Age appears to be a significant effect modifier of the impact of palivizumab on RSV hospitalization risk. Given the rapid decrease of RSV risk with increasing age and the effect modification, careful examination of age thresholds for immunoprophylaxis is warranted.

Age appears to be a significant effect modifier of the impact of palivizumab on RSV hospitalization risk. Given the rapid decrease of RSV risk with increasing age and the effect modification, careful examination of age thresholds for immunoprophylaxis is warranted.

Age-dependent Effectiveness of RSV Immunoprophylaxis

Palivizumab efficacy shows variation between 45 to 78% reduction of hospitalizations for respiratory syncytial virus (RSV) depending on the type of risk-group studied. Based on RSV epidemiology and the risk groups that were targeted in clinical trials current recommendations limit palivizumab utilization to specific age groups. While evidence supports the effect of increasing age on decreasing infection risk, it is unknown whether age modifies palivizumab effectiveness as well.

Objectives: To estimate the effect of age on palivizumab effectiveness in preventing RSV hospitalizations in high-risk children.

Palivizumab efficacy shows variation between 45 to 78% reduction of hospitalizations for respiratory syncytial virus (RSV) depending on the type of risk-group studied. Based on RSV epidemiology and the risk groups that were targeted in clinical trials current recommendations limit palivizumab utilization to specific age groups. While evidence supports the effect of increasing age on decreasing infection risk, it is unknown whether age modifies palivizumab effectiveness as well.

Objectives: To estimate the effect of age on palivizumab effectiveness in preventing RSV hospitalizations in high-risk children.

Conclusions

Study DesignRetrospective cohort study

Data source / study population• Medicaid Extract Files (MAX), Vital Statistics Births and Death Certificates• Children aged 0-2 eligible since birth for Medicaid fee-for-service in TX and

FL between 1999-2004• At least 3 months eligibility between Aug-Mar of any study year• Diagnosis for symptomatic (requiring drug treatment or oxygen) chronic

lung disease or hemodynamically significant congenital heart disease based on in- or outpatient and pharmacy claims within 6 month before season

• Successfully matched to birth certificate via SSN and DoB

Cohort Set-up• Entry during any RSV season month (Oct-Mar) after 2 months in

ambulatory care• Children could re-enter for a second season• Censoring at end of season, loss of eligibility, death, hospitalization for

other reason

Exposure• Palivizumab use determined from pharmacy or physician charges• Current use: claim date plus 30 days according to pharmakokinetics• Former use: day 31 to 60 post claim; overridden by subsequent claim• No use: period before first dose and after former use period(s)

OutcomeFirst RSV-related hospitalization (ICD9-CM 480.1, 466.11, 079.6)

Analysis Cox regression, allowing interaction between younger (2-12 months at index date) and older (13-24 months at index date) children and palivizumab use, while adjusting for other RSV risk factors (see tables).

Study DesignRetrospective cohort study

Data source / study population• Medicaid Extract Files (MAX), Vital Statistics Births and Death Certificates• Children aged 0-2 eligible since birth for Medicaid fee-for-service in TX and

FL between 1999-2004• At least 3 months eligibility between Aug-Mar of any study year• Diagnosis for symptomatic (requiring drug treatment or oxygen) chronic

lung disease or hemodynamically significant congenital heart disease based on in- or outpatient and pharmacy claims within 6 month before season

• Successfully matched to birth certificate via SSN and DoB

Cohort Set-up• Entry during any RSV season month (Oct-Mar) after 2 months in

ambulatory care• Children could re-enter for a second season• Censoring at end of season, loss of eligibility, death, hospitalization for

other reason

Exposure• Palivizumab use determined from pharmacy or physician charges• Current use: claim date plus 30 days according to pharmakokinetics• Former use: day 31 to 60 post claim; overridden by subsequent claim• No use: period before first dose and after former use period(s)

OutcomeFirst RSV-related hospitalization (ICD9-CM 480.1, 466.11, 079.6)

Analysis Cox regression, allowing interaction between younger (2-12 months at index date) and older (13-24 months at index date) children and palivizumab use, while adjusting for other RSV risk factors (see tables).

Methods

Almut G Winterstein PhD1, 2, Christian Hampp PhD4, Paul Kubilis MS1, Arwa Saidi MBBCh3 1Pharmaceutical Outcomes and Policy, College of Pharmacy, 2Epidemiology, Colleges of Medicine and Public Health & Health Professions, 3Pediatrics, College of Medicine, University of Florida, Gainesville, FL

4Office of Surveillance and Epidemiology, CDER, FDA, Silver Spring, MD, United States

The analysis included 14,549 children and 21,825 child-seasons. Censoring occurred because of season end (n=9,001), end of eligibility (n=8,889), 2nd birthday (n=3,341), non-RSV hospitalization (n=542), and death (n=52).

ɸ Data cannot be displayed based on CMS requirement to omit cells with <11 observations.

A total of 617 RVS-related hospitalizations occurred during 2,496,942 days of follow-up (90.2 per 1,000 patient-years during season). The six-months mortality of children hospitalized for RSV infections was 4 per 617 hospitalizations (0.65%).

Hazard Ratios for all RSV Risk Factors, Palivizumab Use, and the Interaction between Use and Age

Crude and Adjusted RSV-Risk per Age

Stratum

The analysis included 14,549 children and 21,825 child-seasons. Censoring occurred because of season end (n=9,001), end of eligibility (n=8,889), 2nd birthday (n=3,341), non-RSV hospitalization (n=542), and death (n=52).

ɸ Data cannot be displayed based on CMS requirement to omit cells with <11 observations.

A total of 617 RVS-related hospitalizations occurred during 2,496,942 days of follow-up (90.2 per 1,000 patient-years during season). The six-months mortality of children hospitalized for RSV infections was 4 per 617 hospitalizations (0.65%).

Hazard Ratios for all RSV Risk Factors, Palivizumab Use, and the Interaction between Use and Age

Crude and Adjusted RSV-Risk per Age

Stratum

The authors have no conflict of interest.The study was funded in part by the Florida Agency for Healthcare Administration. It was conducted in collaboration with the University of Florida Center for Medicaid and the Uninsured. The authors thank Public Health Statistics, Office of Vital Statistics, Florida Department of Health and the Texas Department of State Health Services for the provision of birth and death certificates; and the Centers for Medicare and Medicaid for provision of MAX data.

The authors have no conflict of interest.The study was funded in part by the Florida Agency for Healthcare Administration. It was conducted in collaboration with the University of Florida Center for Medicaid and the Uninsured. The authors thank Public Health Statistics, Office of Vital Statistics, Florida Department of Health and the Texas Department of State Health Services for the provision of birth and death certificates; and the Centers for Medicare and Medicaid for provision of MAX data.

Introduction

The single most important risk factor for RSV infections was age. With every day of age, RSV risk decreased by 0.34% (95% CI: 0.24-0.44), amounting to 9.66% (6.94-12.30) per month of age. Consequently, children at 6 months of age experience a 34% reduction in RSV risk, 51% reduction at age 9 months, 64% at 12 months, 80% at 18 months and 89% at 24 months, each compared to 2 month old infants (Figure).

Given the age-related decreasing risk and differences in palivizumab effectiveness, numbers needed to treat for the two age strata are as follows:

Age 2-12 months: NNT=34 per 6-months seasonAge 13-24 months: NNT=327 per 6-months season

Limitations

RSV hospitalizations may be misclassified as non-specific pneumonia or bronchiolitis.Residual (unmeasured) confounding may exist.

The single most important risk factor for RSV infections was age. With every day of age, RSV risk decreased by 0.34% (95% CI: 0.24-0.44), amounting to 9.66% (6.94-12.30) per month of age. Consequently, children at 6 months of age experience a 34% reduction in RSV risk, 51% reduction at age 9 months, 64% at 12 months, 80% at 18 months and 89% at 24 months, each compared to 2 month old infants (Figure).

Given the age-related decreasing risk and differences in palivizumab effectiveness, numbers needed to treat for the two age strata are as follows:

Age 2-12 months: NNT=34 per 6-months seasonAge 13-24 months: NNT=327 per 6-months season

Limitations

RSV hospitalizations may be misclassified as non-specific pneumonia or bronchiolitis.Residual (unmeasured) confounding may exist.

DiscussionResults

HR 95% CIAge (per day) 0.997 0.996-0.998Gender (male) 1.14 0.97-1.34Race White 1 Black 0.8 0.62-1.04 Hispanic 0.76 0.62-0.94 Others 0.84 0.62-1.14Hospitalization at birth > 7 days 1.28 1.07-1.52Bronchodilators past 1-30 days 2.33 1.94-2.79Respiratory problems past 1-30 days 1.65 1.38-1.97≥ 3 MD/ED visits past 1-30 days 1.76 1.47-2.12Eligibil ity due to Disabil ity 1.95 1.56-2.45Chronic lung disease 1.63 1.21-2.20Gestational age < 29 weeks 1.03 0.80-1.34Gestational age 29-<32 weeks 1.09 0.82-1.45Gestational age 32– 35 weeks 1.42 1.10-1.84Congenital heart disease 1.21 0.91-1.60Cystic fibrosis 0.77 0.20-3.11SCID/AIDS 1.5 0.82-2.75Downs Syndrome 2.33 1.71-3.16Siblings ≤ 5 years of age 1.29 1.09-1.52Multiple Birth 0.88 0.65-1.19

≥ 1 dose No dose Yes No ≥ 1 dose No dose Yes No(n= 2,553) (n=10,121) (n=458) (n=12,216) (n= 1,173) (n=7,978) (n=159) (n=8,992)

Female (%) 1,107 (43.4) 4,525 (44.7) 183 (40.0) 5,449 (44.6) 477 (40.7) 3,517 (44.1) 59 (37.1) 3,935 (43.8)

White (%) 546 (21.4) 2,172 (21.5) 109 (23.8) 2,609 (21.4) 219 (18.7) 1,689 (21.2) 30 (18.9) 1,878 (20.9)

Black (%) 517 (20.3) 2,008 (19.8) 73 (15.9) 2,452 (20.1) 235 (20.0) 1,624 (20.4) 29 (18.2) 1,830 (20.4)

Hispanic (%) 925 (36.2) 5,115 (50.5) 217 (47.4) 5,823 (47.7) 426 (36.3) 3,843 (48.2) 71 (44.7) 4,198 (46.7)

Other (%) 565 (22.1) 826 (8.2) 59 (12.9) 1,332 (10.9) 293 (25.0) 822 (10.3) 29 (18.2) 1,086 (12.1)

Hospitalization at birth > 7 days (%) 1,739 (68.1) 3,855 (38.1) 241 (52.6) 5,353 (43.8) 672 (57.3) 2,838 (35.6) 79 (49.7) 3,431 (38.2)

Eligibil ity due to Disabil ity (%) 962 (37.7) 1,350 (13.3) 114 (24.9) 2,198 (18.0) 756 (64.5) 2,645 (33.2) 104 (65.4) 3,297 (36.7)

Chronic lung disease (%) 1,554 (60.9) 2,000 (19.8) 180 (39.3) 3,374 (27.6) 971 (82.8) 3,022 (37.9) 100 (62.9) 3,893 (43.3)

Gestational age < 32 weeks (%) 1,698 (66.5) 1,447 (14.3) 142 (31.0) 3,003 (24.6) 795 (67.8) 1,965 (24.6) 65 (40.9) 2,695 (30.0)

Gestational age 32– 35 weeks (%) 308 (12.1) 893 (8.8) 53 (11.6) 1,148 (9.4) 109 (9.3) 697 (8.7) 23 (14.5) 783 (8.7)

Congenital heart disease (%) 1,452 (56.8) 8,424 (83.2) 325 (71.0) 9,551 (78.2) 443 (37.8) 5,368 (67.3) 79 (49.7) 5,732 (63.8)

Cystic fibrosis (%) 14 (0.6) 16 (0.2) ɸ 29 (0.2) 14 (1.2) 44 (0.6) ɸ 57 (0.6)

SCID/AIDS (%) 31 (1.2) 106 (1.1) ɸ 130 (1.1) 22 (1.9) 108 (1.4) ɸ 126 (1.4)

Downs Syndrome (%) 76 (3.0) 329 (3.3) 33 (7.2) 372 (3.1) 30 (2.6) 241 (3.0) 18 (11.3) 253 (2.8)

Siblings up to 5 years older (%) 944 (37.0) 3,918 (38.7) 205 (44.8) 4,657 (38.1) 440 (37.5) 3,217 (40.3) 74 (46.5) 3,583 (39.9)

Multiple births (%) 416 (16.3) 516 (5.1) 34 (7.4) 898 (7.4) 190 (16.2) 590 (7.4) 20 (12.6) 760 (8.5)

Age at index date (± std, days) 192.1 (±95.0) 172.0 (±104.6) 166.2 (±99.8) 176.4 (±103.1) 497.8 (±91.1) 544.0 (±106.9) 484.9 (±80.3) 539.0 (±106.3)

Age at index date < 6 months (%) 1,226 (48.0) 5,693 (56.3) 286 (62.5) 6,633 (54.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Respiratory problems past 1-30 days (%) 1,615 (63.3) 5,405 (53.4) 285 (62.2) 6,735 (55.1) 691 (58.9) 3,823 (47.9) 86 (54.1) 4,428 (49.2)

≥3 MD/ ED visits past 1-30 days (%) 2,272 (89.0) 6,202 (61.3) 353 (77.1) 8,121 (66.5) 999 (85.2) 3,452 (43.3) 110 (69.2) 4,341 (48.3)

Bronchodilators past 1-30 days (%) 1,691 (66.2) 4,049 (40.0) 271 (59.2) 5,469 (44.8) 974 (83.0) 3,845 (48.2) 117 (73.6) 4,702 (52.3)

Age 2-12 months at index date Age 13-24 months at index date

Palivizumab prophylaxis RSV-related hospitalization Palivizumab prophylaxis RSV-related hospitalization

HR 95% CIPalivizumab Use, ≤12 months of age Current Use 0.51 0.38-0.68 Former Use 0.76 0.42-1.37 No Use 1Palivizumab Use, >12 months of age Current Use 0.88 0.58-1.33 Former Use 0.97 0.36-2.65 No Use 1Palivizumab Use, >12 months vs. ≤ 12 months Current Use 1.73 1.06-2.83 Former Use 1.28 0.41-4.06 No Use 1.09 0.77-1.54

Crude rate(per 1000

patient-years)No use 3,264 385 118 118

Current use 601 61 101.5 59.7

Former use 90 12 133.3 89.3

No use 2,546 126 49.5 49.5

Current use 298 29 97.3 43.4

Former use 42 4 95.2 48.1

Age

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