DAAs change treatment landscape for children with HCV

From 2013 through 2016, an estimated 2.4 million adults in the United States had a current hepatitis C virus infection. A study published in The American Journal of Public Health reported that the infection rate increased more than twofold between 2004 and 2014 as a result of the opioid epidemic.

Although only about 5% of infants born to women with HCV will develop infection, 11 million children worldwide have been infected with HCV, including 5 million younger than age 19 years who have active HCV. Between 25% and 50% of these children may spontaneously clear their HCV infection by age 3 years, according to the Infectious Diseases Society of America and the American Association for the Study of Liver Disease. The remainder go on to develop chronic infection, which can result in cirrhosis and liver cancer.

In 2016, WHO announced a global goal to eliminate viral hepatitis by 2030. Treating and curing children and teens remains a critical part of reaching this goal. Historically, this population has had limited options for treatment. Direct-acting antiviral agents (DAAs) were first approved for use in adults in 2013. Subsequent DAA approvals for children as young as age 3 years and a multitude of clinical trials have sparked hope for an upcoming generation who can be “cured” of their HCV infection.

“The more patients we can treat and cure, the closer we are to obtaining that goal,” Philip Rosenthal, MD, professor of pediatrics and surgery and director of pediatric hepatology at the University of California, San Francisco, said in an interview.

Infectious Diseases in Children spoke with experts about the latest drug approvals, how they could change the care of children with HCV and how that could affect elimination efforts in the next decade.

Previous standard of care

Historically, many children with HCV were previously treated with a combination of pegylated interferon and ribavirin. Children aged 3 to 18 years who participated in a clinical trial of the combination in 2011 had better success with the drug compared with adults.

Kathleen B. Schwarz, MD, professor of pediatrics emerita at Johns Hopkins University School of Medicine and an associate physician diplomate at the University of California, San Diego School of Medicine, and colleagues reported that 53% of children had nondetectable HCV RNA at least 24 weeks after treatment cessation.

“We probably shouldn’t entirely forget about the efficacy of that combination therapy in terms of eradicating hepatitis C in children around the world because the clearance rates in our trial and others were up to 80%, particularly in children with genotype non-1 with a low viral load of 600,000,” Schwarz said.

However, this treatment combination led to serious side effects. One study published in Medicine found that 72.8% of children treated with the therapy experienced nausea and/or anorexia, and 62.4% had influenza-like symptoms. Other adverse events included neuropsychiatric side effects such as impaired concentration, depression, irritability and insomnia (44.9%) and anemia (18%).

Daniel H. Leung, MD, FAASLD, associate professor of pediatrics at Baylor College of Medicine and director of pediatric hepatology and liver transplant medicine at Texas Children’s Hospital, told Infectious Diseases in Children that many children and adolescents with HCV did not tolerate pegylated interferon and ribavirin, which affected compliance.

“Physicians have long been seeking a treatment for HCV that is completely oral, well-tolerated and easily administered with minimal side effects,” he said.

After the approval of Sovaldi (sofosbuvir, Gilead Sciences) and the now-discontinued Olysio (simeprevir, Janssen Pharmaceuticals) in 2013, at least one DAA was approved every year until 2017. These included Harvoni (ledipasvir/sofosbuvir, Gilead Sciences) and Mavyret (glecaprevir/pibrentasvir, AbbVie Pharmaceuticals).

Although many options became available for adults, the first approvals for adolescents occurred only in 2017, beginning with sofosbuvir for genotypes 2 and 3 and ledipasvir/sofosbuvir for genotypes 1, 4, 5 and 6 in adolescents aged 12 years or older. The FDA approved glecaprevir/pibrentasvir for the same age groups earlier this year. In 2019, ledipasvir/sofosbuvir and sofosbuvir/ribavirin were approved for children aged 3 years and older.

Schwarz said the price of DAAs — up to $84,000 — prevented many children and teens from receiving the medications off-label before their approval in these age groups, so those who could not receive DAAs or enroll in a clinical trial received pegylated interferon and ribavirin on a case-by-case basis. The current cost of the DAAs approved for children in the U.S. is around $20,000 per course of treatment, according to Schwarz.

A new era of treatment

This year, results of several studies were published in Hepatology, including a phase 2, multicenter, open-label study assessing the safety and efficacy of sofosbuvir plus ribavirin in children aged 3 to 11 years with HCV genotypes 2 or 3. Rosenthal, who was the lead author on the study, and colleagues assessed the safety and efficacy of this treatment option for 12 weeks in those with genotype 2 and for 24 weeks in those with genotype 3.

Of the 54 children included in the study, all but one attained a sustained virologic response 12 weeks after treatment completion (SVR12). A 4-year-old child who did not achieve SVR12 discontinued treatment after 3 days because of the drug’s taste. Adverse events for participants aged 6 years or older most commonly involved vomiting (32%) and headache (29%), whereas patients aged 3 to 5 years most frequently reported vomiting (46%) and diarrhea (39%).

A second phase 2, multicenter, open-label study on the safety and efficacy of ledipasvir/sofosbuvir in children aged 3 to 5 years was also published this year by Schwarz and colleagues. Participants received weight-based dosings of the medication in granule form for 12 weeks. All 34 children included in the study had chronic HCV infection with genotype 1 or 4.

Nearly all participants (97%) achieved SVR12. Again, the one child who did not complete treatment discontinued use after 5 days because of the drug’s taste. Although no children experienced serious adverse events, some adverse events were reported, including vomiting (24%), cough (21%) and pyrexia (21%). The study served as the basis for the recent FDA approval for this treatment.

The FDA recently changed the indications for sofosbuvir as well as ledipasvir and sofosbuvir to include new dosing for children aged 3 to 12 years, expanding the options available to younger children with HCV.

FDA approvals for DAA use in adolescents have followed at a blistering speed similar to adults, Leung said.

“In fact, with the advent of next-generation DAA combinations, highly effective regimens in adolescents, including Viekira Pak (ombitasvir/paritaprevir/ritonavir with dasabuvir, AbbVie), were voluntarily discontinued in the U.S. by AbbVie in favor of glecaprevir/pibrentasvir despite a 100% SVR12 in children older than age 12 years with genotypes 1 and 4,” said Leung.

Several studies and trials have supported the safety and efficacy of DAAs in adolescents. In a phase 2, multicenter, open-label study published in 2017, Rosenthal, Schwarz and colleagues further examined the effects of ledipasvir/sofosbuvir in adolescents aged 12 to 17 years infected with HCV genotype 1. In the study, 98% of participants achieved SVR12, and the researchers reported no treatment failures. Those who did not achieve SVR12 (n = 3) were lost to follow-up during or after treatment.

Part one of the phase 3 DORA trial evaluating glecaprevir/pibrentasvir in pediatric and adolescent patients led to the drug’s approval for treatment for any HCV genotype in children over 12 years of age this year. Participants received the adult regimen once daily for 8 to 16 weeks. All 47 adolescents reached SVR12, and no virologic failures or relapses occurred. Additionally, no adverse events caused discontinuation, and no serious adverse events occurred, the researchers reported.

Currently, 14 trials assessing HCV antivirals are recruiting, enrolling by invitation, active or completed in the U.S. Leung said that these medications, when approved and accessible for children, can “completely change the trajectory of a child’s life.”

“HCV is often a generational disease because it’s a silent liver disease,” he said. “Families don’t know they have it, and then they have children and it gets passed on. The real game changer is that if and when we can treat children and cure them of their hepatitis C before they become of childbearing age, we can break the family cycle of the disease and remove that risk for cirrhosis and liver cancer.”

However, Claudette Poole, MD, assistant professor of pediatrics at the University of Alabama at Birmingham, suggested that access to these drugs for children and adolescents may increase the rate in which they are screened for the virus.

“I think we will be more aggressive in terms of screening and diagnosing children with hepatitis C so that we can diagnose them earlier,” she said. “The current practice is to not aggressively screen, and it’s not part of routine obstetrics screening. I think that will change.”

The IDSA and AASLD currently recommend the following for all children perinatally exposed to or infected with HCV:

• All children born to women with HCV should be tested for infection at or after age 18 months.
• Infants who test anti-HCV positive after age 18 months should be tested with HCV-RNA assays at age 3 years and older to confirm chronic HCV infection.
• Treatment with DAAs is recommended so long as they are age 3 years or older, independent of disease severity.

Barriers to use

A recent analysis of DAA cost and access in the U.S. called the medication options “among the most expensive oral medications in history.” According to the authors, the wholesale acquisition price for a 12-week course of sofosbuvir was $84,000, although production costs between $68 and $136. They suggested that patients may pay significantly less after contracts, rebates and discounts.

Even so, many adults, and now children, struggle to access these medications because of requirements made by insurance companies and Medicaid programs, which differ between states and insurance companies. Some may require liver biopsy or noninvasive elastography, as well as a certain stage of fibrosis before they agree to cover these DAAs.

Rosenthal said that, because of the cost, it is “highly unlikely” that DAAs are or will be used off-label for the pediatric population. He has had difficulties in the past getting them approved in adolescents for whom they are indicated.

According to Rosenthal, it could be more beneficial and cost-effective to treat children while they are younger.

“My argument for treating kids would be that if they have this disease, the drug should be given at the youngest age possible,” Rosenthal explained. “If the child still has hepatitis C, I see little harm in treating that child with very effective and safe drugs. Plus, the dosing is smaller, so the actual quantity of drugs per dose is less. I see no downside in treating any child, no matter what their degree of disease or injury in the liver is with this drug.”

Leung has also experienced difficulties in the past gaining access to these drugs for his patients.

“Unfortunately, in the state of Texas, we encounter a lot of hurdles that require several prior authorization letters, peer-to-peer conversations with medical directors, just to get them the medicine that’s already been approved for their exact disease,” Leung said.

Rosenthal agreed that these requirements make it difficult to prescribe DAAs.

“If we were to treat every person in an HMO with these drugs, in 1 months’ time, hospitals would go bankrupt,” he said. “So, they put obstacles in the way of who can gain access to the drug.”

However, Schwarz said a shift in prescribing could potentially occur in the future if liver biopsies are not needed before treatment.

“We used to be very territorial, which got ridiculous,” she said. “One of the reasons we felt strongly in the hepatology community that we should be the treaters was that we usually had to do liver biopsies to assess whether there was disease. There was some spontaneous viral clearance, especially in the interferon era. Interferon can be a miserable treatment, so we generally did a liver biopsy to help us understand the extent of disease. Now, given that the agents are so effective and well-tolerated, most of us don’t think we need a liver biopsy anymore.”

‘Purveyors of hope’

A child’s diagnosis of HCV infection may raise many questions for parents and caregivers, as well as affect their quality of life. In a case series study published in The Journal of Pediatric Nursing, researchers reported that the baseline distress levels of families and children with HCV indicated a poorer quality of life. Further, caregivers reported higher levels of stress, and family function was impaired. The researchers suggested that caregivers may require support during their child’s treatment, and that the effect of intensive treatments on the family unit should be monitored.

With the initial diagnosis, Poole “strongly recommends” that families be referred to a gastroenterologist, hepatologist or infectious disease specialist. Once referred, she said, families may benefit from discussion of treatment options.

Leung noted that counseling of families and children should be individualized based on the child’s age, the family’s wishes and how much the patient or family is willing to disclose to the physician and other people.

“We do tell families that they are not mandated to disclose their diagnosis to teachers or coaches,” he said. “That level of disclosure is built on trust, but we do counsel them on the importance of universal precautions like using gloves and bleach. We counsel them to never share needles or toothbrushes. For adolescents, we also provide a lot of counsel on preventing obesity, avoiding alcohol and binge drinking because we know that they can really cause significant problems in the background of hepatitis C.”

One of the most common questions Rosenthal is asked by parents is if their child can become infected again. He said it is important to stress that children with HCV may become re-infected if they use IV drugs and engage in other behaviors that put them at risk for infection.

According to Schwarz, counseling families about HCV in the interferon era was “fairly dramatic” because physicians had to convince parents that the benefits of a painful therapy outweighed the side effects and protected them from negative long-term outcomes like severe liver disease and hepatocellular carcinoma.

Now, she said, there is no need for physicians to be dramatic in their descriptions of outcomes because of the emergence of DAAs for adolescents and children.

“Probably without thinking about it, I changed my tune,” Schwarz said. “Many families already know about the outcome of hepatitis C in adults. Many families have had someone in the family die of hepatitis C. Now, we’ve become much more purveyors of hope. My research coordinator and I love doing DAA trials because every single family at the end cries because they’re so happy. It’s really very satisfying.”

Reducing the burden

WHO’s global hepatitis elimination goal involves reducing the incidence of hepatitis from 6 million to 10 million cases to 900,000 and reducing the annual number of hepatitis-related deaths from 1.4 million to 500,000. According to Yasir Waheed, PhD, and colleagues, only 3 million cases of HCV were treated between 2015 and 2016. Without commitment from major global donors, they wrote, funding for hepatitis control programs in low- and middle-income countries will continue to be limited.

“Hepatitis elimination needs strong financial and political commitment, support from civil societies and support from pharmaceutical and medical companies around the globe,” they wrote.

Part of this issue, they said, is that only 11% of people with hepatitis B and/or C are diagnosed. The CDC currently recommends that pregnant women in the U.S. should be screened for HCV only if they have risk factors for infection, and the U.S. Preventive Services Task Force issued draft guidance just this year which recommended HCV screening all adults aged 18 to 79 years, including pregnant women.

Findings from a study published in Pediatrics suggested that only 30% of infants born to mothers with HCV between 2006 and 2014 were screened for infection. Only 31% of these children received well-child services.

“It doesn’t matter if you have DAAs available if you don’t detect the majority of children with viral hepatitis,” Schwarz said.

Poole agreed that in the U.S., screening is a major barrier to care for children with HCV, but she hopes that the approval of DAAs can spur more screening.

“It’s hard to come into care for something if you don’t know you have it,” she said. “The fact that these drugs are now available hopefully can change the conversation so that we do a better job of screening patients so they can get into care.”

Leung said that time is no longer the limiting factor in treating more children with DAAs.

“It used to be that there would be a 5- to 8-year lag after adult approval before a clinical trial even got started,” he said. “These days, pediatric clinical trials are happening at such a rapid pace. Even FDA approvals of pediatric indications are happening in as little as 20 months after adult approval.”

Rosenthal said that to improve the care of children with HCV, more approvals are needed for younger ages so insurance companies will have to allow patients access to the drugs.

In order to get these approvals, Schwarz said researchers and manufacturers need to focus on both controlled and uncontrolled trials so that children have a chance to be cured from HCV with safe and effective medications.

“Hepatitis C was discovered only in 1989,” Rosenthal said. “Now, it can be cured. There are few diseases in medical history that have gone from discovery to cure in such a short period of time. That’s a great thing.” – by Katherine Bortz

• References:
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• For more information:
• Daniel H. Leung, MD, FAASLD, can be reached at dhleung@texaschildrens.org.
• Claudette Poole, MD, can be reached through Savannah Koplon: skoplon@uab.edu.
• Philip Rosenthal, MD, can be reached at prosenth@ucsf.edu.
• Kathleen B. Schwarz, MD, can be reached at kschwarz@jhmi.edu.

Disclosures: Leung reports consulting for Merck and receiving grant and/or research support from Abbvie, Gilead and the Cystic Fibrosis Foundation. Poole reports no relevant financial disclosures. Rosenthal reports receiving research support from Gilead, Abbvie and Merck. Schwarz reports consulting for and receiving research funding from Gilead and Roche/Genentech. She also reports receiving research funding from Bristol-Myers Squibb and consulting for UpToDate.