Defer no more: Advances in the treatment and prevention of chronic HCV infection in children

Abstract

Purpose of review:

Direct-acting antiviral (DAA) regimens targeting hepatitis C virus (HCV) are now approved for young children. This review examines recent DAA experience in children, current treatment recommendations and challenges, and potential treatment-as-prevention strategies.

Recent findings:

In 2021 the US FDA extended approval of two pan-genotypic DAA regimens, glecaprevir/pibrentasvir and sofosbuvir/velpatasvir, to children ≥3 years old based on high success rates and reassuring safety profiles in registry trials. Similar performance has been replicated with real-world DAA use in thousands of adolescents and in limited reports of children with high-risk conditions including cirrhosis, cancer, thalassemia, and HIV-coinfection. Treatment without delay is now recommended in the US for viremic children age ≥3 years to prevent disease progression and future spread. To date, treatment expansion is limited by high rates of undiagnosed pediatric infection. Universal prenatal screening will aid identification of perinatally-exposed newborns, but new strategies are needed to boost testing of exposed infants and at-risk adolescents. Postpartum treatment programs can prevent subsequent vertical transmission but encounter frequent loss to follow-up. DAA use in pregnancy warrants continued study.

Summary:

Pediatric HCV is now readily curable. Substantial clinical and public health effort is required to ensure widespread uptake of this therapeutic breakthrough.

Introduction

The development of direct-acting antivirals (DAAs) targeting the viral replication machinery of hepatitis C virus (HCV) has revolutionized HCV treatment in the past decade. DAA-based regimens have safety and efficacy profiles far superior to prior pegylated-interferon and ribavirin regimens, thereby opening the door to new possibilities in HCV control. As a result, leading public health agencies including the World Health Organization have set the ambitious goal of global HCV elimination by 2030 (1).

Addressing HCV in the youngest populations will be critical to achieve HCV elimination. Over 3.2 million children worldwide are chronically infected with hepatitis C virus (HCV) (2). In the US, HCV prevalence has increased dramatically over the past two decades, fueled by the ongoing opioid crisis (3–7). Mother to child transmission accounts for most pediatric HCV infections, with iatrogenic transmission in some low-middle income countries (LMIC) and adolescent injection drug use (IDU) also contributing to the incidence (8). Perinatally-acquired HCV infection establishes chronicity in 60–75% of cases (8, 9). Liver fibrosis progresses slowly, with cirrhosis reported in only 1-2% by age 20 (8–11), but if left untreated the risk of advanced fibrosis accelerates substantially in adulthood (12). Successful treatment of HCV during childhood can avert these long-term consequences and prevent further transmission.

This review details progress in pediatric DAA therapy, real-world experience with these regimens, current diagnostic challenges impeding treatment expansion, and evolution of preventive strategies.

Pan-genotypic oral HCV therapies for children

Building on the successes of DAA regimens in adults, dozens of clinical trials have established the safety and efficacy of several interferon- and ribavirin-free DAA regimens in children with chronic HCV infection (13, 14). The first to receive a pediatric FDA indication was the fixed-dose combination ledipasvir/sofosbuvir (LDV/SOF), approved for treatment HCV genotypes (GT) 1 and 4-6 in adolescents in 2017 and children as young as age 3 years in 2019. The pan-genotypic (GT 1-6) regimen glecaprevir/pibrentasvir (GLE/PIB) became available for adolescents in 2019 and children ages 3 and up in 2021. Another pan-genotypic regimen, sofosbuvir/velpatasvir (SOF/VEL), received FDA approval for children 6 years and older in 2020 with expanded indication down to age 3 years in 2021.

In pediatric registry trials, these pan-genotypic regimens exhibited excellent virologic efficacy with sustained virologic response through at least 12 weeks post-treatment (SVR12) in over 99% of children who completed therapy per protocol, and 98% and 92% of children receiving at least one dose of GLE/PIB (NCT03067129) (15, 16) or SOF/VEL (NCT03022981) (17, 18), respectively. Therapies were well tolerated with the most common adverse events (AE) being mild headache, vomiting, diarrhea, or fatigue. Unlike interferon regimens (19), neither GLE/PIB nor SOF-based regimens appear to impede linear growth (16, 17, 20–22). These advances are reflected in the current US (AASLD/IDSA) and European (EASL) HCV treatment guidelines, recommending weight-based GLE/PIB for 8 weeks or SOF/VEL for 12 weeks as first line therapies for treatment-naïve children ≥3 years without decompensated cirrhosis (23, 24) (Table 1).

Table 1:

Direct-Acting Antiviral (DAA) regimens recommended for children in US and Europe or widely available globally in 2022

Regimen	HCV Genotype	Standard Duration*	FDA Approved Age	Recommended age			Regimens with generic formulations widely available in LMIC (26)
				AASLD/IDSA 2022 (23)	EASL 2022 (24)	WHO 2018 (27, 29)
GLE/PIB	1-6	8 weeks	≥ 3 years	≥ 3 years	≥ 3 years
SOF/VEL	1-6	12 weeks	≥ 3 years	≥ 3 years	≥ 3 years
LDV/SOF	1,4,5,6	12 weeks	≥ 3 years	≥ 3 years		≥ 12 years	x
SOF + RBV	2,3	GT2 - 12 weeks GT3 - 24 weeks	≥ 3 years			≥ 12 years	x
SOF + DAC‡	1-6	12 weeks	≥ 18 years‡				x

^*Treatment-naïve and without decompensated cirrhosis

^‡DAC is not FDA approved for use in children but SOF + DAC is the preferred adult pan-genotypic regimen in many LMIC and has been used in adolescents in some nations (28, 29)

Abbreviations: AASLD: American Association for the Study of Liver Diseases; IDSA: Infectious Diseases Society of America; EASL: European Association for the Study of the Liver; LMIC: Low and middle income countries; GT: genotype; GLE: glecaprevir; PIB: pibrentasvir, SOF: sofosbuvir, VEL: velpatasvir; LDV: ledipasvir; RBV: ribavirin; DAC: daclatasvir.

For many LMIC, generic daclatasvir (DAC) in combination with SOF is the preferred pan-genotypic DAA regimen in adults due to superior pricing (21, 25–27). DAC is not approved for use in pediatrics, but recent pharmacokinetic modeling data indicates safe DAC exposure in children down to 14 kg using an adult formulation (28). Further studies are needed to validate these data clinically and thereby expand pediatric access to treatment globally (29).

Finally, other pan-genotypic regimens are on the horizon for pediatric FDA approval, including sofosbuvir-velpatasvir-voxilaprevir (SOF/VEL/VOX), which has particular value in DAA-experienced adults (23) and demonstrated efficacy and safety in a phase 2 adolescent study (24, 30).

DAA-based regimens in real-world settings & special populations

Clinical experiences with DAA in multiple countries are validating high efficacy rates seen in pediatric registry trials (22, 31). The recently published success of an Egyptian school-based screening and treatment program is the largest demonstration of the real-world efficacy and tolerability of DAA therapy in adolescents. From 2018 to 2019, over 3 million students 15 to 18 years old were screened, of whom 11,477 were HCV-antibody positive (0.38%) and 8,187 were confirmed viremic. Treatment with 12 weeks of domestically manufactured LDV/SOF achieved viral cure in 99.6% of the 7,356 who underwent SVR12 testing (32). The effectiveness and scale of this endeavor raise hopes for similar campaigns to be implemented in other high-prevalence regions or groups.

Shorter duration DAA-based regimens, if sufficient to achieve virologic cure, might improve treatment completion rates and save cost. Fu et al. (2021) found high curative rates with 8 weeks of therapy for both GLE/PIB and several SOF-based regimens (33).

Special populations, including children with advanced liver fibrosis, may require extended or alternative regimens, but experience with DAAs in pediatric patients with cirrhosis remains sparse. Of the at least 15 cases reported in the literature, all who completed the prescribed therapy achieved SVR12, suggesting that DAAs remain potent despite advanced liver disease (13, 22, 31, 34). In addition to curative response, DAA-based treatment may halt or reverse existing liver damage. Several studies in children have demonstrated improvements in non-invasive assessments of liver stiffness at 12 weeks and one year post-treatment, suggestive of possible reversal of liver damage (35–38). However, persistently elevated liver stiffness measures have been documented in some children after HCV cure, such that post-SVR liver monitoring is recommended in children with pre-treatment fibrosis (35–39).

HCV infection is associated with worse disease severity in children with cancer or coexisting hematologic disorders resulting in iron overload. Early eradication of HCV is of paramount importance to prevent liver-related complications. Single patient case reports or case series of successful HCV treatment using DAA regimens have been reported in children with hematologic malignancies and those undergoing hematopoietic stem cell therapy (25, 40–44). Safety profiles were excellent, with no reported DAA-related serious AEs, chemotherapy interruptions or significant toxicities due to drug interactions (25, 40–44). Similarly, multiple case series have reported 100% SVR12 rates after various DAA-based regimens in children with thalassemia (34, 37, 45, 46).

Vertically acquired HIV/HCV co-infection has been associated with lower rates of spontaneous HCV resolution and greater risk of progressive liver disease than HCV mono-infection (47–49). Among HIV/HCV-coinfected adults, HCV treatment is highly efficacious with curative rates comparable to those with HCV monoinfection (50, 51). Thus far, at least 11 cases of successful DAA treatment have been reported in coinfected children (15, 16, 52, 53).

With widespread use of DAA therapy in adults, the risk of HBV reactivation in those with prior or active HBV infection was recognized. In a single-center study of 115 adolescents with hepatitis B virus core antibody positivity +/− surface antigen positivity, no cases of HBV reactivation or hepatic decompensation were observed during DAA treatment. Despite these reassuring findings, we concur with general guidelines for close monitoring for HBV reactivation (by laboratory evaluation or symptom assessment) during HCV treatment in at-risk individuals (those who lack evidence of immunity to hepatitis B surface antigen) (23, 54).

Successful DAA treatment has been described in several pediatric liver transplant candidates (55, 56) and at least 2 adolescent kidney transplant recipients (57). To our knowledge there has not yet been published experience with intentional transplant of solid organs from HCV-viremic donors to pediatric recipients.

Optimal age for treatment of pediatric HCV infection

During the interferon era, therapy was commonly reserved for individuals who had developed significant hepatic fibrosis or compensated cirrhosis (58). The advent of highly efficacious and well-tolerated DAAs shifted this paradigm, such that treatment now is recommended as early as possible for adults (23). Studies demonstrating improvements in hepatic inflammation and fibrosis, extra-hepatic HCV manifestations, and quality of life after viral cure have reinforced these recommendations (23, 59, 60). The accumulating pediatric DAA safety and efficacy data, along with convincing cost-effectiveness studies (61, 62), support a similar paradigm shift toward treatment initiation without delay in all viremic children ages 3 years and up (23) (Table 2). Recent approval of pan-genotypic DAA regimens for this age group means that a substantial cohort of children in whom treatment previously had been deferred are newly eligible and should be treated.

Table 2.

Considerations for timing of HCV treatment in children

Preferred timing	Factors favoring early treatment	Indications for potential treatment delay
At confirmation of HCV viremia in any child age 3 years or older	Concomitant liver disease or co-infection Advanced fibrosis or impaired hepatic function Extrahepatic HCV manifestations (e.g. symptomatic cryoglobulinemia or glomerulonephritis) Immunosuppression (including transplant, chemotherapy) Note: Treatment before age 3 years is not routinely recommended because of higher odds of spontaneous clearance, rare progression to advanced liver disease, and lack of approved DAA in this age group. HCV-related transaminitis with preserved hepatic function is not an indication for DAA treatment before age 3 years.	Inability to swallow tablets or oral granule-sized candies (e.g. cake-decorating sprinkles) in compatible foods without chewing* ➢ Follow-up in 6-12 months to reassess ability to swallow formulation without chewing. Consider pill teaching in older children. Unstable home situation expected to impede adherence to the 2-3 month treatment course ➢ Solicit social services, case management, or extended family to aid. Offer therapy as soon as deemed likely to succeed. Lack of health insurance or denial of coverage ➢ Solicit social services, patient assistance programs ➢ If coverage denied, appeal with AASLD/IDSA guidance. LMIC national treatment programs may defer therapy for children until age 12 years and/or may lack pediatric formulations ➢ Monitor until of weight and age to access therapy

^*Compatible foods for oral granules:

GLE/PIB: soft foods with low water content such as peanut butter, chocolate hazelnut spread, thick jam, cream cheese, or Greek yogurt (66)

SOF/VEL or LDV/SOF: soft, non-acidic foods at room temperature or colder such as chocolate syrup, ice cream, or pudding (65, 107)

The recommendation to defer treatment in children under 3 years stems from natural history studies demonstrating potential spontaneous viral resolution and slow disease progression, high drug costs, practical challenges of drug administration, and lack of approved regimens for this age group (23, 63). In some challenging clinical situations, DAA administration may be indicated, as described in two children under age 1 years who required liver transplant for non-HCV related indications (55, 64). Successful treatment of a 1-year-old otherwise healthy child with transaminitis and nausea/vomiting attributed to HCV infection has been described (56). Of note, hepatic inflammation with mild-moderate transaminitis occurs commonly in the first several years (9), is usually asymptomatic, and is not by itself an indication for early treatment. It remains to be seen whether increasing DAA safety data, declining drug costs, or new discoveries of adverse consequences from unchecked viral replication and hepatic inflammation in early childhood will swing the pendulum towards treatment studies in infants or toddlers.

In a minority of cases, practical challenges with drug administration hinder DAA therapy in children who cannot swallow pills. DAA formulations for young children consist of film-coated granules which are to be given with specific compatible foods and should not be chewed to avoid a bitter taste (65, 66). Intolerance to the oral granule formulation appears to have contributed to early discontinuation and lower intention-to-treat SVR12 rates in trials of children ages 3 to <6 years (13, 18, 67, 68). In our clinical experience, children who inadvertently bite into DAA granules may refuse subsequent doses, even if offered in different foods. Therefore, before prescribing DAA therapy to young children who cannot swallow tablets, we request caregivers assess if their children can swallow (without chewing) granule-sized candies (i.e. cake-decorating sprinkles) mixed in drug-compatible foods. This education and counseling prior to treatment initiation has helped improve our treatment completion rates and identify children better served by treatment deferral and re-evaluation in 6–12 months (Table 2).

Improving diagnosis to expand pediatric DAA treatment uptake

One of the major challenges stymieing HCV elimination efforts through DAA deployment has been the high rates of undiagnosed infections at all ages. Low diagnosis rates in adults prompted the CDC and the U.S. Preventive Services Task Force (USPSTF) to release recommendations in 2020 for one-time universal screening of all adults in addition to annual testing of those with ongoing potential exposures (69, 70). Similarly high rates of undiagnosed infection occur in adolescents, including those with known drug use (71–73). As for adults, elimination of adolescent HCV will likely require one-time screening in adolescence and more frequent testing in those with ongoing exposures.

Although the American Academy of Pediatrics recommends routine HCV testing among infants born to mothers with HCV (74), diagnostic rates for younger perinatally-exposed children have been consistently low, estimated at 10-30% (75–79). Inadequate testing arises due to lack of awareness of maternal HCV infection as well as barriers to testing in perinatally exposed children (80). Recently, universal screening in pregnancy, rather than risk-based, has been widely advocated by several professional societies and adopted by the CDC and USPSTF (69, 70, 81–83). This change was prompted by the continued opioid-related escalation in maternal HCV prevalence (6, 7, 84, 85) and multiple demonstrations that universal screening policies uncover more HCV cases than risk-based strategies and are cost-effective (85) (86–88).

Improved identification of HCV-exposed newborns must be accompanied by appropriate follow-up testing. Bhardwaj et al. found that less than a third of perinatally-exposed children were adequately tested, primarily due to lost follow-up by age 18 months when HCV antibody testing is recommended (76). Earlier testing with HCV RNA assays starting at age 2 months appears sensitive and may improve the identification of children who have acquired HCV (80). Others have proposed universal pediatric testing to definitively address current gaps in diagnosis (39, 89). The expanding availability of DAAs and potential for early treatment of HCV infection may further support universal testing strategies at least during the bimodal peaks of HCV acquisition in childhood (Figure 1).

Figure 1:

Challenges and potential solutions for delivering DAA therapies to HCV-infected mothers and perinatally-infected children.

DAA treatment for prevention of pediatric HCV

HCV elimination efforts must incorporate preventive strategies in conjunction with treatment expansion. Vaccines, one of the most effective prevention tools available, have thus far proven elusive for HCV. Page et al. recently reported the first human efficacy trial of an HCV vaccine, finding that it was well-tolerated without serious AEs but did not protect from development of chronic HCV infection (90).

While we await the future development of prophylactic HCV vaccines, we must now turn to another established strategy of treatment as prevention (91) (Figure 1). Given that DAAs are not approved for treatment during pregnancy or breastfeeding, current strategies emphasize treatment of non-pregnant women of childbearing age including prompt postpartum treatment (after breastfeeding completed) to reduce the risk of vertical transmission in subsequent pregnancies (81). However, rates of successful postpartum treatment completion appear low (92). Co-localization of maternal postpartum, addiction, and HCV management along with infant care can improve rates of maternal treatment and infant testing but, even with intensive medical and sociobehavioral support, many chronically infected women remain untreated (93, 94).

Given the widely acknowledged difficulties impeding postpartum treatment, along with the accumulating evidence of DAA safety in adults and children, a growing chorus is advocating the study of DAA use during pregnancy to cure mothers and prevent vertical transmission (95–99). These calls are reinforced by recognition that pregnancy is often a unique period of medical engagement in otherwise asymptomatic, healthy women. Whereas HCV treatment during pregnancy was previously avoided due to RBV teratogenicity in animal studies (FDA pregnancy category “X”), major DAA agents appear safe in animal testing, receiving Australian pregnancy category B1 (SOF, LDV, VEL, GLE, and PIB) or B3 (DAC) designations (100).

Emerging data on DAA experience in human pregnancy are also encouraging. A phase 1 trial of LDV/SOF given for 12 weeks to 9 GT1-infected women starting at 23-24 weeks gestation resulted in SVR12 in all women, drug levels comparable to non-pregnant women, no clinically significant maternal or infant safety events, and no cases of vertical transmission (101). Additional clinical trials (NCT04382404; NCT05140941) are underway to evaluate SOF/VEL safety and efficacy in pregnancy.

Several additional case reports and small case series report intentional DAA treatment starting at the 2^nd or 3^rd trimester of pregnancy with 100% SVR12 in mothers completing therapy and no cases of vertical transmission (56, 102, 103). Abdallah et al reported first trimester DAA exposure in 100 women who became pregnant while on DAA, with no obvious maternal or fetal safety signal observed. While most stopped DAA at 4-8 weeks into treatment, nine completed the full 12 weeks of SOF + DAC, of which 7 had follow-up viral testing and all achieved SVR12 (104).

Access to safe HCV treatment during pregnancy to achieve cure and prevent vertical transmission is appealing to women with HCV infection (105, 106). Combined with universal screening in pregnancy, DAA treatment during pregnancy could prove a potent mechanism for achieving HCV elimination in women and children, and we believe it should be a high priority for further study. As for now, we agree with the SMFM that routine use of DAA in pregnancy should be limited to a clinical trial.

Conclusions

The last decade has seen tremendous progress in pediatric DAA clinical trials, culminating last year in the approval of two potent, safe, pan-genotypic regimens for children as young as age 3 years. Increasing data indicate that these therapies are highly effective and safe in the real world for asymptomatic children with HCV infection and among those with high-risk conditions. To effectively deliver these therapies to our pediatric patients, pediatricians must partner with specialists to ensure appropriate identification of chronic HCV infection, address practical considerations around DAA tolerability for young children, and tackle socioeconomic issues that may impede treatment access. DAA use in pregnancy could further provide a practical and safe means to reduce pediatric HCV and warrants enthusiastic study. Taken together, widespread expansion of DAA-based treatment in pediatrics could help move us closer than ever to achieving HCV elimination over the next decade.

Key Points:

1. Children with chronic hepatitis C virus (HCV) infection who are 3 years and older should be evaluated for treatment using highly efficacious and safe direct acting antivirals (DAAs).

2. Improved identification of children with perinatal and risk-based HCV exposure is critical to expand treatment access.

3. Current strategies to prevent mother to child transmission focus on treatment of postpartum mothers but could conceivably include DAA treatment during pregnancy in the near future.