Cost-Effectiveness of Strategies for Treatment Timing for Perinatally Acquired Hepatitis C Virus

Megan Rose Curtis; Rachel L Epstein; Pamela Pei; Benjamin P Linas; Andrea L Ciaranello

doi:10.1001/jamapediatrics.2024.0114

. 2024 Mar 11;178(5):489–496. doi: 10.1001/jamapediatrics.2024.0114

Cost-Effectiveness of Strategies for Treatment Timing for Perinatally Acquired Hepatitis C Virus

Megan Rose Curtis ^1,^2,^3,^4,^5,^6,^✉, Rachel L Epstein ^5,^6,⁷, Pamela Pei ¹, Benjamin P Linas ^5,⁶, Andrea L Ciaranello ^1,^2,³

¹Medical Practice Evaluation Center, Massachusetts General Hospital, Boston

²Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston

³Harvard Medical School, Boston, Massachusetts

⁴Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, Massachusetts

⁵Boston Medical Center, Massachusetts

⁶Department of Medicine, Section of Infectious Diseases, Boston University School of Medicine, Massachusetts

⁷Department of Pediatrics, Section of Infectious Diseases, Boston University School of Medicine, Massachusetts

Accepted for Publication: January 10, 2024.

Published Online: March 11, 2024. doi:10.1001/jamapediatrics.2024.0114

^✉

Corresponding Author: Megan Rose Curtis, MD, MS, Division of Infectious Disease, Department of Medicine, Brigham and Women’s Hospital, 15 Francis St, Ste PBB-A4, Boston, MA 02115 (mcurtis0@mgh.harvard.edu).

Author Contributions: Dr Curtis had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Curtis, Epstein, Linas, Ciaranello.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Curtis.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Curtis, Pei, Linas.

Obtained funding: Curtis, Linas.

Administrative, technical, or material support: Ciaranello.

Supervision: Epstein, Linas, Ciaranello.

Conflict of Interest Disclosures: Dr Epstein reported grants from the National Institutes of Health/National Institute on Drug Abuse during the conduct of the study. Dr Linas reported grants from the National Institute on Drug Abuse during the conduct of the study. No other disclosures were reported.

Funding/Support: This work is supported by the National Institutes of Health training grants (T32AI052074 and T32 AI007433), the National Institute on Drug Abuse (P30DA040500), the National Institute on Drug Abuse (1K01DA052821), and the James and Audrey Foster MGH Research Scholar Award.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Meeting Presentation: Findings from this paper were presented at the North American Meeting of the Society for Medical Decision Making; October 23, 2022; Seattle, Washington.

Data Sharing Statement: See Supplement 2.

Additional Contributions: We thank Simeng Li, BS, Ali Rahman Ahmed, BA, Kevin (Kyo Young) Chi, BA, and Shruti Sagar, BA, Medical Practice Evaluation Center, Massachusetts General Hospital, for their assistance in preparation of this manuscript.

^✉

Corresponding author.

PMCID: PMC10928541 NIHMSID: NIHMS1975654 PMID: 38466273

This study developed a state-transition model to project clinical and economic outcomes for children with perinatally acquired hepatitis C virus to investigate the cost-effectiveness of treating at various ages.

Key Points

Question

Is treating 3-year-olds with perinatally acquired hepatitis C virus (HCV) cost-effective compared with treating at older ages?

Findings

In this cost-effectiveness analysis comparing treatment of perinatally acquired HCV at 3, 6, 12, and 18 years old, treatment at 3 years old was associated with higher projected life expectancy (78.36 life years vs 76.10 life years) and lower mean projected discounted health care costs per person ($148 162 vs $164 292) compared with the next best strategy of treating at 6 years old.

Meaning

In this cost-effectiveness analysis, results demonstrated that treating 3-year-olds with perinatally acquired HCV was projected to increase life expectancy and decrease health care costs.

Abstract

Importance

Prevalence of chronic hepatitis C virus (HCV) infection among pregnant people is increasing in the US. HCV is transmitted vertically in 7% to 8% of births. Direct-acting antiviral (DAA) therapy was recently approved for children with HCV who are 3 years or older. The clinical and economic impacts of early DAA therapy for young children with HCV, compared with treating at older ages, are unknown.

Objective

To develop a state-transition model to project clinical and economic outcomes for children with perinatally acquired HCV to investigate the cost-effectiveness of treating at various ages.

Design, Setting, and Participants

The study team modeled the natural history of perinatally acquired HCV to simulate disease progression and costs of a simulated a cohort of 1000 US children with HCV from 3 years old through death. Added data were analyzed January 5, 2021, through July 1, 2022.

Interventions

The study compared strategies offering 8 weeks of DAA therapy at 3, 6, 12, or 18 years old, as well as a comparator of never treating HCV.

Main Outcomes and Measures

Outcomes of interest include life expectancy from 3 years and average lifetime per-person health care costs. Other clinical outcomes include cases of cirrhosis, decompensated cirrhosis, and hepatocellular carcinoma (HCC).

Results

The study team projected that treating HCV at 3 years old was associated with lower mean lifetime per-person health care costs ($148 162) than deferring treatment until 6 years old ($164 292), 12 years old ($171 909), or 18 years old ($195 374). Projected life expectancy was longest when treating at 3 years old (78.36 life years [LYs]) and decreased with treatment deferral until 6 years old (76.10 LYs), 12 years old (75.99 LYs), and 18 years old (75.46 LYs). In a cohort of 1000 children with perinatally acquired HCV, treating at 3 years old prevented 89 projected cases of cirrhosis, 27 cases of HCC, and 74 liver-related deaths compared with deferring treatment until 6 years old. In sensitivity analyses, increasing loss to follow-up led to even greater clinical benefits and cost savings with earlier treatment.

Conclusions and Relevance

These study results showed that DAA therapy for 3-year-old children was projected to reduce health care costs and increase survival compared with deferral until age 6 years or older. Measures to increase DAA access for young children will be important to realizing these benefits.

Introduction

From 2000 to 2019, hepatitis C virus (HCV) prevalence among pregnant people in the US increased 10-fold.¹ Recent data demonstrate that HCV is transmitted in 7% to 8% of births to people with HCV.^2,3 This rise in HCV infections among pregnant people is emerging as a public health concern for women and children.⁴

Highly effective and well-tolerated direct-acting antivirals (DAAs) were recently approved for children with HCV who are 3 years and older.⁵ Treatment reduces risks for cirrhosis, hepatocellular carcinoma (HCC), and liver-related mortality.^6,7 DAA uptake among young children has been low, due in part to concerns about high medication costs and long-term clinical benefits.^8,9 Two model-based analyses using DAA costs from before 2021 estimated that treating children for HCV at 6 years to 12 years old is cost-effective compared with treatment at 18 years old.^10,11 However, neither study extended to a lifetime horizon, nor evaluated treatment at 3 years.

The US Centers for Disease Control and Prevention recently issued updated recommendations for HCV RNA testing of perinatally exposed infants at 2 to 6 months old to avoid loss to follow-up that occurs when waiting until 18 months old for HCV antibody testing.⁴ As these guidelines are implemented, it is likely that many additional children with perinatally acquired HCV will be identified. Clinicians and families will need to decide whether to treat at 3 years or older. The aim of this study was to estimate the value of treating children with DAAs when they become eligible at 3 years old. This analysis incorporates recent DAA costs and a lifetime horizon to capture long-term impacts of chronic HCV, such as cirrhosis, HCC, and liver-related deaths.

Methods

Analytic Overview

We developed a state-transition model to simulate disease progression in children with perinatally acquired HCV over a lifetime horizon (TreeAge Software). We modeled treatment with glecaprevir/pibrentasvir, a pangenotypic DAA that was approved in 2021 for treating children 3 years and older.¹² Our strategies compared treatment initiation at 3 years old, 6 years old, 12 years old, 18 years old, and no treatment. Simulated clinical outcomes included cases of cirrhosis, decompensated cirrhosis, HCC, liver-related mortality, and all-cause mortality. The model projected lifetime health care costs from the health care sector perspective. Lastly, we completed deterministic and probabilistic sensitivity analyses to assess a range of clinically relevant scenarios and ascertain the primary determinants of our findings. Institutional review board approval was not required as this study did not involve human participants. This analysis follows the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) reporting guidelines (eMethods 5 in Supplement 1).

Model Structure

We simulated a cohort of 1000 3-year-olds with perinatally acquired HCV infection and no liver fibrosis.¹³ The model characterizes disease progression through annual transitions between mutually exclusive health states reflecting key clinical conditions of HCV disease (eFigure 1 in Supplement 1). Health states include liver fibrosis stages, cirrhosis complications, and mortality from liver-related and age-adjusted competing risks of death (eMethods 1 in Supplement 1). We modeled liver fibrosis as a series of transitions between the meta-analysis of histological data in viral hepatitis (METAVIR) fibrosis stages: no fibrosis (F0), mild portal fibrosis without septa (F1), moderate portal fibrosis with few septa (F2), severe fibrosis with numerous septa (F3), and compensated cirrhosis (F4).^14,15 Given the limited data regarding cirrhosis complications in pediatric populations, we conservatively simulated the possibility of developing decompensated cirrhosis and HCC only after age 18 years. A modeled individual must reach decompensated cirrhosis or HCC before experiencing risk of liver-related mortality (eFigure 1 in Supplement 1). We also conservatively assumed no added health care costs for individuals with no fibrosis (F0), mild fibrosis (F1), or moderate fibrosis (F2); liver-related health care costs only accrue after development of severe fibrosis (F3). Additional model structure includes a liver transplant health state possible after developing decompensated cirrhosis or HCC, which was incorporated as a scenario analysis.

Strategies and Impact of DAA Treatment

The treatment strategies modeled include treating at 3 years, 6 years, 12 years, and 18 years old with an 8-week course of glecaprevir/pibrentasvir. In this analysis, individuals with decompensated cirrhosis or HCC were not offered treatment, because glecaprevir/pibrentasvir is not approved after development of these conditions. Treatment effectiveness (defined as sustained virologic response at 12 weeks) reflects completion rates from a pediatric randomized clinical trial and a meta-analysis of real-world effectiveness of DAA therapy in adults, which both estimated an effectiveness of 96% (Table 1) (eMethods 2 in Supplement 1).^5,20 If HCV cure is achieved after treatment, fibrosis progression stops, reducing the probability of progression to decompensated cirrhosis and HCC among individuals with cirrhosis at treatment.

Table 1. Model Inputs to Evaluate Cost-Effectiveness of Strategies for Treatment for Children With Perinatally Acquired Hepatitis C Virus (HCV) Infection in the US at Different Ages.

Input parameter	Value	Range evaluated	Distribution	Source
Annual probability of fibrosis progression
No fibrosis to mild fibrosis (F0-F1)	0.208	0.112-0.368	β	Erman et al,¹³ 2019
Mild fibrosis to moderate fibrosis (F1-F2)	0.090	0.040-0.196	β	Erman et al,¹³ 2019
Moderate fibrosis to severe fibrosis (F2-F3)	0.108	0.050-0.224	β	Erman et al,¹³ 2019
Severe fibrosis to cirrhosis (F3-F4)	0.077	0.023-0.246	β	Erman et al,¹³ 2019
Annual probability of complication from cirrhosis
Cirrhosis to decompensated cirrhosis (≥18 y) after SVR	0.002	NA	NA	Greenaway et al,¹¹2021
Cirrhosis to HCC (≥18 y) after SVR	0.005	NA	NA	Greenaway et al,¹¹ 2021
Cirrhosis to decompensated cirrhosis (≥18 y)	0.039	NA	NA	Salomon et al,¹⁶ 2003
Cirrhosis to HCC (≥18 y)	0.021	NA	NA	Salomon et al,¹⁶ 2003
Annual mortality
Mortality from decompensated cirrhosis	0.264	NA	NA	Salomon et al,¹⁶2003
Mortality from HCC	0.351	NA	NA	Salomon et al,¹⁶ 2003
Annual health care costs (US 2022), $
No HCV, HCV with no to moderate fibrosis, treated HCV without cirrhosis^a	1925- 15 064	NA	NA	Blewett et al,¹⁷ 2021
Severe fibrosis (untreated)	20 622	20 068-$21 189	γ	McAdam-Marx et al,¹⁸ 2011
Cirrhosis (untreated and treated)	22 900	21 066-$24 848	γ	McAdam-Marx et al,¹⁸ 2011
Decompensated cirrhosis	60 601	57 445-$63 885	γ	McAdam-Marx et al,¹⁸ 2011
HCC	84 115	76 113-$92 721	γ	McAdam-Marx et al,¹⁸ 2011
Cost of treatment course (US 2022)
3 y	15 972	NA	NA	Merative US,¹⁹ 2024
6 y	21 120	NA	NA	Merative US,¹⁹ 2024
12, 18, and 30 y	26 400	NA	NA	Merative US,¹⁹ 2024
Effectiveness of treatment
Course of glecaprevir/pibrentasvir	0.96	0.95-0.98	β	Jonas et al,⁵ 2021; Lampertico et al,²⁰ 2020

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Abbreviations: HCC, hepatocellular carcinoma; NA, not applicable; SVR, sustained virologic response.

^{^a}

Input parameter ranged from $1925 to $15 064 based on a simulated individual’s age.

As few data inform retention in care between HCV diagnosis and initiation of DAA therapy during childhood, we consulted with experts to conservatively assume that 10% of individuals are lost to follow-up before treatment in the deferred treatment arms. In the base case, we assumed that if treatment was incomplete or unsuccessful there would be no opportunity to reengage in treatment at a later age. Lastly, risk of HCV reinfection after treatment with cure is not included in this analysis.

Model Inputs

We derived HCV disease progression probabilities from a meta-analysis that calculated stage-specific METAVIR progression rates (F0 to F4) among published pediatric HCV cohorts (Table 1).¹³ As complications of cirrhosis among individuals with perinatally acquired HCV only occur in adulthood in this model, transition probabilities between cirrhosis and its complications were estimated from adult literature.^16,21

We derived HCV-related health care costs from a pharmacoeconomics evaluation, which reported yearly per-patient costs for individuals with HCV with severe fibrosis (F3), compensated cirrhosis (F4), decompensated cirrhosis, or HCC.¹⁸ Direct costs included inpatient, outpatient, professional, emergency department services, and prescription drugs (excluding antiviral therapy; eMethods 2 in Supplement 1). We assumed yearly health care costs for individuals after successful HCV treatment to be the same as for the general population, unless they had developed cirrhosis (F4) before treatment. Costs of health care utilization were derived from the Medical Expenditure Panel Survey Household Component.¹⁷ Drug costs were based on wholesale acquisition costs, as reported from Micromedex RED BOOK.¹⁹ Weight-based dosing for children aged 3 to 11 years old leads to costs ranging from $15 840 to $26 400 (eMethods 2 in Supplement 1). For individuals 12 years or older, a course of glecaprevir/pibrentasvir at 300 mg/120 mg costs $26 400 (Table 1).¹⁹ Costs were inflation-adjusted to 2022 US dollars using the US Consumer Price Index, with an annual discount rate of 3%.

Model Validation

We assessed external validity by comparing our model-predicted median age of cirrhosis with data from a cohort of 1049 individuals with pediatric hepatitis C.²² We also compared median time from developing cirrhosis with decompensation with findings from a prospective cohort of individuals with compensated HCV-related cirrhosis and prior modeling studies evaluating treatment of adults with HCV.^21,23

Sensitivity and Scenario Analyses

In 1-way sensitivity analyses, we varied fibrosis progression rates, treatment effectiveness, loss to follow-up (from 0% to 50%), and liver disease health care costs. We also modeled a scenario in which individuals lost to follow-up before treatment at 6 years old or 12 years old were treated at 18 years old. While we did not include liver transplant in our base case due to scarcity of data regarding adults with perinatally acquired HCV, we did perform a scenario analysis using adult estimates of transplant risk and cost (eTable 8 in Supplement 1) to evaluate the impact of including liver transplantation on treatment timing.^24,25 Given emerging data regarding spontaneous clearance, we also performed a scenario analysis assuming 9% of the population spontaneously cleared infection without treatment between age 3 and 5 years.²⁶ Lastly, in a sequence of scenario analyses, we removed key parameters hypothesized to be important in driving model outcomes. To illustrate each parameter’s impact, we performed consecutive scenario analyses in which we successively added each parameter back into the model. We compared the change in life expectancy and health care costs per person between the 2 most optimal strategies.

We evaluated the impact of model parameter uncertainty through probabilistic sensitivity analysis. We defined a probability density function around 9 core model parameters: 4 parameters representing fibrosis progression, each of the 4 liver disease costs, and treatment effectiveness (distributions noted in Table 1). We performed 1000 model simulations of a cohort of 1000 individuals, each time sampling with replacement parameter values from the density functions. We calculated the median and 95% CIs for life expectancy and lifetime health care costs, as well as the probability of each strategy being cost-effective.

Results

Validation

Without treatment, the model predicted a median age of cirrhosis of 35 years, which is within 6% of the predicted median age of cirrhosis in the validation cohort (33 years) (eTable 1 in Supplement 1).²² Median time from cirrhosis to first decompensation was 10 years in the model, which is within 8% of the median 10.8 years reported in prior HCV modeling studies and in a prospective study of patients with compensated HCV cirrhosis.^21,23

Clinical Outcomes

In a cohort of 1000 simulated children over a lifetime horizon, the no treatment strategy led to 926 cases of cirrhosis and 277 cases of HCC (Figure 1). Estimated life expectancy without treatment was 55.70 LYs with 765 liver-related deaths (Table 2; eTable 2 in Supplement 1). Earlier treatment improved clinical outcomes with a monotonic trend in decreased cases of cirrhosis, decompensated cirrhosis, HCC, and life expectancy. For example, when comparing the burden of cirrhosis with no treatment, treating at 18 years reduced cirrhosis cases by 80%, treating at age 12 by 85%, treating at 6 years by 86%, and treating at 3 years by 96%. Similar trends were observed for the burden of decompensated cirrhosis, HCC, and liver-related deaths (Figure 1).

Figure 1. — As seen in this figure, delaying treatment leads to increased burden of liver complications from hepatitis C virus. Notably, 10% of the population was simulated to be lost to follow-up in the base case for strategies of deferred treatment at 6 years old, 12 years old, and 18 years old.

Table 2. Projected Life Expectancy and Costs of Treatment Strategies for Children With Perinatally Acquired Hepatitis C Virus in the US.

Strategy	Undiscounted results		Discounted results
Strategy	Life expectancy, LY	Health care costs, 2022 USD	Life expectancy, LY	Incremental life expectancy, LY	Health care costs, 2022 USD	Incremental costs, 2022 USD
Treat at 3 y^a	78.36	$518 277	32.66	NA	$148 162	NA
Treat at 6 y	76.10	$547 462	32.26	−0.40	$164 292	$16 131
Treat at 12 y	75.99	$560 010	32.23	−0.42	$171 909	$23 748
Treat at 18 y	75.46	$617 008	32.13	−0.52	$195 374	$47 212
No treatment	55.70	$809 989	28.64	−4.02	$279 252	$131 091

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Abbreviation: LY, life years; NA, not applicable; USD, US dollars.

^{^a}

Treating at 3 years old is cost-saving, meaning that it costs less and is more effective than other strategies evaluated.

Costs and Cost-Effectiveness

Projected average per-person discounted lifetime health care costs ranged from $148 162 for treating at 3 years old to $279 252 in the no treatment strategy. Lifetime health care costs were lower with earlier treatment compared with deferred treatment (Table 2).

Treating at 3 years old was a cost-saving strategy: it led to better projected clinical outcomes at a lower cost than the other evaluated strategies (Table 2). Treating all 3-year-olds with perinatally acquired HCV was projected provide an additional 2.26 LYs (0.40 discounted LYs) and to save $16 131 per person in discounted lifetime health care costs compared with deferring treatment until 6 years old.

Sensitivity and Scenario Analyses

Treating at 3 years old continued to be a cost-saving strategy in 1-way sensitivity analyses that varied fibrosis progression rates, treatment effectiveness, and costs of liver disease (eTables 3 through 5 in Supplement 1). Assuming no loss to follow-up in the deferred treatment arms, treating HCV at 3 years old was projected to have equivalent clinical outcomes compared with treating at 6 years old and to save $3307 per person (eTable 6 in Supplement 1). Increasing the probability of loss to follow-up from 0% to 50% led to decreasing projected life expectancy and increasing projected lifetime health care costs (Figure 2; eTable 6 in Supplement 1). In scenario analyses in which the study team simulated individuals who had been lost to follow-up at 6 years old or 12 years old relinking to care for treatment at 18 years old, incorporated liver transplant, and included spontaneous clearance between 3 and 5 years old, treating at 3 years old remained cost-saving compared with the other strategies (eTables 7 through 10 in Supplement 1).

Figure 2. — Because there was no LTFU simulated among the treated at 3 years old strategy, varying LTFU does not change the modeled life expectancy. Similarly, the life expectancy in the strategy for no treatment is not impacted by LTFU. However, as LTFU increases, the difference in life expectancy between treated at 3 years old and the deferred treatment strategies (treated at 6 years old, 12 years old, and 18 years old) increases significantly.

In the sequential scenario analysis, the study team found that removing loss to follow-up, withdrawing additional costs associated with HCV infection, and equalizing treatment costs eliminated the cost-savings associated with treating at 3 years old vs 6 years old. In this first scenario, treating at 3 years old was associated with equivalent life expectancy and higher discounted costs compared with treating at 6 ($1793; undiscounted costs were equivalent). For the next scenario, the study team added back loss to follow-up for the deferred treatment arms. In this scenario, treating at 3 years old was associated with an improved life expectancy (2.26 LYs) and increased health care costs ($3270) compared with treating at 6 years old. The incremental cost-effectiveness ratio of treating at 3 years old compared with 6 years old was $8131 per LY. For the next scenario analysis, additional health care costs associated with HCV disease were added back. This projected that treating at 3 years old would decrease average lifetime health care costs (−$11 020) and improve life expectancy (+2.26 LY) compared with treating at 6 years old. Lastly, adding back the differential cost of treatment by age further increased the savings associated with treating at 3 years old compared with treating at 6 years old to (−$16 131) (Figure 3). In probabilistic sensitivity analysis in which the study team varied fibrosis progression, costs of liver disease, and effectiveness of treatment, treating at 3 years old remained cost-saving in 100% of simulations (eFigure 2 and eTable 11 in Supplement 1; range and distributions listed in Table 1).

Figure 3. — Each scenario along the horizontal axis represents a separate analysis of 1 000 000 trials comparing treating at 3 years old vs 6 years old. Scenario A: components differing from base case include no loss to follow-up, no costs of liver disease, and no difference in treatment costs for older ages. In this scenario, treating at 3 years old is associated with increased costs and decreased life expectancy relative to treating at 6 years old. Treating at 6 years old is cost-saving when compared with treating at 3 years old. Scenario B: components differing from base case include no costs of liver disease and no difference in treatment costs for older ages. In this scenario, treating at 3 years old is associated with increased costs and increased life expectancy relative to treating at 6 years old. The calculated incremental cost-effectiveness ratio of treating at 3 years old compared with 6 years old was $8131 per life year (LY) indicating that treating at 3 years old is cost-effective when compared with treating at 6 years old, assuming a willingness-to-pay threshold of $50 000 per LY. Scenario C: components differing from base case include no difference in treatment costs for older ages. In this scenario, treating at 3 years old is associated with decreased costs and increased life expectancy relative to treating at 6 years old. Treating at 3 years old is cost-saving when compared with treating at 6 years old in this scenario. Base case: In this scenario, treating at 3 years old is associated with decreased costs and increased life expectancy relative to treating at 6 years old. Treating at 3 years old is cost-saving when compared with treating at 6 years old in this scenario.

Discussion

We developed a model of perinatally acquired HCV to simulate disease progression and impact of treating at various ages over a lifetime horizon. Our analysis had 3 main findings. First, compared with deferred treatment strategies, treating HCV at 3 years old leads to improved clinical outcomes (longer life expectancy, fewer cases of cirrhosis and HCC, and fewer liver-related deaths), compared with the next best strategy of treating at 6 years old. Prior modeling studies also demonstrated that treating children with HCV earlier is associated with improved clinical outcomes.^10,11 This analysis adds to these findings by quantifying the lifetime benefits of curing pediatric HCV-related liver disease early.²² DAA therapy is highly effective in curing HCV in pediatric populations.⁵ Guidelines recommend DAA therapy for all children aged 3 years and older; however, it is unlikely that these benefits are being realized given suboptimal uptake of testing and treatment.^{9,27,28,29,30,31,32,33,34,35}

Second, treating HCV at 3 years old is associated with the lowest costs among all strategies and generated substantial cost savings compared with deferred treatment strategies. The cost-savings noted in this study are multifactorial due to averted health care costs for severe fibrosis (F3) and cirrhosis (F4), lower drug costs for younger children, and importantly prevention of loss to follow-up (Figure 3). Previous modeling studies of pediatric HCV have shown that treating 12-year-olds in the US and 6-year-olds in Canada is cost-effective compared with deferring until 18 years old.^10,11 This model incorporates a much lower cost of treatment than prior modeling studies. For example, in the Canadian analysis, a glecaprevir/pibrentasvir course for a 6-year-old was modeled at $46 900,¹¹ whereas the cost for an average 3-year-old was $15 840 in the US in 2022.¹⁹ Additionally, prior modeling studies only followed up individuals over a 20- or 30-year time horizon. Following up individuals over their entire life allows projection of costly complications that occur later in life, such as decompensated cirrhosis and HCC, increasing the lifetime health care costs among individuals with deferred or no treatment.

Third, the clinical benefits and cost savings associated with early HCV treatment were significantly greater if higher loss to follow-up rates were assumed. The incremental life expectancy and incremental health care savings increased with increasing rates of loss to follow-up when comparing treating at 3 years old with deferred treatment strategies (Figure 2; eTable 6 in Supplement 1). Importantly, these modeled benefits may underestimate the true impact of earlier treatment, because loss to follow-up rates before treatment completion are likely even higher than assumed in this analysis (10% in the base case). Greater than 50% of children with perinatally acquired HCV are estimated to be lost to follow-up before adequate testing—far upstream of treatment on the HCV care cascade.^{27,28,29,30,31,32,33,36} Linkage to treatment among adolescents is also estimated to be quite low. For example, a recent analysis of adolescents aged 13 to 21 years old accessing care at federally qualified health centers showed that only 1 individual had initiated treatment.³⁴ Early treatment could obviate the issue of loss to follow-up by addressing HCV before a child can fall out of care. We are not aware of planned clinical trials to evaluate treatment earlier than 3 years old. However, future work to model the impact of treating earlier than 3 years old, balancing trade-offs between loss to follow-up, and unnecessary treatment could be valuable.

Limitations

This analysis includes several assumptions and some limitations. Regarding the natural history of HCV, we structured our model such that cirrhosis complications (decompensated cirrhosis and HCC) do not occur until adulthood. While case series describe these complications among children with perinatal HCV before 18 years,³⁷ to our knowledge, there are no population-level studies to inform these clinical risks in our model. Inclusion of childhood decompensated cirrhosis and HCC would increase the cost savings from earlier treatment and add further support for the need for identification and careful follow-up of children with perinatally acquired HCV. Data were insufficient to inform some model parameters; in these instances, we consistently assumed conditions that would bias away from the benefits of earlier treatment. For example, we were unable to incorporate comorbidities that might accelerate fibrosis progression, such as hematological diseases with iron overload, obesity, cancer, and viral coinfections (HIV and hepatitis B virus) due to lack of pediatric population-level data. Additionally, due to limited pediatric-specific data, we did not adjust our model to account for the differing quality of life associated with HCV complications. Lastly, we were unable to include indirect costs related to HCV infection or treatment, which may be significant, such as stigma, patient mental health status, or caregiver costs.³⁸ However, incorporation of these comorbidities, quality of life adjustments, and indirect costs would be expected to increase the health detriments of HCV in our model and strengthen the finding of increased effectiveness with early treatment. We also excluded HCV reinfection risk. Low HCV incidence in late childhood³⁹ suggests that reinfection of children with treated perinatally acquired HCV would likely occur in adulthood; additionally, given that reinfection risk is not expected to differ by time since prior treatment, reinfection would not impact the comparison between our modeled treatment strategies.

Lastly, in probabilistic sensitivity analysis when we simultaneously varied uncertain parameters, using wide distributions favoring delayed treatment strategies, all simulations favored treating at 3 years old. This highlights the substantial potential for cost savings for early treatment of children with HCV.

Conclusions

In summary, this modeling analysis highlights the economic and health benefits of early intervention to treat HCV when children become eligible at 3 years old. Our model incorporates emerging data regarding the natural history of pediatric disease to validate projected HCV disease progression. It derives parameters for treatment costs and effectiveness specific to young children. This analysis is also, to our knowledge, the first to project the impact of early treatment at age 3 years old on life expectancy. This health economic study suggests that treating HCV at 3 years old costs less and leads to improved health outcomes compared to deferring treatment. One key benefit of treatment at 3 years old is the opportunity to ensure treatment initiation, by beginning this process before children are lost to follow-up.

Supplement 1.

eMethods 1. Relationship of Competing Causes of Mortality

eMethods 2. Additional Details Regarding Model Structure and Parameters

eMethods 3. Model Validation

eTable 1. External validation targets to assess model of natural history of perinatally-acquired hepatitis C virus

eMethods 4. Additional Data and Sensitivity Analyses

eTable 2. Clinical outcomes associated with treatment strategies for children with perinatally-acquired hepatitis C virus in the United States

eTable 3. Sensitivity analysis varying the probability of fibrosis progression

eTable 4. Sensitivity analysis varying treatment efficacy

eTable 5. Sensitivity analysis varying the costs of hepatitis C virus liver disease

eTable 6. Sensitivity analysis varying the probability of loss-to-follow-up (LTFU)

eTable 7. Sensitivity analysis evaluating the scenario in which individuals lost-to-follow-up are linked to treatment at 18 years old

eTable 8. Model inputs for scenario analysis including liver transplantation

eTable 9.a. Scenario analysis incorporating liver transplantation into the model

eTable 9.b. Clinical outcomes incorporating liver transplantation into the model

eTable 10. Scenario analysis evaluating the scenario in which 9% of children spontaneously clear infection before treatment at 6 years old

eTable 11. Probabilistic sensitivity analysis evaluating the impact of uncertainty on life expectancy (LE) and costs

eFigure1. State-transition model for pediatric hepatitis C virus

eFigure 2. Probabilistic sensitivity analysis cost-effectiveness scatterplot

eMethods 5. Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 Checklist

jamapediatr-e240114-s001.pdf^{(733.8KB, pdf)}

Supplement 2.

Data sharing statement

jamapediatr-e240114-s002.pdf^{(14KB, pdf)}

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