=3,992) Sustained (n=3,250) 1, 41,787 (59%)953 (44%) 2, 3867 (89%)720 (66%)