Hepatitis prevention in children begins with immunization

Hepatitis B and C virus infection remain important causes of pediatric liver disease. It is estimated that 60% of adults who have hepatitis C are unaware of their infection, leaving their children vulnerable to infection.

According to Jean P. Molleston, MD, of the department of pediatrics, gastroenterology, hepatology and nutrition at Indiana University School of Medicine/Riley Hospital for Children in Indianapolis, close longitudinal follow-up of these usually asymptomatic children is important to emphasize to parents because these diseases can “progress to chronic liver disease over decades, leading to cirrhosis and high rates of hepatocellular carcinoma.”

In the United States, 0.5% of the population has HBV and 2% to 4% has HCV.

In a presentation at the 2012 Pediatric Academic Societies’ (PAS) Annual Meeting in Boston, Molleston and other experts discussed transmission of hepatitis in the pediatric population, provided tips for managing these patients, and discussed emerging therapies that may provide new hope for this at-risk population.

Hepatitis transmission

Melvin B. Heyman, MD, MPH, chief of pediatric gastroenterology, hepatology and nutrition at University of California at San Francisco Benioff Children’s Hospital, who specializes in treating children with inflammatory bowel disease, moderated the PAS session and spoke with Infectious Diseases in Children after the meeting. He said the first step in evaluating a child for hepatitis A or B is assessing antibody formation or presence of antigens.

“As far as hepatitis A is concerned, emphasizing the importance of immunization is important because it is very easy to prevent this illness through vaccination,” Heyman said.

According to data presented by Molleston, infants can acquire HBV through vertical transmission; many US children with HBV are adopted from other countries where the infection is endemic.

There is a 70% to 90% chance of vertical transmission if the mother is HBV e-antigen positive, according to Molleston. She also said a combination of HBV vaccination and immunoglobulin decreases a newborn’s chance of infection by 90%; cesarean section is not recommended. The infant’s surface antigen and surface antibody should be checked between 9 and 15 months of age to confirm successful immunization and protection.

Another potential area of exposure is a household member with HBV because it is “very stable on environmental surfaces for up to a week,” and infection is possible even when no obvious blood is present, Molleston said.

Children adopted from HBV-endemic regions, such as the Far East, parts of the Middle East, parts of Alaska, the Amazon Basin and sub-Saharan Africa, are at increased risk for HBV and should be screened, according to Molleston.

Management of hepatitis pediatric infection

Kathleen B. Schwarz, MD, professor of pediatrics and director of the Pediatric Liver Center at The Johns Hopkins Hospital in Baltimore, said it is important to manage HBV in mothers known to be positive during the third trimester of pregnancy. Although immunoglobulin and vaccination offer 90% to 95% protection, in mothers who have greater than a 10⁶ HBV DNA load, there is a high rate of vaccination failure.

Schwarz said management of children with HBV should be guided by results of e-antigen and alanine aminotransferase (ALT) testing. If ALT is less than one time the upper limit of normal, the child can be followed every 3 to 6 months, and e-antigen every 6 to 12 months. If the ALT rises, Schwarz recommends following the child every 3 to 6 months, but the e-antigen should be checked more often. Clinicians should consider liver biopsy if there is persistent ALT elevation, and treatment should be considered as indicated.

“If the child’s ALT levels are high, he or she should be followed much more frequently. It is possible the child may be actually undergoing spontaneous e-seroconversion — so treatment should not be rushed without additional ALT values. Treatment should begin if there is persistent HBV. A liver biopsy is optional but useful if child is jaundiced or decompensated, or if there is fulminant HBV with coagulopathy and encephalopathy — then prompt transplant indicated. Jaundice requires immediate treatment,” Schwarz said.

If the child is e-antigen negative and has an ALT greater than two times the upper limit of normal, with HBV greater than 20,000 IU/mL, the condition should be treated, but a liver biopsy is optional. If ALT is a little lower and DNA is less than 20,000 IU/mL, the child could be followed closely with ALT and HBV DNA, and a biopsy should be considered if persistent.

The treatment of HBV before DNA integration results in a better response and a decrease in the lifetime risk for chronic active HBV and cancer, according to Schwarz. Nucleosides and nucleotides do not eliminate the closed circular DNA, so there is a risk of flare after stopping treatment drugs.

Schwarz said the main endpoints of clinical trials involving pediatric patients with hepatitis include the loss of surface antigen and surface seroconversion; e-antigen seroconversion normalizing ALT; reducing DNA and eliminating closed circular DNA; and a reduction of morbidity and mortality.

Interferon-alpha was the first drug approved for children aged 1 year and older. Lamivudine (Epivir, ViiV Healthcare) was the first nucleoside analogue to be approved for children aged 2 years and older; however, chronic administration has resulted in a resistance rate of 70% in 3 years. Adefovir (Hepsera, Gilead Sciences) is not effective in children aged younger than 12 years. Entecavir (Baraclude, Bristol-Myers Squibb) can only be used in children aged older than 16 years, but a multinational trial for those aged at least 2 years is under way; telbivudine (Tyzeka, Novartis), for those aged at least 16 years, carries a neurotoxicity worry. Tenofovir can be used in children aged older than 12 years, but has a negative effect on bone metabolism. A pegylated interferon trial is about to be launched for children aged 3 years and older.

Lamivudine has very high drug resistance rates; Schwartz reported 20% per year, and up to 70% in 3 years. It also is rare to lose surface antigens with lamivudine. For the virologic endpoint, e-seroconversion DNA loss was only 20% to 25%. The entecavir trial is going well and is awaiting results of a phase 3 trial, according to Schwarz.

Consider HCV genotype

Philip Rosenthal, MD, professor of pediatrics and surgery at University of California, San Francisco Medical Center (UCSFMC), said clinicians should use guidance from the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition guidelines for treatment and management of children with HCV.

Molleston said that infected children are most likely to have acquired HCV through vertical transmission. The rate of vertical transmission is about 5%.

“There is a greater risk of transmission if there is a prolonged rupture or if internal fetal heart tone monitoring is used, if the mother has a high viral load or if a mother is also infected with HIV,” she said. However, there is very low risk of HCV transmission through breast-feeding.

Therapies readily accepted by most hepatologists are designed for patients aged older than 18 years, and all pediatric patients need individualized treatment. There are several considerations in treatment of pediatric HCV. The first is age. There is no FDA-approved treatment for HCV for children aged younger than 3 years. Next, HCV genotype should be considered. The degree of liver injury should be considered as well — the practitioner should ensure there would be no decompensation. Rosenthal said a liver biopsy is helpful in this circumstance.

Contraindications to treatment therapy are uncontrolled depressive illness, psychosis and epilepsy because there have been reports of suicide; untreated anemia hemoglobins less than 12 g/dL; renal, heart or lung transplant due to the risk of rejection; autoimmune hepatitis — or other autoimmune conditions that can be exacerbated by interferon/pegylated interferon; untreated thyroid disease; severe concurrent medical disease; or known sensitivity to drugs used to treat HCV.

The FDA has approved pegylated interferon and ribavirin as standards of care for children aged older than 3 years who are infected with all genotypes. The genotype dictates length of treatment — types 1 or 4 need 48 weeks of treatment; types 2 or 3 need 24 weeks.

Rosenthal, who is also medical director of the Pediatric Liver Transplant Program and director of pediatric hepatology at UCSFMC, said trials will soon be launched for use of telaprevir (Incivek, Vertex) and boceprevir (Victrelis, Merck) in children with HCV, but he does not recommend their use in practice until more information is available. Telaprevir and boceprevir have a 75% sustained viral response rate in treatment-naive adults that, according to Rajesh T. Gandhi, MD, division of infectious diseases at Massachusetts General Hospital, “is a major advance that promises to revolutionize HCV treatment.”

Both drugs were used combined with peginterferon and ribavirin, and they delivered significant results in adults. However, there is the risk of drug resistance and side effects, which include anemia for boceprevir and rash, anemia and nausea for telaprevir.

Rosenthal reported factors that predict response to treatment. These included sex (girls respond better to treatment), age, race (blacks have the worst response to peginterferon and ribavirin), weight and insulin resistance. Patients who are vitamin D deficient also do not respond well to treatment. Patients with severe depression, decompensated fibrosis or cirrhosis, and HIV coinfection also may not respond well to treatment. Rosenthal said virus factors also predict treatment response. A high viral load is more difficult to treat.

Impact of genotypes

Genotypes also indicate success. Rosenthal said the overall genotype 1 response is lower than genotypes 2 and 3 for pegylated interferon treatment. Response rates are in the 50% range regardless of genotype, and genotype trumps viral load for treatment purposes. He also noted that IL28B polymorphism — encoded interferon-lambda-3 — correlates with interferon response.

For the favorable genotype CC, Rosenthal said response is in the 80% range, and contrasted that with the unfavorable genotype TT, which has only a 20% to 30% response range. The length of time treatment is needed is less in genotypes 2 and 3.

According to Rosenthal, an NIH-funded drug study concluded that pegylated interferon alpha-2a with ribavirin has been approved for use in children with HCV, and drugs must be used in combination to be effective.

Adverse events associated with pegylated interferon with ribavirin include fever and influenza-like illness, which is highly common and transient; headaches, which are common; myalgias and arthralgias; vomiting; decreased weight (but “most patients have catch-up growth”); neutropenia and anemia, which must be closely monitored; injection site reactions; and alopecia, which is unusual.

When monitoring virologic response, Rosenthal offered these suggestions: “At week 4, rapid virologic response would be ideal to have undetectable serum HCV RNA less than 50 IU/mL. At week 12, early virologic response is undetectable or not greater than two.”

A log drop in HCV RNA is the best predictor of sustained virologic response. At week 24 or 48, end of treatment — the hope is to have undetectable serum HCV RNA. Finally, Rosenthal said at weeks 48 or 72, the hope is that sustained virologic response is undetectable, adding that practitioners should monitor patients’ CBC and neutrophil counts, conduct liver function tests and check glucose levels. A thyroid screen is also useful.

After successful trials in adults of telaprevir and boceprevir, it is hoped that the present trials of these drugs will have the same strong responses in children. Until further treatment options are available, the CDC’s Advisory Committee on Immunization Practices recommends that all children receive the complete hepatitis B vaccination series, with the first dose in the series given at birth. Children and adolescents who have not been previously immunized should also receive the series. There is currently no vaccination for hepatitis C.

Due to the risk of sustained illness and liver injury, parents should be educated about the benefits of HAV and HBV vaccination to prevent infection, especially among uninfected household contacts of children with hepatitis, Molleston said. – by Colleen Zacharyczuk

References:

Heyman MB. Session 1110: Hepatitis B and C: Prevention and Treatment – 2012. Presented at: the 2012 PAS Annual Meeting; April 28-May 1, 2012; Boston. Visit www.cdc.gov/hepatitis/HBV/VaccChildren.htm.

Disclosures:

Dr. Gandhi receives grant funding from Tibotec and has served on a scientific advisory board for Gilead. Dr. Heyman receives NIH funding and research grants from Centocor Ortho Biotech (now Janssen Biotech), Procter & Gamble and Shire. Dr. Molleston receives research funding from Roche, Schering, Bristol-Myers Squibb, and Vertex. Dr. Rosenthal serves as a consultant for Roche and Gilead and receiving research support from Roche. He also receives grant support from Bristol-Myers Squibb and Vertex. Dr. Schwarz receives grant funding from National Institute of Diabetes and Digestive and Kidney Diseases, Roche/Genentech, Bristol-Myers Squibb and Vertex, and she also serves as a consultant for Novartis.

Is routine hepatitis A vaccination effective in reducing outbreaks among children?

Vaccination has been effective, but we must remain vigilant.

Prior to the routine vaccination recommendation, there were recommendations for vaccination among only those in areas where hepatitis A was prevalent. What we found when we did that was that in those areas, the rate of hepatitis A dropped down to the levels where it was not prevalent, so then the question became, “What happens if we expand the recommendations to include all children?” What we found is dramatic decreases across the board, and a drop in pocketed outbreaks such as you see, often at this time of year, when there is food or waterborne exposure.

The important message is we need to remain vigilant for hepatitis A, even with routine vaccination, especially in the case if there has been contact with an adult with jaundice. It is really important to remain vigilant, particularly in children, because often the signs we associate with hepatitis are not obvious, and they could be in contact with and infect a large number of people before we are aware that there is another outbreak.

Joseph Domachowske, MD, professor of Pediatrics, State University of New York Upstate Medical University, Syracuse, N.Y. Disclosure: Dr. Domachowske reports no relevant financial disclosures.

Thanks to vaccination, rates of infection are low and complications are rare.

The hepatitis A vaccine has been stunningly successful, dropping the rate about 99% since the introduction of targeted vaccination programs. The health community noted immediate drops in prevalence when the targeted interventions were first directed among high-risk children (Native Americans and immigrants crossing the border of the southern United States), and now that it has been recommended for all children in the United States, and children who are traveling, the success has been undeniable.

At this time of year, pediatricians would want to remain aware of the signs of hepatitis A, though, even in light of vaccination efforts. If a child presented and was clinically jaundiced, or if the child was sicker than expected and had a gastrointestinal illness, a liver enzyme test would help determine the causative agent. Once you know that the diagnosis is hepatitis, you’d then consider a workup for viral hepatitis, including hepatitis A. Treatment is mainly symptomatic, and thankfully, severe complications from the infection are rare.

If you think you have an outbreak going on, you would want to report that, and help find the source.

Nicholas John Bennett, MB, BCh, PhD, Assistant Professor in Pediatrics, Division of Infectious Diseases, Connecticut Children’s Medical Center, Hartford, Conn. Disclosure: Dr. Bennett reports no relevant financial disclosures.