Ashley M Croft

Mefloquine to prevent malaria: a systematic review of trials.

Abstract Objective: To evaluate the research evidence on the efficacy and tolerability of mefloquine chemoprophylaxis. Search strategy: Any potentially relevant trial from the Cochrane Infectious Disease Groups register of controlled trials; systematic searches of Medline, Embase, Lilacs and Science Citation Index; scanning citations; and consulting drug companies and key investigators. We considered studies in all languages. Inclusion criteria: Trials carried out in non-immune adult travellers, and in non-travelling volunteers, where an attempt had been made to conduct a randomised comparison of mefloquine against placebo or against alternative standard prophylaxis. Results: 37 potentially eligible trials of mefloquine prophylaxis were identified, and 10 met the inclusion criteria. These 10 trials comprised a total of 2750 non-immune adult participants randomised to mefloquine or to a control. One placebo controlled trial examined malaria incidence directly and showed mefloquine to be highly effective in preventing malaria in an area of drug resistance. However, four placebo controlled trials showed that mefloquine was not well tolerated, and withdrawals were consistently higher in mefloquine treatment arms than in placebo arms (odds ratio 3.49 (95% confidence interval 1.42 to 8.56)). Five field trials compared mefloquine with other chemoprophylaxis. Mefloquine was no worse tolerated than other chemoprophylaxis, although there was possibly a trend towards higher withdrawals in mefloquine arms (odds ratio 1.33 (0.75 to 2.36)). Conclusion: One trial showed mefloquine to be effective in preventing malaria, but withdrawal rates, presumably from side effects, were high across most studies. This is likely to impair mefloquines effectiveness in general travellers, and it may therefore not be useful for routine prophylaxis. Mefloquine may be useful in specific situations such as for groups travelling to regions with a high risk of chloroquine resistant malaria and only limited access to effective medical care. Key messages We conducted a systematic review of the effectiveness of mefloquine in malaria chemoprophylaxis and found 10 randomised controlled trials of the drug in non-immune adult participants In placebo controlled trials rates of withdrawal were significantly higher from mefloquine treatment, suggesting that the effectiveness of chemoprophylaxis may be limited by low adherence Five field trials of mefloquine prophylaxis were conducted in non-immune participants, but all were young, fit soldiers, so that the findings of these field trials may not be generalisable to the normal population of general travellers National malaria prevention guidelines should be evidence based, and candidate antimalarial drugs should not be licensed for routine use in prophylaxis until field trials in general travellers of both sexes have confirmed the tolerability of the new regimen

Malaria: prevention in travellers

Definition: Malaria is caused by a protozoan infection of red blood cells with one of four species of the genus plasmodium: P falciparum , P vivax , P ovale , or P malariae .1 Clinically, malaria may present in different ways, but it is usually characterised by fever (which may be swinging), tachycardia, rigors, and sweating. Anaemia, hepatosplenomegaly, cerebral involvement, renal failure, and shock may occur. Incidence/prevalence: Each year there are 300–500 million clinical cases of malaria. About 40% of the worlds population is at risk of acquiring the disease. 2 3 Each year 25–30 million people from non-tropical countries visit areas in which malaria is endemic,4 of whom between 10 000 and 30 000 contract malaria.5 Aetiology/risk factors: Malaria is mainly a rural disease, requiring standing water nearby. It is transmitted by bites6 from infected female anopheline mosquitoes,7 mainly at dusk and during the night. 1 8 In cities, mosquito bites are usually from female culicene mosquitoes, which are not vectors of malaria.9 Malaria is resurgent in most tropical countries and the risk to travellers is increasing.10 Prognosis: Ninety per cent of travellers who contract malaria do not become ill until after they return home.5 “Imported malaria” is easily treated if diagnosed promptly, and it follows a serious course in only about 12% of people. 11 12 The most severe form of the disease is cerebral malaria, with a case fatality rate in adult travellers of 2-6%,3 mainly because of delays in diagnosis.5 Aims: To reduce the risk of infection; to prevent illness and death. Outcomes: Rates of malarial illness and death, and adverse effects of treatment. Proxy measures include number of mosquito bites and number of mosquitoes in indoor areas. We found limited evidence linking number of mosquito …

Adverse effects of the antimalaria drug, mefloquine: due to primary liver damage with secondary thyroid involvement?

BackgroundMefloquine is a clinically important antimalaria drug, which is often not well tolerated. We critically reviewed 516 published case reports of mefloquine adverse effects, to clarify the phenomenology of the harms associated with mefloquine, and to make recommendations for safer prescribing.PresentationWe postulate that many of the adverse effects of mefloquine are a post-hepatic syndrome caused by primary liver damage. In some users we believe that symptomatic thyroid disturbance occurs, either independently or as a secondary consequence of the hepatocellular injury. The mefloquine syndrome presents in a variety of ways including headache, gastrointestinal disturbances, nervousness, fatigue, disorders of sleep, mood, memory and concentration, and occasionally frank psychosis. Previous liver or thyroid disease, and concurrent insults to the liver (such as from alcohol, dehydration, an oral contraceptive pill, recreational drugs, and other liver-damaging drugs) may be related to the development of severe or prolonged adverse reactions to mefloquine.ImplicationsWe believe that people with active liver or thyroid disease should not take mefloquine, whereas those with fully resolved neuropsychiatric illness may do so safely. Mefloquine users should avoid alcohol, recreational drugs, hormonal contraception and co-medications known to cause liver damage or thyroid damage. With these caveats, we believe that mefloquine may be safely prescribed in pregnancy, and also to occupational groups who carry out safety-critical tasks.TestingMefloquines adverse effects need to be investigated through a multicentre cohort study, with small controlled studies testing specific elements of the hypothesis.

Malaria during a multinational military deployment: the comparative experience of the Italian, British and Australian Armed Forces in East Timor

Although their efficacy has been shown to be similar in south-east Asia, doxycycline was less effective than mefloquine for malaria chemoprophylaxis in East Timor. Lower adherence, higher incidence of adverse effects and reduced bioavailability of doxycycline may have been possible causes. Mefloquine seems therefore preferable in arduous and prolonged field conditions.

Exercise and life expectancy

1 Wen CP, Wai JP, Tsai MK, et al. Minimum amount of physical activity for reduced mortality and extended life expectancy: a prospective cohort study. Lancet 2011; 378: 1244–53. 2 Besser LM, Dannenberg AL. Walking to public transit: steps to help meet physical activity recommendations. Am J Preventive Med 2005; 29: 273–80. 3 Ewing R, Bartholomew K, Winkelman S, Walters J, Chen D. Growing cooler—the evidence on urban development and climate change. Washington, DC: Urban Land Institute, 2008. 4 Dumbaugh E. Designing communities to enhance the safety and mobility of older adults: a universal approach. J Planning Lit 2008; 23: 17–36. 5 Lake A, Townshead T. Obesogenic environments: exploring the built and food environments. Persp Public Health 2006; 126: 262–67. as prophet. In any event, neither episode occurred in the context of a randomised controlled trial. We contend, therefore, that the risk of mortality for everyone—prophets included—is 1·0 (1·0–1·0).

Tolerability of antimalaria drugs.

Sir—The multicenter randomized trial reported by Overbosch and colleagues [1] is important for 2 reasons. First, the study shows that when taken as malaria prophylaxis, mefloquine is not well tolerated by many travelers. Of the study participants randomized to receive mefloquine, 67.1% reported 1 adverse event, and, in 6% of mefloquine users, these events were severe (defined as requiring medical advice). The most common category of unwanted effects in the mefloquine treatment arm were neuropsychiatric adverse effects, which were reported by one-third of all mefloquine users [1]. This disturbing finding contradicts the advice in the most recent guidelines on malaria prevention for US travelers issued by the Centers for Disease Control and Prevention (CDC; Atlanta, Georgia); the guidelines state that “mefloquine is the drug of choice for chemoprophylaxis for most travelers [and] is well tolerated at prophylactic dosages” ([2], p. 1767). This assurance, which is plainly incorrect, was based on findings from uncontrolled studies of tourists and Peace Corps volunteers and from mefloquine trials that involved young, healthy soldiers. The CDC guidelines urgently need to be revised now that a randomized trial involving heterogeneous, nonimmune travelers has provided good evidence that mefloquine prophylaxis has the potential to cause harm. Second, the article by Overbosch and colleagues [1] shows that, although earlier studies of atovaquone-proguanil therapy given to lifelong residents of areas where malaria is endemic may indeed have demonstrated that, in those populations, this drug combination has a safety profile that is “similar to placebo” [3, 4], the same is not true of atovaquone-proguanil therapy for nonimmune Western travelers. Of the Overbosch study participants randomized to receive atovaquone-proguanil, 64.5% reported 1 adverse event [1]. If one categorizes headache as a neuropsychiatric adverse event, then neuropsychiatric effects are again the most common category of unwanted effects in users of atovaquone-proguanil, as they are in users of mefloquine. On a point of detail, Overbosch and colleagues refer to trial “subjects” and to “compliance” with appropriate chemoprophylaxis. These terms are obsolete. In modern scientific terminology, those who consent to take part in trials are “participants,” and those consumers who are offered therapy may or may not choose to “adhere” to it. If the therapy involves use of a new or relatively untried drug, they may be wise not to do so [5].

Helminths for induction of remission in inflammatory bowel disease

Summary data For those RCTs (e.g. crossover studies) where the only data avail-able is a summary measure of effect, along with a precision esti-mate, we will use the generic inverse variance method to analysethat data. Unit of analysis issues If any trials have multiple treatment groups, the ‘shared’ compar-ison group will be divided into the number of treatment groupsandcomparisonsbetweeneachtreatmentgroupandthesplitcom-parison group will be treated as independent comparisons. Dealing with missing data Wherethere ismissing data from any one of thefive key domainsin the included studies, we will contact trialists directly to obtainthis missing information.For all outcomes, in all studies, we will carry out analyses, as faras possible, on an intention-to-treat basis, i.e. we will attempt toinclude all participants randomised to each group in the analyses,andwewillanalyseallparticipantsinthegrouptowhichtheywereallocated, regardless of whether or not they received the allocatedintervention.For continuous data that are missing, we will estimate standarddeviations from other available data (e.g. standard errors), or elsewill impute them using methods suggested by Higgins 2011. Wewill make no assumptions about loss to follow up for continuousdata, and will base our analyses on those participants completingthe trial. We will perform a sensitivity analysis by calculating thetreatment effect of including and excluding the imputed data, tosee whether this alters the outcome of the analysis.We will investigate the effect of study withdrawals and exclusionsby conducting worst- versus best-case scenario analyses.If there is discrepancy between the number randomised and thenumber analysed in each treatment group, we will calculate andreport the percentage lost to follow up in each group. If studywithdrawals exceed 10% for any trial, we will assign the worstoutcome to those lost to follow up for dichotomous outcomes,and assess the impact of this sensitivity analysis against the resultsfor those completing the study. Where it is not possible to obtainmissing data, thiswillberecordedinthedataextraction formandreported in the ‘Risk of bias’ table. For included studies, we willnote levels of attrition. We will explore the impact of includingstudies with high levels of missing data in the overall assessmentof treatment effect, by using sensitivity analyses.