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Chronic hepatitis B in Nepal: An Asian country with low prevalence of HBV Infection

Sandwiched between China, a country with high prevalence of hepatitis B surface antigen (HBsAg) and 30% of the world’s HBsAg carriers, and India which has intermediate HBsAg prevalence and 10% of the world’s carriers, Nepal has the lowest prevalence of hepatitis B virus (HBV) infection in Asia, with an HBsAg carrier rate of 0.9%. This treatise discusses the probable causes of this low prevalence based on published literature on the subject. The HBsAg prevalence among pregnant women in Nepal is low (0.5%) and none of those examined were HBeAg positive. The highest prevalence of HBsAg was found in the 6-15 years age group. The low prevalence of this infection in the country was due to an absence of significant vertical transmission and its predominant spread by horizontal transmission among the adolescent age group.


Introduction
Hepatitis B is a common viral infection of man. In about 5% of the infected persons the infection becomes chronic as indicated by persistence of hepatitis B surface antigen (HBsAg) in blood for more than six months. Persons with chronic hepatitis B are at risk of developing liver cirrhosis (LC) and hepatocellular carcinoma (HCC). There are about 400 million chronic carriers of the virus in the world. 1 Global prevalence of chronic hepatitis B virus (HBV) infection varies greatly and countries are defined under low, intermediate or high prevalence regions based on the HBsAg prevalence of <2%, 2-7% and >8%, respectively. 2 Hepatitis B is a parenterally transmitted virus that has adapted for its existence to the basic human activities like close association, sex and child-birth. Transmission of the virus occurs in community in three waves. First wave occurs during perinatal period when the virus is transmitted from infected mothers to infants during delivery and up to first year of life.
Second wave of transmission occurs during childhood by horizontal spread through close contact with infected siblings, father, relatives and friends. And the third wave of spread occurs during adult life through sexual contact, intravenous drug abuse, blood transfusion etc. The risk of chronicity is determined by the age at which the infection is acquired. 3 The infection becomes chronic in 90% among who acquire the infection vertically during the perinatal period up to 1 year of age. The risk of chronic infection is about 30% when it's acquired between 1-5 years of age. And it is only about 2% when the infection is acquired after 5 years of age or in adulthood. Major mode of spread in countries with high disease prevalence like China and Pacific countries is through vertical transmission. In Afro-Asian countries with intermediate prevalence predominant horizontal transmission has been noted during early childhood; and in low prevalence areas of North America, Western Europe and Australia it is through sexual or percutanous transmission during adulthood.
Asian countries are generally classified as moderate to high prevalence regions of HBV infection. 4 Nepal is a small country wedged between China in the north, with a high prevalence of HBV infection with nearly 120 million HBsAg carrier population 5 and India in the south with an intermediate prevalence of the infection and nearly 40 million HBsAg carriers. 6 Nepal is unique in having a low prevalence of HBV infection. 7 This treatise discusses the possible causes for the low prevalence of the HBV infection in Nepal based on published literature on the subject.

Community prevalence of HBsAg in Nepal
Nepal is geographically divided into 3 regions, the Himalayan region in the north bordering China, the hilly region in the middle and the planes or the Terai region in the south bordering India. It is a multi-ethnic country and its 30 million people belong to more than 25 distinct ethnic groups. 8 The first report on the prevalence of HBV infection in Nepal was a community study published in 1990. 7 The study included 2,555 normal subjects (1026 males and 1529 females) of different age groups, belonging to different ethnic backgrounds, from five areas spread over different geographic regions of the country. The study ( Table 1) showed that the prevalence of HBsAg in Nepal was 0.9% (1.6% among males and 0.5% among females). HBsAg was not detected in children below 5 years of age. Highest prevalence of HBsAg of 2.2% was detected in the 6-15 years age group and it rapidly declined as the age advanced. The shape of the anti-HBs curve was different. It progressively increased from 4.2% in 6-15 years age group to 10% in above 41 years age group. The low prevalence of HBsAg among Nepalese was confirmed by another study in 14,300 blood donors 9 and young adults that included 2,585 healthy adult males from different geographic regions of Nepal. [10][11][12]

HBsAg prevalence in pregnant women
The prevalence of HBsAg, anti-HBs and anti-HBc in 722 pregnant women from different ethnic backgrounds in the Kathmandu valley was noted to be 0.5%, 7.3% and 28.5%, respectively. 13 The overall infection rate (presence of any of the above markers of HBV infection) was 36%. None of the HBsAg positive pregnant women were HBeAg positive and 50% were anti-HBe positive. None of the persons with HBV markers gave history of jaundice. These observations suggested that HBV occurred in the community as a transient asymptomatic infection with low level of chronicity.

Prevalence of HBV infection among household contacts of persons with chronic HBV infection
The extent and mode of spread of HBV infection from persons with chronic HBV infection was assessed in a study on 186 close relatives of 45 HBsAg carriers (10 asymptomatic carriers and 35 with chronic liver disease and HCC). 14 Clusters of HBV infection were found among household contacts of persons with chronic HBV infections. The incidence of HBsAg antigenemia was highest among the siblings (31%) compared to offspring (20.5%) or spouses (17.7%) of the index cases ( Table 2), which suggested that predominant horizontal transmission of the infection occurred in this community. A very low incidence of acute hepatitis B of 3-9% among adult patients with acute viral hepatitis 15,16 suggested that sexual transmission is unlikely to be a common mode of spread of the infection in Nepal.

An area with intermediate prevalence of HBsAg in Nepal
The Surkhet valley is situated in west Nepal and has a population of 26,000 (1981 census). Forty-five percent of the people in the valley are below 15 years of age. The valley was initially inhabited mainly by Tharus, an indigenous forest tribe. The Tharus women adopt universal practices of extensive decorative tattooing in arms, legs and chest; and ear and nose piercing for ornamental purpose in girls starting from 5 years  High prevalence of HBsAg was detected in the Tibetans living in Nepal. 19  Nepalese living around these areas. The prevalence of HBsAg among Tibetans was 16% compared to 0.7% among the Nepalese ( Table 4). The dominant HBsAg subtype in Tibetans was 'ayw'. HBeAg was positive in 26% of the Tibetan women positive for HBsAg ( Table 5). The prevalence of HBsAg and HBeAg among children in 0-9 year age group among Tibetans was 20% and 71%, respectively, compared to the absence of HBsAg among Nepalese in the same age group. It was estimated that 27% of HBsAg in children in this community was contributed by perinatal transmission (

Possible cause for low prevalence of HBV infection in Nepal
In South Asian countries the prevalence of HBsAg among pregnant women varies from 2.5% to 3.8% 30,35,37 and about 7.8% to 30.2% of them are HBeAg positive ( Table 7). Vertical transmission of the infection thus occurs only in a small proportion of pregnant women positive for HBeAg, creating a small pool of highly infective young children. This assumption is supported by the finding of HBsAg prevalence of 3.2-6 % in children below 5 years of age ( Table 7). 30

Patterns of CHB infection
The age distribution, mode of transmission and the prevalence of hepatitis B in community have important clinical significance as they help determine the pattern of infection and successful strategies for their clinical management. Three pattern of CHB are described ( Table 8). 40 The first pattern is seen in China and adjoining Asian and Pacific countries where perinatal transmission occurs with very high incidence (90%) of CHB.

Conclusion
Nepal a country poised between two large nations China in the north with a 10% HBsAg carrier rate and India in the south with a 5% carrier rate, interestingly has a markedly low prevalence of 0.9%. The low prevalence of HBV infection in Nepal is due to its spread among adolescents by horizontal transmission. An absence of early childhood transmission was is because of lack of vertical transmission and low prevalence of active infection among pregnant women. This unique HBV distribution and transmission pattern suggests a fourth pattern of CHB infection with HBeAg(-), anti-HBe(+), normal ALT levels and low HBV-DNA levels among the population of Nepal. It is also noteworthy that of the bulk of LC and HCC cases in Nepal are related to hepatic vena caval disease.