Sean Hewitt

Efficacy and safety of dihydroartemisinin-piperaquine (artekin) in Cambodian children and adults with uncomplicated falciparum malaria

The safety and efficacy of a novel combination of dihydroartemisinin (DHA) and piperaquine, Artekin (Holleykin Pharmaceuticals), were assessed in 106 patients (76 children and 30 adults) with uncomplicated falciparum malaria from 2 remote areas in Cambodia. Age-based doses were given at 0, 8, 24, and 32 h. Mean total DHA and piperaquine doses were 9.1 and 73.9 mg/kg, respectively, for children and 6.6 and 52.9 mg/kg for adults. All patients became aparasitemic within 72 h. Excluding the results for 1 child who died on day 4, there was a 96.9% 28-day cure rate (98.6% in children and 92.3% in adults). Patients who had recrudescent infection received low doses of Artekin. Side effects were reported by 22 patients (21%) but did not necessitate premature cessation of therapy. Although Artekin is a promising and inexpensive option for antimalarial therapy, further efficacy and pharmacokinetic studies are needed, especially for its use in children.

Comparison of three antigen detection methods for diagnosis and therapeutic monitoring of malaria: a field study from southern Vietnam

OBJECTIVES To compare the sensitivity, specificity and post‐treatment persistence of three commonly used rapid antigen detection methods.

Permethrin-treated chaddars and top-sheets: appropriate technology for protection against malaria in Afghanistan and other complex emergencies.

Insecticide-treated mosquito nets (ITN) provide excellent protection against malaria; however, they have a number of shortcomings that are particularly evident in politically unstable countries or countries at war: not everyone at risk can necessarily afford a net, nets may be difficult to obtain or import, nets may not be suitable for migrants or refugees sleeping under tents or plastic shelter. There is a need to develop cheaper, locally appropriate alternatives for the most impoverished and for victims of complex emergencies. Afghan women, in common with many Muslim peoples of Asia, wear a veil or wrap known as a chaddar to cover the head and upper body. This cloth doubles as a sheet at night, when they are used by both sexes. A randomized controlled trial was undertaken in which 10% of the families of an Afghan refugee camp (population 3950) in north-western Pakistan had their chaddars and top-sheets treated with permethrin insecticide at a dosage of 1 g/m2 while a further 10% had their chaddars treated with placebo formulation. Malaria episodes were recorded by passive case detection at the camps health centre. From August to November the odds of having a falciparum or vivax malaria episode were reduced by 64% in children aged 0-10 years and by 38% in refugees aged < 20 years in the group using permethrin-treated chaddars and top-sheets. Incidence in refugees over 20 years of age was not significantly reduced. The cost of the permethrin treatment per person protected (US

A randomized controlled trial of insecticide-treated bednets and chaddars or top sheets, and residual spraying of interior rooms for the prevention of cutaneous leishmaniasis in Kabul, Afghanistan

0.17) was similar to that for treating bednets (and cost only 10-20% of the price of a new bednet). An entomological study simulating real-life conditions indicated that host-seeking mosquitoes were up to 70% less successful at feeding on men sleeping under treated chaddars and some were killed by the insecticide. Permethrin-treated top-sheets and blankets should provide appropriate and effective protection from malaria in complex emergencies. In Islamic and non-Islamic countries in Asia, treated chaddars and top-sheets should offer a satisfactory solution for the most vulnerable who cannot afford treated nets.

Control of malaria in Pakistan by applying deltamethrin insecticide to cattle: a community-randomised trial

Anthroponotic cutaneous leishmaniasis (ACL) is a significant public health problem in many towns and cities of south central Asia and the Middle East, resulting in disfigurement and disability which warrants preventive action. A randomized controlled trial was conducted in 1997/98 amongst a non-immune study population of 3666 people in Kabul, Afghanistan, to compare the efficacy of insecticide-treated nets (ITNs), insecticide-treated Islamic cloth wraps (chaddars) used to sleep in, and residual pyrethroid spraying of individual houses for the prevention of ACL. Dosages of insecticide were: ITNs with permethrin, 0.5 g/m2; chaddars with permethrin, 1 g/m2; rooms with lambdacyhalothrin, 30 mg/m2. Cases of ACL were diagnosed on clinical criteria. At the end of the trial period (15 months) the incidence of ACL amongst controls was 7.2%, amongst ITN users 2.4% (OR 0.31, 95% CI 0.2-0.5), amongst impregnated chaddar users 2.5% (OR 0.33, 95% CI 0.2-0.6) and amongst residents of sprayed houses 4.4% (OR 0.60, 95% CI 0.3-0.95). ITNs and impregnated chaddars were equally effective, providing about 65% protective efficacy, with approximately 40% protective efficacy attributable to individual house spraying. No significant differences for age or sex were found between new cases in the intervention and control groups. No serious side-effects were reported and interventions were generally popular; ITNs were the most popular, followed by residual spraying and then impregnated chaddars.

pfcrt Polymorphism and Chloroquine Resistance in Plasmodium falciparum Strains Isolated in Cambodia

BACKGROUND The standard method of malaria control in south Asia, indoor spraying of houses with residual insecticide, is becoming prohibitively expensive to implement and new approaches are needed. Since the regions vector mosquitoes feed predominantly on domestic animals and only secondarily on human beings, to apply insecticide to surfaces of cattle instead might be more costeffective. We aimed to investigate whether domestic livestock treated with deltamethrin (applied by a sponging method) would prove toxic to mosquitoes and therefore aid in malaria control. METHODS Six Afghan refugee settlements in Pakistan were randomly assigned to one of two groups. In one group livestock were treated with deltamethrin during the malaria transmission seasons of 1995 and 1997, whereas in the other group livestock were treated during the 1996 season. Malaria was monitored by passive case detection at village clinics and by cross-sectional surveillance. Mosquitoes were also monitored. FINDINGS According to clinic records the incidence of malaria caused by Plasmodium falciparum decreased by 56% (95% CI 14-78%) and P vivax by 31% (5-50%) in livestock-treated villages. Cross-sectional surveys showed comparable decreases in parasite prevalence. The density and life expectancy of Anopheles stephensi and A culicifacies populations were reduced in treated villages. The efficacy of livestock treatment was similar to that of indoor spraying but campaign costs were 80% less. When applied in a highly endemic settlement, the incidence of falciparum malaria decreased from 280 episodes per 1000 person-years to nine episodes per 1000 person-years. INTERPRETATIONS Insecticide treatment of livestock is a cost-effective and promising alternative for south Asia and other regions where primary vectors are zoophilic.

Anopheline vectors and malaria transmission in eastern Afghanistan

ABSTRACT Plasmodium falciparum chloroquine resistance was first detected in Cambodia in the early sixties. Treatment with chloroquine was abandoned 20 years ago. In vitro chloroquine sensitivity monitoring indicates that all eastern Cambodian isolates were sensitive to chloroquine, whereas most isolates collected from western provinces displayed reduced susceptibility to chloroquine. This indicates that the rate of chloroquine resistance remains high and stable in this region in the absence of chloroquine pressure. Characterization of codons 72 to 78 and 218 to 220 of pfcrt revealed six distinct haplotypes, four of which had never been described. The frequency of each haplotype depended on the geographical origin of the samples. The CVIETIF//ISS haplotype was detected in 92% of western Cambodian isolates and in 11% of isolates collected from the eastern province, where CVMNKIF//ISA and CVIDTIF//ISS predominate. The detection of an intermediate haplotype from a susceptible area with 76T/220A, suggests that acquisition of chloroquine resistance might be a stepwise process, during which accumulation of point mutations modulates the response to chloroquine. The association of the K76T mutation with chloroquine resistance was not clear. The mutation was detected in resistant and susceptible samples, suggesting that additional factors are involved in chloroquine resistance. By contrast, the pfcrt D/N75E mutation was strongly associated with the in vitro chloroquine resistance in Cambodian isolates. The N86 allelic form of pfmdr1 was detected in all isolates, consistent with a poor association with resistance to chloroquine. This indicates that in vitro resistance to chloroquine was associated with accumulation of point mutations in pfcrt.

Resistance of Plasmodium falciparum to antimalarial drugs in a highly endemic area of southern Viet Nam: a study in vivo and in vitro

Anopheline vectors and malaria transmission were studied in 2 river-irrigated, rice-growing districts of eastern Afghanistan from May 1995 to December 1996. Clinical malaria was monitored in 12 rural villages (population 14,538) by passive case detection at local clinics. Adult mosquitoes were collected by space-spraying of living quarters and stables and by cattle bait catches. Mosquito head-thoraces (17,255 specimens) were tested for Plasmodium falciparum and P. vivax circumsporozoite protein (CSP) using enzyme-linked immunosorbent assay. The recorded incidence of P. vivax and P. falciparum was 199 and 41 episodes per 1000 person years, respectively. Twelve species of anopheline were recorded; Anopheles stephensi comprised 82% and A. culicifacies 5%. Eight species tested positive for CSP: A. stephensi, A. culicifacies, A. fluviatilus, A. annularis, A. pulcherrimus, A. maculatus, A. splendidus and A. superpictus. Among infected mosquitoes 46% were positive for P. falciparum, 45% for P. vivax VK-247, and 9% for P. vivax PV-210. Estimates of the feeding rates of infective vectors on humans indicated that A. stephensi would contribute 76% of infective bites, A. fluviatilis and A. pulcherrimus 7% each, and A. culicifacies and A. superpictus 3% each. The overall infective vector feeding rate correlated with the P. vivax incidence rate in the human population. The conventional view of A. culicifacies being the main rural vector and A. stephensi important only in urban settings needs to be reconsidered in western outreaches of the Indo-Pakistan subcontinent.

An entomological investigation of the likely impact of cattle ownership on malaria in an Afghan refugee camp in the North West Frontier Province of Pakistan.

To assess the antimalarial sensitivity of Plasmodium falciparum in vivo and in vitro in a highly endemic area of southern Viet Nam, a field study was conducted (in 1999) at a rubber plantation in Binh Phuoc Province north of Ho Chi Minh City. Fifty patients were treated with either artesunate (4 mg/kg on day 0, then 2 mg/kg on day 1 to 4) or mefloquine (10 mg/kg at 0 h, then 5 mg/kg at 6 h), and their progress was followed for 28 days under standard WHO protocols. Blood spots were taken at baseline from all patients, as well as from those who redeveloped parasitaemia during follow-up, for polymerase chain reaction (PCR) determination of parasite genotypes to assist differentiation of re-infection from recrudescence. Both treatments cleared parasites within 5 days. Of the 25 mefloquine-treated patients, 2 (8%) re-presented with probable re-infections. For artesunate, 4 patients (16%) had re-infections and 5 (20%) had recrudescences. Sensitivity tests in vitro of pre-treatment P. falciparum isolates showed geometric mean IC50 values of 29, 38, 209 and 15 nmol/L for chloroquine (n = 32), mefloquine (n = 33), quinine (n = 31) and artemisinin (n = 31), respectively. There were significant correlations between IC50s for artemisinin and mefloquine (r = 0.72, P = 0.004), and chloroquine and quinine (r = 0.44, P = 0.05). These data show that, although mefloquine has been used for 10 years in Binh Phuoc Province, it remains fully effective, perhaps because an artemisinin derivative is commonly given at the same time. The recrudescence rate for artesunate is similar to those reported in other epidemiological contexts. The present in-vitro data imply that quinine remains effective and that reduced drug pressure has been associated with increased sensitivity of local strains of P. falciparum to chloroquine. Although from one hyperendemic area, these results may have implications for antimalarial prophylaxis and treatment strategies for residents and travellers to southern Viet Nam.

Control of zoophilic malaria vectors by applying pyrethroid insecticides to cattle

Abstract. Field trials were undertaken to determine the effect of close proximity of humans to livestock on the human biting rates exhibited by various anophelines. The results indicate that proximity to cattle and to goats increases the subjects chances of being bitten by anophelines. Man‐biting by Anopheles stephensi rose by 38% (8–68% CI) in the presence of a cow, and by 50% (16–84% CI) in the presence of two goats. Other species exhibited similar trends. These findings explain the results of an earlier trial which revealed that malaria prevalence was higher amongst families that kept cattle than those that did not.