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,

Adherence to HCV Therapy:Relation with Virologic Outcomes and

Changes in Adherence Over Time

Vincent Lo Re, MD, MSCEV. Teal, R. Localio, V. Amorosa, D. Kaplan, R. Gross

Division of Infectious DiseasesCenter for Clinical Epidemiology and Biostatistics

University of Pennsylvania School of Medicine

CCEB

Hepatitis C Virus (HCV) Therapy

• Pegylated interferon (PEG-IFN) + ribavirino Complex treatment regimeno Frequent monitoring of laboratory resultso Office visits to evaluate for adverse effects

• Suboptimal adherence response

Adherence to HCV Therapy

• Prior data:o drug exposure from dosage reductions: SVRo Few data: drug exposure from missed doseso ≥85% adherence: wk 12 HCV RNA declines*

• Unanswered questions:o Differences between PEG-IFN, ribavirino Levels of adherence for virologic responseo Changes in antiviral adherence over time

*Lo Re V et al. Clin Infect Dis 2009;48:186-93.

Specific Aims

• Aim 1: Evaluate relation between adherence to PEG-IFN, ribavirin and virologic responseo Hypothesis: adherence HCV response

• Aim 2: Assess changes in adherence over course of HCV treatmento Hypothesis: Adherence with time

Study Design / Setting

• Retrospective cohort study• Setting: U.S. VA Hepatitis C Case Registry

o Extract of VA records from HCV+ veteranso Demographic, administrative, lab datao Dispensing data on medso 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.

Study Subjects

• Inclusion criteria: o HCV RNA+, HCV genotype 1 – 4o PEG-IFN + ribavirin rx: Jan 2003 Dec 2006o HCV viral load prior to, after treatment start

• Exclusion criteria: o Clinical trial, switched IFN formulation, HIV

• Selection: first treatment course

Adherence: Pharmacy Refills

• Calculated over 12-wk intervals:o 0 – 12 wkso 13 – 24 wkso 25 – 36 wkso 37 – 48 wks

• Initial fills: closest to wks 13, 25, 37• Included in analyses: fill during interval

Data Analysis:Calculation of Adherence

Time

Fill #: 1st Fill 2nd Fill 3rd Fill 4th FillDays: (Day 0) (Day 32) (Day 64) (Day 98)

Days’ Supply% Adherence = ------------------------------------------ x 100Days Between 1st & Final Fills% Adherence = 90 days / 98 days = 92%

Days’ Supply: 30 days 30 days 30 days

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 dateo Collected HCV viral loads Dec. 2008

Data Analysis

• Calculated adherence separately• Adherence categorized into 4 strata

o Examined virologic response in each stratumo Chi-square tests for trend

• Mixed effects regression models o Changes in adherence (each med) over time

Results: Subject Selection9,450 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

3,992Available for EVR Analyses

Results: Patient CharacteristicsCharacteristic All Subjects(n=5,706)

Mean age (yrs, SD) 52 (6)

Male sex (no., %) 5,482 (96%)

Race (no., %)African-AmericanCaucasian

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%)

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 (%)

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 (%)

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

Adherence Over Time

Mean PEG-Interferon Adherence (%, SD)

Mean Ribavirin Adherence (%, SD)

P-Value‡

AdherenceInterval(Weeks) N Adherence N Adherence

0-12 5,706 100% (23%) 5,706 97% (38%) <0.001

13-24 3,542 95% (23%) 3,497 86% (38%) <0.001

25-36 2,501 94% (24%) 2,453 84% (38%) <0.001

37-48 904 89% (30%) 860 76% (40%) <0.001

‡ P-values via paired t-tests

Mean : 3.5% / 12 wksp<0.001

Mean : 6.8% / 12 wksp<0.001

Potential Limitations

• Overestimate actual adherenceo Patients may not take meds after refill

Assoc. with biological surrogate that only responds to antiviral therapy

• Retrospective designo No standardized HCV RNA testing

• Generalizability

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 timeo Greater decline in ribavirin adherence

Implications / Future Directions

• Addition of direct acting antivirals:o Increase complexity o adherence antiviral resistance

• Methods to measure adherence in real timeo Identify non-adherence as soon as it occurs

• Future research emphasis:o Identify risk factors for non-adherenceo Develop interventions

Acknowledgements

• Center for Clinical Epi:o Robert Gross, MD, MSCEo Russell Localio, PhDo Valerie Teal, MS

• Infectious Diseases:o Valerianna Amorosa, MD

• Gastroenterology:o David E. Kaplan, MD

• Funding Sources:o K01 AI07001o Penn CERTo VA Pilot Project Grant

• Patients in VA Hepatitis C Case Registry

CCEB

Results: Virologic Response

Virologic Response (no., %)

HCVGenotype

Early(n=3,992)

Sustained(n=3,250)

1, 4 1,787 (59%) 953 (44%)

2, 3 867 (89%) 720 (66%)