Treatment Of Multidrug-resistant Falciparum Malaria Research Articles

Open label randomized comparison of dihydroartemisinin–piperaquine and artesunate–amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in central Vietnam

Artesunate-amodiaquine (AAQ) is efficacious for the treatment of uncomplicated Plasmodium falciparum malaria in Africa, but little is known about its efficacy in Southeast Asia. We compared the efficacy of dihydroartemisinin-piperaquine (DHP) and AAQ against falciparum malaria in central Vietnam. Open, randomized clinical trial of 116 patients (36 children aged 6-14 years, 80 adults aged 15-60 years) were randomly allocated a 3-day course of either DHP (approximately 2.3 mg/kg dihydroartemisinin plus approximately 18.5 mg/kg of piperaquine per day) or AAQ (approximately 4.4 mg/kg of artesunate plus approximately 10.6 mg/kg of amodiaquine per day). The follow-up period was 42 days. The two drug combinations were well tolerated by all age groups with no obvious drug associated adverse events. Of the patients who completed 42 days of follow-up, 49 were on DHP (15 children, 34 adults) and 49 were on AAQ (14 children, 35 adults). The 42 day cure rates adjusted for reinfection identified by PCR genotyping for the two groups were similar [100% (49/49) and 98% (48/49) for DHP and AAQ, respectively]. With fewer reinfections, DHP appears to possess greater post-treatment prophylactic activity than AAQ. AAQ, an inexpensive artemisinin-based combination, could be an additional option to DHP for the treatment of multidrug-resistant falciparum malaria in Vietnam.

In vitro atovaquone/proguanil susceptibility and characterization of the cytochrome b gene of Plasmodium falciparum from different endemic regions of Thailand

BackgroundThe emergence of Plasmodium falciparum resistant to most currently used antimalarial drugs is the major problem in malaria control along the Thai-Myanmar and Thai-Cambodia borders. Although artemisinin-based combination therapy has been recommended for the treatment of multidrug-resistant falciparum malaria, these combinations are not available for some people, such as travelers from North America. A fixed-dose combination of atovaquone and proguanil (Malarone) has been proved to be effective for the treatment and prophylaxis of malaria which is already approved by countries in North America and Europe. Determination of the phenotypes and genotypes related to atovaquone/proguanil response in Thai isolates of P. falciparum will be useful for rationale drug use. The main purpose of this study was to explore the in vitro atovaquone/proguanil susceptibility of recently adapted Thai isolates of P. falciparum. Genotypic characterization of the cytb gene of these isolates was also determined since it has been reported that point mutations, particularly codon 268 in the cytochrome b gene (cytb) have been linked to atovaquone/proguanil treatment failure.MethodsEighty three P. falciparum isolates collected during 1998 to 2005 from four different multidrug resistance areas of Thailand were determined for the in vitro atovaquone/proguanil susceptibilities using radioisotopic assay. Mutations in the cytb gene were determined by PCR-RFLP and sequence analysis.ResultsThe mean atovaquone and proguanil IC50 was 3.4 nM and 36.5 μM, respectively. All 83 Thai isolates were atovaquone sensitive. None of the 83 isolates contained the mutations at codon 268 of the cytb gene. DNA sequencing of the cytb gene of 20 parasite isolates showed no other mutations.ConclusionIn agreement with a recent efficacy study of atovaquone/proguanil, the present information indicates that atovaquone/proguanil can be one of the drugs of choice for the treatment and prophylaxis of multidrug-resistant falciparum malaria in Thailand.

Efficacy and safety of dihydroartemisinin-piperaquine

Dihydroartemisinin-piperaquine, a fixed-dose combination antimalarial, is an inexpensive, safe and highly effective treatment for uncomplicated falciparum or vivax malaria. Efficacy assessed over 28-63 days has consistently exceeded 95% in the treatment of multidrug-resistant falciparum malaria. More than 2600 patients have been treated with this combination in prospective studies, mainly in Southeast Asia. Tolerability was uniformly good, and no serious adverse effects have been identified. The dosing regimen has been simplified from four doses to once daily over 3 days. More information on efficacy in Africa, and more pharmacokinetic and efficacy data in children are needed.

Efficacy and effectiveness of dihydroartemisinin-piperaquine versus artesunate-mefloquine in falciparum malaria: an open-label randomised comparison

Artemisinin-based combinations are judged the best treatments for multidrug-resistant Plasmodium falciparum malaria. Artesunate-mefloquine is widely recommended in southeast Asia, but its high cost and tolerability profile remain obstacles to widespread deployment. To assess whether dihydroartemisinin-piperaquine is a suitable alternative to artesunate-mefloquine, we compared the safety, tolerability, efficacy, and effectiveness of the two regimens for the treatment of uncomplicated falciparum in western Myanmar (Burma). We did an open randomised comparison of 3-day regimens of artesunate-mefloquine (12/25 mg/kg) versus dihydroartemisinin-piperaquine (6.3/50 mg/kg) for the treatment of children aged 1 year or older and in adults with uncomplicated falciparum malaria in Rakhine State, western Myanmar. Within each group, patients were randomly assigned supervised or non-supervised treatment. The primary endpoint was the PCR-confirmed parasitological failure rate by day 42. Failure rates at day 42 were estimated by Kaplan-Meier survival analysis. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN27914471. Of 652 patients enrolled, 327 were assigned dihydroartemisinin-piperaquine (156 supervised and 171 not supervised), and 325 artesunate-mefloquine (162 and 163, respectively). 16 patients were lost to follow-up, and one patient died 22 days after receiving dihydroartemisinin-piperaquine. Recrudescent parasitaemias were confirmed in only two patients; the day 42 failure rate was 0.6% (95% CI 0.2-2.5) for dihydroartemisinin-piperaquine and 0 (0-1.2) for artesunate-mefloquine. Whole-blood piperaquine concentrations at day 7 were similar for patients with observed and non-observed dihydroartemisinin-piperaquine treatment. Gametocytaemia developed more frequently in patients who had received dihydroartemisinin-piperaquine than in those on artesunate-mefloquine: day 7, 18 (10%) of 188 versus five (2%) of 218; relative risk 4.2 (1.6-11.0) p=0.011. Dihydroartemisinin-piperaquine is a highly efficacious and inexpensive treatment of multidrug-resistant falciparum malaria and is well tolerated by all age groups. The effectiveness of the unsupervised treatment, as in the usual context of use, equalled its supervised efficacy, indicating good adherence without supervision. Dihydroartemisinin-piperaquine is a good alternative to artesunate-mefloquine.

Cultivation and genetics ofArtemisia annuaL. for increased production of the antimalarial artemisinin

Malaria has been treated for over 350 years with quinine and quinine-derived drugs. However, in several areas of the world, some strains of the malarial parasitePlasmodium falciparumhave developed resistance against these drugs. Recently, the World Health Organization (WHO) recommended the use of artemisinin-combination treatments (ACT) as the first-line treatment for multidrug-resistant falciparum malaria. The WHO estimates that current supplies of artemisinin are sufficient for only 30 million ACT, and is foreseeing the need for 130–220 million ACT in 2005 (WHO, 2004). Current research on the production of synthetic artemisinin-like compounds by the Roll Back Malaria project, pharmaceutical companies and academia resulted in a promising synthetic artemisinin-like compound (OZ277) which is currently undergoing phase I clinical trials. In about 5 years this drug is expected to be approved and made available to the public, however, meeting current global demands for ACT depends on the immediate availability of affordable artemisinin-derived drugs. This will involve expansion of the area under cultivation ofArtemisia annuaand improved methods of cultivation and processing of raw material, associated with more efficient methods for extraction and purification of artemisinin from plant material. This review addresses the agricultural, environmental and genetic aspects that may be useful in the successful large-scale cultivation ofA. annuaand for producing the antimalarial artemisinin in areas where it is urgently needed today. It also includes geographic aspects (latitude and altitude), which will help make decisions about crop establishment in tropical countries, and includes a list of Good Agricultural and Collection Practices forA. annua.

A Randomized Comparison of Artesunate‐Atovaquone‐Proguanil versus Quinine in Treatment for Uncomplicated Falciparum Malaria during Pregnancy

There is no safe, practical, and effective treatment for pregnant women infected with multidrug-resistant Plasmodium falciparum. We recruited pregnant Karen women in the second or third trimesters of pregnancy who had uncomplicated falciparum malaria for a randomized, open-label trial with a restricted sequential trial design of 7 days of supervised quinine (SQ7) versus 3 days of artesunate-atovaquone-proguanil (AAP). Eight-one pregnant women entered the study between December 2001 and July 2003; 42 were treated with SQ7 and 39 were treated with AAP. Fever, parasite clearance, and duration of anemia were significantly better with AAP; the treatment failure rate was 7 times lower (5% [2/39] vs. 37% [15/41]; relative risk, 7.1 [95% confidence interval, 1.7-29.2]; P = .001). There were no significant differences in birth weight, duration of gestation, or congenital abnormality rates in newborns or in growth and developmental parameters of infants monitored for 1 year. AAP is a well-tolerated, effective, practical, but expensive treatment for multidrug-resistant falciparum malaria during the second or third trimesters of pregnancy. Despite the small number of subjects, our results add to the growing body of evidence that AAP is safe for the mother and the fetus.

A Randomized, Controlled Study of a Simple, Once-Daily Regimen of Dihydroartemisinin-Piperaquine for the Treatment of Uncomplicated, Multidrug-Resistant Falciparum Malaria

Dihydroartemisinin-piperaquine (DP) is a fixed-combination antimalarial drug increasingly deployed in Southeast Asia. The current regimen involves 4 doses given over 3 days. Simplification of the dose regimen should facilitate treatment adherence and thereby increase effectiveness. In a randomized, controlled, 3-arm trial conducted along the northwestern border of Thailand, the standard 4-dose course of DP (DP4) was compared to an equivalent dose given as a once-daily regimen (DP3) and to the standard treatment of mefloquine-artesunate (MAS3). A total of 499 patients were included in the study. Times to fever and parasite clearance were similar in all groups. The PCR genotyping-adjusted cure rates at day 63 after treatment initiation were 95.7% (95% confidence interval [95% CI], 92.2%-98.9%) for MAS3, 100% for DP4, and 99.4% (95% CI, 98.1%-100%) for DP3. The DP4 and DP3 cure rates were significantly higher than that for MAS3 (P=.008 and P=.03, respectively). All regimens were well tolerated. There were 3 deaths (1 in the MAS3 group and 2 in the DP3 group), all of which were considered to be unrelated to treatment. Rates of other adverse events were comparable between the groups, except for diarrhea, which was more common in the DP4 group (P=.05 vs. the MAS3 group). A once-daily, 3-dose regimen of DP is a highly efficacious treatment for multidrug-resistant falciparum malaria. This simple, safe, and relatively inexpensive fixed combination could become the treatment of choice for falciparum malaria.

Randomized, Controlled Dose‐Optimization Studies of Dihydroartemisinin‐Piperaquine for the Treatment of Uncomplicated Multidrug‐Resistant Falciparum Malaria in Thailand

Dihydroartemisinin-piperaquine (DP) is a new and relatively inexpensive artemisinin-containing fixed-combination antimalarial treatment. An adult treatment course contained 6.4 mg/kg dihydroartemisinin (DHA), which is >40% lower than the level in most artemisinin-containing combinations. This raised the possibility that the efficacy of the current coformulation may not be optimal in the treatment of multidrug-resistant falciparum malaria. In 2 large randomized, controlled studies in Thailand, the recommended dose of DP was compared with a regimen with additional artemisinin derivative (12 mg/kg; DP+) and with mefloquine plus artesunate (MAS3). A total of 731 patients were included: 201 in a hospital-based study and 530 in a community study. Day-28 cure rates in the hospital-based study were 100% (95% confidence interval [CI], 93.9%-100%) in the MAS3 and DP+ groups and 98.3% (95% CI, 91%-99.7%) in the DP group, with a single recrudescence on day 21. In the community study, polymerase chain reaction genotyping-adjusted cure rates on day 63 were 96.1% (95% CI, 92.6%-99.7%) in the DP group, 98.3% (95% CI, 96.1%-100%) in the DP+ group, and 94.9% (95% CI, 91.2%-98.6%) in the MAS3 group (P=.2). Adverse events were few, with an excess of mild abdominal pain in the DP group. The current dosage of DP (6.4 mg/kg DHA and 51.2 mg/kg piperaquine phosphate) given over the course of 48 h is highly effective, safe, and well tolerated for the treatment of multidrug-resistant falciparum malaria, and its efficacy is not improved by the addition of more DHA.

Antimalarial activity of azithromycin, artemisinin and dihydroartemisinin in fresh isolates of Plasmodium falciparum in Thailand

Antibiotics with antimalarial activity may offer an interesting alternative for the treatment of multidrug-resistant falciparum malaria. Azithromycin, a relatively recent semisynthetic derivative of erythromycin, was tested for its in vitro activity against fresh isolates of Plasmodium falciparum. As the reportedly slow onset of action of azithromycin suggests its combination with fast-acting substances, such as artemisinin-derivatives, dihydroartemisinin (DHA) was tested parallel as a possible combination partner. The effective concentrations found for azithromycin in this study (EC 50=29.3 μmol/l, EC 90=77.1 μmol/l blood medium mixture (BMM)) are comparable to those of other antimalarials in the antibiotics class and are considerably higher than those found for mefloquine or quinine. The absence of an activity correlation between azithromycin and chloroquine, quinine and artemisinin emphasises the independence of azithromycin drug response from the sensitivity to these drugs. A weak activity correlation ( ρ EC90=0.352; p=0.028), which could point to a potential cross-sensitivity but is probably of little clinical importance, was found with mefloquine above the EC 50 level. Provided that further clinical trials support the combination of these drugs, DHA may offer an interesting combination partner for azithromycin owing to its rapid onset of action and the comparatively low effective concentrations (EC 50=1.65 nmol/l, EC 90=7.10 nmol/l BMM). This combination may serve as an interesting alternative for tetracycline and doxycycline, which cannot be used in pregnant women and children, and exhibit phototoxicity. Nevertheless, the relatively high cost of this combination, as well as the controversial reports of the clinical efficacy, may limit the usefulness of azithromycin in malaria therapy and require an adjustment of previously used treatment regimens.

Mefloquine pharmacokinetic-pharmacodynamic models: implications for dosing and resistance.

Antimalarial resistance develops and spreads when spontaneously occurring mutant malaria parasites are selected by concentrations of antimalarial drug which are sufficient to eradicate the more sensitive parasites but not those with the resistance mutation(s). Mefloquine, a slowly eliminated quinoline-methanol compound, is the most widely used drug for the treatment of multidrug-resistant falciparum malaria. It has been used at doses ranging between 15 and 25 mg of base/kg of body weight. Resistance to mefloquine has developed rapidly on the borders of Thailand, where the drug has been deployed since 1984. Mathematical modeling with population pharmacokinetic and in vivo and in vitro pharmacodynamic data from this region confirms that, early in the evolution of resistance, conventional assessments of the therapeutic response </=28 days after treatment underestimate considerably the level of resistance. Longer follow-up is required. The model indicates that initial deployment of a lower (15-mg/kg) dose of mefloquine provides a greater opportunity for the selection of resistant mutants and would be expected to lead more rapidly to resistance than de novo use of the higher (25-mg/kg) dose.

Randomized comparison of mefloquine-artesunate versus quinine in the treatment of multidrug-resistant falciparum malaria in pregnancy

Since no effective malaria prevention measures have been identified for pregnant women living on the western border of Thailand, prompt diagnosis and efficient treatment are paramount, although drug resistance in Plasmodium falciparum has narrowed the treatment options. An open randomized comparison of supervised quinine (10 mg salt/kg every 8 h) for 7 days (Q7) versus mefloquine 25 mg base/kg (total dose) plus artesunate 4 mg/kg per day for 3 days (MAS3) was conducted in 1995–1997 in 108 Karen women with acute uncomplicated falciparum malaria in the second or third trimesters of pregnancy. The MAS3 regimen was more effective than the Q7 regimen: day 63 cure rates were 98·2% (95% CI 94·7·100) ( n = 65) for MAS3 and 67·0% (95% CI 43·3·90·8) ( n = 41) for Q7, P = 0·001. The MAS3 regimen was also associated with less gametocyte carriage; the average person-gametocyte-weeks for MAS3 was 2·3 (95% CI 0–11) and for Q7 was 46·9 (95% CI 26–78) per 1000 person-weeks, respectively ( P < 0·001). MAS3 was significantly better tolerated. These evident advantages must be balanced against a possible increased risk of stillbirth with the use of mefloquine in pregnancy. Further randomized studies assessing the safety and efficacy of other artemisinin-containing combination regimens in pregnancy are needed urgently.

Efficacy and pharmacokinetics of atovaquone and proguanil in children with multidrug-resistant Plasmodium falciparum malaria

A trial was conducted in 32 Thai children with uncomplicated multidrug-resistant falciparum malaria to assess the efficacy, safety and pharmacokinetics of atovaquone and proguanil; plasma concentrations of atovaquone, proguanil and its metabolite, cycloguanil, were measured in a subset of 9 children. The children received atovaquone (17 mg/kg/d for 3 d) plus proguanil (7 mg/kg/d for 3 d). Twenty-six children who had only Plasmodium falciparum infection and remained in hospital for 28 d were assessed for drug efficacy. The combination regimen produced a cure rate of 100%. Parasite and fever clearance times were 47 h (range 8–75) and 50 h (range 7–111), respectively. Atovaquone and proguanil were rapidly absorbed, with median time to peak concentrations of 6 h (range 6–24) and 6 h (range 6–12), respectively. Peak concentrations of cycloguanil were achieved between 6 and 12 h (median 6) after administration of proguanil. Mean peak plasma concentration of atovaquone on day 3 was 5·1 μg/mL (SD = 2·1). The day 3 mean peak plasma concentration of proguanil was 306 ng/mL (SD = 108) compared with 44·3 ng/mL (SD = 27.3) for cycloguanil. Mean values for the AUC (area under plasma concentration-time curve) were 161·8 μg/mL · h (SD = 126·9) for atovaquone, 4646 ng/mL · h (SD = 1226) for proguanil, and 787 ng/mL · h (SD = 397) for cycloguanil. Terminal elimination half-lives of atovaquone, proguanil and cycloguanil were estimated as 31·8 h (SD = 8.9), 14·9 h (SD = 3·3) and 14·6 h (SD = 2·6), respectively. No major adverse effect was attributable to the study drugs. Atovaquone/proguanil combination is safe and highly effective, and should be especially valuable for treatment of multidrug-resistant falciparum malaria.

Proguanil polymorphism does not affect the antimalarial activity of proguanil combined with atovaquone in vitro

Clinical studies have shown proguanil ( prog) combined with atovaquone ( atq) to be an effective and safe antimalarial combination for the treatment of multidrug-resistant falciparum malaria. prog is a prodrug, which undergoes hepatic metabolism to its pharmacologically active metabolite cycloguanil ( cyc). Individuals exhibit genetic polymorphism with respect to prog, and can be phenotyped as either extensive metabolizers (EMs) or poor metabolizers (PMs) by measuring their prog cyc concentration ratio in plasma following prog atq administration. PMs produce lower plasma concentrations of cyc than EMs and thus may be more susceptible to prophylaxis or treatment failure. Both prog and cyc potentiate the activity of atq in vitro. The antimalarial activity ex vivo of Thai patients' plasma samples obtained from EMs and PMs given concurrent prog and atq was studied using the K1 isolate of Plasmodium falciparum This isolate is resistant to prog and cyc, but sensitive to atq. Maximum inhibitory dilution profiles of the patients' plasma samples containing prog and atq from EMs and PMs were similar. These findings indicate that differences in plasma drug concentrations between EMs and PMs did not alter the antimalarial activity in vitro against the K1 isolate. The phenotypic status of individuals is not an important issue in the treatment of patients with prog atq .

Pharmacokinetics of halofantrine and n-desbutylhalofantrine in patients with falciparum malaria following a multiple dose regimen of halofantrine

Halofantrine is a new blood schizontocidal drug used for the treatment of multidrug-resistant falciparum malaria. The pharmacokinetics of halofantrine (HAL) and its principal metabolite, N-desbutylhalofantrine (BHAL), was investigated in 6 adult male patients of Melanesian origin with uncomplicated falciparum malaria. The patients received 500 mg of halofantrine hydrochloride at times 0, 6 and 12 h (total 1.5 g). All patients responded to treatment with a mean parasite clearance time of 52.7 h and a mean fever clearance time of 33.8 h. The following kinetic parameters (mean values) were determined for HAL and BHAL, respectively: maximum plasma concentration (Cmax) = 896 and 491 ng.ml-1; time to reach the Cmax (tmax) = 15 and 56 h; elimination half-life (t1/2) = 91 and 79 h and the mean residence time (MRT) = 71 and 102 h. Based on the clinical response the plasma concentrations of HAL and BHAL were adequate for the treatment of uncomplicated falciparum malaria in the 6 patients.