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• W2041315628 abstract "Introduction There are several considerations that should guide the formulation of HIV-specific recommendations on travel immunizations. HIV-infected travellers may have increased susceptibility to infections not only because of immunocompromise, but also through behavioural factors (e.g., risk of hepatitis A infection in homosexual men), and if infected may be more likely to develop serious complications (e.g., an increased risk of chronic hepatitis B infection). At the same time, the efficacy of post-exposure immunization may be reduced or uncertain (e.g., with rabies post-exposure prophylaxis). These factors often lower the threshold for considering pre-travel immunization relative to recommendations for the general population. Furthermore concerns over safety and efficacy of vaccination must be balanced against the risk associated with natural infection and reviewed in the context of the immune restorative effects of HAART. Guidelines on immunization which include HIV-infected persons or are primarily for such persons, including recommendations for travel immunizations, have been produced by several organizations [1–3]. Of these, the British HIV Association (BHIVA) is the only organization to have produced immunization guidelines specifically for HIV-infected individuals [2], which provide the main basis for this review. It is important that physicians outside of the UK also refer to national immunization guidelines, where available. Whereas this review will focus on adult travellers, a number of guidelines are available to guide immunization practice in children [4,5]. Safety of immunization In some cases, the increased risk of adverse reactions either contraindicates the use of certain vaccines or restricts them to HIV-infected persons with good immune function. Traditionally the use of live vaccines has been contraindicated in the setting of HIV infection. However, the immune reconstitution induced by HAART is likely to reduce the risk of adverse events, in many cases shifting the risk–benefit ratio in favour of immunization. Examples of live vaccines that can be cautiously used in HIV-infected persons with good immune status include those against measles, mumps and rubella (MMR), varicella and yellow fever. Other live vaccines remain contraindicated either due to safety concerns in the face of uncertain efficacy, or because inactive vaccines provide a valid alternative. These include the Bacille–Calmette–Guerin (BCG), intranasal influenza, oral typhoid (Ty21a), oral polio (OPV) and cholera CVD103-HgR vaccines. One additional concern is the potential for vaccines to cause transient rises in HIV plasma RNA load as a result of immune activation. Whilst this phenomenon has been reported with some vaccines [6–8], there is no evidence that it has a significant impact on CD4 cell count or clinical progression, and it should not preclude immunization. Efficacy of immunization The immunogenicity and clinical efficacy of vaccination is diminished in HIV-infected persons as compared to immunocompetent recipients [9–12]. Improved responses to a number of vaccines have been observed in persons whose CD4 cell counts have recovered through HAART [13–15]. Even in persons with high CD4 cell counts however, responses may remain lower and less durable than those found in the immunocompetent. In some cases, efficacy can be improved by providing additional or higher vaccine doses [16]. HIV suppression by HAART is associated with improved vaccine efficacy, an effect that may be independent of CD4 cell count [13,14,17]. In patients due to commence HAART it may be reasonable to defer elective immunization until virological suppression is achieved. In addition, depending on the level of risk, one may consider waiting for CD4 cell count recovery > 200 and preferably >400 cells/μl. It should be noted, however, that responses to immunization can be observed in a substantial proportion of patients with CD4 counts < 200 cells/μl. The potential benefits of immunization should not be denied to these patients based on the predicted reduced immunogenicity. If immunization is given to persons with advanced immunodeficiency, further booster doses may be considered following immune recovery with HAART. In all cases, HIV infected travellers should be warned that they may not be fully protected against infection despite vaccination. It is therefore imperative to combine pre-travel immunization with advice regarding water and food hygiene, avoidance of insect bites, safe sex and other relevant strategies to avoid infection. Immunizations are only one of a number of different issues that should be considered in the HIV-infected traveller. This review will not address other important topics such as antimalarial prophylaxis, travel insurance or travel restrictions. Provision of immunization In many countries provision of immunization is often divided between primary and secondary health care. For example in the UK routine immunizations are generally provided in primary care funded by the National Health Service, whereas most travel vaccines are not funded, requiring travellers to pay for such vaccines through Travel Clinics or specialist primary care services. This presents a challenge in the management of the HIV-infected traveller. Specialist HIV clinics are usually the best setting for determining which immunizations are indicated, and may also be able to advise on the appropriate use of travel vaccines, but funding may be an issue. In places where integrated care pathways between primary and secondary care do not exist, it is essential to devise systems by which routine vaccines, and ideally also travel vaccines, are provided to this population group. It will also be helpful for those providing immunizations to HIV-infected persons to have access to specialists in HIV medicine with expertise in Travel Medicine or immunization, who could advise on more difficult cases. Routine immunizations Persons newly diagnosed with HIV infection should be screened for previous exposure or immunity to a number of pathogens, using a questionnaire and, where appropriate, serological tests. The immunization history, particularly for childhood vaccinations, may be uncertain in these patients. In the absence of a reliable history the person should be regarded as potentially susceptible to infection. There are also a significant number of HIV-infected people who have emigrated from the developing world to more affluent countries and may have missed or received incomplete routine childhood immunization (e.g., against measles, mumps and rubella). These patients may be at risk of various infections in their adopted countries, as well as in their country of origin when returning for visits. Table 1 summarizes routine vaccinations which should be considered for all HIV-infected adults as part of their overall care, not purely in relation to travel. The following routine immunizations are considered in the context of the HIV-infected traveller in more detail.Table 1: Routine vaccines for adult HIV-infected travellers that are also part of standard care in most areas.Tetanus, diphtheria and inactivated polio vaccine (IPV) These inactivated vaccines are often given as combined preparations (Td/IPV), although dual (Td) and single-vaccine preparations may also be available. Vaccines for adults contain a lower dosage of diphtheria toxoid than those used in children. There is considerable evidence that each vaccine component is safe and reasonably immunogenic in the setting of HIV infection [18–21]. The live attenuated oral polio vaccine (OPV) is contraindicated in HIV-infected persons, but has been replaced by IPV in developed countries. All HIV-infected persons should have completed a primary vaccination course (three doses at least 1 month apart), followed by two boosters after 5 and 10 years. For adults with a history of complete immunization, a booster is recommended prior to travel. As the longevity of protection may be reduced in HIV-infected persons, reinforcing doses should be given every 10 years if the risk of exposure recurs. Most HIV-infected people who sustain tetanus-prone wounds will not be at risk of developing tetanus if they have received tetanus vaccination within the previous 10 years. The risk may be increased in those with severe immunocompromise, regardless of vaccination history, and in those who received the last booster more than 10 years previously. Tetanus immunoglobulin should be considered for post-exposure prophylaxis in these cases. All exposed individuals who have not had a primary immunization course or booster within the past 10 years should also receive tetanus vaccination. Measles–mumps–rubella (MMR) The live MMR vaccine (and the single-component vaccines) is only recommended in asymptomatic HIV-infected persons with CD4 counts > 200 cells/μl, due to safety concerns in those with profound immunocompromise [22]. Given the recent resurgence of measles, mumps and rubella in some developed countries, the risk of exposure is not limited to travellers. Measles vaccination should be offered routinely to susceptible HIV-infected persons, provided the CD4 cell count is sufficiently high. These persons should receive two doses of MMR (or single measles vaccine), at least 1 month apart. Although responses are often poor in HIV-infected persons [23,24], seroconversion rates improve with HAART [17]. Similarly, it is important to ensure that HIV-infected women of childbearing potential are protected against rubella, and those lacking evidence of immunity should be offered one dose of MMR (or single rubella vaccine). Hepatitis A This inactivated vaccine is generally recommended for men who have sex with men (MSM), injecting drug users, haemophiliacs receiving plasma-derived concentrates and persons with chronic hepatitis B or C. As a result, many HIV-infected persons receive the vaccine regardless of travel needs [25]. Hepatitis A is endemic in most parts of the world, aside from North America, western and northern Europe, Japan and Australia, and it is important to ensure that HIV-infected travellers are protected against the infection. As previous infection is not uncommon, it will often be cost-effective to screen for pre-existing immunity prior to vaccination. Serological responses to hepatitis A vaccination are greater with higher CD4 cell counts, and there is considerable evidence for safety as well as efficacy in HIV infection [13,26,27]. Two or three vaccine doses are generally recommended in HIV-infected persons and either the hepatitis A vaccine or the combined hepatitis A/hepatitis B vaccine may be used for this purpose. There is evidence indicating that three doses of hepatitis A vaccine (given over 6–12 months) increase responses in persons with CD4 counts < 300 cells/μl [13]. Prior to travel, those who have not had two vaccine doses previously, or who had previous doses at low CD4 counts, should be considered for a further booster. Travellers with profound immunocompromise will often have poor responses to vaccination and may therefore be considered for passive immunization. Human normal immunoglobulin (HNIG) may be used to provide protection against hepatitis A, as well as polio and measles. In practice, national policies may limit HNIG availability for this indication. Furthermore, preparations may have variable antibody concentrations and even those with reliable antibody levels confer only short-lived protection not likely to exceed 3–6 months. Hepatitis B The recombinant hepatitis B vaccine is generally recommended for all non-immune HIV-infected individuals, given the significant risk of infection, chronicity and complications after infection. Although response rates are diminished in those with low CD4 cell counts (and in MSM) [28–31] vaccination is safe and reduces the risk of infection in this group [32]. In susceptible HIV-infected persons who have not received a primary course of immunization, a rapid vaccination schedule (four doses at 0, 1, 2 and 12 months) should be started as soon as possible. Although a more rapid schedule (e.g., three doses at 0, 7–10 and 21 days) may be convenient for travellers, there is limited evidence that it induces adequate responses in HIV-infected persons. For HIV-infected persons who mount an adequate response to vaccination, as generally indicated by a level of hepatitis B surface antibody (HBsAb) > 100 IU/l, some authorities advocate annual HBsAb testing and boosters if levels have declined < 100 IU/l [2]. In these patients, a reasonable case can be made for testing HBsAb levels prior to travel and those who have inadequate antibody levels might be offered a booster. Individuals who mount a suboptimal response to the primary vaccination course (HBsAb > 10 but < 100 IU/l) are generally managed by a further booster, which may be repeated prior to travel. Those who fail to respond to the primary vaccination course (HBsAb < 10 IU/l) should be offered a repeat course (three doses). Double-dose vaccine may improve responses in these patients, particularly in those with higher CD4 cell counts [16]. Those who fail to respond to a second vaccine course should be given advice on how to reduce the risk of infection and considered for post-exposure prophylaxis with hepatitis B immunoglobulin if they undergo a significant exposure. Influenza The inactivated, parental influenza vaccine is recommended for all HIV-infected people annually, and is normally given in the early autumn in temperate climates. The vaccine provides reasonable protection against influenza, particularly against severe disease [33], and is generally immunogenic and safe [14,34–37]. Responses correlate with immune status and patients with CD4 counts > 300 cells/μl while on HAART appear to have responses similar to those of healthy controls [14]. Vaccination should be given irrespective of the CD4 cell count however, with the aim of attenuating the impact of influenza. Travellers should be warned that in the tropics influenza occurs all year round and that the influenza season in the Southern hemisphere is April through September. Those travelling to areas of the world experiencing seasonal outbreaks of influenza should ideally receive an influenza vaccine preparation appropriate to the circulating strains at their destination, if available. Recent concern regarding H5N1 avian influenza has prompted increased interest in the use of influenza vaccines. Recommendations for HIV-infected persons are in line with those issued for the general population and include advice on how to reduce the risk of exposure and instructions on prompt reporting of symptoms following a possible contact. Meningococcus Meningococcus vaccination with the conjugate group C vaccine or the newer quadrivalent vaccines (ACWY) is now part of routine childhood schedules in several developed countries. Young adults and teenagers who have not previously been vaccinated are also recommended to receive the vaccine. The main issue for travellers is whether they are visiting areas with high levels of meningococcal disease, or countries that require a certificate of vaccination for certain groups, such as pilgrims to the Haj or Umrah in Saudi Arabia. Group A and increasingly W135 meningococci are common epidemic strains in the sub-Saharan Africa ‘meningitis belt’ and the Middle East respectively. Travellers to these areas may benefit from one of the quadrivalent ACWY vaccines if visiting during the dry season (in Africa) or during epidemics, or if staying for prolonged periods. Although there have been very few studies on the efficacy and safety of these vaccines in HIV-infected persons, and only with the older polysaccharide rather than the newer conjugate types [38–40], there is no evidence for an increased risk of adverse events. Varicella (VZV) Varicella is often severe in those with HIV infection [41]. The live VZV vaccine is currently recommended for asymptomatic or mildly symptomatic HIV-infected children with CD4 cell percentages > 25% [42], based on one study [43]. There are limited data on the efficacy and safety of the vaccine in HIV-infected adults. It is reasonable to assume that given the significant risks associated with natural infection, susceptible HIV-infected adults may benefit from vaccination if the risk of infection is significant. Furthermore antiviral drugs may be used to treat vaccine-strain infection, tempering concerns over safety. Patients who lack a history of either varicella or herpes-zoster should be screened for evidence of immunity, regardless of travel plans. The vaccine might be considered in susceptible asymptomatic HIV-infected adults with CD4 counts > 200 cells/μl. Those who decide to be immunized should receive two doses (3 months apart), and should be advised of potential signs of vaccine-associated disease. Pneumococcus Pneumococcal infection, including invasive pneumococcal disease (IPD) is common in HIV infection and causes substantial morbidity and mortality. There are several polysaccharide and conjugate vaccines available and two of these, the 23-valent pneumococcal polysaccharide vaccine (PPV-23), and the 7-valent conjugate vaccine (CPV-7) have been studied extensively in HIV-infected populations. Whereas clinical efficacy data support the use of CPV-7 in HIV-infected children [11], data on the efficacy of PPV in children and adults are scarce and controversial. Data from patients receiving HAART are particularly limited. Whilst a number of cohort studies support the use of PPV in adults [44–47], the only randomized trial failed to show a benefit, and indeed suggested a possible detrimental effect of vaccination in persons not receiving HAART [48]. Overall, the PPV vaccine appears to be less effective in drug-naive patients with CD4 count < 200 cells/μl, who are those at the greatest risk of pneumococcal disease. Hence, there remains some controversy regarding the use of the PPV vaccine in HIV-infected adults, and although several authorities recommend it, uptake remains poor. Specific travel-related immunizations Yellow fever (YF) YF is a potentially fatal infection endemic in various tropical areas in Africa and America, and a number of countries require an international certificate of vaccination for entry. The available live vaccine has the potential for causing adverse events in immunocompromised individuals, including those with HIV infection [49]. Nonetheless, small studies suggest that the vaccine is safe in those with higher CD4 cell counts [50–52], and this has led to some guidelines suggesting vaccination of selected travellers with CD4 counts > 200 cells/μl [2,3] (Table 2). Aside from the CD4 cell count however, two other factors should determine whether travellers receive this vaccine. First, the genuine risk of being infected should be ascertained, based on the areas of travel. For many travellers to countries where YF vaccine is required or recommended, the real risk is probably low, and vaccination not justified. The second factor is the age of the patient. There is mounting evidence that older travellers are considerably more likely to experience adverse events, including neurotropic or viscerotropic disease following YF vaccination [53]. Such travellers should only be offered vaccination if there is a considerable risk of contracting the infection. Older travellers, those with low CD4 cell counts and those whose risk of exposure is low can be provided with a letter (or certificate) of exemption from vaccination. Travellers at a recognized risk of infection and with CD4 counts > 200 cells/μl should be offered immunization after being informed of the relative risks of YF infection and vaccination.Table 2: Travel-related vaccines available for active immunization.Typhoid HIV-infected persons are at increased risk of infection with Salmonella species and immunodeficiency predisposes to bacteraemia, antibiotic resistance, relapsing disease and persistent infection [54,55]. The live, oral typhoid vaccine (Ty21a) is generally contraindicated in HIV infection. The parental, inactivated vaccine (ViCPs) is both safe and effective in these patients, although responses are reduced at CD4 counts < 200 cells/μl [12]. Typhoid fever is common in most of the developing world and the ViCPs vaccine should be offered to all HIV-infected persons travelling to endemic regions. A booster is generally recommended every 3 years, although travellers with CD4 counts < 200 cells/μl may benefit from an earlier booster. Rabies Canine rabies is endemic throughout most of Asia, Africa and parts of Latin America, posing a risk of infection for travellers to these regions. Safe and immunogenic inactivated cell-culture derived vaccines are available in developed countries for pre- and post-exposure prophylaxis, but data on immunogenicity and clinical efficacy in HIV-infected persons are limited. Responses to vaccination are affected by the disease stage, with low or absent antibody responses reported in some vaccine recipients with CD4 counts < 200–250 cells/μl not treated with HAART [56–59]. Higher and more frequent vaccine doses have been proposed as management options for these patients, but evidence is limited. Due to uncertainties about the efficacy of post-exposure prophylaxis and the most appropriate post-exposure immunization schedule, pre-exposure immunization (three doses on days 0, 7 and 28) should be considered for HIV-infected persons due to travel to dog-rabies endemic areas, together with advice on practical steps to be taken if an animal bite is sustained. If the risk of travel-related exposure re-occurs, a first booster is indicated 1 year after the primary course, with subsequent boosters given after 3–5 years. Following a suspected exposure to rabies, two doses of rabies vaccine may be sufficient in selected HIV-infected persons who have received pre-exposure immunization and are deemed immune competent [60]. Most patients should, however, receive a full post-exposure regimen including human rabies immunoglobulin (HRIG) and five vaccine doses. Although current guidelines indicate that if HRIG is not available until > 7 days after vaccination has started, then it is probably unnecessary, delayed administration should still be considered in immunocompromised HIV-infected persons. Repeated doses of HRIG however should be avoided as they may interfere with the immune response to vaccination. Serological testing between day 14 and 28 is suggested in all HIV-infected persons and strongly recommended in those with CD4 counts < 200 cells/μl. If an acceptable antibody response (> 0.5 IU/ml) is not achieved, a further vaccine dose should be administered. Intradermal vaccination may diminish immunogenicity and is not recommended for HIV-infected persons [61]. Furthermore, the vaccines of nerve tissue origin in use in some developing countries are more reactogenic and less immunogenic than cell culture derived vaccines and not generally recommended if alternative vaccines are available. HRIG is prepared from plasma of hyperimmunized human donors. In developing countries, equine rabies immunoglobulin is sometimes used, but it has a higher incidence of adverse effects and the quality of the product may vary. Tick-borne encephalitis The tick-borne encephalitis (TBE) viruses are endemic in various parts of Europe and Asia, where they are transmitted mainly from spring to early autumn. The risk to the average traveller is small and related to either leisure activities (e.g., hiking, walking and hunting), or working in agriculture and forestry in warm, rural or forested areas of endemic regions. There are little data on the safety and immunogenicity of the inactivated vaccine in HIV infection. Two small studies conducted in the pre-HAART era did not demonstrate significant adverse events, although immunogenicity was reduced at low CD4 counts [62,63]. Travellers to endemic regions who are likely to be exposed to ticks in forest or grassland should consider the standard three-dose vaccination, given in two doses over 3–12 or 4–12 weeks, followed by a third dose 9–12 months later. More rapid schedules are efficacious in healthy individuals and practical for travellers, but have uncertain efficacy in HIV-infected persons. A four-dose vaccination schedule (at 0, 1, 2, and 9–12 months) may improve responses in HIV-infected persons, but evidence remains limited. Japanese encephalitis The Japanese encephalitis (JE) virus is transmitted by mosquito bites and is the leading cause of viral encephalitis in Asia. Infections occur predominantly in rural areas, especially where rice growing and pig farming coexist. The risk of infection is minimal in short-stay travellers (< 1 month), in cities and outside the wet season. The inactivated vaccine should be considered in those travelling to rural areas in South East Asia and the Far East, where JE is endemic, and three or four doses are normally given over 1–2 months prior to travel. An abbreviated schedule given over 2 weeks has been used in healthy individuals but is not recommended in immunocompromised individuals [64]. Only one study of this vaccine has been undertaken in HIV-infected persons, which demonstrated reduced immunogenicity after two vaccine doses, and the absence of safety concerns [65]. There are no data on the immunogenicity of three vaccine doses or on the impact of HAART on vaccine responses. Vaccine recipients should be warned about the risk of hypersensitivity reactions. Boosters are normally recommended after 3 years for those at continued risk. Cholera Cholera is rarely reported in travellers and predominantly among those who travel to the Indian subcontinent. Travellers to countries reporting cases of cholera who follow usual tourist itineraries, use standard accommodation, and observe food safety recommendations do not generally require vaccination. Those with more significant risk should consider immunization, including persons travelling to high risk areas following natural disasters, where safe water supplies cannot be guaranteed (e.g., aid workers assisting in disaster relief or refugee camps). The oral inactivated WC/rBS vaccine (two doses at least 1 week apart) is the vaccine of choice. Although there are limited data on the efficacy and safety of these vaccines in HIV-infected persons, individuals at risk of infection should consider vaccination. Persons with CD4 counts < 100 cells/μl should be advised that responses to vaccination and the level of protection are likely to be reduced [66,67]. Other sources of reference There are a number of web-based resources which are helpful for providing information regarding global infection risks and travel immunizations. CDC (http://www.cdc.gov/travel/) and WHO (http://www.who.int/ith/en/) are two such sites, although national resources may also be available. The BHIVA Immunisation Guidelines can be viewed at http://www.bhiva.org[2]. Acknowledgements We are grateful to the BHIVA Immunisation Committee for their contribution to the guidelines that provide the basis for this review. The BHIVA Immunisation Committee includes the following members: Anna Maria Geretti (Chair), Dr Gary Brook, Ms Claire Cameron, Dr David Chadwick, Prof Robert S Heyderman, Dr Eithne MacMahon, Dr Anton Pozniak, Dr Mary Ramsay and Dr Michaela Schuhwerk. In addition, we wish to thank Prof Judy Breuer, Dr Natasha Crowfort, Dr Charlie Easmon, Prof William Irving, Dr Herwig Kollaritsch, Dr Per Arne Parment and Dr Mary Warrell for their expert advice." @default.
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• W2041315628 title "Immunization of the HIV infected traveller" @default.
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