DAAs provide ‘dramatic’ improvement in outcomes for pediatric patients with HCV

Direct-acting antivirals first received approval for use in adults with hepatitis C in 2013. They were approved for use in children several years later, in 2017.

Since then, the approvals have continued at a “rapid-fire” pace, according to Karen Murray, MD, chair of the Pediatrics Institute at Cleveland Clinic and physician-in-chief at Cleveland Clinic Children’s Hospital. Healio spoke with Murray about the history of HCV treatment in children and how DAAs “have hugely changed the paradigm” in pediatric HCV.

Healio: What were the treatment options for pediatric HCV prior to DAAs?

Murray: Before DAAs, the only treatments we had were interferon-based. In 1998, interferon plus ribavirin was approved; in 2008 and 2011, two different forms of pegylated interferon plus ribavirin were approved. The interferons were the elements of these combination regimens that resulted in relatively rapid viral clearance, but needed to be administered via subcutaneous injection. The ribavirin component, administered orally, was necessary for a sustained virological response (SVR), defined as no detectable virus by polymerase chain reaction, 12 weeks after the end of treatment.

The initial interferon plus ribavirin regimen provided an overall SVR of approximately 30% (some HCV genotypes as high as 40%), with three times weekly dosing. Tolerance of the medications prevented more frequent dosing that might have improved the efficacy of this medication combination.

In 2008, pegylated interferon was approved for use in children chronically infected with HCV. Pegylated interferon takes the same basic interferon molecule and covalently attaches to it polyethylene glycol, making it harder for the body to clear the interferon; instead of the body clearing the interferon medication within 2 days, it was now being cleared in 5 to 6 days. Now interferon could be administered and last longer in the body, and with more even levels than seen when needing to redose every few days. Pegylated-interferon was dosed, again by subcutaneous injection, once per week. In combination with ribavirin, the introduction of pegylated-interferon increased the SVR rate to 50% to 80%, depending on the HCV genotype. Aside from the fact that the interferons needed to be delivered by subcutaneous injection for many months, there were a lot of side effects associated with these interferon plus ribavirin-based therapies, both that made the recipient feel ill, and that needed to be monitored for safety.

Although many were focused on the ability to give subcutaneous medications to children, pediatricians are relatively good at teaching families how to deliver subcutaneous shots at home. For the most part, we would initiate the therapy in our offices and teach the parents how to deliver the shot. Most parents would do that, so the treatment was actually delivered at home, and patients would come in for checkups. But the treatments were long – 6 months to a year – depending on which of the drugs were used. You were talking about either shots three times per week for interferon or once per week for pegylated interferon, for a long time.

Healio: How have DAAs changed treatment outcomes for pediatric patients with HCV?

Murray: DAAs were approved for pediatric use in 2017 – it was very recent. The approvals have occurred at a rapid-fire pace since 2017, as trials are completed and the drugs are approved by the FDA. This is all very recent history.

The ways in which outcomes have improved with the DAAs, compared with the earlier treatments, is dramatic. Patients have gone from at least 6 months with an injection that had many side effects, and resulted in a SVR of – at the best – 80%, to the DAAs, which are oral medications that are given for 8 to 12 weeks, have minimal side effects and result in a SVR of 97% to 100%. It is very hard to argue with that. It changed the face of treatment.

Healio: What barriers prevent children with HCV from receiving treatment with DAAs?

Murray: There are two relevant barriers. The one that is probably the biggest, although it is improving, is financial. These medications were prohibitively expensive. The costs for these medications are now coming down and there are increasingly generics coming on the market that further lower the cost and make them more available. Some insurance companies still resist covering these medications for children but, as time is going on and more DAAs are approved for use in children, it’s becoming easier and easier to get approval for children.

The other barrier is the age group for which DAAs are approved. The youngest age group for which some of the DAAs are approved is 3 years. More of the DAAs are approved in children aged 12 years or older because that’s the age group in which the earlier studies are done; as new studies are completed in the younger children showing safety and efficacy, approval follows. Waiting until age 3 years to treat children with chronic HCV is not a substantial problem for most individuals, as the liver effects of the infection progress slowly. Further, children with chronic HCV are typically without any symptoms, and there may be a spontaneous clearance of the virus (as high as 50% in some series) in the first year anyway, but certainly there is anxiety for the parents.

It is the opinion of most pediatric hepatologists that, if a child is infected with HCV, they should be treated — and, therefore, we should be screening for this infection. That is not currently the recommendation, however. The United States Preventive Services Task Force rendered an opinion in March 2020 that recommends screening for hepatitis C in adults aged 18 to 79 years. It is my opinion that we should be screening individuals below the age of 18 years because we have available treatments now.

Healio: How can clinicians help increase access to this treatment option?

Murray: Because we do not routinely screen for the disease in children, those caring for children have to have a relatively high index of suspicion for HCV. Most of the time, HCV in children — and adults — is asymptomatic, so it will remain undetected unless someone tests for it. We need to think of it, and we need to ask the family about any potential risk factors. Most children who are HCV-positive have gotten it perinatally – because the mother is HCV-positive. Asking questions about the mother’s history that may increase her risk for infection and, therefore, that of the child, is very important. When a child is found to be HCV-positive, it is then important to refer that child to a pediatric hepatologist so that appropriate counseling, and treatment, can be provided.

I also want to mention, and commend, the rapidity with which research leading to DAA approval in children was done. Generally, therapies become available for children after they are approved in adults. It is done this way for a lot of good reasons; as new drugs come on the market, physicians, pharmaceutical companies and the public are worried about conducting a trial in children before they know that the drug is safe in adults because it may have potential side effects. There is a lot to be said for that. Generally, however, the timeline has been much longer with prior medications; it is multiple, multiple years between approval in adults and approval in children, if the approval in children ever comes. In the case of DAAS, the pharmaceutical companies and the investigators really need to be commended for having shortened that timeline substantially for pediatric patients. It was still a couple of years, but it is only a couple of years — compared with 5 to 10 or longer for other agents. That is great. This might serve as a model for other medical investigations in children to really avail children of the best treatments out there.