Don’t Wait: The Benefits of Early Diagnosis in Perinatal Hepatitis C Virus Transmission

(See the Major Article by Gowda et al on pages e3340–6.)) The consequences of the opioid crisis that has swept across the United States in the last decade have been many, not least the significant rise in new hepatitis C virus (HCV) infections in the under-30 age group [1]. Much of this burden has been borne by women of child-bearing age in whom the rate of acute HCV infection jumped almost 4-fold between 2004 and 2014 [2]. As a consequence, HCV rates in pregnancy have also increased, in some cases by as much as 89% [3]. The implications of this are considerable, particularly in the context of the push towards global HCV elimination. The cascade of care relating to perinatal HCV transmission has been well described as suboptimal [4, 5], containing multiple points at which systematic failures of testing and engagement result in a significant proportion of HCV-infected infants remaining undiagnosed, and ultimately untreated. The article by Gowda and colleagues in this issue of Clinical Infectious Diseases addresses an important step in this cascade, notably that of testing of the HCV-exposed infant, providing critically important data on the performance of nucleic acid testing in this setting. Current American Association for the Study of Liver Diseases/Infectious Diseases Society of America guidelines promote HCV antibody (Ab) testing at 18 months as the preferred strategy, supporting only consideration of HCV RNA testing in the infant between 2 and 18 months of age, in part due to concerns over the accuracy and performance of the test in this early period. In this study, the authors used surveillance records to assess the diagnostic performance of 2 HCV RNA reverse transcriptase–polymerase chain reaction tests (lower limit of detection of 50 and 15 IU/mL, respectively). Over a 10-year period from 2008 to 2018, RNA testing was performed at between 2 and 6 months of age in 770 perinatally exposed infants. All 27 positive individuals were correctly identified, and among the negative infants who received subsequent antibody testing, all were confirmed HCV negative. Using a composite case definition, sensitivity and specificity were excellent at 100% (95% confidence interval [CI], 87.5–100%) and 100% (95% CI, 98.3–100%), respectively, providing important reassurance as to the performance of these tests in this setting. There are some caveats that should be noted. First, there was significant loss to follow-up in the infants whose first RNA test was negative. Only 30% of these children were subsequently determined to have had HCV Ab testing at 18 months or older, testifying to the high loss to follow-up rates when testing is delayed. It is possible that some of these children could have had false-negative RNA tests leading to a lower sensitivity estimate; more likely, however, these children would have been confirmed as HCV Ab-negative and this would have tightened the confidence limits around the sensitivity estimate. It is reassuring that this group did not differ in any characteristics that might have suggested a higher risk for infection. Second, the authors do not address the well-recognized occurrence of spontaneous clearance during early life [6]. Up to 25–50% of children may spontaneously clear viremia by age 4 [7]. All but 1 of the initial 28 positive cases had a second RNA test and all of these were confirmed positive. The median initial RNA level was high at 5.7 × 106 log10 IU/L, with no child returning a viral load of less than 104 log10 IU/mL. The median values for the second test, performed a median of 48 days after the first, were not given. It would be of interest to understand the trajectory of viral load measurements longitudinally, as well as to understand whether any of these infants subsequently cleared the virus. Just under half of these positive infants (12/27) were documented as having a follow-up antibody at more than 18 months, suggesting that, even in this group, engagement was not ideal. However, it should be noted that one of the additional caveats of the study is that tests ordered at another practice location were not captured by the Nationwide Children’s Hospital (NCH) electronic health records. Third, it is not known from the methodology how many infants were potentially exposed and not tested for HCV RNA, or how many HCV-infected women were not identified during pregnancy. During the time period of the study, guidelines recommended HCV testing only for pregnant women deemed at risk, a policy documented to result in significant rates of underdiagnosis. Only recently have guidelines been updated to recommend universal prenatal HCV testing. It is likely that the infants tested for HCV RNA in this study represent a fraction of the true exposed population, and a broader, more comprehensive study of the uptake, feasibility, and acceptability of early HCV RNA screening in HCV-exposed infants would help strengthen the formal adoption of such a policy. The cost of RNA over Ab testing should also be considered, although it must be weighed against the benefits of linkage-to-care for both mother and child, and the potential for reduced future disease and/or transmission. Overall, the authors’ evaluation of diagnostic performance is welcome and should encourage providers of pediatric care to embrace the concept of early RNA testing, particularly for infants born to women at high risk for loss to follow-up. Pre- and postnatal care settings are ideal points of engagement with health services for young women, providing an opportunity to improve health outcomes for themselves, their infant, and any subsequent siblings. Packaging an HCV RNA test for exposed infants into timepoints at which well-baby checks occur can help maintain ongoing connection with health services in children found to be positive, plus may also provide an opportunity for education and discussion around treatment options. Direct-acting antiviral (DAA) therapies are increasingly being evaluated in younger age groups, with the most recent recommendations supporting treatment in children as young as 3 years [8]. This lowering of the age range to commence highly effective and safe HCV therapy provides an imperative to test and engage as early as possible, reducing subsequent loss to follow-up. An important opportunity also exists to discuss DAA treatment with the mother, who may put her own health needs second to those of her child. Successful treatment in the mother will prevent any transmission in future pregnancies and, given the excellent safety profile, should be encouraged to commence promptly postdelivery. Discouragingly, treatment uptake by women after delivery is consistently extremely low. Ultimately, the ideal way to impact the HCV care cascade in infants is to prevent perinatal transmission. Occuring in approximately 1 in 20 births to HCV-positive women, rising rates of HCV infections in young women mean that an estimated 1700 infants are infected at birth each year in the United States [9]. Treating HCV RNA–positive women with DAAs during pregnancy is an area that requires urgent attention, both as a means of preventing transmission to the infant but also to ensure women are treated while they are engaged with health services—an issue of particular relevance in the United States where women may lose coverage for treatment after delivery. Early studies of safety and efficacy are now underway, with results anxiously awaited (NCT02683005) https://clinicaltrials.gov/ct2/show/NCT02683005. In summary, the article by Gowda and colleagues provides a welcome piece of evidence to strengthen the case for routine practice change. Despite direction in guidelines, the holes in the perinatal HCV care cascade remain concerning. A more aggressive approach to screening and treating HCV in both mother and child should be pursued if there is to be any chance of achieving HCV elimination goals. Potential conflicts of interest. G. V. M. received grants from Gilead Sciences and Abbvie Inc, outside the submitted work. All other authors report no potential conflicts. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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