Cost-effectiveness Analysis of the National Perinatal Hepatitis B Prevention Program

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Cost-effectiveness Analysis of the National Perinatal

Hepatitis B Prevention Program

WHAT’S KNOWN ON THIS SUBJECT: Infant postexposure prophylaxis prevents perinatal hepatitis B (HepB) virus transmission and mortality and morbidity caused by chronic HepB virus infection. The US Perinatal Hepatitis B Prevention Program (PHBPP) identiﬁes and manages infants born to HepB surface antigen–positive women.

WHAT THIS STUDY ADDS: It presents theﬁrst estimates of the long-term costs and outcomes of postexposure prophylaxis with the PHBPP. It analyzes the effects of the PHBPP, and alternative immunization scenarios, on health and economic outcomes for the 2009 US birth cohort.

abstract

OBJECTIVE:To analyze the cost-effectiveness of the national Perinatal Hepatitis B Prevention Program (PHBPP) over the lifetime of the 2009 US birth cohort and compare the costs and outcomes of the program to a scenario without PHBPP support. PHBPP’s goals are to ensure all infants born to hepatitis B (HepB) surface antigen–positive women receive timely postexposure prophylaxis, complete HepB vaccine series, and obtain serologic testing after series completion.

METHODS: A decision analytic tree and a long-term Markov model represented the risk of perinatal and childhood infections under dif-ferent prevention alternatives, and the long-term health and economic consequences of HepB infection. Outcome measures were the number of perinatal infections and childhood infections from infants born to HepB surface antigen–positive women, quality-adjusted life-years (QALYs), lifetime costs, and incremental cost per QALY gained. The health outcomes and total costs of each strategy were compared incrementally. Costs were evaluated from the health care system perspective and expressed in US dollars at a 2010 price base.

RESULTS:In all analyses, the PHBPP increased QALYs and led to higher reductions in the number of perinatal and childhood infections than no PHBPP, with a cost-effectiveness ratio of $2602 per QALY. In sensitivity analyses, the cost-effectiveness ratio was robust to variations in model inputs, and there were instances where the program was both more effective and cost saving.

CONCLUSIONS:This study indicated that the current PHBPP represents a cost-effective use of resources, and ensuring the program reaches all pregnant women could present additional public health beneﬁts.

Pediatrics2014;133:243–253

AUTHORS:Carolina Barbosa, PhD,a_{Emily A. Smith, MPH,}b

Thomas J. Hoerger, PhD,a_{Nancy Fenlon, RN, MS,}c_{Sarah F.}

Schillie, MD, MPH, MBA,b_{Christina Bradley, BS,}a_{and Trudy}

V. Murphy, MDb

a_{RTI International, Chicago, Illinois; and}b_{Division of Viral} Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention, andc_{Immunization Services Division, National Center} for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia

KEY WORDS

cost-effectiveness, QALY, cost, perinatal, infection, hepatitis B, immunization programs

ABBREVIATIONS

ACIP—Advisory Committee on Immunization Practices CDC—Centers for Disease Control and Prevention CEAC—cost-effectiveness acceptability curve CI—conﬁdence interval

HBIG—hepatitis B immune globulin HBsAg—hepatitis B surface antigen HBV—hepatitis B virus

HepB—hepatitis B

ICER—incremental cost-effectiveness ratio PEP—postexposure prophylaxis

PHBPP—Perinatal Hepatitis B Prevention Program PVST—postvaccination serologic testing QALY—quality-adjusted life-year

Dr Barbosa participated in the concept and design of the study; the collection, analysis, and interpretation of data; and drafted and revised the manuscript. Ms Smith, Ms Fenlon, Dr Schillie, and Dr Murphy participated in the concept and design of the study; the collection, analysis, and interpretation of data; and revised the manuscript. Dr Hoerger participated in the concept and design of the study, the analysis and interpretation of data, and drafted and revised the manuscript. Ms Bradley participated in the collection of data and revised the manuscript. All authors approved the manuscript as submitted.

www.pediatrics.org/cgi/doi/10.1542/peds.2013-0718

doi:10.1542/peds.2013-0718

Accepted for publication Nov 1, 2013

Address correspondence to Carolina Barbosa, PhD, RTI International, 230 West Monroe St, Ste 2100, Chicago, IL 60606-4901. E-mail: cbarbosa@rti.org

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Each year, an estimated 25 000 infants are born to hepatitis B surface antigen (HBsAg)-positive women in the United States.1 _{With no intervention, these}

infants have a 40% to 90% risk of hep-atitis B virus (HBV) infection.2,3

Ap-proximately 90% of infected infants develop chronic HBV infection, which carries a 25% risk of premature death from progressive damage to the liver, leading to cirrhosis, or cancer of the liver.4_{Postexposure prophylaxis (PEP),}

consisting of hepatitis B immune globulin (HBIG) and hepatitis B (HepB) vaccine administered at birth, followed by completion of a 3-dose HepB vaccine series is 85% to 95% effective in pre-venting perinatal HBV infection.4

The Advisory Committee on Immuniza-tion Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) recommends that all pregnant women receive HBsAg screening to ensure that infants of HBsAg-positive women receive PEP.4_{ACIP recommends that infants of}

HBsAg-positive women receive HBIG and HepB vaccine within 12 hours of birth, complete the HepB series, and receive serologic testing (HBsAg and antibody to HBsAg) 1 to 2 months after completing the HepB vaccine series to determine outcomes (HepB immunity by vaccina-tion, nonresponse to vaccinavaccina-tion, or chronic HBV infection) and future management. ACIP also recommends that the small percentage (5%) of infants who fail to respond to an initial HepB vaccine series and remain un-infected receive an additional HepB vaccine series and repeat post-vaccination serologic testing (PVST).

In 1990, the CDC began funding Perinatal Hepatitis B Prevention Programs (PHBPP) in all 64 immunization grant-ees through the 317 program. PHBPP’s goals are to ensure all infants born to HBsAg-positive women receive timely PEP, complete HepB vaccine series, obtain PVST after series completion, and continue medical care appropriate

to their outcomes. These goals are ac-complished through case management activities. Programs report outcomes annually to the CDC.1,4 _{In 2008,}

pro-visional estimates were that 48% of the 25 600 annual estimated births to HBsAg-positive women were identiﬁed and case-managed by PHBPP.1 _Most

HBsAg-positive women and infants case-managed by PHBPP receive med-ical care funded by private insurance or Medicaid, although data on the exact proportions of each have not been collected.1_{More information on PHBPP}

activities is described in Appendix A of the Supplemental Information.

Although economic analyses of the burden and prevention impact of HBV transmission have been conducted,2,5–10

no study has focused on the long-term costs and outcomes of PEP through the current national PHBPP. This study analyzes the effects of the PHBPP on health and economic outcomes attrib-utable to perinatal and early childhood infection (postnatal infection, before age 5 years), determined over the life-time of the 2009 US birth cohort. Costs and outcomes of the current PHBPP (“PHBPP” strategy) are compared in-crementally to a strategy represented by the ACIP recommendations without PHBPP support (“No PHBPP” strategy). The study’s main hypotheses were as follows1_{: the number of perinatal and}

childhood infections will be lower in the PHBPP strategy,2 _{the higher}

quality-adjusted life-years (QALYs) gained with PHBPP will justify the higher program costs, and the program will be cost-effective when compared with the No PHBPP strategy.

METHODS

Overview

Economic evaluation provides a frame-work to allocate resources to effective strategies. Full economic evaluations are evaluations where the costs and con-sequences of at least 2 strategies are

compared and can help with un-derstanding the value for money of each strategy.11,12_{Where 1 strategy does not}

dominate (ie, is not both more effective and less costly), costs and effects are combined in the form of incremental cost-effectiveness ratios (ICERs),

de-ﬁned as the difference in costs (C) di-vided by the difference in mean effectiveness (E), (Cj2Ci)/(Ej2Ei), where j is a more costly strategy than i. The ICER represents the additional cost required to achieve 1 additional unit of outcome. An optimal intervention is one with an ICER that is not more than the decision maker’s intrinsic valuation for an additional unit of the outcome.11,12

In a cost-effectiveness analysis, health benefits associated with the strategies under comparison can be measured and valued by using natural units of outcome (eg, life-years), number of infections, or they can reflect the value individuals place on their health, called utilities. QALYs are a widely used measure of health benefits that incorporate mor-tality and morbidity estimates in a single index. Cost per QALY estimates allow a comparison between different health care interventions that compete for the same pool of resources.

This cost-effectiveness analysis com-pared 2 strategies. In the base-case analysis, the No PHBPP strategy assumes that there is no program targeted at identiﬁcation and man-agement of infants born to HBsAg-positive mothers and that infants do not receive HBIG or PVST. In the PHBPP strategy, a proportion of the infants born to HBsAg-positive mothers are identiﬁed prospectively and managed through the national PHBPP. Those not captured by the PHBPP follow the No PHBPP strategy.

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long-term Markov model, both follow-ing a cohort simulation approach.13,14

Decision Analytic Tree

The decision tree estimated the expected number of infants, born to HBsAg-positive women, who were perinatally and postnatally infected and was used in all cost-effectiveness analyses. The de-cision tree was built in TreeAge Pro 2011 (TreeAge Software, Inc, Williamstown, MA) (Fig 1). All infants born to HBsAg-positive women follow either the No PHBPP or the PHBPP strategy. Four mutually exclusive outcomes were modeled: seroprotection, susceptibility, perinatal infection, and childhood

infection. The cost-effectiveness analy-sis focused on the last 2 outcomes and QALYs lost with each type of infection.

The decision tree model base-case parameters and sources are summa-rized in Table 1. The 24 784 cohort considered in this analysis was the estimated number of infants born to HBsAg-positive mothers in 2009.1,15,16

More than 95% of women were screened for HBsAg in the United States in 2003–2004.4,15 _{Consistent with this}

estimate, and so that all infants born to HBsAg-positive women are modeled, both strategies assume a 100% screen-ing coverage. Vaccine efﬁcacy is as-sumed to confer immunity to chronic

and acute HBV infection acquired peri-natally and during childhood before age 5 years. Efﬁcacy varies by the time ofﬁrst dose of HBIG and HepB vaccine admin-istration, or HepB vaccine without HBIG, and by completion of vaccine series within 9 months or longer periods. The major determinant of the effectiveness of PEP for infants of HBsAg-positive mothers is on-time administration of the initial dose of HepB vaccine and HBIG.17_{Because most available data use}

,24 hours of life as the optimal timing for administering theﬁrst dose of HepB vaccine and HBIG, we also use,24 hours rather than the ACIP-recommended#12 hours. Infants born to HBsAg-positive

FIGURE 1

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TABLE 1 Model Parameters: Base-Case Values and Their Sources, Variations in Sensitivity Analysis and Assumptions, and Probabilistic SA Distributionsa

Parameter Name, Reference No.

Base-Case SAb

Probabilistic SA

Upper Value

Lower Value

Assumption Distribution SE a b

Population and risk of infection Births per year16

4 130 665 — — — — — — —

P mother is HBsAg+1,15 _0.006 _0.008 _0.004 _{CI in ref 15} _b _0.00392 ₂ ₃₈₅

Ninfants to HBsAg+ mother 24 784 — — — — — — —

P HBsAg+ mother is HBeAg+38

0.3 0.36 0.24 620% b 0.1176 4 10

P transmission HBeAg+3,39-42 _0.832 ₁ _0.734 _{Highest and lowest value from 5 studies} _b _NA ₁₅₄ ₃₁

P transmission HBeAg-3,39-42 _0.153 _0.314 _0.037 _{Highest and lowest value from 5 studies} _b _NA ₃₃ ₁₈₃

P of transmission HBsAg+c 0.3567 0.5610 0.2043 Calculated with upper and lower

values of seroprevalence and transmission estimates

— — — —

P of childhood infection among not seroprotected2

0.3 0.36 0.24 620% b 0.1176 4 10

Vaccination coverage for No PHBPP

P Hep1Vacc#24 h27,28 .544 .544 0 Variable set as: 0.5442P

Hep1Vacc+HBIG#24 h

dirichlet NA 18 556 15 555

P Hep1Vacc+HBIG#24h 0 0.544 0 Upper value assumes all infants

receivingﬁrst dose within 24 h in NIS27,28_{data also receive HBIG}

— — —

P Hep1Vacc 24–72 h27,28

0.081 0.081 0.000 Variable set as: 0.0812P

Hep1Vacc+HBIG 24–72 h

dirichlet NA 2746 31 365

P Hep1Vacc+HBIG 24–72h 0 0.081 0 Variable set as: P Hep1Vacc+HBIG

#24 h*(0.081/0.544)

— — —

P Hep1Vacc 72 h–3 mo27,28 _0.313 _— _— _— _dirichlet _NA _{10 677} _{23 434}

P no dose27,28 _0.063 _— _— _— _dirichlet _NA ₂₁₃₂ _{31 979}

P completion in 9 mo29 0.639 0.626 0.652 CI in Smith 20121 b NA 10 734 6064

P PVST 0 0.560 0 Upper value assumes PVST rates equal

to those under program support

— — —

Vaccination coverage for PHBPP

P Hep1Vacc+HBIG#24h1 0.855 — — — dirichlet NA 4339 736

P Hep1Vacc#24 h 0.032 — — — dirichlet NA 162 4913

P Hep1Vacc+HBIG 24–72 h 0.104 — — — dirichlet NA 528 4547

P Hep1Vacc 24–72 h 0.001 — — — dirichlet NA 5 5070

P Hep1Vacc 72 h–3 mo 0.001 — — — dirichlet NA 5 5070

P no dose 0.007 — — — dirichlet NA 36 5039

P completion in 9 mo 0.723 0.868 0.578 620% b NA 3669 1406

P PVST 0.560 1 0.448 220% to 1 b NA 6697 5336

P HBs+ woman is identiﬁed and captured by PHBPP

0.479 1 0.479 Assumed base value as lower bond and

100% coverage for upper bond

b NA 12 033 13 088

Efﬁcacy of HBV vaccine and HBIG by time of administration and completion of vaccination series HBIG+Hep1Vacc#24 h and

remaining doses on time26

0.920 0.970 0.830 Upper and lower values from CI in Lee

et al 200626

for HBIG+vaccine on time

b 0.1372 3 0

HBIG+Hep1Vacc#24 h and remaining doses not on timed

et al 200626for HBIG+vaccine on time

b 0.1372 5 1

HBIG+Hep1Vacc 24–72 h and remaining doses on timee

0.616 0.828 0.460 Assuming only 10% cut on efﬁcacy as

upper value (0.92*0.9). Lower value is a conservative assumption of cutting efﬁcacy in half (0.92/2)

— — — —

HBIG+Hep1Vacc 24–72 h and remaining doses not on timef

— — — —

Hep1Vacc#24 h and remaining doses on time26

et al 200626

for vaccine on time

b 0.196 3 1

Hep1Vacc#24 h and remaining doses not on timeg

et al 200626

for vaccine on time

b 0.196 3 2

Hep1Vacc 24–72 h and remaining doses on timeh

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TABLE 1 Continued

Parameter Name, Reference No.

Base-Case SAb

Probabilistic SA

Upper Value

Lower Value

Assumption Distribution SE a b

Hep1Vacc 24–72 h and remaining doses not on timei

— — — —

Hep1Vacc 72 h–3 mo and remaining doses on timej

0.323 0.648 0.241 Assuming same SA values as when

ﬁrst dose is given 24–72 h

— — — —

Hep1Vacc 72 h–3 mo and remaining doses not on timek

0.269 0.540 0.201 Assuming same SA values as when

ﬁrst dose is given 24–72 h

— — — —

Cost parameters Cost per 1 vaccine dose43

$22 — — — — — — —

Administrative costs for 1 vaccine dose44

$14 — — — — — — —

Cost of HBIG45

$121 $146 $97 620% — — — —

Cost of anti-HBsAg Test46

$15 — — — — — — —

Blood drawn cost46 $3 — — — — — — —

Cost of HBsAg screening test46 $15 — — — — — — —

Cost of outpatient consultation47 $61 — — — — — — —

Cost of identiﬁcation in PHBPP per infantl

$783 $929 $472 For upper value the bootstrapped of

CI used, for lower value the total cost for all grantees divided by the total number of infants was used

g 75 110 7

Cost of management in PHBPP per infantl

$769 $890 $552 g 62 154 5

Markov model inputsm Cost due to HBV perinatal and

childhood infection Cost of perinatal infection

diagnosed at infection

$24 117 $28 941 $19 294 620% g 9454 7 3706

Cost of perinatal infection not diagnosed at infection

$9831 $11 797 $7865 620% g 3854 7 1511

Cost of childhood infection diagnosed at infection

$11 643 $13 972 $9315 620% g 4564 7 1789

Cost of childhood infection not diagnosed at infection

$3713 $4455 $2970 620% g 1455 7 570

QALYs loss due to HBV perinatal and childhood infection QALY loss due to perinatal

infection diagnosed at infection

0.7656 0.9187 0.6125 620% g 0.3001 7 0.1

QALY loss due to perinatal infection not diagnosed at infection

1.1851 1.4221 0.9481 620% g 0.4646 7 0.2

QALY loss due to childhood infection diagnosed at infection

0.2560 0.3072 0.2048 620% b 0.1003 5 13

QALY loss due to childhood infection not diagnosed at infection

0.5161 0.6193 0.4129 620% b 0.2023 3 2

HBeAg+, hepatitis B e antigen positive; HBsAg+, hepatitis B surface antigen positive; Hep1Vacc,ﬁrst dose of HepB vaccine; NA, not applicable; NIS, National Immunization Survey; P, probability; SA, sensitivity analysis;—, no value was assumed in the sensitivity analysis or no distribution was assigned to the parameter.

a_{Calculation of all inputs detailed in Appendix A of the Supplemental Information.}

b_{Upper and lower values for sensitivity analyses were informed by the CI of the parameter estimate or if CIs were not available, upper and lower values were set at}6_{20% of the base value. For}

other variables, upper and lower values were based on previous studies and educated guesses.

c_{Calculated as (P transmission HBeAg+*P HBsAg+mother HBe+) + (P transmission HBeAg-*(1}2_{P HBsAg+mother HBe+)).} d_{Assuming low end of Lee et al}26_{CI for HBIG+Hep1Vacc}#_{24 h and remaining doses on time.}

e_{Calculated as 0.92*0.67, assuming a decrease in ef}ﬁ_{cacy of 33%.}17,18 f_{Calculated as 0.87*0.67, assuming a decrease in ef}ﬁ_{cacy of 33%.}17,18

g_{Assuming low end of Lee et al}26_{CI for Hep1Vacc}#_{24 h and remaining doses on time.} h_{Calculated as 0.72*0.67, assuming a decrease in ef}ﬁ_{cacy of 33%.}17,18

i_{Calculated as 0.6*0.67, assuming a decrease in ef}_fi_{cacy of 33%.}17,18 j_{Calculated as 0.4824*0.67, assuming a decrease in ef}fi_{cacy of 33%.}17,18 k_{Calculated as 0.402*0.67, assuming a decrease in ef}_fi_{cacy of 33%.}17,18

l_Authors’_{calculations by using self-reported grantee data to CDC from PHBPP grantees in 49 US states (excluding Alaska), 5 cities (Chicago, Houston, New York City, Philadelphia, San Antonio),}

and the District of Columbia. CIs around individual cost estimates were calculated by using bootstrapping.48

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women who do not complete the HepB vaccine series, or who have delays in completing the series, are signiﬁcantly more likely to develop chronic infection than infants who receive timely PEP.18,19

The number of children receiving PHBPP services was calculated from PHBPP data reported to the CDC (infants born in 20081_{and 2009, CDC unpublished data),}

which included the number of identiﬁed and case-managed infants born to HBsAg-positive women and the number receiving HBIG and HepB vaccine.1_Unit

costs included HepB vaccine dose, vaccine administration, program costs, screening all pregnant women, HBIG, and PVST with outpatient consultation.

Markov Model

A Markov model of disease progression was used to estimate the HepB-related lifetime medical costs and QALY losses associated with perinatal and child-hood HBV infections. These were then used as inputs to the decision tree. The Markov model was built in Microsoft Visual Studio 2008.

We deﬁned early diagnosis as diagnosis of infection soon after infection (100% probability of diagnosis for infants who are serologically tested) and late di-agnosis as detection of infection at a 1% annual rate,20–22 _{or when the infection}

becomes symptomatic. We estimated hepatitis-related costs and QALY loss for early and late diagnosis and for perina-tal and childhood infection. Table 1 shows that perinatal infections have higher costs and greater QALY losses than childhood infections, because chronic HBV infection is more common after perinatal infection (90% vs 30%).4

For both types of infections, early di-agnosis leads to earlier and more mon-itoring, and more effective treatment than late diagnosis, resulting in higher costs but lower QALY loss. Appendices A and B in the Supplemental Information provide detailed explanations of the cal-culation of each parameter in Table 1 and

a detailed description of the Markov model, respectively.

Analysis Outcomes

The combined decision tree and Markov models quantiﬁed the number of peri-natal and early childhood infections from infants born to HBsAg-positive women. The other main outcome measures were QALYs, lifetime costs, and incremental cost per QALY gained. Costs were evalu-ated from the health care system per-spective and expressed in 2010 US dollars. Future costs and QALYs were discounted at a 3% annual rate.11,12

For each strategy, expected health outcomes were the number of perinatal and childhood infections and QALYs lost with infection. Expected total costs were the sum of strategy costs and the present value of discounted future health care costs associated with monitoring and treating HBV infection and its complications.

Cost-effectiveness Analysis

ICERs were estimated.23_{The ICER}

rep-resents the additional cost to achieve 1 less QALY loss due to infection. The preferred strategy is determined by comparing the ICER to what decision makers are willing to pay for an addi-tional QALY. No consensus has been reached on decision makers’ willing-ness to pay in the United States, al-though a $50 000/QALY benchmark has been used in several studies.24

Proba-bilistic sensitivity analysis was con-ducted to incorporate uncertainty in model parameters. Monte Carlo simu-lation was used to calculate the com-bined impact of the model’s various uncertainties.25_{The distributions used}

are presented in Table 1. Uncertainty in the model was described using a cost-effectiveness acceptability curve (CEAC)23

to graphically show the probability that 1 strategy is more cost-effective than the other based on decision makers’ will-ingness to pay for an additional QALY.11,23

Sensitivity Analyses

One-way sensitivity analyses were conducted to estimate the impact of changing each key parameter in-dividually. A series of multiway sensi-tivity analyses changed several variables simultaneously to create 6 hypothetical scenarios: (1) pessimistic and optimistic vaccine efficacy sce-narios, using lower or upper bounds of the confidence interval (CI) from Lee et al26_forfi_{rst dose of vaccine and HBIG}

and 50% or 10% cut in the remaining variables’efﬁcacy, respectively; (2) no maternal screening cost: the cost of screening all pregnant women in both strategies was excluded; (3) same di-agnosis probability: assumed all peri-natal and childhood infections were diagnosed at infection (early di-agnosis); (4) perfect PHBPP: assumed that all infants born to HBsAg-positive women were identiﬁed and managed by a perfect program (100% coverage), all infants received HBIG and HepB vaccine within 24 hours and completed all doses within 9 months, and all infants were serologically tested post-vaccination; (5) No PHBPP, where all

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HBIG. Scenario 6 also assumed that PVST would be done at the same rate as in the program strategy.

Because program costs relied on self-reported data (as detailed in Appen-dix A in the Supplemental Information), which might not have captured all the identiﬁcation and management-related costs, a threshold analysis on program costs was conducted.

RESULTS

Base-Case Results

Table 2 presents the cost-effectiveness results for the base-case analysis. The lifetime costs for the No PHBPP strategy were the costs of screening all pregnant women ($60 018 562), the cost of rou-tine vaccination ($1 943 035), and the long-term medical costs associated with late diagnosis of perinatal and childhood infections ($52 364 741). The PHBPP had higher lifetime costs ($120 319 857) and better health out-comes relative to No PHBPP. The life-time costs of the PHBPP included the costs of screening all pregnant women ($60 018 562), identifying in-fants born to HBsAg-positive women ($9 304 521), managing those infants ($8 977 101), the cost of PEP with HBIG and HepB vaccine, with additional HepB series and PVST for infants who failed to respond to the initial HepB vaccine se-ries ($4 221 035), and long-term HepB-related medical costs ($37 798 101). Compared with No PHBPP, the PHBPP was associated with 2351 fewer total infections (1485 perinatal and 866 childhood), 2304 less QALYs lost, and an ICER of $2602 per QALY. Hence, if decision

makers are willing to pay at least $2602 per QALY gained, the PHBPP can be con-sidered cost-effective.

Figure 2 presents the CEAC. The prob-ability that the PHBPP is cost-effective increases as health gains are more highly valued; if decision makers are willing to pay∼$6000 for an additional QALY, the PHBPP is cost-effective.

Sensitivity Analyses

Figure 3 shows the effect of the 1-way sensitivity analyses on the ICERs. The probability of HBV transmission had the highest impact on the ICER. With higher transmission probabilities, the program was more cost-effective, and with lower transmission probabilities, the ICER was higher. Overall, changing each variable had a moderate to small

effect, and the ICER never surpassed $6500 per QALY.

Table 3 presents the results of the multiway sensitivity analyses. Under a pessimistic vaccine efﬁcacy scenario, the PHBPP was slightly more costly and less effective than in the base-case scenario, with a slightly higher ICER ($3060 per QALY). Under the optimistic vaccine efﬁcacy scenario, the PHBPP had lower costs and higher QALYs gained than in the base-case scenario. Excluding the cost of screening all pregnant women did not have an im-pact on the ICER. With early diagnosis of all infections, the PHBPP was cost-saving (less costly and more effective than vaccination only). This is caused by the higher cost and lower QALY loss related to early diagnosis of perinatal

TABLE 2 Base-Case Estimates of Lifetime Costs, Infections, Perinatal Infections, Childhood Infections, and QALYs Lost for No PHBPP and PHBPP, Together With Incremental Analysis

Total Costa Total

Infections

Perinatal Infections

Childhood Infections

Total QALYs Losta

ICER ($/ QALY)

No PHBPP $114 325 741 6816 4423 2393 6476

PHBPP $120 319 857 4464 2938 1527 4173

PHBPP Versus No PHBPP $5 994 115 22351 21485 2866 22304 $2602

a_{Costs and QALYs are discounted at a 3% annual rate. Costs in US dollars at a 2010 price base.}

FIGURE 2

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FIGURE 3

Sensitivity analysis. Shows the range of ICERs (horizontal axis; $/QALY) for lower and upper bound input values (vertical axis), when the PHBPP is compared with no program. For example, higher transmission rate leads to a more cost-effective program and vice versa.

TABLE 3 Multiway Sensitivity Analysis: What-If Scenarios

Total Cost, $a Total

Infections

Total Perinatal Infections

Total Childhood Infections

Total QALYs Losta

ICER, $ ($/QALY)

(1a) Pessimistic vaccine efﬁcacy scenario

No PHBPP 124 070 020 8084 5246 2838 7681

PHBPP 131 789 282 5571 3682 1889 5159 3060

(1b) Optimistic vaccine efﬁcacy scenario

No PHBPP 95 993 164 4430 2874 1555 4209

PHBPP 104 482 875 2669 1752 918 2509 4994

(2) No maternal screening cost

No PHBPP 54 307 179 6816 4423 2393 6476

PHBPP 60 301 294 4464 2938 1527 4173 2602

(3) Same diagnosis probability (all diagnosed at infection)

No PHBPP 196 488 335 6816 4423 2393 3998

PHBPP 170 959 339 4414 2938 1476 2627 Cost saving

(4) Perfect PHBPP

No PHBPP 114 325 741 6816 4423 2393 6476

PHBPP 133 862 135 1257 1109 148 922 3517

(5) No PHBPP where allﬁrst HepB doses#72 h are given with HBIG, no PVST

No PHBPP 103 458 773 5098 3308 1790 4844

PHBPP 114 658 166 3570 2357 1212 3322 7358

(6) No PHBPP where allﬁrst HepB doses#72 h are given with HBIG, with PVST

No PHBPP 119 464 037 4941 3308 1632 4297

PHBPP 122 996 909 3487 2357 1130 3037 2804

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and childhood infections. Under the assumption of a perfect program, the higher costs of the program ($133 862 135 vs $120 319 857 in the base-case) led to many more infections avoided and hence, less QALYs lost. Under this as-sumption, there were only 1257 infec-tions and the ICER was $3517 per QALY. Providing HBIG to all infants who received aﬁrst dose of HepB within 72 hours in the No PHBPP strategy resulted in an ICER of $7358 per QALY. This is related to the higher impact of this assumption in the No PHBPP strategy where the higher costs related to HBIG administration are offset by lower future complication costs and QALYs lost related to HepB infections. However, also providing PVST in the No PHBPP strategy reduced the ICER of sce-nario 5 to $2804 per QALY because PVST leads to earlier treatment but reduces only childhood infections and not peri-natal infections, which are associated with higher future costs.

The threshold analysis on the program costs showed that assuming a $50 000 per QALY maximum willingness to pay, the cost of PHBPP identiﬁcation could be up to $54 000 per infant and the costs of PHBPP management could be up to $68 000 per infant. This is well above the base-case values of $783 and $769 for the costs of identiﬁcation and management per infant.

DISCUSSION

When the PHBPP is compared with a strategy that follows ACIP recom-mendations without the support of the program, the ICER is $2602 per QALY, and when this strategy also considers HBIG and HBIG with PVST, the ICER is between $7358 and $2804 per QALY, which by most standards suggests that the PHBPP is cost-effective in avoiding perinatal and childhood infections.30,31

The costs and outcomes of immuniza-tion strategies to prevent HBV trans-mission in the United States have been evaluated.2 _{Comparing prevention of}

perinatal HBV infection with a situation of no immunization, in 1991 Margolis et al2_{reported a total of 4703 perinatal}

and childhood infections prevented from 11 400 HBsAg-positive women. To understand our results within the context of those presented by Margolis et al,2_{we compared the PHBPP to a}

hy-pothetical scenario of no vaccination in a separate analysis (results available on request). Scaled to our estimate of 24 784 HBsAg-positive mothers, the number of infections prevented in Margolis et al2_{would be analogous to}

10 224 infections avoided, close to our estimate of 9159 infections prevented when the PHBPP is compared with a situation of no immunization. The slightly lower number of infections prevented in our models is caused by the use of a lower transmission rate (updated to take into account current seroprevalence estimates), and a slightly lower efﬁcacy of PEP that takes into account current compliance rates by timing ofﬁrst and remaining doses of PEP doses. Margolis et al2 _{did not}

account for PEP compliance (they as-sumed the same value as routinely administered vaccines) and did not cost a speciﬁc perinatal prevention program. Therefore, program cost estimates are not directly compara-ble. Margolis et al2_presented

cost-effectiveness results from a third-part payer’s perspective in which only direct medical costs were included. They also presented net beneﬁt estimates from a broader perspective in which medical direct costs and morbidity- and mortality-related work-loss costs were included. When a broader perspective was adopted, Margolis et al2_reported

that the perinatal prevention strategy generated cost savings. Following our health care system perspective on costs and health economic guidelines that recommend that mortality-related productivity losses should not be in-cluded in cost-effectiveness studies with QALYs, we excluded mortality-related

work-loss costs.11,12 _{Thus, we do not}

compare our ICER with that presented by Margolis et al,2_{because the authors}

did not present ICERs in the form of cost per QALYs and included different cost categories.

Other data limitations could have af-fected the results. The HepB vaccine efﬁcacy with HBIG starting within 24 hours of birth was taken from a recent meta-analysis based on 3 trials, and HepB vaccine efﬁcacy without HBIG was based on 4 trials.32_{Despite the small}

number of studies, the estimates are within the range of results from studies not included because they were not randomized controlled trials.33,34 _The

efﬁcacy of HepB vaccine and HBIG when the ﬁrst dose is delayed and when all vaccine doses are not completed on time was determined by the authors’ calculations relying on 2 studies.17,18

These areas of uncertainty were con-sidered in the probabilistic and multi-way sensitivity analyses.

Another important data limitation relates to the cost of the PHBPP. Program costs were based on aggregate data reported by PHBPP grantees. We ex-cluded outliers and used bootstrap techniques to account for imperfections of the data. However, it is possible that cross-subsidies (eg, ofﬁce space, utili-ties, shared equipment, hospital per-sonnel time for communication, and liaising with PHBPP staff) were not captured in the reports. More accurate costs are needed for future analyses.

In addition to the data limitations, more general issues remain. Some beneﬁts of the PHBPP have been underestimated. Recent evidence suggests vaccination confers immunity into early adulthood.35–37

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herd immunity, which would require a dynamic transmission model approach in which the risk of infection changes over time. Our results showed that the program is a potentially cost-effective intervention, even without the additional beneﬁts that would accrue from dynamic effects like herd immunity. A dynamic transmission model might further en-hance this result. Finally, the beneﬁts of PHBPP might have been further un-derestimated because we did not include maternal evaluation and management of household and sexual contacts.

CONCLUSIONS

This study presents the ﬁrst cost-effectiveness analysis of the US PHBPP. The simulation of a perfect PHBPP sce-nario showed that an expansion of the current recommendations to all infants at risk would lead to a reduced number of perinatal and childhood infections, with an ICER of $3517 per QALY. Our model pre-dicted that the current PHBPP represented a cost-effective use of resources, and that expansion of the program could represent an economically efﬁcient method to pre-vent further morbidity and mortality.

ACKNOWLEDGMENTS

We acknowledge the contributions by Perinatal Hepatitis B Prevention Coordi-nators Julie Lazaroff, New York City Department of Health and Mental Hy-giene, and Patrick Fineiis, Michigan De-partment of Community Health, for providing useful comments on the model; and by Qian Li from the CDC’s National Center for Immunization and Respira-tory Diseases who analyzed data from the 2010 National Immunization Pro-gram to determine HepB vaccine cover-age at intervals relevant to this analysis.

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(Continued fromﬁrst page)

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

FINANCIAL DISCLOSURE:The authors have indicated they have noﬁnancial relationships relevant to this article to disclose.

FUNDING:RTI International’s work on the project was supported by Centers for Disease Control and Prevention contract 200-2009-30991 TO3. Theﬁndings and conclusions in this article are those of the authors and do not necessarily represent the ofﬁcial position of the Centers for Disease Control and Prevention or the Agency for Toxic Substances and Disease Registry.

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