Norah Terrault, MD, MPH
University of California

San Francisco, California

Key Concepts:

- Chronic liver disease, including cirrhosis, represents the 10th most common cause of death in the U.S. Viral hepatitis is the commonest cause of chronic liver disease with an estimated 1.25 million, 2.7 million and 70,000 individuals with chronic hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus (HDV) infection, respectively.

- In the U.S., the prevalence of markers of past or chronic HBV infection is low until age 12, increasing thereafter, and is similar among males and females. The factors associated with chronic HBV infection are ethnicity (highest in non-Hispanic blacks), number of sexual partners, marital status, foreign birth, level of education, and illicit drug use.

- In the U.S., chronic HCV infection is more common in males than females and the peak prevalence is in those aged 30-39 years. HCV alone or in combination with alcohol accounts for about (60% of newly diagnosed cases of chronic liver disease.

- The prevalence of HDV in the U.S. is low. The groups with the highest prevalence of infection are injection drug users and multiply-transfused individuals (e.g. hemophiliacs).

- The risk factors for acquisition of HBV, HCV and HDV are well-established. Understanding the modes of transmission is critical in designing prevention strategies to reduce the burden of chronic liver disease.

- The geographical distribution of viral genotypes of HBV, HCV and HDV are known. Correlations between specific viral genotypes and clinical outcomes, such as disease severity and response to anti-viral treatments, are under study.
 

Epidemiological studies conducted over the past several decades have provided estimates of disease burden due to hepatitis C virus (HCV), hepatitis B virus (HBV), and hepatitis D virus (HDV), not only in the U.S., but in order areas of the world. Studies have detailed the changing incidence and prevalence of chronic viral hepatitis and the shifting importance of specific risk factors for viral acquisition. Such studies are necessary for ongoing preventive strategies. Molecular methodologies have come to play an important role in studying chronic viral disease. Genotype and quasispecies analyses have proven to be invaluable in understanding the evolution of each virus over time within the population, investigating viral transmission events between persons, and understanding the role of viral heterogeneity in disease expression and clinical outcomes.

The burden of chronic liver disease in the U.S. is unknown, although estimates of prevalence and incidence indicate the chronic viral hepatitis is the commonest cause of chronic liver disease. The asymptomatic nature of chronic liver disease means that many persons affected with disease are unrecognized. Three different sources of information are available to estimate the relative contribution of HCV, HBV, and HDV to the total burden of chronic liver disease in the U.S. These include: (i) death registries; ii) population-based prevalence and incidence studies; and (iii) convenience samples or referred patients. Population-based studies provide the most accurate estimates of disease prevalence and incidence, whereas death registries and convenience samples generally provide information on the symptomatic subset of persons with chronic liver disease.

 Table 1.  Trends in chronic liver disease and cirrhosis mortality, United States, 1980-1997  

                                        1980                          1997

Number of deaths                      30,583 8                         25,175 10
Rank (total)

Age-adjusted death rate/
100,000 Male, age-adjusted
death rate/100,000 Female, 
age-adjusted death rate/100,000         12.2 -- --                  7.4  12.4  5.4
CDC: National Vital Statistics Reports
(http://www.cdc.gov/nchs/about/major/dvs/mortdata.htm)

Death Registry Statistics - Mortality Estimates for Chronic Liver Disease
The Centers for Disease Control and Prevention (CDC) National Center for Health Statistics captures trends in death rates in the United States (http://ww.cdc.gov/nchs/about/major/dvs/mortdata). In 1997, chronic liver disease including cirrhosis ranked as the 10th most frequent cause of death (Table 1). Mortality varied by age with a rate of 16.7 per 100,000 among those 45-54 years, 24.1 per 100,000 among those 55-64 years, and 31.4 per 100,000 among those 65-74 years. Death rates among men were twice as high as women and rates among blacks and Hispanics were higher than whites. For example, the death rate per 100,000 among persons aged 45-64 years was 19.0 for whites, 27.5 for blacks, and 32.6 for Hispanics. Mortality from cirrhosis and chronic liver disease over the past four decades has changed. Death rates increased steadily in the 1950s and 1960s, peaked in the mid-1970s, and declined thereafter. In 1997, the age-adjusted death rate from chronic liver disease and cirrhosis was 7.4 per 100,000 population, a decline of 38.3% since 1979.

The underlying etiology of liver disease among those dying of liver disease also has changed over time. Among the listed causes of death due to chronic liver disease in 1989, alcohol was the most common, present in 46.1%. However, nearly half of the liver-related deaths were of unspecified cause and HCV-associated liver disease was underrepresented because testing for HCV was not available at the time. A revised estimate of the causes of death due to chronic liver disease in the United States between 1970-1988, based upon prevalence data from other sources, showed that alcohol alone accounted for only 24% of deaths and viral hepatitis accounted for 54% (Figure1).

While useful in documenting changes in mortality due to chronic liver disease over time, death registries capture only the most severe end of the disease spectrum and interpretation of changes in death rate can be difficult in the absence of additional information. For example, a decline in death rate may be the result of a change in the rate of detection, a true reduction in incidence, or improved survival among prevalent cases.

 Table 2.  Estimates of chronic disease burden for 

viral hepatitis in the United States, 2000  
 

Disease Burden HBV HCV HDV
Chronic infections 1.25 million 2.7 million 70,000
Chronic liver disease Death annually 5,000 8,000 - 10,000 1,000

Sources: NHANES III and CDC, unpublished data
 

Prevalence of Viral Hepatitis in the U.S.
Population-based studies provide the best estimates of the burden of chronic HBV disease in the U.S. The population-based NHANES surveys have provided useful estimates of the total number of persons infected with chronic viral hepatitis in the U.S. (Table 2). NHANES II was conducted between 1976 and 1980 and NHANES III was conducted between 1988 and 1994.

In the NHANES III survey, serum samples from participants were tested for anti-HBc first, and if positive, HBsAg and anti-HBs were obtained. Chronic HBV infection was defined by the presence of HBsAg and anti-HBc. The age-adjusted seroprevalence of HBV infection was 4.9% (95% CI: 4.3%, 5.6%), with 0.5% of patients having anti-HBc as their only marker of past HBV infection (1). The prevalence was similar in males (5.7%, 95% CI: 4.9%, 6.6%) and females (4.1%, 95% CI: 3.4%, 5.0%). The prevalence of past and chronic HBV infection was low until the age of 12 years (Figure 2), thereafter increasing in all racial groups. The highest prevalence was in non-Hispanic blacks (Figure 2). Independent predictors of chronic HBV infection after adjustment for age were non-Hispanic black ethnicity, high number of sexual partners, cocaine use, divorced or separated marital status, foreign birth, and having less than a high school education. However, there were interactions between race, sociodemographic variables and behavioral risk factors. The increased prevalence of HBV infection after age 12 (puberty) and the association of HBV infection with number of sexual partners and early age of first intercourse, are consistent with sexual contact being the primary mode of HBV transmission. The relative contribution of injection drug use to the burden of HBV disease cannot be discerned from the NHANES data since information on this risk behavior was not collected. Additionally, NHANES sampled only civilian, noninstitutionalized persons living in households, which may underestimate the seroprevalence of HBV by omitting persons (homeless and incarcerated) who would be predicted to be at higher risk of infection.

The seroprevalence of HBV in the U.S. is low compared to other areas of the world. However, surveys among specific ethnic subgroups within the U.S. highlight focal areas of high prevalence. The prevalence of HBsAg-positivity among Alaskan natives was 6.4%, on average, with prevalence rates varying from 0-20% in different villages (2). In first-generation Asian-Americans from Taiwan, mainland China, the Philippines, Vietnam, Korea and Japan, HBsAg positivity ranged from 5% to 15%; other serological markers of HBV infection ranged from 43% to 65% (3). These high prevalence groups are often the target of specific intervention programs (2).

The age-adjusted seroprevalence of HBV infection was 5.5% in the NHANES II survey and 4.9% in the NHANES III survey, a difference that was not statistically different ¹. These data suggest the prevalence of HBV did not change significantly between the years 1976 and 1994. Since routine immunization of infants only began in 1992 and adolescents in 1995, the study time period may be too short to detect the benefits of HBV vaccination on disease prevalence (4). Other studies in populations with higher endemic rates of HBV infection have demonstrated the positive impact of a comprehensive program of infant and childhood vaccination (5, 6). In Taiwan, the prevalence of HBV infection (HBsAg-positivity) in children less than 9 years of age declined from 10% in 1984, prior to the vaccination program, to <1% in 1994, 10 years after the implementation of the program. More importantly, the annual incidence of hepatocellular carcinoma in children decreased from 0.52 per 100,000 in 1974-1984 to 0.13 per 100,000 in 1984-1986 (5). Thus, vaccination programs are changing the seroprevalence of HBV in the world. Prior to 1980, most countries in Southeast Asia were areas of high HBV endemicity with seroprevalence rates as high as 15-20%. Now, China is the only country in Asia considered to be hyperendemic for HBV infection. Korea, the Philippines, Taiwan and Thailand have intermediate endemicity (prevalence rates 2-7%), and Japan, Singapore, Sri Lanka and Malaysia have low endemicity (prevalence rates <2%) (7).

 Table 3.  Prevalence of HCV infection in the U.S. and other countries*  


                                                                    Prevalence
Author, Year     N                 Population             Anti-HCV   HCV RNA      Comments
Alter, 2000    21,241     Noninstitutionalized civilians   1.8%       1.3%     Excluded incarcerated and 
                          from 89 randomly selected                            homeless individuals.
                          locations in U.S. (NHANES III)                       Oversampled from ages(5
                                                                               and (60, blacks and
                                                                               Mexican Americans. 


Bellentani,    6,917      Residents of 2 Northern Italian   2.6%      2.3%    69% of eligible residents
1999                      towns (Dionysos Study)                              participated. "Well-to-do"
                                                                              population - in top 10 per
                                                                              capita income cities in Italy.
                                                                              Excluded ages (12 and (65
                                                                              yrs. 
                                                                                  

Dubois, 1997   6,283       Volunteers from 4 regions in     1.15%     0.93%   Individuals had to be 
                           France who were undergoing                         registered with the maj
                           Routine medical check-ups                          social security system (85%
                                                                              of residents). Excludes ages
                                                                              less than 20 and more than 
                                                                              59 yrs.
   
* Includes only population-based studies 
   

In the NHANES III survey, the prevalence of anti-HCV was 1.8% (95% CI: 1.5%, 2.3%) corresponding to an estimated 3.9 million persons who have been infected with HCV⁸. Again, since this study excluded incarcerated and homeless individuals, the true seroprevalence may be slightly higher. The prevalence of HCV RNA detection among anti-HCV positive persons was 73.9% (95% CI: 65.8%, 83.0%), which corresponds to an estimated 2.7 million individuals with chronic HCV infection. HCV was more prevalent among males (2.5%) than females (1.2%) and more prevalent among non-Hispanic blacks (3.2%) than non-Hispanic whites (1.5%). Those aged 30-39 years had the highest prevalence and accounted for 65% of all persons with detectable anti-HCV. The lowest rates of anti-HCV detection were among persons aged = 19 or ( 70 years.

Using NHANES III seroprevalence data and age-specific incidence rates from the CDC sentinel surveillance study, the annual incidence of acute HCV infection in the U.S. over the past 30-40 years has been estimated by modeling (9). This model predicts a low incidence period prior to 1965 (0-45 new infections per 100,000 persons), a transition period in the 1970s, and a high incidence period in the late 1980s with 100-200 new HCV infections per 100,000 persons per year. The model predicts that persons born between 1940-1965 would be at greatest lifetime risk of acquiring HCV infection. The model also was used to predict changes in prevalence over time. The number of persons with infection of ( 20 years' duration, who will be potentially at risk for cirrhosis and other complications, was estimated to increase substantially before peaking in 2015 (assuming no change in the incidence of HCV infection and ignoring the potential benefits of anti-viral therapy).

The prevalence of HCV in the U.S. varies with the population studied. For example, in blood donors, the seroprevalence of anti-HCV is only 0.3%, a lower prevalence than in the general population because blood donors are a highly select group of individuals that have been screened for risk factors and serologic markers of other infectious agents (10-11). Among referred or hospitalized patients with chronic liver disease, HCV infection is common and likely represents the "tip of iceberg" in terms of the total population of HCV-infected individuals. A referred or hospitalized population represents the subgroup of HCV-infected persons with more serious complications of disease and the demographics of hospitalized patients differs from that of HCV-infected persons in the general population. For example, in the Central Harlem study, the chronic liver disease cases were 65% male and 75% African-American and the case-fatality rate was 14% (14). The presumed etiology of chronic liver disease was HCV in 12%, alcohol 29%, and HCV plus alcohol in 46%; the remainder were of other etiologies (14).

A brief comparison of the results of NHANES with population-based surveys from other countries services to highlight geographical similarities and differences in HCV prevalence (Table 3). In a study of 6283 volunteers from 4 of 22 geographical regions in France, aged 20 to 59 years, the age- and gender-adjusted anti-HCV positive rate was 1.15% (95% CI: 0.8%, 1.3%) and prevalence was inversely related to socioprofessional status (12). In the Dionysos study in Northern Italy, the prevalence of anti-HCV was 2.6%; prevalence increased with age and, in contrast to the U.S., was more common in women than men (ratio of men to women = 0.7) (13).

Since Hepatitis D is not a reportable disease and not included in the International Classification of Diseases, population-based data on the seroprevalence of chronic HDV are not available. An estimated 70,000 persons have chronic HDV infection in the U.S. (CDC, unpublished data) (Table 2). Seroprevalence rates in the U.S. vary dramatically depending upon the subgroup evaluated but the pattern, in general, is typical of an area of low endemicity (15). Seroprevalence is low in blood donors (1.4% to 8%), intermediate in residents of mental institutions and other settings of less intense percutaneous or mucosal exposure, and highest in those with repeated percutaneous exposures such as injection drug users (20-53%) and hemophiliacs (48-80%) (16-19). Among patients with chronic HBV infection referred to gastroenterologists, the HDV seroprevalence rates vary from 13% to 41%, average 27% (20, 20A, 21).

Highly endemic areas are surprisingly disparate geographically and include the Amazon basin, parts of northern South America, parts of Africa, and Romania. In these areas, the HDV seroprevalence is 20% in HBsAg-positive persons and up to 90% in persons with HBV-associated chronic liver disease (15, 21a). Intermediate areas of HDV seroprevalence include southern Italy, parts of Eastern Europe, the Middle East, Africa and some Pacific Island groups. These areas have prevalence rates up to 15% among HBsAg-positive individuals and 30-50% in persons with HBV-associated liver disease. As the seroprevalence of HBV infection declines in response to vaccination programs, the prevalence of HDV infection can be expected to fall as well (5, 6). A study from Italy found the prevalence of HDV infection decreased from 23.4% in 1987 to 14.4% in 1992 among the HBV patients referred to liver clinics (22). While ascertainment bias or changes in referral practices may explain the change in anti-HDV prevalence between 1987-1992, a lower prevalence of HDV infection in the 0-29 years age group but not in the older subjects suggested there was a true decline in prevalence (22). In addition to a decreased pool of chronic HBsAg carriers, reductions in family size, improved socioeconomic conditions, and changes in intravenous drug use behaviors may be additional factors that contributed to the decline in prevalence (22).

Incidence of Chronic Viral Hepatitis
Sentinel surveillance for chronic liver disease is a relatively new undertaking of the CDC and provides an additional measure of the disease burden associated with chronic viral hepatitis. Beginning in 1998, the CDC began surveillance for newly diagnosed cases of chronic liver disease among adults in three geographically district areas of the U.S. (Connecticut, California and Oregon). The goals of surveillance were to provide annual estimates of the number of patients with newly diagnosed chronic liver disease within the general population, determine the proportion of chronic liver disease cases due to viral hepatitis, and to examine risk factors and comorbid conditions that influenced disease expression. Data from the first 21 months of surveillance in New Haven County, Connecticut showed an "incidence" of chronic liver disease of 31/100,000 persons (22a). Hepatitis C virus infection alone or in combination with alcohol was the commonest cause of chronic liver disease, accounting for 58% of cases (22a). Chronic HBV infection alone or in combination with HCV accounted for only 4% of cases. In 14% of cases insufficient information was available to make a diagnosis. A comparison of this incidence rate to that of Jefferson County, Alabama in 1989 (CDC, unpublished data) shows a substantial increase in the incidence of chronic liver disease in the past decade and a greater proportion of chronic liver disease attributable to HCV infection (Figure 3).

Risk Factors for Hepatitis B Virus
Hepatitis B virus is a parenterally transmitted virus which is acquired from exposure to infected blood or body secretions. Adolescents and adults account for the majority of reported cases of hepatitis B in the U.S. and sexual contact is the most common route of transmission. Perinatal and early childhood infections are much less frequent.

Perinatal Infection
The CDC estimates that at least 20,000 infants are at risk annually for HBV infection through perinatal sources (23). Rates of HBsAg-positivity in mothers vary among ethnic groups with higher rates among Asians (foreign-born), Hispanics and Blacks. The risk of transmission is higher in HBeAg-positive mothers. Rates of HBeAg-positivity average 30% among women of Asian descent and 20% among all other racial groups (24). Identification of HBsAg-positive mothers is critical for the prevention of HBV transmission from mother to infant. Currently, the CDC estimates that at least 90% of women are being screened for HBsAg prior to or at the time or delivery (4). However, the women who are not being screened are at greater risk of being HBsAg-positive (25).

Early Childhood Infection
Specific ethnic groups residing in the U.S., including Alaskan Eskimos, Pacific Islanders, and infants of first-generation immigrant mothers from countries of moderate to high HBV endemicity, are at risk of early childhood infection. The estimated risk of HBV acquisition within the first 5 years of life ranges from 5% to 40% for these children, with the highest risk for infants of HBsAg-positive mothers who are not infected at birth. Immunization of infants as part of the childhood immunization schedule and catch-up vaccination of susceptible children is the primary method of preventing infection. Focused vaccination programs, which started in the late 1980s, have successfully reduced the prevalence of HBV infection in children (6).

Infection Among Adults
Sexual activity is the most common mode of HBV transmission in North America and other countries where the prevalence of HBV infection is low. There was an initial decline in the incidence of HBV infection among men having sex with men in the 1980s, followed a subsequent decline among heterosexual men and women, and injection drug users in the 1990s. That being said, injection drug use and sexual activities remain the most frequently identified risk factors among adults with HBV infection (24). As with perinatal transmission, sexual transmission is facilitated by active viral replication in the infected individual (26). Factors positively correlated with HBV infection in adults are number of sexual partners, number of years of sexual activity, and a history of sexually transmitted diseases (STDs). In general, vaccination coverage of adults in high-risk groups, such as men who have sex with men and patients with STDs, has been low (27).

In the U.S. and Western Europe, injection drug use remains an important mode of HBV transmission. Risk of infection increases with duration of drug use, so that serological markers of ongoing or prior HBV infection are almost universal after five years of use (28). Other recognized modes of HBV transmission include working in a health-care setting (( 3% of cases in the U.S,); and transfusions, dialysis and other overt blood contacts (1% total). Nosocomial spread of HBV infection in hospitals, particularly in dialysis units, has been well described (29). HBV infection has been linked to multiple-use heparin vials and exposure to contaminated dental instruments and finger-stick devices (24, 29a). Transmission from health care worker to patient, while rare, has been reported (30). Acupuncture has been associated with outbreaks of HBV infection (31).

In about one-third of persons with HBV infection, no risk factor can be identified (32). These persons tend to be of lower socioeconomic level and belong to minority populations. Undisclosed sexual risks or illicit drug use may account for a proportion of these unknown cases.

Risk Factors for Hepatitis C Virus Transfusion of infected blood or blood products, use of contaminated dialysis equipment, transplantation of infected organs, and sharing of contaminated needles among injection drug users are well-recognized modes of HCV transmission. Sexual contact and perinatal exposure are associated with HCV infection but HCV transmission by these routes is relatively inefficient.

The prevalence of specific risk factors in persons with HCV infection has changed over the past 10 years. Although transfusion of HCV-infected blood or blood products was a common mode of HCV transmission in the past, this currently represents a rare mode of transmission. Following the introduction of blood donor screening and surrogate hepatitis tests, the proportion of patients with acute community-acquired hepatitis who reported a history of blood transfusion declined from an average of 17% in 1982 - 85, to 6% in 1986-88, to 4% in 1990-93 (33, 34). As transfusion-related cases of HCV declined, the proportion attributed to non-transfusion-related causes increased (34). Therefore, in cross-sectional studies of risk factors among persons with HCV infection, blood transfusion and injection drug use account for an approximately equal proportion of cases (about 30% each) in those whose exposure occurred more than 10 years ago (33). In persons whose exposure occurred within the last 10 years, injection drug use is the most common mode of acquisition, accounting for 60% of cases (33). The prevalence of other risk factors (e.g. occupational) have remained relatively constant over time (33).

In addition to the changing prevalence of risk factors over time, the proportion of persons without identifiable risk factors, so called "sporadic" HCV infection, has decreased. Among acutely infected persons identified by the CDC Sentinel Surveillance study between 1989-1994, 33% had no identifiable risk factor. More recently, that proportion has dropped to 10% (35). Individuals with "sporadic" infection are characterized by lower socioeconomic status (in one third), reports of high-risk behavior such as imprisonment, a history of one or more STDs, and use of non-injection illicit drugs suggesting that some of the "Sporadic" cases may be secondary to occult percutaneous exposures (36). Underreporting of past high risk behaviors such as injection drug use, overlooked transfusions received in infancy, and unrecognized percutaneous exposure within the community may explain a proportion of the sporadic cases of HCV infection. The prevalence of HCV infection is different "risk" groups is summarized in Table 4.

Table 4. Estimated prevalence of hepatitis C in different "at risk" groups  
 

Risk Factor Prevalence of HCV
Persons with hemophilia 74 - 90%
treated before 1987
Injection drug users 72 - 89%
Chronic hemodialysis 0 - 64% (average 10%)
Persons reporting history of STD 1 - 10% (average 6%)
Persons receiving blood transfusion 5 - 9% prior to 1990
Infants born to HCV RNA 5% (average) positive mothers
Men who have sex with men 4% (average)
Long-term sexual partners of 0.5 - 3% HCV-infected persons in monogamous relationship
General population 1.8%
Volunteer blood donors 0.16%
Adapted from MMWR: Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Centers for Disease Control and Prevention, 1998;47-5.
 

Blood Transfusion
Prior to 1985, the incidence of transfusion-associated hepatitis (TAH) was 8-10 per 100 persons transfused (37). Transfusion practices changed in the mid-1980's in response to concerns regarding HIV, with a subsequent fall in the rate of TAH by about 50% (37). With the introduction of first generation anti-HCV tests in the early 1990's, the rate of HCV acquisition via blood products declined by a further 80%and current estimates of the incidence of TAH are <1% (37). Donation of blood by seronegative donors during the infectious window period prior to seroconversion, accounts for the vast majority of the current residual risk of TAH (-80%). Nucleic acid testing for HCV RNA can reduce the infectious window from 70 days (average) to 10-29 days (38). Thus, the use of nucleic acid testing to screen blood products is expected to reduce the risk of HCV from 1:100,000 (current risk per unit transfused) to 1:500,000 - 1:1,000,000 (38).

Patients requiring blood products (clotting factors, immune globulin) from pooled donors have a high rate of HCV-positivity. The prevalence of anti-HCV in patients with hematological disorders who were transfused with clotting factors prior to the institution of viral inactivation and removal measures, is nearly 100%. Changes in product manufacturing as well as the use of screening assays have significantly reduced the incidence of HCV transmission in this population.

Injection Drug Use
The prevalence of HCV infection among drug users in the U.S. varies from 72% to 89% (48). The factor most consistently associated with anti-HCV positivity is duration of drug use. In the largest study of injection drug users, HIV coinfection, Black race, drug use within the preceding 6-month period, and use of injection cocaine were also found to be independently associated with HCV infection (39). Acquisition of HCV infection is rapid among drug users with anti-HCV seroprevalence rates of 54%, 78%, 83%, and 94%, among users of less than a year, 1 year, 5 years, and more than 10 years, respectively (39). Among newly diagnosed cases of chronic liver disease secondary to HCV in 1998, -60% report an antecedent history of intravenous drug use (CDC, Chronic Liver Disease Surveillance, unpublished data).

Dialysis and Other Nosocomial Sources
Dialysis units are the commonest setting for nosocomial transmission of HCV. A 1995 national surveillance study of 2647 dialysis centers found an anti-HCV prevalence of 10.4% in patients and 2.0% in staff (40). However only 39% and 16% of dialysis units performed routine testing of patients and staff, respectively. Additionally, serological assays may underestimate the prevalence of HCV infection in dialysis patients, since they are relatively immunocompromised. Virological assays identify a greater proportion of infected individuals (41). The annual incidence of HCV infection in one study was 3% and none of the patients who seroconverted had received a transfusion or used injection drugs (41a). Dialysis-specific risk factors associated with anti-HCV positivity include a history of prior blood transfusion volume of blood transfused, and duration of hemodialysis. Failure to ascertain community exposures to HCV, such as injection drug use, may lead to an overestimation of the contribution of dialysis to risk of HCV acquisition. The mechanism of HCV transmission in dialysis units is believed to be breaches in routine dialysis unit procedures and precautions (42). Person-to-person transmission of HCV among patients not sharing dialysis equipment but treated in the same room has been documented (43). Although hemodialysis patients constitute a risk group for HCV acquisition, they account for only 1% of persons with chronic infection. Other than dialysis, nosocomial transmission of HCV is rare in the U.S.

The seroprevalence of anti-HCV among healthcoare workers in the U.S. ranges from 0.7 to 2.0% (48). The variability in seroprevalence reflects the different exposures associated with specific healthcare jobs, the prevalence of HCV in the patient population served by the healthcare worker, and the frequency of other risk factors for HCV in the healthcare worker. The incidence of HCV seroconversion following needlestick injury or accidental cuts with sharp instruments is 1.8% on average (varies from 0% to 7%) (48). The presence of viremia in the source is associated with a higher rate of seroconversion than if the source is anti-HCV positive alone. Other factors which may influence the risk of HCV seroconversion include whether the needle was hollow-bore, the size of the inoculums, and host susceptibility. Transmission from physician to patient has been documented with in the context of an invasive surgical procedure (44) but such reports are extremely rare.

Perinatal Exposure
While passively acquired anti-HCV is frequent in newborns of HCV-infected mothers, transmission of infection only occurs in 5% (average) (45, 46). Factors that have been associated with the risk of transmission are presence of HCV viremia, maternal HIV status, and viral titer at the time of delivery. Breastfeeding does not appear to increase the risk of HCV transmission (45).

Sexual Contact
The available data suggests that HCV can be sexually transmitted but the efficiency of transmission is low. In long-term studies of heterosexual couples in relationships of 15-20 years duration, the rate of HCV-positivity among the sexual partners of HCV-infected persons was 0.5 to 3% and the vast majority of couples in these studies did not use condoms (48). One study suggested that transmission from an infected male to an uninfected female partner might be more efficient than from an infected female to an uninfected male partner (47). In contrast to the low frequency of anti-HCV positivity in couples in long-term relationships, 20% of persons with newly-identified HCV infection report sexual contact with a HCV-positive person or more than 2 sexual partners, in the preceding 6 month period, as their only risk factor for HCV acquisition. However, acquisition from an unacknowledged percutaneous exposure cannot be completely ruled out in these cases. Cross-sectional and case control studies have shown that persons with a high number of sexual partners, non-use of condoms, history of other STDs, and sex with trauma are more frequently HCV-positive than persons who do not report these high-risk sexual behaviors. Thus, recommendations regarding the prevention of HCV transmission differ for persons in long-term steady relationships and those with multiple partners (48).

 Table 5.  HBV genotypes and serotypes: Geographical distribution  


Genomic                                Areas of High
Group         Serotype                  Prevalence

A             adw2  ayw 1            Northwestern Europe, 

                                     U.S. Central Africa 

B             adw2  ayw1             Indonesia, China Vietnam 

C             adw2  adrq+            East Asia Korea, China, Japan 
              adrq- ayr              Polynesia Vietnam 

D             ayw2  ayw3             Mediterranean area India 

E             ayw4                   West Africa 

F             adw4q-                 Central and South America, 
              adw2  ayw4             Polynesia 

G             adw2                   France, U.S. 


References: 

Magnius Lo and  Norder H, Intervirology 38:24-34, 1995. 

Blitz L. Pujol F, Swenson P, et al. J Clin Microbiol 36:648-51,1998. 

Stuyver L, De Gendt S, Van Geyt C, et al. J Gen Virol 81:67-74,2000 
 

Risk Factors for Hepatitis D Infection
Injection drug use is the commonest mode of HDV transmission in the U.S. (15). Sexual transmission of HDV is less efficient than transmission of HBV, but is a well-recognized risk factor. In men having sex with men who deny a history of injection drug use, the risk of HDV infection increases with the number of sexual partners and frequency of rectal intercourse (49). Among prostitutes, prevalence rates of HDV range from 6% to 21% with the highest rates among prostitutes who also use injection drugs (50).

Chronic Hepatitis B Virus
Four subtypes of HBsAg named adw, ayw, adr and ayr were identified in the 1970's. An additional nine different subtypes were later identified, designated ayw 1-4, adw 1-4, and adrq +/ adrq-. Sequencing of viral genomes and comparison of complete genomes in the 1980's led to a reclassification of HBV heterogeneity into genotypes (Table 5). At the level of the S-gene, a difference of ( 4% nucleotides defines different HBV genotypes (51).

 Table 6.  Distribution of HCV genotypes in the U.S.  


Author, Year      N            Population                        Genotypes (%)  1a      1b     2a 


Alter, 2000      250      Randomly selected civilians           57    17   3.5   11   7.4     0.9    3.2 
                          from 89 locations (NHANES III) 


Zein, 1996       179      Consecutive patients from 4           58    21   2.0   13    5        1     -- 
                          tertiary referral centers 


Mahaney, 1994     98      Referred for treatment trials         36   38    6.1   9.2   6.1    1.0     -- 

Reddy, 1996      414      Participants in treatment trial       32   26    5     10    13      --      9 

McHutchison,1998 456      Participants in treatment trial       72   18    9      --   -- 

Davis, 1998      354      Participants in treatment trial       56   17    25     --   -- 
 

While associations between HBV genotypes and specific clinical outcomes require further study, an interesting relationship between HBV genotype and the G-to-A mutation at nucleotide 1896 in the precore region has been elucidated. The precore mutation has been found to be most frequently associated with genotype D and rarely associated with genotype A. Mutations in the core region in genotype D HBV are predicted to increase the stability of the stem-loop structure, which is critical for the viral pregenomic encapsidation signal, whereas these same mutations in HBV genotype A have a destabilizing effect on the stem region (52). Additional studies have suggested HBV genotypes may be important determinants of disease severity. Preliminary data have linked HBV genotype with responsiveness to interferon among HBeAg-negative patients (52a) and risk of HCC (53). Genotype D and total number of accumulated mutations throughout the HBV precore/core gene have been associated with more severe recurrent disease following liver transplantation (54).

Chronic Hepatitis C Virus
At least six different genotypes and more than 90 subtypes of HCV have been identified (55). HCV genotype 1 predominates in the U.S., accounting for approximately 65-75% of infections (Table 6). The genotype distribution among HCV RNA positive persons in NHANES III was 56.7% type 1a, 17.0% type 1b, 3.5% type 2a, 11.4% type 2b, 7.4% type 3a, 0.9% type 4 and 3.2% type 6. There was a lower prevalence of type 1b and higher prevalence of type 1a in the NHANES III study (population-based) compared to referred or treated patient populations (Table 6). In other parts of the world, genotypes 1b (Europe, East Asia), 2a (Southeast Asia), 3a (India), 4 (Egypt and the Middle East), and 5A (South Africa) predominate (Figure 4). The time of divergence of the HCV genotypes isolated from different geographical regions has been estimated to be more than 500-2000 years for viral types and more than 300 years for viral subtypes (56).

Whether specific HCV genotypes are associated with more severe histological disease or greater risk of cirrhosis or hepatocellular carcinoma is controversial. For example, several studies, predominantly from Europe and Southeast Asia, have found HCV type 1b to be more prevalent in patients with cirrhosis and hepatocellular carcinoma than in patients with chronic hepatitis or asymptomatic blood donors. This finding is compatible with HCV type 1b being more pathogenic, but additional studies have shown that the association is likely due to a cohort effect, i.e. there is an overrepresentation of HCV type 1b among older patients who had a longer duration of disease (57).

The relationship between HCV genotype and response to interferon and nterferon/ribavirin therapy is well established. Sustained response rates are significantly lower in patients with genotype 1 compared to genotypes 2 or 3 (58, 59).

Chronic Hepatitis D Virus
Genetic analyses of HDV isolates from different geographical areas indicate there are at least three genotypes (60). Genotype 1 is the most common and geographically diverse with distribution in Western Europe, North Africa, the Middle East, Turkey, Japan, Taiwan, and the U.S. Genotypes II and III have a much more restricted distribution. Type II has been isolated from patients in Japan and Taiwan, where it coexists with genotype I. Genotype III has been found in patients from Peru and Columbia. These different distribution patterns likely reflect interactions between the HDV genotypes and dominant HBV genotypes in specific geographical areas, such as has been described for HDV genotype III and HBV genotype F in northern South America (61). The genotype distribution also reflects the migration of populations over time, and geographical clustering of cases indicate that HDV was introduced relatively recently into the U.S. compared to Southern Europe and Northern Africa (62). Studies on the relationship between HDV genotype and severity of disease are limited. Preliminary studies have linked genotype II with milder disease and genotype III with severe disease (63, 20a). Disease severity in patients with genotype I appears to vary from mild to severe.

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