Christine Luxemburger

Effects of artesunate-mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: a prospective study

BACKGROUND Worsening drug resistance in Plasmodium falciparum malaria is a major threat to health in tropical countries. We did a prospective study of malaria incidence and treatment in an area of highly multidrug-resistant P. falciparum malaria. METHODS We assessed incidence of P. falciparum malaria and the in-vivo responses to mefloquine treatment over 13 years in two large camps for displaced Karen people on the northwest border of Thailand. During this time, the standard mefloquine dose was first increased, and then combined artesunate and mefloquine was introduced as first-line treatment for uncomplicated P. falciparum malaria. FINDINGS Early detection and treatment controlled P. falciparum malaria initially while mefloquine was effective (cure rate with mefloquine [15 mg/kg] and sulphadoxine-pyrimethamine in 1985, 98% [95% CI 97-100]), but as mefloquine resistance developed, the cure rate fell (71% [67-77] in 1990). A similar pattern was seen for high-dose (25 mg/kg) mefloquine monotherapy from 1990-94. Since the general deployment of the artesunate-mefloquine combination in 1994, the cure rate increased again to almost 100% from 1998 onwards, and there has been a sustained decline in the incidence of P. falciparum malaria in the study area. In-vitro susceptibility of P. falciparum to mefloquine has improved significantly (p=0.003). INTERPRETATION In this area of low malaria transmission, early diagnosis and treatment with combined artesunate and mefloquine has reduced the incidence of P. falciparum malaria and halted the progression of mefloquine resistance. We recommend that antimalarial drugs should be combined with artemisinin or a derivative to protect them against resistance.

Effects of artemisinin derivatives on malaria transmissibility

BACKGROUND On the western border of Thailand the efficacy of mefloquine in the treatment of falciparum malaria has declined while gametocyte carriage rates have increased, which suggests increased transmissibility of these resistant infections. We compared the following antimalarial drugs in relation to subsequent Plasmodium falciparum gametocyte carriage: mefloquine, halofantrine, quinine, and the artemisinin derivatives. METHODS Between 1990 and 1995 we assessed gametocytaemia in a series of prospective studies of antimalarial drug treatment in 5193 adults and children with acute uncomplicated falciparum malaria in an area of malarious hill forest on the western border of Thailand. Weekly parasite counts from thick and thin blood films were done during the 4-week (1990-93) or 9-week (1993-95) follow-up period. Gametocyte positivity rates and person gametocyte week (PGW) rates were calculated to measure gametocyte carriage and transmission potential. FINDINGS In primary P falciparum infections the gametocyte carriage rate was significantly higher after treatment with mefloquine than after treatment with the artemisinin derivatives (PGW 34.1 [95% CI 25.2-42.9] vs 3.9 [1.9-5.9] per 1000 person weeks; relative risk 8.0 [4.1-15.6]; p<0.0001). Recrudescent infections were associated with increased gametocyte carrier rates (relative risk 2.2 [1.6-3.0]; p<0.0001), but retreatment with artemisinin derivatives reduced subsequent gametocyte carriage 18.5 fold [3.5-98] compared with mefloquine retreatment and 6.8 fold (3.1-15.1) compared with quinine retreatment (p<0.001). The introduction of the artemisinin derivatives in routine treatment at this study site in mid 1994 was associated with a reduction in the subsequent incidence of falciparum malaria of 47 (25-69)% INTERPRETATION Although environmental changes affect vector numbers, and hence malaria incidence, artemisinin derivatives were found to reduce the transmission potential of falciparum malaria. Widespread introduction of artemisinin derivatives in the treatment of falciparum malaria may prevent the spread of multidrug resistance.

The epidemiology of severe malaria in an area of low transmission in Thailand.

The predisposing factors, clinical presentation, and outcome of severe malaria in a Karen community living on the western border of Thailand were studied over a period of 2 years. This was an area of low malaria transmission (approximately one infection per person per year), where asymptomatic malaria is unusual. In a population of 4728 persons, who had good access to facilities for malaria diagnosis and treatment, there were 2573 cases of vivax malaria, none of whom died, and there were 5776 cases of falciparum malaria, 303 (5%) of whom had severe malaria and 11 (0.2%) of whom died-a case fatality rate of 1.9 per 1000 (95% confidence interval [CI] 1.0-3.3). The risks of developing severe malaria and dying declined steadily with age. The clinical features of severe malaria differed between children and adults. Anaemia was more common in children under 5 years old than in older children and adults, whereas the incidence of cerebral involvement increased with age. Severe malaria was 3 times (95% CI 1.4-6.2) more common in pregnant than in non-pregnant women, but was 4.2 times (95% CI 2.3-7.9) less common in patients with mixed Plasmodium falciparum and P. vivax infections than in those with P. falciparum alone, suggesting that P. vivax may attenuate the severity of P. falciparum malaria.

Cardiac effects of antimalarial treatment with halofantrine

In a prospective electrocardiographic study of Karen patients with acute uncomplicated falciparum malaria, mefloquine (25 mg/kg) had no cardiac effects (n = 53), but halofantrine (72 mg/kg) induced consistent dose-related lengthening of the PR and QT intervals in all 61 patients treated. The likelihood of significant QTc prolongation (by more than 25% or a QTc of 0.55 s1/2 or more) was greater after halofantrine as retreatment following mefloquine failure than as primary treatment (7/10 vs 18/51; relative risk 2.0 [95% Cl 1.1-3.4], p = 0.04). More than 60% of the effect occurred with three doses of halofantrine (24 mg/kg). The arrhythmogenic potential of halofantrine should now be investigated.

Mefloquine-resistant falciparum malaria on the Thai-Burmese border

Mefloquine is the treatment of choice for uncomplicated multiresistant falciparum malaria, and in combination with sulphadoxine and pyrimethamine (MSP) at a single dose of 15/30/1.5 mg/kg, respectively, has been used in Thailand for the past 6 years. In 1985-86, MSP cured over 98% of 5192 patients with falciparum malaria on the Thai-Burmese border. 4 years later we studied the efficacy of MSP in 395 patients at the same location. The cure rate at 28 days was 70.8% (95% Cl 67-77.2%). The proportion of early treatment failures (in whom parasitaemia did not clear) had risen from 0.27 to 3.7% (p less than 0.0001). Failure rates were 50% in children under 6 years old, 29% in the 6-15 age group, and 19% in adults (p less than 0.001). Patients with early treatment failure were retreated with 25 mg/kg mefloquine, but 27% had a further recrudescence of infection within 28 days. The mean (95% Cl) serum mefloquine concentration at the time of first recrudescence was 638 (546-730) ng/ml, a value previously associated with successful treatment. Mefloquine concentrations were no lower in those with recrudescent infections than in age-matched successfully treated patients, suggesting that pharmacokinetic factors were not responsible for the high treatment-failure rate. Plasmodium falciparum has developed resistance to mefloquine rapidly, despite the addition of sulphadoxine and pyrimethamine and strict control of drug administration. The MSP combination should now be abandoned.

The epidemiology of malaria in a Karen population on the western border of Thailand

From November 1991 to November 1992 a prospective, descriptive study of malaria epidemiology was conducted in a Karen population on the western border of Thailand. Two study groups were selected at random and more than 80% of the subjects were followed for one year. In Group 1, comprising 249 schoolchildren (aged 4-15 years), daily surveillance for illness was combined with fortnightly malaria surveys. These children experienced 1.5 parasitaemic infections per child-year (95% confidence interval [CI] 1.3-1.7), of which 68% (193/285) were symptomatic (Plasmodium falciparum 84%, P. vivax 57%). The estimated pyrogenic densities were 1460/microL for P. falciparum and 181/microL for P. vivax. In Group 2, comprising subjects of all age from 428 households, malaria was diagnosed during two-monthly surveys, at weekly home visits, and otherwise by passive case detection. Malaria and splenomegaly prevalence rates were low in all age groups (spleen index 2-9%; P. falciparum prevalence rate 1-4%; P. vivax 1-6%). Group 2 subjects had 1.0 infections per person-year (95% CI 0.9-1.1), most of which were symptomatic (312/357; 87%). Malaria infections clustered in households. Overall, P. vivax caused 53% and P. falciparum 37% of the infections (10% were mixed), but whereas P. vivax was most common in young children, with a decline in incidence with increasing age, P. falciparum incidence rates rose with age to a peak incidence between 20 and 29 years, although the risk of developing a severe malaria decreased with increasing age. There was no death from malaria during the study. P. falciparum infections were more common in males, subjects with a history of malaria before the study, and in those who had travelled outside their village. These findings suggest a higher transmission rate for P. vivax than P. falciparum, although adults still suffered symptomatic malaria due to both species. The 2 malaria parasites found in this area contribute approximately 50% of infections each, but their clinical epidemiology is very different.

Randomised double-blind placebo-controlled trial of SPf66 malaria vaccine in children in northwestern Thailand

Summary Background Previous efficacy trials of SPf66 malaria vaccine have produced conflicting results in different populations. We report a randomised double-blind trial of the SPf66 vaccine conducted in Karen children aged 2–15 living in a malarious region of northwestern Thailand. Recombinant hepatitis B vaccine was used as a comparator. Methods The study had a power of 90% to detect an efficacy of 30%, defined as a reduction in the incidence of first cases of symptomatic falciparum malaria after three doses of vaccine. 1221 children received three immunisations and were eligible for the primary efficacy analysis. Intense active and passive case detection continued over 15 months of follow-up. Findings The SPf66 vaccine was well tolerated, although 26 children had mild or moderately severe local or systemic allergic reactions, compared with none in the comparator group. The vaccine was immunogenic; after three doses, 73% of recipients had seroconverted. There were no deaths due to malaria during the study. During the 15-month period of evaluation there were 379 first cases of symptomatic falciparum malaria (195 in the SPf66 recipients, 184 in the comparator group); an SPf66 efficacy of −9% (95% Cl -33 to 14, p=0·41). No significant differences between the two study groups in parasite density or any other measure of malaria-related morbidity were detected. Interpretation These findings are consistent with a recent study showing lack of efficacy of SPf66 among Gambian infants and differ from earlier positive reports from South America and evidence of borderline efficacy from Tanzania. We conclude that SPf66 does not protect against clinical falciparum malaria and that further efficacy trials are not warranted.

Artesunate/mefloquine treatment of multi-drug resistant falciparum malaria

On the western border of Thailand, in an area endemic for multi-drug resistant Plasmodium falciparum malaria, therapeutic responses were assessed in 1967 patients with uncomplicated falciparum malaria treated with 3 d of artesunate (total dose 12 mg/kg) plus mefloquine (total dose 25 mg/kg). The regimen was well tolerated and resulted in a rapid clinical response; within 48 h, 96% of patients were aparasitaemic and 94% were afebrile. After correcting for reinfections, the cure rate by day 42 was 89% (95% confidence interval [95% CI] 87-91%). Three independent factors were found to predict recrudescence: age < 14 years (adjusted hazards ratio [AHR] = 1.6, 95% CI 1.1-2.3), initial parasitaemia greater than > 40,000/microL (AHR = 1.6, 95%, CI 1.2-2.2), and pure P. falciparum infections (AHR = 1.8, 95% CI 1.3-2.7). These 3 factors combined accounted for 62% of all treatment failures. Patients who received mefloquine on admission with a high admission parasitaemia (> 40,000/microL) had a three-fold (95% CI 1.3-7) risk of subsequent recrudescence compared with those who received their mefloquine on the second or third day (P = 0.01). There has been no decline in the efficacy of the 3 d artesunate plus mefloquine regimen since it was introduced in 1992. This regimen is safe, well tolerated, and highly effective in the treatment of multi-drug resistant falciparum malaria.

Bed nets for the prevention of malaria and anaemia in pregnancy

A prospective comparison of the antimalarial efficacy of bed nets was conducted with 341 pregnant women living in a mesoendemic malarious area of the Thai-Burmese border. Women in 3 adjacent study sites were allocated at random to receive either a single size permethrin-impregnated bed net (PIB), a non-impregnated bed net (NIB), or to a control group who used either their own family size non-impregnated bed net (FNIB) or no net. In one study site, but not the other 2, PIB significantly reduced parasite densities and, together with FNIB, reduced the incidence of malaria in pregnancy from 56% to 33% (relative risk = 1.67, confidence interval = 1.07-2.61, P = 0.03, allowing for parity). Anaemia proved a more sensitive marker of bed net antimalarial efficacy than parasite rates. The incidence of anaemia (haematocrit < 30%) at all study sites was significantly lower at delivery in the PIB (27%) and FNIB groups (21%) than in the NIB group (41%) or those using no net (56%). This suggests that a significant proportion of the malaria in pregnancy in this mesoendemic area was sub-patent. Both patent Plasmodium falciparum parasitaemia and anaemia were associated with a reduction in birth weight. Infant mortality was high (16%) and strongly associated with prematurity, low birth weight and maternal anaemia. PIB were well tolerated and had no apparent adverse effect on the pregnancy or infant development. Although the overall effect of bed nets on patent parasitaemia was marginal, they were associated with a significant reduction in maternal malaria-associated anaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Halofantrine versus mefloquine in treatment of multidrug-resistant falciparum malaria

The continuing spread of multidrug resistance in Plasmodium falciparum malaria makes the search for alternative treatments ever more urgent. We have investigated the relative efficacy of halofantrine and mefloquine in two paired randomised trials on the Thai-Burmese border, a multidrug-resistant area. In the first trial, 198 patients with acute uncomplicated falciparum malaria were randomly assigned either the standard halofantrine regimen (24 mg/kg) or mefloquine (25 mg/kg). The cumulative failure rates by day 28 were 35% with halofantrine and 10% with mefloquine (p = 0.0002). In the second study of 437 patients, a higher dose of halofantrine (8 mg/kg every 8 h for 3 days = 72 mg/kg) was both more effective and better tolerated than mefloquine 25 mg/kg; the failure rates were 3% and 8% (p = 0.03), respectively, or 1% vs 6% after adjustment for possible reinfections (p = 0.009). The rate of failure was higher after retreatment than after primary treatment in all study groups. Halofantrine 72 mg/kg was especially effective in the retreatment of these recrudescent infections; the failure rate was 44% with mefloquine and 15% with high-dose halofantrine (relative risk 3.0 [95% CI 1.2-7.3], p = 0.008). Thus, high-dose halofantrine is better tolerated and more effective than mefloquine for the treatment of uncomplicated falciparum malaria in this area. However, evidence of possible cardiotoxicity will need to be investigated fully before a role can be established for halofantrine in the treatment of multidrug-resistant malaria.