The widespread use of effective antiretroviral therapy (ART) has largely transformed HIV infection into a chronic disease in an increasing number of individuals and countries. Travelers infected with HIV may now travel to virtually any global destination if their immune status is intact.
Many HIV-infected persons from the developed and developing world are experienced travelers. In a retrospective analysis from a northern California clinic prior to the availability of effective ART, 20% of HIV-infected persons had traveled to a foreign country within the preceding 2 years, with 60% of these trips to developing countries,(1) and only half of these patients consulted with a physician prior to travel.(2) Although this study population is not representative of the majority of HIV-infected individuals in the United States and abroad, the study authors reported that HIV-infected persons often traveled regardless of the severity of their illness, and frequently decided to embark upon exotic travel despite clinical progression of their HIV disease or a major medical crisis, because of the realization that they might soon become unable to undertake such travel.(2) As the survival and quality of life of HIV-infected persons receiving ART continue to improve, and as global collaborations on research and treatment continue to grow in scope, an ever-increasing number of HIV-infected persons can be anticipated to travel overseas, whether for recreational or work-related reasons.
| Pretravel Advice|
| Pretravel Screening|
It is prudent for HIV-infected travelers to be well informed. The infectious risk that HIV-infected travelers face in developing countries is higher than for the general population, although the risk for patients with ART-stabilized immune function is unknown. The occurrence of HIV-related complications will often directly correlate with immune status, and thus HIV-infected travelers with CD4 counts of <200 cells/µL will likely be exposed to a significant risk of infection, therapy status notwithstanding. Individuals with low CD4 counts are also less likely to respond to vaccinations. Thus, pretravel screening requires a full and balanced assessment of the degree of immunosuppression, the risks of morbidity and mortality associated with the vaccine-preventable diseases in the destination of interest, medications needs, and the travel itinerary, including possible risky behaviors or environmental exposures. Details of the itinerary that can provide important clues to risk include knowledge of lodging, budget, duration, and vaccine or medication contraindications. Factors associated with a higher incidence of travel-related complications include prolonged travel, backpacking, low-budget travel, foreign-born individuals returning to visit family and friends (because expatriates may have more prolonged travel to more remote areas in their native countries, may have waning immunity to pathogens to which they are no longer exposed on a regular basis, and because they may be less cognizant of recommended preventative measures, including vaccination, prophylaxis for specific infections, and environmental risks), and emergency travel (which may be associated with inadequate time for preparatory advice, optimized pretravel vaccine administration, or chemoprophylaxis).(3) In particular, those HIV-infected travelers planning long-term trips should identify a health care facility in their destination country that has expertise and adequate resources to treat both common locally acquired ailments and HIV-related complications. Finally, certain situations may warrant a change in the itinerary if the risk is substantial and cannot be avoided, such as travel to areas endemic for malaria during pregnancy, travel to areas endemic for yellow fever without pretravel vaccination, or severe immunosuppression and travel to isolated rural areas without adequate medical resources. An excellent resource for travel advice, current vaccine recommendations, and updated information on regional outbreaks worldwide is provided by the U.S. Centers for Disease Control and Prevention (CDC) at http://www.cdc.gov/travel/yb/index.htm.
| HIV Infection and Travel Restrictions|
The HIV-infected international traveler should be advised that >150 countries have established entry restrictions for those seropositive for HIV. Some countries, with the objective of stopping the spread of HIV infection at their borders, serologically screen incoming travelers, particularly those staying for extended visits. Others may deny entry to travelers carrying antiretroviral medications. These restrictions, which target mainly long-term travelers requesting residency or educational or work-related visas, are not endorsed by the World Health Organization (WHO), and their effectiveness in limiting the spread of HIV to any given country has been challenged. Nevertheless, to avoid problems, HIV-infected travelers who plan to stay in a country for a substantial period or to work or study abroad should be aware of the policies and requirements of individual countries, usually obtainable from consular officials.(4,5) An unofficial list compiled by the U.S. Department of State can be found at http://travel.state.gov/travel/tips/brochures/brochures_1230.html.
| Preventing Travelers' Diarrhea|
In developing countries where hygiene may be poor, HIV-infected and immunocompetent travelers alike are at high risk for food- and waterborne diseases. Travelers should assiduously avoid raw fruits and vegetables, raw or undercooked seafood or meat, tap water, ice made from tap water, unpasteurized milk and dairy products, and food and beverages purchased from street vendors. Steaming hot foods, fruits that are peeled by the traveler personally, bottled (carbonated) beverages, and hot beverages such as tea or coffee, which have been prepared with freshly boiled water, are considered safe. Bottled water that meets European Union (EU) standards or has undergone distillation, ozonation, or reverse osmosis can be considered sterilized for both bacteria and parasites.
Waterborne infections (eg, cryptosporidiosis, giardiasis, or leptospirosis) can also be acquired from swallowing water during recreational water activities. Swimming in water that may be contaminated with sewage or animal waste should be avoided. Travelers should avoid direct skin contact with soil and sand by wearing shoes and protective clothing and by using towels when sitting or lying in areas where fecal contamination of soil is likely. Because of the increased risk for some infections (eg, Cryptosporidium, Salmonella, and Campylobacter) associated with handling certain animals, HIV-infected travelers should wash their hands after handling pets, avoid contact with pet feces, and refrain from contact with reptiles (eg, snakes, lizards, iguanas, and turtles), birds (eg, chicks and ducklings), and young farm animals, particularly animals with diarrhea.
When only local water is available for drinking or toothbrushing, water should be vigorously boiled for at least 1 minute after sedimentation, and then allowed to cool to room temperature. Boiling will kill bacteria and parasites and their cysts (eg, Giardia, Entamoeba, and Cryptosporidium) at all altitudes, as well as viruses at low altitudes. Boiling for 3 full minutes will kill all viruses at altitudes above 2,000 meters (6,562 feet).(5,6)
When boiling is not feasible, alternative methods include use of portable water filtration units in conjunction with chemical treatments. Portable filters confer various degrees of protection against microbes, and the manufacturer's instructions should be closely followed. Commercial filters with pore size no greater than 1 µm remove parasites and their cysts. Microstrainer filters with pore sizes in the 0.1- to 0.3-µm range can remove both parasites and bacteria, which average about 0.4 µm in size, but may clog unless a prefilter is incorporated into the system. Both of these systems must be used concurrently with chemical disinfection to ensure removal of viruses. Other available units on the market include filters with iodine-impregnated resins that are most effective against bacteria and some viruses; however the contact time with iodine in the filter is too short to kill some parasites (eg, Cryptosporidium and Giardia). Reverse-osmosis filters can remove parasites, bacteria, and viruses, but they are expensive, larger than most other filters, become rapidly plugged by muddy or cloudy water, and, in some instances, the membrane can be damaged by chlorine in water. Filters that use ultraviolet light, activated carbon, or pentiodide-impregnated resins alone are not effective against Cryptosporidium. Unfortunately, there are very little data in the literature evaluating specific brands or models of filters for removal of bacteria or viruses in water.
Chemical treatments alone can be used for the disinfection of water when other methods are unavailable. Tincture of iodine and tetraglycine hydroperiodide tablets (eg, Globaline, Potable Aqua, or Coghlan's) are available at most sporting goods stores and pharmacies. All of these methods have caveats to their use, and manufacturers' instructions should be followed closely. For example, when using iodine tablets, water must stand for a minimum of 30 minutes, and 15 hours must be allowed if there is concern for Cryptosporidium. Very cold or turbid water must also stand for several hours prior to use and the number of tablets should be doubled. Cloudy water should be strained through a clean cloth prior to disinfection. Finally, chlorine, in various forms, can also be used, although its germicidal activity varies greatly with pH, temperature, and organic content of the water to be purified.
| Preventing Sexually Transmitted Diseases, Including HIV|
Studies of travelers in the United Kingdom, including HIV-infected travelers, have revealed that approximately 10-20% of individuals between the ages of 18 and 34 engage in sexual relations with a new partner when abroad, most commonly with other travelers, locals, or commercial sex workers.(3,4) Long-term travelers and expatriates should avoid unprotected sexual contacts that can result in the spread of HIV (including drug-resistant strains) in the host country. Reinfection of HIV-infected individuals with a different HIV strain or clade (superinfection) has been documented, with associated development of persistent high-level HIV viremia and a loss of almost 300 CD4 cells/µL within 4 months after the presumed time of superinfection.(7) In addition, as more than a dozen major subtypes of HIV have been identified around the world, reinfection with a different clade of HIV may accelerate disease progression or limit subsequent antiretroviral choices. Likewise, the traveler engaging in unprotected sexual behavior is at increased risk of acquiring many sexually transmitted diseases, including some that can lead to severe sequelae in the setting of HIV infection (eg, syphilis and central nervous system [CNS] infection, hepatitis B and chronic liver disease, human papillomavirus [HPV] and genital or anal cancer, and human herpesvirus 8 [HHV-8] and Kaposi sarcoma). Education remains the best preventive measure, including frank discussion with the HIV-infected traveler about the risks associated with new sexual contacts. The sexually active traveler should bring a plentiful supply of latex condoms, as availability may be limited in rural areas and developing countries.
| Medical Exposure to HIV|
Travelers to developing countries should similarly be aware of the risk of HIV infection via contaminated injections, needles, or other invasive medical procedures, and infected blood or blood products. Blood transfusions may be a source of new HIV and hepatitis B and C infections in many parts of the developing world, and long-term travelers should prospectively identify safe donors in their country of travel by documenting blood types and cross-match compatibilities for emergency transfusion needs. The traveler should pack an adequate supply of disposable needles and syringes and condoms from the United States because of the frequent lack of availability and questionable quality of condoms in some developing countries.
| Continuing Antiretroviral Therapy|
Although compliance with ART at home can be a challenge, traveling on a busy schedule with changing time zones can add an extra degree of difficulty. Because all newly prescribed antiretroviral regimens require close monitoring for adverse events within the first few weeks of therapy, making changes in an antiretroviral regimen should be postponed until the patient has returned from an exotic trip, if possible. In addition, because antiretroviral drugs are not uniformly available throughout the world, an adequate supply should be carried in hand baggage to avoid losing them. Initiating a change in ART regimens within 1 month prior to travel is ill advised as patients frequently develop moderate to severe drug toxicities during the first month of therapy.
Drugs such as ritonavir or lopinavir/ritonavir may require refrigeration, and many protease inhibitors may not be chemically stable at extreme temperatures. Patients receiving indinavir should be counseled to increase fluid intake in the tropics because higher insensible losses of fluid may predispose them to nephrolithiasis. Finally, antiretroviral medications have important pharmacokinetic interactions with other drugs that must be kept in mind. Although some interactions, such as with the antimalarials, are still being elucidated, others, such as the prolonged effects of sedatives often prescribed for airline flights, are well known. Nevertheless, with advanced planning and consultation with an experienced practitioner, HIV-infected travelers can pursue safe, enjoyable stays throughout the world while maintaining their ART regimens.
| Medications and Prophylactic Agents to Consider|
When visiting developing countries, HIV-infected travelers should follow standard travel recommendations and be sure to bring an adequate supply of prescription medications and supplies (extra needles, syringes, and bandages), sunscreen, and documentation of vaccinations. Topical antifungals, antimicrobials, and steroids for dermatologic conditions are useful to have. Patients prone to sinusitis after airplane travel may consider bringing decongestants and empiric short courses of antibiotics such as azithromycin or doxycycline.
| Preventing Insect-Borne Illnesses|
HIV-infected persons are more prone to severe sequelae of certain insect-borne illnesses (eg, leishmaniasis and Chagas disease), and all travelers to developing regions at high risk for insect-borne diseases such as malaria, dengue, Japanese encephalitis, leishmaniasis, and Chagas disease should avoid infested habitats, and pack mosquito netting and insect repellents. DEET (N,N-diethyl-3-methylbenzamide), a broad-spectrum repellant that remains the gold standard for protection, is effective against many species of mosquitoes, biting flies, chiggers, fleas, and ticks. The possible toxicities of DEET have been extensively evaluated. With over 40 years of use and following nearly 8 billion human applications, fewer than 50 serious adverse events have been reported in the literature, most occurring in cases of long-term, heavy, and frequent application.(8) Although no correlation has been found between concentration of DEET and toxicity, concentration of DEET does correlate with protective efficacy. Formulations containing at least 24% DEET can provide complete protection after a single application for an average of 5 hours, and, in some studies, as long as 12 hours.(8) Controlled-release formulations do not appear to be more effective. Other currently available methods of unproven efficacy include topical application of IR3535, Skin-So-Soft Bath Oil (Avon Products, New York, NY) and soybean oil-based repellants, ingestion of garlic or thiamine (vitamin B1), and wearing small devices that emit sounds that supposedly repel mosquitoes.(8) Wristbands impregnated with either DEET or citronella are also inadequately protective, providing only local protection at the site where they are worn.(8) Repellents for children should contain no more than 10% DEET. DEET can be washed off with marked perspiration or rain, and efficacy is lost with rising outdoor temperatures. In these situations, repeated applications may be necessary. Travelers should apply sunscreen prior to application of DEET (see http://www.cdc.gov/ncidod/dvbid/westnile/qa/insect_repellent.htm). Travelers to highly endemic areas or those planning prolonged outdoor exposure can also impregnate their mosquito netting and clothing with permethrin spray, which can be effective for 2 weeks, even after up to 5 or 6 laundering cycles.(5) Protective clothing with long sleeves and pant legs is advised, particularly at dusk and dawn when malaria-carrying Anopheles female mosquitoes are prone to biting, or in daylight hours in areas where dengue is endemic. Combined use of all of these measures can reduce insect bites substantially.
| Travelers' Diarrhea: Prophylaxis|
Prophylactic medication for travelers' diarrhea is not routinely recommended in HIV-infected travelers, due to concerns of adverse effects and the possibility of promoting drug resistance. However, in non-HIV-infected travelers, several studies have shown that prophylactic antimicrobials can reduce the risk of diarrhea.(4) Thus, in selected circumstances where exposure to unsanitary conditions may convey a high risk and CD4 cell count is <200 cells/µL, prophylaxis with an antibiotic such as a fluoroquinolone may be warranted (eg, ciprofloxacin 500 mg once a day). Alternative agents include trimethoprim-sulfamethoxazole (TMP-SMX), which has also been shown to be effective as a prophylactic agent when taken once daily, but because of the emergence of drug-resistant enteric pathogens to this agent throughout the developing world, and because of the common occurrence of cutaneous rash and fever in HIV-infected individuals exposed to TMP-SMX, the use of this agent is generally not advised. Nonantimicrobials, such as bismuth subsalicylate, can also be used for prophylaxis, although bismuth subsalicylate can decrease the bioavailability of doxycycline by 30-50% for those taking doxycycline for malaria prophylaxis.(3)
| Travelers' Diarrhea: Self-Treatment|
Travelers' diarrhea is common, particularly in those visiting developing countries, and accounts for >60% of all illnesses affecting tourists.(3) The risk among HIV-infected travelers may be magnified, particularly when CD4 cell counts are low. Commonly implicated pathogens include enterotoxigenic Escherichia coli (ETEC), Campylobacter, Salmonella, and Shigella, although in 40% of travelers' diarrhea cases an etiology is never identified.(3) HIV-infected travelers visiting developing countries should carry an antimicrobial agent such as ciprofloxacin (500 mg twice a day for 3-7 days) to be used empirically should severe or persistent diarrhea develop. As is the case for nonimmunocompromised travelers, if the diarrhea is severe and does not respond to empirical therapy, if stool is bloody, if fever occurs with shaking chills, or if dehydration ensues, then a physician should be consulted. In less severe cases of diarrhea without systemic symptoms, antimotility agents may be tried without antibiotics. Antimotility agents are generally not contraindicated even in the presence of dysentery unless there is a high clinical suspicion for Clostridium difficile colitis, but should generally be discontinued in the event of increasing abdominal pain or systemic toxicity on therapy.
| Malaria Prophylaxis|
The relationship between HIV infection and incidence or severity of malaria is not well established.(9) In pregnancy, there is evidence that HIV infection increases the incidence of placental malaria. Malaria is not considered an HIV-related opportunistic infection and the natural history of malarial infection is not affected by HIV coinfection, in contrast to other protozoal infections (eg, toxoplasmosis, visceral leishmaniasis, and cryptosporidiosis). Until recently, malaria was also thought to not speed the clinical progression of HIV disease. However, recent reports have determined that HIV RNA plasma levels are increased during malaria infection, and studies in vitro indicate that immune activation mediated by proinflammatory cytokines may contribute to HIV disease progression.(4) The importance of adherence to malaria chemoprophylaxis should therefore be emphasized in HIV-infected travelers.
As with non-HIV-infected travelers, the choice of antimalarial prophylaxis depends on the destination, and is currently recommended for all travelers to sub-Saharan Africa (excluding parts of South Africa), the Indian subcontinent, Southeast Asia, Central and South America, parts of Mexico, North Africa, Haiti, and the Dominican Republic. Up-to-date regional prophylaxis recommendations from the CDC can be found at http://www.cdc.gov/travel/regionalmalaria/index.htm. Chloroquine, mefloquine, doxycycline, and the combination drug Malarone (atovaquone plus proguanil) are commonly used, with mefloquine the most frequently indicated prophylactic for travelers to areas where chloroquine-resistant Plasmodium falciparum or Plasmodium vivax are endemic.
Available data addressing possible interactions between antimalarial compounds--which are usually metabolized by the cytochrome P450 system--and antiretroviral drugs are scarce. Although no data exist on proguanil, chloroquine, or doxycycline, concomitant use of mefloquine and ritonavir may lead to lowered plasma levels of ritonavir,(4) although mefloquine does not appear to have any interaction with indinavir or nelfinavir.(10) Until evidence indicates otherwise, HIV-infected travelers on ART should adhere to standard antimalarial recommendations, unless particular adverse effects (such as nausea, diarrhea, strange dreams, dizziness, insomnia, headaches, or, less commonly, psychosis or seizures occurring while on mefloquine, or gastrointestinal adverse effects or cutaneous reactions while on doxycycline) interfere with antiretroviral adherence.
| Region-Specific Opportunistic Infection Prophylaxis|
HIV-infected travelers, particularly those who are severely immunocompromised, must be wary of exposure to local opportunistic infections that are endemic in specific locations. Geographically focal infections that pose high risk to HIV-infected travelers include visceral leishmaniasis (occurring in Bangladesh, Brazil, India, Nepal, Sudan, Central and South America, northern Asia, the Middle East, and Africa), and fungal pathogens including Penicillium marneffei (occurring in northern Thailand, Vietnam, Laos, Singapore, Malaysia, Burma, Indonesia, Hong Kong, and southern China), coccidioidomycosis (occurring in Arizona, central and Southern California, New Mexico, western Texas, Utah, and parts of Central and South America), paracoccidioidomycosis (occurring in Central and South America), and histoplasmosis (occurring in the Midwest and central United States, and Central and South America). Common infections that occur worldwide and have been reported to occur with increased frequency or severity in HIV-infected persons include pneumococcal disease, tuberculosis, non-typhi Salmonella infection, hepatitis A and B, and influenza A. Although previous reports did not describe high prevalences of Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia (PCP) in developing countries,(4) more recent observations suggest that the numbers may be rising.(11)
Thus in certain unusual circumstances described below, primary chemoprophylaxis against regional opportunistic infection may be warranted.
Coccidioides immitis (see chapter "Coccidioidomycosis and HIV") is a soil-dwelling dimorphic tissue fungus endemic in the southwestern United States, northwestern Mexico, and parts of Central and South America. Although infection is usually self-limited to a mild upper respiratory illness in healthy persons, protracted illness and extrapulmonary dissemination is common in the setting of advanced HIV disease. In endemic areas, infection with C immitis contributes to substantial morbidity and mortality among HIV-infected persons, with a high estimated cumulative incidence of 25% over 41 months.(6) HIV-infected travelers visiting endemic areas should avoid exposure to windstorms or large dust clouds, or ground-disturbing activities such as building construction, landscaping, farming, or archaeological excavation. If exposure cannot be avoided, HIV-infected travelers can decrease their risk by wearing particle filter masks, driving in vehicles with enclosed air-conditioned cabs, or, if participating in construction or dust-generating activities, performing dust-control measures such as wetting the soil before disturbing the earth. Primary prophylaxis with fluconazole (100 mg once daily) may be warranted in these special circumstances.
Histoplasma capsulatum (see chapter "Histoplasmosis and HIV"), a dimorphic fungus, is the most common endemic mycosis in the United States,(12) and is associated with exposure to bat or bird droppings. Most recently, outbreaks have been reported in healthy travelers who returned from Central and South America after engaging in recreational activities associated with spelunking, adventure tourism, and ecotourism. HIV-infected travelers should avoid risky behaviors or environments, such as exploring caves, particularly those that contain bat droppings. After engaging in high-risk activities, boots should be hosed off and clothing placed in airtight plastic bags for laundering. Transportation of soil, guano, and other potential fomites should be avoided. Although antifungal treatment is not recommended for the majority of HIV-uninfected persons with acute histoplasmosis, because advanced HIV may predispose to disseminated disease, treatment is generally recommended. If exposure cannot be avoided, primary prophylaxis with itraconazole (200 mg once daily) has been shown to prevent primary histoplasmosis in the setting of HIV infection in endemic areas.(13)
Penicillium marneffei (see chapter "Penicilliosis and HIV") is an unusual dimorphic fungus endemic in discrete regions in Southeast Asia, including northern Thailand and Vietnam, and is further discussed later in this chapter. The majority of infections occur in immunosuppressed HIV-infected residents of endemic areas, usually with CD4 counts <200 cells/µL. Itraconazole (200 mg once daily) has been shown to be an effective primary prophylactic in HIV-infected residents of northern Thailand (14) and should be considered for HIV-infected travelers who plan an extended visit to endemic regions, particularly rural areas, and especially when CD4 counts are <200 cells/µL.
As would be expected, the degree of immunocompetence correlates with the degree of immunologic response to vaccinations. Many vaccinations (influenza, hepatitis A, and hepatitis B) produce suboptimal antibody titers following vaccination at lower CD4 cell counts.(15-17) Unfortunately, severely immunocompromised HIV-infected individuals are also at the highest risk of complications of vaccine-preventable diseases. Thus, assessment of the risks and benefits usually supports administration of inactivated and, in certain cases, live-attenuated vaccines to HIV-infected persons at high risk of exposure. Current travel recommendations are summarized in Table
1. In general, vaccine effectiveness in an HIV-infected individual with a CD4 cell count <300 cells/µL is likely to be decreased, and vaccination is usually not considered useful when the CD4 cell count is <100 cells/µL.(4) Although initial reports suggested that the administration of routine vaccinations might lead to an increase in HIV viral load,(16) subsequent data have shown that any such increase is transient, not associated with sustained decreases in CD4 count, and that HIV RNA levels can be expected to return to baseline 4-6 weeks following administration of vaccine or even sooner if the patient is receiving effective ART.(18,19) Early concerns regarding the deleterious effects of vaccinations on long-term survival appear to be unsubstantiated.
| Routine Vaccinations|
Preparation for travel should include a review and updating of routine vaccinations, including diphtheria-tetanus, pneumococcal, and influenza. Infection with Streptococcus pneumoniae remains a significant cause of morbidity and mortality in HIV-infected persons in both developed and developing countries. For this reason, despite unclear evidence of protective efficacy,(20) the polysaccharide pneumococcal vaccine is recommended for all HIV-infected persons with a CD4 count >200 cells/µL. Vaccination against influenza, which occurs year-round in the tropics, is also advised for HIV-infected travelers, who are at risk of influenza-related complications.(21) Travelers from the northern hemisphere visiting the southern hemisphere (and vice versa) may not receive influenza vaccination because of the provider's failure to remember the winter/summer differences between the hemispheres. Symptomatic and asymptomatic infants and children infected with HIV should receive all routinely recommended inactivated vaccines on schedule, including acellular pertussis (DtaP), Haemophilus influenzae type B (Hib), inactivated polio (IPV), polysaccharide pneumococcal vaccine, influenza, and hepatitis B vaccines.(21) Asymptomatic HIV-infected children should also receive the measles-mumps-rubella (MMR) and varicella vaccines.(22) The 7-valent conjugate pneumococcal vaccine is also recommended for HIV-infected children under the age of 5 years.(23)
| Specific Recommendations|
As a general rule, killed or inactivated vaccines are safe for use in immunocompromised travelers. Live vaccines should be avoided, especially when the CD4 cell count is <200 cells/µL, as viral replication after administration of live, attenuated virus vaccines can be enhanced and prolonged in the setting of HIV infection. The exceptions to this rule, measles and, in special circumstances, yellow fever, are discussed below.
In the setting of HIV infection, antibody responses to the measles vaccine can be variable. Despite this, current CDC recommendations are to vaccinate all asymptomatic HIV-infected persons with MMR if routinely indicated or in the setting of prolonged travel to endemic areas for measles, and vaccination should be considered for symptomatic HIV-infected persons who are not severely immunosuppressed.(5) Vaccination with the measles vaccine does not appear to be associated with severe or unusual adverse events when the degree of immunosuppression is mild.(5) However, the MMR is contraindicated when immunosuppression appears to be severe. This is primarily due to a single report of measles pneumonitis occurring in a measles vaccinee in the setting of advanced AIDS.(5) Immune globulin should be considered for measles-susceptible, severely immunocompromised travelers who are anticipating travel to measles-endemic countries.
| Yellow Fever|
Yellow fever vaccine is an attenuated live virus vaccine with uncertain safety and efficacy in the setting of HIV infection. Limited data regarding yellow fever vaccination among asymptomatic HIV-infected persons suggest that seroconversion rates following vaccination are low. One month after receiving a 17D yellow fever vaccination, only 70% of 33 HIV-infected adults with CD4 cell counts >200 cells/µL developed neutralizing antibody.(24) In comparison, yellow fever vaccine typically induces seroconversion among >90% of healthy adults. Among HIV-infected infants simultaneously vaccinated with a 17D yellow fever vaccine and measles vaccine, only 3 of 18 developed neutralizing antibody to yellow fever compared with 74% of 57 HIV-seronegative infants who simultaneously received the two vaccines.(24) Because of the question of decreased efficacy, measuring neutralizing antibody response to vaccination should be considered before travel. In addition, possible adverse effects, including a theoretical risk of encephalitis, remain of concern. Although large clinical or epidemiologic studies to evaluate the risks of vaccination in HIV-infected persons have not been performed, it was recently reported that 44 HIV-infected persons with CD4 count >200 cells/µL received yellow fever vaccine without adverse reaction.(24)
Travelers with asymptomatic HIV infection who have adequate immune system function and who cannot avoid potential yellow fever exposure should therefore be offered yellow fever vaccination and be monitored closely for possible adverse effects. If the only reason for vaccinating an asymptomatic HIV-infected person is an international travel requirement, rather than an increased risk for infection, a waiver letter from the physician can be carried. If travel to a high-risk yellow fever-infected zone is necessary and immunization is not given, travelers must be advised of the risk, take the appropriate mosquito precautions and be provided with a vaccination waiver letter. There is no evidence that family members or close personal contacts can transmit the attenuated yellow fever vaccine strain to immunocompromised HIV-infected individuals, and therefore they may be safely vaccinated in the appropriate setting.
| Typhoid Fever|
Typhoid vaccination is not required for international travel, but is recommended for travelers to areas where there is a recognized risk of exposure to Salmonella typhi (the Indian subcontinent, Asia, Africa, and Central and South America), and particularly in those who will have prolonged exposure to potentially contaminated food and drink or will be traveling in smaller cities, villages, and rural areas, or in the setting of known local epidemics. Given the increased risk of bacteremia from Salmonella infection in HIV-infected individuals, HIV-infected travelers should be given the inactivated parenteral typhoid vaccine instead of the live-attenuated oral typhoid vaccine. Because vaccination with inactivated typhoid vaccines in healthy immunocompetent persons provides only 70% protection against infection,(5) HIV-infected travelers should be advised to be meticulous with food and water precautions.
Although efforts to eradicate polio continue worldwide, pockets of endemicity still exist in sub-Saharan Africa and south Asia. Poliomyelitis was eliminated in 1991 from the western hemisphere, where all reported outbreaks of polio are now vaccine associated. HIV-infected travelers should receive the inactivated polio vaccine at least 4 weeks before international travel if they have not been previously vaccinated. Given the handful of cases in the literature of vaccine-associated paralytic polio and prolonged poliovirus excretion following administration of live oral polio vaccine (OPV) in the setting of HIV infection, this vaccine is contraindicated in this population. Because healthy persons may excrete poliovirus for up to 20 days following OPV vaccination,(5) IPV is recommended for household members and close contacts of HIV-infected persons as well.
| Hepatitis A and B|
Hepatitis A vaccine should be considered routinely in HIV-infected travelers who visit developing countries, as hepatitis A is the most frequently occurring vaccine-preventable disease among travelers. In addition, coinfection with HIV and hepatitis B and/or C is common, and acute infection with hepatitis A may precipitate acute liver decompensation in individuals with pre-existing chronic liver disease. Ingestion of feces-contaminated water or food, such as raw seafood, is the usual source of infection. A single dose of hepatitis A vaccine must be given at least 7 days prior to travel, and will confer a 90% protective efficacy within 2-4 weeks in immunocompetent vaccines.(5) The duration of immunity after the second dose is estimated to be 10 years or longer. Coadministration of passive immunity (85-90% protection) with gamma-globulin should be reserved for the HIV-infected traveler anticipating imminent travel (<2 weeks), at a separate injection site from that of the hepatitis A vaccine. Concurrent administration of most vaccines is not contraindicated with gamma-globulin, except for the measles and varicella vaccines.
Tuberculosis is a serious health problem in developing countries, with recent data from WHO suggesting that isoniazid resistance is now relatively common throughout the world. Currently, the attenuated Bacillus Calmette-Guerin (BCG) vaccine is given in most developing countries to reduce the severe consequences of miliary tuberculosis and tuberculous meningitis in infants and children, but BCG has variable reported efficacy in preventing tuberculosis in adults. In addition, there have been >25 reported cases of disseminated infection following BCG vaccination in HIV-infected persons, with a high associated mortality rate.(25-27) Current recommendations are that BCG vaccination should not be administered to HIV-infected infants and children living in endemic areas, even if the risk of acquiring tuberculosis is high, and avoidance of BCG vaccination is similarly recommended for HIV-infected adults and travelers. Instead, HIV-infected travelers should be advised to avoid exposure to known tuberculosis-infected patients in crowded environments (eg, hospitals, prisons, or homeless shelters), and those who will be working in health care settings where tuberculosis-infected patients are likely to be encountered should wear appropriate masks known to have efficacy in preventing the transmission of tuberculosis.
| Illnesses in HIV-Infected Individuals Returning from International Travel|
As in non-HIV-infected persons, trauma (eg, motor vehicle or hiking accidents, drowning, violence) and exacerbations of underlying diseases are important causes of mortality during international travel. It is important to remember that any clinical event may be HIV-related, travel-related, or neither. Retrospective studies have emphasized the common occurrence of diarrhea (2) and skin disorders (28) in HIV-infected travelers; these conditions have cumulatively been reported to occur in up to 30% after a median of 3 weeks of travel to developing countries. As in HIV-uninfected travelers, syndromic distinctions are useful in the differential diagnosis of travel-related illness. Although there are no published data on the frequency of travel-related complications among HIV-infected patients receiving effective ART, it is likely that the risk of acquiring atypical travel-related illnesses (eg, prolonged diarrhea, disseminated mycobacterial or fungal infections) will continue to be significant in patients with CD4 counts <200 cells/µL at the time of exposure.
| Undifferentiated Fever|
The causes of prolonged undifferentiated fever in the HIV-infected individual are protean, and any significant fever must be considered HIV related unless proven otherwise. In addition to specifically travel-related causes, the differential diagnosis should include mycobacterial infection (eg, tuberculosis, Mycobacterium avium, or infection with other mycobacteria), disseminated fungal infection (eg, cryptococcosis or other endemic mycoses), CNS infections (eg, toxoplasmosis or cryptococcal meningitis), pulmonary infections (eg, tuberculosis, PCP, or nocardia, fungal, and bacterial pneumonias), other systemic bacterial infections (eg, Bartonella infection, Salmonella bacteremia), systemic viral illnesses (cytomegalovirus disease, HIV-induced febrile illness in the setting of recent ART interruption), occult malignancy (especially lymphoma, Kaposi sarcoma, Hodgkin disease, and other lymphoproliferative disorders), drug reactions,(29,30) and non-HIV-related, non-travel-related infections (eg, skin and soft tissue infection, intra-abdominal abscesses, endocarditis, viral illnesses, undiagnosed rheumatologic illness or malignancy).
If the history, physical, and appropriate laboratory tests do not suggest one of the above etiologies, important historical factors can be useful in narrowing the differential diagnosis of travel-related fever. These include the incubation period of the illness after return from the endemic area, associated symptoms, compliance with antiretroviral agents or opportunistic infection prophylaxis, level of precautions used with regard to food, drink, sexual encounters, and more specific exposures (eg, barefoot walking, animal or insect exposure, freshwater exposures, travel to rural areas, or travel to areas with known epidemics). Routine evaluation of patients as determined by the incubation period, risk factors, and associated symptoms may include thick and thin smears for malaria; blood cultures to rule out bloodstream infections (eg, meningococci, salmonellae, staphylococci, streptococci, or enteric pathogens); urine, sputum, and stool cultures; serologies; and antigen testing.
The incubation periods of common travel-related causes of fever are listed in Table
| Specific Causes of Undifferentiated Fever|
Malaria is the infection most associated with fatality in travelers to developing countries. P falciparum is responsible for the majority of deaths, with 90% of cases occurring in individuals who have returned from sub-Saharan Africa within the past 30 days.(31,32) Concurrent respiratory or gastrointestinal symptoms should not dissuade clinicians from considering the diagnosis of malaria. P vivax is the second most common species of malaria seen in travelers and is more typically associated with travel to Central America, South America, Asia, or Oceania.
Although there is limited evidence of clinical interaction between HIV and malaria, several recent studies from Africa have suggested that pregnant HIV-infected women have a higher risk of malaria acquisition, that HIV/malaria-coinfected pregnant women have a higher risk of preterm delivery, and infants born to these women are prone to low birth weight.(33) Thus, an HIV-infected pregnant woman with history of recent travel to a malaria-endemic area and new onset of fever merits immediate evaluation for the presence of malarial parasites by thick and thin smears, and assessment of species and degree of parasitemia. Depending on the severity of illness, strong consideration should be given to hospitalization for observation and treatment until clinical improvement is apparent.
| Typhoid Fever|
Despite the common occurrence of relapsing nontyphoidal Salmonella bacteremia in HIV disease, by 1999 there were only 5 reported cases of S typhi bacteremia in HIV-infected travelers.(34) This may reflect the protective benefit of opportunistic infection prophylaxis with TMP-SMX, antiretroviral therapy incorporating zidovudine (AZT, which has in vitro activity against Salmonella species), or other agents. Typhoid fever typically has a longer incubation period and relatively insidious onset when compared to other causes of febrile illnesses in travelers. The majority of travelers with typhoid fever after returning to the United States report travel in the prior 2-6 weeks in India, Pakistan, or Mexico.(35) Fatigue, fever, headache, abdominal pain, constipation, and dry cough are common symptoms. "Rose spots" (faint pink macules) are reported in up to 30% of patients, and biopsy of these lesions is usually culture positive for S typhi. Fevers rise to 103°-104°F by the third week of illness, and gastrointestinal bleeding, perforation, and altered sensorium are common complications at this stage.(36) Diagnosis is usually made by culture of blood or bone marrow. Treatment has been complicated by the emergence of multidrug resistance, and empiric therapy with quinolones or third generation cephalosporins while awaiting results of antimicrobial susceptibilities is recommended.
| Dengue, Leptospirosis, Rickettsial Diseases, Ehrlichiosis, Meningococcal Disease: Fever, Headache, Myalgias, and Rash|
As in non-HIV-infected patients, dengue is a common cause of fever in travelers to the tropics and subtropics. In 2002, dengue reemerged in the island of Maui for the first time in over 50 years. Fever, retro-orbital headache, myalgias ("breakbone fever") are classic signs and occur 4-8 days after mosquito exposure (Aedes species). Lymphadenopathy, petechial or maculopapular rash, leukopenia, and thrombocytopenia are commonly seen. Treatment is primarily supportive, and nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin are relatively contraindicated because of increased bleeding risk in the setting of thrombocytopenia. Rickettsial illnesses (Rickettsia africae, Rickettsia conorii, Orientia tsutsugamushi) and ehrlichial infections can be seen in patients with tick exposure and with relatively short incubation periods. The classic symptoms of fever, headache, and myalgia, and short incubation period are characteristic of rickettsial and ehrlichial infection. Patients with rickettsial infection may also have rash or eschar (eg, necrotic lesion at the site of the tick bite) and leukopenia or thrombocytopenia. Severe ehrlichial infection leading to septic shock has been described in advanced HIV infection.(37) Treatment is usually with a tetracycline and should be begun promptly. The diagnosis is subsequently confirmed by serology or by the visualization of morulae (intracellular inclusions in granulocytes or monocytes) in peripheral blood or bone marrow smears.
Leptospirosis also has a short incubation period and typically presents with retro-orbital headache, fever, myalgias, and rash. Freshwater exposure (eg, canoeing, kayaking, and swimming or wading through flooded areas) is a common risk factor. Patients may also present with aseptic meningitis, uveitis, hepatitis, acute renal insufficiency, and pulmonary hemorrhage. Penicillin is the treatment of choice for life-threatening infection, and tetracyclines are an alternative class of active agents.
Meningococcemia is extremely common in sub-Saharan Africa and in travelers to Mecca (Saudi Arabia). The classic presentation is that of fever, headache, and centrifugal petechial, or macular rash with rapid development of septic shock, with or without concurrent purulent meningitis. There is no evidence of interaction between HIV and meningococcal disease reported to date.
| Travel-Related Febrile Illnesses with Altered Natural Histories in HIV Infection|
Although HIV infection may not increase risk of acquiring certain opportunistic infections, the clinical course may be more severe in the setting of HIV infection, and travelers to endemic areas should be informed and take appropriate precautions. For example, pneumococcal infection, cryptococcosis, and tuberculosis remain extremely common infections in HIV-infected patients throughout the world. As described previously in this chapter, acute fungal pneumonia (eg, histoplasmosis, coccidioidomycosis, and blastomycosis) are relatively common travel-related illnesses with short incubation periods that present with a more fulminant course in the setting of HIV.(12)
P marneffei (see chapter "Penicilliosis and HIV") is an emerging systemic opportunistic infection in Southeast Asia (China, Thailand, Cambodia), and it is the third most common opportunistic infection in HIV-infected patients in Thailand. Although the portal of entry and environmental reservoir of the organism remain obscure, the organism appears to be associated with bamboo rat habitats in Southeast Asia. The disease resembles disseminated histoplasmosis in patients with AIDS and is characterized by fever, night sweats, weight loss, cough, pulmonary infiltrates, pancytopenia, hepatosplenomegaly, and lymphadenopathy. Mucosal ulcers are seen and cutaneous involvement can mimic molluscum contagiosum or disseminated cryptococcal infection with characteristic multiple umbilicated nodules or papules.(38) There have been multiple case reports of P marneffei infection in HIV-infected patients after travel to endemic areas. Fungal culture of blood, bone marrow, or skin lesions is usually diagnostic, and review of peripheral blood smear will occasionally reveal the presence of a yeastlike organism that divides by fissuring rather than by budding (like Histoplasma). Amphotericin B or itraconazole are the preferred treatment options.
Visceral leishmaniasis (kala-azar, caused by Leishmania donovani and other species), transmitted by the bite of infected sand flies, is endemic in the Middle East, the Indian subcontinent, North and sub-Saharan Africa, and South America. Leishmaniasis is also an emerging opportunistic infection associated with sharing of infected needles in intravenous drug use. Typically, patients present with fever, pancytopenia, and hepatosplenomegaly. Gastrointestinal ulceration is a common finding of visceral leishmaniasis in HIV-infected individuals.(39) Diagnosis is made by culture or biopsy of bone marrow, splenic tissue, or ulcerative gastrointestinal lesions, and treatment is most commonly with sodium stibogluconate or liposomal formulations of amphotericin B.
Chagas disease (caused by Trypanosoma cruzi) is endemic in much of Central and South America and is transmitted through the bite of an infected reduviid bug. Initial presentation is with edema and pain at the site of entry (Romana sign) and regional adenopathy, with chronic complications of myocarditis and disseminated disease occurring years later. Intracranial chagomas (mass lesions) and encephalitis have increasingly been reported in the setting of HIV disease and can mimic CNS lymphoma or toxoplasmosis.(40)
| Cutaneous Disease in HIV-Infected Travelers|
Fever and rash in the setting of disseminated infection can be severe and may be HIV related, travel related, or neither. Disseminated fungal or mycobacterial infections can characteristically present with multiple nodules, whereas endocarditis, meningococcemia, Salmonella infection, leptospirosis, rickettsial disease, dengue, and disseminated strongyloidiasis all may present with a macular or vasculitic rash. Childhood exanthems, arboviral infections, enteroviral infection, secondary syphilis, and disseminated varicella infection are also in the differential diagnosis.
Other skin infections for which HIV-infected travelers may be at increased risk include staphylococcal folliculitis, botyriasis (hyperkeratotic plaques in intertriginous areas due to staphylococci), impetigo due to staphylococci or streptococci, and echthyma gangrenosum, seen in the setting of profound neutropenia or advanced disease and usually due to Pseudomonas aeruginosa. Candidal folliculitis and tinea infections occur at high frequency in HIV-infected travelers. Pruritic papular eruptions are frequently due to insect bites, chiggers, fleas, or mosquitoes and are usually treated with topical steroids.(41) Nodular lesions with visible movement of maggots within are characteristic of myiasis, which is due to the botfly in Central America and the tumbu fly in sub-Saharan Africa. Migratory skin lesions are seen with multiple helminthic infections including visceral larva migrans (eg, dog hookworm, Ancylostoma braziliense) and cutaneous strongyloidiasis (eg, larva currens). Chronic cutaneous ulcers in patients who have traveled to the Middle East or Indian subcontinent are commonly due to cutaneous leishmaniasis. Lastly, patients with HIV are more prone to infection with scabies (Sarcoptes scabei), and severe infestations (Norwegian or crusted scabies) can be seen in immunosuppressed patients with HIV. Treatment is with repeated applications of permethrin plus removal of crusts over several days, or with single dose ivermectin.(42)
| Diarrheal Illnesses|
| Acute Travelers' Diarrhea|
Acute travelers' diarrhea is a classic constellation of watery diarrhea associated with cramps, nausea (up to 60%), and, less frequently, fever or vomiting (<10%). As discussed previously, the most commonly isolated organisms are ETEC, and species of Campylobacter, Salmonella, and Shigella. Other commonly reported organisms from various case series are listed in Table
3. ETEC is associated with up to 70% of cases of travelers' diarrhea in travelers to Central or South America. The average duration of symptoms is 5 days, and the development of fever, bloody stools, or systemic toxicity should lead to the prompt initiation of antimicrobial therapy. Most studies have shown that the average duration of travelers' diarrhea is 3-5 days, and that antimicrobial therapy reduces the severity and duration of symptoms by 1-2 days.(43,44)
Quinolones have emerged as the treatment of choice for travelers' diarrhea, but are contraindicated in pregnant women and in children. Common treatment regimens for travelers' diarrhea are listed in Table
3. In severely ill individuals, quinolone therapy should be continued for at least 3 days. Most experts recommend longer courses (10-14 days) for treating HIV-infected patients with bacteremia associated with Campylobacter, Shigella, or Salmonella gastrointestinal infections. Unless there is a clinical suspicion for C difficile infection, antimotility agents may be used as well. Antimotility agents in conjunction with antimicrobial therapy, compared with antimicrobial therapy alone, have been demonstrated not to result in increased severity or duration of symptoms or increased duration of fecal shedding in documented Shigella gastroenteritis.(45) Maintenance therapy with quinolones or TMP-SMX is recommended for patients with CD4 cell count <200 cells/µL and Salmonella bacteremia because of the high incidence of recurrence when antimicrobial therapy is discontinued.(46) Unfortunately, quinolone resistance is beginning to emerge throughout the developing world in many of these gastrointestinal pathogens.
| Chronic Diarrhea in HIV-Infected Travelers|
If diarrhea continues despite treatment with a quinolone, consideration should be given to the possibility of quinolone-resistant enteric pathogens, particularly Campylobacter jejuni, for which macrolide therapy has documented efficacy. Chronic diarrhea may also be due to protozoal infections such as Entamoeba histolytica, Giardia lamblia, Cryptosporidium species, Cyclospora cayetensis, Microsporidium species, or Isospora belli in HIV-infected travelers. Routine evaluation should include obtaining stool for ova and parasites, Giardia antigen testing, and modified acid fast stain of stool for Cryptosporidium, Microsporidium, and Cyclospora species. Further workup using gastrointestinal upper endoscopy with small bowel biopsy and colonoscopy can be pursued, especially if there is significant weight loss associated with the chronic diarrhea (see chapter "Gastrointestinal Manifestations of HIV"). Primary treatments for most of the usual pathogens are listed in Table
3. The possibility of antiretroviral medication-induced diarrhea or C difficile disease should also be considered, as well as the myriad causes of diarrhea in HIV disease unrelated to travel, including disseminated M avium, cytomegalovirus gastrointestinal disease, and HIV enteropathy. It is important to emphasize that antiretroviral therapy is the treatment of choice of several of these recalcitrant causes of chronic diarrhea, as outlined in Table
3. In addition, chronic diarrhea may develop due to tropical sprue, a poorly understood cause related to bacterial overgrowth, which responds to doxycycline, or inflammatory bowel disease unrelated to travel.(47)
|| ||Centers for Disease Control and Prevention. Health information for international travel, 2001-2002 (Yellow Book). Available at: http://www.cdc.gov/travel.|
|| || McKinsey DS, Wheat LJ, Cloud GA, Pierce M, Black JR, Bamberger DM, Goldman M, Thomas CJ, Gutsch HM, Moskovitz B, Dismukes WE, Kauffman CA. Itraconazole prophylaxis for fungal infections in patients with advanced human immunodeficiency virus infection: randomized, placebo-controlled, double-blind study. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis. 1999 May; 28(5): 1049-56.|
|| || French N, Nakiyingi J, Carpenter LM, Lugada E, Watera C, Moi K, Moore M, Antvelink D, Mulder D, Janoff EN, Whitworth J, Gilks CF. 23-valent pneumococcal polysaccharide vaccine in HIV-1-infected Ugandan adults: double-blind, randomised and placebo controlled trial. Lancet. 2000 Jun 17; 355(9221): 2106-11.|
|| || Cetron MS, Marfin AA, Julian KG, Gubler DJ, Sharp DJ, Barwick RS, Weld LH, Chen R, Clover RD, Deseda-Tous J, Marchessault V, Offit PA, Monath TP. Yellow fever vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2002.
MMWR Recomm Rep. 2002 Nov 8; 51(RR-17): 1-11.|
|| || Paddock CD, Suchard DP, Grumbach KL, Hadley WK, Kerschmann RL, Abbey NW, Dawson JE, Anderson BE, Sims KG, Dumler JS, et al. Brief report: fatal seronegative ehrlichiosis in a patient with HIV infection. N Engl J Med. 1993 Oct 14; 329(16): 1164-7.|