Chapter 5.4 – Malaria issues in special hosts -Travellers with co-morbidities: Canadian recommendations for the prevention and treatment of malaria

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An Advisory Committee Statement (ACS) from the
Committee to Advise on Tropical Medicine and Travel (CATMAT)

Preamble

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

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

Chapter 5: Malaria issues in special hosts

5.4 Prevention in special host — Travellers with co-morbidities

The prevention, diagnosis and management of malaria in travellers with underlying medical conditions present a number of challenges. Deleterious interactions between malaria and underlying conditions may result in increased susceptibility to and severity of malaria or risk of complications of the underlying condition. Drug interactions with chronic-use medications must be considered when prescribing malaria chemoprophylaxis or treatment. Some underlying health conditions may be exacerbated by or preclude the use of one or more antimalarial medications.

The potential for adverse drug interactions should always be considered when recommending malaria chemoprophylaxis. A drug interaction check should be undertaken routinely unless the travellers’ medications are known to be safe with the proposed antimalarial agent.

Immunocompromised hosts

i. HIV/AIDS: There is a significant and complex interaction between human immunodeficiency virus (HIV) and P. falciparum. Acute malaria stimulates HIV-1 replication, resulting in increased viral loads that may hasten disease progression^{Reference 1}, ^{Reference 2} and increase transmission risk. HIV infection impairs immune responses to malaria and increases both the incidence and severity of malaria^{Reference 2}, ^{Reference 3}. HIV infection may increase the risk of malaria treatment failure^{Reference 4} with risk increasing as CD4 counts decline^{Reference 5}, ^{Reference 6}, ^{Reference 7}. Women who are co-infected with HIV and malaria may have a higher risk of mother-to-child HIV transmission as well as an increased risk of congenital malaria^{Reference 8}, ^{Reference 9}, ^{Reference 10}.

The potential for drug interactions between antimalarial and antiretroviral agents must be considered whenever an antimalarial prophylaxis or treatment is prescribed to an HIV-infected person on antiretroviral therapy. Protease inhibitors and non-nucleoside reverse transcriptase inhibitors may interact with antimalarials, resulting in toxicity or reduced effectiveness of either drug^{Reference 11}. Table 1 summarizes general antiretroviral and antimalarial drug interactions. Despite the limited information available, it is recommended that specific drug interactions be reviewed whenever antimalarials are prescribed for a traveller taking antiretroviral compounds.

Table 5.4.1: General antiretroviral and antimalarial drug interactions (11)

Drug	Summary of interactions
Chloroquine	No documented significant interactions Ritonavir: potential increase in chloroquine levels
Mefloquine	Non-nucleoside reverse transcriptase inhibitors (NNRTIs):  may decrease mefloquine levels Protease inhibitors (PIs): possible decrease in mefloquine or PI levels
Doxycycline	No interactions with NNRTIs or PIs ddI – avoid use with tablets / oral suspension. (Videx EC capsules: no interaction)
Atovaquone - proguanil	Azidothymidine (AZT): increased AZT levels, routine dose adjustment not required NNRTIs and PIs: avoid co-administration due to risk of sub therapeutic atovaquone levels

In addition to assessing for drug interactions, consideration must also be given to the risk of overlapping adverse effect profiles^{Reference 11}. Consultation with a travel or tropical medicine expert in conjunction with the traveller’s HIV specialist is recommended.

ii. Asplenia: Asplenia increases the risk, magnitude and duration of parasitemia, even among partially immune individuals in malaria-endemic countries^{Reference 12}, and severe and fatal malaria has been reported in travellers with asplenia^{Reference 13}. Standby self-treatment should be considered in addition to prophylactic measures if remote regions are being visited and/or access to care is limited (see Chapter 5.3) including section on stand-by emergency treatment). Fever in an asplenic individual may represent malaria or infection with an encapsulated bacterial organism, so antibacterial standby treatment should also be discussed/provided ^{Reference 14}. Given the risk of postsplenectomy bacterial sepsis, use of doxycycline for malarial prophylaxis may be preferred over other options due to its antibacterial activity^{Reference 15}.

iii. Other immunosuppressive conditions: There is limited information about the natural history of malaria in individuals with other immunocompromising conditions and treatments, such as biologic agents. The severity and mortality of malaria may be increased and therefore immune compromised travellers should receive extra attention directed at securing optimal adherence to both personal protective measures against arthropod exposure and malaria chemoprophylaxis. The potential for adverse drug interactions must be considered when prescribing malaria chemoprophylactic agents to travellers using immunosuppressive medications. The major interactions between antimalarials and anti-rejection drugs are listed in Table 2. Collaboration between transplant specialists and travel medicine prescribers and, in some cases, a pre-travel trial with monitoring of drug levels, may be beneficial to optimize malaria chemoprophylaxis for these patients.

Table 5.4.2: Potential interactions between anti-rejection drugs and antimalarials

Antimalarial	Antirejection agent	Potential effect
Chloroquine	Tacrolimus Cyclosporine	Prolonged QT Increased cyclo levels
Mefloquine	Cyclosporine Tacrolimus	Prolonged QT Prolonged QT
Doxycycline	Mycophenolate	Decreased myco levels
Atovaquone	No reported interactions to date

Other conditions

i. Cardiovascular: Mefloquine has not been confirmed to be linked to arrhythmias when used for prophylaxis in a small research study^{Reference 16}, although aberrant atrioventricular conduction was reported in a case study^{Reference 17}. There are reports of mefloquine, doxycycline and proguanil potentiating warfarin, resulting in abnormal coagulation and sometimes bleeding^{Reference 16}, ^{Reference 18}, ^{Reference 19}, ^{Reference 20}, ^{Reference 21}. If these medications are used (including proguanil as a component of Malarone®), a medication trial should be done several weeks in advance of travel and serial testing of the International Normalized Ratio should be done to allow adjustment of the anticoagulant dose both before and after travel.

ii. Neurologic disorders: Seizure disorders may be exacerbated by chloroquine and mefloquine, so alternative agents should be used. There is no evidence that febrile seizures in children are a contraindication for these drugs. Concurrent use of anticonvulsant drugs that induce hepatic microsomal enzymes (e.g., barbiturates, phenytoin, carbamazepine) may decrease serum levels and half-life of doxycycline, and may require dosage adjustment^{Reference 21} (see Chapter 8).

Myasthenia gravis: Acute infections, including malaria, may trigger exacerbations of myasthenia gravis; therefore optimal malaria prevention through adherence to chemoprophylaxis and effective use of insect personal protective measures should be reinforced. Chloroquine, mefloquine and doxycycline have all been associated with worsening of myasthenic symptoms and should be avoided although doxycycline has less frequently been associated with worsening myasthenic symptoms compared to chloroquine and mefloquine and a trial of therapy prior to travel may be considered in stable patients, particularly for those with only ophthalmologic symptoms. Although atovaquone-proguanil has not been linked with worsening of myasthenic symptoms, proguanil monotherapy has been reported to worsen symptoms^{Reference 22} and a trial of therapy prior to travel would be prudent. Both proguanil and doxycycline have the benefit of a short half-life, compared to other prophylactic choices, thus potentially limiting the duration of worsened symptoms compared to long acting agents. Primaquine has not been associated with myasthenic symptoms; therefore, it may be an option for prophylaxis of P. falciparum infection (after ruling out G6PD deficiency) in myasthenic travellers who are unable to tolerate doxycycline and atovaquone-proguanil.

If an acute episode of malaria occurs, treatment options may be limited, and it may be difficult to determine if deterioration in myasthenic symptoms is due to the effects of acute malaria or malaria treatment. Quinine has been reported to cause a myasthenia-like syndrome^{Reference 23} and deterioration in patients with myasthenia^{Reference 24}. Lumefantrine and the artemesinin derivatives have not been reported to trigger or worsen myasthenic symptoms but there are also no reports of use of these agents in myasthenic patients. Because of the risk of severe decompensation with respiratory compromise, travellers with active myasthenia gravis should avoid travelling to areas where tertiary care may be difficult to access in a timely manner and should ensure they carry adequate medical evacuation insurance.

iii. Psychiatric disorders: Dose related neuropsychiatric adverse effects are well recognized with mefloquine and to a lesser extent with chloroquine^{Reference 25}, ^{Reference 26}. Predisposing factors for possible significant adverse neuropsychiatric events include: female gender, low body mass index, prior history of adverse neuropsychiatric reactions to mefloquine, and previous significant psychiatric diagnoses^{Reference 27}. Although the link between mefloquine and serious mental reactions has not been clearly established, mefloquine should not be prescribed for travellers before completing a careful assessment of history of depression, generalized anxiety disorder or psychosis^{Reference 28}, ^{Reference 29}. There are no data demonstrating that attention deficit disorder increases the risk of neuropsychiatric side effects; however, it is prudent to ensure that psychiatric conditions such as those noted above do not co-exist^{Reference 30}.

iv. Hepatic or renal dysfunction: Moderate to severe hepatic or renal dysfunction may result in significant alteration in antimalarial medication levels. If the course of action is unclear after review of a standard reference, consultation with a travel/tropical medicine expert is recommended. Table 3 outlines antimalarial drug considerations for individuals with renal or hepatic disease.

Table 5.4.3: Antimalarial Drug considerations for individuals with renal or hepatic disease (31–35)

Drug	Renal	Hepatic	Recommendations
Chloroquine	95% excreted in urine	Partial hepatic metabolism	Caution for use in hepatic impairment, (dose adjustment may be required) and in presence of concurrent use of hepatotoxic agents. Caution for use in renal impairment – dosage adjustment may be required.
Mefloquine	9% excreted unchanged in urine	Metabolized in liver (CYP 3A4) and excreted predominantly in bile and feces	Caution for use in hepatic impairment. No dose adjustments required for renal failure or dialysis.
Doxycycline	30-50% excreted unchanged, does not accumulate in renal insufficiency	Partial hepatic metabolism – prolonged half- life may occur with significant hepatic impairment.	No dose adjustment in renal failure or dialysis. Dose adjustment may be required for hepatic disease. Avoid in severe liver dysfunction.
Proguanil	< 40% excreted unchanged in urine	Partial hepatic metabolism of proguanil (CYP 2C19).  Metabolites excreted in urine	No dose change for mild to moderate renal impairment.  Contraindicated if creatinine clearance is < 30 mls. / min due to potential drug accumulation. No change for mild to moderate hepatic impairment.  Not studied in patients with severe hepatic impairment – use with caution.
Atovaquone	Minimal	> 90% Excreted unchanged in feces

v. Miscellaneous conditions:

Psoriasis: Antimalarials, particularly chloroquine and hydroxychloroquine, have been reported  to trigger acute flares of psoriasis; however there is no consensus on whether this constitutes a contraindication for the use of these agents^{Reference 36}, ^{Reference 37}. When making recommendations for malaria chemoprophylaxis in the presence of psoriasis, chloroquine should generally be avoided and alternative agents recommended. There is insufficient evidence to consider psoriasis an absolute contraindication to the use of chloroquine, however, if chloroquine is chosen, travellers with psoriasis should be made aware of the potential risk of exacerbation. The risk of exacerbation of psoriasis with use of mefloquine, atovaquone/ proguanil and doxycycline is not substantiated based on current literature.

Glucose-6-phosphate dehydrogenase deficiency (G6PD): While G6PD deficiency may impart a degree of resistance to malaria infection, this is not absolute and effective malaria prevention is important. Use of primaquine is contraindicated in the presence of G6PD deficiency due to high risk of hemolysis, which can be life threatening. Chloroquine is considered contraindicated by the manufacturer in the presence of G6PD deficiency, although significant hemolysis is unlikely at prophylactic doses. Hemolysis is not a concern for use of other antimalarials when used in prophylactic doses.

Porphyria: With the exception of atovaquone proguanil, all of the first line malaria chemoprophylactic agents are considered possibly porphyrinogenic and are recommended for use with precaution and only if no safer alternative exists. Atovaquone proguanil is considered “probably not porphyrinogenic” and may be used without special precautions^{Reference 38}. Evidence for safety of doxycycline in porphyria is conflicting^{Reference 38}.

Table 5.4.4: Evidence-based medicine recommendations

Recommendations	EBM rating
Individuals who are immunosuppressed or have other co-morbidities should consult with a travel medicine or infectious disease expert in conjunction with the principal physician for their underlying condition prior to travelReference 39.	B III
Potential drug interactions and overlapping toxicities warrant careful review before antimalarial drugs are prescribed for individuals with chronic medical conditions, including HIV infectionReference 12.	A I
HIV-infected individuals who are pregnant or have advanced immune suppression should be encouraged to choose non malaria endemic locations or defer travel until after pregnancy or restoration of immune function.	BIII
Standby antimalarial therapy should be provided to asplenic travellers who may experience delays in accessing appropriate care for febrile illness.	AII
A pre-travel trial with INR testing should be done if mefloquine, doxycycline or proguanil (including atovaquone-proguanil) are to be used in individuals taking warfarinReference 18, Reference 19, Reference 20, Reference 21.	AII
Chloroquine and mefloquine should be avoided in the presence of a chronic seizure disorder.	EII
Chloroquine and mefloquine should be avoided in travellers with myasthenia gravis.	EIII
Mental health history should be carefully reviewed prior to recommending use of mefloquine to ensure that psychotic, depressive or anxiety disorders are absentReference 28.	AI
Travellers with psoriasis should be aware of the potential risk of exacerbation of psoriasis with malaria chemoprophylaxis.	BIII
Mefloquine, doxycycline and atovaquone-proguanil should be preferred over chloroquine for use in patients with underlying psoriasis.	BIII
Primaquine should not be used as chemoprophylaxis in the presence of G6PD deficiency.	EII
Atovaquone-proguanil may be the preferred choice for malaria prophylaxis in the presence of porphyria.	BIII
Abbreviation: EBM, evidence-based medicine; PPM, personal protective measures. Note: For a description of the categories and quality of evidence of the recommendations, see Appendix IV.

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