Indian Pediatrics 2001; 38: 349-371
Hepatitis B in India: A Review of Disease Epidemiology
Hepatitis B is an illness well defined by clinical and virological studies. The World Health Organization (WHO) has considered it as a disease of public health importance. It has recommended universal immunization against it by including a vaccine into Expanded Program for Immunization (EPI) schedule for children(1). However, the Government of India has not yet recommended the universal use of this vaccine. The Indian Academy of Pediatrics (IAP), the premier professional organization representing pediatricians has recommended its use in its immunization schedule(2). Prescription of this vaccine has increased dramatically over the last few years, the vaccine being offered to those who can afford it. In fact, many private schools are organizing immu-nization programs against Hepatitis B(3).
Universal immunization is usually recommended for any disease that causes significant morbidity; both in terms of numbers as well as in terms of the severity of the consequences of the infection including mortality, provided a safe and effective vaccine is available. Hepatitis B is believed to satisfy both these criteria with an estimated prevalence in India between 3% to 7% and its sequelae of chronic hepatitis, cirrhosis and hepatic carcinoma. The goal of immunization program against hepatitis B is to reduce the incidence of and possibly eliminate hepatocellular carcinoma and chronic liver disease by reducing the number of HBV carriers in the population. This effect can possibly be evaluated only after a few decades have passed. This goal is clearly different from that of the other vaccines included in the EPI, which reduce the childhood mortality and morbidity.
To judge the utility of HBV vaccination program, it is important to have the baseline data about the extent of the problem, the incidence and prevalence of various long-term complications of chronic HBV infection. Since the implementation of universal immunization requires a significant commitment in terms of resources, we have reviewed those aspects of epidemiology of hepatitis B infection which are essential to decision making about such immunization strategy. Therefore, we have specifically looked at the (i) prevalence, (ii) natural history of HBV infection and (iii) vaccine effectiveness.
A MEDLINE search was undertaken using the key words "Hepatitis B, prevalence, epidemiology, natural history, transmission, carrier". In the studies pertaining to prevalence of infection only Indian studies were included. In other areas, as Indian literature was scarce, other countries’ experiences especially from developing countries were also identified. In addition manual search was carried out for many Indian journals, which are not indexed. Wherever possible the full article was reviewed by two authors (RL, YJ). In cases of difference of opinion a third author (SKK) was consulted to reach a consensus. If the full article could not be traced, the abstract was used. The 95% confidence intervals for the prevalence studies were calculated by the authors using the prevalence reported and the sample size of the study.
One hundred and twenty eight articles were finally included in the review. The results of the review are discussed under the three broad headings identified previously, viz., (i) prevalence, (ii) natural history and (iii) vaccine effectiveness.
1.1. Criteria for Diagnosis
Only the studies using third generation assays for detection of Hepatitis B surface antigen (HBsAg) were selected, as these assays are more sensitive and specific than the earlier assays(4). In all the studies the samples were subjected to an assay only once.
1.2 . Study Population
To estimate the magnitude of the disease in the community, we require representative community-based sampling. However, most studies have used voluntary blood donors and pregnant women attending antenatal clinics. This has been mainly done as both groups are easily accessible and are a part of the existing national blood safety norms or clinical/surveillance guidelines for other diseases (HIV, syphilis). The results of studies in these two groups are presented below:
(a) Blood donors: Eight reports were available on prevalence of Hepatitis B surface antigen (HBsAg) in blood donors - both voluntary and replacement(5-12). Table I shows the prevalence figures in blood donors from eight locations in different parts of the country using the different diagnostic tests. In most of the reports, the study years were not mentioned clearly. The prevalence in voluntary blood donors (VBD) was usually around 2% except in Madras where it was reported as 7%(10). In the replacement donors, the prevalence reported in Vellore and Jaipur were 3.8% and 3.1% respectively(11,12).
(b) Pregnant Women: The prevalence figures available from the eight studies done among pregnant women ranged from 2.26% to 5%(13-20) (Table I). The weighted average was calculated to be 2.8% [95% CI 2.6-3.1%].
(c) Tribal / Rural Population: The only study done in the rural area was on hospitalized non- hepatitis patients where the prevalence was very high (11.3%)(21). In the tribal areas of Madhya Pradesh two studies reported prevalence rates of 15.7%(22) and 4.4%(23).
(d) Children: Only two studies in India have assessed the age related HBsAg prevalence in children. In one study, the positivity rate was 2.1% in preschool age group(24) and it was 4.9% in children below 15 years age group in the second study(25). In the first study, the HBsAg positivity in children less than 1 year age (n = 320) was 2.5% (95% CI 0.78%- 4.21%), in children in the 1-3 year age group (n = 353) was 2.3% (95% CI 0.73%-3.86%) and in children in the age group 4-5 years was 1.6% (n = 309) (95% confidence interval: 0.2%-3%)(24). In the second study, the prevalence was estimated as 0% (n = 6), 2% (95% CI 0%- 3.88%) (n = 50), and 6.8% (95% CI 1.5%-12.05%) (n = 88) in 0-4, 5-9, and 10-14 years age groups, respectively(25).
Data on Hepatitis B ‘e’ antigen (HBeAg) positivity in the Indian population is limited. In the available studies, the HBeAg positivity in HBsAg positive pregnant women ranges from 7.8% to 47.8%(14,15,17). However, the sample size in these studies was small (n = 23 to 322). There are speculations over high prevalence of precore mutants (mutations that inhibit the production of HBeAg), in which the infected persons remain HBeAg negative but are highly infectious(26).
1.3. Issues in the Estimation of Prevalence of Hepatitis B Infection in India
Most authorities believe that India falls in the intermediate zone of HBV prevalence i.e., prevalence between 2% and 7%. This figure is based on studies contributed mainly by blood bank screening programs and screening of healthy pregnant women attending antenatal clinics(5-20).
As mentioned earlier, for the assessment of prevalence of a disease/condition, the sample selected should be representative of the whole population and should be adequate. There were no reports which had study subjects who were representative of the Indian population. Although, blood donors and antenatal women provide "convenient" samples, the results from these groups cannot be extrapolated to general population for the following reasons: (a) There is lack of well-defined inclusion/exclusion criteria in most studies; this may have led to inclusion of high-risk groups into the study. (b) As most of the blood banks are in urban centers, it is likely that most of the subjects apparently were from urban areas. Since, nearly 75% of our population is rural, community based data from different regions of the country are required. In a WHO collaborative study, no definite pattern of urban/rural differences emerged(25). However, the likelihood of prevalence being different in rural areas exists.
The estimated prevalence of a disease will also depend on the criteria for diagnosis: the more strict and specific the criteria, the lower will be the error in estimating the prevalence in the population. As no test has 100% sensitivity and 100% specificity, misclassifica-tion errors (False positives and false negatives) are bound to occur. Misclassification errors assume greater importance when the preva-lence of a disease is low, as proportionately, the error may be high, quite often even higher than the actual prevalence itself.
In a disease condition/ infection, which has a low prevalence, the true prevalence can be estimated by the following equation(27):
Estimated prevalence –
(1 – specificity)
Taking the single test positivity prevalence (for HBsAg) as 3% (Table 1) and sensitivity/specificity of test as 98%/98%(28) the true prevalence comes to about 1% using the formula mentioned above. In fact, as shown by Tu et al.(27), for any test, (1-specificity) should be less than the estimated prevalence for any meaningful interpretation of a test. It is evident from the formula given above, that if the test positivity prevalence is less than (1- specificity), the numerator is a negative number and thus, no meaningful interpretation is possible.
On the basis of available literature and the reasons mentioned above, the true prevalence of HBV carriers in India is likely to be between 1% and 2%, thus qualifying India as a low prevalence area.
Therefore, to address this issue, a test with high specificity and sensitivity has to be used. In the studies reviewed, HBsAg was determined only once and anti HBc antibodies were not estimated. There was no determination of HBsAg status after an interval of 6 months to confirm carrier status except in one study(8). These studies have actually reported only the prevalence of ‘test positivity’. In a low disease prevalence setting, the test should be done twice to confirm (both tests being positive) a condition, as is the case with testing for HIV infection; this increases the specificity. The purpose of HBsAg testing in donated blood is to identify blood that is not suitable for transfusion. So, the test used has to be highly sensitive; a few false positives will not affect the screening program. Therefore, a single estimation is acceptable for screening in blood banks. However, for estimation of prevalence of HBV infection in the population, it is imperative to perform the tests twice.
There are inadequate data regarding HBV carrier rates in the pediatric age group in India (24,25). Information in this age group is essential to understand the problem of Hepatitis B in our country; and to formulate the plan for prevention of this infection.
2.1. Modes of Transmission
Hepatitis B is transmitted almost exclusively by blood or body secretions that carry the virus. Majority of the studies has addressed the issue of perinatal transmission. Studies estimating the importance of horizontal transmission and other modes of transmission in adolescents and adults in India are conspicuously absent. These figures can only be calculated roughly from the population prevalence figures and the contribution of perinatal transmission, for which data exists.
2.1.1. Perinatal Transmission
Data on perinatal transmission (Table II) suggest that an infant has 65%-88% probability of acquiring HBV infection from a carrier mother, if she is both HBsAg and HBeAg positive(15,29-34). The risk of acquisition of HBV infection from HBsAg positive and HBeAg negative carrier mother ranges from 12.2%-31%(15,29,30); the overall risk of acquiring infection through this route being 18.6%-50% depending on the proportion of HBeAg positive mothers (15,29,30,35). An Indian study(15) had shown an overall transmission risk of 18.6% from HBsAg carrier mothers and a 3% risk in the control group [HBsAg negative mothers].
2.1.2. Postnatally Acquired Infection From HBsAg Carrier Mothers.
Beasley et al.(36) studied the incidence of HBV infection in infants of HBsAg carrier mothers who had received only HBIg (Hepatitis B Immunoglobulin) at birth and hence were protected for only the initial 6 months of life. The annual incidence of HBV infection in these children was 26% (mean follow up period of 17.5 months) with the highest rate of 57% for infants of HBeAg positive carrier mothers. The overall chronic carriage rate in children who acquired HBV infection postnatally was estimated to be 45.7%(36). This suggests that, in absence of active immunization at birth, children of carrier mothers are at a significant risk of acquiring infection, even if they escape infection in early infancy by the perinatal route.
2.1.3. Horizontal Transmission
Accurate information on horizontal transmission is possible only if a cohort of newborns is followed up by repeated testing for HBsAg among those remaining seronegative. A review of seroprevalence surveys(37) was performed using population based, cross sectional prevalence surveys of HBV serological markers performed in developing countries in Asia, Africa and South Pacific region. Since the studies included in the review were cross-sectional, this may reduce the value of the observations. The total number of subjects available for study in the analysis were 2134 in 0.5-4 years age group, 1457 in 5-9 years and 1549 in 10-14 years age groups. The survey observed that the prevalence of HBsAg carriage and anti-HBs was higher in 5-9 years than in 0.5-4 years age groups. Unlike HBV antibody (anti HBs) prevalence, HBsAg carriage rates did not increase across 5-9 and 10-14 years age groups. This suggested that horizontal transmission play an important role in children less than 10 years of age. Horizontal transmission after 5-9 years contributes little to the prevalence of virus carriers in the population(37). The study concluded that horizontal transmission of hepatitis B virus is common in areas endemic for the virus, occurring especially in preadolescent children.
A multicentric, cross-sectional study conducted in India(24), however, revealed that the carrier rates amongst children of the three age groups were almost equal. Also, the carrier rate among infants less than 1 year age (2.5%) was almost same as that for older children (2%). This suggested little role, if any, for horizontal transmission. On the basis of the results, the authors recommended that it will not be wise to introduce HBV vaccine in EPI in India(24). Another cross-sectional study showed a progressive rise in HBsAg carrier rate with increasing age [0% in 0-4 years (n = 6); 2% (95% CI 0%-3.88%) in 5-9 years (n = 50); 6.8% (95% CI 1.5%-12.05%) in 10-14 years (n = 88)](25). However, there was no significant difference in the age specific anti-HBs prevalence [0-4yr: 11.1% (n = 9); 5-9yr: 12.9% (n = 62); 10-14yr: 13% (n = 108)]. While the HBsAg carrier rates seem to increase with increasing age, the anti-HBs positivity remains uniform across the age groups. The anti-HBs positivity data suggest little, if any, role for horizontal transmission. The numbers of children in 0-4 years age group are negligible; therefore, no definite conclusions can be drawn from this study.
Studies are also available determining the risk of infection in the family contacts of a carrier, a patient with acute HBV infection and of patients with chronic HBV infection(38); but the exact contribution of this mode of transmission to overall carrier pool could not be estimated. In fact, the sequence of acquisition of infection in the family could not be determined in these studies.
2.1.4. Parenteral Transmission (Percuta-neous Transmission)
Percutaneous or parenteral transmission is one of the modes of spread of hepatitis B virus. Infection can occur with transfusion of blood or blood products, though the risk of transmission has been reduced significantly because of introduction of compulsory HBsAg screening in blood banks. Reports indicate that after routine screening of blood donors for HBsAg is done, the risk of HBV infection is about 2.8 cases per 1000 units transfused(39). If anti-HBc screening is also done to exclude persistent low level carriers and those in the window period of acute infection, the risk declines to 1 in 200,000 per unit of blood transfused(40). Nearly one third of the hemophilic patients have serologic evidence of hepatitis B infection as a result of exposure to repeated blood transfusions(41).
The other mode of percutaneous spread is the exposure associated with repeated or one time sharing of contaminated syringes and needles by users of illicit drugs. This mode may be important also in areas where health facilities are primitive and use of disposable (not repackaged plastics) a rarity. Occasionally, repeated use of syringes and needles without sterilization has led to outbreaks of hepatitis B infection(42).
Transmission of HBV by percutaneous route also may occur as a result of inadvertent (or inapparent) inoculation after the use of shared razors(43,44), by tattooing(45,46) or ear piercing(47). However, the exact contribution of these modes of transmission has not been estimated.
2.1.5. Issues in the Modes of Transmission of Hepatitis B virus.
Of the various modes of transmission, the perinatal route is most well studied(15,29-35). These studies show that the infant of a mother, who is carrying both HBsAg and HBeAg, has the highest risk of acquiring the HBV infection by the perinatal route. The overall risk may vary from one population to another, being dependent on the prevalence of HBeAg positivity in the pregnant women(15,29-35).
A study from Taiwan suggests that the children of carrier mothers are at significant risk of acquiring the infection (annual risk of infection being 26%) from the latter, even if they escape infection in early infancy by perinatal route(36). However, the same figures may not be applicable to our population, as the HBeAg positivity in India is lower than that in Taiwan(15).
The relative contributions of horizontal and vertical transmission to the carrier pool in India are not known. There are hardly any studies on the age-related incidence of HBV infection and risk of chronicity of infection acquired at different age groups from India. Hospital based investigations suggest that HBV is responsible for nearly one-third of acute sporadic hepatitis in India(48-50). However, a community based retrospective study on individuals with history of jaundice in 3 months prior to the study found that HAV and HEV caused 88% of laboratory-diagnosed cases of endemic viral hepatitis(51) while HBV was implicated in less than 5% cases. Presently, the rate of horizontal transmission is estimated by subtracting the contribution made by perinatal transmission from the known population prevalence. This method does not take into account the contribution of parenteral/ percutaneous modes of transmission. Various Indian authors have used different available data to highlight greater importance of either perinatal or horizontal mode of transmission(52,53).
While perinatal transmission is the major contributor to the carrier burden in countries with high prevalence, such as Taiwan, the same may not be true for low prevalence countries. The relative importance of these modes will determine the most appropriate preventive strategy, the target population, and the timing of immunization. The determination of the relative contributions of these two major modes is also important to estimate the risk and the magnitude of complications due to chronic HBV infection, as the risk of complications depends on the age of acquisition of the infection. For all these reasons, it is important to conduct studies to answer these questions.
2.2. Risk of Chronicity
Acute hepatitis B can cause death due to fulminant hepatic failure, but it is the chronic complications of this infection, which cause the greatest disease burden. The rate of chronicity due to infection varies with age at the time of acquiring the infection, as discussed below(15,35,54-56).
2.2.1. Perinatally Acquired Infection
Various studies have determined the chronicity rate of HBV infection acquired by perinatal route to be 75% (1 year follow up) (15) and 92% (7.5 month follow up)(35). In the Indian study(15), 17 of the 35 infants, who were initially HBsAg positive, were followed up (10-14 months). Of these, four became negative for all markers. In another study(35), 38 of 63 positive babies had had blood specimens taken after their first positive specimen (average 7.5 months follow up). Thirty-five (92%) of these remained positive during follow up.
2.2.2. Acute Hepatitis B Infection at Different Ages
McMahon et al.(54) prospectively studied the risk of chronic carriage rate after acute HBV infection in different age groups and the clinical expression of the disease. Nearly 20% of children less than 10 years of age became carriers after acute hepatitis B, while only 7.7% of the adults older than 30 years became carriers (n = 26). However, measures to exclude reactivation of chronic hepatitis B in adults were not taken. They also concluded that only 3.8% of patients with symptomatic acute hepatitis B became carriers compared with 14.8% of those with subclinical infection (54).
Beasley et al.(55) estimated the annual incidence of HBV infection in preschool Taiwanese children (mean age 29 months) to be 5% and the risk of chronic carriage to be 23%. These studies suggest that with increasing age of acquisition of HBV infection, the risk of becoming a carrier declines progressively.
A study from Greece(56) examined the natural history of acute HBsAg positive hepatitis in adults with an attempt to differentiate acute clinical hepatitis B infection from exacerbation of chronic HBV hepatitis. The authors observed that the carrier rate in patients with acute hepatitis B was only 0.2%. However, on inclusion of patients with chronic HBV infection with exacerbation, the carrier rate rose to 8.4%, similar to that reported earlier in literature(57). Other researchers also have reported low risk of chronic liver disease after acute hepatitis B (58,59). Koff estimated that the true order of magnitude of persistent HBV infection after acute hepatitis B in adult populations may be close to 2%(60).
On the basis of available literature, one can conclude that the risk of developing HBV carrier state is maximum if infection is acquired by perinatal route and this risk declines markedly as the age at infection increases(15,35,54-56). The risk decreases to less than 5% if the infection is acquired in adulthood(54,56,60) compared with the risk of upto 90%, if the infection is acquired by the perinatal route(15,35). Care should be taken to differentiate exacerbation of chronic hepatitis B from acute hepatitis especially in adults, since failure to do so will overestimate the risk of chronicity.
2.3. Duration of Carrier State
A chronic HBV carrier is a person who has been HBsAg positive for 6 months or more. A healthy / asymptomatic HBV carrier is defined as an asymptomatic person who is detected to have HBsAg on routine testing and who has normal serum aminotransferase activity. Follow-up studies conducted in adults with HBsAg positivity have shown the spontaneous HBsAg seroconversion (implying the clearance of HBV infection) rates to be between 0.3 and 1.7% per annum(61-66). Whether these figures are applicable to children who acquire the infection by the perinatal route is not known.
2.4. Natural History of Chronic HBV Infection
The large majority of HBsAg carriers have normal liver function. Studies suggest that nearly 65-80% of adult asymptomatic carriers have normal aminotransferase levels (63,66,67).
Studies on the histopathology of liver in asymptomatic carriers have used the old classification of chronic liver disease - chronic persistent hepatitis (CPH), chronic active hepatitis (CAH) and cirrhosis. The classi-fication is now considered outdated. The present evaluation of liver biopsy for chronic hepatitis includes staging (the extent of fibrotic changes) and grading (the degree of necro-inflammatory changes). As there is no literature on the natural history using recent classi-fication, we will use the terms CPH, CAH, cirrhosis when discussing natural history. These studies may be affected by sampling error; a single biopsy specimen may not be representative of the liver pathology.
2.4.1. Asymptomatic Carriers with Normal Liver Function
Liver histology of asymptomatic carriers with normal liver function tests [majority of whom were blood donors] reveal normal liver or minimal or nonspecific changes in 75-90%. Chronic active hepatitis (CAH) was seen in only 1-5% of these individuals. The remaining had chronic persistent hepatitis (CPH) (63,64,68) (Table III).
Popper et al.(68) reviewed literature and observed that follow-up biopsies 2-7 years after initial examination in 364 persons revealed an unchanged liver histologic appearance in 80.4%, improvement in 5.7%, worsening in 12.6% and transition to cirrhosis in only 1.1%. de Franchis et al.(64) and Feinman et al.(69) have also reported similar results. These studies had only adults as the subjects. No studies could be identified where histology was performed in asymptomatic children who acquired HBV infection early in life, though follow up studies with children having chronic hepatitis B have been undertaken(70-72).
Chronic carriage of hepatitis B virus (HBV) is an important risk factor in the development of several serious diseases. Nearly three-fourths of the adult chronic carriers have normal liver function(63,66,67). Less than 5% of these have CAH on liver histopathology; the majority has normal histology or minimal changes (63,64,68). The liver histology is relatively stable over a period of time in these carriers(64,68,69).
2.4.2. Carriers with Deranged Liver Function
Most of the studies have reported on a small number of patients (varying from 13 to 85). On pooling the data from these studies on liver histology in carriers with deranged liver function tests, 86.5% had normal histology or nonspecific changes or CPH and 13.5% had CAH with or without cirrhosis (63,66,69,73-78).
2.4.3. Outcome of Chronic Persistent Hepatitis
A number of studies in the literature report serial liver biopsies in patients with HBsAg positive chronic persistent hepatitis (69,71,72,79-84). In most of these studies, only occasional cases progress to chronic active hepatitis or cirrhosis. However, these studies are plagued by small sample size (n = 6-16).
Weissberg et al.(85) in their study estimated the 5 year survival in adults (mean age 35.1 years) with chronic persistent hepatitis B to be 97%.
2.4.4. Outcome of Chronic Active Hepatitis
Available literature suggests that about 20% of individuals with chronic active hepatitis B progress to cirrhosis over a variable period of time(71,86-90). In these studies the sample sizes were small and not all patients underwent a second liver biopsy on follow up.
Weissberg et al.(85) found that the estimated 5 year survival rates for patients with CAH alone was 86% [n = 128] and for those with CAH and cirrhosis was 55% (n = 130). The authors observed that there was lack of women both in the study group as a whole and also in the group with more severe forms of disease suggesting that the disease is milder in women.
Fattovich et al.(91) followed 105 HBsAg positive patients with chronic hepatitis [CPH = 46, CAH without cirrhosis = 59] for 1-16 years [mean 5.5 years]. The mean histological follow up was 3.7 years. Majority of the patients were males (76.2%). The authors calculated the annual incidence of cirrhosis to be 5.9%; the cumulative probability of developing cirrhosis at the end of 5 years was 20% (mean age at entry 30 + 9 years). In this study, the outcome of CPH and moderate CAH was similar, only CAH with bridging necrosis had a poorer prognosis(91). In a Korean study(92), 9% of the patients with chronic active hepatitis developed liver cirrhosis within 5 years. In a much larger study [n = 684], Liaw et al.(93) calculated the cumulative probability of developing cirrhosis in patients with chronic hepatitis (mean age at entry 32.2 + 10 years; males 87.1%) at 5 years was 15% with the risk increasing with age of study subjects. However, the authors did not calculate the risk of developing cirrhosis separately in various categories of chronic hepatitis. The risk of developing cirrhosis is higher in patients with HBeAg positivity. The annual incidence of HCC in adults with chronic hepatitis has been reported to between 0.5% and 0.8%(94,95).
In patients with cirrhosis, the annual incidence of hepatocellular carcinoma ranges from 2% to 7%(92,95,96). Fattovich et al. reported lower annual rates of 1.2% from Europe(97). The estimated 5 year survival in patients who have cirrhosis is reported to be about 50% to 80%(92,95,96); with the survival being more for compensated patients than for decompensated ones.
On the basis of the available literature, the prognosis in CPH in HBsAg carriers appears to be excellent(69,71,72,79-84). However, the number of subjects in all these studies is very small. The adult carriers with CAH have 9-20% risk of developing cirrhosis over a five-year period(91-93). Two to seven percent of adult cirrhotics (associated with HBV infection) develop hepatocellular carcinoma every year(92,94, 95, 96- 99). However, there is evidence to prove that the sequelae of chronic hepatitis B infection are less frequent and milder in females(61,65,85,100).
The risk of developing CAH in healthy HBsAg carriers in Alaska was calculated to be 193.3 and 158.2 per 100,000 carrier years for males and females respectively(43). Similarly, the figures for cirrhosis were 107.4 and 94.9 respectively. However, in this study, baseline biopsies were not performed.
2.4.5. Studies in Children
Only a few studies have been reported in pediatric age group regarding the natural history. Most of these have followed children with HBV infection clinically and serologically. Little information is available on serial histologic examination in these children.
Children with chronic HBV infection acquired perinatally are mostly asymptomatic. Even with active inflammation, jaundice or growth failure is uncommon. However, severe liver diseases including cirrhosis and hepa-tocellular carcinoma may develop insidiously during childhood or later in adulthood.
More than 90% of children with perinatally acquired HBV infection are HBeAg positive at the initial stage of infection(101-103). During this stage, the child is tolerant to HBV and virus replication is high, the child is highly infectious and an important source of horizontal infection, particularly in day-care centers. The amino-transferases are usually normal or mildly elevated. The HBeAg positivity can persist for years, as discussed below.
Spontaneous clearance of serum HBeAg does occur with increasing age of the child. Viral replication is reduced during this process. This clearance is preceded by elevation of aminotransferases. After detection of elevation of aminotransferases, nearly 40% of the children clear HBeAg within one year(104). In a long term follow up study, the annual HBe seroconversion rate was found to be 4-5% in children older than 3 years of age and less than 2% in children younger than that(101). Children who were brought for medical care had higher cumulative HBeAg clearance rates (42.4%) than those who were recruited by screening (14.6%), because of the above mentioned reason.
The aminotransferases gradually return to normal after HBeAg clearance and anti- HBe develops. However, HBV DNA may continue to be present. Bortolotti et al. followed up 39 children after HBe seroconversion and found 87% had detectable HBV DNA by PCR within 5 yrs of follow up and in 58% at ten years after seroconversion(105). Aminotransferases continued to be normal in 92% whereas 8% had slightly elevated ALT. Acute exacerbation with reactivation of HBV and reelevation of aminotranferases is unusual in children(72).
Liver histology in HBsAg-positive children generally reveals mild inflammation and fibrosis(106,107). Chang et al. found CPH in only 3 of the 18 asymptomatic children while 15 had minimal histologic changes (106). In symptomatic children or children with raised aminotransferases, liver biopsy has features of CAH in nearly 50-60%(12,103, 108-110).
Follow up studies evaluating change in histology are limited(70-72,111,112). In an Italian study, nine children born to carrier mothers were followed up for 5-10 years(70). These children had chronic hepatitis on the baseline liver histology. Five children with CAH at presentation showed complete remission within 6 years while 3 children who had minimal changes initially did not show any change during the follow up period. Bortolotti et al. in another study on 292 hepatitis B positive children with persistent elevation of aminotransferases found cirrhosis on initial liver biopsy in 10 (3.4%)(111). However, none of the other 207 children who underwent one or more repeat liver biopsy developed cirrhosis during follow up of 4.0 + 2.5 years. The histologic lesions in these children were stable during this period. The authors concluded that cirrhosis might be an early complication of chronic HBV infection in some children.
The inadequate available data suggest that chronic HBV infection is associated with mild and stable liver disease in childhood. Data on the progression of chronic liver disease in children are limited. The results of adult follow up studies may not be applicable to children. At present it may not be possible to give a clear time course for progression of chronic HBV infection in children.
2.4.6. Sex Differences
Once infected with HBV, males are more likely to remain persistently infected, whereas females are more likely to be transiently infected and to develop anti HBs. Although both sexes may be equally infected at birth, males are more likely to develop chronic hepatitis (by ratio of upto 1.5 : 1). More males than females develop cirrhosis of liver (3 : 1) and as greater proportion develop liver cancer (by ratio of upto 5-6 : 1). So, ultimately, hepatocellular carcinoma (HCC) becomes predominantly a disease of males (85,93,113-115). The factors accounting for higher number of cases among males may be due to other reasons like greater exposure to chemical carcinogens.
2.4.7. Risk of Hepatocellular Carcinoma (HCC) in Long Term HBsAg Carriers
A number of studies in adults have estimated an annual incidence of HCC in HBsAg carrier upto 0.5% (Table IV). The higher figures are from Taiwan(116), Japan (117) and Alaska(61,65), whereas no cases of HCC were observed in follow up studies from Canada(62,69) and Italy(64), but these latter studies had fewer participants. In these studies, the majority of individuals were over 40 years of age.
Three of the studies(116-118) included only males. Three other studies observed signi-ficantly lower rates in females (61,65,100). Though HCC has been reported in children(119,120), the incidence rates appear to be lower than those in adults.
The relation of HBV to HCC has been demonstrated by both epidemiologic and molecular studies. Globally, HBV may probably be the etiologic agent for 75-90% of HCC(116). The annual incidence of HCC in adult chronic carriers has varied from 0-0.5% in different reports(61,62,64,69,70,100,116-118). The variability may be explained by differences in the geographical areas, race and the proportion of females in the study population. The data suggest that after perinatal acquisition of HBV infection, the risk of HCC appear after a latency of 30-50 years.
A large number of studies and reviews have quoted a particular study(116) to arrive at the conclusion that the carriers have a 25% lifetime risk of developing cirrhosis or HCC. This conclusion may however be valid only for males, since this(116) and other studies (117,118) have looked at males only. The risk of HCC is much lower for females(61,65, 100).
2.4.8 Overall Sequelae of HBV Infection
Based on our review, we have tried to estimate the frequency of various stages in the natural history of the infection, which is shown in Fig. 1. Three fourths of the adult carriers have normal liver function tests (LFT). Of those who have normal LFT, upto 5% have CAH, of whom upto 10-20% may develop cirrhosis over the next 5 years. Only occasional cases of cirrhosis have been reported in those with normal or non-specific histological changes. Fifteen per cent of those who have abnormal LFT are likely to have CAH on histology. With these assumptions derived from adult carriers (mean age 30- 40 years), a 3% antigenemia in a population of 10 million (e.g., the state of Delhi) is likely to result in 920 cases of cirrhosis per year i.e., 9.2 cases per 100,000 population per year; with the derived antigenemia prevalence of 1%, the number is likely to be 307 per year. One has to consider that the pattern and numbers are likely to be different as this estimate has been derived from studies on natural history in adults and absence of good data in children. As has been discussed above, the disease is likely to be milder in children. A dynamic model taking into account the infection rates and chronicity at different ages and the sequelae of chronic hepatitis B is difficult to construct because of lack of information on disease epidemiology in different age groups in India.
There are two types of Hepatitis B vaccines available: plasma derived and recombinant yeast-derived vaccine. Most of the studies conducted in neonates were post exposure in principle, i.e., infants born to hepatitis B carrier mothers were the study subjects. Initial studies used a combination of Hepatitis B immuno-globulin and vaccine; the results suggested that the combination is highly effective in reducing the incidence of chronic antigenemia in neonates born to carrier mothers who were HBsAg positive (30,32,33,121). The protective efficacy rates in these studies ranged from 90.5% to 100%. The use of the combination is costly and for this reason, this approach may not be feasible in poor, developing nations. This prompted a number of investigators to evaluate the protective efficacy ratio of vaccine alone (30,32,34,121, 122).
The protective efficacy rates (PER) range from 67% to 96%. They were associated with chronic carriage rate of 3.4% to 21.4%. There appears to be a wide disparity between the yeast-derived and plasma derived vaccine results, despite the fact that the plasma derived product is a superior immunogen(123). Though the results with use of vaccine alone in this setting (HBIG not administered) are encouraging, additional controlled studies with larger sample size are required to ascertain whether active immunization alone can be considered a viable alternative to the combined immunization for infants born to HBsAg positive carrier mothers.
The vaccine is highly immunogenic; the seroconversion and seroprotection rates are greater than 95% after 3-dose vaccine course, irrespective of the schedule. Available litera-ture suggests that the protection offered by the vaccine lasts for at least 8-10 years (124-126). Even though, the anti HBs antibody levels may decline with time, presence of memory cells and anamnestic response would continue to provide protection against HBV infection(127).
The prevalence of HBsAg positivity (based on a single assay) in blood donors and pregnant women ranges from 0.7% to 7%, with most studies reporting values of around 2%. On the basis of available literature and the reasons discussed above, the true prevalence of HBV carriers in India is likely to be between 1% and 2%. The major one is the use of only a single test and not two sequential tests on a blood sample. The others are the absence of commu-nity-based data and possibility of inadvertent inclusion of high-risk individuals in the samples, especially among the blood donors.
Three fourths of the adult carriers have normal liver function tests (LFT). Of those who have normal LFT, upto 5% have CAH, of whom upto 10-20% may develop cirrhosis over the next 5 years. Only occasional cases of cirrhosis have been reported in those with normal or non-specific histological changes. Fifteen per cent of those who have abnormal LFT are likely to have CAH on histology. Two to seven percent of the adult cirrhotics (associated with HBV infection) develop HCC every year. The annual incidence of HCC in adult chronic carriers (>30-40 years age) has been reported to be 0-0.5%. One has to consider that the pattern and numbers are likely to be different for the whole population as this estimate has been derived from studies on natural history in adults. These estimates are based on studies done in the west and the high prevalence areas of Asia. The available studies have not evaluated the contribution of hepatitis C co-infection to development of hepato-cellular carcinoma.
Most of the data on the occurrence of HCC is in adult males; extrapolation to the whole population is likely to lead to further overestimation, as the complication rates are lower in women.
There is no doubt that very safe and efficacious vaccines are available to protect against HBV infection
We suggest from our review that the prevalence of HBsAg positivity and associated disease in India has been probably over-estimated. The prevalence estimates have not taken into account the overestimation due to inclusion of false positives, study samples being from blood donors and urban bias of the studies. Use of ‘test positivity’ data from the blood donors or pregnant women for defining the prevalence of HBV infection is not justifiable. Ideally two sequential tests should be performed before an individual is diagnosed to have HBV infection. Even though the literature suggests that some HBsAg negative individuals may test positive for HBV DNA(128), this possibly will not affect our conclusions. The formula that we have used to estimate the true prevalence also corrects for the less than 100% sensitivity of the test. Selective use of morbidity data may have led to over projection of chronic sequelae. Another reason for overestimation is because data on frequency of sequelae in males have been extrapolated to females whereas there appears to be a much lower rate of sequelae in women.
To judge the impact and cost benefit ratio for Hepatitis B immunization in India, analysis should be performed based on ‘true prevalence’ data. Further, in order to identify the correct strategy for such an immunization program, the relative importance of perinatal and horizontal transmission has to be defined for our population. If perinatal transmission is an important contributor to the carrier burden, then early immunization schedule starting at the earliest after birth has to be implemented; otherwise it may be acceptable to defer the first dose till one and a half months of age, which is more feasible, as one could merge it with existing schedule.
There is an urgent need for proper epidemiologic determination of the prevalence of HBV infection and associated morbidity/ mortality in India. This should be done taking into account the diversity in the country and the need for representation to all the sections of the population. While immunization programs in high-prevalence regions like Taiwan have led to significant decline in the prevalence, the same rate of decline may not be seen in low prevalence areas. It is important to have accurate baseline data, so that the impact of the immunization can be judged objectively.
Contributors: RL, YK and SKK reviewed the subject and drafted the paper. KA and CSP provided the statistical inputs and helped in the drafting of the paper. SKK will act as the guarantor for the manuscript.