Prevention of Viral Hepatitis

Jules L. Dienstag

Viral hepatitis is an infectious disease of the liver that is estimated to afflict more than 5 million people and to cause several thousand deaths in the United States each year. Although the majority of those infected are asymptomatic or minimally symptomatic, chronic viral hepatitis is associated with substantial morbidity, and fulminant hepatitis, which is often fatal, may develop in a small proportion of acutely infected patients.

Prevention of infection and prophylaxis against clinical disease are prime objectives in the management of viral hepatitis. The primary physician has the major responsibility for these tasks because patients and their contacts often present at a time during acute infection when infectivity is high. Prevention of viral hepatitis requires knowledge of the common modes of viral transmission, the periods of maximal communicability, and the efficacy of globulin preparations and vaccines.

EPIDEMIOLOGY AND RISK FACTORS

Viral Types

Five distinct types of viral hepatitis are recognized: A through E. Although other types of hepatitis viruses (e.g., “hepatitis G”) have been described, none has proved to be a true hepatitis virus or to account for the small proportion of cases that cannot be linked serologically to hepatitis viruses A through E.

Sources of Outbreaks (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15)

In general, outbreaks of hepatitis are often traced to a source of hepatitis A virus (HAV) or, in developing countries, to hepatitis E virus (HEV). Occasionally, clusters of hepatitis B follow exposure of several persons to contaminated needles or blood products. Among urban adults presenting to a primary care physician with sporadic cases of acute hepatitis, hepatitis B accounts for approximately 50% of cases, hepatitis C for 15%, and hepatitis A for the remainder. More than 95% of transfusion-associated cases were attributable to hepatitis C; however, the frequency of transfusion-related cases has been reduced dramatically to negligible levels by excluding blood donors with risk factors for viral hepatitis as well as the use of sensitive screening tests for hepatitis C (see later discussion). Hepatitis D is caused by a defective virus that infects only in the presence of infection with hepatitis B virus (HBV). Chronic infection with HBV is prevalent in 0.1% to 0.5% (1 million persons), and chronic infection with hepatitis C virus (HCV) is prevalent in 1.6% (4 million persons) of the US population.

Hepatitis A (1,2,13,14,16)

HAV is shed in the feces, and transmission occurs predominantly by the fecal-oral route (e.g., ingestion of contaminated food, water, shellfish). Prior exposure to hepatitis A is manifested by the presence of antibody to HAV (anti-HAV), which confers lifelong immunity. Many patients older than the age of 60 years test positive for anti-HAV, but acute infection is rare in this age group. Because children and adolescents are least likely to have had previous exposure to the virus, they are the most susceptible to infection. Spread of infection is greatest where poor sanitary conditions and crowding exist, with prevalences as high as 75% among low-income people, compared with 20% to 30% for residents in middle- to upper-income neighborhoods. In developed countries, the prevalence of anti-HAV and of immunity to the virus has fallen by approximately 10% per decade since the 1970s. The downside of this declining prevalence of anti-HAV is the growing prevalence of susceptibility to infection in population subgroups that heretofore had been immune. The resulting shift in acute cases from the very young, in whom the disease tends to be subclinical, to adults, in whom the disease tends to be associated with jaundice and is relatively severe, has translated into an increased frequency of clinically apparent, severe hepatitis A in adults. Acute hepatitis A does not progress to chronic infection.

Hepatitis B (3,4,7,9,17)

Hepatitis B can be transmitted both by percutaneous and nonpercutaneous modes of spread. The application of sensitive screening methods for the detection of HBV has essentially eliminated posttransfusion hepatitis type B. Reliance on blood obtained from volunteer donors, which is less likely to contain the virus, in addition to blood donor exclusion practices and screening tests to prevent transfusion-transmitted HIV infection and
hepatitis C has also contributed to reducing the frequency of hepatitis B after transfusion. Injection drug use remains a common route of exposure. Perinatal transmission from mother to offspring accounts for most HBV infections in the Far East and Africa, whereas sexual transmission is an important and efficient mode of spread in the United States and other Western countries. About 0.1% of healthy blood donors, reflective of the general population, are infected; the percentages increase markedly for injection drug users and patients exposed to blood, such as hemophiliacs and patients in hemodialysis units. Surgeons, laboratory technicians, oral surgeons, and other medical personnel exposed to blood and body fluids are at increased risk for contracting hepatitis B. Spread of infection to patients from health care personnel who are infected with HBV is a rare event.

Hepatitis C (5,6,9,12,18, 19, 20, 21, 22, 23, 24, 25, 26 and 27)

Hepatitis C, initially labeled “non-A, non-B hepatitis,” was first recognized in transfusion recipients and found to be the predominant type of hepatitis after transfusion. In the 1970s, it occurred in up to 10% of transfusion recipients, usually within 1 to 3 months after they had received blood from volunteer donors. The frequency of infection fell with the adoption of surrogate tests for hepatitis C (e.g., alanine aminotransferase, antibodies to hepatitis B core antigen), the exclusion of blood donors at risk for HIV infection (further reduced by the use of screening tests for HIV—see Chapter 7), and the direct testing for antibodies to HCV (followed by testing for HCV RNA). Currently, the risk for hepatitis C after transfusion is barely measurable, and transfusion-associated infections are almost never encountered. Hepatitis C can be spread by any percutaneous route, such as needlestick inoculation (˜3 % risk of infection) or self-injection among drug users. The risk for hepatitis C resulting from sexual or perinatal transmission is believed to be very low, on the order of 1% to 5%. In about one third of patients with acute hepatitis C and in almost all volunteer blood donors with hepatitis C, risk factors are not readily apparent; however, in most such cases, remote or less obvious percutaneous exposures—predominantly long-forgotten, transient injection drug use—can be identified or inferred. Although acute hepatitis C is a rare event nowadays in the general population, chronic hepatitis C is encountered regularly (1.6% prevalence, peaking in the fifth decade), primarily among persons infected decades ago, during the 1960s and 1970s, when experimentation with injection drug use was common.

Hepatitis D (Delta Hepatitis) (10, 11, 15)

Hepatitis D, or delta hepatitis, is caused by a defective RNA virus that requires coinfection with HBV (a DNA virus) to support its replication. Infection with this agent occurs either simultaneously with acute hepatitis B infection (coinfection) or is superimposed on chronic hepatitis B (superinfection). Like hepatitis B, hepatitis D is transmitted by percutaneous inoculation and intimate contact. In nonendemic areas, such as the United States and Western Europe, hepatitis D is confined primarily to populations with frequent percutaneous exposures, such as injection drug users and hemophiliacs. In endemic areas, such as the Mediterranean countries, hepatitis D is transmitted primarily through intimate contact. Hepatitis D tends to be rare in the United States.

Hepatitis E (28, 29 and 30)

Hepatitis E, prevalent in India, Asia, Central America, and developing countries, is transmitted by the fecal-oral route. Similar epidemiologically and clinically to hepatitis A, hepatitis E tends to be recognized clinically in a population cohort somewhat older than that for, and almost invariably immune to, hepatitis A and is more likely to cause severe, even fatal hepatitis, especially in pregnant women. Rarely encountered clinically in the United States except for imported cases from endemic countries, hepatitis E does not cause chronic infection. Approximately 20% of US blood donors harbor antibodies to HEV and appear to have been infected subclinically by nonvirulent viral genotypes common in zoonotic reservoirs (swine).

NATURAL HISTORY

Both hepatitis A and hepatitis E are self-limited and do not lead to chronic liver disease; however, hepatitis B, C, and D can cause chronic hepatitis and cirrhosis; long-standing chronic hepatitis B and C can be complicated by hepatocellular carcinoma.

Hepatitis A (1,2,8,13,16)

Hepatitis A has an average incubation period of 30 days (range, 15 to 45 days) from the time of exposure to the onset of symptoms. An early manifestation of disease is elevation of serum aminotransferase levels, which occurs about 1 week before the onset of flulike symptoms. Fecal shedding of HAV occurs well before the rise in aminotransferase levels and up to 2 weeks before the development of symptoms. HAV can be detected in serum for no more than a few days, and the virus disappears from stool within 2 to 3 weeks, usually at the same time as the onset of jaundice and resolution of prodromal symptoms. A fall in virus levels parallels a rise in the titer of anti-HAV, which persists indefinitely. Initially, anti-HAV is of the immunoglobulin M (IgM) class; during convalescence, anti-HAV of the immunoglobulin G (IgG) class becomes predominant. Therefore, a diagnosis of acute hepatitis A can be made by detecting IgM anti-HAV in a single serum sample. No episodes of chronic hepatitis or a carrier state result from hepatitis A infection. Fatalities are rare; fewer than 5% of cases of fulminant hepatitis result from HAV infection, but cases of increased clinical severity are becoming more common (see prior discussion).

Hepatitis B (3,4,7,17,22,31)

Hepatitis B is a much more variable disease. The incubation period averages 12 weeks, with a range of 4 weeks to 6 months.

Acute Infection

About 2 to 4 weeks before the onset of symptoms, the viral envelope protein, hepatitis B surface antigen (HBsAg), appears in the serum, followed by a rise in aminotransferase levels and symptoms. This viral antigen usually is cleared from the serum by 4 to 6 months; persistence of HBsAg in serum beyond 6 months is considered chronic infection. Symptoms of acute hepatitis B typically last 4 to 6 weeks, but the clinical expression of acute hepatitis B is very variable, ranging from clinically inapparent disease to fulminant hepatitis (in 0.1% of acute cases) with hepatic failure and death. Determinants of disease severity include age, immunologic competence, undefined host factors, viral genotype, and virulence of the virus.

Chronic Infection

Approximately 1% to 2% of patients with clinically apparent disease progress to having chronic infection and continue to harbor circulating HBsAg. A much larger number of cases of chronic
hepatitis B do not originate as clinically apparent acute illness; thus, the number of chronic cases is much larger than anticipated based on the number of recorded acute cases. Among patients with chronic hepatitis B, some have detectable serologic markers of high-level virus replication and some remain inactive carriers. Those with high-level replication tend to be highly infectious for contacts and to have chronic hepatitis that is progressive and of at least moderate severity, whereas inactive carriers lack evidence of high-level virus replication, infectivity, or liver injury (see later discussion). A relatively high degree of immunologic tolerance to the virus characterizes persons who acquire HBV infection in the early decades of life (e.g., highlevel HBV DNA levels, near normal ALT activity, minimal liver injury), while lower levels of tolerance emerge during middle decades (e.g., rising ALT, evidence for liver injury and progressive hepatic fibrosis). The fatality rate for acute hepatitis B is about 0.1%; however, among those requiring hospitalization, the mortality rate is 1%. Although hepatocellular carcinoma is rare in immunocompetent patients who become chronically infected following adulthood acute infection, this dreaded complication of chronic HBV infection is common among those who become chronically infected after perinatally acquired acute infection. In Asia, where perinatal infection is the most common route of exposure, the lifetime risk of death from cirrhosis and hepatocellular carcinoma has been reported to be as high as 40%.

Serology

Antibody to HBsAg (anti-HBs) is produced early during infection but becomes detectable with commercially available serologic assays only as HBsAg disappears. Almost all patients with self-limited acute hepatitis B acquire detectable levels of anti-HBs, which persist indefinitely and correlate with subsequent immunity.

Antibody to the nucleocapsid core of HBV (anti-HBc) appears in the circulation within 1 week or so after HBsAg becomes detectable and persists indefinitely. Occasionally, during late acute infection, an interval occurs in which HBsAg has already disappeared and anti-HBs has not yet become detectable. This so-called window period can be identified by the presence of isolated anti-HBc; however, now that tests for HBsAg and anti-HBs are so sensitive, this window period is encountered very rarely among patients with acute hepatitis B. Most cases in which anti-HBc occurs in the absence of HBsAg and anti-HBs represent HBV infection in the remote past. In rare instances, isolated anti-HBc represents a false-positive test result, whereas in patients at high risk for bloodborne infections (e.g., injection drug users), isolated anti-HBc may represent low-level HBV infection in which the level of HBsAg does not exceed the detection threshold. On the other hand, isolated anti-HBc can be detected in a proportion of injection drug users with chronic hepatitis C, and in this setting, the presence of low-level HBV infection cannot be demonstrated in serum or liver, even with sensitive amplification assays.

A test for anti-HBc of the IgM class (IgM anti-HBc) can distinguish between acute or relatively recent acute hepatitis B (IgM positive) and infection in the remote past or current chronic infection (IgM negative), in which anti-HBc is of the IgG class. In a small proportion of cases of acute hepatitis B, HBsAg does not reach the threshold for detection; in such cases, a diagnosis of acute hepatitis B can be established by detecting IgM anti-HBc.

Hepatitis B e antigen (HBeAg) is a second product of the gene that codes for the nucleocapsid core; its presence signifies highlevel virus replication. As such, patients with HBeAg have a high level of circulating virions and infectivity and substantial liver injury. HBeAg becomes detectable in all patients early during acute hepatitis B, and therefore, this test has no clinical utility during early acute hepatitis B; however, if circulating HBeAg persists beyond the first 3 months of acute hepatitis, the likelihood of chronic infection is increased.

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