51成人动漫

Expert Critique

FROM THE ASCO Reading Room

Chioma Ihunnah, MD, MPH Gastroenterology & Hepatology Fellow University of Connecticut Health Center

Chronic hepatitis C virus infection (CHC) is generally regarded as a disease of adulthood. Surprisingly, however, approximately 23,000 to 46,000 children in the United States are infected with CHC. A majority of these patients contracted the disease via vertical transmission.

While many adults with CHC have benefited from highly effective direct acting-antiviral (DAA) oral treatments, children have not enjoyed the same benefits. Data has been limited on the safety and efficacy of DAAs in children. Prior to April 2017, the FDA-approved medications for CHC in pediatric patients focused on interferon-alpha, pegylated interferon-alpha (2a and 2b), and ribavirin. Data presented at the European Association for the Study of the Liver (EASL)/International Liver Congress (ILC) meeting in 2016, as well as published in Hepatology by Balistreri and colleagues, led to the recent changes. In April 2017, the FDA approved the use of sofosbuvir with ribavirin and the combination of sofosbuvir/ledipasvir in children ages 12 to 17. Dr. Karen Murray from the University of Washington School of Medicine and Seattle Children鈥檚 Hospital presented data on the use of a ledipasvir and sofosbuvir regimen for children ages 6 to 11 at EASL/ILC in April 2017. Studies of DAA use for chronic hepatitis C are ongoing in pediatric populations.

Full Critique

While hepatitis C virus (HCV) is uncommon in children and adolescents, some doctors are still faced with figuring out the best ways to deal with it. According to the , about 0.15% of children ages 6 to 11, and 0.4% of those ages 12 to 19, are estimated to be infected, which means that between 23,000 and 46,000 children in the U.S. have the virus.

But the actual numbers of children and youth infected remain uncertain, because screening is not routinely conducted in this population. Plus, infected children may remain symptomless for years.

The rates, numbers, and patterns of disease vary across the country, but one physician interviewed by 51成人动漫 said he has seen an upswing in his practice -- something he attributes to an epidemic of heroin use in the Midwest states, including where he is located in Ohio.

"We are seeing a significant increase in hepatitis C in children and adolescents; we see two to three new cases per week," said William Balistreri, MD, director emeritus of the Pediatric Liver Care Center of the Cincinnati Children's Hospital. Pediatric HCV cases are often associated with HCV heroin-using women of childbearing age, and adolescents who use IV drugs or who have high-risk sexual behaviors.

If a woman has HCV infection during pregnancy, there is a 1 in 20 chance that her baby will acquire HCV through perinatal or vertical transmission. But infants whose mothers have higher viral loads have an increasing risk of infection, he said.

A key to recognizing some of these patients would be to screen infants born to mothers who are IV-drug abusers, babies who are born with drug-abuse withdrawal symptoms, and adolescents who may be abusing drugs, he said.

With children in North America where HCV rates are very low, general testing programs are generally not considered -- except for children immigrating from countries where HCV prevalence is high. But in developing countries such as Pakistan and Egypt, where rates are higher due to unsafe medical procedures as well as other routes of exposure, there is a need for more widespread testing, said Naveed Janjua, PhD, of the BC Hepatitis Services at the in Vancouver.

According to Mel Krajden, MD, BCCCDC's director, the rate of HCV among tested women is declining overall -- taking into account that women born after the baby-boom generation generally have lower rates of HCV.

But what should one do with the pediatric population and pregnant women with HCV? When it comes to moms-to-be who have HCV, there is the problem that the safety of direct-acting agents (DAAs) has not been tested during pregnancy.

"If you have a pregnant woman now, you would probably not treat her, because you don't know about the safety of the drug, and there is a low overall risk of transmitting the virus to the child," Krajden said in an interview. "If you had a woman who is planning to become pregnant and is hep-C positive, then you could justify treating her."

Information from the ALF states that about 40% of infants infected through vertical transmission spontaneously clear the disease by 2 years of age, with some reports showing that some children clear the virus up to age 7. As for children who remain chronically infected from birth, most have mild liver disease, with up to 80% having minimal to no liver scarring by age 18.

On the other hand, a reported 20% to 25% have more aggressive disease and can develop advanced scarring cirrhosis by 8 years of age, according to the ALF. Adolescents who acquire the disease have a pattern of disease and outcome similar to that of adults.

Most children do not exhibit symptoms of HCV, but those in high-risk situations should be tested, Balistreri said. With a positive diagnosis, the steps to take are (1) to educate the child (if old enough) and parents about the short-term and long-term risks of the disease and how progression might occur; and (2) to determine the status and severity of the disease and the risk and benefits of approved treatment strategies.

"Currently, the only approved therapy for children is the combination of pegylated interferon -- alpha-2a or alpha-2b -- given with ribavirin." Results from the show that 50% of treated children had good durability of sustained virological response (SVR) from treatment, especially in those with a favorable genotype.

"This treatment entails a difficult course of weekly injections," Balistreri noted. "Because those treatment regimens have significant adverse effects, I'm not sure how broadly they are being used."

However, approval of some DAAs for the pediatric population may be around the corner, and would be a game-changer: "I think most people would agree that when we have approval of all oral, interferon-free (and ribavirin-free), safe and effective drugs, treatment should not be withheld until the child develops advanced disease."

In fact, a recent study by Balistreri and colleagues in , showed the DAA regimen of ledipasvir (LDV)-sofosbuvir (SOF) was highly effective in children and adolescents with chronic HCV genotype 1 infection. The study included 100 patients ages 12 to 17 who received a combination tablet of 90 mg of ledipasvir and 400 mg of sofosbuvir given once daily for 12 weeks. All but two subjects (who did not complete the study) achieved SVR at 12 weeks post-treatment.

An even more recent study -- Balistreri was also a co-author -- found that the treatment, in doses adjusted for use in children ages 6 to 11, resulted in SVR12 rates of 99% and was well tolerated. The open-label study included 90 children with genotypes 1, 3, or 4 at 31 sites in Australia, New Zealand, the U.K., and the U.S. and was presented in April 2017 at the .

All told, a total of 87 children received 12 weeks of treatment with LDV/SOF, one GT1 treatment-experienced cirrhotic patient was treated for 24 weeks, and two GT3 patients had LDV/SOF plus ribavirin for 24 weeks. At this point, the use of LDV and/or SOF for the treatment of HCV in children under age 12 and weighing less than 35 kg remains investigational.

In the meantime, doctors can fall back on use of the , published in 2012. The problem is they don't contain new information from the past few years.

Said Balistreri: "Since we don't have all the answers about this disease in children, I think pediatric patients with HCV with hepatitis C should be involved with a center where they could be enrolled in clinical trials and evaluated by a pediatric hepatologist who understands the issues."