Improved efficacy with amodiaquine instead of chloroquine in sulfadoxine/pyrimethamine combination treatment of falciparum malaria in Uganda: experience with fixed-dose formulation

Amodiaquine (AQ) is an affordable compound, chemically related to chloroquine (CQ) but often effective against CQ resistant Plasmodium falciparum. In Uganda, a pre-packed fixed-dose combination of CQ plus sulfadoxine/pyrimethamine (CQ+SP) called Homapak is used in the home based management of fever program (HBM). We performed a single blind randomized trial to determine the efficacy of AQ+SP in comparison with the fixed-dose CQ+SP (Homapak) in the treatment of uncomplicated falciparum malaria in Ugandan children aged 6 months to 5 years. The study was done in 2004 at Walkuba Health Center, a sub-urban area in Jinja district, Uganda. Primary outcome was the day 14 per protocol clinical and parasitological response according to the WHO. A total of 183 children were included (mean age 28 months) and 90% completed 28 days of follow up. The day 14 adequate clinical and parasitological response was 70.9% for CQ+SP and 97.4% for AQ+SP (p<0.001). In those given CQ+SP, treatment failure rates for the 6 months to 2 years age group were much higher (48.2%) than in the older children (18.2%, p=0.004). The day 28 PCR adjusted parasitological failure rates were also higher in the CQ+SP (31.3%) than in the AQ+SP group (13.1%) (p=0.003), with a higher gametocyte carriage among the CQ+SP group. We conclude that the efficacy of AQ+SP was significantly superior to the fixed-dose CQ+SP (Homapak), particularly among the youngest children. Thus, AQ could be used instead of CQ in combination with SP to improve the effectiveness against falciparum malaria in Uganda.     

Efficacy of chloroquine, amodiaquine, sulfadoxine-pyrimethamine, chloroquine-sulfadoxine-pyrimethamine combination, and amodiaquine-sulfadoxine-pyrimethamine combination in Central African children with noncomplicated malaria

This paper reports a two-phase study in Bangui, Central African Republic (CAR): first, we assessed the clinical efficacy to chloroquine (CQ), sulfadoxine-pyrimethamine (SP), and amodiaquine (AQ), then we tested the efficacy of two combinations: CQ + SP and AQ + SP. We used the standard 14-day WHO 2001 protocol to compare therapeutic responses in children under 5 years of age with acute uncomplicated Plasmodium falciparum malaria in Bangui between February 2002 and March 2004. The overall treatment failure rates with CQ, AQ, SP, CQ + SP, and AQ + SP were 40.9%, 20.0%, 22.8%, 7.2%, and 0%. These findings suggest that the Ministry of Health should recommend an interim policy with AQ + SP combination as the first-line antimalarial drug in Bangui until best alternative treatments like artemisinin-based combination therapies (ACTs) become available at low prices in the CAR.     

Efficacy of chloroquine and sulphadoxine-pyrimethamine either alone or in combination before introduction of ACT as first-line therapy in uncomplicated Plasmodium falciparum malaria in Jalpaiguri District, West Bengal, India

Objective In India, till recently, Chloroquine was used as first‐line therapy in areas with Chloroquine sensitive Plasmodium falciparum malaria cases. The National Vector Borne Disease Control Programme (NVBDCP) has introduced artemisinin combination therapy (ACT) as first‐line option to treat all P. falciparum cases in the country. This study was carried out to ascertain the efficacy of Chloroquine and Sulphadoxine‐Pyrimethamine, either alone or in combination, before the launch of ACT by NVBDCP. Methods A total of 300 P. falciparum malaria cases were enrolled randomly in three study arms, Chloroquine (CQ), Sulphadoxine‐Pyrimethamine (SP) and Chloroquine plus Sulphadoxine‐Pyrimethamine (CQ + SP). All patients were followed up for 28 days as per WHO (Assessment and Monitoring of Antimalarial Drug Efficacy for the Treatment of Uncomplicated Falciparum Malaria, Geneva, 2003) Protocol. Paired blood samples of treatment failure cases were collected and subjected to MSP 1, MSP 2 and GLURP genotyping for differentiation between re‐infection and recrudescence. The data were analysed by Kaplan–Meier survival curve according to WHO standard procedures. Results The overall failure rate including both early treatment failure (ETF) and late treatment failure (LTF) of CQ, SP and CQ + SP were 61%, 14% and 8%, respectively, in the study area. Of 60 recurrent malaria cases, genotyping was successful in 49 cases, revealing that most of the (46/49; 94%) cases of recurrent malaria were due to recrudescence. Conclusion In Jalpaiguri District the overall failure rate of CQ was 61% and of SP 14%, which was well above the WHO recommended cut‐off threshold level (10%) for change of drug policy.     

A randomized comparative study of chloroquine, amodiaquine and sulphadoxine-pyrimethamine for the treatment of uncomplicated malaria in Ghana

The study examined the efficacy of chloroquine (CQ), amodiaquine (AQ) and sulphadoxine-pyrimethamine (SP) for the treatment of uncomplicated Plasmodium falciparum malaria in Ghana. A total of 351 children were randomized to receive either of the three study drugs. Patients were evaluated using the WHO 14-day in vivo antimalarial testing guidelines. The 14-day adequate clinical and parasitological response analysis revealed that CQ, 46.7% (95% CI 37.5, 56.0) has the least efficacy compared with AQ, 86.1% (95% CI 78.3, 91.8) and SP, 77.6% (95% CI 68.9, 84.8). Late parasite failures were also lower and similar in the AQ and SP (9.6% and 10.3%) than in the CQ (32.5%) group. However, CQ and AQ groups showed better fever clearance compared with SP throughout except for day 7 and after when possibly due to its significant late clinical failures, clearance by CQ was lower. Our findings suggest that CQ is no longer useful in Ghana and should be replaced as a first-line treatment of malaria. Replacement of CQ preferably with AQ combination treatment will be an effective and an affordable alternative for the treatment of uncomplicated malaria.     

Low efficacy of amodiaquine or chloroquine plus sulfadoxine-pyrimethamine against Plasmodium falciparum and P. vivax malaria in Papua New Guinea

Because of increasing resistance to 4-aminoquinolines in Papua New Guinea, combination therapy of amodiaquine (AQ) or chloroquine (CQ) plus sulfadoxine-pyrimethamine (SP) was introduced as first-line treatment against uncomplicated malaria in 2000. The purpose of this study was to monitor in vivo efficacy of the current standard combination therapy against Plasmodium falciparum and P. vivax malaria. Studies were conducted between 2003 and 2005 in the Simbu, East Sepik, and Madang Provinces in Papua New Guinea according to the revised protocol of the World Health Organization (WHO) for assessment of antimalarial drug efficacy. Children between six months and seven years of age with clinically overt and parasitologically confirmed P. falciparum or P. vivax malaria were treated according to the new policy guidelines (i.e., AQ plus SP given to patients weighing < 14 kg and CQ plus SP given to patients weighing < 14 kg). Children were monitored up to day 28 and classified according to clinical and parasitological outcome as adequate clinical and parasitological response (ACPR), early treatment failure (ETF), late clinical failure (LCF), or late parasitological failure (LPF). For P. falciparum malaria, polymerase chain reaction (PCR)-corrected treatment failure rates up to day 28 ranged between 10.3% and 28.8% for AQ plus SP and between 5.6% and 28.6% for CQ plus SP, depending on the region and the year of assessment. Overall treatment failure rate with AQ or CQ plus SP for P. vivax malaria was 12%. Our results suggest that the current first-line treatment in Papua New Guinea is not sufficiently effective. According to the new WHO guidelines for the treatment of malaria, a rate of parasitological resistance greater than 10% in the two dominant malaria species in the country justifies a change in treatment policy.     

Antimalarial efficacy of sulfadoxine-pyrimethamine, amodiaquine and a combination of chloroquine plus sulfadoxine-pyrimethamine in Bundi Bugyo, western Uganda

We report below an in vivo antimalarial efficacy study conducted in 2002 in Bundi Bugyo, a district of western Uganda housing a large displaced population. We tested sulfadoxine-pyrimethamine (SP), amodiaquine (AQ) and the combination chloroquine plus SP (CQ + SP). A total of 268 children with uncomplicated Plasmodium falciparum malaria were followed-up for 28 days according to WHO recommendations, with PCR genotyping to distinguish late recrudescences from re-infections. PCR-adjusted failure proportions at day 28 were 37.0% (34/92, 95% CI 27.1-47.7) in the SP group, 20.6% (14/68, 95% CI 11.7-32.1) in the AQ group and 22.8% (18/79, 95% CI 14.1-33.6) in the CQ + SP group. Early failures were particularly frequent in the SP group (15.2%). Clearance of gametocytes was slower in the SP and CQ + SP groups than in the AQ group. This study suggests that, in Bundi Bugyo, CQ + SP (Uganda's first-line regimen) will need to be replaced by a more efficacious regimen. Across Uganda, the deployment of SP containing combinations may not be a feasible long-term strategy. For Bundi Bugyo, we recommend a combination of artesunate and AQ. Our study also confirms previous findings that resistance is considerably underestimated by 14-day follow-ups. Antimalarial policy decisions should therefore be based on 28-day studies, with PCR adjustment to distinguish re-infections.     

Efficacy of monotherapies and artesunate-based combination therapies in children with uncomplicated malaria in Somalia

In order to guide the antimalarial treatment policy of Somalia, we conducted therapeutic efficacy studies of routinely used antimalarial monotherapies as well as artemisinin-based combination therapies (ACTs) for uncomplicated malaria in three sentinel sites during 2003-2006. Therapeutic efficacy of chloroquine (CQ), amodiaquine (AQ) and sulfadoxine/pyrimetahmine (SP) monotherapies, and artesunate plus SP (AS + SP) or AQ (AS + AQ) were evaluated in children 6 months to 10 years old with uncomplicated malaria. For the assessment of the monotherapies, 2003 WHO protocol with 14-day follow-up was used while the 2005 WHO protocol with 28-day follow-up was used for testing the ACTs. Of the monotherapies, CQ performed very poorly with treatment failures varying from 76.5% to 88% between the sites. AQ treatment failure was low except for Janale site with treatment failure of 23.4% compared to 2.8% and 8% in Jamame and Jowhar, respectively. For SP, treatment failures from 7.8% to 12.2% were observed. A 28-day test of artemisinin-based combinations, AS + SP and AS + AQ, proved to be highly efficacious with cure rates of 98-100% supporting the choice of AS + SP combination as first line treatment for uncomplicated malaria for Somalia.     

Comparison of the therapeutic efficacy of chloroquine and sulphadoxine-pyremethamine in children and pregnant women

Objective To compare the parasitological failure rates of under‐fives and pregnant women with parasitaemia treated with chloroquine (CQ) or sulphadoxine‐pyrimethamine (SP). Methods During a clinical trial of CQ, SP, amodiaquine (AQ) and SP plus AQ combination for malaria treatment in pregnant women in Ghana, a parallel study of treatment of children below 5 years of age with symptomatic malaria with CQ and SP was undertaken. Four hundred and fifty pregnant women with malaria parasitaemia and 203 children with malaria parasitaemia were randomized to receive CQ or SP. They were followed up and parasitological failure by days 14 and 28 after the start of treatment was assessed. Results Polymerase chain reaction (PCR)‐uncorrected parasitological failure rates by day 28 after the start of treatment with CQ were 58.5% (55/94), 38.5% (45/117), 31% (13/42) and 8.2% (4/49) in children, primigravidae, secundigravidae and multigravidae, respectively. For those treated with SP the rates by day 28 were 36.4% (32/88), 27.1% (29/107), 6.1% (3/49) and 3.8% (2/52) in children, primigravidae, secundigravidae and multigravidae, respectively. In both CQ and SP treatment arms, children were twice as likely to experience recrudescence as pregnant women (RR 2.1 [95% CI 1.6–2.6] P < 0.0001) by day 28 after the start of treatment. Conclusions Parasitological failure rates were significantly lower in asymptomatic pregnant women, particularly in multigravidae, compared with symptomatic children. Reliance on drug sensitivity results observed in children only to decide on antimalarial regimes for pregnant women may not be appropriate.     

Efficacy of combination therapy with artesunate plus amodiaquine compared to monotherapy with chloroquine, amodiaquine or sulfadoxine-pyrimethamine for treatment of uncomplicated Plasmodium falciparum in Afghanistan

INTRODUCTION: In South and Central Asia resistance to chloroquine (CQ) has reached unmanageable levels, and resistance to sulfadoxine-pyrimethamine (SP) is emerging. Amodiaquine (AQ) is widely used in the region, and elsewhere shows only partial resistance to CQ. In Afghanistan, one option for slowing the spread of resistance and improving treatment outcomes is the use of artemisinin combination therapy (ACT). METHODS: The efficacy of CQ, AQ, SP and amodiaquine plus artesunate (AQ/AS) in the treatment of uncomplicated falciparum malaria was investigated using standard World Health Organization (WHO) procedures. Malaria patients were randomized to four treatment groups: 268 were enrolled and 240 completed the trial. RESULTS: There was a high level of cross-resistance between CQ and AQ resistance: adequate clinical and parasitological response by day 42 was 11% after CQ treatment and 9% after AQ treatment. The trend of treatment failure between AQ and CQ was almost identical. Cure rates were considerably improved by the addition of artesunate to AQ or by use of SP; adequate clinical and parasitological response being 72% for AQ/AS and 92% for SP. The combination of AS/AQ substantially reduced the odds of treatment failure relative to AQ monotherapy by day 42 [odds ratio (OR) = 0.03, 95% confidence interval (CI) 0.01-0.1] in addition to reducing the proportion of patients with gametocytes throughout the 42-day period. Gametocyte carriage rate was only marginally higher in the SP than in the CQ- and AQ-treated groups. CONCLUSION: The therapeutic and parasitological cure rates with AS/AQ were inadequate, and the criteria for deploying ACT - namely to prevent further selection of drug resistance from a position of low frequency - was not met in the region. An alternative drug combination to AQ/AS is required for Afghanistan.     

Comparative efficacy of aminoquinoline-antifolate combinations for the treatment of uncomplicated falciparum malaria in Kampala,Uganda

Resistance to chloroquine (CQ) requires its replacement as first-line therapy for uncomplicated malaria in much of Africa. Combination therapy may improve efficacy and delay the selection of resistant malaria parasites. Combinations of sulfadoxine-pyrimethamine (SP) with 4-aminoquinolines offer affordable and available alternatives to CQ. We conducted a randomized, single-blinded trial to compare the efficacy of SP monotherapy with combinations of SP and either CQ or amodiaquine (AQ) for the treatment of uncomplicated falciparum malaria in patients over 6 months of age in Kampala, Uganda. Of the 448 patients enrolled, 428 (95%) completed follow-up. Clinical treatment failure after 14 days occurred in 21/140 (15.0%, 95% CI 9.5-22.0%) SP-treated, 11/152 (7.2%, 95% CI 3.7-12.6%) SP/CQ-treated, and 0/136 (0%, 95% CI 0-2.7%) SP/AQ-treated patients. Combination therapies were safe and offered superior efficacy to SP monotherapy. SP/AQ was the most efficacious. This low-cost combination regimen may provide an optimal alternative to CQ for the treatment of uncomplicated malaria in Uganda.     

Evidence basis for antimalarial policy change in Sierra Leone: five in vivo efficacy studies of chloroquine, sulphadoxine-pyrimethamine and amodiaquine

OBJECTIVES: To provide nationally relevant information on the antimalarial efficacy of chloroquine (CQ), sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) in Sierra Leone, with a view to updating antimalarial policy in the country. METHODS: Between October 2002 and May 2003, standard WHO methodology for in vivo efficacy assessment was used in five sites to study the therapeutic response of 6-59 months old uncomplicated Plasmodium falciparum malaria cases treated with CQ (n = 247), SP (n = 353) or AQ (n = 434). Follow-up was of 28 days, with polymerase chain reaction genotyping to distinguish late recrudescences from re-infections. RESULTS: Overall 85.3% of patients reached an analysable endpoint. CQ failure proportions were very high, ranging from 39.5% (95% CI: 25.0-55.6) in Kabala to 78.8% (65.3-88.9) in Kailahun. Early failures under CQ were frequent. SP efficacy was also disappointing, with failure from 23.2% (13.9-34.9) in Kabala to 46.1% (35.4-57.0) in Kailahun. AQ resistance was more moderate, ranging from 5.4% (1.8-12.1) in Makeni to 29.8% (20.3-40.8) in Kailahun, with almost no early failures. AQ also provided more rapid fever and parasite clearance. CONCLUSION: In a consensus meeting organized by the Ministry of Health and Sanitation, and based on these findings, artesunate (AS) + AQ and artemether-lumefantrine (Coartemtrade mark) were identified as the only options to rapidly replace CQ. The choice fell on AS + AQ because of expected high efficacy, lower cost in a blister presentation, and the absence of safety data on artemether-lumefantrine in pregnancy. Donor support is required to support this policy change. Throughout Africa, as SP resistance increases, these two regimens are probably the only options available while newer combinations are developed. Efficacy studies should focus on testing AQ and AS + AQ.     

Amodiaquine, sulfadoxine-pyrimethamine, and combination therapy for uncomplicated falciparum malaria: a randomized controlled trial from Burkina Faso

Increasing resistance to chloroquine necessitates the evaluation of other antimalarial therapies in Africa. We compared the efficacies of amodiaquine (AQ), sulfadoxine-pyrimethamine (SP), and AQ + SP for the treatment of uncomplicated falciparum malaria in a randomized trial of patients 6 months of age or older in Bobo-Dioulasso, Burkina Faso. Of the 944 patients enrolled, 829 (88%; 53% under 5 years of age) were assigned 28-day efficacy outcomes. For all regimens, early treatment failures were uncommon (< 2%). Considering all treatment failures based on WHO criteria, AQ + SP was most efficacious (failures in 4.2%), followed by SP (9.1%) and AQ (17.9%; P < 0.02 for all pairwise comparisons). Considering only clinical failures, relative efficacies were similar (failures in 2.1% with AQ + SP, 6.5% with SP, and 13.2% with AQ; P < 0.02 for all pairwise comparisons). The risk of recrudescence was lower with AQ + SP (2.1%) compared with SP (6.1%, P = 0.02) and AQ (8.1%, P = 0.001). Risks of new infection were lower with AQ + SP (2.1%) and SP (2.4%) compared with AQ (9.1%, P < 0.001 for both comparisons). No serious adverse events were seen. AQ + SP appears to offer a highly effective, inexpensive, and available therapy for the treatment of uncomplicated malaria in Burkina Faso.     

A randomized trial of chloroquine, amodiaquine and pyrimethamine-sulphadoxine in Gambian children with uncomplicated malaria

The increasing occurrence of chloroquine-resistant Plasmodium falciparum in sub-Saharan Africa makes it essential to reconsider current recommendations for the treatment of uncomplicated P. falciparum malaria. In an open, randomized trial, we have compared chloroquine (CQ), amodiaquine (AQ), and pyrimethamine-sulphadoxine (PS) in rural Gambian children with uncomplicated P. falciparum malaria. Three hundred children were randomly assigned at the time of consultation (Do) to oral treatment with 25 mg/kg CQ, 25 mg/kg AQ (both given over 3 days), or 1.25/25 mg/kg PS. They were reviewed on day 7 (D7) and day 28 (D28) for symptoms, malaria parasitaemia, and packed cell volume (PCV). Significantly more children treated with PS compared to CQ (17 vs 7%, P=0.03) or AQ (17 vs 3%, P=0.001) returned with clinical complaints during the first 3 days after treatment. Five of these patients had a generalized convulsion (4 from the AQ group, 4 from the PS group), of whom 4 developed cerebral malaria. At D7, significantly more patients treated with CQ compared to AQ (25 vs 7%, P=0.0009) or PS (25 vs 4%, P=0.0001) were parasitaemic. By D28, the cumulative number of parasitological failures was significantly higher in the CQ group compared to the AQ group (65 vs 35%, P=0.0001), and significantly higher in the AQ group compared to the PS group (35 vs 14%, P=0.001). Overall, 91% of parasitological failures observed during the study period were symptomatic and were consequently treated with an alternative anti-malarial drug. Over the 28-day study period the mean PCV increased significantly less in the CQ group than in the PS group (1.2 vs 3.8%, P=0.016) and was lower in the CQ group than in the AQ group (1.2 vs 2.7%, P=0.12, not significant). These results suggest that PS acts more slowly than 4-aminoquinolines in controlling the clinical features of malaria, and that AQ can be considered as an interim alternative to CQ in the first-line therapy of uncomplicated malaria in African areas of high CQ resistance.     

The safety and efficacy of sulfadoxine-pyrimethamine,amodiaquine, and their combination in the treatment of uncomplicated Plasmodium falciparum malaria

The safety and efficacy of amodiaquine (AQ), sulfadoxine-pyrimethamine (SP), and coadministered AQ+SP was assessed in 351 Tanzanian children (age range, 6-59 months) with uncomplicated Plasmodium falciparum malaria. This open, randomized study followed the 28-day World Health Organization (WHO) protocol and evaluated safety using clinical and laboratory parameters. Children receiving SP were more likely to vomit during follow-up (32% vs. 17%: P = 0.03), and SP alone resulted in prolonged fever clearance times. Although Day 7 and Day 14 clinical and parasitological cure rates were similar, by Day 28 45% of children treated with AQ demonstrated R1 resistance and 27.5% were clinical failures compared with 25% and 6.3%, respectively, for SP alone. Coadministered AQ+SP was safe, combined the greater clinical (96.2%) and parasitological (64.2%) efficacy of SP with the more rapid symptom resolution of AQ, and reduced the incidence of gametocytemia during follow-up (AQ+SP 12.6% vs. SP 29.9%; P = 0.001). The level of R1 resistance to SP may herald a rapid decline in its efficacy as SP drug pressure increases. Coadministration of AQ+SP may delay this.     

Efficacy of sulphadoxine-pyrimethamine alone or combined with amodiaquine or chloroquine for the treatment of uncomplicated falciparum malaria in Ugandan children

The rapid development of falciparum resistance to sulphadoxine-pyrimethamine (SP) in East and Central Africa has raised concerns as to the efficacy of combining it with another drug. In 2002, we assessed the efficacy of SP alone and combined with amodiaquine (AQ/SP) or chloroquine (CQ/SP) in Ugandan children with uncomplicated falciparum malaria. At day 14, adequate clinical response was 100% (84/84) for AQ/SP, 93% (92/101) for CQ/SP and 91% (73/80) for SP. At day 28, parasitological failure (RI-RIII) occurred in 16% (13/80) of children treated with AQ/SP, in 48% (48/100) of those treated with CQ/SP and in 61% (48/79) of those treated with SP alone. Compared with the AQ/SP arm, the odds for parasitological failure at day 28 were five times higher (95% CI, 2-10) in the CQ/SP group and sevenfold higher (95% CI, 3-17) in that of SP alone. CQ/SP does not offer any significant added benefit over SP alone while AQ/SP is an efficacious low-cost combination. These findings have important policy implications for Uganda and other resource-constrained African countries faced with the problematic choice of a new first-line antimalarial treatment in a context of high CQ resistance.     

A randomized, placebo-controlled, double-blind trial on sulfadoxine-pyrimethamine alone or combined with artesunate or amodiaquine in uncomplicated malaria

The therapeutic efficacy of sulfadoxine-pyrimethamine (SP) alone, SP plus amodiaquine (AQ), and SP plus artesunate (AS) was assessed in a randomized, placebo-controlled, and double-blind trial among 438 children with uncomplicated Plasmodium falciparum malaria in northern Ghana. Clinical and parasitological responses were monitored for 28 days following treatment; 86%, 98% and 97% of SP-, SP + AQ-, and SP + AS-treated patients achieved adequate clinical and parasitological response (ACPR) within 2 weeks, respectively. Parasite clearance was better with SP + AS than with SP or SP + AQ treatment but re-infections were more common. Polymerase chain reaction (PCR)-corrected rates of ACPR at day 28 were 72.2% for SP, 94.1% for SP + AQ (P < 0.0001), and 94.5% for SP + AS (P < 0.0001). Gametocyte prevalence and density 1 week after treatment were highest in children treated with SP, and lowest in patients receiving SP + AS. No severe adverse events attributable to study medication were observed. In northern Ghana, more than one of four children suffered SP treatment failure within 4 weeks. Both SP + AQ and SP + AS are efficacious alternative therapeutic options in this region. Although SP + AS and SP + AQ treatments have virtually identical cure rates, rapid parasite clearance and pronounced gametocidal effects are the advantages of the former, whereas cost and a lower rate of late re-infections are those of the latter.     

Efficacy, safety, and selection of molecular markers of drug resistance by two ACTs in Mali

We conducted a randomized single-blinded trial comparing the efficacy and safety of artesunate (AS) + amodiaquine (AQ, 3 days) versus AS (3 days) + sulfadoxine-pyrimethamine (SP, single dose) versus AS monotherapy (5 days) in Southern Mali. Uncomplicated malaria cases were followed for 28 days. Molecular markers of drug resistance were determined. After identification of recrudescences by genotyping, both artemisinin-based combination therapies (ACTs) reached nearly 100% efficacy at Day 14 and Day 28 versus 98.3% and 96.5% for AS, respectively (P > 0.05). AS + SP significantly selected DHFR and DHPS mutations associated with sulfadoxine and pyrimethamine resistance (P < 0.001), and AS + AQ equally selected PfCRT and PfMDR1 point mutations associated with chloroquine and AQ resistance (P < 0.001). No significant adverse event attributable to any of the study drugs was found. The ACTs were efficacious and safe, but the selection of markers for resistance to the partner drugs raises concerns over their lifespan in areas of intense malaria transmission.     

Efficacy of chloroquine, sulphadoxine-pyrimethamine and amodiaquine for treatment of uncomplicated Plasmodium falciparum malaria in Kajo Keji county, Sudan

To provide advice on the rational use of antimalarial drugs, Médecins Sans Frontières conducted a randomized, an open label efficacy study in Kajo Keji, an area of high transmission of malaria in southern Sudan. The efficacy of chloroquine (CQ), sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) were measured in a 28-day in vivo study, with results corrected by PCR genotyping. Of 2010 children screened, 115 children aged 6-59 months with uncomplicated Plasmodium falciparum malaria were randomized into each group to receive a supervised course of treatment. Of these, 114, 103 and 111 were analysed in the CQ, SP and AQ groups, respectively. The overall parasitological failure rates at day 28 were 93.9% [95% confidence interval (CI) 87.3-97.3] for CQ, 69.9% (95% CI 60.0-78.3) for SP, and 25.2% (95% CI 17.7-34.5) for AQ. These results provide important missing data on antimalarial drug efficacy in southern Sudan. They indicate that none of the drugs could be used in monotherapy and suggest that even in combination with artemisinin, cure rates might not be efficacious enough. We recommend a combination of artemether and lumefantrine as first-line treatment for uncomplicated P. falciparum malaria cases in Kajo Keji county.     

Tolerability of amodiaquine and sulphadoxine-pyrimethamine, alone or in combination for the treatment of uncomplicated Plasmodium falciparum malaria in Rwandan adults

OBJECTIVE: To assess the tolerability and efficacy of amodiaquine (AQ)+sulphadoxine-pyrimethamine (SP), the first-line malaria treatment in Rwanda. METHOD: Randomized, double-blind trial in 2003 in Kigali town. A total of 351 adult patients with uncomplicated Plasmodium falciparum malaria were randomly allocated to one of the following treatments: AQ+SP, AQ or SP. We followed patients until day 14 after treatment and recorded adverse events (AEs) and clinical and parasitological outcomes. RESULTS: One hundred and eighteen patients reported at least one AE: 40% in the AQ, 39% in the AQ+SP and 21% in the SP groups. The AE was classified as possibly related to the antimalarial treatment for 86 patients. The Risk Ratio for at least one AE after treatment was significantly and about fourfold higher in patients receiving AQ or AQ+SP than in patients receiving SP. Pruritus and fatigue were significantly more frequent in patients treated with AQ or AQ+SP than in those receiving SP. Severe AEs, such as fatigue, nausea, dizziness and vomiting, were observed in four patients treated with AQ, in 10 treated with AQ+SP and in one patient treated with SP. CONCLUSION: Amodiaquine+SP is not well tolerated and a substantial proportion of patients experienced pruritus and fatigue, thus decreasing their compliance and compromising the first line treatment implementation at national level. This renders AQ-containing regimens sub-optimal; better-tolerated treatments should be identified.     

Efficacy of artesunate plus amodiaquine, artesunate plus sulfadoxine-pyrimethamine, and chloroquine plus sulfadoxine-pyrimethamine in patients with uncomplicated Plasmodium falciparum in the Comoros Union

Health policy makers in Comoros Union have considered a policy change recommending combination treatment to control malaria. We evaluated the efficacy of three antimalarial drug combinations, taken orally, to enable the authorities to make an evidence-based choice. The study was carried out in patients of 2-70 years old in Moroni, Moheli and Anjouan in 2003. We enrolled 168 patients with uncomplicated malaria from 1097 outpatients screened at the health centres. One hundred and fifty-eight patients, of whom half were under five years old, (mean age=11.1+/-13.9 years), were followed up for 14 days. According to PCR adjusted outcome, the therapeutic efficacy of artesunate+amodiaquine (AS+AQ) (n=54) and artesunate+sulfadoxine-pyrimethamine (AS+SP) (n=53) was 100%, whereas that of chloroquine+sulfadoxine-pyrimethamine (CQ+SP) was 98% (50/51). The key difference between these treatments was the higher parasite clearance rate on Day 2 obtained with artesunate-containing combinations (P<0.001). These results provide a baseline for monitoring changes in the susceptibility of Plasmodium falciparum to artesunate+amodiaquine and artesunate+sulfadoxine-pyrimethamine (ACTs) in the Comoros Union. Health policy changes involving the replacement of chloroquine in the Indian Ocean subregion are discussed.