Efficacy and safety of tafenoquine for malaria chemoprophylaxis (1998-2020): A systematic review and meta-analysis.

BACKGROUND: In 2018, tafenoquine was approved for malaria chemoprophylaxis. We evaluated all available data on the safety and efficacy of tafenoquine chemoprophylaxis. METHODS: This systematic review followed the PRISMA guidelines and was registered on PROSPERO (CRD42019123839). We searched PubMed, Embase, Scopus, CINAHL and Cochrane databases. Two authors (JDM, PS) screened all papers. RESULTS: We included 44 papers in the qualitative and 9 in the quantitative analyses. These 9 randomized, controlled trials included 2495 participants, aged 12-60 years with 27.3% women. Six studies were conducted in Plasmodium spp.-endemic regions; two were human infection studies. 200 mg weekly tafenoquine and higher dosages lead to a significant reduction of Plasmodium spp. infection compared to placebo and were comparable to 250 mg mefloquine weekly with a protective efficacy between 77.9 and 100% or a total risk ratio of 0.22 (95%-CI: 0.07-0.73; p = 0.013) in favour of tafenoquine. Adverse events (AE) were comparable in frequency and severity between tafenoquine and comparator arms. One study reported significantly more gastrointestinal events in tafenoquine users (p ≤ 0.001). Evidence of increased, reversible, asymptomatic vortex keratopathy in subjects with prolonged tafenoquine exposures was found. A single, serious event of decreased macular sensitivity occurred. CONCLUSION: This systematic review and meta-analysis of trials of G6PD-normal adults show that weekly tafenoquine 200 mg is well tolerated and effective as malaria chemoprophylaxis focusing primarily on Plasmodium falciparum but also on Plasmodium vivax. Our safety analysis is limited by heterogenous methods of adverse events reporting. Further research is indicated on the use of tafenoquine in diverse traveller populations.

Imported Malaria in Countries where Malaria Is Not Endemic: a Comparison of Semi-immune and Nonimmune Travelers.

The continuous increase in long-distance travel and recent large migratory movements have changed the epidemiological characteristics of imported malaria in countries where malaria is not endemic (here termed non-malaria-endemic countries). While malaria was primarily imported to nonendemic countries by returning travelers, the proportion of immigrants from malaria-endemic regions and travelers visiting friends and relatives (VFRs) in malaria-endemic countries has continued to increase. VFRs and immigrants from malaria-endemic countries now make up the majority of malaria patients in many nonendemic countries. Importantly, this group is characterized by various degrees of semi-immunity to malaria, resulting from repeated exposure to infection and a gradual decline of protection as a result of prolonged residence in non-malaria-endemic regions. Most studies indicate an effect of naturally acquired immunity in VFRs, leading to differences in the parasitological features, clinical manifestation, and odds for severe malaria and clinical complications between immune VFRs and nonimmune returning travelers. There are no valid data indicating evidence for differing algorithms for chemoprophylaxis or antimalarial treatment in semi-immune versus nonimmune malaria patients. So far, no robust biomarkers exist that properly reflect anti-parasite or clinical immunity. Until they are found, researchers should rigorously stratify their study results using surrogate markers, such as duration of time spent outside a malaria-endemic country.

Profile of illness in Syrian refugees: A GeoSentinel analysis, 2013 to 2015.

Screening of 488 Syrian unaccompanied minor refugees (< 18 years-old) in Berlin showed low prevalence of intestinal parasites (Giardia, 7%), positive schistosomiasis serology (1.4%) and absence of hepatitis B. Among 44 ill adult Syrian refugees examined at GeoSentinel clinics worldwide, cutaneous leishmaniasis affected one in three patients; other noteworthy infections were active tuberculosis (11%) and chronic hepatitis B or C (9%). These data can contribute to evidence-based guidelines for infectious disease screening of Syrian refugees.

Eye disorders reported with the use of mefloquine (Lariam(®)) chemoprophylaxis--A drug safety database analysis.

BACKGROUND: Between 80 and 90 million travellers visit malaria endemic areas annually and many require malaria chemoprophylaxis. The characterization of the risk and nature of eye disorders occurring during the use of malaria chemoprophylaxis is relevant for travel medicine advisors. METHODS: We did a database analysis on eye disorder adverse events reported for mefloquine (as Lariam®) using the F. Hoffmann-La Roche global drug safety database for the time frame February 1984 to January 18th, 2011. These adverse event reports were reviewed by a trained ophthalmologist. The analysis focused on 3 categories of eye disorders--Category 1: visual acuity; Category 2: anatomical parts of the eye and Category 3: neuro-ophthalmic events. To put our analysis in context, an extensive literature search on "mefloquine" and "eye disorders" was conducted. RESULTS: A total of 591 cases with 695 events assigned to the "Eye disorder" SOC in individuals exposed to mefloquine chemoprophylaxis were reported. The highest proportion of events (n = 493, 70.9%) was in Category 1: visual acuity (mainly visual impairment and blurred vision), followed by Category 3: neuro-ophthalmic events (n = 124, 17.8%). The majority of visual adverse events were non-serious but 37.7% (n = 223) of cases were classified as serious. Nine events of maculopathy were reported and 48 cases with 53 events described symptoms of optic neuropathy. CONCLUSIONS: Mefloquine, like other anti-malarials, may be associated with eye disorders. Prescribers of anti-malarials should inform travellers regarding the risk of potential ocular side effects. Users of chemoprophylaxis who experience visual disorders should be referred to an ophthalmologist.

Mefloquine at the crossroads? Implications for malaria chemoprophylaxis in Europe.

Since its introduction to the market in 1985, mefloquine has been used for malaria chemoprophylaxis by more than 35 million travellers. In Europe, in 2014, the European Medicines Agency (EMA) issued recommendations on strengthened warnings, prescribing checklists and updates to the product information of mefloquine. Some malaria prevention advisors question the scientific basis for the restrictions and suggest that this cost-effective, anti-malarial drug will be displaced as a first-line anti-malaria medication with the result that vulnerable groups such as VFR and long-term travellers, pregnant travellers and young children are left without a suitable alternative chemoprophylaxis. This commentary looks at the current position of mefloquine prescribing and the rationale of the new EMA recommendations and restrictions. It also describes the new recommendations for malaria prophylaxis that have been adapted by Switzerland, Germany, Austria and Italy where chemoprophylaxis use is restricted to high-risk malaria-endemic areas.

Comparative benefit of malaria chemoprophylaxis modelled in United Kingdom travellers.

BACKGROUND: Chemoprophylaxis against falciparum malaria is recommended for travellers from non-endemic countries to malarious destinations, but debate continues on benefit, especially with regard to mefloquine. Quantification of benefit for travellers from the United Kingdom (UK) was modelled to assist clinical and public health decision making. METHODS: The model was constructed utilising: World Tourism Organization data showing total number of arrivals from the UK in countries with moderate or high malaria risk; data from a retrospective UK Clinical Practice Research Datalink (CPRD) drug utilisation study; additional information on chemoprophylaxis, case fatality and tolerability were derived from the travel medicine literature. Chemoprophylaxis with the following agents was considered: atovaquone-proguanil (AP), chloroquine with and without proguanil (C ± P), doxycycline (Dx), mefloquine (Mq). The model was validated for the most recent year with temporally matched datasets for UK travel destinations and imported malaria (2007) against UK Health Protection Agency data on imported malaria. RESULTS: The median (mean) duration of chemoprophylaxis for each agent in weeks (CPRD) was: AP 3.3 (3.5), C ± P 9 (12.1), Dx 8 (10.3), Mq 9 (12.3): the maximum duration of use of all regimens was 52 weeks. The model correctly predicted falciparum malaria deaths and gave a robust estimate of total cases--model: 5 deaths from 1118 cases; UK Health Protection Agency: 5 deaths from 1153 cases. The number needed to take chemoprophylaxis (NNP) to prevent a case of malaria considered against the 'background' reported incidence in non-users of chemoprophylaxis deemed in need of chemoprophylaxis was: C ± P 272, Dx 269, Mq 260, AP 252; the NNP to prevent a UK traveller malaria death was: C ± P 62613, Dx 61923, Mq 59973, AP 58059; increasing the 'background' rate by 50% yielded NNPs of: C ± P 176, Dx 175, Mq 171, AP 168. The impact of substituting atovaquone-proguanil for all mefloquine usage resulted in a 2.3% decrease in estimated infections. The number of travellers experiencing moderate adverse events (AE) or those requiring medical attention or drug withdrawal per case prevented is as follows: C ± P 170, Mq 146, Dx 114, AP 103. CONCLUSIONS: The model correctly predicted the number of malaria deaths, providing a robust and reliable estimate of the number of imported malaria cases in the UK, and giving a measure of benefit derived from chemoprophylaxis use against the likely adverse events generated. Overall numbers needed to prevent a malaria infection are comparable among the four options and are sensitive to changes in the background infection rates. Only a limited impact on the number of infections can be expected if Mq is substituted by AP.

Childhood vaccination associated adverse events by sex: a literature review.

BACKGROUND: Most approved medicines, including vaccines can be associated with adverse events. A vaccine adverse event is defined as any untoward medical occurrence which follows vaccination, but which does not necessarily have a causal relationship with the administration of the vaccine. METHODS: The objective of this structured literature review is to analyse the adverse events reported with vaccinations usually done during childhood and adolescence: human papilloma virus vaccine, hepatitis B vaccine and measles-mumps-rubella vaccine. We evaluated the vaccine literature on children and adolescents by sex. We searched the Cochrane Database, Medline (Pubmed) and Embase using predefined terms. RESULTS: Of the 417 publications retrieved from searches in the 3 databases, 89 papers (21%) were identified as potentially relevant to the review. On further scrutiny 41 of these satisfied the criteria for inclusion in the analysis. Serious adverse events related to vaccinations were rare. We found some possible sex related vaccine adverse events. Few trials however reported adverse events by age and sex and very few analyses evaluated the observed differences. CONCLUSIONS: Despite earlier calls for sex-specific analyses of clinical studies, we found that vaccine trials were rarely reported and published by sex. Prospectively collated vaccine safety data in children and adolescents should be analysed by age and sex, so that clinical trial results can form an evidence base for vaccine practice recommendations.

Antimalarial chemoprophylaxis and the risk of neuropsychiatric disorders.

BACKGROUND: Case reports and epidemiological studies have associated the use of mefloquine with neuropsychiatric adverse events. METHODS: We used the General Practice Research Database to conduct a follow-up study with a nested case-control analysis. We assessed the risk of developing first-time anxiety, stress-related disorders/psychosis, depression, epilepsy or peripheral neuropathies in patients using mefloquine, chloroquine and/or proguanil, or atovaquone/proguanil for malaria chemoprophylaxis, as compared to unexposed travelers. RESULTS: Compared to non-users of antimalarials, the adjusted odds ratio in the nested case-control analysis for users of mefloquine, chloroquine and/or proguanil, or atovaquone/proguanil were 0.71 (95% CI 0.56-0.90), 1.04 (95% CI 0.74-1.46), and 0.73 (95% CI 0.61-0.86) for anxiety or stress-related disorders combined, 0.54 (95% CI 0.41-0.71), 1.06 (95% CI 0.71-1.59), and 0.75 (95% CI 0.62-0.91) for depression, 0.69 (95% CI 0.35-1.36), 1.41 (95% CI 0.54-3.67), and 0.75 (95% CI 0.42-1.36) for epilepsy, and 1.22 (95% CI 0.50-2.99), 1.59 (95% CI 0.41-6.15), and 1.05 (95% CI 0.54-2.03) for neuropathies, respectively. The risk of all outcomes was higher in females than in males across all exposure categories. CONCLUSIONS: The risk of neuropsychiatric disorders was similar for users and for non-users of anti-malarial chemoprophylaxis, with evidence for elevated risks in some subgroups.

Pregnancy and fetal outcomes after exposure to mefloquine in the pre- and periconception period and during pregnancy.

BACKGROUND: Pregnant women who travel to malarious areas and their clinicians need data on the safety of malaria chemoprophylaxis. METHODS: The effect of exposure to mefloquine on pregnancy and offspring outcomes was evaluated using the F. Hoffmann-La Roche global drug safety database for the time frame 31 January 1986 through 26 October 2010. We investigated pregnancy and fetal outcomes in maternal, paternal, and both-parent exposure cases with a focus on congenital malformations and fetal loss. The main outcome measures were birth defect prevalence and types of malformations. RESULTS: A total of 2506 cases of mefloquine exposure during pregnancy or in the pre- and periconception period were evaluated. Most cases were maternal prospective (outcome of the pregnancy unknown at the time of reporting; n = 2246 [89.6%]) followed by maternal retrospective cases (outcome of the pregnancy known at the time of reporting; n = 227 [9.0%]), with small numbers of paternal and both-parent exposure cases. Of the total 2246 mefloquine maternal prospective exposures (95.2%), 2139 occurred before conception and/or during the first trimester. Of 1383 maternal prospective cases with known outcome, 978 (70.7%) resulted in delivery, 405 (29.3%) resulted in abortion (112 spontaneous, 293 therapeutic), and 43 resulted in birth defects, corresponding to a birth defect prevalence of 4.39% (43 of 978). Prospective cases overall showed no specific pattern of birth malformations. CONCLUSIONS: The drug safety database analysis of mefloquine exposure in pregnancy showed that the birth defect prevalence and fetal loss in maternal, prospectively monitored cases were comparable to background rates.

Use of mefloquine in children - a review of dosage, pharmacokinetics and tolerability data.

BACKGROUND: Use of anti-malarial medication in children is hampered by a paucity of dosage, pharmacokinetic and tolerability data. METHODS: Data on the use of mefloquine in children, particularly in young children weighing less than 20 kg, were reviewed using PubMed literature and reports on file. RESULTS: Chemoprophylaxis data: Two studies with a total of 170 children were found. A simulated mefloquine plasma profile showed that doses to achieve protective chemoprophylaxis blood concentration of mefloquine of approximately 620 ng/mL (or 1.67 µmol/L) in children should be at least 5 mg/kg. This simulated plasma profile in children corresponds to that seen in adult travellers using a weekly prophylaxis dose of 250 mg. This reinforces current practice of using weight-based dosage for children. Clearance per body weight is higher in older children. For children who travel to malaria risk areas tablets can be broken and crushed as required. It is necessary to disguise the bitter taste of the drug. Treatment data: Mefloquine treatment (alone or in combination) data are available for more than 6000 children of all age and weight categories. The stereoselectivity and pharmacokinetic profile of mefloquine in children is similar to that observed in adults. There is higher clearance in older children (aged 5-12 years) compared to younger children (aged 6-24 months). Mefloquine treatment is well tolerated in infants (5-12 kg) but vomiting is a problem at high doses. This led to the use of a "split dose" regimen with 15 mg/kg initially, followed 12 hours later by 10 mg/kg. Mefloquine 125 mg has been used as intermittent preventive treatment (IPT) and was found to be efficacious in reducing episodes of malaria in a moderate-transmission setting but vomiting was a problem in 8% of children aged 2-11 months. Mefloquine is also used as a component of artemisinin combination therapy (ACT) in small children. The combination artesunate plus mefloquine is a WHO approved first-line treatment for uncomplicated malaria in Africa. CONCLUSION: Currently available data provide a scientific basis for the use of mefloquine in small children in the chemoprophylaxis setting and as a part of treatment regimens for children living in endemic areas.

Travellers' malaria--'one shoe does not fit all'.

Travellers' malaria is an exciting topic. It is a field in flux with evolving options for chemoprophylaxis, self-diagnosis, self-treatment, risk/strategy analyses and surveillance. Ideologies vary and experts differ but debate is needed and can bring change. The launch of a new thematic series in the Malaria Journal--"Travellers' malaria"--creates an ideal forum to bring together research papers, reviews, opinion papers and commentaries, and will hopefully stimulate debate.

The position of mefloquine as a 21st century malaria chemoprophylaxis.

BACKGROUND: Malaria chemoprophylaxis prevents the occurrence of the symptoms of malaria. Travellers to high-risk Plasmodium falciparum endemic areas need an effective chemoprophylaxis. METHODS: A literature search to update the status of mefloquine as a malaria chemoprophylaxis. RESULTS: Except for clearly defined regions with multi-drug resistance, mefloquine is effective against the blood stages of all human malaria species, including the recently recognized fifth species, Plasmodium knowlesi. New data were found in the literature on the tolerability of mefloquine and the use of this medication by groups at high risk of malaria. DISCUSSION: Use of mefloquine for pregnant women in the second and third trimester is sanctioned by the WHO and some authorities (CDC) allow the use of mefloquine even in the first trimester. Inadvertent pregnancy while using mefloquine is not considered grounds for pregnancy termination. Mefloquine chemoprophylaxis is allowed during breast-feeding. Studies show that mefloquine is a good option for other high-risk groups, such as long-term travellers, VFR travellers and families with small children. Despite a negative media perception, large pharmaco-epidemiological studies have shown that serious adverse events are rare. A recent US evaluation of serious events (hospitalization data) found no association between mefloquine prescriptions and serious adverse events across a wide range of outcomes including mental disorders and diseases of the nervous system. As part of an in-depth analysis of mefloquine tolerability, a potential trend for increased propensity for neuropsychiatric adverse events in women was identified in a number of published clinical studies. This trend is corroborated by several cohort studies that identified female sex and low body weight as risk factors. CONCLUSION: The choice of anti-malarial drug should be an evidence-based decision that considers the profile of the individual traveller and the risk of malaria. Mefloquine is an important, first-line anti-malarial drug but it is crucial for prescribers to screen medical histories and inform mefloquine users of potential adverse events. Careful prescribing and observance of contraindications are essential. For some indications, there is currently no replacement for mefloquine available or in the pipeline.

Cost-effectiveness analysis of malaria chemoprophylaxis for travellers to West-Africa.

BACKGROUND: The importation of malaria to non-endemic countries remains a major cause of travel-related morbidity and a leading cause of travel-related hospitalizations. Currently they are three priority medications for malaria prophylaxis to West Africa: mefloquine, atovaquone/proguanil and doxycycline. We investigate the cost effectiveness of a partial reimbursement of the cheapest effective malaria chemoprophylaxis (mefloquine) for travellers to high risk areas of malaria transmission compared with the current situation of no reimbursement. METHODS: This study is a cost-effectiveness analysis based on malaria cases imported from West Africa to Switzerland from the perspective of the Swiss health system. We used a decision tree model and made a literature research on the components of travel related malaria. The main outcome measure was the cost effectiveness of malaria chemoprophylaxis reimbursement based on malaria and deaths averted. RESULTS: Using a program where travellers would be reimbursed for 80% of the cost of the cheapest malaria chemoprophylaxis is dominant (i.e. cost saving and more effective than the current situation) using the assumption that currently 68.7% of travellers to West Africa use malaria chemoprophylaxis. If the current usage of malaria chemoprophylaxis would be higher, 82.4%, the incremental cost per malaria case averted is € 2'302. The incremental cost of malaria death averted is € 191'833.The most important factors influencing the model were: the proportion of travellers using malaria chemoprophylaxis, the probability of contracting malaria without malaria chemoprophylaxis, the cost of the mefloquine regimen, the decrease in the number of travellers without malaria chemoprophylaxis in the reimbursement strategy. CONCLUSIONS: This study suggests that a reimbursement of 80% of the cost of the cheapest effective malaria chemoprophylaxis (mefloquine) for travellers from Switzerland to West Africa is highly effective in terms of malaria cases averted and is cost effective to the Swiss health system. These data are relevant to discussions about the cost effectiveness of malaria chemoprophylaxis reimbursement for vulnerable groups such as those visiting friends and relatives who have the highest risk of malaria, who are least likely to use chemoprophylaxis.

Malaria chemoprophylaxis: strategies for risk groups.

The risk of malaria for travelers varies from region to region and depends on the intensity of transmission, the duration of the stay in the area of endemicity, the style of travel, and the efficacy of preventive measures. The decision to recommend chemoprophylaxis to travelers to areas with a low risk of malarial infection is especially difficult because the risk of infection must be balanced with the risk of experiencing side effects. If the risk of side effects by far exceeds the risk of infection, the traveler needs information on measures against mosquito bites and advice on prompt diagnosis and self-treatment. The risk is difficult to quantify, and the absolute risk for travelers to most areas is not known, especially because the populations at risk are unknown. We propose here that the best approximation of the risk to the traveler to a specific area is to use the risk to the indigenous population as a guideline for the risk to the traveler, and we provide examples on how risk in the indigenous population can be used for the estimation of risk of malarial infection for travelers. Special groups are long-term visitors and residents, who often perceive risk differently, cease using chemoprophylaxis, and rely on self-diagnosis and treatment. For long-term visitors, the problem of fake drugs needs to be discussed. Strategies for chemoprophylaxis and self-treatment of pregnant women and small children are discussed. So far, malaria prophylaxis is recommended to prevent Plasmodium falciparum infections, and primaquine prophylaxis against persistent Plasmodium vivax and Plasmodium ovale infections in travelers is not recommended.