The incidence of hepatitis C virus (HCV) infection more than quadrupled during 2010 through 2020 in the United States, with the highest rates and increases among persons 20–39 years of age¹. Increasing HCV infections among reproductive age adults has resulted in higher numbers of infants with perinatal HCV exposure^1,2. studies estimate that 5.8% (95% CI, 4.2%–7.8%) of infants born to HCV-infected persons acquire hepatitis C perinatally and approximately 80% of those infants develop chronic HCV infection^3,4

Curative hepatitis C treatment is approved for use in children beginning at 3 years of age^7,8. The identification of children with perinatally acquired HCV is the first step. CDC and USPSTF hepatitis C screening recommendations among adults, updated in 2020 and followed with similar recommendations from the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine in 2021, call for hepatitis C screening of all pregnant persons during every pregnancy. Testing recommendations for infants with perinatal exposure to HCV have been developed by medical organizations with variability in timing and type of test recommended^7-10. Recommendations include HCV antibody testing at age 15 to 18 months, allowing time for passively acquired maternal antibodies to clear, followed by HCV RNA testing for children with reactive antibody results or HCV RNA detection either once or twice in the first year of life starting at 2 months of age^7-12. Differences in recommendations can contribute to inconsistent implementation by providers.

Recognition of perinatal exposure requires maternal HCV screening and communication of positive results to the child’s health provider. Universal pediatric HCV screening could overcome these barriers, but the cost-effectiveness of this approach has not been evaluated. Optimal timing of pediatric evaluation is also unclear. Attendance at recommended well-child visits is highest immediately after birth, including among low-income populations with limited access to care¹³. HCV testing among exposed children at age 18 months or older does not usually exceed 50%, and various assessments have found that only 10–30% receive testing ^14-18. Current testing algorithms call for anti-HCV testing at or after 18 months followed by an HCV RNA test when antibody tests are reactive. Accelerating pediatric HCV evaluation among exposed children from age 18 months or older to age 2–6 months using an HCV RNA test with reliable results, could increase the number of infected children identified by providing testing while more children are engaged in routine care. While HCV RNA testing is more expensive than anti-HCV testing, the cost-effectiveness of an HCV RNA-only testing strategy has not previously been evaluated and must be weighed against high loss to follow-up when testing is delayed.

This modeling study aimed to identify the optimal strategy for identifying children with perinatally acquired HCV infection by assessing the impact and cost-effectiveness of several strategies: a single HCV RNA test during age 2–6 months of age compared with anti-HCV with reflex to HCV RNA at age 18 months or later; each testing approach among children with known perinatal HCV exposure was compared with universal screening among all children.

We used a decision analysis framework to compare testing strategies for a cohort of US infants born in 2021. Primary considerations for defining each strategy were timing of testing and type of test used. We defined four testing strategies based on combinations of the type of test, including anti-HCV, HCV RNA, and anti-HCV with reflex to HCV RNA, and timing of test at either age 2–6 months or age 18 months or older. Estimates for sensitivity and specificity of each type of test came from published studies^19,21. Although some previous recommendations suggest the use of two HCV RNA tests in order to capture transient viremia, we modeled the use of a single HCV RNA test because assays currently used in the United States have greatly improved and now routinely detect HCV viral loads of 15 I.U./ml or less²². We modeled these strategies: Anti-HCV with reflex to HCV RNA at 18 months among children known to be perinatally exposed (i.e., baseline comparison strategy); HCV RNA testing at 2–6 months among children known to be perinatally exposed (Test Strategy 1); universal anti-HCV with reflex to HCV RNA at 18 months among all children (Test Strategy 2); universal HCV RNA testing at 2–6 months among all infants (Test Strategy 3).

Compared with the baseline comparison strategy each of the three alternative testing strategies resulted in an increased number of children tested and improved health outcomes (Table 2). Additionally, Test Strategy 1, representing the testing of known HCV perinatally exposed children at age 2–6 months with an HCV RNA test, was cost-saving compared with the baseline comparison strategy, with a population-level difference in cost of $469,671. Compared with the baseline comparison strategy, each of the two universal testing strategies resulted in an increase in QALYs and an increase in total costs. Test Strategy 2, representing universal testing of children at age 18 months or older with anti-HCV and reflex to HCV RNA test, increased population-level costs by over $38 million (ICER=26,105) and Test Strategy 3, representing universal testing of children at age 2–6 months with HCV RNA test, increased population-level costs by over $129 million (ICER=35,887), compared with the baseline comparison strategy.

One-way interval sensitivity analysis on the proportion of pregnant persons screened for HCV infection indicated that Test Strategy 1, testing of known HCV perinatally exposed children at age 2–6 months with an HCV RNA test, was cost-saving and resulted in improved health outcomes in all scenarios. Additionally, as a higher proportion of pregnant persons were screened, the cost per unit of beneficial health outcomes increased in the two universal testing scenarios (Figure). Population-level results for two scenarios that assume 65% and 90% of pregnant persons are screened for HCV infection are presented in Table 4 (online). A comparison of the two universal testing strategies (Test Strategy 2 and Test Strategy 3) against Test Strategy 1 at different assumptions of the percent of persons screened for HCV infection is presented in Table 3. Compared with Test Strategy 1, universal testing of children with anti-HCV tests at 18 months results in higher costs and fewer QALYs in all scenarios in which at least 60% of pregnant persons are screened for HCV infection. Results from the probabilistic sensitivity analysis on all model inputs are presented in Table 5 (online). Notably, across all model runs, Test Strategy 1 was dominant over the baseline comparison strategy, resulting in lower cost and improved health outcomes. Population-level results from the scenario sensitivity analysis assuming higher rates of vertical transmission and clearance are presented in Table 6 (online). In this scenario analysis, Test Strategy 1 identified 76% more documented HCV infections and had an ICER of $455, compared with the baseline comparison strategy.

The objective of this modeling study was to identify the optimal testing strategy that should be used to diagnose perinatally acquired HCV infections. All three comparison strategies resulted in more children tested and better population-level health outcomes including fewer cases of hepatocellular carcinoma, decompensated cirrhosis, liver transplants, and HCV-related deaths, compared with the currently accepted standard of anti-HCV testing at age 18 months or older. Testing of known perinatally exposed children at age 2–6 months with an HCV RNA test compared with the baseline strategy resulted in population-level cost-savings of $469,671. As expected, more testing in each of the universal comparison strategies resulted in increased QALYs, but also over $38 million in increased population-level costs for anti-HCV with reflex to HCV RNA at age 18 months or older and over $129 million in increased population-level costs for testing of all children at age 2–6 months with an HCV RNA test. As uptake of testing recommendations for HCV infection during pregnancy continues to increase, the difference in the number of infections identified between universal testing strategies and testing children with known exposure will continue to decline.

These analyses indicate the optimal timing and most efficient test is a single HCV RNA during age 2–6 months among children perinatally exposed to HCV. Factors driving these results include pediatric loss to follow up, , high attendance at well-child visits in the first 6 months of life, and highly sensitive nucleic acid testing with reliable results starting at age two months. Testing further from birth is associated with loss to follow up and may reduce the likelihood that perinatal exposure will be documented in the child’s medical record (e.g., change of providers, loss of custody etc.). This is especially true as HCV-exposed children are disproportionately publicly insured, and infants born to HCV-infected mothers are more likely to be involved with child services and foster care^17,37,38. One study assessing >150,000 children at two health networks spanning 20 states, determined children rarely missed 2-month, 4-month, and 6-month well-care visits, while 15-month and 18-month visits were attended by less than half of publicly insured children¹³. With advancements in analytical sensitivity allowing detection of low-level viremia, nucleic acid testing for diagnosis of perinatally acquired HCV infection in early infancy provides excellent diagnostic performance^19,22.

. Among exposed children, the increased number of children diagnosed with a single HCV RNA at younger ages with the 2–6 month strategy was cost-saving and had corresponding improved health outcomes, compared with the widely recommended 18 month strategy using anti-HCV with reflex to HCV RNA. The success of these strategies relies heavily on widespread testing during pregnancy and transfer of information to providers caring for infants. Updated CDC hepatitis C screening guidelines call for testing of all pregnant people during each pregnancy but testing currently remains below 50%³⁹. At current levels of HCV testing among pregnant persons, a universal approach using anti-HCV testing at 18 months or older costs an additional $142,764 per infection diagnosed, and HCV RNA testing at 2–6 months an additional $187,561 per infection diagnosed, compared with testing known exposed children with an HCV RNA test at age 2–6 months. As the proportion of pregnant persons tested approaches 90%, universal testing strategies result in diminishing return with costs per additional diagnosed infection increasing to $705,403 for anti-HCV testing, and $273,813 for HCV RNA testing. Cost per additional diagnosed pediatric infection for either universal strategy become prohibitive as the proportion of pregnant persons screened for HCV infection exceeds 70%.

Results of this analysis should be interpreted with a few limitations. First, there are limited data on the proportion of infants with perinatal exposure that would be tested at 2-6 months and 18 months. Inputs were based on a single study of infant follow-up at each time period and may not be generalizable to all settings. Second, we only quantified costs and health outcomes among children. We did not quantify any potential costs or benefits that would be gained by the resulting diagnosis and treatment of a birthing parent because of identifying an HCV infection in their child. Additionally, we assumed perinatally-acquired infections undiagnosed in childhood would not be diagnosed and treated later in life, which may result in an overestimate of poor outcomes among persons with undiagnosed perinatal infections. Third, to align with current recommendations^7,10 we assumed treatment occurs at or after age 3 years in all strategies and there was no difference in linkage to treatment or costs associated follow-up testing that providers may recommend prior to 3 years of age. Evaluating approaches in which treatment was initiated at different ages was outside of the scope of this study, which focused on testing strategies. Fourth, the model of HCV disease progression does not include coinfections with HIV, hepatitis B, or other infections, which could alter quality (and length) of life, progression of HCV infection, and associated medical costs. Finally, for universal testing strategies, we did not model program implementation costs that would likely be incurred in such a large scale up of HCV testing, which results in an underestimate of total costs for the universal strategies.

. Identifying optimal strategies for diagnosis of perinatally infected children that are cost-effective are essential for preventing morbidity and mortality associated with complications from perinatal HCV infection, improving individual and population health outcomes, and achieving national hepatitis C elimination goals.