|Year : 2004 | Volume
| Issue : 1 | Page : 72-91
|Hepatitis B virus infection in children in India
Malathi Sathiyasekaran, VS Sankaranarayanan
Consultant Pediatric Gastroenterologist, Kanchi Kamakoti CHILDS Trust Hospital, Chennai, India
Click here for correspondence address and email
|How to cite this article:|
Sathiyasekaran M, Sankaranarayanan V S. Hepatitis B virus infection in children in India. Hep B Annual 2004;1:72-91
| Introduction|| |
Hepatitis B virus (HBV) infection is an international health problem and it is therefore crucial that India with an estimated prevalence of 2-7% needs to take decisive steps in controlling the scourge. A major route of acquisition of this infection is by perinatal transmission. Infection acquired in the neonatal period and early childhood is responsible for the vast majority of chronic HBV infection with its attendant complications of cirrhosis and hepatocellular carcinoma. Interruption of childhood HBV infection results in a significant decline in the prevalence of chronic HBV infection and its sequelae. Introduction of antivirals and interferon for children with chronic hepatitis has opened avenues for scientific research to identify children who would benefit from this therapy. Universal immunization is recommended as the best solution to decrease the prevalence of the disease. It is therefore necessary to understand the epidemiology, natural history, clinical features, indications for treatment, and rationale for immunoprophylaxis in Indian children.
Prevalence and incidence of HBV infection in children in India
HBV infection in children varies worldwide depending on the prevalence of the region. India lies in the intermediate prevalence zone and therefore children born here are at a significant risk of exposure to this infection.
Prevalence of HBsAg
The HBsAg positivity in children below 15 years in India ranges from 1.3 - 12.7% while in adults it is 3.3 -8.6%. The age related HBsAg prevalence has been assessed in several studies. In a multicentric study Tandon et al have reported a positivity rate of 2.1% in the preschool age group In this study the positivity in children less than 1 year age was 2.5%, in the 1-3 year age group it was 2.3%, and in the 4-5 years age group it was 1.6% [Table - 1]
Similar studies were also conducted by other workers. Sobeslavsky et al estimated a prevalence of 0% in 0-4 years, 2% in 5-9 years and 6.8% in 10-14 years age group [Table - 2]
A population based study in Chennai revealed a higher prevalence of 12.5% in children less than one year, 9.4% in 1-5 years, 6.3% in 6-10 years and 7.8% in 11-15 years age group [Table - 4].
A similar prevalence was noted by Panda et al from Delhi who identified 12.2% HBsAg positivity in 1-5 years and 10% in 6-15 years age group [Table - 3]. These studies highlight the fact that the prevalence varies in different regions in India and the overall positivity ranges from 1.3-12.7%.
Prevalence of Anti HBs
The cumulative infection rate (anti-HBs positivity) in children less than 15 years was also analysed and was 20.5% (CI 16.6 -24.4) in Delhi, 29.3% in (CI 24.1-34.5) in Chennai and 12.9% (CI 7.9-17.9) in Pune as depicted in the above tables.
The high rate of anti-HBs positivity, i.e. 16.9% and 43.7% in children <1 year of age as reported in the multicentric study and from Chennai was linked to the possibility of maternal transfer of antibodies.
Routes of Transmission
The important routes of transmission of HBV are perinatal(vertical) and horizontal. The horizontal transmission includes percutaneous route, blood transfusion, contact from family members and sexual transmission. Perinatal transmission is a unique form of transmission different from that seen in adults. This transmission carries the highest risk of chronic HBV infection and a low incidence of acute hepatitis. In India as in other developing countries, an important mode of transmission of HBV is perinatal (approximately 33%). The risk of a mother infecting the baby is best correlated with the proportion of women of child bearing age who are HBsAg and HBeAg positive.
During the perinatal period, the infants are exposed to maternal blood through placental tear, trauma related to birth and contact of conjunctiva and other mucous membranes with blood and other body secretions. If a mother has HBV infection there is a high risk of transmission of the infection during labour and delivery. In-utero infection occurs rarely. The isolation of HBsAg in cord blood does not necessarily indicate in-utero infection, and may represent transient antigenaemia.The data on perinatal transmission suggest that an infant has 60-90% probability of acquiring HBV infection from a mother who is HBsAg and HBeAg positive
HBsAg positivity in pregnant women
The HBsAg positivity in antenatal pregnant women in India ranges from 1-12.3% with a mean of 4.22% [Table - 5]. Regional variation occurs and the risk of transmission is determined by the replicativity of the virus indicated by HBeAg positivity. The risk of HBV transmission depends not only on the host factors, but also on the survival and persistence of HBV in the population, prolonged shedding of the virus by the HBeAg positive mothers and the hygienic conditions of the environment.
The replicative status of Hepatitis B virus in pregnant women.
The HBsAg positive antenatal pregnant women from India have a HBeAg positivity range of 7.8-47.8 percent [Table - 6] based on seven different studies with a mean of 24 percent.
The studies on the vertical transmission of HBV in India have shown a transmission rate from HBeAg positive mothers to their children in the range of 58-90% with a mean of 73.76%. The transmission by mothers who are only HBsAg positive (HBeAg and anti HBe negative) ranges from 5.5-20% with a mean of 15.36% [Table7]. Nayak et al from Delhi documented an overall transmission risk of 18.6% from HBsAg positive mothers and 3% risk in the control group (HBsAg negative).
Since a significant proportion of antenatal mothers in India are HBsAg and HBeAg positive, children born to these mothers should be given adequate protection soon after birth. Screening of antenatal women and immunization of a select group is not desirable and universal immunization should be the goal in India.
Postnatally acquired infection from HBsAg positive mother
It has been well documented by Beasley that in the absence of active immunization at birth, children of HBsAg positive mothers are at a significant risk of acquiring infection later in infancy, even if they escape the perinatal route.
The significance of horizontal transmission of HBV infection in India has been stressed by Aggarwal et al who have reported that majority of children acquire infection later in life by horizontal route (85%) and therefore chronic liver disease in India tends to present in adulthood. The following two studies however do not support this multicentric study by Tandon et al [Table - 1] did not show any difference in the HBsAg positivity in the three age groups. Sobeslavsky showed a progressive increase in incidence with age but there was no specific difference in the age related anti-HBs prevalence. The Anti-HBs positivity data does not suggest any significant role of horizontal transmission. The rate of horizontal transmission is often estimated by subtracting the contribution made by perinatal transmission from the known population prevalence. This estimate is likely to be erroneous as it does not take into account the proportion due to parenteral or percutaneous modes of transmission.
Transmission by breastfeeding
Breastfeeding has been suggested as an additional mechanism by which infants may acquire HBV infection from HbsAg positive mothers as small amounts of HBsAg have been detected in some samples of breast milk. However, there is no evidence that breastfeeding increases the risk of mother to child transmission compared to the high risk from exposure to maternal blood and body fluids at birth. Mothers can therefore feed the baby and initiate active immunization for their offspring as per schedule.
Horizontal transmission from household contacts is a well recognized mode of transmission. The two well-documented studies from India have reported a high HBsAg positivity in household contacts of chronic HBV patients. Dhorje et al detected a positivity of 80% in contacts of HBV patients versus 48% in household contacts of HBV negative patients. The study by Thyagarajan et al identified a positivity of 24.2% in family members of chronic HBV patients against 4.4% among members of HBsAg negative blood donors. This highlights the importance of screening all contacts of HBsAg positive individuals and administration of active immunization.
Transfusion of blood and blood products is another important route of transmission of HBV. The risk of transmission through this route has decreased considerably following the introduction of stringent blood screening procedures. Even after routine screening for HBsAg the risk of infection is 2.8 cases per 1000 units transfused. This risk can be reduced to 1 in 200000 per unit of blood transfused if anti-HBc is screened. This method of screening will exclude those donors with low titres of HBsAg and who are in the window period.
Risk of hepatitis B infection in multi transfused children in India.
The risk of hepatitis B infection in children requiring repeated blood transfusions is quite high and the HBsAg positivity among thalassemic children in India varies from 7.5-59.6%. This rate of transmission can be reduced by good donor screening and administration of HBV vaccine routinely at the time of diagnosis to all children with thalassemia or other blood disorders requiring mulitiple transfusions.
Percutaneous spread can also occur due to repeated use or sharing of contaminated needles. The non availability of disposable syringes is a definite risk as regards exposure to HBV. The other modes of transmission in Indian children are probably the common practices such as ear, tongue or nose piercing, tattooing and use of shared razors during tonsure. Some of these practices may have a religious background and therefore escape the stipulated precautions.
Natural history of HBV infection in children
The natural history of HBV infection is dependent on the immune system of the host, HBV genotype, age and route of acquisition of the virus. The incidence of chronicity is high when vertical transmission occurs and decreases as the age of the child increases and the possibility of horizontal transmission is evident. As in adults, the outcome of chronic HBV infection depends on the severity of the liver disease at the time HBV replication is arrested. The natural history of chronic hepatitis B in children is marked by spontaneous flares of disease activity with pronounced elevations of ALT.
Phases of chronic HBV infection in children
In adults and older children, chronic HBV infection consists of two phases: a replicative phase with active liver disease and a non-replicative phase with remission of the disease. In children with perinatally acquired infection, an additional phase is seen which is not accompanied by active liver disease. This phase is the immune tolerance stage secondary to exposure to HBV or HBV related antigens early in life.
Replicative phase - immune tolerance phase
This phase is evident in perinatally acquired HBV infection or infection acquired in early childhood and represents a period of high viral multiplication with absent or minimal immune response by the host. A high level of HBV DNA with minimal liver damage is the hallmark of this stage. This phase may last up to 10 to 30 years and is accompanied by a low spontaneous HBeAg clearance. During the first three years of life, the annual spontaneous clearance is less than 2%. Eventually 70% of children will develop anti-HBe and clear HBeAg before adulthood.
The mechanism of immune tolerance is not known. It is suggested that a transplacental transfer of maternal HBeAg may induce a specific unresponsiveness of helper T cells to HBeAg. This immune suppression results in ineffective cytotoxic T-lymphocyte response to HBcAg since HBeAg and HBcAg are highly crossreactive at the T cell level. HBeAg is recognized as a self-antigen leading to lack of immune response against it and to the hepatitis B core antigen. An important component of the cell-mediated immune response against HBV is directed towards the abundant core antigen present on the hepatocyte and this response is not present in this phase. No medication is effective in this stage of the illness and hence no active treatment is necessary. However, these children have to be on regular follow up to detect the onset of liver damage. There is no therapy available currently to hasten or retard the progress of the disease into the next phase. These children are highly infective to others.
Replicative phase - immune clearance
The transition from the first to the second phase occurs between the ages of 15 to 35 years. During this phase spontaneous HBeAg clearance occurs at an annual rate of 10 to 20%. This is the phase where maximum liver damage occurs. It is similar to acute hepatitis B except that the immune response is not as potent. The damage to the hepatocytes is more indolent and results in inflammation and mild to moderate elevation in transaminases with subsequent fibrosis. During this period sero conversion from HBeAg to HBeAb can occur. This phase may remain silent or present as acute hepatitis or even liver failure. It is important that children in this stage of the illness are diagnosed and treated properly because the long term prognosis depends upon the duration of this stage . The longer the duration the more is the damage. A viral load level of <10 5sub DNA copies per ml is taken as the cut off beneath which on going viral multiplication is unlikely. The prognosis of the liver disease will depend upon the degree of underlying liver damage when seroconversion occurs. All treatment strategies aim to reduce the duration of this phase of the disease.
Integrative phase - non replicative
This phase is also called non replicative-low replication phase. This is the phase in which the rate of HBV multiplication decreases, and the transaminases are normal or near normal. The characteristic serology here is negative HBeAg and positive HBeAb. The seroconversion to anti-HBe is an important event in the natural history of chronic hepatitis B. This event is characterized by a brief and self limiting rise in transaminases followed by biochemical and histological remission. This is also the phase when viral DNA integration occurs. These children are infective to others but at a much lower rate than HBeAg positive individuals. They may go on to develop cirrhosis and hepatocellular carcinoma. There is no need to treat these patients unless they have elevated liver enzymes or an 'active disease' on liver biopsy. These findings would then suggest the presence of a precore mutant infection.
Integrative phase - viral clearance
In this phase, HBsAg becomes negative and the child become HBsAb positive. Viral replication ceases and the child is labeled as cured. This occurs in most of the children with acute hepatitis. However, immunosuppression may lead to reactivation of infection. The prognosis in chronic HBV infection is dependent on the stage at which the viral multiplication decreases i.e. patient seroconverted from HBeAg positivity to HBeAb positivity. If this conversion occurs before significant liver damage (cirrhosis) occurs, then the prognosis is good.
Clinical features of Hepatitis B virus infection
In India, hepatitis A virus is still a major cause of sporadic acute viral hepatitis in children. Hepatitis B virus as a causative agent ranges from 3.7 - 16.3% [Table - 8].
The frequency of HBV infection in sporadic acute hepatitis as shown in the various studies is more or less uniform over the last 10 years. Panda et al in the multicentric study of children 1-15 years showed that the frequency of HBV increased with age from 11.5% in <5 years to 57.5% in > 10 years age group. Thapa et al have also documented an increasing incidence of HBV infection with age.
Clinical pattern of acute HBV in Indian children.
The clinical manifestations do not vary among the different types of acute hepatitis. Singh et al reported that the biochemical parameters such as serum bilirubin and amino transferases were significantly more deranged in type B infection compared to type A. The recovery from sporadic acute hepatitis type B was not significantly different as compared to other form of hepatitis. It should be stressed that the different types of hepatitis cannot be readily distinguished on the basis of signs and symptoms or biochemical profile alone.
Acute Liver Failure
Studies on acute liver failure in children in India have shown that the prime aetiological agent is type A virus, and hepatitis B virus was responsible in only 3% to 14%., Infection with HBV does not seem to play a role in increasing the mortality. The outcome of acute liver failure as analysed by Poddar was 29.6% in type A and 25 % in type B indicating that Hepatitis B virus may not be a prognostic factor in acute liver failure.
Hepatitis B viral infection as the causative agent of chronic liver disease in children varies from 6% in the study by Ganguly, 12% as observed by Yachha and less than 10% as reported by Bhave. This is very different to the high incidence, i.e., 93% reported by Bortolotti from Italy. 30-40% of children with chronic hepatitis B can progress to cirrhosis and hepatocellular carcinoma.
These are not very common but arthritis, arthralgia, papular acrodermatitis, glomerulonephritis and aplastic anemia have been reported.
The management of hepatitis B virus infection in children depends on whether the infection is acute or chronic. The stage of the disease is the most important facter that decides the therapy. Children who are in the immune tolerant stage do not require active therapy.
Acute hepatitis B requires only supportive management. There is no role for antivirals or interferon.
Chronic hepatitis B
The critical issue in the treatment of childhood HBV infection is selection of patients. Chronic Hepatitis B viral infection results in 3 groups of children: children who are asymptomatic without liver disease but have a very high viral load, children who are HBsAg positive, without liver disease and no viral multiplication and a third group with liver disease and ongoing viral multiplication. The third group will fulfill the criteria for active treatment.
The aim of treatment in children is the same as in adults - to stop ongoing viral replication and prevent or minimize liver damage. The goal of treatment is to achieve seroconversion to anti-HBe with normalization of transaminases level and ideally subsequent loss of HBsAg. Interferon and Lamivudine are the only pharmacological agents which are currently recommended for therapy of chronic hepatitis B.
Interferon (IFN) is approved for therapy in children with chronic HBV infection. The criteria for IFN selection are : children more than 2 years of age with chronic hepatitis B, characterized by HBsAg and HBeAg positivity, significant HBV DNA levels, transaminases more than twice normal and activity on liver biopsy. IFN is not recommended in children with normal transaminases, inactive liver histology or HBeAg -ve (unless the infection is due to a pre-core mutant). The efficacy of IFN in children has been established though the number of studies in children are much less than in adults. The success rate ranges from 16-44%. Sarin's group has documented marginally different response between the vertically acquired (41%) and horizontally acquired (46%) groups. The response increased to 52% on follow up. These children tolerated the drug well, 60% had flu like symptoms, bone marrow suppression was seen in 12% and spontaneous bacterial peritonitis occured in 4%. IFN had to be discontinued only temporarily. Neutropenia and thrombocytopenia were rarely observed. Hypothyroidism, pancreatitis, depression, fatigue and hearing loss are less common in children compared to adults. The dose of IFN advocated is 5 million units/m 2sub /dose given subcutaneously daily for 6 months. In children, IFN can be given before the child goes to sleep so that some of the side effects can be minimized.
Monitoring of children
Children should be monitored frequently both clinically and biochemically. They should be evaluated clinically every two weeks for the first 2 months and then every month. During evaluation, SGPT and complete blood count are checked. HBeAg can be tested once in 3 months and HBV DNA at the start and at the end of treatment.
The use of lamivudine as monotherapy in the management of chronic hepatitis B has not produced encouraging results. However, the combination of IFN with lamivudine 3-4 mg/kg for 6-12 months has shown promising results. Lamivudine is well tolerated in children with minimal side effects. The development of resistance should be kept in mind before recommending this form of therapy for prolonged periods. The lamivudine withdrawal flare noted in adults has not been reported in children. Lamivudine can be prescribed in decompensated liver disease. The duration of therapy is till HBeAg disappears from the serum, anti-HBe appears, or if neither occurs, till HBV DNA becomes persistently undetectable.
Newer agents such as pegylated interferon and adefovir dipivoxil have not been recommended in children as yet.
The existing data on children from India indicates an enormous disease burden that needs to be curbed as early as possible. The cost of treating chronic hepatitis B with interferon or end stage liver disease with liver transplant is far beyond the reach of an average Indian. The answer to this problem is an effective and safe vaccine that should be incorporated into the existing immunization programme. This vaccine should be started early in life to interrupt perinatal transmission, cover infants to prevent child to child transmission and also protect older individuals who are at a risk of infection.
The recombinant genetically engineered hepatitis B vaccine has gained world wide acceptance. Its safety and protective efficacy has been established and it is now recommended all over the world.
Dose and schedule :
The recommended pediatric dosage is 3 doses of 10 mg given intramuscularly at 0,1 and 6 months interval. This dose can be given till the age of 12 years. Older children and adults require 3 doses of 20mg at the same interval. This induces a protective antibody response in more than 95% of infants, children and adolescents.
Reduction in dose could have marked effect on the cost of the vaccine. Studies show that doses 5 mg and 2 mg can induce good seroconversion of 98% and 90% respectively but the long-term protection is doubtful. Various dosage schedules have been tried but the final consensus is that the ideal pediatric dosage including that for neonates is 10mg.
The vaccine is regarded as a safe vaccine with minimal side effects such as soreness, fever and headache.
Duration of protection
Three doses of vaccine administered in the recommended schedule confers life long immunity.
Integration of HB vaccine with the existing DPT vaccination
The compliance of the vaccination can be increased by combining it with DPT though the dose schedules for these vaccines are different. The GMT with 0, 1 & 6 months schedule is 10 times higher than 0, 1 & 2 months schedule, both in children and adolescents implying a better and longer seroefficacy in the 0, 1 & 6 months schedule.
WHO has recommended 2 schedules according to the endemicity either with or without zero dose. The Indian Academy of Pediatrics has recommended 2 schedules based on the WHO regime., Vaccination of all babies at birth followed by 6 weeks and 14 weeks later. This will prevent perinatal transmission and also result in a higher GMT as the duration between the 2nd and 3rd doses is 10 weeks. Those children who have missed their zero dose can be vaccinated at 6, 10 & 14 weeks along with the DPT. However, the latter schedule may not result in high GMT.
Vaccination of Preterm & Low Birth Weight
The available evidence suggests that preterm and low birth weight (CBW) babies given the first dose soon after birth produce antibodies in the protective range. Bhave et al have shown that a 4 dose schedule inclusive of a booster at 12 months is effective in LBW babies in India.
Vaccination of babies born to HBsAg positive mother
Babies born to mothers who are HBsAg positive should receive active immunization soon after birth. Administration of Hepatitis B Immune Globulin (HBIG) if available and feasible should be given within 6 hours of birth. Active immunization without immunoglobulin is as protective as combination and therefore all steps should be taken to initiate the first dose of active immunization at birth.
Children with chronic hepatitis B infection are usually asymptomatic but are at a great risk of progressing to chronic liver disease and hepatocellular carcinoma. Hepatitis B infection in children in India is a preventable national problem. Prevention of this infection should be given top priority and only a united effort by the medical personnel, medical institutions, health departments and the government will help to eradicate this silent killer.
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Consultant Pediatric Gastroenterologist, Kanchi Kamakoti CHILDS Trust Hospital, Chennai
Source of Support: None, Conflict of Interest: None
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5], [Table - 6], [Table - 7], [Table - 8]
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