Global epidemiology and burden of hepatitis C

Microbes and Infection 4 (2002) 1219–1225 www.elsevier.com/locate/micinf

Current focus

Global epidemiology and burden of hepatitis C W. Ray Kim * Division of Gastroenterology and Hepatology and Internal Medicine, Mayo Clinic and Foundation, 200 First Street, SW, Rochester, MN 55905, USA

Abstract Despite rapid progress in our knowledge of hepatitis C virology and pathogenesis, little is known about the current and future burden of this infection throughout the world. Prevalence and population-based studies have suggested that complications of the liver disease associated with chronic hepatitis C infection may potentially require substantial health care resources and generate very high costs for medical systems in the United States, Europe and worldwide. Careful understanding and assessment of hepatitis C health and economic burdens are likely to guide better programs for the management of infected individuals and the prevention of complications. © 2002 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. Keywords: Hepatitis C; Epidemiology; Health care costs; Mortality; Morbidity

1. Introduction Viral hepatitis remains an important public health concern, in both developing and developed countries. While the epidemiology of viral hepatitis A and B is generally well established, data about viral hepatitis C are all but limited. As hepatitis C virus (HCV) was discovered only a little over a decade ago, considerable uncertainty exists about the frequency, natural course, and socioeconomic burden of infection around the world. Unlike hepatitis A or B, from which spontaneous recovery is the rule, hepatitis C infection becomes chronic, in approximately 75% of people who acquire HCV, predisposing them to the potential risk of serious long-term clinical sequelae, such as cirrhosis and hepatocellular carcinoma [1]. This places HCV among major threats to public health as well as one of the known infectious causes of cancer. HCV is a blood-borne pathogen, which may be transmitted through parenteral exposure to contaminated blood or body fluids. Factors most strongly associated with HCV infection are injection-drug use and receipt of blood transfusion before 1990 [2]. Other risk factors include use of in adequately sterilized medical equipment, high-risk sexual behaviors, and social or cultural practices such as body piercing, circumcision, and tattooing. Perinatal transmission occurs but is not very efficient, except in mothers with HIV

* Corresponding author. Tel.: +1-507-266-7054; fax: +1-507-266-1856. E-mail address: [email protected] (W. Ray Kim). © 2002 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. PII: S 1 2 8 6 - 4 5 7 9 ( 0 2 ) 0 1 6 4 9 - 0

co-infection. Although HCV can be recovered from the saliva of infected persons, casual contact has not been associated with transmission [3]. HCV is endemic to most parts of the world. It remains the most common cause of posttransfusion hepatitis worldwide and is a leading cause of end-stage liver disease. Available data indicate that there is considerable geographic variation in the incidence and prevalence of HCV infection. Likewise, the impact of hepatitis C-related illness on the health, longevity, healthcare resource utilization and economic productivity is expected to differ across different regions of the world. This review is written to present a summary of available information on the global epidemiology and burden of hepatitis C.

2. Global epidemiology of hepatitis C It is difficult to ascertain the incidence (new onset of infection) of HCV accurately, because acute infection is asymptomatic in most cases. Thus, most epidemiologic data available to date describe prevalence (current presence) of the infection. The most representative epidemiologic data may be obtained from carefully designed population-based surveys [4]. However, such a study is a large undertaking and population-based data are not available from most parts of the world. Instead, most studies report prevalence data obtained from select populations, most commonly blood donors, to estimate the frequency of HCV infection. In

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interpreting data derived from blood donors, one must be aware that they are likely to underestimate the true prevalence, because even first-time blood donors tend to be self-selected, such that individuals at high risk of HCV infection may not reach the screening process prior to donation [5]. Furthermore, differences in sensitivity and specificity of tests used in screening for potential donors may confound regional differences in the prevalence of HCV infection. These caveats notwithstanding, the World Health Organization (WHO) has compiled data on the epidemiology of hepatitis C worldwide. A comprehensive review was first reported in 1997 and then updated subsequently [6–9]. In the 1997 report, an extensive literature search identified 266 journal articles, which had reported seroprevalence of HCV in various subgroups of populations from different countries globally [6]. Of the 266 studies identified, 116 studies covering 116 countries/areas were selected using criteria of representativeness such as size of the sample, age and gender characteristics, and geographical and ethnic distribution. While the papers identified were still heterogeneous with regard to the age, gender, and geographic distributions, it is nevertheless possible to obtain some useful estimates from the report. In Table 1, the prevalence of hepatitis C is shown for six regions of the world, as divided by the WHO: Africa, Americas, Eastern Mediterranean, Europe, South-East Asia and Western Pacific regions [6]. The estimated number of people with positive anti-HCV around the world was 169.7 million, with an overall seroprevalence of 2.9%. As approximately 75% of people with anti-HCV are chronically infected with the virus, the number of people with the infection may be approximately 127 million around the world, with a prevalence of 2.2%. Since no data were available from 57 countries, the true number of people with HCV infection may be substantially higher. Fig. 1 illustrates country-specific prevalence of antiHCV, as reported by WHO’s updated report in January 2000 [7]. HCV prevalence levels have been grouped as <1, 1–2.4, 2.5–4.9, 5–10 and >10%. Although HCV is globally present, the prevalence pattern roughly parallels that of socioeconomic development. Lower prevalence estimates are reported from Western Europe, North America, and Australia. Countries at the higher end of the spectrum are

found in Africa, Asia, and South America. The highest prevalence (17–26%) has been reported from Egypt.

3. Implication of geographic variation in epidemiology of hepatitis C Wasley and Alter at the Center for Disease Control and Prevention (CDC) analyzed the relationship between the prevalence of HCV infection and transmission pattern [4]. Based on a limited number of population-based studies on the age-specific prevalence of HCV infection, three epidemiologic profiles of HCV transmission could be discerned (Fig. 2). In the first pattern (US and Australia), the overall prevalence is generally low. The age-specific prevalence is highest in middle age, with the peak prevalence occurring among adults 30–49-years-old. Most HCV transmission seems to have occurred in the relatively recent past (10–30 years ago) and primarily among young adults. In the United States, CDC estimates that the incidence of newly acquired HCV infection was low before 1965, increased steadily through 1980, and remained high through 1989 [10]. Since 1989, the incidence of HCV infection has declined more than 80%. In the second pattern (Japan and Italy), the age-specific prevalence is low in children and young adults but increases steadily among older persons. This pattern is consistent with the risk for HCV infection having been greatest in the distant past (30–50 years ago). In the third pattern, the prevalence of HCV infection increases steadily with age, and high rates of infection are observed among persons in all age groups. This pattern, seen in Egypt, indicates an ongoing high risk for acquiring HCV infection. The CDC group further postulated a relationship between the prevalence of HCV and the route of transmission [4]. Table 2 expands on the CDC group’s suggestion about this relationship. In countries with low prevalence where most infections are acquired in young adults, injection-drug use has been the predominant route for HCV transmission. HCV transmission occurs very efficiently among intravenous drug users. After 5 years of exposure, up to 90% of individuals acquire infection with HCV. Another potential mechanism of infection that may account for this pattern is sexual transmission. However, the efficiency of sexual transmis-

Table 1 Prevalence of anti-HCV in the six WHO regions WHO region

Total population (million)

Percentage prevalence

Number of people with anti-HCV (million)

Number of countries with no data available

Africa America Eastern Mediterranean Europe Southeast Asia Western Pacific

602 785 466 858 1500 1600 5811

5.3 1.7 4.6 1.0 2.2 3.9 2.9

31.9 13.1 21.3 8.9 32.3 62.2 169.7

12 7 5 19 3 11 57

.

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Fig. 1. Global prevalence of hepatitis C (June 1999 data) (from Wkly. Epidemiol. Rec. 75 (3) (2000) 17–28).

Fig. 2. Patterns in age-specific prevalence of hepatitis C (from A. Wasley, M.J. Alter, Epidemiology of hepatitis C: geographic differences and temporal trends. Semin. Liver Dis. 20 (2000) 1–16. By permission of Thieme Medical Publishers).

sion of HCV remains somewhat questionable, and it is likely to account for a small proportion of cases [11]. In many individuals, high-risk sexual activities may simply represent a surrogate marker of other risk factors such as illicit drug use [3]. Nosocomial route of HCV transmission has been described in healthcare settings in low-prevalence countries and may represent an important concern in selected subgroups of patients such as patients on chronic hemodialysis [12,13]. In countries with intermediate prevalence, healthcarerelated procedures performed by professionals and nonprofessionals appear to have been a major mode of HCV transmission. In Japan and Italy, geographic clustering of infections has been attributed not only to transfusions from

Table 2 Relationship between route exposures and prevalence pattern (modified from ref 4) Importance of Exposure Exposure

Low prevalence

Intermediate prevalence

High prevalence

Illicit drug use Transfusions Sexual transmission Perinatal transmission Health care related .

Very high Very low Low Very low Low

Intermediate Low Low Low High

Low Low Low Intermediate Very high

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unscreened donors but also to unsafe injection practices [14,15]. Examples of the latter include re-use of contaminated glass syringes and administration of injectables outside healthcare settings, using shared syringes among multiple individuals. In addition, folk medicine practices may have played an important role in countries like Japan, in which traditional remedies such as acupuncture have been performed using nonsterile instruments. In these countries, injection-drug use appears to have played a minor role, compared to low-prevalence regions. More recently, how ever, transmission by injection-drug may be increasing in both Japan and Italy. In countries where the risk for HCV infection has remained high for many decades, there may be a number of processes by which transmission of hepatitis C is perpetuated. Similarly to countries with intermediate prevalence, it is likely that healthcare-related procedures have been the major source for transmission. In Egypt, transmission of HCV has been attributed to unsafe injection practices associated with re-use of glass syringes during mass campaigns to treat schistosomiasis in the past [16]. In many developing countries, supplies of sterile syringes may be limited and, in fact, transmission of blood-borne pathogens via unsafe injections has been recognized in Romania, Moldova, and Pakistan [4]. In addition to unsafe injection practices, inadequate disinfection of equipment used for medical and dental procedures may also be an important source of HCV transmission in developing countries. Further, given the background prevalence, perinatal infection may play a significant role in sustaining the high prevalence in this setting. The risk of perinatal transmission among babies borne to mothers with HCV infection is estimated to be around 6% [4]. While this is substantially less efficient than HBV (20–60% transmission, depending on the titer of the virus), 6% of the large number of infants born to HCV-carrying mothers in these countries still represents a substantial addition each year to the pool from which the infection may be sustained. Understanding these differences in the pattern of prevalence and transmission of hepatitis C across countries and regions of the world has an important implication in recognizing the source and mechanism of infection, assessing its future burden and formulating strategies to reduce further propagation. For example, in the US and other countries where the emergence of HCV infection was a relatively recent event, public health officials are concerned that the magnitude of the burden of HCV-related chronic liver disease has yet to be realized [10]. In contrast, in countries where HCV infection has been in existence from the distant past, the burden of disease may not change drastically in the future, although in general, these countries tend to have limited means to intervene to circumvent present and future consequences of HCV infection. One report noted that 90% of patients with HCV who are in need of treatment today cannot afford it [17].

4. Global burden of hepatitis C The term, disease burden, encompasses a number of aspects of the impact of a disease on the health of a population, including the frequency of disease, as measured by incidence and prevalence; effects on longevity, such as case-fatality rate and years of life lost because of premature death; morbidity including decrease in health status, quality of life and severity and duration of disability; and the economic impact including direct healthcare expenditures and indirect costs related to lost income from premature death or disability [18]. Information about disease burden is essential to the development of national and international health policies for prevention and control of disease and injury. With regard to hepatitis C, as with other newly identified diseases, data on its global burden are sparse. Even the most basic parameters of disease burden, such as mortality and direct healthcare costs, are not widely available. A recently reported study, the Global Burden of Disease study, compiles comprehensive measures of fatal and non-fatal health outcomes of illnesses and injuries worldwide [19–22]. The study was conducted in the mid-1990s by the World Bank and WHO to gather reliable information for the purpose of international health policy decisions. The study also attempted to provide objective epidemiological assessment for major human illnesses and measure the burden of disease as a basis for cost-effectiveness analyses. While hepatitis C was not directly addressed in the Global Burden of Disease study, useful insights may be gleaned from information about liver disease in general and limited estimates about viral hepatitis (hepatitis B and C combined). 4.1. Mortality Table 3 summarizes available data from the Global Burden of Disease study about the prevalence and mortality of liver cirrhosis and hepatocellular carcinoma [23]. The table also contains estimates attributable to hepatitis B. In the absence of hepatitis C-specific data, the burden of HCV may be approximated by extrapolating from the known prevalence of HBV and HCV, if one assumes that the risk of liver cirrhosis and hepatocellular carcinoma is comparable between people with HBV and HCV. While the merit of such an assumption is subject to debate, no populationbased data are available for HCV on a global scale. With that caveat in mind, one might estimate that of 8.3 million people with liver cirrhosis in 1990, hepatitis C was the underlying cause in 1.4 million, approximately 10% of whom died that year. Similarly, of 858 000 people with hepatocellular carcinoma, approximately 170 000 may be secondary to HCV. Of these, approximately 100 000 people are estimated to have died that year.

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Table 3 Prevalence of and mortality from liver cirrhosis and hepatocellular carcinoma in the world, from all causes, hepatitis B and C (1990) Category

All Causes

HBV (worldwide prevalence 400 000)

HCV (worldwide prevalence 130 000)

Prevalence of liver cirrhosis Death from liver cirrhosis Prevalence of hepatocellular carcinoma Death from hepatocellular carcinoma .

8315 779 858 501

4284 401 530 309

1400 130 170 100

Figures about hepatitis C are estimated from the ratio of the prevalence between hepatitis B and C (see text for details). Figures are in thousands.

4.2. Morbidity

4.3. Economic burden

Data are even sketchier about morbidity related to HCV. To measure the overall impact of a disease based on shortened life as a result of premature death and loss of well-being and productivity during life as a result of disability, the Global Burden of Disease study uses a summary parameter referred to as disability-adjusted lifeyear (DALY) [20]. It is a concept similar to healthy year equivalent and includes weights for time spent in less-thanperfect health. For example, if liver cirrhosis shortens life by 10 years and makes the last 5 years of life half as healthy as without cirrhosis, the impact of cirrhosis in that individual would be expressed as 12.5 DALYs lost (10 × 1.0 + 5 × 0.5). Table 4 summarizes the overall burden of liver disease including hepatitis B and C reported by the Global Burden of Disease study [24]. First, one notes that liver disease overall accounted for a relatively small proportion of the global burden of all diseases and injuries. Liver disease accounted for 1.6% of the global burden from all causes, compared to the leading causes, such as ischemic heart disease (9.9%), depression (6.1%), and cerebrovascular disease (5.9%) in developed countries and lower respiratory infections (9.1%), diarrheal diseases (8.1%) and perinatal illnesses (7.3%) in developing countries. Second, as the Global Burden of Disease was not able to separately enumerate cirrhosis and liver cancers secondary to HBV and HCV, the proportion attributed to hepatitis B and C represents a significant underestimation. If one extends assumptions used for Table 3, the total burden related to HCV may be as high as 4.2 million DALYs. Diseases that have similar global burden include colorectal cancers (4.6 million DALYs), breast cancer (4.2 million DALYs), and peptic ulcer disease (2.8 million DALYs).

Economic impact of hepatitis C on a global scale is extremely difficult, if not impossible, to estimate, because of significant differences across countries in healthcare delivery and payment systems, standards for medical care, cultural and value systems, and economic productivity. In the United States, several studies have estimated the economic burden of hepatitis C. A recently published study in the US, The burden of Gastrointestinal Diseases, sponsored by the American Gastroenterological Association (AGA), was undertaken to estimate the prevalence and annual economic burden of common gastrointestinal disorders, including hepatitis C, liver cirrhosis and hepatocellular carcinoma [25]. Data were obtained from publicly available national data sets and other proprietary databases. The total cost for each disease in cluded estimates of both direct and indirect costs. Direct costs include those related to goods or services associated with treatment including physician care, inpatient hospital care, outpatient hospital care, emergency (urgent) care, and pharmaceutical therapy. Indirect costs were broadly defined to include costs such as work loss, as measured by time away from work as a consequence of gastrointestinal disease. Table 5 summarizes the prevalence and cost data for liver disease in general and hepatitis C in particular, as reported in the AGA study. It was estimated that approximately 2.5 million Americans had hepatitis C, which incurred $693 million in healthcare services and $51 million in indirect costs in 1998. An additional 5.5 million people had cirrhosis and 10 million primary liver cancers from causes other than hepatitis C. Of direct costs attributable to hepatitis C, the largest proportion was from outpatient activities (Fig. 3). It was

Table 4 Disability-adjusted life years (DALYs) loss in 1990 Disease category

Cirrhosis HCC HBV and HCV All cause .

Developed

Developing

World

Rank

DALYs

Rank

DALYs

Rank

DALYs

%

18 48 68 –

2345 510 91 160 994

24 38 67 –

10 837 6039 2045 121 8244

25 40 68 –

13 182 6550 2136 1 379 238

0.96% 0.47% 0.15% 100%

Data are in thousands.

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Table 5 Burden of liver disease in the United States (1998 estimates) Diagnosis

Prevalencea

Direct costb

Indirect costb

Total costb

Cirrhosis HCC Hepatitis C .

5490 10 2530

$1421 $1266 $693

222 78 51

$1642 $1344 $744

a b

Number of people in US with disease in thousands. $US in millions.

estimated that some 317 000 physician office visits for hepatitis C incurred $23.9 million in physician services. In addition, there were 46 000 visits to hospital outpatient departments (including emergency department) with total costs of $10.5 million. Prescription and over-the-counter medications were the single largest item in costs related to hepatitis C. The reported sales of combination of interferon alfa-2b and ribavirin for the year 1999 were $530 million. With regard to hospital care costs, the AGA study estimated that there were 61 000 inpatient stays related to hepatitis C, 91% of which were for secondary diagnoses of hepatitis C. These hospitalizations generated $20.7 million in physician fees and $107.9 million in facility costs, for a total of $128.6 million. In another study based on 1995 data, there were 26 700 hospitalizations and 2600 deaths in nonfederal acute-care hospitals in the US for liver diseases caused by HCV. Total charges for these hospitalizations were $514 million [26]. The two studies are not directly comparable because of a number of differences in methods. The AGA study likely underestimated the cost of liver disease from hepatitis C, because it only included 20% of hospital costs in cases for which hepatitis C was a secondary diagnosis. In many such cases, however, hepatitis C is only a secondary diagnosis to a more direct reason for hospitalization such as cirrhosis, variceal bleeding, or hepatocellular carcinoma. The second study may be an overestimate because it utilizes charges (billed amount) as opposed to costs, and gave full credit (100% instead of 20%) to cases with any significant liver disease diagnosis and hepatitis C.

Fig. 3. Direct cost of hepatitis C (1998 data, in millions) (from The Burden of Gastrointestinal Diseases (monogram). The American Gastroenterological Association, 2001. By permission of the American Gastroenterological Association).

Thus, the true inpatient costs for hepatitis C-related liver disease may lie somewhere between the estimates from the two studies. Based on the AGA estimates, the combined total cost attributable to hepatitis C is at least $744 million. Thus, the total cost per person infected with hepatitis C ($744 million/2.5 million persons) is $294, including $274 in direct costs and $20 in indirect costs. Again, these likely represent underestimation of the true economic burden. However, it does point out that it is only a minority of people with HCV infection that incur healthcare costs. This is consistent with population-based data on the natural history of HCV infection that serious liver disease only occurs in a small number of people after many years of infection. On the other hand, once liver disease is established, hepatitis C can require intensive healthcare resources and generate very high costs, particularly in patients with end-stage liver disease.

5. Concluding remarks This review provides a summary of data available on the epidemiology and burden of hepatitis C in the world. It is apparent throughout the review, however, that critical data are lacking to make accurate estimates on a global scale. First, generalizable measures of disease frequency are best obtained by population-based data. As was pointed out earlier, most prevalence data available currently are derived from blood donors and likely represent underestimation of the true prevalence. Second, longitudinal assessment of the same population is necessary to understand transmission, natural history and consequences of infection. These data are lacking in most countries. Third, the age-specific prevalence data across the board show that a large portion of infection occurs in young adulthood. This suggests that there is a need for more studies to understand transmission in this particular age group as well as opportunities for public health interventions to curb exposure of the susceptible. Fourth, while the current data may underestimate the frequency of HCV infection, its burden may have been overestimated because of co-morbid conditions that are frequently present in individuals with HCV. For example, a substantial proportion of patients with severe liver disease and hepatitis C also have chemical dependence or mental health problems, both of which are known to present significant health burden to society independently. If the

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contribution of these co-existent illnesses is not properly accounted for, the burden measured for hepatitis C will represent an overestimate. Finally, accurate assessment of the burden of hepatitis C related illnesses is a crucial element in objective evaluation of the cost-effectiveness of intervention programs for treatment of existing patients or prevention of further transmission.

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Acknowledgements This work was supported by a grant from the National Institutes of Health (DK-34238).

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