What's New -- Part 2: Viral Hepatitis in Children

From Medscape Infectious Diseases > Expert Reviews and Commentary
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What's New -- Part 2: Viral Hepatitis in Children
Hepatitis C, D, E, and G in Children
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See Part One;  hepatitis A and B.
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Ravi Jhaveri, MD

Authors and Disclosures

Posted: 07/06/2011
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What Do You Need to Know About Hepatitis in Kids?

A 28-year-old woman, new to the community, presents to the pediatric clinic of a rural community health center with her almost 1-week-old infant. She reports that she has "chronic" hepatitis C but denies taking any current medications. She is uncertain if the obstetric provider who she saw several months ago performed any testing, but she is certain she was not tested at the hospital where she delivered.
What will you do?
Why are the hepatitis viruses considered together? They have little in common from a virology standpoint other than that they infect the same organ. In general, the symptoms result from the body's immune response, not infection itself. The key differences are:

• Transmission route;
• Incubation period;
• Clinical manifestations; and
• Availability of a vaccine.

This activity is a continuation of Part 1 which discussed hepatitis A and B.

Hepatitis C in Children

Hepatitis C virus (HCV) is a flavivirus that is remotely related to other flaviviruses including yellow fever and West Nile. This is a single–stranded, plus-sense RNA virus similar to hepatitis A virus (HAV) with a genome size of approximately 9500 base pairs that encodes for a single large polyprotein that is cleaved to form individual viral proteins. The virus displays marked heterogeneity around the world with 6 distinct genotypes. Additionally there are numerous quasispecies attributable to "hypervariable" regions of the envelope, which allow it to mutate to evade the host immune response. Every time the body creates antibodies, the virus mutates to escape those antibodies, allowing it be 1 step ahead of the immune system. This ability presents a major obstacle to the development of a vaccine.

Transmission of Hepatitis C
HCV is transmitted by contact with contaminated blood or blood-containing body fluids with intravenous drug use representing a major mode of transmission. Another major source of transmission was via blood transfusions prior to 1992, which was the first year when enough antigen was used to insure that a negative result was reliable.
The way that most children are infected is as a result of mother-to-child vertical transmission, which occurs in approximately 5%-10% of pregnancies in women infected with HCV. Fortunately, children usually resolve high levels of viremia at a much higher rate than adults for reasons that are incompletely understood. While maternal coinfection with HIV previously resulted in much higher rates of vertical transmission, treatment with highly active antiretroviral agents (HAART) during pregnancy has dramatically reduced these rates and transmission from mothers with comorbid HIV and HCV to their infants is now equivalent to the rate seen in mothers with mono-infection.
The virus could be transmitted via other routes but substantial proof is lacking. Breastfeeding has been examined in several studies, and it is unlikely that transmission occurs; breastfeeding by an HCV-positive mother is not contraindicated by the Centers for the Disease Control and Prevention (CDC). As is the case for most women, HCV-positive women should be encouraged to breastfeed.
While sexual transmission most likely does occur, it is not an efficient mode of transmission. Studies of HCV-discordant couples have documented transmission rates of 1%-3%. Even this number may be inflated as it is unclear if there were other independent risk factors, such as a blood transfusion or other medical procedure, in the noninfected partner.
Microscopic blood exposures, such as those that result from sharing razors or toothbrushes, have been documented as a source of transmission, as has contamination in endoscopy suites and during dental procedures. While there has been concern about transmission due to tattooing, modern day tattooing at a reputable tattoo art house that recognizes and abides by safety recommendations, such as equipment replacement guidelines, is unlikely to be the source of infection. The CDC does not consider tattooing to be a risk factor or a reason for HCV testing. However, tattoos done 20 or 30 years ago or those done in other countries, such as Vietnam during the war, are a major risk factor.

Clinical Manifestations of Hepatitis C
Acute subclinical hepatitis is most common after bloodborne exposure and symptoms, if they occur, are indolent and may not occur until months or years after infection. While fever, fatigue, and jaundice can occur, patients may not have any symptoms until they present with signs of end-stage liver disease. Most children with HCV will be asymptomatic.

Diagnostic Evaluation of Hepatitis C

Testing for HCV infection consists of checking for antibody to HCV (ie, immunoassay, enzyme immunoassay, or enhanced chemiluminescence immunoassay and, if recommended, a supplemental antibody test).^[1]

Click To Enlarge Table

Figure 1. Proposed HCV diagnostic evaluation.

The first question to ask when evaluating a child who is antibody positive for HCV is whether they are RNA positive? A positive HCV antibody test may indicate resolved infection, and if so, then there is no need for any further evaluation. It is reasonable to repeat the test an additional time in 6-12 months to insure both that the original result was not a laboratory error and that RNA is not present; families of children who are still negative can be reassured that infection is resolved, and there is no need for further monitoring.

Children who are RNA+ do require an assessment of liver function and genotype, however. Recent research has recognized a gene polymorphism within the interleukin 28B (IL28B) gene, which is associated with an interferon lambda. Patients with this genotype of European descent achieve a sustained virologic response (SVR) rate to therapy of approximately 80% as compared with a 50% SVR in patients of African descent with the same CC genotype.^[2] Both response rates however, are higher than those seen in patients with either a heterozygote TC or a homozygous TT genotype. These genetic polymorphisms, and their distribution throughout the world, explain a large part of the varying response to treatment in patients of differing ethnicity and race.

IL28B studies have not yet been completed in children, though early data from some retrospective studies indicate that the impact on response to therapy of this polymorphism in children is comparable to adults. Commercial tests are available, though there are no current recommendations for widespread testing.
A liver biopsy should be performed in patients with HCV genotype 1 as this is the only reliable methodology for determining degree of liver fibrosis.
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Figure 2. Proposed diagnostic algorithm for vertically exposed infants.
Infants born to HCV RNA- women do not require testing since the mother's RNA status indicates she is not viremic and thus cannot transmit virus to her infant. It is uncertain if testing should be conducted at birth in infants born to women who are HCV RNA+. This early testing not been shown to be an effective marker and may only reflect transient infection that will clear spontaneously. However, these parents often are very concerned and will benefit from an early referral to a gastroenterologist or hepatologist who is able to answer their questions about the natural history of HCV and review appropriate monitoring for their infants. .
An assessment for hepatitis C RNA and liver function at 1-2 years of age should be considered. Infants negative at that time warrant one additional assessment of RNA status and LFTs approximately 1 year later. Children negative at that time can be considered to have resolved their viremia. Infants who are positive at those 2 times are chronically infected and will require long-term follow-up with a specialist.
The long and the short of it is that children with HCV typically do well. Overall transmission is only 3%-5%, which means that approximately 95% of children will either never be infected or will resolve their infection spontaneously.

Management of Hepatitis C
The standard of care for treatment of HCV is pegylated interferon (Peg-IFN) and ribavirin. Following 48 weeks of therapy, the SVR is 40%-50% for genotype 1a/1b, which is the predominant genotype in the western hemisphere. An SVR of 80% can be achieved in patients with genotype 2 or 3, a minority genotype in the West, after only 24 weeks of therapy.

The importance of this dual therapy for children was established by the Pegylated Interferon +/- Ribavirin for Children With Hepatitis C (PED C) trial.^[3] This multicenter trial established that the addition of ribavirin to Peg-IFN resulted in 53% SVR as compared with 21% SVR following treatment with Peg-IFN and placebo.

There is an argument that all patients with IL28B genotype should be treated with a goal of viral eradication. However, it is still uncertain if that is the case, and the development of new agents in the future may affect the treatment paradigm. Children with a significant level of fibrosis should begin therapy immediately.

What's New With Hepatitis C?

The treatment paradigm for HCV is going to change significantly with the approval of 2 new protease inhibitors, telaprevir and boceprevir. Boceprevir was approved by the US Food and Drug Administration (FDA) on May 13, 2011 to be used in combination with Peg-IFN and ribavirn in patients over the age of 18 years. Telaprevir was approved just 1 week later, also to be used in conjunction with standard therapy for patients with liver disease aged 18 years and older. Unfortunately both agents are only effective against genotypes 1a/1b, so they are not going to be helpful in the parts of the world where genotypes 2 and 3 predominate. However, in the Western world, they represent a major advance. Use of these agents pushes the SVR rate to almost 70% when used in combination with the current standard of care. How and when these agents will be implemented in the treatment of children remains to be determined. I am not aware of any current research examining use of these agents in children though it is reasonable to expect that, with the approval of these agents, pediatric studies will be considered.

These agents are used for only 12 weeks early in the course of the disease.

Currently there are no reliable means for the prevention of HCV. Anti-HCV intravenous immunoglobulin preparations have not demonstrated efficacy. Vaccines are under development but are a long way away from human trials. Improved efforts to effectively screen for asymptomatic infection is likely to be the most effective method to reduce the spread of infection.

The availability of reliable genotype testing will change diagnostic assessment though the appropriate use of these tests in children is still being sorted out. Additionally, the new protease inhibitors, currently only approved for adults, will likely filter down to children in the future, impacting therapeutic options.

Hepatitis D in Children

A 15-year-old boy with known hepatitis B infection has been asymptomatic and doing well living the life of a typical teenager. One week ago he developed fever accompanied by nausea, vomiting, mild abdominal pain, and lethargy. Both he and his mother assumed he had a "bug" and he was treated symptomatically. Over the course of the next several days, his fever resolved though he continued to be anorexic and lethargic with intermittent complaints of nausea. He now has developed jaundice associated with dark-colored urine.

What is most likely the cause of these symptoms?

Clinical Picture of Hepatitis D

Hepatitis delta or hepatitis D (HDV) is a replication-defective RNA virus and requires coinfection with hepatitis B virus (HBV) to complete the assembly of its viral particles. HDV is found worldwide, but the prevalence varies in different geographical areas. HDV infection in the United States is relatively uncommon, though prevalence in intravenous drug users may be between 1%-10%. As with HBV, HDV transmission is via infected blood and blood products. The exception is vertical transmission during pregnancy, which does not occur.^[4]

Infection with HDV can occur at the time of the initial coinfection with HBV, or as a superinfection in a person previously infected with HBV. If acquired as an initial coinfection, symptoms usually resolve and immunity is long lasting. Individuals who acquire HDV when already infected with HBV infection are more likely to develop chronic infection and more severe symptoms. HDV acquired either concurrently with HBV or as a later coinfection presents with acute signs of hepatitis including jaundice, fever, and abdominal pain. It can present with acute signs in a patient with HBV who otherwise was doing well. The clinical course of this superinfection is depicted in Figure 3.

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Figure 3. Clinical course: HBV-HDV superinfection.
From the Centers for Disease Control Division of Viral Hepatitis. Viral Hepatitis Resource Center.^[5]


Diagnosis and Management of HDV

HDV should be considered in any person with a history of HBV who develops acute symptoms. Serologic testing for HDV is available. There is no specific treatment for HDV infections and immunosuppressive therapy and antiviral drugs have all proved ineffective.
Prevention of HDV-HBV coinfection centers around appropriate use of HBV vaccine or postexposure prophylaxis. Chronic HBV carriers should be educated about transmission and high-risk behaviors.

Hepatitis E in Children

An 18-year-old, previously healthy girl and her family returned from a year spent in India as missionary workers approximately 3 weeks ago. Since their return, the child has been noted to be fatigued and anorexic with intermittent complaints of nausea. The parents assumed her symptoms were the result of her recently diagnosed pregnancy and the transition back to the United States and treated her symptomatically. However, over the last 4-5 days she has developed jaundice, fever, and now complains of acute abdominal pain. She is evaluated at her obstetric office and hepatitis serology and liver function testing is ordered. However, over the ensuing 24 hours she rapidly deteriorates, requiring intensive care. Over the course of 48 hours, she expires from fulminant hepatic failure.

Clinical Picture of Hepatitis E
Hepatitis E virus (HEV) is also a small, nonenvelope, single–stranded, plus-sense RNA virus. It's about the same size as HAV. HEV is a more recently recognized virus that represents a unique Hepeviridae family with 2 distinct geographic subtypes, the Asian and Mexican strains. Like HAV, transmission is via fecal/oral contact, and outbreaks have been reported in developing countries, though sporadic cases also occur. Inevitably the source of the outbreaks is contaminated water. HEV outbreaks have been reported in areas with war or major conflict and following major natural disasters. In subsequent disruptions in public health infrastructure, you will see HEV outbreaks. In endemic areas including Central and Southeast Asia, North and West Africa, and Mexico, HEV is responsible for most cases of acute hepatitis.
Most patients diagnosed with HEV in the United States are travelers who acquired the virus in a foreign country. Recent data support the emergence of a milder form of the virus that causes subclinical infection in regions in the United States that are likely to be associated with swine exposure or other wild animal exposure, but this is still yet to be fully defined. The attack rate for HEV appears to be 50 times less than seen with HAV. Only 1% of HEV-exposed patients will develop acute infection compared with the 50%-75% attack rate following exposure to HAV.
HEV causes acute hepatitis in about 75% of infected patients. The incubation period is quite varied, ranging from 15-65 days. The symptoms can vary from mild to severe and are virtually identical to HAV or HBV. Typically, symptoms increase with age. There is no chronic infection with HEV, and it has not been shown to cause cirrhosis or hepatocellular carcinoma.
The rate of fulminant hepatic failure is approximately 20 times higher in pregnant patient vs their nonpregnant counterparts and risk increases as pregnancy advances, with third trimester infection associated with a 50% mortality rate. The cause of this devastating impact of HEV during pregnancy is not understood. The relationship between HEV and pregnancy was recognized following a major outbreak in the Darfur region of Sudan. Fulminant hepatic failure is rare in nonpregnant patients.


Diagnosis and Management of HEV

HEV-RNA can be detected in stool from 1 week prior to the onset of symptoms and for more than 2 weeks after the onset.

Click To Enlarge Table

Figure 4. Clinical and serologic timeline for HEV.
From Jhaveri R. Textbook of Pediatric Infectious Diseases. Editors: Feigin, Cherry, Daimler-Harrison, Kaplan. In Press. WB Saunders: Philadelphia.
As depicted in figure 4, the relationship between serologic markers and clinical symptoms in HEV infection is similar to that of HAV with the exception of a longer period during which HEV RNA is detectable in serum. The pattern follows that seen with other hepatitis viruses in that the viral markers precede symptoms, with antibodies appearing later in the course of infection.
HEV can be detected by testing either for viral RNA or antibody response to the virus. Polymerase chain reaction (PCR) for HEV RNA is available on a research basis for detection of viral genetic material. Testing for immunoglobulin M antibody against HEV is available at several referral laboratories.
Treatment for HEV is symptomatic. The focus in management should be on prevention. In countries endemic for HEV, precautions should be taken to avoid contaminated water and food (boiling water before drinking, peeling fruits and vegetables, avoiding ice in beverages). As part of prenatal counseling, pregnant women should be advised not to travel to countries where HEV is endemic.

What's New With Hepatitis E?

An experimental vaccine for HEV has been developed and tested in a large-scale, phase 2 trial of men in the Nepalese army.^[6] Efficacy was 95.5% after 3 doses. A more recent phase 3 trial of healthy adults in China reported 100% efficacy after 3 doses.^[7] Economic considerations may limit wide-scale use of this vaccine.

Hepatitis G in Children

Hepatitis G (HGV) was originally identified as the result of an investigation of transfusion recipients with mild asymptomatic increase in transaminases. PCR analysis yielded a sequence similar to that of HCV. This virus was named HGV at the time, though it is now referred to has GB virus and is subdivided into 3 distinct genotypes, types A, B, and C. GBV-C was the original HGV and is now recognized to have 5 major genotypes.^[8]

Clinically, GBV-C is a nonentity that is not associated with disease. There are no current recommendations for screening.

Interestingly, HIV patients coinfected with GBV have been found to have a reduced mortality rate for reasons that are currently unknown.^[9] It is possible that the virus causes an inhibition of HIV replication, or it may simply be a marker for other factors that produce a favorable HIV response.

Summary and Conclusion

The Table summarizes transmission and infection types for each of the hepatitis viruses.

Table: Summary of Hepatitis Viruses

Viral Agent	Main Route of Acquisition	Acute/Chronic Infection
HAV	Fecal/oral transmission	Acute only
HBV	Bloodborne contact, vertical transmission, sexual transmission	Acute and chronic
HCV	Bloodborne contact, vertical transmission	Acute and chronic
HDV	Bloodborne contact	Acute and chronic
HEV	Fecal/oral transmission	Acute only

The most important news with regard to these infections is the newer agents now available for treatment of HCV. While not approved for use with children, it is reasonable to anticipate that future research will elucidate their role in the management of children. The recognition of the impact of genotype on response, and the availability of reliable methods to determine genotype, make these studies even more important.

• References
• What Do You Need to Know About Hepatitis in Kids?
• Hepatitis C in Children
• Hepatitis D in Children
• Hepatitis E in Children
• Hepatitis G in Children
• Summary and Conclusion

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