Travel medicine and HIV infection

Introduction

Travel medicine is an exciting interdisciplinary specialty that has developed rapidly in response to the needs of the travelling population worldwide. The development of travel medicine as a discipline is a recent advance in itself. This has been recognized in the UK by the Department of Health in its new strategy for combating infectious disease, which confirms the need for specialists in travel medicine. ¹ The field of travel medicine has grown dramatically as a greater number of people travel to exotic and remote destinations with approximately 600 million travellers crossing international borders annually. However, studies suggest that only about 8% seek pre-travel health advice, and many receive information from practitioners who are ill-equipped to provide current and accurate information. Travel medicine has become increasingly complex due to dynamic changes in global infectious disease epidemiology, changing patterns of drug resistance and a rise in the number of travellers with chronic health conditions. ² In general, the risk of becoming ill during international travel depends on the region of the world visited, as well as factors such as age, health status, length of stay and planned activities. To reduce the risk of illness or injury abroad, a health-care provider should be consulted, ideally four to six weeks before international travel. In addition, children, the elderly, pregnant women and immunocompromised travellers may be particularly vulnerable to certain problems while travelling and may require more specialized counselling. ³ Since the introduction of highly active antiretroviral treatment (HAART) in 1996, there have been substantial reductions in deaths and hospital admission rates in the developed nations. Increasing numbers of HIV-infected people are back in work and are travelling for holiday, family or business reasons. ⁴ Patients with CD4 counts below 200/μL have a substantial threat of opportunistic infections, which can be acquired both in an everyday environment and through travel. Furthermore, the effectiveness of vaccinations in this group of patients is reduced. ⁵ Travelling to tropical and subtropical countries significantly increases the chance of encountering infectious organisms ⁶ but Furrer et al. ⁷ found that visiting tropical countries was associated with a lower risk of progression to AIDS, indicating that travelling is a proxy for good health. Pre-travel consultation in travel clinics has been shown to decrease the rate of illness during travel. ⁸ It is quite clear, however, that travel clinics can only be effective if travellers use them. In Québec, Canada, there are almost a 100 travel health clinics offering preventive services to travellers for a population around seven million and just about 15% of Québec travellers at risk consult a travel clinic. ⁹ One study performed in London found that just 11 HIV-infected persons sought pre-travel medical consultation ¹⁰ and another one in the USA found that only one HIV-infected patient consulted a travel medicine expert before travel. ¹¹ Experts generally bemoan the low attendance rates in travel clinics and many strategies have been suggested to increase frequency of pre-travel consultation ⁸ Although many clinicians attending HIV-infected patients are specialists in infectious and parasitic diseases some of them may not feel able to advise a traveller. Before evaluating an individual for a pre-travel consultation, it is the responsibility of the clinician to determine his or her own limitations. A threshold should be set for when a referral might be made to a travel medicine specialist, considering the traveller's best interest and the need to provide the most complete and up-to-date information. ¹² This paper reviews the health problems that persons with HIV infection may face during international travel and their prevention.

Antiretroviral Therapy

If in the pre-HAART era many patients travelled under severe imunnosuppression with a strong desire to take a last chance to travel. ¹³ Now-a-days many HIV-positive travellers benefit from advances in antiretroviral (ARV) therapy with increased survival, better quality of life and reduced risk of opportunistic infections. ⁶ A newly started ARV regimen should be proven to be effective and well tolerated for at least three months before long-term travelling takes place. ⁵ If the CD4+ count is <200/μL, then starting therapy is of paramount importance for the patient's health and travelling should be delayed, until the patient is well established on therapy and the CD4+ count has risen to >200/μL. ⁶ One recent study of HIV-infected travellers (in which 79.4% of travellers were under ARV therapy) found a median CD4 count of 451/μL. ¹⁰

Adherence is even more difficult abroad than it is at home for a number of reasons: taking ARV medication abroad is a big concern for many HIV-positive travellers as it might lead to disclosure of someone's HIV status; being on holiday means very often a change in lifestyle; changes in time zones; drug interactions of HAART with either other medication (various chemoprophylactic agents, antibiotics, antihistamines, etc.) or recreational drugs; and storage requirements. ⁶ In a study from UK, 27 people (11.3%) stopped their ARV treatment at the time of travel to the USA. Of the 27 discontinuing treatment, only 15 (55.5%) sought medical advise before stopping ARV treatment and one individual developed a non-nucleoside reverse transcriptase inhibitors (NNRTI)-based mutation. ⁴ A sufficient amount of ARV drugs should be packed, preferably in the hand luggage as suitcases can get lost. HIV-positive travellers should be informed that many countries restrict entry of travellers with HIV infection. ARV drugs found in baggage at customs may lead to exclusion.

Enteric Infections

Reduced immunological defence and diminished gastric acid production increase the risk for gastrointestinal infections in HIV patients. Travellers must strictly observe proper water and food hygiene. The following food and drink are to be avoided: raw fruit or vegetables that are not peeled; raw or undercooked meat or fish dishes; tap water; ice cubes made from tap water; unpasteurized milk or milk products; food prepared or distributed under insecure hygienic circumstances. ⁵ Water-borne infections might result from swallowing water during recreational activities. To reduce the risk of enteric infections, patients should avoid swallowing water during swimming and should not swim in water that might be contaminated. Travellers’ diarrhoea is a frequent problem of immunosuppressed travellers, as it is in the general travelling population; however, antibiotic prophylaxis is not routinely recommended. ¹⁴ Although by 2006, Brazil had managed to validate interruption of vector-borne transmission of Trypanosoma cruzi by Triatoma infestans, ¹⁵ oral transmission of T. cruzi is possible and outbreaks caused by juice of Euterpe oleraceae, an amazonic fruit, are described. ¹⁶ Reactivation of Chagas disease is in the list of AIDS-defining disease in Brazil. ¹⁷

Malaria

Malaria, a potentially life-threatening disease, is largely preventable by means of taking appropriate antimalarials and avoidance of insect bites. Permethrin-impregnated bed nets, mosquito repellents, protective clothing and footwear, mosquito coils and sleeping in air-conditioned rooms will significantly reduce the chance of a nocturnal bite by the female anopheles mosquito. Although earlier reports did not find any association, more recently evidence has been accumulating that HIV infection and malaria interact with one another. ¹⁸ Malaria does not behave like an opportunistic infection. However, the details on the interaction between HIV and malaria are widely unknown. Malaria seems to increase HIV replication through proinflammatory cytokines. ⁵ HIV-infected pregnant women appear to have a higher malaria risk. Malaria-HIV co-infection in pregnancy is associated with increased parasitaemia and a higher incidence of prematurity as well as low birth weight.

A significant association of mother-to-child transmission of HIV with placental malaria was shown. Because the risk of HIV transmission increases with the level of HIV viral load in the plasma, adequate prophylaxis and treatment of malaria could have a significant impact on the transmission of HIV from mother to child. ¹⁸ Non-pregnant HIV-infected malaria patients demonstrated a negative influence of the HIV infection on the clinical course of malaria, a higher risk for severe malaria in patients with low CD4+ T-cell counts and a high frequency of atypical malaria manifestation, e.g. respiratory or intestinal symptoms. ⁵

Available data suggest that there is probably no interaction between the NRTI and malaria drugs. Common drugs used for malaria prophylaxis are chloroquine, mefloquine, doxycycline and atovaquone/proguanil. No clinically significant interaction is expected among NNRTI and these drugs. Protease inhibitors (PI) inhibit hepatic cytocrome p450 enzymes and share this with many antimalarials. Ritonavir, the most potent inhibitor of CYP3A4, do not increase mefloquine levels, but the levels of ritonavir plasma levels are decreased by mefloquine. ⁶ Coadministration of lopinavir or ritonavir, and atovaquone may result in decreased concentrations of atovaquone. The clinical significance is unknown, however, an increase in atovaquone dose may be needed. ¹⁹ No clinically significant interaction is expected among PI, except ritonavir, and chloroquine and proguanil. Quinine, artemisinin and lumefantrine are used for treatment of malaria. Quinine is extensively metabolized by CYP3A4. Exposure could be increased by ritonavir or ritonavir-containing boosted PI regimens. Quinine is either contraindicated or has to be used with great caution. Careful monitoring of drug levels to avoid fatal arrhythmias is necessary. Artemisinin, and its derivatives such as artesunate and artemether, are rapidly metabolized via CYP3A4 to a biologically active metabolite, dihydroartemisinin. Although the parent drugs and dihydroartemisinin all have antimalarial activity, dihydroartemisinin has greater potency than the parent drugs. Inhibition of CYP3A4 would reduce dihydroartemisinin, but increase concentrations of the parent drug and potentially increase the half-life of the parent drug. The effects of PI and NNRTI are unclear. ¹⁹ Lumefantrine is extensively metabolized by CYP3A4. Lumefantrine does not seem to prolong the QT interval and is much safer than halofantrine. Nevertheless, interactions with PIs and NNRTIs are likely and the manufacturer's summary of product characteristics advises that coadministration with CYP3A4 inhibitors is contraindicated. ¹⁹

Vaccinations

A travel medicine consultation is an opportunity to check and complete routinely recommended immunizations such as tetanus/diphtheria, pneumococcal influenza and hepatitis B vaccinations. The only vaccine required by International Health Regulations is yellow fever vaccination for travel to certain countries in sub-Saharan Africa and tropical South America. Meningococcal vaccination is required by the government of Saudi Arabia for annual travel during the Hajj. Some vaccines are recommended to protect travellers from illnesses present in other parts of the world and to prevent the importation of infectious diseases across international borders. Which vaccinations are needed depends on a number of factors including destination, the season of the year and previous immunizations.

Live vaccines (MMR [measles, mumps and rubella], oral polio, oral typhoid, varicella, yellow fever and BCG [bacillus Calmette-Guerin]) should be avoided in severely immunocompromised travellers (CD4+ <200/μL) due to the risk of dissemination and serious complications. For individuals with CD4+ cell counts above 500/μL live vaccines are generally safe. The exceptions to that rule are BCG and oral typhoid, contraindicated in HIV-infected people. In people with asymptomatic HIV disease and a CD4+ count >200/μL yellow fever vaccination can be considered if there is a substantial risk of exposure. ²⁰

Killed and subunit vaccines that may be administered safely to persons with HIV are hepatitis A and B, influenza, Japanese encephalitis, meningococcal, pneumococcal, Salk polio, rabies, Vi typhoid and Tetanus/diphtheria. If any of the above vaccines are indicated then they should be administered as early as possible whilst the immune function is still preserved. ⁶ Salk polio vaccine is preferred to oral polio vaccine (OPV) in HIV-infected patients due to the risk of paralytic poliomyelitis associated with OPV in these patients. ⁶ Although developed countries have low rates of vaccine-preventable diseases, outbreaks of measles and mumps were recently reported in Switzerland, Germany, Spain and USA, mainly in nonvaccinated people.^21,22

Concern has been raised by the observation that many vaccines may induce a discrete increase in HIV virus load after vaccination as a result of activation of the immune system. It has now been shown that the HIV RNA increase following vaccination is transient and that the HIV RNA level usually returns to baseline four to six weeks after administration of the vaccine or even sooner if the patient is receiving ARV treatment. ²³

Sexually Transmitted Diseases

Sexual activity increases during travel. Safer sex should be reinforced. HIV-infected individuals may still acquire hepatitis B or C, or, rarely, a superinfection with a non-clade B HIV strain. Travel-associated infections are mainly caused by non-B subtypes and circulating recombinant forms and contribute to an increase in HIV-1 diversity. This increase has in turn led to the emergence of new recombinant forms. Increased HIV-1 diversity has implications for diagnostic and treatment efficacy (although data remain limited), and for future vaccine programmes. ²⁴ In Germany, an estimated 5-10% of HIV infections are acquired during holidays. ⁵

Other Infections

Some geographically focal infections may pose an increased risk of severe outcome for immunocompromised persons. Leishmania-HIV co-infections have been reported from Africa, India, Brazil and European Mediterranean countries. ¹⁸ Preventive measures against mosquito bites should be followed in order to avoid leishmanial infections.

Most agents of endemic mycoses are thought to enter the pulmonary tract after inhalation of infective spores. In areas endemic for Penicillium marneffei (southeast Asia, Southern China) and Coccidioides immitis (south-west parts of the USA, parts of Central and South America), increased exposure to dust or soil should be avoided (e.g. construction sites, agriculture, garden work, excavations, storms). Histoplasma capsulatum is prevalent worldwide in soil contaminated with bird and bat droppings. Exposure might happen during eco or adventure tourism and should be avoided by HIV-infected persons. ⁵

Many developing areas have high rates of tuberculosis. HIV-infected individuals should avoid risk areas such as hospitals, prisons or homeless-shelters or wear adequate facemasks.

High Altitude

The term ‘altitude illness’ describes those medical conditions directly attributed to hypobaric hypoxia. Rapid ascent to altitudes above 2500 m often results in the syndrome known as acute mountain sickness. The principal symptoms are headache, nausea, vomiting, anorexia, fatigue, dizziness and sleep disturbance. ²⁵ Acetazolamide is an acceptable altitude sickness prophylactic medication for those travellers visiting areas over 2500 m above sea level. ²⁵ Allergic reactions to acetazolamide are extremely rare, but the drug is related to sulphonamides and should not be used by sulpha-allergic persons. ²⁶ Acetazolamide may be used with caution in HIV-infected patients since side-effects related to trimethoprim-sulphamethoxazole has been noted in 10% of patients without HIV infection and about 50% of patients with HIV. ²⁷

Travel Restrictions

Although contentious as a measure of health policy is not recommended by the WHO, more than 150 countries have adopted entry restrictions for travellers infected with HIV. It's generally well known that HIV-infected people cannot visit the USA except in very special circumstances. But other countries also place restrictions on either temporary or long-term visits by individuals with HIV. The most reliable way of finding out if a country restricts entry by people with HIV is to call the embassy or consulate. ⁵

Conclusions

In most instances international travel is feasible for HIV-infected persons, however pre-travel preparation of travellers with HIV infection needs to be carefully planned and executed, including vaccination, prophylactic medications and advice regarding safe food, drink, conduct and lifestyle behaviour. HIV-infected patients should be more aware of the necessity for medical counsel prior to travel. It is hoped that this review can lead to a closer collaboration between HIV and travel health clinics.