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Unique Challenges of Hepatitis C in Infants, Children, and Adolescents
ARTICLE IN PRESS Clinical Therapeutics/Volume &, Number &, 2018
Unique Challenges of Hepatitis C in Infants, Children, and Adolescents D1X XClaudia Espinosa, D2X XMD, MSc1; D3X XRavi Jhaveri, MDD24X X ; and D5X XA. Sidney Barritt IV, MD3 1
Division of Pediatric Infectious Disease, University of Louisville School of Medicine, Louisville, Kentucky; Division of Infectious Disease, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina; and 3Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 2
TAGEDPABSTRACTTAGEDN Purpose: Hepatitis C, a chronic disease with deadly consequences, is no longer predominantly a disease of older people. Methods: A limited search was conducted of the relevant literature on 2 topics: (1) the impact of hepatitis C on infants exposed by vertical transmission; and (2) the impact of hepatitis C infection on infected children and adolescents. The findings were supplemented by the first-hand experience of the authors. Findings: Young people, including women of childbearing age, infants, children, and adolescents, are being especially affected by hepatitis C infection secondary to the intravenous drug use and opioid epidemic. Unfortunately, estimates of disease in young populations are all misleading because universal screening has not been implemented. Implications: Lack of implementation of policies for screening and therapy on most affected populations will be responsible for perpetuation of this infection. In the era of highly effective therapy and a regimen that is approved by the US Food and Drug Administration for children, this outcome is unacceptable. (Clin Ther. 2018;&:1 9) © 2018 Elsevier Inc. All rights reserved. Key Words: DAAs, direct-acting antiviral, HCV, hepatitis C virus, MTCT, mother-to-child transmission, MTCT.
TAGEDH1OBJECTIVETAGEDN summarize unique challenges faced by infants, children, and adolescents infected with hepatitis C and their providers.
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TAGEDH1VERTICAL TRANSMISSION OF HCV AND TESTING IN EXPOSED INFANTSTAGEDN The hepatitis C virus (HCV) is an enveloped RNA virus belonging to the Flaviviridae family, with exceptional genetic variability.1 Shortly after HCV identification in the late 1980s, its association with blood transfusions was evident.2 In contrast, recognition of the relationship between HCV and mother-to-child transmission (MTCT) was delayed, mainly due to challenges in available testing.3 All genotypes identified thus far can be transmitted from the infected mothers to their infants. The major route of transmission for children before HCV widespread screening of blood products in 1992 was blood transfusions. Presently, HCV transmission from the chronically infected mother to the infant is the main route of acquisition of HCV infection in children worldwide.2 However, in the current era of opioid abuse and rising cases of HCV, it is possible a population-level analysis in the United States would show that cases in teens far surpass those MTCT cases in infants.
Mother-to-Child Transmission The mechanisms that lead to MTCT are not well understood. As a blood-borne pathogen, HCV infection during childbirth is conceivable, but after a detailed examination of viral sequences, MTCT is known to occur as early as the first trimester.4 Unlike other perinatal infections such as hepatitis B or HIV, the risk of HCV MTCT is low. Several studies have Accepted for publication July 16, 2018. https://doi.org/10.1016/j.clinthera.2018.07.010 0149-2918/$ - see front matter © 2018 Elsevier Inc. All rights reserved.
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ARTICLE IN PRESS Clinical Therapeutics reported different MTCT rates, but a meta-analysis estimated the rate of transmission to be 5.8% (95% CI, 4.2 7.8).5 In the past, this rate was reportedly higher if the mother was co-infected with HIV.3,6 9 Currently, it is recognized that HCV MTCT rates are comparable among HIV-infected and non-HIV coinfected women as long as HIV viral loads are well controlled while taking highly active antiretroviral therapy.10
perinatal acquired HCV, many will have abnormal liver enzyme levels within the first year of life.9 In addition, HCV-infected infants have higher rates of spontaneous HCV clearance compared with acutely infected adults. About 25% to 50% of infants infected with HCV at birth will clear the virus within the first 2 years of life.15,18
Risk Factors for HCV MTCT
The American College of Obstetricians and Gynecologists and, until recently, the AASLD/IDSA recommended HCV screening of pregnant women only in those with known or suspected risk factors such as present use or history of IVDU or intranasal illicit drug use, percutaneous exposures in unregulated settings, HIV infection, or those undergoing evaluation for sexually transmitted infection.14,19 A positive anti-HCV antibody finding should be followed with HCV RNA measured by polymerase chain reaction (PCR) to assess viremia. A negative PCR result will reassure patients and providers about the low likelihood of MTCT. However, follow up of the infant has been suggested.12 A positive HCV PCR result implies that the infant should be evaluated for HCV.19 Transfer of maternal antibodies to the fetus during the last trimester makes antibody testing in the exposed infants impractical before 18 months of age, the time point at which clearance of all HCV maternal antibodies is expected. The Centers for Disease Control and Prevention and the American Academy of Pediatrics recommend HCV RNA PCR in younger exposed children.20,21 The sensitivity of this test in infants aged <1 month is low (»22%) but excellent in older children (>95%). Hence, HCV RNA PCR should be performed in those aged >1 month.22,23 Cord blood testing, conversely, has no value because its results are often positive in uninfected infants.9 Currently, there is not enough evidence to recommend a particular algorithm to manage infants perinatally exposed to HCV. Studies performed in the early 2000s reported intermittent viremia in perinatally exposed infants, but this finding should be interpreted carefully because older PCR techniques were used.24 Well-designed studies using newer PCR techniques are not available. Thus, some experts recommend repeating a PCR test at 6 to 12 months of age after a negative test result at 2 or 3 months.12,25 Others recommend the use of only 1 PCR test before 2 to 6 months of age
Only pregnant women with detectable HCV viremia can transmit the virus to their infants.11 Higher rates of MTCT have also been associated with maternal intravenous drug use (IVDU). This relationship has been attributed to peripheral blood mononuclear cell infection.11 13 Recognized risk factors that increase MTCT include prolonged rupture of membranes, internal fetal monitoring, and episiotomy; amniocentesis, mode of delivery, and breastfeeding (as long as the nipples are not cracked or bleeding) have not been associated with increased risk of MTCT.14 It is worth highlighting that cesarean section has been evaluated in multiple studies and has not been shown to decrease transmission.9,15,16 It is not recommended by either the Society for Maternal Fetal Medicine (SMFM) or the American Association for the Study of Liver Diseases (AASLD)/Infection Diseases Society of America (IDSA) HCV guidelines panel unless there is a primary obstetric indication for the procedure.
Hepatitis C and the Fetus Conflicting reports have been published on the effect of chronic HCV in the fetus. A meta-analysis published in 2016 assessed the risk of HCV infection in fetuses with intrauterine growth restriction and low birth weight.17 Only 7 observational studies were included, and after controlling for multiple factors such as smoking, preeclampsia, and drug abuse, HCV infection seemed to increase the odds of both intrauterine growth restriction and low birth weight. Nevertheless, the authors urged caution when interpreting the results because some covariates were not comparable in matched groups. They also suggested that more studies are needed to draw stronger conclusions.
Hepatitis C and Infancy The majority of infants infected with HCV are asymptomatic. Nonetheless, in infants diagnosed with
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Testing of Pregnant Women and Infants Perinatally Exposed to HCV
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ARTICLE IN PRESS C. Espinosa et al. in addition to HCV antibody at 18 months of age.19,26,27 A positive PCR result is highly suggestive of MTCT because the posttest probability of HCV infection in infants aged >1 month of age is high (73%) and increases in older ages (90%). Notwithstanding, a single HCV PCR test is deemed insufficient to diagnose infection, and 2 different positive test results are needed for an infant to be considered infected. HCV- infected children should be followed up over time by a provider who specializes in their care. At 18 months of age, if the antibody is negative, the child is considered uninfected, although some suggest obtaining alanine transaminase levels along with the antibody and, if elevated, recommend performing additional follow-up with PCR testing in the future.12 Based on AASLD/IDSA guidelines, we recommend the algorithm as detailed in Figure 1.19
Burden of Perinatal Hepatitis C The current epidemic of IVDU throughout the United States is directly related to the upsurge in the number of HCV cases affecting predominantly white young people living in rural areas.2,28,29 Women of childbearing age have been disproportionately affected, and several states have documented an increased
number of HCV detection among women giving birth and their perinatally exposed infants.30 33 In the United States, there are »30,000 HCV chronically infected women giving birth to »1700 infected infants each year.30 Unfortunately, most likely those numbers will continue to understate the burden of maternal and perinatal HCV as long as screening for pregnant women remains risk-based and mechanisms to improve reporting remain unchanged. Universal screening for pregnant women is the first step to improving HCV perinatal surveillance and moving toward HCV elimination because risk-based screening is ineffective in identifying all exposed infants.34 Currently, there is significant discussion about considering universal screening among pregnant women in the United States, and the AASLD/IDSA has updated their recommendation supporting universal screening (Category IIb, Level C).19 However, implementation of this recommendation can be challenging. To date, Kentucky is the only state that has made significant advances in this regard. In 2015, the Kentucky Department of Public Health increased awareness and boosted reporting of HCV-infected pregnant women and their exposed infants by requesting mandatory instead of voluntary reporting of those cases. Other
Figure 1. Proposed algorithm to screen and follow up perinatally exposed children with hepatitis C virus (HCV). *Optimal timing is unknown.
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ARTICLE IN PRESS Clinical Therapeutics jurisdictions such as the Department of Public Health in Philadelphia, Pennsylvania, increased identification of cases by surveillance registries.33 In April 2018, the Kentucky General Assembly passed legislation mandating that all providers assess pregnant women for HCV and permanently document the results in the medical record of both mother and child so follow-up can be guaranteed.35 It is still too soon to predict how this law will affect surveillance and linkage to care of infants perinatally exposed to HCV. Resources to properly follow up HCV-infected mothers and their children should also be established and standardized. For example, to improve identification and follow-up of HCV perinatally exposed infants, the Pediatric Infectious Diseases Clinic at the University of Louisville (Louisville, Kentucky) implemented a protocol at delivery centers and distributed to neonatologists in the Louisville metropolitan area. The protocol prompts providers to actively identify mothers at risk and recruit their exposed infants for follow up at the Pediatric Infectious Diseases Clinic. This process was established in 2015, and as shown in Figure 2, both the number of visits as
well as the number of individual patients increased exponentially. Despite the apparent success “capturing” those infants, there is a high “no-show” rate. Other studies have reported low proportions of follow-up among this challenging population.36 38 Interventions such as the aforementioned might not be easy to implement in many health care settings, as they require substantial resources to properly follow up these HCV-exposed infants. Additional challenges observed in this specific population are the high rate of neonatal abstinence syndrome (NAS), prolonged length of stay likely secondary to NAS, and multiple social challenges. Among the latter are those specifically affecting IVDU populations, including the lack of recognition of the importance of follow-up.39
Treatment of HCV-Infected Pregnant Women and Their Infants Immunoprophylaxis and other preventive strategies to eliminate HCV MTCT are not available for HCVinfected pregnant women or their infants. Ribavirinbased therapies for HCV are contraindicated in pregnancy, and there is insufficient safety data on the use of
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Figure 2. Number of children and number of clinic visits to the Pediatric Infectious Diseases Clinic at the University of Louisville for hepatitis C perinatal exposure evaluation.
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ARTICLE IN PRESS C. Espinosa et al. direct-acting antivirals (DAAs) in pregnant women. However, a pharmacokinetic and safety study of ledipasvir and sofosbuvir in pregnant women is underway.40 The results of this trial are not yet available, and the SMFM recommends against the use of any DAAs except under the well-controlled environment of a clinical trial.14 Despite the lack of clinical data on DAA use in pregnancy, several authors have supported the role of those safe and effective antiviral agents in this specific population. Some have hypothesized those medications will be feasible interventions in the near future.41,42 Suppression of viremia, elimination of infection in the pregnant woman (who might not have accessed the health care system otherwise), and subsequent eradication of MTCT are significant motivations for supporting the use of DAAs in pregnant women.43 In the meantime, identifying viremic women to avoid procedures associated with increased risk of HCV MTCT as recommended by the SMFM may be useful, especially at the time of delivery. Currently, therapy for infants who acquire the virus through MTCT is not available, and given the rate of spontaneous HCV clearance along with the lack of clinical symptoms, justification for therapy at an early age may be challenging.
TAGEDH1HCV BURDEN IN ADOLESCENTS AND STRATEGIES FOR ERADICATIONTAGEDN Burden of Pediatric Hepatitis C HCV infection is a well-known etiology of chronic liver disease worldwide and contributes a significant burden to health care use and patient suffering.44 HCV is a leading cause of chronic liver disease, cirrhosis, hepatocellular carcinoma, and liver transplantation.19 Patients infected with HCV are generally believed to be older and part of the baby boomer population. Historically, this scenario has been the case, with the adolescent and young adult population comprising only a minority of chronic HCV cases. Currently, there are >11 million children worldwide living with HCV; of these, 50,000 live in the United States.45 Due to recent events, chiefly the opiate crisis, there are ongoing epidemiologic shifts in the demographic characteristics of HCV infection in which HCV is increasing in incidence and prevalence in younger populations. In a study of the Kids’ Inpatient Database from 2006 to 2012, the number of hospitalizations of children with HCV increased by
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37%.46 The vast majority of these admissions were among adolescents and young adults (up to age 20 years). There was a strong association with substance abuse among these patients as well, which increased over time from 25% to 41% in 2012. Because children are not usually admitted for complications of HCV, these inpatient admissions were likely driven by substance abuse and represent only the “tip of the iceberg” in terms of the total HCV burden in this population.29 Further evidence of a change in the epidemiology of HCV comes from an examination of state health department websites. Of 28 states reporting data, HCV prevalence among young adults (ages 20 39 years) exceeded that of baby boomers (born 1945 1965) in 11 states and was equal in 4 states. There were another 11 states where HCV incidence in young adults showed sustained increases over time. Only 2 states reported a greater HCV prevalence among baby boomers compared with young adults.47 Many of these states have significant numbers of adolescents in their newly identified cases of HCV. These data show a marked shift toward younger patients in HCV population characteristics. The Centers for Disease Control and Prevention recommended birth cohort screening of baby boomers only 6 years ago due to the concern that risk-based screening left too many cases undiscovered.48 The state public health data reflect a cohort-based screening strategy for baby boomers and a risk-based strategy for young adults; thus, it is reasonable to assume the young adult prevalence is significantly underestimated. As possible changes to HCV-screening strategies among young adults are considered, it is important that adolescents be included in the discussion. A recent analysis examined various strategies for how universal testing could be implemented in these patient groups and the cost-effectiveness of each method.49 The authors showed that one-time HCV screening of young adults, including adolescents, is very cost-effective, with counselor-initiated, rapid testing being the most cost-beneficial. However, any strategy analyzed outperformed the current practice of risk-based screening in adolescents and young adults when the population HCV seroprevalence was 0.59%.
Treating Pediatric Hepatitis C as Part of Total Virus Eradication As adolescent and young adult HCV cases increase in incidence and prevalence, these populations must be included in any eradication strategy. Without treatment and cure, they represent a reservoir for continued
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ARTICLE IN PRESS Clinical Therapeutics spread of infection and, among women of childbearing age, a risk of vertical transmission. Modeling simulations of HCV infection and treatment have shown that the 95% sustained virologic response rate (SVR) of current DAA therapies is not enough to achieve population-wide cure. What is required is wider application of antiviral treatment to all infected patients.50 There may be considerable resistance to treating some adolescent populations, especially because many HCV infections are linked to substance abuse. Historically, a large proportion of patients have therapy deferred due to substance abuse problems.51 Many myths surrounding HCV therapy in the setting of substance abuse have been debunked, even in the era of combination therapy of first-generation DAAs with interferon.52 Among the myths surrounding therapy in the setting of substance abuse are those of safety, lower SVRs, and patients generally not being appropriate for therapy. Patients with substance abuse issues can be treated safely provided that they are properly supported by multidisciplinary teams that include mental health and substance abuse services.53,54 Despite a low rate of subsequent HCV reinfection, patients with substance abuse problems, when treated, achieve the same SVRs as other patients.55,56 Finally, young patients, believed to be poor treatment candidates due to substance abuse issues, run the risk of further spread of infection and disease progression. These patients may become more difficult to treat in the future and will become more expensive to care for as their liver disease advances. Most communities have resources to assist with therapy for adults with substance abuse and, as the opiate crisis receives more attention, funding for such resources may increase.57 Because resources to treat and assist adolescents are either wholly inadequate or completely lacking in many areas, this process will need to change in a substantive way. As with most multidisciplinary efforts, pretreatment planning is essential.58
Cost-effectiveness of Hepatitis C Therapy in a Pediatric Population Treatment strategies with DAAs are cost-effective in the adult population and generally have an incremental cost-effectiveness ratio of less than $50,000 per quality-adjusted life year with some variability depending on the regimen.59 61 Until recently, the only available cost-effective data for pediatric HCV therapy have
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been with outdated treatment regimens that include interferon. As multiple HCV therapeutic regimens have become available, treatment costs have diminished. Applying these adult-approved pan-genotypic regimens to a pediatric population yields an incremental costeffectiveness ratio of $10,000 to $21,000 per qualityadjusted life year. Furthermore, there is a cost benefit for treating these children early, rather than deferring therapy until adulthood, at which point they may be lost to follow-up, lose insurance, or experience disease progression.62
Implementation of Hepatitis C Therapy There is convincing evidence of the following: (1) HCV represents a significant health care burden; (2) treating adolescents (even in the setting of substance abuse) needs to be part of an overall strategy for total virus eradication; and (3) therapy is costeffective.19,44,45 Thus, practical implementation of therapy is the next goal. As of May 2018, only one regimen has been approved by the US Food and Drug Administration for the treatment of children with HCV. Sofosbuvir/ledipasvir and sofosbuvir/ribavirin regimens are approved for pediatric use as young as age 12 years.19 SVRs in this population exceed 95% for a 12-week treatment course. Adult-approved pangenotypic regimens are currently under study in children but are not yet approved by the US Food and Drug Administration (www.clinicaltrials.gov: NCT03067129; NCT03022981). Most currently pediatric- and adult-approved regimens are 1 pill per day and do not require on-treatment monitoring, enabling therapy at the primary care provider level rather than relying on pediatric infectious disease or gastroenterology specialists who are few in number relative to the burden of disease. Obtaining medication requires a specialty pharmacy and often prior insurance approval. After treating the adult population with DAAs for 5 years, the pharmaceutical industry now has a wellestablished system to make therapy available without a burdensome approval process. State Medicaid plans approve DAA therapy for adults, even in the setting of substance abuse, with some variation among states in terms of documentation of abstinence, substance abuse counseling, or therapy required. If one uses public health treatment of tuberculosis as a potential model, infected patients are identified and treated with the supervision of public health nurses for a short period of time. A similar system could be developed for HCV-
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ARTICLE IN PRESS C. Espinosa et al. infected adolescents and young adults. Patients are identified in their primary care setting and referred into an organized system that procures DAAs from private insurance, public insurance, or industry-sponsored charity programs. This same system monitors and documents their response to therapy, while educating them on ways to reduce the risk of future reinfection. In all, such a system could move from diagnosis to treatment to cure in <6 months.
TAGEDH1CONCLUSIONSTAGEDN With the advent of DAA therapy for HCV, there is the prospect of eradication of HCV within a generation. For this goal to be realized, however, all pockets of HCV must be treated and cured. Although progress has been made identifying and treating the baby boomer generation, the opiate and injection drug use crisis has brought other demographic groups into focus, namely children, adolescents, young adults, and women of childbearing age and their infected infants. To break the cycle of transmission, health care providers must acknowledge that risk-based screening is inadequate. Only when universal screening is in place will we identify more patients infected with HCV. Once cases have been discovered, overcoming perceived barriers to treatment linkage to care become key. Treatment can now occur at the primary care level in many instances, and the pathway from diagnosis to completed therapy to assessment of cure can take place in <6 months. HCV is a disease that can be eradicated, but we must not become complacent due to the current high efficacy and ease of DAA therapy.
TAGEDH1ACKNOWLEDGMENTSTAGEDN Dr. Espinosa has received grant support from Gilead and has participated in clinical trials sponsored by Gilead. Dr. Jhaveri has participated in clinical trials sponsored by Gilead, AbbVie, and Merck and has received grant support from Merck. No industry sponsored or influenced any aspect of this study's design, collection, analysis, or interpretation of the data; writing of the manuscript; or the decision to submit this manuscript for publication. Dr. Espinosa is part of AstraZeneca speaker bureau. This relationship did not result in conflict of interests. None of the other authors received any monetary support that did not result in conflict of interests.
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Dr. Espinosa, Dr. Jhavari, and Dr. Barrit contributed equally to the conceptualization, literature search, figure creation, data collection, and writing of this manuscript. All authors contributed equally to the development of this manuscript.
TAGEDH1CONFLICTS OF INTERESTTAGEDN Dr. Espinosa and Dr. Jhaveri have been principal investigator and sub-investigators in clinical trials sponsored by companies that have antivirals used in the treatment of hepatitis C. However, none of those companies support any aspect of the conceptualization or development of this manuscript.
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ARTICLE IN PRESS C. Espinosa et al. 39. Krans EE, Rothenberger SD, Morrison PK, et al. Hepatitis C virus knowledge among pregnant women with opioid use disorder. Matern Child Health J. 2018;22:1208–1216. 40. Chappell C. Study of Hepatitis C Treatment During Pregnancy (HIP). https://clinicaltrials.gov/ct2/show/ NCT02683005?term=sofosbuvir +and+pregnancy&rank=1. 41. Cervino L, Hynicka LM. Direct-acting antivirals to prevent vertical transmission of viral hepatitis C: when is the optimal time to treat? Ann Pharmacother 2018; 1060028018772181. 42. Dibba P, Cholankeril R, Li AA, et al. Hepatitis C in Pregnancy. Diseases. 2018;6. 43. Barritt 4th AS, Jhaveri R. Treatment of hepatitis C during pregnancy— weighing the risks and benefits in contrast to HIV. Curr HIV/AIDS Rep. 2018;15:155–161. 44. Galbraith JW, Donnelly JP, Franco RA, et al. National estimates of healthcare utilization by individuals with hepatitis C virus infection in the United States. Clin Infect Dis. 2014;59:755–764. 45. Jhaveri R, Grant W, Kauf TL, et al. The burden of hepatitis C virus infection in children: estimated direct medical costs over a 10-year period. J Pediatr. 2006;148:353–358. 46. Barritt 4th AS, Lee B, Runge T, et al. Increasing prevalence of hepatitis C among hospitalized children is associated with an increase in substance abuse. J Pediatr. 2018;192: 159–164. 47. Morse A, Barritt 4th AS, Jhaveri R. Individual state hepatitis C data supports expanding screening beyond baby boomers to all adults. Gastroenterology. 2018;154: 1850-1.e2. 48. Smith BD, Morgan RL, Beckett GA, et al. Hepatitis C virus testing of persons born during 1945 1965: recommendations from the Centers for Disease Control and Prevention. Ann Intern Med. 2012;157:817–822. 49. Assoumou SA, Tasillo A, Leff JA, et al. Cost-effectiveness of one-time
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hepatitis C screening strategies among adolescents and young adults in primary care settings. Clin Infect Dis. 2018;66: 376–384. Davis GL, Alter MJ, El-Serag H, et al. Aging of hepatitis C virus (HCV)infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513–521. 521.e1-6. Evon DM, Verma A, Dougherty KA, et al. High deferral rates and poorer treatment outcomes for HCV patients with psychiatric and substance use comorbidities. Dig Dis Sci. 2007;52:3251–3258. Bonner JE, Barritt 4th AS, Fried MW, et al. Time to rethink antiviral treatment for hepatitis C in patients with coexisting mental health/substance abuse issues. Dig Dis Sci. 2012;57: 1469–1474. Knott A, Dieperink E, Willenbring ML, et al. Integrated psychiatric/ medical care in a chronic hepatitis C clinic: effect on antiviral treatment evaluation and outcomes. Am J Gastroenterol. 2006;101:2254–2262. Grebely J, Genoway K, Khara M, et al. Treatment uptake and outcomes among current and former injection drug users receiving directly observed therapy within a multidisciplinary group model for the treatment of hepatitis C virus infection. Int J Drug Policy. 2007;18:437–443. Grebely J, Dalgard O, Conway B, et al. Sofosbuvir and velpatasvir for hepatitis C virus infection in people with recent injection drug use (SIMPLIFY): an open-label, single-arm, phase 4, multicentre trial. Lancet Gastroenterol Hepatol. 2018;3:153–161. Zanini B, Covolo L, Donato F, et al. Effectiveness and tolerability of
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combination treatment of chronic hepatitis C in illicit drug users: meta-analysis of prospective studies. Clin Ther. 2010;32:2139–2159. Simpatico TA. Vermont responds to its opioid crisis. Prev Med. 2015;80:10–11. Bonner JE, Barritt 4th AS, Fried MW, et al. Tangible resources for preparing patients for antiviral therapy for chronic hepatitis C. Dig Dis Sci. 2012;57:1439–1444. Corman S, Elbasha EH, Michalopoulos SN, et al. Cost-utility of elbasvir/ grazoprevir in patients with chronic hepatitis C genotype 1 infection. Value Health. 2017;20:1110–1120. Rattay T, Dumont IP, Heinzow HS, et al. Cost-effectiveness of access expansion to treatment of hepatitis C virus infection through primary care providers. Gastroenterology. 2017;153. 1531-43.e2. Rein DB, Wittenborn JS, Smith BD, et al. The cost-effectiveness, health benefits, and financial costs of new antiviral treatments for hepatitis C virus. Clin Infect Dis. 2015;61:157– 168. Nguyen JT, Barritt AS, Jhaveri R. Cost Effectiveness of Early Treatment with Direct-Acting Antiviral Therapy in Adolescent Patients with Hepatitis C Virus Infection. Pediatric Academic Societies 2018 Annual Meeting.
Address correspondence to: Claudia Espinosa, MD, MSc, Department of Pediatrics, Division of Pediatric Infectious Diseases, University of Louisville, 571 S Floyd St, Suite 321, Louisville, KY 40202. E-mail: [email protected]
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Unique Challenges of Hepatitis C in Infants, Children, and Adolescents D1X XClaudia Espinosa, D2X XMD, MSc1; D3X XRavi Jhaveri, MDD24X X ; and D5X XA. Sidney Barritt IV, MD3 1
Division of Pediatric Infectious Disease, University of Louisville School of Medicine, Louisville, Kentucky; Division of Infectious Disease, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina; and 3Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 2
TAGEDPABSTRACTTAGEDN Purpose: Hepatitis C, a chronic disease with deadly consequences, is no longer predominantly a disease of older people. Methods: A limited search was conducted of the relevant literature on 2 topics: (1) the impact of hepatitis C on infants exposed by vertical transmission; and (2) the impact of hepatitis C infection on infected children and adolescents. The findings were supplemented by the first-hand experience of the authors. Findings: Young people, including women of childbearing age, infants, children, and adolescents, are being especially affected by hepatitis C infection secondary to the intravenous drug use and opioid epidemic. Unfortunately, estimates of disease in young populations are all misleading because universal screening has not been implemented. Implications: Lack of implementation of policies for screening and therapy on most affected populations will be responsible for perpetuation of this infection. In the era of highly effective therapy and a regimen that is approved by the US Food and Drug Administration for children, this outcome is unacceptable. (Clin Ther. 2018;&:1 9) © 2018 Elsevier Inc. All rights reserved. Key Words: DAAs, direct-acting antiviral, HCV, hepatitis C virus, MTCT, mother-to-child transmission, MTCT.
TAGEDH1OBJECTIVETAGEDN summarize unique challenges faced by infants, children, and adolescents infected with hepatitis C and their providers.
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TAGEDH1VERTICAL TRANSMISSION OF HCV AND TESTING IN EXPOSED INFANTSTAGEDN The hepatitis C virus (HCV) is an enveloped RNA virus belonging to the Flaviviridae family, with exceptional genetic variability.1 Shortly after HCV identification in the late 1980s, its association with blood transfusions was evident.2 In contrast, recognition of the relationship between HCV and mother-to-child transmission (MTCT) was delayed, mainly due to challenges in available testing.3 All genotypes identified thus far can be transmitted from the infected mothers to their infants. The major route of transmission for children before HCV widespread screening of blood products in 1992 was blood transfusions. Presently, HCV transmission from the chronically infected mother to the infant is the main route of acquisition of HCV infection in children worldwide.2 However, in the current era of opioid abuse and rising cases of HCV, it is possible a population-level analysis in the United States would show that cases in teens far surpass those MTCT cases in infants.
Mother-to-Child Transmission The mechanisms that lead to MTCT are not well understood. As a blood-borne pathogen, HCV infection during childbirth is conceivable, but after a detailed examination of viral sequences, MTCT is known to occur as early as the first trimester.4 Unlike other perinatal infections such as hepatitis B or HIV, the risk of HCV MTCT is low. Several studies have Accepted for publication July 16, 2018. https://doi.org/10.1016/j.clinthera.2018.07.010 0149-2918/$ - see front matter © 2018 Elsevier Inc. All rights reserved.
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ARTICLE IN PRESS Clinical Therapeutics reported different MTCT rates, but a meta-analysis estimated the rate of transmission to be 5.8% (95% CI, 4.2 7.8).5 In the past, this rate was reportedly higher if the mother was co-infected with HIV.3,6 9 Currently, it is recognized that HCV MTCT rates are comparable among HIV-infected and non-HIV coinfected women as long as HIV viral loads are well controlled while taking highly active antiretroviral therapy.10
perinatal acquired HCV, many will have abnormal liver enzyme levels within the first year of life.9 In addition, HCV-infected infants have higher rates of spontaneous HCV clearance compared with acutely infected adults. About 25% to 50% of infants infected with HCV at birth will clear the virus within the first 2 years of life.15,18
Risk Factors for HCV MTCT
The American College of Obstetricians and Gynecologists and, until recently, the AASLD/IDSA recommended HCV screening of pregnant women only in those with known or suspected risk factors such as present use or history of IVDU or intranasal illicit drug use, percutaneous exposures in unregulated settings, HIV infection, or those undergoing evaluation for sexually transmitted infection.14,19 A positive anti-HCV antibody finding should be followed with HCV RNA measured by polymerase chain reaction (PCR) to assess viremia. A negative PCR result will reassure patients and providers about the low likelihood of MTCT. However, follow up of the infant has been suggested.12 A positive HCV PCR result implies that the infant should be evaluated for HCV.19 Transfer of maternal antibodies to the fetus during the last trimester makes antibody testing in the exposed infants impractical before 18 months of age, the time point at which clearance of all HCV maternal antibodies is expected. The Centers for Disease Control and Prevention and the American Academy of Pediatrics recommend HCV RNA PCR in younger exposed children.20,21 The sensitivity of this test in infants aged <1 month is low (»22%) but excellent in older children (>95%). Hence, HCV RNA PCR should be performed in those aged >1 month.22,23 Cord blood testing, conversely, has no value because its results are often positive in uninfected infants.9 Currently, there is not enough evidence to recommend a particular algorithm to manage infants perinatally exposed to HCV. Studies performed in the early 2000s reported intermittent viremia in perinatally exposed infants, but this finding should be interpreted carefully because older PCR techniques were used.24 Well-designed studies using newer PCR techniques are not available. Thus, some experts recommend repeating a PCR test at 6 to 12 months of age after a negative test result at 2 or 3 months.12,25 Others recommend the use of only 1 PCR test before 2 to 6 months of age
Only pregnant women with detectable HCV viremia can transmit the virus to their infants.11 Higher rates of MTCT have also been associated with maternal intravenous drug use (IVDU). This relationship has been attributed to peripheral blood mononuclear cell infection.11 13 Recognized risk factors that increase MTCT include prolonged rupture of membranes, internal fetal monitoring, and episiotomy; amniocentesis, mode of delivery, and breastfeeding (as long as the nipples are not cracked or bleeding) have not been associated with increased risk of MTCT.14 It is worth highlighting that cesarean section has been evaluated in multiple studies and has not been shown to decrease transmission.9,15,16 It is not recommended by either the Society for Maternal Fetal Medicine (SMFM) or the American Association for the Study of Liver Diseases (AASLD)/Infection Diseases Society of America (IDSA) HCV guidelines panel unless there is a primary obstetric indication for the procedure.
Hepatitis C and the Fetus Conflicting reports have been published on the effect of chronic HCV in the fetus. A meta-analysis published in 2016 assessed the risk of HCV infection in fetuses with intrauterine growth restriction and low birth weight.17 Only 7 observational studies were included, and after controlling for multiple factors such as smoking, preeclampsia, and drug abuse, HCV infection seemed to increase the odds of both intrauterine growth restriction and low birth weight. Nevertheless, the authors urged caution when interpreting the results because some covariates were not comparable in matched groups. They also suggested that more studies are needed to draw stronger conclusions.
Hepatitis C and Infancy The majority of infants infected with HCV are asymptomatic. Nonetheless, in infants diagnosed with
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Testing of Pregnant Women and Infants Perinatally Exposed to HCV
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ARTICLE IN PRESS C. Espinosa et al. in addition to HCV antibody at 18 months of age.19,26,27 A positive PCR result is highly suggestive of MTCT because the posttest probability of HCV infection in infants aged >1 month of age is high (73%) and increases in older ages (90%). Notwithstanding, a single HCV PCR test is deemed insufficient to diagnose infection, and 2 different positive test results are needed for an infant to be considered infected. HCV- infected children should be followed up over time by a provider who specializes in their care. At 18 months of age, if the antibody is negative, the child is considered uninfected, although some suggest obtaining alanine transaminase levels along with the antibody and, if elevated, recommend performing additional follow-up with PCR testing in the future.12 Based on AASLD/IDSA guidelines, we recommend the algorithm as detailed in Figure 1.19
Burden of Perinatal Hepatitis C The current epidemic of IVDU throughout the United States is directly related to the upsurge in the number of HCV cases affecting predominantly white young people living in rural areas.2,28,29 Women of childbearing age have been disproportionately affected, and several states have documented an increased
number of HCV detection among women giving birth and their perinatally exposed infants.30 33 In the United States, there are »30,000 HCV chronically infected women giving birth to »1700 infected infants each year.30 Unfortunately, most likely those numbers will continue to understate the burden of maternal and perinatal HCV as long as screening for pregnant women remains risk-based and mechanisms to improve reporting remain unchanged. Universal screening for pregnant women is the first step to improving HCV perinatal surveillance and moving toward HCV elimination because risk-based screening is ineffective in identifying all exposed infants.34 Currently, there is significant discussion about considering universal screening among pregnant women in the United States, and the AASLD/IDSA has updated their recommendation supporting universal screening (Category IIb, Level C).19 However, implementation of this recommendation can be challenging. To date, Kentucky is the only state that has made significant advances in this regard. In 2015, the Kentucky Department of Public Health increased awareness and boosted reporting of HCV-infected pregnant women and their exposed infants by requesting mandatory instead of voluntary reporting of those cases. Other
Figure 1. Proposed algorithm to screen and follow up perinatally exposed children with hepatitis C virus (HCV). *Optimal timing is unknown.
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ARTICLE IN PRESS Clinical Therapeutics jurisdictions such as the Department of Public Health in Philadelphia, Pennsylvania, increased identification of cases by surveillance registries.33 In April 2018, the Kentucky General Assembly passed legislation mandating that all providers assess pregnant women for HCV and permanently document the results in the medical record of both mother and child so follow-up can be guaranteed.35 It is still too soon to predict how this law will affect surveillance and linkage to care of infants perinatally exposed to HCV. Resources to properly follow up HCV-infected mothers and their children should also be established and standardized. For example, to improve identification and follow-up of HCV perinatally exposed infants, the Pediatric Infectious Diseases Clinic at the University of Louisville (Louisville, Kentucky) implemented a protocol at delivery centers and distributed to neonatologists in the Louisville metropolitan area. The protocol prompts providers to actively identify mothers at risk and recruit their exposed infants for follow up at the Pediatric Infectious Diseases Clinic. This process was established in 2015, and as shown in Figure 2, both the number of visits as
well as the number of individual patients increased exponentially. Despite the apparent success “capturing” those infants, there is a high “no-show” rate. Other studies have reported low proportions of follow-up among this challenging population.36 38 Interventions such as the aforementioned might not be easy to implement in many health care settings, as they require substantial resources to properly follow up these HCV-exposed infants. Additional challenges observed in this specific population are the high rate of neonatal abstinence syndrome (NAS), prolonged length of stay likely secondary to NAS, and multiple social challenges. Among the latter are those specifically affecting IVDU populations, including the lack of recognition of the importance of follow-up.39
Treatment of HCV-Infected Pregnant Women and Their Infants Immunoprophylaxis and other preventive strategies to eliminate HCV MTCT are not available for HCVinfected pregnant women or their infants. Ribavirinbased therapies for HCV are contraindicated in pregnancy, and there is insufficient safety data on the use of
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Figure 2. Number of children and number of clinic visits to the Pediatric Infectious Diseases Clinic at the University of Louisville for hepatitis C perinatal exposure evaluation.
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ARTICLE IN PRESS C. Espinosa et al. direct-acting antivirals (DAAs) in pregnant women. However, a pharmacokinetic and safety study of ledipasvir and sofosbuvir in pregnant women is underway.40 The results of this trial are not yet available, and the SMFM recommends against the use of any DAAs except under the well-controlled environment of a clinical trial.14 Despite the lack of clinical data on DAA use in pregnancy, several authors have supported the role of those safe and effective antiviral agents in this specific population. Some have hypothesized those medications will be feasible interventions in the near future.41,42 Suppression of viremia, elimination of infection in the pregnant woman (who might not have accessed the health care system otherwise), and subsequent eradication of MTCT are significant motivations for supporting the use of DAAs in pregnant women.43 In the meantime, identifying viremic women to avoid procedures associated with increased risk of HCV MTCT as recommended by the SMFM may be useful, especially at the time of delivery. Currently, therapy for infants who acquire the virus through MTCT is not available, and given the rate of spontaneous HCV clearance along with the lack of clinical symptoms, justification for therapy at an early age may be challenging.
TAGEDH1HCV BURDEN IN ADOLESCENTS AND STRATEGIES FOR ERADICATIONTAGEDN Burden of Pediatric Hepatitis C HCV infection is a well-known etiology of chronic liver disease worldwide and contributes a significant burden to health care use and patient suffering.44 HCV is a leading cause of chronic liver disease, cirrhosis, hepatocellular carcinoma, and liver transplantation.19 Patients infected with HCV are generally believed to be older and part of the baby boomer population. Historically, this scenario has been the case, with the adolescent and young adult population comprising only a minority of chronic HCV cases. Currently, there are >11 million children worldwide living with HCV; of these, 50,000 live in the United States.45 Due to recent events, chiefly the opiate crisis, there are ongoing epidemiologic shifts in the demographic characteristics of HCV infection in which HCV is increasing in incidence and prevalence in younger populations. In a study of the Kids’ Inpatient Database from 2006 to 2012, the number of hospitalizations of children with HCV increased by
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37%.46 The vast majority of these admissions were among adolescents and young adults (up to age 20 years). There was a strong association with substance abuse among these patients as well, which increased over time from 25% to 41% in 2012. Because children are not usually admitted for complications of HCV, these inpatient admissions were likely driven by substance abuse and represent only the “tip of the iceberg” in terms of the total HCV burden in this population.29 Further evidence of a change in the epidemiology of HCV comes from an examination of state health department websites. Of 28 states reporting data, HCV prevalence among young adults (ages 20 39 years) exceeded that of baby boomers (born 1945 1965) in 11 states and was equal in 4 states. There were another 11 states where HCV incidence in young adults showed sustained increases over time. Only 2 states reported a greater HCV prevalence among baby boomers compared with young adults.47 Many of these states have significant numbers of adolescents in their newly identified cases of HCV. These data show a marked shift toward younger patients in HCV population characteristics. The Centers for Disease Control and Prevention recommended birth cohort screening of baby boomers only 6 years ago due to the concern that risk-based screening left too many cases undiscovered.48 The state public health data reflect a cohort-based screening strategy for baby boomers and a risk-based strategy for young adults; thus, it is reasonable to assume the young adult prevalence is significantly underestimated. As possible changes to HCV-screening strategies among young adults are considered, it is important that adolescents be included in the discussion. A recent analysis examined various strategies for how universal testing could be implemented in these patient groups and the cost-effectiveness of each method.49 The authors showed that one-time HCV screening of young adults, including adolescents, is very cost-effective, with counselor-initiated, rapid testing being the most cost-beneficial. However, any strategy analyzed outperformed the current practice of risk-based screening in adolescents and young adults when the population HCV seroprevalence was 0.59%.
Treating Pediatric Hepatitis C as Part of Total Virus Eradication As adolescent and young adult HCV cases increase in incidence and prevalence, these populations must be included in any eradication strategy. Without treatment and cure, they represent a reservoir for continued
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ARTICLE IN PRESS Clinical Therapeutics spread of infection and, among women of childbearing age, a risk of vertical transmission. Modeling simulations of HCV infection and treatment have shown that the 95% sustained virologic response rate (SVR) of current DAA therapies is not enough to achieve population-wide cure. What is required is wider application of antiviral treatment to all infected patients.50 There may be considerable resistance to treating some adolescent populations, especially because many HCV infections are linked to substance abuse. Historically, a large proportion of patients have therapy deferred due to substance abuse problems.51 Many myths surrounding HCV therapy in the setting of substance abuse have been debunked, even in the era of combination therapy of first-generation DAAs with interferon.52 Among the myths surrounding therapy in the setting of substance abuse are those of safety, lower SVRs, and patients generally not being appropriate for therapy. Patients with substance abuse issues can be treated safely provided that they are properly supported by multidisciplinary teams that include mental health and substance abuse services.53,54 Despite a low rate of subsequent HCV reinfection, patients with substance abuse problems, when treated, achieve the same SVRs as other patients.55,56 Finally, young patients, believed to be poor treatment candidates due to substance abuse issues, run the risk of further spread of infection and disease progression. These patients may become more difficult to treat in the future and will become more expensive to care for as their liver disease advances. Most communities have resources to assist with therapy for adults with substance abuse and, as the opiate crisis receives more attention, funding for such resources may increase.57 Because resources to treat and assist adolescents are either wholly inadequate or completely lacking in many areas, this process will need to change in a substantive way. As with most multidisciplinary efforts, pretreatment planning is essential.58
Cost-effectiveness of Hepatitis C Therapy in a Pediatric Population Treatment strategies with DAAs are cost-effective in the adult population and generally have an incremental cost-effectiveness ratio of less than $50,000 per quality-adjusted life year with some variability depending on the regimen.59 61 Until recently, the only available cost-effective data for pediatric HCV therapy have
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been with outdated treatment regimens that include interferon. As multiple HCV therapeutic regimens have become available, treatment costs have diminished. Applying these adult-approved pan-genotypic regimens to a pediatric population yields an incremental costeffectiveness ratio of $10,000 to $21,000 per qualityadjusted life year. Furthermore, there is a cost benefit for treating these children early, rather than deferring therapy until adulthood, at which point they may be lost to follow-up, lose insurance, or experience disease progression.62
Implementation of Hepatitis C Therapy There is convincing evidence of the following: (1) HCV represents a significant health care burden; (2) treating adolescents (even in the setting of substance abuse) needs to be part of an overall strategy for total virus eradication; and (3) therapy is costeffective.19,44,45 Thus, practical implementation of therapy is the next goal. As of May 2018, only one regimen has been approved by the US Food and Drug Administration for the treatment of children with HCV. Sofosbuvir/ledipasvir and sofosbuvir/ribavirin regimens are approved for pediatric use as young as age 12 years.19 SVRs in this population exceed 95% for a 12-week treatment course. Adult-approved pangenotypic regimens are currently under study in children but are not yet approved by the US Food and Drug Administration (www.clinicaltrials.gov: NCT03067129; NCT03022981). Most currently pediatric- and adult-approved regimens are 1 pill per day and do not require on-treatment monitoring, enabling therapy at the primary care provider level rather than relying on pediatric infectious disease or gastroenterology specialists who are few in number relative to the burden of disease. Obtaining medication requires a specialty pharmacy and often prior insurance approval. After treating the adult population with DAAs for 5 years, the pharmaceutical industry now has a wellestablished system to make therapy available without a burdensome approval process. State Medicaid plans approve DAA therapy for adults, even in the setting of substance abuse, with some variation among states in terms of documentation of abstinence, substance abuse counseling, or therapy required. If one uses public health treatment of tuberculosis as a potential model, infected patients are identified and treated with the supervision of public health nurses for a short period of time. A similar system could be developed for HCV-
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ARTICLE IN PRESS C. Espinosa et al. infected adolescents and young adults. Patients are identified in their primary care setting and referred into an organized system that procures DAAs from private insurance, public insurance, or industry-sponsored charity programs. This same system monitors and documents their response to therapy, while educating them on ways to reduce the risk of future reinfection. In all, such a system could move from diagnosis to treatment to cure in <6 months.
TAGEDH1CONCLUSIONSTAGEDN With the advent of DAA therapy for HCV, there is the prospect of eradication of HCV within a generation. For this goal to be realized, however, all pockets of HCV must be treated and cured. Although progress has been made identifying and treating the baby boomer generation, the opiate and injection drug use crisis has brought other demographic groups into focus, namely children, adolescents, young adults, and women of childbearing age and their infected infants. To break the cycle of transmission, health care providers must acknowledge that risk-based screening is inadequate. Only when universal screening is in place will we identify more patients infected with HCV. Once cases have been discovered, overcoming perceived barriers to treatment linkage to care become key. Treatment can now occur at the primary care level in many instances, and the pathway from diagnosis to completed therapy to assessment of cure can take place in <6 months. HCV is a disease that can be eradicated, but we must not become complacent due to the current high efficacy and ease of DAA therapy.
TAGEDH1ACKNOWLEDGMENTSTAGEDN Dr. Espinosa has received grant support from Gilead and has participated in clinical trials sponsored by Gilead. Dr. Jhaveri has participated in clinical trials sponsored by Gilead, AbbVie, and Merck and has received grant support from Merck. No industry sponsored or influenced any aspect of this study's design, collection, analysis, or interpretation of the data; writing of the manuscript; or the decision to submit this manuscript for publication. Dr. Espinosa is part of AstraZeneca speaker bureau. This relationship did not result in conflict of interests. None of the other authors received any monetary support that did not result in conflict of interests.
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Dr. Espinosa, Dr. Jhavari, and Dr. Barrit contributed equally to the conceptualization, literature search, figure creation, data collection, and writing of this manuscript. All authors contributed equally to the development of this manuscript.
TAGEDH1CONFLICTS OF INTERESTTAGEDN Dr. Espinosa and Dr. Jhaveri have been principal investigator and sub-investigators in clinical trials sponsored by companies that have antivirals used in the treatment of hepatitis C. However, none of those companies support any aspect of the conceptualization or development of this manuscript.
TAGEDH1REFERENCESTAGEDN 1. Forns X, Bukh J. The molecular biology of hepatitis C virus. Genotypes and quasispecies. Clin Liver Dis. 1999;3:693– 716. vii. 2. Millman AJ, Nelson NP, Vellozzi C. Hepatitis C: review of the epidemiology, clinical care, and continued challenges in the direct acting antiviral era. Curr Epidemiol Rep. 2017;4:174–185. 3. Ohto H, Terazawa S, Sasaki N, et al. Transmission of hepatitis C virus from mothers to infants. The Vertical Transmission of Hepatitis C Virus Collaborative Study Group. N Engl J Med. 1994;330:744–750. 4. Fauteux-Daniel S, Larouche A, Calderon V, et al. Vertical transmission of hepatitis C virus: variable transmission bottleneck and evidence of midgestation in utero infection. J Virol. 2017;91. 5. Benova L, Mohamoud YA, Calvert C, et al. Vertical transmission of hepatitis C virus: systematic review and metaanalysis. Clin Infect Dis. 2014;59:765–773. 6. Hunt CM, Carson KL, Sharara AI. Hepatitis C in pregnancy. Obstet Gynecol. 1997;89:883–890. 7. Mazza C, Ravaggi A, Rodella A, et al. Prospective study of mother-to-infant transmission of hepatitis C virus (HCV) infection. Study Group for Vertical Transmission. J Med Virol. 1998;54:12–19. 8. Ferrero S, Lungaro P, Bruzzone BM, et al. Prospective study of mother-to-infant transmission of hepatitis C virus: a 10year survey (1990-2000). Acta Obstet Gynecol Scand. 2003;82:229–234. 9. Mast EE, Hwang LY, Seto DS, et al. Risk factors for perinatal transmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy. J Infect Dis. 2005;192:1880–1889.
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Address correspondence to: Claudia Espinosa, MD, MSc, Department of Pediatrics, Division of Pediatric Infectious Diseases, University of Louisville, 571 S Floyd St, Suite 321, Louisville, KY 40202. E-mail: [email protected]
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