Kevin C. Kain

Atovaquone-Proguanil versus Mefloquine for Malaria Prophylaxis in Nonimmune Travelers: Results from a Randomized, Double-Blind Study

Concerns about the tolerability of mefloquine highlight the need for new drugs to prevent malaria. Atovaquone-proguanil (Malarone; GlaxoSmithKline) was safe and effective for prevention of falciparum malaria in lifelong residents of malaria-endemic countries, but experience in nonimmune people is limited. In a randomized, double-blind study, nonimmune travelers received malaria prophylaxis with atovaquone-proguanil (493 subjects) or mefloquine (483 subjects). Information about adverse events (AEs) and potential episodes of malaria was obtained 7, 28, and 60 days after travel. AEs were reported by an equivalent proportion of subjects who had received atovaquone-proguanil or mefloquine (71.4% versus 67.3%; difference, 4.1%; 95% confidence interval, -1.71 to 9.9). Subjects who received atovaquone-proguanil had fewer treatment-related neuropsychiatric AEs (14% versus 29%; P=.001), fewer AEs of moderate or severe intensity (10% versus 19%; P=.001), and fewer AEs that caused prophylaxis to be discontinued (1.2% versus 5.0%; P=.001), compared with subjects who received melfoquine. No confirmed diagnoses of malaria occurred in either group. Atovaquone-proguanil was better tolerated than was mefloquine, and it was similarly effective for malaria prophylaxis in nonimmune travelers.

Atovaquone-proguanil versus chloroquine-proguanil for malaria prophylaxis in non-immune travellers: a randomised, double-blind study

BACKGROUND Chloroquine plus proguanil is widely used for malaria chemoprophylaxis despite low effectiveness in areas where multidrug-resistant malaria occurs. Studies have shown that atovaquone and proguanil hydrochloride is safe and effective for prevention of falciparum malaria in lifelong residents of malaria-endemic countries, but little is known about non-immune travellers. METHODS In a double-blind equivalence trial, 1083 participants travelling to a malaria-endemic area were randomly assigned to two treatment groups: atovaquone-proguanil plus placebos for chloroquine and proguanil, or chloroquine, proguanil, and placebo for atovaquone-proguanil. Follow-up was by telephone 7 and 60 days after travel and at a clinic at 28 days. Serum samples were tested for antibodies to a malaria circumsporozoite protein. Blood and serum samples of participants with a potential malaria diagnosis were tested in a reference laboratory. FINDINGS 7 days after travel, at least one adverse event was reported by 311 (61%) of 511 participants who received atovaquone-proguanil and 329 (64%) of 511 who received chloroquine-proguanil. People receiving atovaquone-proguanil had a lower frequency of treatment-related gastrointestinal adverse events (59 [12%] vs 100 [20%], p=0.001), and of treatment-related adverse events of moderate or severe intensity (37 [7%] vs 56 [11%], p=0.05). There were fewer treatment-related adverse events that caused prophylaxis to be discontinued in the atovaquone-proguanil group than in the chloroquine-proguanil group (one [0.2%] vs ten [2%], p=0.015). INTERPRETATION Overall the two preparations were similarly tolerated. However, significantly fewer adverse gastrointestinal events were observed in the atovaquone-proguanil group in than in the chloroquine-proguanil group.

Plasmodium falciparum malaria in Laos: chloroquine treatment outcome and predictive value of molecular markers.

A 28-day treatment trial was undertaken, to determine the efficacy of chloroquine in Laos and to assess the predictive value of molecular markers (cg2, pfmdr1, and pfcrt) that were previously linked to chloroquine resistance. In total, 522 febrile patients were screened for falciparum malaria by rapid diagnostic assays. Of 81 patients (15.5% prevalence) who were positive by the assays and microscopy, 48 were eligible to participate in the 28-day trial. Nine patients defaulted. Chloroquine cured 54% (95% confidence interval, 45.8-61.8) of falciparum-infected patients. Of 18 (46%) patients with treatment failure, 13 (72%) experienced high-grade resistance. Polymorphisms in cg2 and the N86Y mutation in PfMDR1 were not predictive of treatment outcome. A mutation in PfCRT (K76T) was perfectly associated with in vivo chloroquine resistance. However, K76T was also present in in vivo-sensitive isolates, which suggests that the presence of this mutation was necessary, but not sufficient, to predict in vivo outcome in this cohort.

Malaria chemoprophylaxis in the age of drug resistance. I. Currently recommended drug regimens

As international travel becomes increasingly common and resistance to antimalarial drugs escalates, a growing number of travelers are at risk for contracting malaria. Parasite resistance to chloroquine and proguanil and real or perceived intolerance among patients to standard prophylactic agents such as mefloquine have highlighted the need for new antimalarial drugs. Promising new regimens include atovaquone and proguanil, in combination; primaquine; and a related 8-aminoquinoline, tafenoquine. These agents are active against the liver stage of the malaria parasite and therefore can be discontinued shortly after the traveler leaves an area where malaria is endemic, which encourages adherence to the treatment regimen. Part 1 of this series reviews currently recommended chemoprophylactic drug regimens, and part 2 will focus on 8-aminoquinoline drugs.

Advances in malaria diagnosis

Malaria is a leading cause of mortality worldwide and accurate diagnostic testing for malaria can potentially save an estimated 100,000 lives annually. New technologies have the potential to circumvent limitations of the traditional diagnostic method, light microscopy, which is labor intensive and requires considerable technician expertise. Immunochromatographic tests, which are easy to use in field conditions and relatively inexpensive, offer a potential solution to the problem of malaria overtreatment in resource-poor endemic countries. Assays based on the PCR are highly sensitive, can be used for unambiguous species identification and, thus, may increasingly complement or even replace light microscopy in developed countries. Experimental diagnostics using flow cytometry and mass spectrometry are currently under investigation for high-throughput screening.

Travel Patterns and Risk Behavior in Solid Organ Transplant Recipients

BACKGROUND International travel is associated with an increased risk of enteric, vector-borne and bloodborne infections. The risk of acquiring travel-related illness is higher in those who are immunocompromised. However, little is known about travel practices and risk behaviors in transplant recipients who travel. We herein profile transplant recipients who travel, and characterize their pre-travel precautions, travel activities, burden of illness, and exposure history. METHODS With the use of a standardized and validated questionnaire, patients attending a transplant clinic were surveyed regarding recent travel and risk behaviors. RESULTS Of 267 transplant recipients who participated, 95 (36%) indicated that they had recently traveled outside Canada and the USA. Their mean age was 49.9 years, 54% were male, and 54% were born outside Canada. Eighty-six percent of travelers were receiving at least two immunosuppressive drugs at the time of their trip. Sixty-six percent of travelers sought pre-travel advice, primarily from their transplant physician. Sixty-three percent traveled to areas where hepatitis A is endemic, but only 5% had received hepatitis A immunization. Fifty percent traveled to dengue- and malaria-endemic areas, but,25% adhered to mosquito prevention measures. Ten percent reported behaviors that exposed them to blood or body fluids, including injections, body piercing, and casual sexual activity. CONCLUSIONS Solid organ transplant recipients represent a unique group of compromised travelers; however, few were adequately protected against travel-associated enteric, vector-borne and bloodborne pathogens.

Malaria Chemoprophylaxis in the Age of Drug Resistance. II. Drugs That May Be Available in the Future

All current regimens of malaria chemoprophylaxis have serious drawbacks as a result of either suboptimal efficacy, difficulty with medication compliance, or adverse events. Two 8-aminoquinolines may be approaching registration, with primaquine having completed its prophylactic field testing and tafenoquine having begun advanced field testing at the end of 2000. Primaquine has long been used for management of relapses of malaria, but in the past decade, it has been reexamined for use in malaria prevention in order to stop infection in the liver. In field trials performed in Indonesia and Colombia, the efficacy of primaquine for malaria prevention was approximately 90%, compared with that of placebo. Because of its short half-life, primaquine requires daily administration. For adults, the prevention regimen is 30 mg base daily (0.5 mg base/kg/day), and it can probably be discontinued soon after departure from an area where malaria is endemic. To kill parasites that already exist in the liver, terminal prophylaxis is given after exposure to relapses of malaria infection; for adults, such prophylaxis usually consists of 15 mg base (0.3 mg base/kg/day) given daily for 2 weeks. Primaquine-induced gastrointestinal disturbances can be minimized if the drug is taken with food. Neither primaquine nor tafenoquine should be given to persons with glucose-6-phosphate dehydrogenase deficiency, to avoid the development of potentially severe drug-induced hemolysis. Tafenoquine is an analogue of primaquine that is more potent than the parent drug. Field trials in Kenya, Ghana, Gabon, and Southeast Asia have demonstrated an efficacy rate of approximately 90% for tafenoquine. Its long half-life allows for infrequent dosing (currently tested at 200 mg base/week), and its effect on parasites at the liver stage may allow for drug discontinuation at the time of departure from the area of endemicity.

Atovaquone/proguanil for the prophylaxis and treatment of malaria

Increases in international travel and escalating drug resistance have resulted in a growing number of travelers at risk of contracting malaria. Drug resistance and intolerance to standard agents such as chloroquine, sulfadoxine/pyrimethamine and mefloquine has highlighted the need for new antimalarials. The recently licensed fixed combination of atovaquone and proguanil hydrochloride (Malarone™) is a promising new agent to prevent and treat Plasmodium falciparum malaria. Randomized controlled trials have shown that atovaquone/proguanil is well tolerated and efficacious for the prevention and treatment of drug-resistant P. falciparum malaria. Atovaquone/proguanil is active against the liver stage of P. falciparum malaria parasites and when used as a prophylactic agent it can be discontinued shortly after leaving malaria-endemic areas, offering a clear advantage for drug adherence.

Imported Plasmodium vivax Malaria ex Pakistan

BACKGROUND According to WHO, 1.5 million cases of malaria are reported annually in Pakistan. Malaria distribution in Pakistan is heterogeneous, and some areas, including Punjab, are considered at low risk for malaria. The aim of this study is to describe the trend of imported malaria cases from Pakistan reported to the international surveillance systems from 2005 to 2012. METHODS Clinics reporting malaria cases acquired after a stay in Pakistan between January 1, 2005, and December 31, 2012, were identified from the GeoSentinel (http://www.geosentinel.org) and EuroTravNet (http://www.Eurotravnet.eu) networks. Demographic and travel-related information was retrieved from the database and further information such as areas of destination within Pakistan was obtained directly from the reporting sites. Standard linear regression models were used to assess the statistical significance of the time trend. RESULTS From January 2005 to December 2012, a total of 63 cases of malaria acquired in Pakistan were retrieved in six countries over three continents. A statistically significant increasing trend in imported Plasmodium vivax malaria cases acquired in Pakistan, particularly for those exposed in Punjab, was observed over time (p = 0.006). CONCLUSIONS Our observation may herald a variation in malaria incidence in the Punjab province of Pakistan. This is in contrast with the previously described decreasing incidence of malaria in travelers to the Indian subcontinent, and with reports that describe Punjab as a low risk area for malaria. Nevertheless, this event is considered plausible by international organizations. This has potential implications for changes in chemoprophylaxis options and reinforces the need for increased surveillance, also considering the risk of introduction of autochthonous P. vivax malaria in areas where competent vectors are present, such as Europe.

Atovaquone/Proguanil: The Need for Family Protection

An increasing number of families, including children and the elderly, are seeking more adventurous travel in exotic parts of the world. Holiday destinations now include once-remote regions such as subSaharan Africa and New Guinea. This increase in visits to tropical and subtropical regions, combined with widespread chloroquine-resistant malaria, now places millions of Western travelers at risk of infection annually. At least 30,000 travelers from industrialized countries are reported to contract malaria each year and approximately 1 in 100 travelers who acquire Plasmodium falciparum malaria will die.