Efficacy of chloroquine,sulfadoxine-pyrimethamine,and mefloquine for the treatment of uncomplicated Plasmodium falciparum malaria on the north coast of Peru

As part of an effort to assess antimalarial drug resistance in Peru, we carried out 14-day in vivo efficacy trials of chloroquine (CQ; 25 mg/kg) and sulfadoxine-pyrimethamine (SP; 25 mg/kg of the sulfadoxine component) for the treatment of uncomplicated Plasmodium falciparum infections at three sites on the northern coast of Peru. Mefloquine (MQ; 15 mg/kg) also was evaluated at one site. The results from all three sites were similar. Of the 53 patients treated with CQ, 58.5% had RII/RIII responses. No RIII failures were observed among the 112 patients who received SP, but 4.5% and 1.8%, respectively, had RII and RI responses. All 33 patients treated with MQ showed a sensitive response. Early treatment failures were observed in 27.1% of the CQ patients but in no patients receiving SP or MQ. Late treatment failures were seen in 59.3% of the CQ patients and 6.4% of the SP patients but in none of those treated with MQ. Based on these findings and because of concern about the potential for development of resistance if SP were used alone, the National Malaria Control Program is planning a change in malaria treatment policy to SP-artesunate combination therapy for this region of the country.     

Therapeutic efficacy of chloroquine plus sulphadoxine/ pyrimethamine compared with monotherapy with either chloroquine or sulphadoxine/pyrimethamine in uncomplicated Plasmodium falciparum malaria in Laos

In a southern border province of Lao PDR, we compared the efficacy of antimalarial drug combinations in patients aged >or=1 year with uncomplicated Plasmodium falciparum malaria: monotherapy with either mefloquine (MQ), chloroquine (CQ), or sulphadoxine/pyrimethamine (SP) vs. the combination of both CQ and SP. Follow-up time was 14 days. Of 265 P. falciparum positive patients, 119 were enrolled in the drug trial. Significantly more patients treated with CQ than with SP developed early or late treatment failure [44.8%vs. 17.9%, relative risk (RR) = 2.51, 95% CI 1.03-6.12]. In the SP group, 82.1% were sensitive and 17.9% were treatment failures. The combination treatment CQ plus SP resulted in 83.3% sensitivity and 16.7% treatment failures. Combination treatment has no advantage over monotherapy with SP (RR = 1.01, 95% CI 0.8-1.3). All patients who received MQ for treatment (total dose 25 mg/kg) were cured within the 14 days of follow-up. The findings of this study suggest that use of CQ as first-line treatment of uncomplicated malaria in the Lao PDR has to be reconsidered. The combination of both CQ and SP has been discussed as a cost-effective alternative treatment, but in our patient population achieved no better results than single therapy with SP.     

Comparison of chloroquine, sulfadoxine/pyrimethamine, mefloquine and mefloquine-artesunate for the treatment of falciparum malaria in Kachin State, North Myanmar

Multi-drug resistant falciparum malaria is widespread in Asia. In Thailand, Cambodia and Vietnam the national protocols have changed largely to artesunate combined treatment regimens but elsewhere in East and South Asia chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) are still widely recommended by national malaria control programmes. In Kachin State, northern Myanmar, an area of low seasonal malaria transmission, the efficacy of CQ (25 mg base/kg) and SP (1.25/25 mg/kg), the nationally recommended treatments at the time, were compared with mefloquine alone (M; 15 mg base/kg) and mefloquine combined with artesunate (MA; 15:4 mg/kg). An open randomized controlled trial enrolled 316 patients with uncomplicated Plasmodium falciparum malaria, stratified prospectively into three age-groups. Early treatment failures (ETF) occurred in 41% (32/78) of CQ treated patients and in 24% of patients treated with SP (18/75). In young children the ETF rates were 87% after CQ and 35% after SP. Four children (two CQ, two SP) developed symptoms of cerebral malaria within 3 days after treatment. By day 42, failure rates (uncorrected for reinfections) had increased to 79% for CQ and 81% for SP. ETF rates were 2.5% after treatment with M and 3.9% after treatment with MA (P > 0.2). Overall uncorrected treatment failure rates at day 42 following M and MA were 23% and 21%, respectively. Chloroquine and SP are completely ineffective for the treatment of falciparum malaria in northern Myanmar. Mefloquine treatment is much more effective, but three day combination regimens with artesunate will be needed for optimum efficacy and protection against resistance.     

Efficacy of sulfadoxine/pyrimethamine in the treatment of uncomplicated Plasmodium falciparum malaria in Republic of Congo

Congo is facing frequent failures of treatment of Plasmodium falciparum malaria with chloroquine (CQ), which is still recommended and used as a first-line drug. In Pointe-Noire and Brazzaville, the two largest cities that contain approximately 60% of the population of Congo, we compared the efficacy of CQ versus sulfadoxine/pyrimethamine (SP) for treatment of uncomplicated malaria in children 6-59 months old (mean = 33 months) using the standard World Health Organization (WHO) 14-day in vivo test in two phases between 1999 and 2002. Patients enrolled were randomly assigned to receive SP (25 mg/kg of sulfadoxine and 1.25 mg/kg of pyrimethamine) or CQ (25 mg/kg). In the first phase of the study, 46 patients were assigned to the CQ (n = 23) or SP (n = 23) groups in Pointe-Noire and 52 children were assigned to the CQ (n = 26) or to SP (n = 26) groups in Brazzaville. Results were interpreted according to the WHO lot quality assurance sampling method, and treatment failure rates for SP versus CQ were < 25% versus > 25% in both cities. In the second phase of the study, we accurately determined the actual proportion of treatment failures for SP in Brazzaville. Thus, in 75 of the 80 children enrolled and followed-up until day 14, no clinical or parasitologic failure was recorded and no serious adverse reaction was observed. Since the CQ treatment failure rate exceeds the unacceptable upper limit, SP seems well to be an appropriate alternative for the first-line treatment of uncomplicated P. falciparum malaria, at least in the settings of the present study.     

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.     

A community perspective on the efficacy of malaria treatment options for children in Lundazi district, Zambia

In 1996, Zambia's Ministry of Health made sulfadoxine-pyrimethamine (SP) available as a second-line antimalarial. SP differs from chloroquine (CQ) in ways that might affect parents' acceptance of the drug, resulting in possible delays in seeking treatment if parents perceive SP as less efficacious. A multifaceted study consisting of a rapid community ethnographic assessment to examine local attitudes and perceptions toward malaria, a 14-day in vivo drug efficacy study comparing clinical and parasitological efficacy of CQ, SP, and SP with paracetamol (PCM) in children under five, and a qualitative study examining caretakers' perceptions of drug efficacy helped to guide implementation of the new drug policy. The rapid ethnographic study indicated that the community was aware of malaria as an illness best treated with modern medicines, particularly CQ. The drug efficacy study demonstrated a 25% level of clinical failures compared to none with SP, and 30% of the children treated with CQ had either RIII or RII parasitological failures whereas none occurred in children treated with SP. Most parents perceived that their children were improving and that the drugs were working. Parents in the SP groups were most pleased and readily accepted SP as a new drug. The addition of PCM did not improve perceptions of SP efficacy, contradicting conventional wisdom regarding the need for direct antipyretic action for parents to perceive a drug as efficacious. The combined results reflected a community that was in the beginning stages of evaluating a new malaria therapy mostly unknown to them. Perceptions of efficacy of CQ were beginning to shift, indicating a readiness for accepting a new drug based on its shown biological efficacy. Parasitological and clinical failure rates reinforced the need to fully implement the changed national policy as soon as possible, and to consider a change in first-line therapy.     

Efficacy of mefloquine and sulfadoxine-pyrimethamine for the treatment of uncomplicated Plasmodium falciparum infection in Machinga District, Malawi, 1998.

In response to the spread of chloroquine-resistant Plasmodium falciparum, Mala?i changed its first-line antimalarial drug in 1993 from chloroquine to sulfadoxine-pyrimethamine (SP). Surveillance data has suggested that resistance to SP may be increasing. We compared the efficacy of SP with a potential successor, mefloquine (MQ). By use of a modified World Health Organization in vivo protocol, children infected with P. falciparum were randomized to receive SP (sulfadoxine 25 mg/kg) or MQ (15 mg/kg). We observed combined RII and RIII parasitologic failures of 20.0 and 22.0% in the SP and MQ arms, respectively. Among those in the MQ arm, the relative hazard of failing with a Day 2 drug level < 500 ng/mL was 10.6 times higher than those with levels > or = 500 ng/mL. Given the decreased efficacy of the first-line antimalarial drug and the high failure rates of MQ at this lower dosage, Mala?i should consider assessing the efficacy and feasibility of alternative drugs to treat uncomplicated falciparum malaria.     

A systematic approach to the development of a rational malaria treatment policy in Zambia

Despite the spread of chloroquine-resistant Plasmodium falciparum throughout sub-Saharan Africa, chloroquine (CQ) remains the first-line treatment for uncomplicated infection in most countries. To assess the efficacy of CQ and sulphadoxine-pyrimethamine (SP) in Zambia, studies using a standardized 14-day in vivo test were conducted at 6 geographically representative sites. Febrile children ≤ 5 years of age were treated with standard doses of CQ or SP and monitored for parasitological failure (using modified WHO criteria) and clinical failure (fever with parasitaemia after completion of therapy). RII/RIII (high to moderate level) parasitological failures were identified in 34% to 70% of CQ-treated children (total N = 300) at the 6 sites and clinical failures in 31% to 48%. SP testing at 2 sites identified RII/RIII failures in 3% and 17% of children and only 1 clinical failure at each site. Because of the high levels of CQ resistance identified in these trials, the Ministry of Health of Zambia convened a national consensus meeting which recommended that Zambia's national malaria treatment policy be modified to make SP available at all health facilities for use in persons who fail initial therapy with CQ. In addition, selected sites, staff, and the methodology from these studies were used to implement a sentinel surveillance system for antimalarial drug efficacy. This systematic approach to antimalarial drug efficacy testing could be easily replicated in other countries seeking to reassess their malaria treatment policies.     

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.     

Sulfadoxine-pyrimethamine monotherapy in Tanzanian children gives rapid parasite clearance but slow fever clearance that is improved by chloroquine in combination therapy

Following widespread chloroquine (CQ) resistance, sulfadoxine plus pyrimethamine (SP) is now the first line antimalarial drug in a number of African countries including Tanzania. Unlike CQ, SP has no antipyretic effects, a feature that might delay fever clearance, and by acting on late stage parasites, SP could theoretical be slow in parasite clearance. We therefore assessed the antipyretic effects of CQ in therapeutic combination with SP, and the speed of parasite clearance by SP in an open-labelled, randomized trial of CQ alone (n=39), SP alone (n=39), SP plus CQ (n=37) and SP plus paracetamol (PCM) (n=38) in children with uncomplicated malaria. Over 72 h, there were eight (20.5%) treatment failures in the CQ group but none in the other groups. Although not significant (P > 0.1), irrespective of resistance CQ alone had a shorter median survival time to fever clearance than SP alone (54 vs. 60 h). SP plus CQ had a highly significantly shorter median survival time to fever clearance than SP alone (48 vs. 60 h) (P < 0.001). Although borderline (P=0.038), the median survival time to parasite clearance was significantly longer in SP plus PCM (72 h) than SP alone (48 h). Irrespective of resistance, CQ alone had a median survival time to parasite clearance equal to that of SP alone (48 h). Parasite clearance by SP was rapid and at the end of 72 h, most (77.3%, 95% confidence interval: 69.6, 85.0) of the children on SP (as a group) had become aparasitaemic. The findings rule out concerns on possible delayed parasitological and clinical responses to SP that could result from its action on late stage parasites. Despite its diminishing antimalarial activity, CQ has beneficial in vivo antipyretic effects in therapeutic combination with SP.     

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.     

Assessment of therapeutic response of Plasmodium falciparum to chloroquine and sulfadoxine-pyrimethamine in an area of low malaria transmission in Colombia

Although chloroquine (CQ) resistance was first reported in Colombia in 1961 and sulfadoxine-pyrimethamine (SP) resistance in 1981, the frequency of treatment failures to these drugs in Colombia is unclear. A modified World Health Organization 14-day in vivo drug efficacy test for uncomplicated Plasmodium falciparum malaria in areas with intense malaria transmission was adapted to reflect the clinical and epidemiologic features of a low-intensity malaria transmission area in the Pacific Coast Region of Colombia. Patients > or =1 year of age with a parasite density > or =1,000 asexual parasites per microliter were enrolled in this study. Forty-four percent (24 of 54) of the CQ-treated patients were therapeutic failures, including 7 early treatment failures (ETFs) and 17 late treatment failures (LTFs). Four (6%) of 67 SP-treated patients were therapeutic failures (2 ETFs and 2 LTFs). Therapeutic failure in the CQ-treated group was associated with an age <15 years old (P < 0.01), but was not associated with initial parasite density, the presence of CQ or sulfa-containing drugs in urine, or a history of malaria. The high level of therapeutic failures to CQ detected in this study underscores the need and importance of drug efficacy evaluation in the development of a rational national antimalarial drug policy. The relatively low level of therapeutic failures to SP compared with other South American countries raises further questions regarding factors that might have prevented the rapid development of in vivo resistance to this drug combination.     

The efficacy of sulfadoxine-pyrimethamine alone and in combination with chloroquine for malaria treatment in rural Eastern Sudan: the interrelation between resistance, age and gametocytogenesis

OBJECTIVE: To compare the efficacy of sulfadoxine-pyremethamine (SP)+chloroquine (CQ) combination treatment against falciparum malaria with SP treatment alone. METHOD: In-vivo study of 254 patients with uncomplicated Plasmodium falciparum malaria in rural eastern Sudan, where the population is semi-immune. RESULTS: Sulfadoxine-pyremethamine treatment alone cured 68.3% (41/60) and SP+CQ cured 63.4% (123/194). Early and late treatment failures occurred in both treatment groups. Host age (as a marker for immunity) and parasite gametocytogenesis (as a marker for transmissibility) were significantly associated with SP resistance. Patients who were cured were significantly older (median age 21 years) than patients whose treatment failed (median age 12 years). Gametocyte production was significantly higher in patients with treatment failure (0.72 vs 0.45) and associated with younger age. Gametocyte counts were comparable between both groups until day 7 of follow up; thereafter, they were significantly higher in patients with treatment failure. However, the longevity of gametocytes was comparable in both treatment groups. CONCLUSION: Chloroquine did not improve the parasite response to SP. Age was strongly associated with clearance of SP-resistant parasites. The fast rise of SP resistance may partially be due to selection of SP resistant parasites and expansion of the resistant population through the gametocytogenic effect of SP.     

Therapeutic responses of Plasmodium vivax and P. falciparum to chloroquine, in an area of western India where P. vivax predominates

In 2003-2005, following an increase in the local incidence of human malaria, the therapeutic efficacy of chloroquine (CQ) in the treatment of Plasmodium vivax and P. falciparum malaria was evaluated in the Anand district of Gujarat state, in western India. After oral administration of CQ, clinical and parasitological responses were measured over a follow-up period of 28 days, following the standard protocol of the World Health Organization. Most of the recurrent infections were checked, by genotyping, to see whether they were the result of treatment failure or re-infection during the follow-up. At the primary health centre (PHC) in Deva, all 57 P. vivax cases included in the study responded to CQ within 3 days. At the Pansora PHC, however, only 59 [90.8%, with a 95% confidence interval (CI) of 83.7%-97.8%] of the 65 P. vivax cases appeared to respond completely, recurrent infections being observed in the other six cases (9.2%; CI=2.2%-16.3%). Of the four recurrent infections checked by genotyping, however, only two appeared to be the result of true treatment failure. Twenty-seven (81.8%; CI=67.2%-94.4%) of the 33 P. falciparum cases who were enrolled in the study, all from Pansora PHC also showed apparent treatment failure, with one early failure, 17 late clinical failures and nine late parasitological failures. All 23 P. falciparum cases that showed apparent treatment failure and were investigated by genotyping appeared to be true cases of failure, none showing any evidence of re-infection during follow-up. The mean parasite-clearance times for those infected with P. falciparum, both those considered CQ-sensitive and the treatment failures, exceeded 2 days. These results indicate the presence of CQ-resistant P. vivax and P. falciparum in Anand district. The high frequency of CQ failure against P. falciparum observed in this study led to a change in the drug policy at the Pansora PHC, with artemisinin-based combination therapy now being used for the first-line treatment of P. falciparum malaria. Chloroquine remains the recommended first-line treatment for P. vivax infections in the area but the treatment failure seen in at least two P. vivax cases indicates a need for further monitoring of the therapeutic efficacy of CQ against such infections, in central Gujarat and elsewhere.     

Marked differences in the prevalence of chloroquine resistance between urban and rural communities in Burkina Faso

BACKGROUND: Chloroquine (CQ) resistance has reached high levels in Africa in recent years. Little is known about variations of resistance between urban and rural areas. OBJECTIVES: To compare the rates of in vivo resistance to CQ and the prevalences of the main molecular marker for CQ resistance among young children from urban and rural areas in Burkina Faso. METHODS: The current analysis used the frame of a randomized controlled trial (ISRCTN27290841) on the combination CQ-methylene blue (MB) (n=177) compared to CQ alone (n=45) in young children with uncomplicated malaria. We examined clinical and parasitological failure rates as well as the prevalence of the Plasmodium falciparum chloroquine resistance transporter gene (pfcrt) T76 mutation. RESULTS: Clinical and parasitological failure rates of CQ-MB differed significantly between urban (70%) and rural areas (29%, p<0.0001). Likewise, CQ failure rates were higher in the urban setting. Matching this pattern, pfcrt T76 was more frequently seen among parasite strains from urban areas (81%) when compared to rural ones (64%, p=0.01). In the presence of parasites exhibiting pfcrt T76, the odds of overall clinical failure were increased to 2.6-fold ([1.33, 5.16], p(LR)=0.005). CQ was detected at baseline in 21% and 2% of children from the urban and the rural study area, respectively (p(Chi)=0.002). CONCLUSION: Even within circumscribed geographical areas, CQ efficacy can vary dramatically. The differences in the prevalence of pfcrt T76 and in CQ failure rates are probably explained by a higher drug pressure in the urban area compared to the rural study area. This finding has important implications for national malaria policies.     

Chloroquine or sulfadoxine-pyrimethamine for the treatment of uncomplicated,Plasmodium falciparum malaria during an epidemic in Central Java,Indonesia

A recent malaria epidemic in the Menoreh Hills of Central Java has increased concern about the re-emergence of endemic malaria on Java, which threatens the island's 120 million residents. A 28-day, in-vivo test of the efficacy of treatment of malaria with antimalarial drugs was conducted among 167 villagers in the Menoreh Hills. The treatments investigated, chloroquine (CQ) and sulfadoxine-pyrimethamine (SP), constitute, respectively, the first- and second-line treatments for uncomplicated malaria in Indonesia. The prevalence of malaria among 1389 residents screened prior to enrollment was 33%. Treatment outcomes were assessed by microscopical diagnoses, PCR-based confirmation of the diagnoses, measurement of the whole-blood concentrations of CQ and desethylchloroquine (DCQ), and identification of the Plasmodium falciparum genotypes. The 28-day cumulative incidences of therapeutic failure for CQ and SP were, respectively, 47% (N = 36) and 22% (N = 50) in the treatment of P. falciparum, and 18% (N = 77) and 67% (N = 6) in the treatment of P. vivax. Chloroquine was thus an ineffective therapy for P. falciparum malaria, and the presence of CQ-resistant P. vivax and SP-resistant P. falciparum will further compromise efforts to control resurgent malaria on Java.     

Efficacy of amodiaquine alone and combined with sulfadoxine-pyrimethamine and of sulfadoxine pyrimethamine combined with artesunate

The safety and the efficacy of amodiaquine (AQ) alone, AQ plus sulfadoxine-pyrimethamine (SP) (AQ plus SP), and artesunate (ART) plus SP (ART plus SP), three possible alternatives to chloroquine (CQ), were investigated in 379 Rwandan children 6-59 months old with uncomplicated Plasmodium falciparum malaria who visited one urban/peri-urban health center and two rural health centers. The three treatment regimens were well tolerated and no serious adverse effects were observed. Children treated with AQ plus SP had less clinical failures than those treated with ART plus SP (odds ratio [OR] = 0.25, 95% confidence interval [CI] = 0.06-0.81, P = 0.01) or AQ alone (OR = 0.33, 95% CI = 0.07-1.10, P = 0.08). Even after new infections were excluded, AQ plus SP was still significantly more efficacious than ART plus SP (P = 0.05). At day 14, the mean packed cell volume was significantly higher in the AQ plus SP group compared with the ART plus SP group (P = 0.02) and with the AQ alone group (P = 0.01). In Rwanda, AQ plus SP has been chosen to replace CQ as a first-line treatment. However, this is considered an interim measure and new combinations, possibly co-formulated, should be identified and tested.     

Detection of in-vivo chloroquine resistance in Plasmodium falciparum from Rameswaram Island, a pilgrim centre in southern India

Resistance to chloroquine (CQ) in Plasmodium falciparum is one of the main causes of the wide-spread resurgence of malaria in India and a challenge to the effective control of the disease. In the pilgrim centre of Rameswaram Island, malaria has persisted despite the various control measures undertaken over the years. When CQ resistance in Rameswaram was investigated in vivo, recrudescent parasitaemias were observed in 25 (58%) of the 43 study subjects who were given CQ and completed follow-up, all occurring between days 10 and 28 (late treatment failures). The results of the msp(1), msp(2) and glurp genotyping of paired samples of P. falciparum, collected on day 0 and the day of recrudescence from 23 of the apparent treatment failures, indicated that 21 (91%) of the 23 were probably true treatment failures. All of the paired samples harboured parasites with the K76T mutation in their pfcrt genes, and subsequent sequencing of nine day-0 samples revealed the SVMNT haplotype in all nine. This is the first report of in-vivo drug resistance in P. falciparum from Rameswaram Island. Such resistance, which is probably the result of the indiscriminate use of CQ and/or the import of malaria from mainland India, warrants a change in the drug regimen used locally for the first-line treatment of uncomplicated, P. falciparum malaria, to make treatment more effective and slow the development and spread of more foci of CQ resistance.     

Chloroquine and sulphadoxine-pyrimethamine efficacy for uncomplicated malaria treatment and haematological recovery in children in Bobo-Dioulasso,Burkina Faso during a 3-year period 1998-2000

We determined the parasitological resistance and the clinical failure to chloroquine (CQ) and sulphadoxine-pyrimethamine (SP) by the WHO 14-day in vivo test over three consecutive years in 948 children aged 6-59 months with uncomplicated malaria attending four health centres in the province of Houet, Burkina Faso. Children were alternatively allocated to either CQ or SP. Packed cell volume (PCV) was measured at days 0 and 14. Parasitological resistance (RI, RII and RIII) to CQ was 18% (83 of 455) and to SP <1% (two of 308). Clinical failure with CQ was 12% (53 of 455) with no evidence of increase over time. Only one case of clinical failure was detected among the children treated with SP. The prevalence of anaemia (PCV <25%) was about 40% at day 0 and had decreased substantially by day 14 in both groups. However, in children treated with SP the prevalence of anaemia at day 14 was significantly lower than in those treated with CQ:RR = 3.15 (95% CI: 1.33-7.42, P = 0.008). CQ and SP are still efficacious for the treatment of uncomplicated malaria in children, at least in this area of Burkina Faso. However, the prevalences of CQ resistance reported from other areas of the country are worrying because of its potential spread. Regular surveillance of resistance to commonly used antimalarial drugs should continue.     

Increasing antimalarial drug resistance in Uganda and revision of the national drug policy

Chloroquine (CQ) resistance was first documented in Uganda in 1988. Subsequent surveillance of antimalarial drug resistance, conducted by the Ugandan Ministry of Health and several research organizations, suggests that resistance to CQ is now widespread, reaching critical levels in many areas of the country. In June 2000, the Ministry of Health held a National Consensus Meeting to evaluate the available drug efficacy data and review the national antimalarial drug policy. After extensive debate, the combination of CQ + sulfadoxine-pyrimethamine (SP) was chosen to replace CQ as the first-line treatment of uncomplicated malaria as an interim policy. This review evaluates the in vivo drug efficacy studies conducted in Uganda since 1988 and issues confronted in revision of the drug policy. The Ugandan experience illustrates the challenges faced by sub-Saharan African countries confronted with rising CQ resistance but limited data on potential alternative options. The choice of CQ + SP as a provisional policy in the absence of prerequisite efficacy, safety and cost-effectiveness data reflects the urgency of the malaria treatment problem, and growing pressure to adopt combination therapies. Surveillance of CQ + SP treatment efficacy, collection of additional data on alternative regimens and active consensus building among key partners in the malaria community will be necessary to develop a rational long-term antimalarial treatment policy in Uganda.