SEA-Hepat.-5 SEA-EPI-141 Distribution: General
Prevention of Hepatitis B in India An Overview
World Health Organization Regional Office for South-East Asia New Delhi August 2002
(C) World Health Organization (2002) This document is not a formal publication of the World Health Organization (WHO), and all rights are reserved by the Organization. The document may, however, be freely reviewed, abstracted, reproduced or translated, in part or in whole, but not for sale or for use in conjunction with commercial purposes. The views expressed in documents by named authors are solely the responsibility of those authors.
CONTENTS Page 1. HEPATITIS B IN INDIA: BURDEN OF DISEASE ANALYSIS................................1 1.1 1.2. 1.3 1.4 1.5 2. Introduction.............................................................................................1 Background .............................................................................................1 Hepatitis B Immunization ........................................................................3 Hepatitis B in India ..................................................................................4 Conclusions and Implications...................................................................9
INCLUSION OF HEPATITIS B VACCINE IN NATIONAL IMMUNIZATION PROGRAMME IN INDIA: A REVIEW OF ECONOMIC ANALYSES .................10 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 Introduction...........................................................................................10 Economic Analyses in Health Care.........................................................11 Relevant Economic Analysis of Hepatitis B Vaccines in other Parts of the World ........................................................................18 Economic Analyses of Hepatitis B Vaccines in India ...............................19 Cost-benefit Analysis..............................................................................27 Summary of Findings of Cost-effectiveness Studies in India ....................27 Possible Limitations of Cost-effectiveness Studies in India ......................29 Conclusions ...........................................................................................32
3.
ACTION PLAN FOR INTRODUCTION OF HEPATITIS B VACCINE INTO IMMUNIZATION SERVICES IN INDIA ..................................32 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 Introduction...........................................................................................32 Goals and Objectives of Hepatitis B Immunization ................................34 Strategies for Hepatitis B Immunization .................................................35 Approach to Vaccine Introduction: Phased Introduction ........................36 Vaccine Logistics....................................................................................38 Cold Chain Logistics ..............................................................................39 Administrative Aspects ...........................................................................40 Training .................................................................................................40
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3.9. Information, Education, Communication (IEC) .......................................41 3.10 Programme Evaluation...........................................................................42
Annexes 1. 2. 3. 4. 5. 6. 7. 8. Studies of HBsAg Prevalence in India..............................................................51 Estimate HBsAg Prevalence by State, India......................................................53 Studies on Hepatitis B E Antigen (HBeAg) Prevalence Among Pregnant Women, India......................................................................54 Estimates (Provisional) of Hepatitis Disease Burden in a Single Year Birth Cohort, India ....................................................................55 Summary of Available Studies on Cost Effectiveness of Hepatitis B Vaccination in the Indian Population ...........................................57 Summary of Main Baseline Findings of Various Studies ..................................66 Vaccine Logistics for Implementation of Monovalent Hepatitis B Vaccine (2001-2002)......................................................................................67 Estimated Expenses for IEC (Information, Education and Communication Activities), Training and Evaluation of Introduction of Hepatitis B Vaccine ...........................................................68 Time Table for Activities Related to Introduction of Hepatitis B Vaccine ........................................................................................69
9.
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ACKNOWLEDGEMENT We acknowledge with appreciation the valuable inputs provided by Dr. Craig Shapiro, Temporary Advisor to the Regional Director, World Health Organization, South-East Asia Region, Dr. Charu Prakash, Short-Term Consultant, World Health Organization, South-East Asia Region, Dr. Rakesh Aggarwal, Additional Professor, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow and Dr. Sudhansh Malhotra, Assistant Commissioner Child Health, Deptt. Of Family Welfare, Ministry of Health and Family Welfare, Govt. of India, in producing this comprehensive document.
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1. 1.1
HEPATITIS B IN INDIA: BURDEN OF DISEASE ANALYSIS Introduction Hepatitis B is a major public health problem worldwide. Approximately 30% of the world’s population, or about 2 billion persons, have serological evidence of either current or past infection with hepatitis B virus. Of these, an estimated 350 million have chronic (lasting more than six months, and often for lifetime) HBV infection and at least one million chronically infected persons die each year of chronic liver disease, including cirrhosis and liver cancer. The hepatitis B vaccine is highly safe and effective, and prevents HBV infection and its serious consequences. The World Health Organization (WHO) recommends that hepatitis B vaccine should be given routinely to children in all countries. The purpose of this document is to review data regarding the disease burden due to hepatitis B in India, as a basis for a decision to introduce hepatitis B vaccine into the national immunization programme.
1.2.
Background (1) General features of Hepatitis B virus HBV, the cause of hepatitis B infection, is a DNA virus. The outer surface membrane of HBV contains hepatitis B surface antigen (HBsAg). Detection of HBsAg in the serum of an individual indicates that the person is currently infected with the virus. Detection in the serum of hepatitis B e antigen (HBeAg), a soluble protein in the inner core of the virus, correlates with the presence of virus in large amounts and is associated with greater infectivity.
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Prevention of Hepatitis B in India: An Overview
Another agent, called hepatitis D virus (HDV), is an incomplete virus that requires the presence of HBV infection for replication. HDV cannot multiply in the absence of hepatitis B virus. Persons with acute or chronic HBV infection are at risk of infection with HDV. HDV infection in a person with chronic HBV infection significantly increases the risk and rapidity of serious outcomes of HBV infection, including cirrhosis and liver failure.
(2) Clinical features of hepatitis B Infection with HBV can cause both short-term (acute) disease and long-term (chronic) disease. Acute hepatitis B occurs approximately 45-160 days after exposure to the virus. Symptoms associated with acute HBV infection typically include abdominal pain, nausea, fatigue, and jaundice (yellowing of the skin and eyes), but can range from none to occasionally fulminant hepatitis and death within days or weeks of onset of symptoms. Young children with acute HBV infection generally do not have symptoms. In comparison, adults with acute HBV infection are more likely to develop symptoms; however, even among them, a large majority (75%) of HBV infections go entirely unnoticed. Acute HBV infection can lead to one of several outcomes. Most patients with acute infection recover from the infection in a few weeks to a few months and become immune. A small minority (nearly 1% of those with symptomatic acute hepatitis) persons with acute HBV infection develop a serious illness, known as fulminant hepatitis, which is fatal in a large majority within days or weeks of onset of symptoms. Some persons with acute HBV infection develop a chronic infection. The risk of development of chronic HBV infection depends on the age at which HBV infection acquired. If the infection is acquired soon after birth, the risk of it becoming chronic is around 90%. This rate rapidly come down with increase in age at the time of infection, and by the age of six years, reaches the adult level of around 5%. Most of the serious outcomes due to HBV infection occur in persons who develop chronic HBV infection. Persons with chronic HBV infection may be asymptomatic for decades after infection; however, these persons are at high risk of eventually developing liver cirrhosis and/or primary liver cancer. The risk of death from HBV-related liver cancer or cirrhosis is approximately 25% for persons who become chronically infected during childhood and approximately 15% for persons who become chronically infected at an older age.
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Prevention of Hepatitis B in India: An Overview
(3) Transmission of Hepatitis B virus HBV is found in blood and blood-derived body fluids of infected persons. Transmission results by either percutaneous or mucosal exposure to blood or other infectious body fluids. The primary routes of HBV transmission areperinatal (from mother to baby at birth)--the risk of HBV infection among infants born to HBV-infected mothers ranges from <10% to >85%, with higher rates of transmission from mothers who are HBeAg-positive and lower rates of transmission from mothers who are HBeAg-negative; child to child, through frequent interpersonal contact of non-intact skin or mucous membranes with blood-containing secretions, or perhaps saliva from unsafe injections and transfusions, sexual contact, and tattooing and scarification. In regions with intermediate and high endemicity of HBV infection, HBV infections can occur at any age, but tend to predominate among infants and children. This is the age period when acute infection is more likely to develop into chronic infection.
1.3
Hepatitis B Immunization (1) Hepatitis B vaccine Hepatitis B vaccine has been available for several decades, and is highly safe and effective in preventing HBV infection and the development of its serious consequences. By preventing HBV infection, hepatitis B vaccine also protects against HDV infection. Two types of hepatitis B vaccine are available, plasma-derived and recombinant. Plasma-derived vaccine is prepared from purified HBsAg from the plasma of persons with chronic HBV infection. Recombinant hepatitis B vaccine is made using HBsAg synthesized by genetic engineering techniques. There are no significant differences in safety, immunogenicity, or efficacy between the two types of hepatitis B vaccines. Manufacture of plasma-derived vaccine includes several inactivation processes, each of which is adequate to kill the HBV. Plasma-derived vaccine is therefore entirely safe. The choice between the two types of vaccines should be based on cost, availability and other considerations and not efficacy.
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Prevention of Hepatitis B in India: An Overview
(2) Strategies for Hepatitis B immunization In 1991, the Global Advisory Group of the Expanded Programme on Immunization of WHO recommended that by the year 1997, hepatitis B vaccine should be introduced into national immunization programmes in all countries. This strategy was approved by the World Health Assembly in 1992. The high proportion of chronic infection that is acquired during childhood can be prevented by routine infant immunization. Numerous studies have shown that adding hepatitis B vaccine into the EPI is highly cost-effective, even in areas with low HBV endemicity. In adding hepatitis B vaccine into EPI, an important consideration is whether a birth dose of hepatitis B vaccine should be used to prevent perinatal transmission. Issues to consider in determining the priority for preventing perinatal HBV transmission include the relative contribution of perinatal transmission to the overall hepatitis B disease burden and the feasibility of delivering the first dose of hepatitis B vaccine at birth. In countries in which a high proportion (>40%) of pregnant women are hepatitis B e antigen (HBeAg) positive (e.g., Asia), incorporating a birth dose for all infants is generally indicated. In countries in which a low proportion (<10%) of pregnant women are HBeAg-positive (e.g., Africa), use of a birth dose is encouraged, if feasible (e.g., in birthing hospitals). When resources allow, additional strategies for hepatitis B immunization like catch-up vaccination of older children, adolescents and adults may be undertaken.
1.4
Hepatitis B in India (1) Methods to determine disease burden due to hepatitis B The primary methods to assess the disease burden associated with HBV infection are: surveillance for acute hepatitis B; measuring deaths from cirrhosis and hepatocellular carcinoma; and serosurveys to determine the prevalence of HBsAg (serologic marker of chronic HBV infection) among the general population or population subgroups. Data from each of these sources are available in India. However, limitations of the data for India are similar to that in other countries. Specifically, for acute disease surveillance, there is a likelihood of significant underreporting, because reporting depends on health Page 4
Prevention of Hepatitis B in India: An Overview
care workers informing higher administrative levels regarding cases they see in practice; cases, more frequently among children, are frequently asymptomatic and therefore not detected by surveillance for acute disease; and many persons with jaundice or other symptoms of viral hepatitis do not have serological testing, therefore it is not possible to determine the type of infection. Measuring deaths from cirrhosis and hepatocellular carcinoma is also subject to limitations of likely underreporting, and lack of etiological information (e.g. hepatitis B serologic status) available for deaths due to these causes. Also, primary hepatocellular carcinoma may be confused with secondary neoplasms of the liver. Issues to consider in interpreting seroprevalence data include the representativeness of the study sample, the quality (e.g. sensitivity and specificity) of testing, and inability to distinguish between acute and chronic HBV infection by HBsAg testing alone. The following review of studies on the disease burden of hepatitis B in India is based on an active search for all available studies, including a Medline search for articles published from 1975 to early 2000, and contacting researchers and other sources for unpublished data.
(2) Acute hepatitis B In 1994 and 1995 respectively, 110138 and 110012 cases of patients with acute jaundice (all causes) were reported to the Ministry of Health and Family Welfare, Government of India, corresponding to an annual rate of roughly 11 cases per 100,000 population. However, reporting of acute viral hepatitis is not required in India. The Ministry of Health and Family Welfare informally collects information on cases of patients with acute jaundice, but reporting is incomplete and etiological data are not collected. Because hepatitis laboratory testing is expensive and not readily available, few patients who seek clinical care for symptoms of hepatitis undergo serological testing. While not assessing the absolute numbers of cases of acute hepatitis B, several studies have evaluated the percentage of cases of acute jaundice that are caused by various types of hepatitis viruses. These populations generally include patients attending hospitals. The results of these studies show wide variation, and range from 9% to 62% HBsAg seropositivity among acute cases, with most studies in the range of 20% to 30% (Dass Gupta et al 1981, Dharmadhikari et al 1990, Ichhpujani et al 1991, Mallaya 1989, Panda et al
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1989, Sebastian et al 1990, Tandon et al 1984, and Tandon et al 1983). Many of these studies tested only for HBsAg and not for markers of acute HBV infection (e.g., IgM antibody to hepatitis B core antigen, anti-HBc IgM). In one study which used anti-HBc IgM testing, 10.4% patients presenting to Delhi hospitals with jaundice were anti-HBc IgM positive (Prakash 1998a). Several studies have looked at the role of HBV as a cause of fulminant hepatic failure. In three series of patients with fulminant hepatic failure, the proportions positive for HBsAg were 12.7% (Irshad et al 1994b), 31% (Raju et al 1989), and 22% (Tandon et al 1991a) respectively. Few studies of acute hepatitis B have examined risk factors among patients. One study conducted in the early 1990s among 160 cases and age and sex matched controls found that receiving injections with reusable needless in the six months prior to onset of illness was associated with development of acute hepatitis B (Narendranathan et al 1993). In India, unsafe injections may be an important source of HBV infection.
(3) Chronic liver disease and liver cancer Few data are available regarding the incidence of chronic liver disease in India as there is no surveillance system for the purpose. Vital statistics data are not reported with a separate category for chronic liver disease (instead, such deaths are reported in the category of “diseases of the digestive system”). Population-based cancer registries have been established by the Indian Council of Medical Research in Bangalore, Mumbai, Chennai, Delhi, Bhopal and Barshi. From these data, it has been estimated that approximately 11000 to 12500 new cases of liver cancer occur each year in India (articles not available for review). This rate of 11 per 1 000 000 is low compared to other countries in Asia and other parts of the world, and may be due to underdiagnosis and underreporting. Various studies have examined the proportion of persons with HBV infection among persons with chronic liver disease. Among patients diagnosed with chronic liver disease, the prevalence of HBsAg ranged from 33% to 75% (Acharya et al 1993, ICMR 1993, Kant et al 1995, Krishnamurthy et al 1976, Pal et al 1974, Sakhrie et al 1977, Sarin 1996, Sarin et al (in press), Sarin et al 1988, Singh et al 1976a, Sundaram et al 1990, and Sundaravalli et al 1988). Page 6
Prevention of Hepatitis B in India: An Overview
Other series of patients with cirrhosis show HBsAg positivity ranging from 56% to 70% of cases (Aikat et al 1977, Dharmadhikari et al 1990, Hill et al 1977, Kant et al 1995, Kelkar et al 1975, Kelkar et al 1973a, Saxena et al 1984, Singh et al 1976b, and Sundaram et al 1990). Histopathological studies of patients with liver cancer indicate evidence of HBV infection in 60% to 70% of cases (Kant et al 1995).
(4) Studies of HBsAg prevalence The most complete data providing a picture of hepatitis B disease burden in India come from HBsAg seroprevalence studies. Over the last several decades, numerous researchers have conducted seroprevalence studies in India. Such studies must be evaluated carefully and interpreted with caution, because these are often not population-based. This review of seroprevalence studies focuses on those among populations that were more representative (e.g. general population, pregnant women, voluntary blood donors) rather than studies among specific risk groups (e.g. haemodialysis patients). In interpreting the results of seroprevalence studies, sensitivity and specificity of the laboratory tests used also need to be taken into consideration. These studies are based on different techniques for detection of HBsAg in serum. These tests may differ in their sensitivity (ability to avoid false negatives) and specificity (ability to avoid false positives). Based on the characteristics of the test (like sensitivity, specificity, reproducibility, time taken for testing, and ease of performance of test), the tests may be of different generations, the more efficient tests being of a higher generation. Of the tests used in the studies under consideration, the first generation tests include immunodiffusion (ID), agar gel diffusion (AGD), and indirect haemagglutination (IHA), the second generation tests include reverse passive haemagglutination (RPHA), immunoelectrophoresis (IEOP), and countercurrent immunoelectrophoresis (CIEP) and the third generation tests include enzyme immunoassay (EIA) or enzyme-linked immunosorbent assay (ELISA), and radioimmunoassay (RIA). The results of HBsAg seroprevalence studies in various population groups in India are shown in Annex 1. Among population-based studies, HBsAg prevalence among general population groups ranged from 0.1% to 11.7%, being between 2% to 8% in most studies, and among pregnant
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Prevention of Hepatitis B in India: An Overview
women 0.6% to 11.2%. HBsAg prevalence rate among blood donors ranged from 1% to 4.7%. In an attempt to obtain a better picture of the geographical distribution of HBV infection in India, summary prevalence rates were determined for states for which data were available. Because the studies were done in a variety of populations, only the crude measure of the midpoint of the range of HBsAg prevalence observed in each state (rather than a weighted average) was used. The results are shown in Annex 2. While no data are available for many states, there does not appear to be any substantial geographical variation, with the possible exception of higher rates in the northeast (based on two studies). Assuming a HBsAg carrier rate of 5%, the total number of HBV carriers in the country is estimated to be about 50 million. This forms nearly 15% of the entire pool of HBV carriers in the world.
(5) HBeAg positivity among HBsAg-Positive pregnant women Besides the overall HBsAg prevalence, the hepatitis B e antigen (HBeAg) prevalence among carriers, especially pregnant women, is an important source of information for determining potential modes of HBV transmission in a population and underscores importance of giving a dose of hepatitis B vaccine soon after birth. Annex 3 presents results from available studies on the prevalence of HBeAg among pregnant women who are HBsAg positive. HBeAg prevalence among pregnant women who are HBsAg positive ranges between 7.8% and 47%, with most studies showing 18% or less. It appears that the HBeAg prevalence in India among HBsAg carriers is in general more similar to that in Africa (10%) than that in East Asia (30%-50%). Therefore the potential for perinatal HBV transmission in India is possibly lower than that in East Asia.
(6) Studies on hepatitis D Hepatitis D virus (HDV) infection in HBV carriers is not infrequent in the Indian population. Several studies have examined the prevalence of hepatitis D antigen or antibodies to HDV in sera from various patient groups.
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Prevention of Hepatitis B in India: An Overview
Seropositivity for delta infection (delta antigen and/or delta antibody) has been reported in about 7% to 20% of patients with acute hepatitis B, 13% to 17% of HBsAg carriers, 5% to 60% of patients with chronic liver disease, and 7% to 63% of patients with fulminant hepatic failure due to HBV infection (Amrapurkar et al 1992, Bhargava et al 1990, Desai et al 1990, George 1992, Gupta et al 1993, Irshad et al 1994b, Jyotsna et al 1998, Kochhar et al 1989, Pal et al 1987, Sumathy et al 1990, and Yadav et al 1990).
(7) Estimates of numbers of HBV infections in India The Hepatitis Branch of the US Centers for Disease Control and Prevention (CDC) has developed a computer-based model for estimating the number of HBV infections and serious disease outcomes in a population, using as input data the results of HBV prevalence studies and other data. This computer software allows the user to vary input parameters. It should be noted that the model is still being developed and evaluated. Data collected in this review were used in this model to obtain provisional estimates of the number of HBV infections and serious outcomes due to HBV infection in India (Annex 4). The input assumptions were an HBsAg prevalence of 5% among women of childbearing age (Annex 1), HBeAg prevalence of 15% among HBsAg positive women (Annex 3), a prevalence of 15% of any marker of HBV infection among five year old children and 40% among persons 30 years of age or older (Kant et al 1995, Sobeslavsky 1980, and Tandon et al 1991b). Using these data for a single year birth cohort (surviving infants) of 22 646 467 infants, over 9 million are estimated to acquire HBV infection during their lifetime, an estimated 1507000 will develop chronic HBV infection, and nearly 200 000 will die of acute or chronic consequences of HBV infection (Annex 4).
1.5
Conclusions and Implications Countries are classified on the basis of HBV endemicity as having high (8% or more), intermediate (2-7%), or low (less than 2%) depending on the prevalence in general population of hepatitis B carrier state. The prevalence of chronic HBV infection in different studies from India ranges from 2% to 10%, being below 8% in most studies. Therefore, India has intermediate to high
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Prevention of Hepatitis B in India: An Overview
endemicity, largely the former, for HBV infection. Based on available data, there does not appear to be substantial geographical variation in HBV prevalence. Based on an average HBsAg positivity rate of 5%, the total HBV carrier pool in India is estimated at 50 million. Reliable data on the exact burden of HBV disease in the form of number of cases of acute hepatitis B, chronic liver disease due to HBV and hepatocellular carcinoma associated with HBV are not available. It is estimated that of the nearly 22.6 million children born in India every year, over 9 million will acquire HBV infection during their lifetime, 1 507 000 will develop chronic HBV infection, and nearly 200 000 will die of acute or chronic consequences of HBV infection. Data on frequency of different routes of transmission of HBV infection in India are scanty. However, the low frequency of HBeAg positivity among HBsAg positive persons suggests that perinatal transmission is unlikely to be a major route.
2.
INCLUSION OF HEPATITIS B VACCINE IN NATIONAL IMMUNIZATION PROGRAMME IN INDIA: A REVIEW OF ECONOMIC ANALYSES Introduction A vaccine is available for prevention of HBV infection. This vaccine is highly effective and is entirely safe, except for minor local adverse effects. The protection provided by the vaccine is long lasting. More than 100 countries have already incorporated this vaccine in their national immunization programme. In countries that have implemented universal childhood hepatitis B immunization, HBV carrier rates have declined markedly and incidence rates of long-term consequences like liver cancer have shown a decrease. However, India has not yet included this vaccine in its immunization programme. The reasons for this are believed to be economic.
2.1
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Prevention of Hepatitis B in India: An Overview
It may be useful to carry out a cost -benefit analysis to arrive at a decision on introduction of hepatitis B vaccine in the India’s national programme of immunization.
2.2
Economic Analyses in Health Care Decision making process is a crucial element in the field of medicine, including public health. In making public health decisions, administrators and health policy- makers have to decide what to promote and what to pay for. Any public health programmeme requires resources (input), in the form of material, money and personnel, and results in health benefits or improvement (output). These inputs and outputs, being in different units, may be difficult to compare. Decision making is even more difficult if there are several public health programmemes competing for the same scarce resources. Economic analysis techniques allow for quantitative representation of inputs and outputs for a health care programme and thus facilitate decision making. Inputs are usually expressed in monetary terms. Output is measured either in clinical terms (improved health, duration of life, quality of life, etc) or in monetary terms. A decision can then be taken whether expected outputs justify the expected inputs (Kuo, 2000; Szucs 2000). Economic analyses can be based on experience gained either from a pilot project or from a similar programme that is in operation in another country. However such real-life data are frequently not available and modelling techniques are used for economic assessment of health care interventions.
(1) Types of economic analysis There are essentially three types of economic analysis for assessment of the economic impact of a health intervention like introduction of a new vaccine (Kuo, 2000; Szucs 2000). These are: cost-effectiveness, cost-utility and costbenefit analysis. Although these three procedures are very similar in
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Prevention of Hepatitis B in India: An Overview
consideration of costs, they differ in the manner in which outcomes are measures and valued. In a cost-effectiveness analysis, the effect of the intervention is measured using one or more simple health parameters, viz. ‘number of infections prevented’, ‘number of deaths prevented’, or ‘life years gained’, etc. In a costutility analysis (sometimes considered as a special case of cost-effectiveness analysis), effects of health care intervention are expressed as improvement in health using a composite measure of morbidity (reduction in quality of life) and mortality due to a disease, e.g. quality-adjusted life-years (QALY) or disability-adjusted life years (DALY). Cost-effectiveness and cost-utility analyses allow calculation of amount spent for each life-year or QALY (or DALY) gained, and thus allow comparison of different public health interventions. In a cost-benefit analysis, the benefits are also, like costs, expressed in monetary terms. In cost-benefit analysis, if estimated net benefits of an intervention exceed its net costs, its introduction is justified in economic terms (Kuo, 2000). The most appropriate type of economic analysis depends on the question to be answered. For use of a vaccine as a public health measure, e.g. universal infant hepatitis B immunization, a cost-benefit approach may be more appropriate than cost-effectiveness analysis (Szucs 2000). In comparison, for recommended vaccines, e.g. use of a vaccine for travellers’ diarrhoea, cost-effectiveness analysis may be more useful. Cost-effectiveness and cost-utility approaches are better when several competing health care options are to be compared. Cost-benefit approach, on the other hand, can be useful in deciding if one health intervention under consideration should be used or not. For performing an economic analysis, data on three major aspects are needed. These are: (a) costs of the intervention, (b) cost-savings from introducing the intervention, and (c) disease burden. The discussion here refers primarily to immunization programmes, in particular hepatitis B vaccination in developing countries with intermediate to high HBV endemicity rates.
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Prevention of Hepatitis B in India: An Overview
(2) Calculation of cost of a public health intervention Costs of a public health intervention include direct and indirect costs. Direct costs are further of two types: capital costs and recurrent costs. In relation to a vaccination programme, direct costs include the following; all these costs must be included in an economic analysis: Capital costs Recurrent costs
Ø Ø Ø Ø Ø
Transport Buildings Cold chain equipment Sterilization equipment Other equipment, including spare parts
Ø Ø Ø Ø
Vaccine, including costs of transportation Syringes and related supplies Salaries of immunization staff and programme managers Transportation costs including costs of fuel, vehicle maintenance, etc. Maintenance of cold chain equipment Training of staff Information campaign Cost of safe disposal of material Other supplies, such as stationary
Ø Ø Ø Ø Ø
Cost of vaccine and syringes is easy to determine. Other recurrent costs are often expressed as a composite figure per contact with the child. These recurrent costs are relatively small if a new vaccine is given simultaneously with a vaccine already included in the immunization programme. Capital costs can be included in the analysis either separately or as a part of vaccine administration costs; most analyses follow the latter technique. Indirect costs include expenditure on travel and on work time lost by the parents of the child being immunized. These costs should be included in an analysis from the societal perspective. However, since the schedule recommended by WHO for hepatitis B vaccination is similar to that for Page 13
Prevention of Hepatitis B in India: An Overview
diphtheria-pertussis-tetanus vaccine, no additional contact between the parents and immunization personnel is needed. Thus, accounting for indirect costs may not be required.
(3) Calculation of effectiveness, utility or benefits To accurately measure the effects of introduction of a vaccine, one needs to know the burden of disease being prevented, in terms not only of its prevalence and incidence, but also the morbidity and mortality associated with it. Consequences of hepatitis B infection, in the form of cirrhosis and liver cancer, appear over several years or decades. Data on long-term sequelae of HBV infection are therefore relatively limited and are from industrialized countries with low HBV endemicity. Data from countries that are highly endemic for hepatitis B are not available. However, with epidemiologic modelling, disease burden due to HBV infection and the reduction that may be expected in it with the introduction of the immunization programme can be calculated fairly well. Various denominators that have been used for assessing the costeffectiveness of hepatitis B immunization programmes include: number of cases of chronic HBV infection (chronic HBV carriers) prevented, number of cases of cirrhosis or liver cancer prevented, number of deaths prevented and number of life years gained. For cost-utility analysis, number of qualityadjusted life years (QALY) or number of disease-adjusted life years (DALY) gained can be used. For cost-benefit analysis, calculation of cost-savings is required. Such savings include direct medical costs of hospitalization and outpatient visits, e.g. for hepatoma, cirrhosis, and acute and fulminant hepatitis. The cost of treatment of these conditions can vary greatly between different countries. In industrialized countries, patients with chronic HBV infection are treated with costly interferon treatment and those with end-stage liver cirrhosis due to HBV infection may undergo liver transplantation. Economic analyses from these regions therefore include the costs saved on account of reduction in frequency of these interventions following hepatitis B immunization. In developing countries, these treatments are not easily available, or their cost is Page 14
Prevention of Hepatitis B in India: An Overview
not paid by the public exchequer. Hence, in these regions, cost savings in these forms of treatment must not be counted among the benefits of hepatitis B immunization programme. Calculation of cost savings should instead be based on the usual amount spent by patients in these countries on the treatment of the disease consequences of the infection.
(4) Calculation of cost-effectiveness Various public health interventions differ not only in their costs but also in their effectiveness i.e. the health-gain that they provide. The ratio of cost of a public health intervention to health-gain is termed as its cost-effectiveness, cost-utility or cost-benefit, depending on the nature of the denominator (a health parameter, a composite index of morbidity and mortality, or in monetary terms, respectively). The lower this ratio, the more effective an intervention is. A country’s per capita GNP is a good measure of the order of the magnitude of economic value of a year of life or QALY, and may serve as a good benchmark for decision making.
(5) Concept of marginal costs, marginal benefits and marginal cost-effectiveness Cost-effectiveness (or cost-utility or cost-benefit) ratio can be calculated separately for various alternatives (say immunization and no immunization). A better measure is to calculate the difference in costs and effectiveness between the different approaches, usually starting with the one that is the cheapest and least effective. These values are called marginal cost and marginal effectiveness. The ratio of marginal cost to marginal effectiveness is known as marginal (or incremental) cost-effectiveness. This ratio represents the additional cost for each additional unit of health-gain achieved with a particular intervention.
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Parameter Costs
Option A Cost A
Option B Cost B
Difference [Cost B – Cost A] or Marginal cost of option B [Effectiveness A – Effectiveness B] or Marginal effectiveness of option B (Marginal cost)/ (Marginal effectiveness) or Incremental costeffectiveness of option B
Effectiveness
Effectiveness A
Effectiveness B
Cost-effectiveness
Cost A/ Effectiveness A
Cost B/ Effectiveness B
(6) Other important concepts in relation to economic analysis Perspective of economic analysis in healthcare An economic analysis can be done from one of several viewpoints. For instance, an economic analysis could represent the way an individual, a society, a health care provider (like health maintenance organization, insurer or employer), or the government looks at the question. The perspective of an analysis is the point of view it represents. Analyses based on different perspectives can arrive at different conclusions, and it is important that the perspective corresponds to the type of decision to be taken. For decisions that are to be made in public interest or whose cost will be borne by the public, a societal perspective should be used. Thus, for a decision on the inclusion of hepatitis B vaccine, it is imperative that the economic analysis is from a societal perspective.
Time frame of analysis The time frame of an analysis depends on the nature of the disease condition it deals with, and the nature of the intervention. For instance, since the benefits of hepatitis B immunization occur after several years, analysis of this intervention has
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to be spread over either the entire life span or at least for the duration of productive life.
Discounting Cost of intervention and savings in health costs may extend over several years. People generally prefer to spend a given amount at a future date than spending that amount today. This preference for future costs is included in economic analysis in the form of ‘discounting’. Discounting is not an adjustment for inflation. It actually represents the greater importance of money available today over that available in the future, even if there was no inflation whatsoever. Discounting can also be done for health care benefits. Thus, a year of life gained several years later in future may be considered less important than a year of life gained at present time. Discounting for health effects is, however, not as well accepted as that for costs. (Szucs 2000) It has been recommended that results of economic analysis should be presented both without and with discounting (usually at a rate of 3% to 5%).
Sensitivity analysis Cost-effectiveness analyses are frequently subject to some degree of uncertainty. The parameters used in a decision model may not be known with accuracy. Errors in these assumptions may influence, at times markedly, the results of an analysis. Sensitivity analysis allows assessment of the effect of variations in the value of the variable(s) on the analysis results about which one is uncertain. These variables could relate to cost, to disease rates (e.g. incidence or prevalence of disease) or to benefits (e.g. quality of life, years of life gained, etc). During sensitivity analysis, the model is run several times making changes in the values of the parameter(s). If different values of the parameter give similar answer to the problem, the applicability of results obtained from the model becomes more certain. Sensitivity analysis also allows determination of a threshold, i.e. a value of the variable in question, at which two alternative public health approaches Page 17
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have identical value. Below this value of the variable, one strategy is preferable and above this value, the other strategy is preferable. Sensitivity analysis is one of the most powerful attributes of economic analysis. Such analyses must be undertaken in every economic analysis to test for robustness of the results obtained.
2.3
Relevant Economic Analysis of Hepatitis B Vaccines in other Parts of the World Most economic analyses of hepatitis B vaccination programmes have been done in industrialized, high-income countries with low HBV-endemicity rates (Jonsson et al, 1991; Hatziandreu et al 1991; Ginsberg et al, 1992a and 1992b; Demicheli et al, 1992; Margolis et al 1995; Fenn et al, 1996; Garuz et al, 1997; Edmunds 1998; Wiewiora-Pilecka, 2000). Such analyses may not be applicable to the Indian population. Only a few analyses have been done for countries with intermediate-to-high HBV endemicity and low-income levels. The results of these studies (Hall et al, 1993; Miller and McCann, 2000) are summarized below.
(1) Hall et al, 1993 This is the only published economic evaluation based on real experience of introduction of hepatitis B vaccine in a high endemicity country. Data on cost (both capital and recurrent) and coverage rate were obtained from the Gambian national immunization programme. Health effects, in the form of reduction in HBV carrier rate and incidence of liver cancer, were obtained from community surveys and national cancer register. Deaths from cirrhosis, and indirect savings by way of reduction in acute illness and loss of productivity were not taken into account. The cost of averting a hepatitis B carrier was found to be approximately US$ 40, and that of preventing death from liver cancer US$ 150-200. Inclusion of deaths due to cirrhosis would have reduced the cost of each death prevented even further. The authors compared the cost of averting death from liver cancer with that of averting death other vaccine-preventable diseases. This revealed Page 18
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hepatitis B vaccine to be less cost-effective than measles and tetanus, but more cost-effective than polio and diphtheria. (2)
Miller and McCann, 2000
This study used a single-year birth cohort model to estimate the impact of introducing several different childhood vaccines. The effect of universal childhood hepatitis B immunization was modelled separately in countries with different HBV endemicity rates and different income levels. Expected annual deaths from HBV were estimated from HBV carrier rate. The exact method for doing this has not been provided. Direct costs were calculated using vaccine cost of US$ 0.50 per dose and vaccine administration cost of US$ 0.18 per dose (for low income group countries). Indirect costs and treatment costs averted were not included in the model. The authors assumed that an intervention was cost-effective when the cost per life year saved was less than the per capita gross national product of the country. For low-income countries with intermediate HBV endemicity, the cost per life year saved was calculated as US$ 14 to US$ 19, indicating that introduction of hepatitis B vaccine was cost-effective for all countries.
2.4
Economic Analyses of Hepatitis B Vaccines in India A number of economic analyses of the inclusion of hepatitis B vaccine in the national immunization programme in India have been done (Aggarwal and Naik, 1994; Aggarwal and Naik, 1996, Prakash, 1999a, Prakash, 1999b, Miller and Kane 2000; Aggarwal et al 2002). The methods used, assumptions made and detailed results of these available cost-effectiveness studies in India have been summarized in Table 1. These studies are discussed individually in detail below.
(1) Aggarwal and Naik, 1994 This study compared the cost-effectiveness of two types of hepatitis B immunization programmes, namely universal childhood immunization against
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hepatitis B and selective immunization against hepatitis B (i.e. screening of pregnant women for hepatitis B surface antigen followed by immunization only of infants born to mothers who test positive). The study found that universal immunization is a more cost-effective strategy for prevention of HBV infection in India. This analysis based its major assumptions on a large study of hepatitis B transmission among 8/575 pregnant women in northern India to their newborns (Nayak et al, 1987). These included a HBsAg carrier rate among pregnant women of 3.7% and HBeAg positivity rate among HBsAg carriers of 7.8%. It was assumed that, 19% of the infants born to HBsAg-carrier mothers would develop HBV infection by the age of six months, and that infection would become chronic in 75% of those infected. Among the infants born to HBsAg-negative mothers, 3% were assumed to develop HBV infection and 50% of these were assumed to develop chronic infection. Based on these data, an estimate of contribution of perinatal transmission to the total HBV carrier pool was made. In addition, relative costs, effectiveness and costeffectiveness of two vaccination strategies, universal immunization or selective immunization only of infants born to HBsAg positive mothers, was calculated. For this, hepatitis B vaccine effectiveness rates of 95% for infants born to HBsAg-negative mothers and 75% for infants born to HBsAg-positive mothers were used. In the universal immunization group, hepatitis B vaccine cost was assumed as US$ 1.00 per vaccine dose and vaccine administration costs as US$ 1.30 per child (for all 3 doses). In the selective immunization group, these costs were assumed to be twice as high as those in the universal immunization group, and the unit cost of HBsAg testing among mothers as US$ 2.0. Compliance rate was assumed as 100%. Cost of treatment of complications of chronic HBV infection was not taken into account. Costeffectiveness was expressed as money spent for each HBV carrier prevented. Analysis in terms of years of life gained or QALY gained was not done. Using these assumptions, it was estimated that (a) perinatal transmission was likely to be responsible for only 14% of all HBV carriers in the Indian population, (b) selective immunization only of infants born to HBsAg-positive mothers would bring about only a minor reduction in the number of new carriers (through 12%), (c) universal infant immunization beginning at birth would bring about a 7.6-fold greater reduction in the number of new carriers (through 92%), (d) the cost of universal immunization programme would be 1.85-fold higher than that of selective immunization (being US$ 4.3 and US$ Page 20
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2.32 per newborn child, respectively), (e) the cost per HBV carrier prevented was 3.9-fold lower for the universal immunization programme (US$ 126) than for the selective immunization programme (US$ 495). Sensitivity analysis was not done on any of the assumptions made. The study concluded that universal immunization was the only effective strategy for the control of the HBV infection in India, and that selective immunization was unlikely to lead to significant changes in hepatitis B disease burden.
(2) Aggarwal and Naik, 1996 This analysis was essentially a minor modification of the analysis reported by these authors earlier (Aggarwal and Naik, 1994) in that the cost estimates for vaccination were revised slightly downwards. All other assumptions remained unchanged. In the universal immunization group, hepatitis B vaccine cost was assumed as US$ 0.75 per vaccine dose and vaccine administration costs as US$ 0.33 per dose. In the selective immunization group, these costs were assumed to be twice as high as those in the universal immunization group, and the unit cost of HBsAg testing among mothers as US$ 2.0. The conclusions reached were largely similar to those reached in these authors’ previous analysis. Thus, universal immunization, as compared to selective immunization, (a) led to 7.6-fold greater reduction in the number of new carriers (92%, versus 12%), (b) cost 1.45-fold more (US$ 3.25 versus US$ 2.24 per newborn child, respectively), and (c) 5.2-fold more cost-effective (US$ 95 verus US$ 498 per carrier prevented). The study also concluded that, in India, universal immunization was the only effective strategy for the control of HBV infection in India, and that selective immunization was unlikely to lead to significant changes in hepatitis B disease burden.
(3) Prakash, 1999a and 1999b This study was an economic evaluation (Prakash 1999a) of universal immunization against hepatitis B as a part of the Expanded Programme on
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Immunization (EPI) in India. This was done by incremental cost-effectiveness analysis, comparing this strategy with a “do-nothing” approach, that is, no immunization against hepatitis B. The study was an incidence-based cohort analysis where a decision tree (Markov Model) was constructed to estimate the expected costs and the expected effectiveness of the strategy, for the target population. Two cohorts, one with no hepatitis B immunization and the other which was immunized against hepatitis B at birth were followed up through their life time for hepatitis B infection acquired vertically at birth and the consequences thereof. The natural history of the disease was estimated from available literature. Horizontal transmission of HBV was not taken into account. In this analysis, HBV carrier rate among pregnant mothers in India was assumed as 9.5%, and HBeAg positivity rate among HBsAg-positive mothers was assumed as 12%; these rates were based on data obtained by the author in a small study. Further, it was assumed that the risk of HBV transmission from a HBsAg-positive mother to her newborn infant was 90% if the mother was HBeAg-positive and 15% if the mother was HBeAg-positive. Further, among infants born to HBeAg-positive mothers, the risk of HBV infection would be 90%; of such infected children, 2.8% would develop acute hepatitis, 90.2% would develop HBV-carrier state and 7% would be entirely asymptomatic. Among infants born to HBeAg-negative mothers, the risk of HBV infection was assumed as 15%, with 3.2% developing acute hepatitis, 15.7% developing HBV-carrier state and 81.1% being asymptomatic. Among infants with acute hepatitis B, 25% were expected to die of fulminant hepatitis and the remaining were expected to have disease resolution. Among HBVcarriers, 90% would develop chronic hepatitis (80% chronic persistent hepatitis and 20% chronic active hepatitis). Of those with chronic active hepatitis, 12.5% would be expected to develop cirrhosis or primary hepatocellular carcinoma. Vaccine cost was assumed to be US$ 0.75 per paediatric dose and costs of administration as US$ 0.19 per dose. Vaccine coverage rate was assumed to be 52%, vaccine wastage rate as 10% and vaccine efficacy in preventing HBV infection as 95%. Life expectancy for the population was modelled on the standard (ideal) life table. It was assumed that chronic persistent hepatitis due to HBV would develop at the age of 40 years and such patients would live till the age of 70 Page 22
Prevention of Hepatitis B in India: An Overview
years. Chronic active hepatitis was assumed to develop at age of 40 years and lead to death at the age of 55 years. Patients with cirrhosis were assumed to live for an average of 45 years. Costs of treatment of complications of HBV infection in India was estimated on the basis of number of inpatient and outpatient care episodes available from other geographical regions and costs of each inpatient and outpatient encounter from available Indian data. Liver transplantation and costs of interferon treatment were not included. Only direct costs of medical care were taken into account. The perspective was societal. The measure of effectiveness used in the study was Disability-Adjusted Life Years (DALYs) gained. A discount rate of three percent was used for calculation of costs. The effects were calculated with a discount rate of three percent, as well as with zero discounting. The cost-utility ratio was computed in 1993 US$ 27.36 per DALY gained. This ratio is well within the range of commonly accepted and implemented public health interventions. Sensitivity analysis was done for discount rate for effects (baseline 3%; alternative value = 0%). Using zero discount rate for effects, cost-effectiveness was US$ 19.08 per DALY gained. Several uncertainty analyses (using Latin hypercube sampling) were carried out to test the robustness of results to changes in variables whose values were uncertain (Prakash 1999b). The most important factors that influenced the cost-effectiveness were HBsAg positivity rate in carrier mothers and vaccination coverage. Other important variables were vaccine cost and vaccine efficacy. Vaccine wastage and HBeAg prevalence (i.e. infectivity of carriers) were less important, and treatment costs (in-patient and out-patient) had negligible influence on the result. The results of this study have not yet been published. The study has two major limitations. First, horizontal transmission of HBV, which is estimated to play a much larger role as compared to vertical transmission in India, was not taken into account. Accounting for horizontal transmission would make the HBV vaccination even more cost-effective than the author’s estimate. Second, the HBsAg carrier rate among pregnant women assumed in the model was
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relatively high. A lower assumption for this parameter is likely to make the vaccination less cost-effective than the author’s estimates. The two limitations may be expected to cancel out each other’s effect, at least partially.
(4) Miller and Kane, 2000 This study examined the cost-effectiveness of routine infant immunization. The authors assumed a 4% hepatitis B carrier rate in the Indian population, hepatitis B vaccine cost of US$0.50 per paediatric dose, 80% vaccine coverage, 10% vaccine wastage, and 95% vaccine efficacy. Further, they assumed that 20% of carriers will die of cirrhosis or liver cancer at an average age of 45 years. The average life expectancy of the birth-cohort was assumed as 66 years (in year 2040). Morbidity and cost of treatment of complications of HBV infection were ignored. Both undiscounted and discounted analyses were done (discount rate of 3% for health benefits). It was estimated that among a single-year birth cohort of 24 million infants, 193 000 would die of HBV- related liver disease. Hepatitis B vaccination, with the assumed coverage and efficacy rates, would save an estimated 147 000 lives for a cost between US$ 46 million dollars. The cost per death averted was US$ 312, and the marginal cost per year of life saved was US$ 12. Use of discounting increased the cost per death averted to US$ 1178 and cost per year life saved to US$ 66. Sensitivity analysis was done on the mortality rate due to cirrhosis and liver cancer among HBV carriers. Using a higher rate of 27% (compared to baseline rate of 20%), the number of deaths due to liver cirrhosis or liver cancer in a single-year birth cohort would be expected to be 261 000. Hepatitis B vaccination would prevent 198 000 of these deaths. The undiscounted cost per death averted was US$ 231, and the marginal cost per year of life saved was US$ 9 per year. Discounting increased these to US$ 873 and US$ 49 per life year, respectively. Sensitivity analysis on other parameters like hepatitis B carrier rate in the Indian population, cost of vaccine, vaccine coverage rate, vaccine efficacy rate, was not performed.
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(5) Aggarwal et al, 2002 Cost-effectiveness/cost-utility analysis This recent unpublished study provides the most detailed assessment of the cost-effectiveness of inclusion of hepatitis B vaccine in the India’s national immunization programme. It consists of two parts: (i) a cost-effectiveness / cost-utility analysis, and (ii) a cost-benefit analysis. This study used a decision analysis approach and Markov modelling to compare the costs and health effects in two single-year birth cohorts, one of these received hepatitis B vaccination and the other did not. These cohorts were then compared to assess the marginal cost, marginal effectiveness and incremental cost-effectiveness of the introduction of universal infant hepatitis B immunization. The baseline analysis in this study assumed 4% hepatitis B carrier rate in the Indian population, 75% vaccine coverage, 95% vaccine efficacy and 10% vaccine wastage rate. The cost of vaccine was assumed as US$ 0.50 per dose and that of vaccine administration as US$ 0.50 per dose. The health effects of hepatitis B carrier state were modelled using a Markov analysis. It was assumed that (i) hepatitis B carriers will progress to cirrhosis at a defined rate every year (none in the 0-9 year age-group, 0.5% annually in the 10-19 year age group, 1% every year with age >20 years), (ii) patients with cirrhosis will develop decompensated cirrhosis or liver cancer at a rate of 5% annually, and (iii) patients with decompensated cirrhosis or liver cancer would die at a rate of 20% annually. Both HBV carriers and noncarriers were subject to the age-specific death rates of the Indian population. Quality of life for patients with compensated liver cirrhosis was assumed as 0.95, and that for patients with decompensated cirrhosis of liver as 0.50. Cost-effectiveness was calculated in terms of amount spent per life year gained or amount spent per QALY gained. Both undiscounted and discounted analyses (with 3% discount rate for life years or QALY) were done. The cost-effectiveness/cost-utility analysis in this study showed that inclusion of hepatitis B vaccine in India’s national immunization programme should lead to a reduction in HBV carrier rate from 4.0% to 1.15% (a reduction Page 25
Prevention of Hepatitis B in India: An Overview
of 71%).In a single-year birth-cohort of 25 million children, this amounted to a reduction of 712 500 carriers. The immunization programme was estimated to lead to an increase in life expectancy of 0.15 years, and a gain of 0.17 QALY per child. The cost to the programme per carrier averted was US$ 98.7; cost per life year gained was US$ 19.06 and cost per QALY gained was US$ 16.26. These values are much lower than the per capita GNP of the Indian population, and well within the range of health care interventions considered as useful and worthy of spending public money. Several sensitivity analyses were done. These are summarized in Annex 5. Lower HBV carrier rate was associated with increase in cost per life year or QALY saved. However, even with carrier rate as low as 1%, the cost per life year was only US$ 76.22 and cost per QALY only US$ 65.06. Increase in cost of immunizing each child to two-fold (US$ 6.0 for three doses for one child) increased the cost per life year to US$ 38.10 and that per QALY to US$ 32.54; both these values are within the cost-efficacy estimates considered acceptable for public health interventions. The baseline analysis assumed a vaccine efficacy rate of 95%. It has been calculated that perinatal transmission accounts for only a minority of hepatitis B carriers in India. Concern has been expressed that administration of first dose of hepatitis B vaccine at six weeks may not prevent perinatal transmission, leading to reduced vaccine efficacy. However, with reduction of vaccine efficacy to as low as 70% (corresponding to perinatal transmission being responsible for around 30% to 35% of carriers), the cost-effectiveness of the immunization programme did not change much. Changes in the rate of vaccine wastage did not alter its cost-effectiveness significantly. Changes in vaccine coverage rate influenced the effectiveness of the programme but not cost-effectiveness, because reduced coverage rate also proportionately reduces the costs. Life years after 70 years of age may not be as productive as those below this age. This study also looked at the gain in life years and QALY before the cohort reached the age of 70 years. These gains were 0.11 life-years and 0.13 QALY respectively, at a cost of US$ 25.84 per life-year and US$ 21.56 per QALY. Page 26
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Discounted analysis (discount rate for benefits = 3% per year) found the cost per discounted life-year gained to be US$ 101.70 and cost per discounted QALY as US$ 82.94.
2.5
Cost-benefit Analysis The cost-benefit analysis used the same assumptions as for the costeffectiveness analysis, except that costs of treatment of complications of chronic HBV infection were also included in the analysis. Cost of treatment of liver cirrhosis was assumed as Indian Rupees 2 000 (US$ 1.00 = approximately INR 50) at onset and INR 2000 annually thereafter, and that of decompensated cirrhosis as INR 5 000 at onset and INR 5 000 annually thereafter. Indirect costs and money lost due to loss of work and reduction in life span were not included in the analysis. Both undiscounted and discounted (discount rate = 3% for costs) were undertaken. In the undiscounted analysis, cost-savings in the treatment of complications of chronic HBV infection, i.e. liver cirrhosis and liver cancer, induced by hepatitis B immunization programme would more than offset the entire expenditure on the immunization programme. Threshold analyses were done based on variations in the cost of treating complications of chronic HBV infection. Threshold for immunization to be the preferred option over ‘no immunization’ was found to be 0.30 times the baseline cost assumptions for treating complications of chronic HBV infection in undiscounted analysis and 1.15 times the baseline assumptions in undiscounted analysis.
2.6
Summary of Findings of Cost-effectiveness Studies in India Annex 6 summarizes the main findings of various cost-effectiveness studies on universal childhood vaccination that have been undertaken in India. Also included is a column showing the entire range of values obtained for each cost-effectiveness parameter in various studies, and the results of studies from other parts of the world that may be applicable to Indian situation.
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Despite differences in the model and methodology used, various costeffectiveness and cost-utility studies are unanimous in that inclusion of hepatitis B vaccine in the national programme of immunization will be costeffective.
Cost per carrier prevented Four studies looked at the cost per HBV carrier prevented, and found this to be US$ 126, 95, 63 and 99, respectively, providing values in a relatively narrow range. The difference in the values arrived at in these studies was primarily due to differences in price estimates for hepatitis B vaccine.
Cost per death averted This parameter was calculated in one study and was found to be US$ 231312 (undiscounted) and US$ 873-1178 (discounted). The undiscounted cost of each death averted is expectedly somewhat larger than that recorded in a study in Gambia (US$ 150-200; Hall et al, 1993), where HBV endemicity rate is much higher than in India.
Cost per life year gained Two studies calculated this value. Undiscounted estimates were US$ 9-12 and US$ 19, respectively, and discounted values (discount rate = 3% for health benefits in both studies) were US$ 49-66 and US$ 102, respectively. The difference in the results of these two studies is primarily related to differences in assumption about the cost of HBV vaccination (US$ 2.07 and US$ 3.00 per child, respectively).
Cost per QALY (or DALY) gained Two studies calculated this value. In one study, undiscounted cost was US$ 16 and discounted value (discount rate = 3% for health benefits) was US$ 83. In the second study, cost per QALY gained was US$ 27. The assumptions of second study are not fully known and hence it is not possible to determine the reason for differences in estimates arrived at in the two studies.
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Comparison of marginal cost effectiveness in terms of US$ per life year gained and per QALY gained with India’s per capita GNP (World Bank, 2001) favored inclusion of hepatitis B vaccine in the national immunization programme.
Cost-benefit analysis This type of analysis was done in only one study. It found that savings in health care costs for complications of HBV infection would exceed the amount spent on hepatitis B immunization. This too suggests that universal childhood hepatitis B immunization should be introduced in India.
2.7
Possible Limitations of Cost-effectiveness Studies in India This section addresses various limitations which may exist in the available economic analyses and their impact, if any, on the conclusions drawn.
Variability in data on HBsAg carrier rate in Indian population Various studies on hepatitis B carrier rate in India have shown widely different results. This variation is most likely related to sampling errors, and does not reflect a genuine variation in different geographical regions or in various subgroups in the population. Various cost-effectiveness studies have used carrier rates of 3.7% to 5%. This raises a concern that the results of cost-effectiveness studies may not be applicable to subpopulations with a lower HBsAg prevalence rates. However, sensitivity analyses performed in two of the cost-effectiveness studies showed that immunization was cost-effective over a wide range of carrier rates (even as low as 1%).
Vaccine coverage rates According to data from Ministry of Health and Family Welfare, Government of India, coverage rates for DPT and OPV were 73% (Ministry of Health and Family Welfare, 1999). A lower vaccine coverage rate, as has been reported in some other surveys, (International Institute of Population studies, 2000),
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may affect the effectiveness of the immunization programme adversely. However, sensitivity analyses in two studies showed that variations in this parameter influenced the cost-effectiveness only marginally.
Vaccine efficacy It may be argued that all the studies used vaccine efficacy rates of 95%, based on studies done elsewhere and vaccine efficacy data from India were not taken into account. However, use of data from other countries appears appropriate since (i) there are no large Indian long-term follow-up studies of vaccine recipients; (ii) efficacy rates for prevention of carrier stage have uniformly been exceeded 95%, and (iii) there is no reason to suspect a lower vaccine efficacy rate in the Indian population.
Perinatal transmission may not be prevented without a vaccine dose at birth HBeAg positivity rates among HBV carriers in India are fairly low. Hence, perinatal transmission is likely to be responsible for only a small minority of HBV carriers. In one study, this was calculated as 14% (Aggarwal and Naik, 1994). Hence, failure to provide birth dose will not affect the effectiveness of vaccination, and hence its cost-effectiveness, much.
Failure to include indirect costs None of the studies explicitly mentioned inclusion of indirect costs. This may have made the vaccination programme look too attractive. However, this may not be required since the recommended hepatitis B immunization schedule does not need any extra contact with children, additional indirect costs are likely to be minimal.
Failure to account for acute and fulminant hepatitis None of the studies has taken into account morbidity and mortality due to acute and fulminant hepatitis B. This however does not alter the conclusions drawn since (a) the morbidity due to these clinical presentations is short-lasted and mortality rare, and (b) their inclusion would, if anything, make vaccination strategy even more cost-effective.
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Vaccine cost used were much lower than the current market costs Most studies used vaccine costs in the range of US$ 0.5 to 1.00 per pediatric dose. The current retail price of the vaccine in the market is higher than that. However, bulk purchases of hepatitis B vaccine lead to marked reduction in price and, in several instances, even lower prices have been offered.
Hepatitis B vaccine may be diverted to adults Hepatitis B vaccine differs from other childhood vaccines in that it is useful in adults too, and this may increase the chances of its pilferage, thereby increasing programme costs. Two of the four analyses did consider 10% and 20% vaccine wastage rates and this should cover the excessive pilferage, if any.
Estimates of cost and QOL, and discounting rate used are arbitrary Indian data on these aspects are not available. Though errors in assumptions may affect the results of economic analyses, the rates used appear quite reasonable. The estimates used for cost of treatment of complications of chronic HBV infection were quite low and that for quality of life for patients with cirrhosis (0.95 on a scale of 0 to 1) fairly high. Thus, these estimates were, weighed against the policy of universal childhood immunization.
All studies look at single-year birth cohort and not beyond it All the studies have looked at the effect of hepatitis B immunization on a single-year birth cohort, i.e. all children born during a one-year period. In practice, reduction of carrier rate in a birth cohort by hepatitis B vaccine may be expected to reduce the opportunities for infection of the younger generations. Since siblings and playmates are a frequent source of horizontal transmission of hepatitis B, this effect can be expected to appear soon. A reduction in HBV transmission will also lead to an increase in age at transmission. Since the chance of HBV infection becoming chronic decreases rapidly with increase in age at the time of acquisition of infection, a further reduction in HBV carrier rate may be expected. These effects are non-linear and hence difficult to model (Medley et al, 2001). However, these effects will make HBV infection even more, and what is suggested by the available economic analyses. Page 31
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2.8
Conclusions A review of available studies on economic analysis of hepatitis B vaccine in India’s national immunization programme shows that this vaccine is highly cost-effective in terms of cost per life year gained and cost per QALY gained. In all the available studies, even on excluding the cost-savings on expenditure for treatment of complications of chronic HBV infection, cost per life year gained and cost per QALY gained are much lower than the country’s per capita GNP. In addition, the only available cost-benefit analysis shows that the cost of HBV immunization programme will be offset by savings in treatment costs of long-term sequelae of chronic HBV infection. The assumptions made in these analyses appear reasonable. Sensitivity analyses for several of the parameters confirm the robustness of the conclusions reached. The similarity of results obtained in various analyses, despite the use of different models for calculations, further confirms the validity of these conclusions. This review of various economic analyses strongly supports inclusion of hepatitis B vaccine in India’s national programme of immunization.
3. 3.1
ACTION PLAN FOR INTRODUCTION OF HEPATITIS B VACCINE INTO IMMUNIZATION SERVICES IN INDIA Introduction Based on the prevalence of hepatitis B carrier state in the general population, countries are classified as having high (8% or more), intermediate (2-7%), or low (less than 2%) HBV endemicity. India has intermediate endemicity of hepatitis B, with hepatitis B surface antigen (HBsAg) prevalence between 2% and 10% among populations studied. The prevalence does not vary significantly by region in the country. The number of HBsAg carriers in India has been estimated to be over 40 million. It has been estimated that, of the nearly 22.6 million infants forming a single-year birth cohort in India, over 1.5 million will develop chronic HBV infection, and nearly 200 000 will die of acute or chronic consequences of this infection.
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Hepatitis B e antigen (HBeAg) prevalence rate among pregnant women who are HBsAg positive ranges between 8% and 47%, being 18% or less in most studies. Therefore, perinatal transmission is unlikely to be a major route of acquisition of HBV infection in India. Several cost-effectiveness analyses of inclusion of hepatitis B vaccine in India’s national immunization programme have been conducted. These analyses indicate that with universal childhood hepatitis B immunization in India will be highly cost-effective, with cost per life year gained of US$ 9 to 19 (US$ 49-102 after discounting) and cost per quality-adjusted life year (QALY) gained of US$ 16 to 27 (US$ 83 after discounting). The cost of preventing each HBV carrier will be US$ 63 to 99. These analyses thus support the need to incorporate routine infant immunization with hepatitis B vaccine in India’s national immunization programme.
National Immunization Programme in India After successful eradication of smallpox in India, an Expanded Programme on Immunization (EPI) was started in the country with BCG, DPT and OPV in 1978. This programme was introduced in a phased manner due to financial and infrastructural constraints. In 1985, it received a major boost, with the launch of Universal Immunization Programme, in the form of increased funding, better availability of vaccines, and establishment of a cold chain. In that year, measles antigen was added to the list of childhood vaccines included in the EPI. The programme was gradually extended from 30 districts in 1985-86 to the entire country by 1989-90. To date, the use of hepatitis B vaccine in Indian children has been fairly limited. A pilot hepatitis B vaccination programme was conducted in East Delhi beginning late 1996 using vaccine donated by the WHO. In this pilot project, between 200,000 to 300,000 doses of hepatitis B vaccine were administered to infants. The objective of this pilot project was to assess the feasibility of including hepatitis B vaccine into Universal Immunization Programme (UIP), and to assess the requirement for forms and educational material. In this pilot project, three-dose coverage rate among the target population was estimated to be around 60%. Following the pilot project, the Government of Delhi successfully introduced hepatitis B all over Delhi. Experience from this pilot project has been incorporated in the proposed plan for phased introduction of hepatitis B vaccine in India. Page 33
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In addition, two states (Kerala and Haryana) began hepatitis B vaccination using a cost-recovery strategy. These programmes were, however, discontinued because of logistic difficulties. These projects were endeavours of the state governments. Unfortunately, the experience of these projects and the lessons learnt from them were not documented. During the last few years, hepatitis B vaccine has been available in the private sector in urban areas for those who can afford it. The Indian Academy of Paediatrics, which is the highest professional body of paediatricians in the country, has advocated hepatitis B vaccine as part of routine immunization schedule. Many doctors therefore administer hepatitis B vaccine to patients and children under their care. Many schools and non-governmental voluntary organizations have been organizing hepatitis B vaccination drives on a payment basis. Though these drives possibly reflect public acceptance and demand for hepatitis B vaccine, these have not reached the rural population and the urban poor. It is important to note that over 90% of immunization in India is provided by the public sector. Government of India is also supporting planned state programmes for introduction of new vaccines in the routine immunization. These include the Government of Andhra Pradesh’s partnership project with the Gates Children’s Vaccine Programme at Path. This project is expected to (i) help in development of IEC resource material and (ii) provide experience with training of staff, planning of cold chain and other vaccine logistics planning. These will prove useful when the national-level programme is launched. Government of India is now working towards a planned phasing-in of hepatitis B vaccine, based on the capacity of the states and districts and sustainable funding. The opportunity afforded by GAVI and the Vaccine Fund is appreciated and now there is government approval for sustaining this programme through planned allocation of national resources.
3.2
Goals and Objectives of Hepatitis B Immunization The ultimate goal of hepatitis B vaccination is to reduce morbidity and mortality associated with chronic HBV infection, including cirrhosis and liver
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cancer. However, because the long-term consequences of HBV infection occur several years after infection, this goal will take a long time to attain. Therefore, the following short-term goals and objectives have been defined:
Ø Ø Ø Ø Ø
Phased introduction of hepatitis B vaccine into Expanded Programme of Immunization (EPI) beginning in the year 2002. Delivery of hepatitis B and all other EPI vaccines according to safe injection practices. Training of health care workers, and sensitization of policy makers and the community about HBV infection and hepatitis B vaccine. Reduction in vaccine wastage by promoting an open vial policy. Reduction in prevalence of HBsAg among 3-5 year old children through 55%, compared to the prevalence in the pre-vaccine period, by 2008.
3.3
Strategies for Hepatitis B Immunization (1) Vaccine preparation In addition to monovalent hepatitis B vaccine, a polyvalent preparation that combines hepatitis B vaccine with diphtheria-tetanus-pertussis vaccine in a single injection has recently become available. Such combined vaccines decrease the number of injections that a child receives at each visit, make distribution of vaccine easy and reduce the requirement for storage space. It is currently proposed to use monovalent hepatitis B vaccine in multidose vials. Several companies manufacture hepatitis B vaccine in India. These companies have the capacity to provide adequate vaccine for routine infant immunization. Due to increased competition and with bulk purchases, the price of hepatitis B vaccine has dropped substantially to as low as US$ 0.40 per dose.
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Vaccination Schedule The proposed new schedule for childhood immunization using monovalent hepatitis B vaccine is given in Table 1 below: Table 1: Proposed childhood vaccination schedule, India Vaccine BCG OPV DPT Hepatitis B Measles Schedule Birth 6 weeks, 10 weeks, 14 weeks 6 weeks, 10 weeks, 14 weeks 6 weeks, 10 weeks, 14 weeks 9 months
(2)
Birth dose of Hepatitis B vaccine
Because of low rate of HBeAg-positivity among persons with chronic HBV infection in India, perinatal HBV transmission probably accounts for a minor proportion of HBV transmission. Further, only about 25% of all births in India take place in hospitals. Therefore, a birth dose of hepatitis B vaccine is not being incorporated in the EPI schedule. Feasibility of providing a birth dose to neonates of women who deliver in hospital may be considered at a future date.
3.4
Approach to Vaccine Introduction: Phased Introduction Approach paper to the Ninth Five-Year-Plan had recommended the introduction of hepatitis B vaccine into the routine immunization programme of the country. However, this was not possible because of limitation of resources and preoccupation of state governments and field health staff with activities related to polio eradication. As the country is fast approaching the stage of zero-incidence of polio, activities relating to polio eradication are being rapidly scaled down. This would lead to release of resources, both financial and human, for undertaking fresh initiatives. Concurrently, the Ministry of Health and Family Welfare (MOHFW), Government of India, has taken measures to strengthen the routine immunization programme as well as
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to improve the reach of reproductive and child health services. The stage is therefore set for the introduction of hepatitis B vaccine in the routine immunization programme in India. Given its vast size, the financial and logistical constraints, and the fact that India is currently in the middle of a five-year planning cycle, it is not possible to introduce hepatitis B vaccine to all states and districts in India simultaneously. Instead, the hepatitis B vaccine must be introduced in phases, over a period of years. Although data are limited for some states, the prevalence of HBV infection is relatively homogenous in various parts of the country (with some pockets of high prevalence). Therefore, the order of various regions of the country for phasing-in will be determined mainly by their vaccination performance and their capacity (including availability of cold chain) to incorporate a new vaccine into the immunization schedule. The benefits of this gradual phasing in vaccination include: (i) need for less funds during the initial years, and (ii) providing an opportunity to assess the operational feasibility of the programme and to take mid-term corrective measures based on experience in the regions where vaccine is initially introduced. It is therefore proposed to introduce hepatitis B vaccine, during Phase I, in 15 metropolitan cities (Phase IA) and in 32 rural districts (located in 17 states), which have satisfactory coverage rates for other EPI vaccines (Phase IB). The planned duration for this phase is two years (part of ninth five-year plan period, and rolling into the Tenth Five-Year Plan period (2002-2007). Phase II of the introduction of hepatitis B vaccine will correspond with the Tenth Five Year Plan. The detailed plan for this phase will be incorporated in to the Tenth Five Year Plan document. The Ministry of Health and Family Welfare intends to make the vaccine available in additional districts with the intention of covering all the districts in phases over the next Five Year Plan, 2003-2006. The India UIP also plans to introduce AD syringes for administration of all vaccines in areas where hepatitis B vaccine is introduced. As far as possible, Indian UIP wants to have a uniform system of injection for all vaccines.
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3.5
Vaccine Logistics (1) Vial size Indian EPI currently uses 10-dose vials of DPT vaccine. To facilitate introduction of hepatitis B vaccine into the existing EPI, it is proposed to use 10-dose vials.
(2) Wastage Vaccine wastage has been currently estimated as approximately 25%, i.e. five percent higher than that for DPT to account for expected leakages during the phasing-in period. However, prior to the introduction of hepatitis B vaccine, a study will be undertaken to determine baseline wastage rates and reasons. This will help evolve strategies to reduce vaccine wastage. Vaccine manufacturers are soon likely to start attaching vaccine vial monitors (VVMs) to all hepatitis B vaccine vials to indicate whether the vaccine has been damaged by heat. Once VVMs become commonplace, an open vial policy will be encouraged to reduce vaccine wastage. Special attention will need to be given to prevent use in non-targeted populations.
(3) Vaccine requirements The estimated number of doses of monovalent hepatitis B vaccine that will be required over the next two years (2002-2003) is presented in Annex 7. These estimates were produced using the following assumption of 25% vaccine wastage rate in 2002 and 20% in 2003.
(4) Injection safety Currently, reusable glass syringes and needles and sterilization equipment like autoclaves/double rack steam sterilizers are used throughout India. The quality and safety of injection techniques and sterilization is uncertain. The Government desires to improve injection safety and is planning to conduct a comprehensive injection safety assessment and use the findings for improvement. However, UIP is committed to moving from using re-sterilizable
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syringes and needles to auto-disable (AD) syringes in accordance with the WHO-UNICEF-UNFPA policy statement on injection safety.
3.6
Cold Chain Logistics Introduction of hepatitis B vaccine, whether in the form of monovalent or combination vaccine, will require an assessment of cold-chain capacity. This will be particularly important if a decision to use monovalent hepatitis B vaccine is made. In addition, as compared to other EPI vaccines, the hepatitis B vaccine is relatively heat stable but is easily destroyed by freezing. Therefore, storage and shipping procedures to prevent freezing of vaccines at all levels of the cold chain will need attention. Under the Immunization Strengthening Project (World Bank), a major effort, not only to replace but also to expand the cold chain, has been undertaken over the last two years. Several states (Andhra Pradesh 2001, Madhya Pradesh 2000, Orissa 2000 and Uttar Pradesh 1999) have conducted assessment of their cold chain requirements. In these states, it has been shown that the need for cold chain space can be addressed by moving equipment form some districts with excess refrigerators to those that are deficient. This fact was proved to be true when these districts successfully conducted national immunization days for polio immunization, without any cold chain capacity constraints. Some ongoing activities of the Government of India regarding the cold chain are: (1) Procurement of additional cold chain equipment and vaccine vans that would be required in the next three years through the Immunization Strengthening Fund. (2) Assistance from KfW of Germany for cold chain is already in progress and the equipment is being installed in priority districts. (3) Solar refrigerators provided by JICA are also being installed in eastern India. (4) Funds from the Immunization Strengthening Fund are available for maintenance of the existing cold chain equipment. Even though the government is convinced that cold chain will not be a major problem in the target districts, the Government of India will conduct Page 39
Prevention of Hepatitis B in India: An Overview
further district-specific cold chain capacity assessment. As a first step in this process, the Government of India has approached the WHO/Regional Office cold-chain expert to conduct a brief review of the cold chain space requirement in these districts. The cold-chain expert has calculated the extra cold chain space required. District Programme Officers have been requested to review the cold chain system prior to introduction of hepatitis B vaccine in all districts, in order to ensure that refrigerators are working properly.
3.7
Administrative Aspects All UIP forms, administrative and training materials will need to be revised/updated to include hepatitis B vaccine. These include:
Ø Ø Ø Ø Ø Ø
Immunization schedule Immunization card Daily tally sheet Vaccine register Vaccination register Monthly report forms
These materials will be created during the 6-month preparatory period from July-November, 2001.
3.8
Training Consideration will be given to separate training of EPI staff through a National “Training of the Trainer” programme. National trainers will train mid-level managers at national and regional level, who will in turn train field workers. The training will be integrated with Universal Immunization Programme (UIP) or IMCI training programmes, as much as possible. The India UIP will use funding made available through the World Bank for these training activities. Programme for Appropriate Technology in Health / Bill And Melinda Gates Children’s Vaccine Programme (PATH/CVP) has also been approach and has agreed to provide the required training materials. Page 40
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3.9.
Information, Education, Communication (IEC) Success of an immunization programme lies in creating awareness about it in parents, the general public, decision-makers, community groups, and health care workers. IEC activities are, therefore, an important part of implementation of hepatitis B immunization programme. The addition of hepatitis B vaccine to the national immunization programme can improve the coverage of other EPI vaccines. This is related to renewed motivation among health workers to deliver a new vaccine to the population. In addition, inclusion of a new vaccine in the immunization programme creates increased awareness the public and among health care staff about benefits provided by vaccination leading to an increase in participation rates. The MOHFW acknowledges the difficulty of introducing a new vaccine in 15 metro cities and 32 districts all over the country. To strengthen the local capacity, the MOHFW will approach partner agencies to fund recruitment and hiring of a hepatitis B accine introduction advisor, to coordinate and monitor smooth introduction of the vaccine. In Phase II of the vaccine introduction, during the 10th five -year plan, the MOHFW will assign four more coordinators to monitor introduction of the vaccine in four zones of the country. Creation of a national-level advisory group, that will include leading hepatologists and paediatricians, will also be considered to assist the efforts of the MOHFW in the smooth introduction of the vaccine. Between July and September 2002, information materials on hepatitis B and hepatitis B vaccine for parents, the general public, and key decision makers and community leaders will be prepared. Information materials appropriate for medical and nursing staff in academic and private facilities will also be developed. A national-level workshop including policymakers, nongovernmental voluntary organizations, Ministry of Health staff, and clinicians will be held to disseminate information. Consideration will also be given to incorporating this information into IMCI training, if feasible. Important messages for these groups will include the following: (i) hepatitis B infection and its consequences, (ii) how the virus is transmitted, (iii)
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benefits of hepatitis B vaccine, (iv) who should receive hepatitis B vaccine; and (v) how many doses of hepatitis B vaccine should the infants receive, and at what age. Specific materials to be revised include posters, leaflets and stickers.
3.10
Programme Evaluation The ultimate objective of hepatitis B immunization is to prevent chronic HBV infection and its long-term consequences (cirrhosis and liver cancer). However, these outcomes are difficult to measure. Also, since most HBV infections in children are asymptomatic, disease surveillance cannot be used to evaluate the impact of hepatitis B immunization. Furthermore, cirrhosis and liver cancer caused by HBV infection generally do not occur until adulthood. Therefore, indirect measures of programme impact must be used. In addition to monitoring the introduction process, the following methods can be used to evaluate implementation of hepatitis B immunization.
(1) Monitoring introduction of hepatitis B vaccine The experience of districts where the vaccine is introduced in the first phase would be useful to the districts where it is introduced later. Close monitoring will therefore be essential in the first phase. It should include visits of the national hepatitis B vaccine introduction advisor, joint site visits of the hepatitis B vaccine introduction advisor with the national staff to selected districts, and preparation of reports by the states describing their experience, including any problems encountered and suggestions for improvement. Aspects to be reviewed should include acceptability to the public, ease of use and acceptability to health staff, coverage of infants with each dose, and appropriate storage, distribution and use of hepatitis B vaccine.
(2) Evaluating programme effectiveness The effectiveness of introduction of hepatitis B vaccine can be evaluated by measuring coverage through (i) routine reports, and (ii) coverage surveys. For both of these, hepatitis B vaccine indicators and targets can be the same as those for DTP3. Coverage surveys may provide more accurate information than routine reports. Serological surveys can be used to provide serological evidence of receipt of vaccination. Such surveys can also provide data on reduction in Page 42
Prevention of Hepatitis B in India: An Overview
rates of HBV infection, compared to baseline HBsAg positivity data already available. Thus, a serological survey of 3-5 year old children conducted approximately five years after the full implementation of hepatitis B immunization programme and comparison with results from children of similar age in previous surveys can provide data on the programme’s effectiveness of the programme.
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Sundaram C, Reddy CR, Ramana GV, et al. Hepatitis B surface antigen, hepatocellular carcinoma and cirrhosis in south India: an autopsy study. Indian J Pathol Microbiol 1990; 33: 334-8. Sundaravalli N, Nedunchezian VSS, Sriramachari S, et al. HBs antigenemia in chronic liver disorders in infancy and childhood. Trop Gastroenterol 1988; 9: 80-2. Szucs T. Cost-benefits of vaccination programmemes. Vaccine 2000; 18 (Suppl): S4951. Tandon BN, Gandhi BM, Joshi YK, et al. Etiological spectrum of viral hepatitis and prevalence of markers of hepatitis A and B virus infection in north India. Bull WHO 1984; 62: 67. Tandon BN, Irshad M, Acharya SK, et al.Hepatitis C virus infection is the major cause of severe liver disease in India. Gastroenterol Jpn 1991a; 26 (suppl. 3): 1460. Tandon BN, Irshad M, Raju M, Mathur GP, Rao MN. Prevalence of HBsAg and antiHBs in children and strategy suggested for immunization in India. Indian J Med Res 1991b; 93: 337-9. Tandon BN, Joshi YK, Gandhi BM, et al. Epidemiology of HBsAg carriers In India. A holistic approach to control of hepatitis B reservoir. J Gastroenterol Hepatol 1986; 1: 39-43. Tandon BN, Nayak NC, Tandon HD, et al. Acute viral hepatitis with bridging necrosis. Collaborative study on chronic hepatitis. Liver 1983; 3: 140. Thakur TS, Goyal A, Sharma V, et al. Incidence of Australia antigen (HBsAg) in Himachal Pradesh. J Commun Dis 1990; 22: 173-7. Thyagarajan SP, Subramanian S, Sundaravelu T, et al. HBsAg carriers among hospital personnel. J Assoc Physicians India. 1981; 29: 941. Vyas KK, Mathur AK, Vyas RK. A study of prevalence of hepatitis b surface antigen among pregnant women. J Obstetr Gynaecolov India 1983; 33: 778-81. Wiewiora-Pilecka D. Cost-benefit analysis of the Polish hepatitis B prevention programmeme. Vaccine 2000; 18 (Suppl 1): S52-4 World Bank. The World Bank Group. Development data: Country data. Cited December 20, 2001. Available from: URL: http://www.worldbank.org/data/ countrydata/countrydata.html. Yadav SK, Jain AK Gupta S, et al. Delta infection in HBV related liver diseases. Indian J Gastroenterol 1990; 9 (Suppl): A61.
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Prevention of Hepatitis B in India: An Overview
Annex 1
STUDIES OF HBSAG PREVALENCE IN INDIA Population studied State/UT Voluntary blood donors Kerala Maharashtra Maharashtra Maharashtra Maharashtra Maharashtra Tamil Nadu Tamil Nadu West Bengal Delhi Delhi Delhi Jammu & Kashmir Chandigarh General population Andhra Pradesh Karnataka Kerala Maharashtra Maharashtra Tamil Nadu Tamil Nadu Tamil Nadu Uttar Pradesh West Bengal West Bengal West Bengal Arunachal Pradesh Arunachal Pradesh Delhi Delhi Delhi Himachal Pradesh ELISA ELISA IEO, AGD AGD IEOP CIEP ID IEOP ID CIEP ELISA CIEP RPHA ID ELISA ELISA RPHA 737 816 475 420 625 123 127 531 846 199 NA 960 755 296 952 1,800 1,982 500 3.3 4.0 2.0 1.4 4.0 1.6 2.3 0.8 1.2 0 3.0 5.0 5.8 8.5 0.1 11.7 2.2 3.6 Singh et al 2000 Singh et al 2000 Shanmugham et al 1978 Kelkar et al 1973b Kotwal et al 1973 Thyagarajan et al 1981 Blumberg et al 1970 Hill et al 1973 Mittal et al 1980 Hill et al 1970 Chakraborthy et al 1977 Chowdhury et al 1999 Prasad et al 1983 Prasad et al 1983 Sama et al 1971 Irshad et al 1992 Tandon et al 1991b Thakur et al 1990 CIEP ELISA ELISA ELISA ELISA ELISA IEOP 8085 3104 3095 3883 3455 1042 1321 35 395 680 132093 20435 7900 1470 1.0 4.7 3.7 2.0 2.0 2.1 2.3 2.2 2.0 2.7 2.5 2.6 1.1 1.5 Jayaprakash et al 1983 Satoskar et al 1992 Elavia et al 1991 Elavia et al 1991 Elavia et al 1991 Mohite et al 1999 Hill et al 1973 Singhvi et al 1990 Roychoudhury et al 1989 Dutta et al 1972 Nanu et al 1997 Irshad et al 1994a Makroo et al 1989 Pal et al 1973 Type of test No. of subjects % HbsAg positive Reference
ID, IEOP EIA RPHA IEOP, ID
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Prevention of Hepatitis B in India: An Overview
Population studied State/UT Jammu & Kashmir Pregnant women Karnataka Kerala Kerala Maharashtra Maharashtra Maharashtra Rajasthan Rajasthan Rajasthan Rajasthan Uttar Pradesh Uttar Pradesh Uttar Pradesh Uttar Pradesh Delhi Delhi Delhi Delhi Delhi Manipur Chandigarh Chandigarh Chandigarh Karnataka Delhi Students Kerala
Type of test
No. of subjects 144
% HbsAg positive 9.7
Reference Dutta et al 1975
RPHA IEOP, AGD CIEP CIEP, RIA IHA RIA AGD, CIEP CIEP ELISA CIEP RPHA,CIEP, AGD ELISA RPHA RPHA, ELISA ELISA ELISA ELISA ELISA ELISA ELISA RPHA, ELISA ELISA ELISA ELISA
400 400 1475 1276 2000 1276 500 1,000 295 500 400 206 400 157 8575 598 837 8431 850 13 1000 4137 2337 1553 982
5.0 3.0 3.0 0.6 5.0 0.6 1.0 2.2 6.8 1.0 4.8 8.7 4.8 10.0 3.7 11.2 3.6 2.6 6.3 7.7 2.3 2.6 2.5 4.0 2.5
Kulkarni et al 1988 Shanmugham et al 1982 Shanmugham et al 1978 Khatri et al 1980 Gill et al 1995 Panda et al 1991 Vyas et al 1983 Gupta et al 1985 Prakash et al 1998b Vyas et al 1983 Datta et al 1988 Prakash et al 1998b Khatri et al 1980 Sharma et al 1996 Nayak et al 1987 Prakash et al 1998b Tandon et al 1986 Panda et al 1991 Mittal et al 1996 Prakash et al 1998b Biswas et al 1989 Sehgal et al 1992 Gupta et al 1992 Patnaik et al 2000 Tandon et al 1991
Children <5 yrs of age
IEOP, AGD
0.6
Shanmugam et al 1978
Type of diagnostic assay used (information not available unless otherwise stated): ID = immunodiffusion; AGD = agar gel diffusion; IHA = indirect haemagglutination; RPHA = reverse passive haemagglutination; IEOP = immunoelectrophoresis; CIEP = countercurrent immunoelectrophoresis; EIA = enzyme immunoassay; ELISA = enzyme linked immuno sorbent assay; RIA = radio immunoassay.
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Prevention of Hepatitis B in India: An Overview
Annex 2
ESTIMATE HBsAg PREVALENCE BY STATE, INDIA Region, State North Chandigarh Delhi Himachal Pradesh Jammu & Kashmir Uttar Pradesh South Andhra Pradesh Karnataka Kerala Tamil Nadu Northeast Arunachal Pradesh Manipur East West Bengal West Rajasthan Maharashtra 4 10 3.9 (1.0-6.8) 2.8 (0.6-5.0) 4 2.5 (0.0-5.0) 2 1 7.1 (5.8-8.5) 7.7 1 3 5 5 3.3 4.5 (4-5) 1.8 (0.6-3.0) 1.5 (0.8-2.3) 4 12 1 2 5 2.0 (1.5-2.6) 5.9 (0.1-11.7) 3.6 5.4 (1.1-9.7) 5.6 (1.2-10.0) No. of studies HBsAg Prevalence Midpoint (Range)
No data available: Andaman & Nicobar Islands, Assam, Bihar, Dadra & Nagar Haveli, Daman & Diu, Goa, Gujarat, Haryana, Lakshadweep, Madhya Pradesh, Meghalaya, Mizoram, Nagaland, Orissa, Pondicherry, Punjab, Sikkim, Tripura
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Prevention of Hepatitis B in India: An Overview
Annex 3
STUDIES ON HEPATITIS B E ANTIGEN (HBeAg) PREVALENCE AMONG PREGNANT WOMEN, INDIA Area North India New Delhi Mumbai Chandigarh North India Chandigarh No. women tested 1,112 850 2,000 2,337 8,575 1,000 HBsAg positive % 9.5 6.3 5.0 2.5 3.7 2.3 HBeAg positive % 12 18 12 26 8 47 Reference Prakash 1998b Mittal et al 1996 Gill et al 1995 Gupta et al 1992 Nayak et al 1987 Biswas et al 1989
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Prevention of Hepatitis B in India: An Overview
Annex 4
ESTIMATES (PROVISIONAL) OF HEPATITIS DISEASE BURDEN IN A SINGLE YEAR BIRTH COHORT, INDIA EPIDEMIOLOGICAL SUMMARY (A) Disease Events Disease Events Total HBV infections Acute symptomatic hepatitis B cases Chronic HBV infections HBV-related deaths: Fulminant acute hepatitis B Cirrhosis Hepatocellular carcinoma Total (B) Number of Infections by Age at Acquisition of Infection Age of Acquisition Perinatal Infection Early Childhood Infection Late Infection Total Infections (C) Age of Acquisition Perinatal Infection Early Childhood Infection Late Infection Total Infections Number of Infections 249,111 3,147,859 5,661,617 9,058,587 Number of Chronic Infections 224,198 943,961 339,126 1,507,286 10,835 46,239 145,913 205,286 Number 9,058,587 2,581,924 1,507,286
Number of Chronic Infections by Age of Acquisition of Infection
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Prevention of Hepatitis B in India: An Overview
(D)
Number of Deaths by Age at Acquisition of Infection Number of Deaths 36,472 137,427 31,487 205,386 Number of Infections Early Childhood 2,964,423 173,245 10,191 3,147,859
Perinatal Infection Early Childhood Infection Late Infection Total Deaths (E) Number of Infections by Serostatus of Mother Perinatal 0 96,247 249,111
Serostatus of Mother HBsAg-negative HBsAg-positive, HBeAg-negative Total
Late 5,455,800 203,818 1,998 5,661,617
HBsAg-positive, HBeAg-positive 152,864
Appendix. Input values and assumptions Prevalence HBsAg among women of child bearing age: Prevalence HBeAg among HBsAg-positive women of childbearing age Prevalence of any marker of HBV infection among 5 year olds: Prevalence of any marker of HBV infection among 30+ year olds: 5 15 15 40
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Annex 5 SUMMARY OF AVAILABLE STUDIES ON COST EFFECTIVENESS OF HEPATITIS B VACCINATION IN THE INDIAN POPULATION Sr. No. 1. Study Aggarwal and Naik, 1994 Methods used Comparison of universal infant immunization versus selective immunization (screening of pregnant women with HBsAg test, and immunization only of infants born to HBsAg positive mothers) with hepatitis B vaccine Assumptions Hepatitis B carrier rate HBeAg positivity rate among carrier mothers = 3.7% = 7.8% Results Perinatal transmission likely to be responsible for only 14% of all HBV carriers. Effectiveness of two approaches Resultant HBV carrier rates Selective Universal =3.25% =0.29% Sensitivity analysis/Additional analysis/Limitations Limitations Sensitivity analysis not done. Compliance assumed as 100%. Did not include ‘no vaccine’ option.
HBV infection rates among infants during the first six months of life Mother HBsAg-positive Infection rate Chronicity rate Mother HBsAg-negative Infection rate Chronicity rate Vaccine efficacy rates With HBsAg-positive mother With HBsAg-negative mother: =75% =95% = 3% = 50% = 19% = 75%
Proportion of carriers prevented Selective Universal Universal immunization Cost Selective immunization Universal immunization Universal immunization programme US$ 4.30 per child US$ 2.32 per child 1.85-fold higher =12% =92% =7.6-times more effective
Sr. No.
Study
Methods used Costs
Assumptions
Results Cost-effectiveness (Cost per HBV carrier prevented) Selective immunization Universal immunization Universal immunization = US$ 126 = US$ 495 3.9 times more cost-effective
Sensitivity analysis/Additional analysis/Limitations
For universal immunization Vaccine Administration cost Vaccine Administration cost HBsAg testing 2. Aggarwal and Naik, 1996 Comparison of universal infant immunization versus selective immunization (screening of pregnant women with HBsAg test, and immunization only of infants born to HBsAg positive mothers) with hepatitis B vaccine = US$ 1.00/dose = US$ 0.43/dose
For selective immunization = US$ 2.00/dose = US$ 0.87/dose = US$ 2.00/test
Most estimates were similar to those in the preceding row, except for costs (Aggarwal and Naik, 1994) except the following: Costs For universal immunization Vaccine Administration cost = US$ 0.75/dose = US$ 0.33/dose
Perinatal transmission likely to be responsible for only 14% of all HBV carriers. Effectiveness of two approaches Resultant HBV carrier rates Selective Universal =3.25% =0.29%
Limitations Sensitivity analysis not done. Compliance assumed as 100%. Did not include ‘no vaccine’ option.
Proportion of carriers prevented Selective: Universal: Universal immunization =12% =92% =7.6-times more effective
For selective immunization Vaccine Administration cost HBsAg testing = US$ 1.50/dose = US$ 0.67/dose = US$ 2.00/test
Sr. No.
Study
Methods used
Assumptions
Results
Sensitivity analysis/Additional analysis/Limitations
Cost Selective immunization Universal immunization Universal immunization programme = US$ 3.25 per child = US$ 2.24 per child =1.45-fold higher
Cost-effectiveness (Cost per HBV carrier prevented) Selective immunization Universal immunization Universal immunization 3. Prakash, 1999a; Prakash, 1999b Incremental costeffectiveness comparison of hepatitis B as part of Expanded Programme of Immunization versus ‘donothing’ using decision tree (Markov model) Societal perspective. Only direct costs. Only vertical transmission included; horizontal transmission not considered. HBV carrier rate HBeAg-positive rate among carriers Disease transmission rate From HBeAg-positive mothers From HBeAg-negative mothers = 90% = 15% = 9.5% = 12% = US$ 95 = US$ 498 =5.6 times more costeffective Sensitivity analysis showed that if effects were not discounted, costeffectiveness was US$ 19.08 per DALY gained. Uncertainty analysis showed that the most important factors that influenced cost-effectiveness were: (a) HBsAg positivity in carrier mothers, and (b) vaccination coverage.
US $ 23.76 per DALY gained
Sr. No.
Study
Methods used
Assumptions Disease rates in infected neonates (%) Neonatal disease Acute hepatitis HBV carrier No symptoms Mother’s HBeAg status Positive 2.8% 90.2% 81.1% Negative 3.2% 15.7% 7.0%
Results
Sensitivity analysis/Additional analysis/Limitations Factors which had negligible effect on result were: (a) vaccine wastage, (b) HBeAg prevalence among carriers, and (c) treatment costs of hepatitis B. Limitations • HBsAg positivity rate assumption (9.5%) may be too high. Horizontal transmission of HBV was ignored. Has not been published yet.
Disease progression among HBV carriers: 90% develop chronic hepatitis, of which 80% have chronic persistent hepatitis and 20% chronic active hepatitis. Of chronic active hepatitis, 12.5% develop cirrhosis or liver cancer. Survival Chronic persistent = 70 y age hepatitis Chronic active hepatitis Cirrhosis/liver cancer = 55 y age = 45 y age
• •
Healthy persons: ideal life table (US$ / per dose) Vaccine cost Administration cost =0.75 =0.19
Costs of treatment of complications based on Indian data Discount rate for costs: Discount rate for benefits =3% =0%, 3%
Sr. No.
Study
Methods used
Assumptions
Results US $ 23.76 per DALY gained
Sensitivity analysis/Additional analysis/Limitations Sensitivity analysis showed that if effects were not discounted, costeffectiveness was US$ 19.08 per DALY gained.
Uncertainty analysis showed that the most important factors that influenced cost-effectiveness were: (a) HBsAg positivity in carrier mothers, and (b) vaccination coverage.
Factors which had negligible effect on result were: (a) vaccine wastage, (b) HBeAg prevalence among carriers, and (c) treatment costs of hepatitis B.
Limitations • HBsAg positivity rate assumption (9.5%) may be too high. Horizontal transmission of HBV was ignored. Has not been published yet.
• •
Sr. No. 4.
Study Miller and Kane, 2000
Methods used Costeffectiveness of routine infant immunization against hepatitis B
Assumptions • Vaccine cost • Additional administration cost • Coverage rate • Vaccine efficacy • Average life expectancy • Lifetime mortality due to cirrhosis or HCC • Average age at death due to HBV • Discount rate • No treatment costs =US$ 0.50 per dose; = US$ 0.19 per dose = 80% =95% = 66 years (in year 2040) =20%; =45 years = 0%, 3%
Results Cost per year of life saved Undiscounted Discounted = US$ 12 = US$ 66
Sensitivity analysis/Additional analysis/Limitations Sensitivity analysis only on one parameter (life-time risk of mortality due to HBV) With a life-time risk of mortality due to HBV of 27%, Cost per year of life saved Undiscounted Discounted =US$ 9 =US$ 49
Cost per death averted: Undiscounted Discounted = US$ 312 = US$ 1178
Total cost per year = US$ 46 million for a single-year birth-cohort (for vaccine, does not include cost of administration) Should save 147000 to 198000 lives in a single-year birth-cohort
Cost per death averted: Undiscounted Discounted Limitations Limited sensitivity analysis. Treatment costs were not considered. =US$ 231 =US$ 873
5a.
Aggarwal et al, 2002
Incremental costeffectiveness comparison of hepatitis B as part of Expanded Programme of Immunization versus ‘donothing’ using decision tree (Markov model)
Societal perspective HBsAg carrier rate Coverage rate Vaccine efficacy Vaccine cost per dose; Vaccine administration cost Discount rate for benefits = 4%; = 80%; = 95%; = US$ 0.50 = US$ 0.50 per dose; = 0%, 3%
Undiscounted Reduction in carrier rate from 4% to 1.15% Increase in life = 0.15 years expectancy of the entire birthcohort = 0.17 years Increase in QALY lived for entire birthcohort Cost per carrier = US$ 98.7 prevented Cost per year of = US$ 19.06 life saved Cost per QALY = US$ 16.26 of life saved
On hepatitis B carrier rate Carrier rate % Cost per life year US$ 76.22 38.10 25.40 19.06 15.24 12.70 9.52 Cost per QALY US$ 65.06 32.54 21.68 16.26 13.02 10.84 8.14
1 2 3 4 5 6 8
Sr. No.
Study
Methods used
Assumptions
Results Discounted (discount rate for benefits = 3%) Cost per year of life saved Cost per QALY of life saved = US$ 101.70 = US$ 82.94
Sensitivity analysis/Additional analysis/Limitations On cost of immunization Cost of 3 doses Total) US$6 US$5 US$4 US$3.0 US$2 Cost per life year US$ 38.10 31.76 25.40 19.06 12.70 Cost per QALY US$ 32.54 27.12 21.68 16.26 10.84
Disease progression rates Chronic hepatitis B to cirrhosis Age 0-9 Age 10-19 Age > 20 Nil 0.5% per year 1.0% per year 5% per year 20% per year
Cirrhosis to decompensated cirrhosis Decompensated cirrhosis to death Quality of life Healthy person or HBsAg carrier: Cirrhosis of liver Decompensated cirrhosis:
On vaccine efficacy rate Efficacy rate Cost per life year US$ 25.86 24.14 22.63 21.30 20.11 19.06 18.10 Cost per QALY US$ 22.04 20.60 19.32 18.18 17.18 16.26 15.46
1.0 0.95 0.50
70 75 80 85 90 95 100
Mid-year correction applied in Markov analysis
Sr. No.
Study
Methods used
Assumptions
Results
Sensitivity analysis/Additional analysis/Limitations On vaccine wastage rate Wastage Efficacy rate 30% 20% 10% 0% Cost per life year US$ 21.78 19.06 16.94 15.24 Cost per QALY US$ 18.58 16.26 14.46 13.02
On vaccine coverage rate Coverage New % fall rate rate carrier % rate % US$ 4.00 2.48 2.10 1.72 1.34 1.15 0.96 0.58 0.20 US$ Nil 38 48 57 67 71 76 86 95
40 50 60 70 75 80 90 100
Benefits limited to age of 70 years Life years = 0.11/child gained QALY = 0.13/child gained Cost per life year =US$25.84 gained Cost per QALY =US$21.56 gained
Sr. No. 5b.
Study Aggarwal et al, 2002
Methods used Incremental cost-benefit comparison of hepatitis B as part of Expanded Programme of Immunization versus ‘donothing’ using decision tree (Markov model). Similar to 4 above but including the costs of care of complications of chronic HBV infection.
Assumptions Same as 4 above. Additional assumptions: Treatment of liver disease Cirrhosis (compensated) At onset: Thereafter INR 2000 INR 2000 per year Undiscounted
Results
Sensitivity analysis/Additional analysis/Limitations Sensitivity analysis including threshold analysis based on variations in cost of treating complications of chronic HBV infection
Immunization is cheaper than ‘no immunization’. Discounted for cost (@ 3%) Per life year gained Per QALY gained = US$ 2.18 = US$ 2.56
Decompensated cirrhosis At onset: Thereafter INR 5000 INR 5000 per year
In undiscounted analysis, threshold for immunization to be the preferred option over ‘no immunization’ was 0.30 times the baseline cost assumptions for treatment of complications of chronic hepatitis B virus infection
In discounted analysis, threshold for immunization to be the preferred option over ‘no immunization’ was 1.15 times the baseline cost assumptions for treatment of complications of chronic hepatitis B virus infection
DALY = Disability-adjusted life year HBV = hepatitis B virus HBsAg = Hepatitis B virus surface antigen HBeAg = Hepatitis B virus e antigen QALY = Quality-adjusted life year INR = Indian Rupee US$ = US Dollar
Prevention of Hepatitis B in India: An Overview
Annex 6
SUMMARY OF MAIN BASELINE FINDINGS OF VARIOUS STUDIES Studies from other regions for comparison Miller and McCann, 2000 (For intermediate 14-19
Indian studies Aggarwal et al, 2002 Parameter
Miller and Kane, 2000
Aggarwal and Naik, 1994 and 1996 Prakash, 1999a and 1999b
Cost per carrier prevented Cost per life year gained Undiscounted Discounted
95-126
63 9 – 12 49-66 27 231312 8731178
99 19 102 16 83
63-126 9-19 49-102 16-27 83 231-312 873-1178
Cost per DALY Undiscounted or QALY Discounted Cost per death prevented Undiscounted Discounted
Missing data indicate that the value was not calculated in the particular study. QALY = Quality-adjusted life-year DALY = Disability-adjusted life-year
Hall et al, 1993 (Gambia) 40 150-200
Range
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Prevention of Hepatitis B in India: An Overview
Annex 7
VACCINE LOGISTICS FOR IMPLEMENTATION OF MONOVALENT HEPATITIS B VACCINE (2001-2002) 2002 Surviving infants in millions Target children Number of doses Estimated vaccination coverage rate Estimated wastage rate Buffer stock of 25% additional Total vaccine doses required in millions AD syringe for hepatitis B vaccine in millions AD syringe for other vaccines Total AD syringes (including 5% wastage) Safety boxes required (millions) Total cost in US Dollars • • • * In different group of population. The buffer stock rate is not expected to decline in the first year. Based on 28 million surviving infants during 1999, with increase each year of 1%. Vaccination coverage for three doses of vaccine is based on attaining higher coverage than that of DPT3 measured in 1999 survey (50%) due to plans for training and education about benefits of new vaccine, minimal expected side effects compared with DPT; increased coverage estimated each year. Target number = surviving infants x estimated vaccination coverage rate. Vaccination programme to begin in July 2002. Based on maximum wastage rate of 25% for first year using 10 dose vials, with reductions each year to minimum of 10%; Total doses calculated during first year = target number of children x 3 doses x 1.25 x 1.25 (25% buffer); subsequent years calculated without buffer and with estimated increasing coverage estimates and decreasing wastage factors. Total syringes = target number of children x 3 doses x wastage factor (5% wastage gives factor of 100/100-95 = 1.0526).
2003 189 9324 1 709 391 3 doses 90% 20% 25%* 7.72 5.58 25.46 32.41 0.32
727 806 549 321 3 doses 85% 25% 25%* 2.06 2.05 9.36 11.91 0.12
By 2008 (Annual requirement) 25 3 doses 90-93% 20-15% 0 112.22 88.59 324.85 413.44 4.13
• • • •
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Prevention of Hepatitis B in India: An Overview
Annex 8
ESTIMATED EXPENSES FOR IEC (INFORMATION, EDUCATION AND COMMUNICATION ACTIVITIES), TRAINING AND EVALUATION OF INTRODUCTION OF HEPATITIS B VACCINE
Phase I A 2001 Training IEC Evaluation Total • • 50,000 30,000 20,000 100,000
Phase I B 2002 80,000 70,000 30,000 180,000
Phases II 2003-2006 320,000 150,000 100,000 570,000
Activities from regular budget All figures are in USD
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Prevention of Hepatitis B in India: An Overview
Annex 9
TIME TABLE FOR ACTIVITIES RELATED TO INTRODUCTION OF HEPATITIS B VACCINE Aug-Oct 2001 Recruit hepatitis B vaccine introduction advisor2 Procurement of hepatitis B vaccine Assessment of cold chain 1
Jan-Feb 2002
2002
2003-2006
X X X X X
Revision of training materials Revision of all immunization forms (schedule, immunization card, reporting, etc.) Training of EPI staff in all districts IEC2 campaign for hepatitis B vaccine introduction Introduction of hepatitis B vaccine at all sites Monitoring of introduction and feedback Ongoing training Review of reported hepatitis coverage data National coverage survey 1 2
X X X X X X X X X X X
Formal cold chain assessment will begin in October 2001 Information, Education, communication
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