Author: Dr Norah Terrault University of California San Francisco 2008-07-14
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| Hepatitis A virus. CDC |
Hepatitis
A virus (HAV) is the most common cause of acute hepatitis (liver
inflammation and injury) in the United States. The way the infection
presents can vary from being without symptoms to, on rare occasions,
being life-threatening. Generally, unless complicated by other
conditions, the infection runs its course
without any permanent damage to the infected individual. Acute infection with HAV does not turn into a chronic condition.
HAV is a member of the Picornaviridae family of viruses, and is a unique member of the genus Hepatovirus.
The virus consists of an RNA genome surrounded by an icosahedral capsid
(a 20-sided protein shell) (Figure right- Source: www.cdc.gov). 
HOW DOES HEPATITIS A VIRUS CAUSE HEPATITIS?
HAV is a hepatotrophic virus, meaning the virus replicates only within the liver. After ingestion, the virus is absorbed from the stomach and small intestine into the blood. The infected blood reaches the liver providing the virus access to the liver cells, the sole environment where the virus can multiply. The replicating virus is released from the liver cells into bile (a fluid that the liver releases, which helps in digestion), which, in turn, is secreted into the stool. During the period of viral replication in the liver cells, the immune system mounts an attack on the virus to try to control infection. This immune response results in inflammation and liver cell injury, which is termed “hepatitis.” After recovery from the acute infection, the liver usually returns to normal (the hepatitis resolves) and there are no residual liver effects. The virus does not cause chronic hepatitis, like hepatitis B virus or hepatitis C virus.FREQUENCY OF HAV INFECTION IN THE GENERAL POPULATION
In 2005, there were an estimated 42,000 cases of acute HAV infection in the US (1). Prior to 1995, the numbers of new cases of hepatitis A in the United States had been cyclic, with nationwide outbreaks occurring every 10 to 15 years. However, since the introduction of the HAV vaccine in 1995, the frequency of acute hepatitis due to HAV has been steadily declining in all age groups at risk for infection (Figure below).
Source: MMWR Surveillance Summaries, Surveillance for Acute Hepatitis ---- United States 2005
March 16, 2007/56(SS03);1-24.
Currently the estimated annual incidence of HAV in the US is only 1.5 per 100,000 persons, which represents an 85% decline in the number of new cases since 1995. The declining number of cases over the past decade highlights the positive impact of hepatitis A childhood immunization programs.
Currently, the most commonly identified risk factor among reported cases of acute HAV infection is contact with an infected household member or sexual partner (Figure below).
Other risk factors for HAV include:
March 16, 2007/56(SS03);1-24.
Currently the estimated annual incidence of HAV in the US is only 1.5 per 100,000 persons, which represents an 85% decline in the number of new cases since 1995. The declining number of cases over the past decade highlights the positive impact of hepatitis A childhood immunization programs.
WHO IS AT RISK FOR GETTING ACUTE HAV INFECTION?
Hepatitis A can affect anyone. The virus is transmitted by person-to-person contact and by ingestion of contaminated food and water. HAV is found in stool and is transmitted to another person if they put anything in the mouth that has been contaminated with stool from an infected person. Poor personal hygiene and improper food handling practices are the most common ways that the virus spreads from person to person. Contaminated blood products have rarely transmitted HAV.Currently, the most commonly identified risk factor among reported cases of acute HAV infection is contact with an infected household member or sexual partner (Figure below).
Other risk factors for HAV include:
- International travel: the majority of reported travel-related cases were associated with travel to Mexico and Central or South America
- Men who have sex with men
- Daycare attendees and workers and those in contact with them
- Injection drug use
- Eating raw shellfish from contaminated waters
- Sporadic food outbreaks
- Receipt of blood from person with acute hepatitis
In nearly half of the reported cases of acute HAV infection, a definitive source of infection cannot be identified.
http://www.cdc.gov/ncidod/diseases/hepatitis/index.htm
WHAT IS THE USUAL COURSE OF ACUTE HEPATITIS A INFECTION?
Acute hepatitis A infection can vary from being an asymptomatic condition to being severe enough to cause fulminant (sudden and severe) liver failure, which requires liver transplantati on. The severity of symptoms increases with age; young individuals usually having milder symptoms and less frequent need for hospitalization compared to those over the age of 50 years (Table 1). The risk of dying from liver failure caused by acute hepatitis A is quoted as 1% overall, but again varies by age (Table 1). Adults over the age of 50 years have a 2.2% risk of dying with acute HAV infection. HAV does not cause a chronic infection so once an individual recovers from acute infection with HAV, their liver will be normal. Persons with acute hepatitis A infection who recover have protective antibodies that will provide lifelong protection against another infection with the virus.
Table 1: Risk of Complications Varies by Age of Infection
Age
of Infection Rate of Hospitalization for Infection
Fatality Rate
<5 years 25% 0%
6-14 years 17% 0%
14-39 38% 0.7%
40-59 41% 1.1%
>60 years 47% 2.2%
Source: MMWR Surveillance Summaries, Surveillance for Acute Hepatitis ---- United States 2005. March 16, 2007/56(SS03);1-24. <5 years 25% 0%
6-14 years 17% 0%
14-39 38% 0.7%
40-59 41% 1.1%
>60 years 47% 2.2%
The average incubation period for HAV is 30 days, with a range of 15-50 days. Thus, most individuals experience symptoms about a month after coming into contact with the virus. The symptoms for acute HAV are not specific for this virus, but rather are the same symptoms seen in patients with hepatitis of many causes. Symptoms include:
- Fatigue
- Nausea, vomiting, loss of appetite
- Diarrhea, possibly weight loss
- Fever
- Pain in the right upper portion of the abdomen
- Jaundice (yellowing of skin and eyes): this is seen in less than 10% of young children (less than 6 years of age) but is seen in the majority of older children and adults who are become infected.
- Dark urine
Persons with other chronic diseases are at higher risk for a complicated course. For example, patients with chronic liver diseases due to other causes, such as chronic hepatitis C or alcoholic liver disease are at risk of severe HAV infection. Acute HAV infection in persons with compromised immune systems, such as those with HIV infection, can have a slower recovery of their liver test abnormalities and more variable course.
Laboratory Test Abnormalities
In persons with HAV infection, the most important laboratory abnormalities are:
- Marked elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), usually greater than1000 IU/L. These tests reflect the severity of liver inflammation and injury.
- There may also be changes in the tests that reflect liver function, including the serum total and direct bilirubin (which correlates with the severity of jaundice), prothrombin time (a measure of clotting capacity), and albumin (a measure of protein production and destruction).
The time course for acute HAV infection is depicted in the figure below. The virus is detectable in the stool and blood during the symptomatic phase of infection. This means that the individual is infectious during this phase and at risk of transmitting the virus to others. Typically the disappearance of the virus from stool and blood coincides with the resolution of the symptoms, but in some cases the shedding of virus in stool can persist for months. Prior studies have shown that the virus is present in the highest concentration in the stool and in lesser concentrations in blood and saliva.
HOW IS THE DIAGNOSIS OF ACUTE HEPATITIS MADE?
Since the symptoms for acute HAV infection are not specific, laboratory tests are needed to confirm the diagnosis of acute HAV infection. Blood tests for hepatitis A infection are undertaken in patients who have symptoms of hepatitis (loss in appetite, nausea, abdominal pain, jaundice) and elevated ALT levels. The diagnosis is based on the detection of antibodies against HAV (Table 2). In most infected individuals, antibodies against HAV will be detected within 2-3 weeks after exposure and are detectable 5-10 days before the onset of symptoms.- Antibodies to HAV of IgM type (anti-HAV IgM) are diagnostic of the condition. The level of IgM antibody to HAV gradually decreases and disappears within six months in the vast majority of persons.
- Antibodies to HAV of IgG type (anti-HAV IgG) also develop during the acute infection, but slightly later than the IgM form, and are persistent for the lifetime of the individual. This antibody, anti-HAV IgG, confers lifelong protection against HAV infection.
Table 2: Interpretation of Diagnostic Tests for HAV Infection
HAV IgG HAV IgM Interpretation
Positive Positive Acute HAV infection
Negative Positive Acute HAV infection (earlier phase than above)
Positive Negative No acute HAV infection - person has protective immunity
Negative Negative No acute HAV infection and no immunity – at risk for getting HAV in future
PREVENTING HAV INFECTION
Protection against HAV infection is available in two forms:- HAV vaccine (inactivated viral proteins that stimulate your immune system to make protective antibodies)
- Immune globulin (antibodies against HAV given by intramuscular injection).
HAV Vaccines
- The two inactivated vaccines licensed in the United States, Havrix (GlaxoSmithKline, Research Triangle Park, North Carolina) and VAQTA (Merck, Whitehouse Station, New Jersey) are given in a two-dose series administered six months apart.
- Both vaccines are highly effective with 97-100% of healthy children, adolescents and adults developing a protective level of antibody after one injection; after the second does, essentially 100% of persons have protective levels of antibody.
- There is also a combination of HAV and HBV vaccines available (Twinrix; GlaxoSmithKline, Research Triangle Park, North Carolina), administered in a dosing schedule of zero (first dose), one, and six months (after the first done) (The concentration of inactivated HAV in the combination HAV-HBV vaccine formulation is half that included in the HAV vaccine available from the same manufacturer, so the combination vaccine is not recommended for pre or post-exposure prophylaxis (prevention of infection after actual or possible exposure to the virus), but can be used for routine HAV vaccination (no recent exposure to the virus).
- The recommended doses and schedule of injections is shown in the Table below. Booster shots are currently not recommended. Protective levels of antibody have been documented for up to 10 years and are predicted to persist at detectable levels for at least 20 years.
Hepatitis A Vaccines
Vaccine Product Age of Vaccine Recipient (yrs) Dose (volume) Timing of Doses
HAVRIX (HAV) 1-18 720 EL.U (0.5 ml) 0, 6-12 mos
>18 1440 EL.U (1 ml) 0, 6-12 mos
VAQTA (HAV) 1-18 25 U (0.5 ml) 0, 6-18 mos
>18 50 U (0.6 ml) 0, 6-18 mos
TWINRIX (HAV + HBV) 1-18 Not recommended --
>18 720 EL.U + 20mcg 0, 1, 6 mos
Who Should be Vaccinated Against HAV?
Since 1999, it has been recommended that all children be vaccinated against HAV. The following persons are recommended to undergo vaccination as they are at higher risk of contracting the infection or are at higher risk of severe disease if they become infected:
- Men who have sex with men
- Injection and non-injection drug users
- International travelers
- Persons who have clotting factor disorders
- Persons with chronic liver disease
Certain groups of individuals have lower response rates to the HAV vaccine. These are patients with other medical conditions that reduce the immune response to the vaccine.
- HIV-infected individuals have lower seroconversion rates than those without HIV infection. A recent meta-analysis of eight studies analyzing HAV vaccine efficacy in HIV-infected patients reported an overall response rate of 64% (2). This means 36% of vaccinated persons with HIV infection did not develop protection against HAV infection. Vaccine efficacy was reduced in the setting of advanced HIV infection (low CD4 cell count).
- Patients with advanced liver disease, especially those with complications of cirrhosis.
- Transplant recipients: Response to HAV is seen in about 20% of vaccinated transplant patients (3), presumably due to the immune suppressive effects of the anti-rejection medications.
Post-Exposure Prophylaxis (Recent Exposure to HAV)
For persons who have been exposed to HAV within the prior two-week period, post-exposure prophylaxis should be given to prevent symptomatic infection. As noted above, there are two forms of prophylaxis available: HAV vaccine and immunoglobulin (IG).
- IG is effective in all ages, regardless of concurrent medical conditions, and is given as an intramuscular injection at the dose of 0.02 ml/kg. HAV vaccine is usually given at the same time if there is a need for lifelong protection.
- HAV vaccination can be used in selected individuals. A large randomized study showed that receipt of HAV vaccine within the first two weeks after HAV exposure is as effective as IG in preventing HAV infection (4). Since the study only included healthy individuals between the ages of 2-40 years, HAV vaccine alone (instead of IG) is recommended only in these individuals. Older persons with other health conditions should receive IG as their primary prevention.
- If given in a timely fashion (within two weeks of exposure to HAV), both IG and HAV vaccine are highly effective in preventing HAV infection, with less than 5% of persons becoming symptomatic (5).
TREATMENT OF ACUTE HEPATITIS A
There are no specific medications to treat acute HAV infection.Management is supportive, and focused on alleviating symptoms associated with hepatitis.
For most patients this includes:
- Bed rest
- Insuring adequate fluid intake (especially if vomiting and diarrhea present)
- Use of analgesics (pain relievers) in limited amounts for fever and joint pains
Individuals with acute HAV infection can spread the infection to others. The time when they are at risk for doing so is the week prior to being sick and the first week of the illness. For this reason, individuals should return to school or work only after they have recovered from their illness. For persons working in specific jobs, such as the food handlers or day care workers, clearance from their doctor may be needed before they can return to work.
Treatment of Fulminant HAV Infection
Although rare, fulminant hepatitis is a potentially life-threatening complication of acute hepatitis A infection. Fulminant hepatitis is the most severe manifestation of HAV infection occurring in 1% of cases overall. The risk of fulminant hepatitis is increased in older individuals (over 50 years of age) and those with preexisting chronic liver disease (of any cause).
Individuals with fulminant hepatitis due to HAV need to be managed in a tertiary referral center (usually a major hospital with a full complement of services) with access to liver transplantation. The ultimate therapy for patients developing HAV-associated liver failure is liver transplantation, although some patients with severe hepatitis will recover without the need for liver transplantation. In a nationwide study in the U.S., 29 adults with fulminant liver failure caused by HAV infection between 1998 and 2005 were identified. Fifty-five percent of these patients spontaneously recovered, 31% required liver transplantation, and 14% died without receiving a liver transplant (6). This study also reported that the number of persons in the US presenting with fulminant liver failure due to acute HAV infection has decreased between 1998 and 2005. This decrease may reflect the effect of higher rates of vaccination in the general population.
References
- Wasley A, Miller J, Finelli L. Surveillance for acute viral hepatitis --- United States, 2005. MMWR Surveillance Summaries 2007;56(SS03):1-24.
- Laurence JC. Hepatitis A and B immunizations of individuals infected with human immunodeficiency virus. Am J Med 2005;118 Suppl 10A:75S-83S.
- Arslan M, Wiesner RH, Poterucha JJ, Zein NN. Safety and efficacy of hepatitis A vaccination in liver transplantation recipients. Transplantation 2001;72(2):272-6.
- Victor JC, Monto AS, Surdina TY, Suleimenova
SZ, Vaughan G, Nainan OV, et al. Hepatitis A vaccine versus immune
globulin for postexposure prophylaxis. N Engl J Med 2007;357(17):1685-94
. - MMWR.
Update: Prevention of Hepatitis A After Exposure to Hepatitis A Virus
and in International Travelers. Updated Recommendations of the Advisory
Committee on Immunization Practices (ACIP). MMWR Weekly
2007;56(41):1080-108
4. - Taylor RM, Davern T, Munoz S, Han SH, McGuire B, Larson AM, et al. Fulminant hepatitis A virus infection in the United States: Incidence, prognosis, and outcomes. Hepatology 2006;44(6):1589-97.