ARCHIVED - Canada Communicable Disease Report

Statement on Hepatitis Vaccines for Travellers

Preamble

The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to tropical infectious disease and health risks associated with international travel. PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and the medical community caring for travellers.

Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer(s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.

Introduction

Viral hepatitis is a common infection primarily caused by five viruses: hepatitis A virus (HAV), hepatitis B virus (HBV) and hepatitis C virus (HCV) occurring worldwide, as well as hepatitis D virus (HDV) and hepatitis E virus (HEV) found predominantly in developing countries. Viral hepatitis is considered the most common travel-related, vaccine-preventable disease among travellers to developing countries. Some hepatitis viruses (i.e. HAV, HEV) are transmitted primarily by the enteric route, whereas others (i.e. HBV, HCV, HDV) are transmitted through parenteral exposure. Unsafe sexual practices may also expose travellers to some viral hepatitis. Most travellers presenting with viral hepatitis after travel are infected with HAV (60%), 15% with HBV and 25% with non-A, non-B hepatitis^{Footnote 1}. Currently, only HAV and HBV are preventable through vaccination. HDV is indirectly vaccine preventable, as HBV immunity protects against HDV infection. The Canadian Immunization Guide provides additional information on HAV and HBV vaccines.

Hepatitis A

HAV is an RNA virus of the Picornaviridae family, formerly classified as enterovirus type 72, now classified in its own genus – Hepatavirus^{Footnote 2}. While 1.5 million cases are reported worldwide every year, the true incidence is likely much greater^{Footnote 3}. The virus is almost always spread through the fecal-oral route either by direct contact with infected persons or indirectly through ingestion of fecally contaminated food or water, especially raw or undercooked shellfish^{Footnote 4}. The virus can survive in a dried state for at least a week in ambient conditions and can survive in water for as long as 10 months^{Footnote 5}. Person-to-person transmission, including sexual contact, is another mode of transmission^{Footnote 6}. Hepatitis A is one of the most common vaccine-preventable diseases in travellers to developing world countries, and has the highest mortality and morbidity rates of any vaccine-preventable infection in travellers^{Footnote 7Footnote 8}.

The incubation period of HAV is 15 to 50 days with a mean of 28 days^{Footnote 6}. The resulting illness causes anorexia, nausea, fever, fatigue and jaundice in adults and older children. The virus is present in bile, blood, stools and liver during the late incubation period and the early acute phase of the illness. The period of infectiousness is highly variable but is typically from 2 weeks before onset of symptoms until a week or so after the onset of jaundice. During this time the virus is excreted in the feces. Viral shedding can be greatly prolonged in immunocompromised persons. The average duration of illness is 1 month, but lethargy and weakness can last up to 12 months. More serious disease with liver necrosis, fulminant liver failure and death is uncommon. However, disease severity is high in those with pre-existing chronic liver disease and is age related: case fatality rates among adults > 40 years of age are at least 2%, increasing to > 10% among hospitalized individuals > 60 years of age^{Footnote 9Footnote 10}. The disease is usually asymptomatic in younger children, in whom it may be mistaken for influenza or general malaise. However, these children may shed the virus for several months and thereby become an efficient reservoir for spreading HAV to susceptible individuals around them^{Footnote 9}.

The early antibody response is of the IgM class and persists for several months. During convalescence, IgG antibodies become predominant, and positive titres persist indefinitely, conferring lifelong immunity^{Footnote 9}.

There is no chronic hepatitis and no resulting carrier state associated with HAV^{Footnote 11}.

Prevention

Travellers to countries where poor sanitation and hygiene standards facilitate fecal-oral transmission should closely follow food and water precautions as described in the CATMAT statement on travellers' diarrhea^{Footnote 12}, to minimize the possibility of contracting HAV.

The risk of HAV for non-immune travellers to developing countries had been estimated to be as high as 1 to 5/1,000 per month, cases in males being 1.5 times higher than in females^{Footnote 13}. More recent data on Swiss travellers suggest that the risks of acquiring HAV have markedly decreased over the last 10 to 15 years, with more recent estimates of 0.1 to 1/1,000 per month^{Footnote 13}. This still represents a significant risk of illness. In addition, the risk may be much higher for low-budget travellers, volunteer humanitarian workers and immigrants visiting friends and relatives in their homelands, who may be eating in poorer hygienic conditions^{Footnote 13}.

Among those who spent their childhood in less than affluent conditions in developing countries, immunity to HAV was once thought to be virtually 100%^{Footnote 1}. However, in more recent years younger populations who have spent their childhood in developing countries may be more susceptible to HAV, given general improvements in hygiene and sanitation^{Footnote 14-Footnote 16}. Hence, some adults who grew up in developing countries and the majority of those who grew up in developed countries may not be immune to HAV unless their previous medical or travel history indicates that they may already have suffered from the illness or unless they were born before1945^{Footnote 17}. Evidence of prior exposure to HAV varies directly with age. For example, about one-third of the adult Canadian population has serologic evidence of exposure to HAV by age 40^{Footnote 18}. Depending on the cost of testing, the party bearing the cost and whether time permits, it may be cost-effective to test adults who were born before 1945 or have lived in HAV-endemic regions for anti-HAV IgG before their travel, and those susceptible can then be immunized. If time does not permit, one can still send off serum for anti-HAV IgG and administer the first dose of HAV vaccine at the same time. Further post-travel booster doses of HAV vaccine would not be necessary if the HAV IgG serologic results turn out to be positive. There is no contraindication to administering these vaccines to someone who is already immune to HAV.

Hepatitis A in young children is generally a mild disease^{Footnote 19}, and immunization in this age group is primarily indicated to prevent their spreading the disease to non-immune individuals upon their return home. Children > 1 year of age should be immunized. In fact, a growing number of public health specialists are advocating universal HAV immunization programs for children, similar to the standard that already exists for HBV immunization in most developed countries^{Footnote 20Footnote 21}.

Preparations used for immunization

Immune globulin

In the past, immunoprophylaxis for HAV relied exclusively on passive immunization with immune globulin (Ig) preparations. Ig can prevent clinically apparent HAV if administered before exposure and can attenuate the disease if administered during the early incubation period. The advent of active immunizing agents has made the use of Ig virtually obsolete for the purposes of travel prophylaxis. The only exceptions would be those for whom use of the HAV vaccines is contraindicated or may not be effective (see Immunocompromised Travellers).

It has been recommended previously that simultaneous administration of Ig and active HAV vaccine should be used if travel is planned within 2 to 4 weeks^{Footnote 1}. However, it is now clear that an effective serologic response to active HAV vaccines is rapid enough that use of Ig is not necessary^{Footnote 22Footnote 23}. In fact, co-administration of Ig with active HAV vaccines could lead to lower antibody levels than use of the active vaccine alone^{Footnote 24}. Considering the relatively long incubation period for HAV and the demonstrated efficacy of post-exposure use of active HAV vaccine, administration of active HAV vaccine up to the day of departure is considered appropriate and efficacious^{Footnote 23}.

Hepatitis A vaccines

There are several inactivated HAV vaccines licensed in Canada (see Table 1). There are also two combined HAV and HBV vaccines for adults and children, as well as a combined HAV and typhoid vaccine. All are made from HAV adapted from cell culture, inactivated with formalin and adsorbed to an aluminum hydroxide adjuvant. There is no international standardized reference for the antigen content of the various vaccines, and so this is expressed differently for each product.

Antibody concentrations achieved after immunization with HAV vaccines are 10 to 100 times lower than antibody levels following natural infection and could, therefore, be undetectable using the usual diagnostic assays. Protective levels of antibody (> 20 mIU/mL) are achieved in nearly 100% of recipients within 4 weeks after immunization^{Footnote 25}. Two weeks after the first dose of these vaccines, over 70% have protective levels of antibody^{Footnote 19Footnote 22}. Given the incubation period of hepatitis A, this indicates that vaccination immediately before travel will afford adequate protection^{Footnote 23Footnote 26}.

If the second dose is delayed past the recommended interval it can be given at any time without repeat of the first^{Footnote 27Footnote 28}. Several studies have shown that a different HAV vaccine can be used for the second dose no matter which was used for the first⁽²⁹⁾. After the second dose of vaccine protective levels of antibody will likely persist for at least 10 to 20 years if not for life^{Footnote 27Footnote 30-Footnote 34}. Some have even suggested that booster doses are not required after completion of the primary vaccination two-dose course^{Footnote 25}.

The booster dose in adults should be the full initial dose, but it has been shown that, although boosting with the full adult dose will initially give somewhat higher geometric mean titres of antibody, protective and long-lasting antibody levels may be achieved with either full or pediatric half-doses in adolescents^{Footnote 36}.

Given the similar reactogenicity, immunogenicity and safety of all four monovalent HAV vaccines, the data would indicate that monovalent HAV vaccines can be used interchangeably. Routine serologic testing after vaccination against HAV is unnecessary because of the very high serologic response rates.

Concurrent immunizations
As there are indications for immunization against HBV in most travellers^{Footnote 37Footnote 38}, concurrent immunization with both HAV and HBV vaccines is strongly recommended if it has not already been given as part of routine childhood immunization. For those who are susceptible to both HAV and HBV, a combined hepatitis A and B vaccine can be used (see Table 1). It should be noted that while one dose of the combined vaccine, Twinrix^® Adult or Twinrix^® Junior, will result in protective HAV antibody levels, higher geometric mean titres will be achieved if two doses are given before travel^{Footnote 39}. A single dose of Twinrix^® Adult or Twinrix^® Junior prior to travel will not provide adequate protection against HBV and will only provide about 70% protection against HAV. For travellers who present 21 to < 28 days before departure, a rapid dosing vaccination schedule for adults only of 0, 7 and 21 days for Twinrix^® Adult has demonstrated high protective antibody levels for both HAV and HBV^{Footnote 39}, with a booster dose required at 12 months to achieve long-term immunity. For travellers presenting < 21 days before departure, monovalent hepatitis A and B vaccines should be administered separately, with the completion of both immunization series required after travel.

Concurrent administration of the HAV vaccines with typhoid vaccine (both oral and parenteral) and/or yellow fever vaccine is safe and immunogenic^{Footnote 40}. A combined HAV/typhoid inactivated parenteral vaccine, ViVaxim^™, is licensed in Canada (see Table 1) and may provide a convenient option for those requiring protection against both^{Footnote 41}. ViVaxim^™ can be given as a booster dose for HAV vaccine^{Footnote 41}. There are also some data to indicate that simultaneous administration of HAV vaccine with diphtheria, poliovirus (oral and parenteral), tetanus, cholera, Japanese encephalitis or rabies vaccines does not decrease the immune response to either vaccine or increase the frequency of reported adverse events^{Footnote 42-Footnote 44}.

Side effects
The side effects of HAV vaccines are mild and transient. Local reactions such as soreness and redness at the injection site happen in about half of recipients. Headache and malaise have also been infrequently reported.

Pregnancy
HAV vaccines, like other inactivated viral vaccines, are almost certainly safe in pregnancy and lactation^{Footnote 45}. There should, however, be a clear indication for giving the vaccine before it is administered during pregnancy, because safety in pregnancy has not been clearly established.

Contraindications
HAV vaccines should not be given to any person who has had an anaphylactic reaction to any component of the vaccine preparation.

Immunocompromised travellers
HAV vaccines are safe in HIV-positive individuals and do not accelerate the onset of AIDS^{Footnote 46}. Administering Ig immediately before travel will ensure that protective levels of antibody are adequate for short-term (up to 6 months) travel and could be considered in this group of travellers, with or without administration of active HAV vaccine.

Vaccine storage
HAV vaccines should be stored between 2° C and 8° C and should not be frozen, but it has been demonstrated that HAV vaccine may be equally effective after being kept at 37° C for 1 week as when it is stored at the recommended temperature^{Footnote 47}.

Hepatitis B

HBV is a DNA virus of the Hepadnaviridae family. It is estimated that there are 300 million HBV carriers worldwide, of whom approximately 250,000 will suffer from HBV-related disease and die annually^{Footnote 1}. The virus is highly transmissible and is spread through various modes of transmission, including perinatal, percutaneous and person-to-person close bodily contact such as sexual contact^{Footnote 1}. In travellers, HBV can be transmitted through sexual contact, use of unsterile equipment during medical or dental care, tattooing, body piercing, acupuncture, receipt of blood transfusions or injection drug use^{Footnote 1Footnote 6Footnote 37Footnote 38}. Hepatitis B is among the most common vaccine-preventable diseases in travellers, with a significant mortality and long-term morbidity potential^{Footnote 6}.

The incubation period of HBV is 45 to 160 days with a mean of 120 days^{Footnote 6}. The resulting illness causes malaise, anorexia, nausea, fever, myalgias, arthralgias, fatigue and jaundice. The virus is present in blood, and extremely high viremia facilitates transmission. The period of infectiousness can be lifelong in some who have persistent viremia. Although 90% of adults infected with HBV recover completely, fulminant HBV occurs in 1% to 2% and chronic infection in approximately 10%, eventually leading to a chronic carrier state that may result in cirrhosis and hepatocellular carcinoma^{Footnote 6}.

Those who completely recover from acute HBV infection will show an early IgM antibody response to core antigen (anti-HBc IgM). During convalescence, IgG antibodies will develop against both core and surface antigen (anti-HBc and anti-HBs IgG antibodies), conferring lifelong immunity.

Prevention
Travellers to countries in which HBV is highly or moderately endemic, including the Far East, the Middle East, Africa, South America, Eastern Europe and Central Asia, where HBV carrier rates of 2% to 20% exist in the general population, should adopt safer sexual practices and avoid any voluntary skin piercing activity. However, it is very difficult for travellers to avoid involuntary unpredictable exposures such as accidents and the need for urgent health care requiring invasive procedures in developing countries. Up to 10% and 64% of European, North American and Australian travellers to HBV-endemic regions are at high risk and potential risk respectively of unintentional exposure to HBV^{Footnote 38Footnote 48Footnote 49}. High risk of exposure has been defined as occurring when travellers engage in unprotected sex, undergo invasive medical/dental interventions or receive tattoos, body piercing or acupuncture. Reuse of injection equipment in the absence of sterilization has been documented worldwide, with the highest rates in South East Asia and the Middle East^{Footnote 50}.

The risk of HBV for non-immune travellers to developing countries has been estimated to be 0.2 to 0.6/1,000 per month ^{Footnote 1Footnote 37Footnote 51}, which is comparable to the more recent estimated risks of HAV. In addition, the risk may be much higher for travellers seeking more risky adventures and those working in a health care setting^{Footnote 1}.

As all provinces and territories in Canada administer universal HBV immunization programs, an increasing majority of Canadian travellers will be protected against HBV infection. It is not necessary to test previously immunized travellers for anti-HBs IgG antibodies prior to their travel, unless they are health care workers who have never had their anti-HBs titres verified. Health care workers planning to work overseas who have no documentation of protective antibodies should be reimmunized and retested for antibody response at least 1 month (but no later than 6 months) after the last dose of their vaccination series.

A growing number of public health and travel medicine specialists are advocating HBV immunization for all travellers, both to protect susceptible travellers for their immediate trip and to provide "catch-up" immunization in addition to already existing public health HBV immunization programs for infants and children^{Footnote 37Footnote 38}. For travellers who have no or an incomplete history of hepatitis B vaccination, completion of a vaccination series is recommended prior to departure. Should time constraints not allow for completion of the series, one injection of HBV vaccine administered before travel will still provide some protection against HBV and will initiate a series of HBV vaccinations that can be completed after travel.

Preparations used for immunization

Hepatitis B vaccines

There are four recombinant HBV vaccines licensed in Canada (see Table 1). There are also two combined HBV and HAV vaccines for adults and children. All HBV vaccines contain purified HBsAg (surface antigen) made from a genetically engineered yeast strain and adsorbed onto aluminum hydroxide.

Protective levels of antibody (> 10 mIU/mL) are achieved in nearly 100% of children following the full course of three injections, whereas in adults lower seroconversion rates of 80% to 95% are seen^{Footnote 1Footnote 37Footnote 52}. Two months after the first two doses of HBV vaccine, over 50% to 95% have protective levels of antibody^{Footnote 37}. A rapid dosing HBV vaccination schedule of 0, 7 and 21 days has also demonstrated excellent short-term seroprotective antibody levels^{Footnote 53}. A final booster dose given at 12 months is necessary to provide long-term protective immunity. Given the efficacy and safety of HBV vaccines, the risks of involuntary and voluntary exposure to HBV in many travellers, the severe consequences of HBV infection, the protective efficacy of HBV vaccine against HDV infection, and the consensus recommendation for universal HBV immunization in all Canadian provinces and territories, pre-travel consultation provides an opportunity to offer HBV vaccination for all travellers^{Footnote 37Footnote 38}.

If the final booster dose of HBV vaccine is delayed past the recommended interval it can be given at any time without restarting the immunization schedule. HBV vaccines are interchangeable; hence, a different HBV vaccine can be used for subsequent doses regardless of which was used for the initial doses. After the final dose of vaccine, protective immunity is considered to be lifelong^{Footnote 37}.

Routine serologic testing after vaccination against HBV is unnecessary, with the exception of health care workers and immunocompromised persons who should confirm their seroprotection.

Concurrent immunizations
As HAV immunization is indicated for all travellers to developing countries, concurrent immunization with both HAV and HBV vaccines is strongly recommended. For those who are susceptible to both HAV and HBV, a combined HAV and HBV vaccine can be used (see Table 1). It should be noted that while two doses of the combined vaccine, Twinrix^® Adult or Twinrix^® Junior, will result in protective HBV antibody levels in 50% to 95% of recipients, higher rates of seroprotection may be achieved if three doses using a rapid dosing schedule are given before travel^{Footnote 39}. A single dose of Twinrix^® Adult or Twinrix^® Junior before travel will not provide adequate protection against HAV or HBV. For travellers who present 21 to < 28 days prior to departure, a rapid dosing vaccination schedule of Twinrix^® Adult (for adults only) of 0, 7 and 21 days has demonstrated high protective antibody levels for both HAV and HBV^{Footnote 39}, with a booster dose required at 12 months to achieve long-term immunity. For travellers presenting < 21 days before departure, monovalent hepatitis A and B vaccines should be administered separately, with the completion of both immunization series required after travel.

Concurrent administration of HBV vaccines with other vaccines is considered both safe and immunogenic.

Side effects
The side effects of HBV vaccines are mild and transient. Local reactions such as soreness and redness at the injection site are common and self-limited. A number of studies have demonstrated no link between HBV vaccine and chronic fatigue syndrome, multiple sclerosis, Guillain-Barré syndrome, rheumatoid arthritis or sudden infant death syndrome.

Pregnancy
HBV vaccines can be used safely in pregnancy and lactation.

Contraindications
HBV vaccines should not be given to any person who has had an anaphylactic reaction to any component of the vaccine preparation.

Immunocompromised travellers
HBV vaccines are safe in HIV-positive individuals and do not accelerate the onset of AIDS, but the immune response should be verified after immunization since additional booster doses may be necessary^{Footnote 54}. However, it must be remembered that commercially available assay methods may not be sensitive enough to detect the lower protective levels of antibody that the vaccines induce.

Vaccine storage
HBV vaccines should be stored between 2° C and 8° C and should not be frozen.

Hepatitis C

HCV is an RNA virus of the Flaviviridae family, genus Hepacivirus. Although the infection is rarely reported in association with international travellers^{Footnote 55}, it is estimated that 123 to 170 million persons are infected worldwide^{Footnote 56}. It can lead to acute hepatitis, chronic hepatitis and cirrhosis. HCV is responsible for up to 70% of all hepatocellular carcinomas^{Footnote 1}. The virus is transmitted primarily through activities that result in the exchange of blood. Therefore the highest risks of exposure for international travellers would include injection drug use, receipt of unscreened blood products and percutaneous procedures involving unsterile equipment, including medical and dental procedures, body piercing, tattooing and acupuncture^{Footnote 55}. The risks of acquiring HCV from a percutaneous injury are substantial, as high as 3% to 10%^{Footnote 57}. The risk of sexual transmission of HCV is considered to be lower, in the order of 0.0% to 0.6% following a single unprotected sexual contact that involves traumatic sex with mucosal injury^{Footnote 58}. Hepatitis C has become a more serious global problem than HBV, as it accounts for two-thirds of deaths from chronic liver disease, is more likely to progress to hepatocellular carcinoma than HBV and has no preventive vaccine^{Footnote 1}.

The incubation period of HCV ranges from 2 weeks to 6 months, commonly 6 to 9 weeks^{Footnote 59}. The resulting illness is indistinguishable from other causes of viral hepatitis and includes malaise, anorexia, nausea, vomiting, vague abdominal discomfort and fatigue it progresses to jaundice less often than HBV. The period of infectiousness may be lifelong in most of those with chronic liver disease. Although 60% to 90% of those infected may initially be asymptomatic, chronic HCV occurs in 50% to 80%^{Footnote 59}.

Diagnosis is confirmed with the detection of antibody to HCV as well as HCV RNA measurements. The degree of immunity following infection is not known. There are at least six major genotypes and over 100 subtypes of HCV, and experimental chimpanzee models have demonstrated repeated infections with the virus, suggesting a lack of protective immunity from natural infection^{Footnote 59}.

Prevention
Travellers to countries in which HCV is endemic, including most developing world countries where prevalences of up to 10% exist in the general population^{Footnote 60Footnote 61}, should avoid any skin piercing activity, in addition to adopting safer sexual practices. As it is very difficult for travellers to avoid involuntary unpredictable exposures such as accidents and the need for urgent health care requiring invasive procedures in developing countries, great care should be taken when seeking medical care involving percutaneous or invasive procedures. Reuse of injection equipment in the absence of sterilization has been documented worldwide, the highest rates occurring in South-East Asia and the Middle East^{Footnote 50}. In addition, the screening of blood and blood products for HCV does not take place in most developing countries^{Footnote 62}.

Although not quantified, the risk of HCV for travellers to developing countries is likely higher for those seeking more risky adventures (i.e. injection drug use, body piercing, tattooing, and acupuncture) and those working in a health care or humanitarian setting^{Footnote 1}.

As human immunoglobulin does not provide protection against HCV and no vaccines exist against HCV, personal preventive measures are all that travellers have to protect themselves. Travellers already infected with HCV should receive HAV and HBV immunizations, if not already performed by their primary care provider, to prevent catastrophic complications, including fulminant hepatitis, that could occur if they acquired HAV or HBV superinfection in addition to their existing HCV infection.

Hepatitis D

HDV is a defective RNA-containing virus, also known as "delta antigen", associated with severe or fulminant hepatitis when occurring as a superinfection in a previously HBV-infected person. An estimated 15 million individuals are infected with HDV worldwide, primarily in high-prevalence regions, including Italy, parts of Eastern Europe, the Amazon basin, Colombia, Venezuela, Western Asia, and some Pacific Islands^{Footnote 1}. Modes of transmission of HDV are similar to those of HBV, with injection drug use being the most common mode of transmission in endemic areas. The prevalence of HDV in HBV-infected injection drug users has been reportedly as high as 31% to 91%^{Footnote 1}. The rate of sexual transmission of HDV is considered to be low⁽¹⁾. HDV infection alone appears to be innocuous, as its replication requires co-infection with HBV.

The incubation period of HDV ranges from 2 to 8 weeks^{Footnote 63}. The resulting illness is an abrupt onset of fulminant hepatitis in an individual co-infected with HBV. The period and degree of infectiousness are not known. In Europe and the United States, 25% to 50% of fulminant HBV cases are associated with HDV co-infection^{Footnote 63}.

Diagnosis is confirmed with the detection of antibody to HDV as well as HDV viremia using reverse transcription polymerase chain reaction (PCR). The degree of immunity following infection is not known, and infectivity may persist for life, even in the absence of measurable viremia^{Footnote 63}.

Prevention
Travellers to countries in which HDV and HBV are endemic should avoid any skin piercing activity in addition to adopting safer sexual practices. HBV carriers travelling to HDV-endemic countries should be particularly vigilant in avoiding high-risk skin piercing and sexual practices. Although no vaccine exists against HDV, immunization of HBV-susceptible persons against HBV is protective against HDV as well.

Hepatitis E

HEV is an RNA virus that morphologically resembles caliciviruses and is therefore provisionally classified in the Caliciviridae family^{Footnote 64}. It is the major cause of enterically transmitted epidemic non-A non-B hepatitis worldwide. Although first recognized during an epidemic of hepatitis in India in 1978, its distribution is now know to be widespread with epidemics reported in Africa, South Asia, South-East Asia, China, the Middle East, Mexico, Greece and Russia^{Footnote 64}. South and South-East Asia appear to have a particularly high HEV endemicity^{Footnote 65}. Cases have even been described in Western European countries in the absence of foreign travel^{Footnote 66}. Despite this relatively high global HEV endemicity in the developing world, HEV seroconversion is uncommonly seen in travellers, including those who may be inclined to take more risks^{Footnote 67}. However, HEV has reportedly been demonstrated to constitute 5% to 10% of acute viral hepatitis cases in international travellers, including fulminant fatal cases^{Footnote 68}. The virus is primarily spread through the fecal-oral route mostly through ingestion of fecally contaminated water^{Footnote 1}. Direct person-to-person transmission is uncommon⁽¹⁾. Vertical transmission from mother to fetus or infant has been described^{Footnote 69}.

The incubation period of HEV ranges from 15 to 64 days^{Footnote 64}. The resulting illness is similar to HAV with anorexia, nausea, fever, fatigue and jaundice. The case fatality rate among adults is similar to that of HAV (0.5% to 2%) but among women in the third trimester of pregnancy it rises up to 20% among women who are infected^{Footnote 64}. The period of infectiousness is not known, but the virus has been detected in stool as long as 4 weeks after ingestion of contaminated water^{Footnote 64}.

Diagnosis is confirmed with the detection of IgM antibody to HEV in blood as well as HEV RNA in serum and stool using PCR. The degree and duration of immunity following infection is not known. There is no chronic hepatitis and no resulting carrier state associated with HEV.

Prevention
Travellers to countries where HEV is endemic should always follow food and water precautions, as described in the CATMAT statement on travellers' diarrhea^{Footnote 12}, to minimize the possibility of contracting HEV.

Although the risk of acquiring HEV for most travellers to developing countries may be low, the absence of a vaccine makes food and water precautions the only practical preventive measures. Frequent hand washing may also help reduce the risk of HEV exposure.

Hepatitis E Vaccine

There is currently no available immunoprophylaxis against HEV. Although human immunoglobulin preparations may contain low concentrations of anti-HEV IgG, use of these has not provided adequate protection against HEV^{Footnote 1Footnote 64}. An HEV vaccine using recombinant capsid protein has reached Phase II/III clinical trials, but its use may be greatest in the developing world, where HEV is most endemic. Some have argued that the incidence of the disease in international travellers is so low that the cost-effectiveness of an HEV vaccine may not be justifiable at this time^{Footnote 70}.

Recommendations

Table 2 presents evidence-based medicine categories for the strength and quality of the evidence for the recommendations that follow (Table 3).

Update

This statement will be updated every 4 years or when new information becomes available.

References

*Members: Dr. P.J. Plourde (Chair); Dr. D. Werker (Executive Secretary); Dr. C. Beallor; Dr. K. Gamble; Ms. A. Henteleff; Dr. S. Houston; Dr. S. Kuhn; Dr. A. McCarthy; Dr. K.L. McClean; Dr. J.R. Salzman; Dr. J.D. MacLean.

Liaison Representatives: Dr. C. Greenaway; Mrs. A. Hanrahan; Dr. C. Hui; Dr. P. Teitelbaum; Dr. Anita Pozgay

Ex-Officio Representatives: Dr. J. Given, Dr. F. Hindieh; Dr. J.P. Legault; Dr. P. McDonald; Dr. N. Marano; Dr. P. Arguin; Dr. P. Charlebois; Dr. A. Duggan; Dr. M. Tepper

Member Emeritus: Dr. C.W.L. Jeanes.

Consultant: Dr. S. Schofield.

†This statement was prepared by Dr. P.J. Plourde and approved by CATMAT.