Management of pediatric HCV poses challenges for parents, physicians

Clinicians dealing with pediatric hepatitis C virus infection currently have a key choice to make: treat children with toxic and moderately effective interferon-based therapy or wait until safer, more powerful direct-acting antivirals move through clinical trials and gain FDA approval for this population. As directly acting antivirals cure HCV in record numbers of adults, at the moment, for children, it is all just a matter of hope and speculation.

But, of course, the wait for approval is not the only challenge these clinicians face. The treatment of pediatric patients often necessitates two separate conversations for any one case: one conversation with the child and one conversation with the parent. Understanding what to explain and how to explain it is critical to achieving outcomes.

Vertical transmission of HCV remains an area where there are insufficient data. This contributes to general uncertainty about the number of undiagnosed pediatric HCV infections that exist and how to manage them. Another issue is whether HCV has any short-term or long-term developmental effects on the children who acquire it.

Then there are adolescents with HCV, many of whom are injection drug users. Pediatric specialists often must shift gears and address a host of adult issues when dealing with older children who have acquired the infection through drug use.

For Maureen M. Jonas, MD, attending physician and clinical director of hepatology, director of the Center for Childhood Liver Disease at Boston Children’s Hospital and professor of Pediatrics at Harvard Medical School, case identification may be the most important first step in dealing with pediatric HCV. “There are a lot of children out there who have not been diagnosed,” she said in an interview. She acknowledged that in the big picture of dealing with baby boomers and the cost of therapy, testing children is not as pressing of a need. “But I’m sure they are out there. They give blood when they are 17; they find out that they have HCV at that point. This is something we need to think about.”

In the meantime, studies investigating novel directly acting antiviral (DAA) therapies in pediatric patients are underway. This presents a unique opportunity to better understand the disease in children.

Waiting for therapies

Philip Rosenthal, MD, professor of pediatrics and surgery and director of Pediatric Clinical Research, Pediatric Hepatology and Liver Transplant Research and Pediatric Hepatology at the University of California, San Francisco, outlined the process by which medications are approved in pediatric populations.

“Adults are the guinea pigs for pediatric studies,” he said in an interview. “Once approved in adults, then studies can proceed in children. But of course children are not little adults, so pharmacokinetic studies to assess the correct dosing, safety and toxicity are required, especially in growing children.”

Rosenthal said that it is necessary to note the effects on height and weight, along with Tanner staging.

“We don’t know the proper dose to give a 4-year-old,” Jonas added. On a practical level, “most children have trouble swallowing pills, so special formulations need to be produced.”

The journey from phase 1 trials to FDA approval for pediatric patients can be a long one, according to Rosenthal. “Unfortunately, in order to do all these steps, anywhere from a year or 2 or more is required,” he said.

Hanaa El-Karaksy, MD, professor of pediatrics and head of the pediatric hepatology unit at Cairo University Pediatric Hospital and Kasr Al-Ainy Medical School, Cairo University, is hopeful about the timelines.

“Previously, when pegylated interferon plus ribavirin was approved for use in adults, 5 years lapsed before they were approved in children,” she said. “At that time, treatment courses were longer, at 48 weeks. With the shorter courses for HCV treatment with DAAs, this period will be much shorter to get approvals for the newer agents in children.”

Jonas is encouraged by the activity in the pharmaceutical industry.

“Pharma has entered the pediatric market relatively early and is committed to getting the therapies approved in this population,” she said. “We are grateful for these open-label studies. People are comfortable with doing these trials.”

For El-Karaksy, it remains a concern that interferon-based therapies are still the standard of care in many pediatric HCV populations.

“In 2014 the World Gastroenterology Organization is still recommending the dual therapy of peginterferon 2b and ribavirin for patients with HCV in resource-limited regions due to the high cost of new DAAs. These recommendations are now outdated and invalid after the negotiation of the Egyptian government for the relatively low price of sofosbuvir [Sovaldi, Gilead Sciences],” she said.

Talking to parents, children

What all of this means is that clinicians are forced to have difficult conversations in the clinic, according to El-Karaksy.

“We have recently adopted a new approach in treatment of HCV-infected children,” she said. “Before administering the currently available therapies, parents are counseled about the efficacy and side effects of those therapies.”

Parents are then given the option for their children to be treated with interferon-based treatment or wait for the approval of new regimens.

“The former choice is made by parents who worry that infection is associated with ongoing inflammation or fibrosis,” El-Karaksy said. “Treatment at a younger age, with shorter disease duration, provides better response. Those children suffer fewer side effects. The latter choice is made by parents who are aware that most infections in children are asymptomatic, that infectivity is less in children, that current therapies have side effects and that newer therapies are more effective and will, hopefully, be available soon.”

“The conversation has changed radically in the last 2 years,” Jonas said. “Now the conversation is why we are not treating everybody. We are trying to explain why we are waiting; why we aren’t treating patients with interferon.”

A unique component to the discussion is that the children often don’t feel sick, according to Jonas. “They don’t know they have an infection, the parents don’t see anything wrong,” she said. “We rarely see cirrhosis in young children, so we’re trying to explain why we may have to treat this asymptomatic disease.”

This sentiment was echoed by Daniel H. Leung, MD, assistant professor of pediatrics at Baylor College of Medicine and medical director of the Viral Hepatitis Clinic at Texas Children’s Liver Center. “Children with HCV rarely ever develop symptoms such as jaundice, ascites, or icterus and may even have normal transaminases,” he said.

Further compounding the issue is parental guilt. “It is a complicated social situation,” Jonas said. “We have to explain it to the parents, and they have to weigh explaining it to family friends, the baby sitter, teachers, others who are in contact with the child. I typically counsel against disclosing this infection to these contacts, since the universal precautions they should already have in place for all children are completely sufficient in this setting.”

Rosenthal offered a practical solution. “I do not think there is an issue with explaining HCV infection to an adult parent,” he said. “I would utilize the very excellent lay information provided by the CDC, Liver Foundation, drug manufacturers.”

Leung built on this point. “Pediatricians have the primary responsibility of identifying children who are at risk of HCV exposure,” he said. “A thorough review of social and family history with questions about IV drug use, family history of HCV, which is often generational, or other high-risk situations such as needle sticks, unregulated blood transfusions, tattoos/piercings, multiple sexual partners, should be directed to both the family and adolescent child. While this can be awkward, time must be taken to address these risk factors.”

Rosenthal acknowledged, though, that explaining the infection to very young children is difficult. “Depending on the age of the child and their comprehension, I try to explain that they have an infection that we need to monitor and that they may need to take medicine, just like when they get an ear infection or a sore throat,” he said.

Camille Raynes-Greenow, PhD, a senior research fellow and NHMRC Career Development Fellow at the Sydney School of Public Health, The University of Sydney, put the issue in epidemiological terms. Findings from some of her research indicate that follow-up care of children with HCV is difficult. “Although we didn’t specifically discuss challenges of caring for infected children, many of the clinician participants reported that the families did not attend clinic appointments and did not respond to requests for follow-up,” she said. “Most of the children in our study had lost contact of their notifying pediatrician. This is not to say that they are not being cared for by another, but anecdotal data suggested that care tended to be ad hoc and opportunities for treatment were being missed.”

Reducing vertical transmission

The primary mode of HCV transmission among children in 2015 is still mother to child, according to Leung. “Rates range from 5% to 7%,” he said. “There are roughly 8,000 new pediatric cases per year in the U.S.”

For Jonas, though, vertical transmission remains relatively uncommon. “Still, we are not doing enough to prevent perinatal transmission,” she said.

One issue is that many women may not know they are infected, according to Jonas. Another is that the clinical community is still wrestling with the puzzle of preventing transmission early in life.

“There would need to be a sea change to suggest testing all pregnant women for HCV where, once HCV status is known, we would treat during pregnancy or around the time of delivery,” she said. “But at this point, we don’t have those strategies in place, and there is no effective method of preventing perinatal transmission, so it is difficult to advocate for testing every pregnant woman. All of that needs to be worked out if we are going to change policy and reduce perinatal transmission.”

She admitted, however, that many of these issues have been investigated, and it is unclear whether active HCV-related intervention in pregnant women is worth the investment of resources.

Rosenthal believes so. “This is a significant issue because, routinely, children do not even get labs, let alone testing for HCV,” he said, but he offered a practical approach. “Testing for HCV would occur if there were lab abnormalities obtained in the course of a work-up. For example, we would test if abnormal serum transaminases were detected in a child born to a mother who was known to be HCV-positive, or in a child with risk factors such as use of illegal drugs or homelessness.”

Selvapatt and colleagues assessed 10 years of screening and outcome data to evaluate whether universal antenatal screening would be a cost-effective intervention. Findings for 35,355 women who were screened between Nov. 1, 2003, and March 1, 2013, underwent analysis. HCV antibodies were found in 0.38% of the cohort, with 0.22% viremic and 0.12% newly diagnosed infections. The rate of vertical transmission among newly diagnosed mothers was 6.8%.

Clinicians initiated treatment and achieved a 74% sustained virologic response rate at a total cost of £5,469 per newly diagnosed patient. Cost-effectiveness data indicated that £2,400 was required for each quality-adjusted life-year (QALY) gained, while novel DAAs would incur a cost of £9,139 per QALY gained. The researchers noted that this is significantly lower than the £20,000 to £30,000 per QALY gained willingness-to-pay threshold for policy advisory bodies.

“This study demonstrates that an antenatal screening and treatment program is feasible and effective, at a cost considered acceptable,” the researchers concluded.

Understanding epidemiology

Raynes-Greenow and colleagues conducted prospective national surveillance for HCV infections in Australia. Results indicated a low rate of new infections, with just 45 confirmed cases over 5 years. In 40 of those cases, the mother had positive HCV serostatus. The researchers, however, acknowledged that the data may be an underestimate of the actual incidence.

“Opportunistic investigation of children at risk for HCV, improved education regarding vertical transmission for health care providers and increased coordination of childhood HCV services are required to improve recognition and management of children with HCV,” they wrote.

“There are several reasons that we suspect pediatric HCV was underestimated in this study and in general,” Raynes-Greenow told Infectious Diseases in Children, “First, children infected with HCV identified in this study were identified through active surveillance. This system relies on several factors lining up, including the pediatrician identifying a child at risk of infection, gaining consent, testing the child for HCV and then reporting the positive case to the [Australian Paediatric Surveillance Unit].”

She added that in Australia, children at risk of infection are those who have been exposed in countries with higher prevalence — many of whom are recent immigrants — or those whose parents are infected themselves. Also at risk are children with parents who engage in high-risk activities such as IV drug use. “In general, the latter group of people have less engagement with medical practitioners and are less inclined to consider their child at risk of infection,” she said. “Therefore, there is less opportunity for testing.”

Clinicians should take every opportunity to test children who are potentially at risk, according to Raynes-Greenow, but she acknowledged that this is not always possible, largely because of the reasons stated above.

“Antenatal care is an obvious opportunity to discuss HCV screening of infants,” she said. “Ideally, discussing the benefits of early detection and encouraging mothers to be aware of their own HCV status are good ways to reduce their risk of disease.”

Consequences of HCV

Another area of debate involves the short- and long-term effects of HCV in children. Jonas and colleagues investigated linear growth in children treated with peginterferon with or without ribavirin. Six years after treatment, results from a subset of patients indicated that this treatment had no long-term effects on growth.

“They are perfectly healthy in general in the long-term,” Jonas said.

Leung agreed. “Although there appears to be some variability in the duration of growth effects, overall, there were no long-term effects on height observed,” he said.

Abu Faddan and colleagues investigated how HCV impacts cognitive function in children with normal liver functioning. Compared with controls, children with HCV demonstrated significantly higher serum levels of IL-6 and IFN-. Children in the HCV group also experienced a significant effect in terms of vocabulary, comprehension, and abstract visual reasoning, quantitative reasoning and bead memory tests compared with controls. Short-term memory and intelligence quotient also were significantly poorer in children with HCV compared with controls.

“Abu Faddan and colleagues suggest a relationship between endogenous cytokines and cognitive function in children which may be better addressed in a multisite study such as PEDS-C,” Leung said.

Conversely, Rodrigue and colleagues showed no “global impairment” in quality of life or functioning on a cognitive, behavioral or emotional level. Rather, they found increased caregiver stress, which they hypothesized could be associated with cognitive changes.

“While the natural history of HCV in children is mildly progressive, with less than 2% developing cirrhosis before adulthood, the negative impact of HCV on cognitive function even in early stages and development of autoimmune features and growth stunting before and after treatment of HCV with pegylated interferon and ribavirin should not be ignored,” Leung said.

“There is very little good information on how HCV impacts cognitive function,” Jonas said. “There have been systematic assessments of large populations, but they didn’t find anything cognitive at baseline.”

Delgado-Borrego and colleagues investigated adiponectin levels in a cohort of 86 children aged 5 to 17 years with HCV infection and found that high BMI among them was associated with lower adiponectin levels. They suggested vigilance in treating overweight children with the disease.

In another study, Gupta and colleagues examined post-treatment outcomes in children with HCV who also had end-stage liver disease. They aimed to determine whether the pediatric end-stage liver disease (PELD) scoring system impacted these outcomes. Results indicated improvements in survival after transplantation between 1994 and 2010. “Early follow-up demonstrates a trend toward improved pediatric HCV liver transplant graft and patient survival in the post-PELD era,” the researchers concluded. “Superior outcomes may be attributed to pre-transplant factors, improved surgical technique and better treatment options for HCV infection.”

Other areas of concern

It is generally agreed that adolescent patients with HCV present a unique set of challenges.

“As they get older, we see a lot more complications,” Jonas said. “We see comorbidities and much more drug use.”

“In adolescents, the biggest issue is compliance, especially in injection drug users,” Rosenthal said. “Compliance with the treatment regimen may be exceedingly difficult. Of course, if a patient does not take the medicine as prescribed, the likelihood of treating the infection diminishes. I try to impress upon the adolescents that they are good candidates for the therapy and that if they can comply with the treatment regimen, then the likelihood of eradicating the infection is high.”

Rosenthal recommended providing the patient with highly detailed information about what is involved in treatment and what they are likely to expect in terms of visits, blood draws, dosing and outcomes. “This goes a long way in improving compliance and successful treatment in adolescents,” he said.

No discussion of HCV can be complete without discussing the cost of therapy. However, many clinicians, including Jonas, are unconvinced that FDA approval in the pediatric market will impact pricing scales. “The numbers are a fraction of the adult population, so this won’t be a large increase for payers,” she said. “Pediatric indications will be a tiny percent and they won’t feel it.”

For Leung, though, approval in pediatric populations is more than just a matter of finances.

“I expect DAAs to have a profound impact on both the attitude towards HCV therapy and ultimately the outcome among children and families,” he said.

Another unexplained phenomenon is that HCV infection spontaneously resolves in some children around age 3 years. This may offer clues to cure. “We need more education around that,” Jonas said.

For Raynes-Greenow, the epidemiological challenge of identifying undiagnosed children remains the most significant concern, followed by the reduced opportunity for screening.

Jonas agreed, but found hope in the fragmentary nature of these mysteries. “This is a relatively limited patient population,” she said. “Counseling of friends and family of patients can be difficult, and, of course, perinatal transmission remains a concern. There are a lot of challenges, but they are small challenges. Hopefully, we will have great therapies in the next few years and many of these issues will be resolved.”“— by Rob Volansky

Editor Note: This article was previously published in HCV Next, a SLACK Incorporated publication.

• References:
• Abu Faddan NH, et al. J Viral Hepat. 2014;doi:10.1111/jvh.12373.
• Delgado-Borrego A, et al. J Pediatr Gastroenterol Nutr. 2015;doi:10.1097/MPG.0000000000000604.
• El Sherbini A, et al. Aliment Pharmacol Ther. 2015;doi:10.1111/apt.13221.
• Gupta M, et al. Pediatr Transplant. 2015;doi:10.1111/petr.12408.
• Jonas MM, et al. J Pediatr. 2014;doi:10.1016/j.jpeds.2014.08.010.
• Raynes-Greenow C, et al. J Paediatr Child Health. 2015;doi:10.1111/jpc.12904.
• Rodrigue JR, et al. J Pediatr Gastroenterol Nutr. 2009;48:341-7.
• Selvapatt N, et al. J Hepatol. 2015;doi:10.1016/j.jhep.2015.05.015.

• For more information:
• Hanaa El-Karaksy, MD, can be reached at 44 Mohei El-Deen Abu El-Ezz St. Dokki, Cairo, 12311, Egypt; email: hanaakaraksy@kasralainy.edu.eg.
• Maureen M. Jonas, MD, can be reached at Division of GI-Hunnewell Ground, Boston Children’s Hospital, 300 Longwood Ave. Boston, MA, 02115; email: maureen.jonas@childrens.harvard.edu.
• Daniel H. Leung, MD, can be reached at 6621 Fannin St. Houston, TX 77030; email: dhleung@texaschildrens.org.
• Camille Raynes-Greenow, PhD, can be reached at Edward Ford building (A27), The University of Sydney, NSW 2006 Australia; email: camille.raynes-greenow@sydney.edu.au.
• Philip Rosenthal, MD, can be reached at 550 16th St., 5th Floor, Mail code 0136, San Francisco, CA 94143; email: PROSENTH@ucsf.edu.

Disclosures: El Karaksy and Raynes-Greenow report no relevant financial disclosures. Jonas reports being a consultant for Gilead and receiving research support from Bristol-Myers Squibb, Echosens, Gilead and Roche. Leung reports receiving grant/research support from AbbVie, Bristol-Myers Squibb, Gilead and Roche and being on the medical advisory board for Vertex. Rosenthal reports receiving research support from Abbvie, Bristol-Myers Squibb, Gilead, Roche/Genentech and Vertex; he also reports being a consultant for Abbvie, Gilead and Retrophin.