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.     

In vivo responses to antimalarials by Plasmodium falciparum and Plasmodium vivax from isolated Gag Island off northwest Irian Jaya, Indonesia.

There is renewed interest in the rich nickel and cobalt deposits of Pulau Gag, an isolated but malarious island off the northwest coast of Irian Jaya. In preparation for an expanded workforce, an environmental assessment of malaria risk was made, focusing upon malaria prevalence in the small indigenous population, and the in vivo sensitivity of Plasmodium falciparum and P. vivax to chloroquine (CQ) and sulfadoxine/pyrimethamine (S/P), the respective first- and second-line drugs for uncomplicated malaria in Indonesia. During April-June 1997, mildly symptomatic or asymptomatic malaria infections were found in 24% of 456 native residents. Infections by P. falciparum accounted for 60% of the cases. Respective day 28 cure rates for CQ (10 mg base/kg on days 0 and 1; 5 mg/kg on day 2) in children and adults were 14% and 55% (P < 0.005). Type RII and RIII resistance characterized only 5% of the CQ failures. Re-treatment of 36 P. falciparum CQ treatment failures with S/P (25 mg/kg and 1.25 mg/kg, respectively) demonstrated rapid clearance and complete sensitivity during the 28-day follow-up period. More than 97% of the P. vivax malaria cases treated with CQ cleared parasitemia within 48 hr. Three cases of P. vivax malaria recurred between days 21 and 28, but against low drug levels in the blood. The low frequency of RII and RIII P. falciparum resistance to CQ, the complete sensitivity of this species to S/P, and the absence of CQ resistance by P. vivax are in contrast to in vivo and in vitro test results from sites on mainland Irian Jaya.     

Therapeutic efficacy of chloroquine against uncomplicated, Plasmodium falciparum malaria in south-western Saudi Arabia.

The results of annual random screening indicated that Plasmodium falciparum strains showing chloroquine (CQ) resistance in vitro became increasingly common in the Jazan region of south-western Saudi Arabia between 1986 and 1998 (chi(2) for trend = 50.027; P < 0.001). This worrying trend and the emergence of a micro-epidemic in 1997-1998 prompted an assessment of the therapeutic efficacy of CQ against uncomplicated, P. falciparum malaria in the area. The in-vivo testing of sensitivity to CQ was carried out in 291 clinically manifest, microscopically positive cases of P. falciparum malaria. Most of these patients (88%) were successfully treated with a single standard regimen of CQ therapy. The other 36 patients (12%) showed early treatment failure or a poor response to the CQ, although all of these were then successfully treated with a single standard dose of sulfadoxine-pyrimethamine (Fansidar), as a replacement therapy. Those unsuccessfully treated with CQ were generally younger (t = 2.625; P = 0.01) and tended to have higher body temperatures (t = -2.62; P = 0.012) and higher levels of parasitaemia at initial presentation (P > 0.000) than those who responded well to the drug. Although CQ remains a reasonably effective drug for the treatment of malaria in the Jazan region, and therefore will be kept as the first-line drug for the foreseeable future, failure of CQ efficacy must be carefully monitored in the area.     

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.     

In vivo chloroquine resistance and prevalence of the pfcrt codon 76 mutation in Plasmodium falciparum isolates from the Republic of Congo

Chloroquine (CQ) resistance in Plasmodium falciparum has been particularly associated with mutations in the pfcrt gene. The present study was carried out in the malaria hyperendemic town of Brazzaville (Republic of Congo, Central Africa) where CQ is still recommended and used as a first-line drug for P. falciparum malaria. We assessed the efficacy of CQ in vivo, and the association between pfcrt mutation at codon 76 and treatment outcome in 50 children with uncomplicated malaria. The failure rate on day 28 was 95.7% and the pfcrt K76T mutation was present in 100% of isolates. No variation in the multiplicity of infection was observed in pre- and post-treatment isolates. In further 87 isolates from uncomplicated patients not treated with CQ, the mutation was detected in 98.5% of isolates. This study confirms the high level of in vivo resistance to CQ and shows the high prevalence of pfcrt K76T mutation in the Republic of Congo.     

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.     

Molecular assessment of Plasmodium falciparum resistance to antimalarial drugs in China

Objective  In China, Chloroquine (CQ) and sulfadoxine–pyrimethamine (SP) were abandoned for the treatment of falciparum malaria 20 years ago due to resistance. Subsequent field studies showed a trend of declining CQ and SP resistance in the country. The main purpose of this study was to analyse the molecular markers of antimalarial resistance and thereby to assess the possibility of reintroduction of CQ or SP for falciparum malaria treatment.
Methods  Plasmodium falciparum field isolates were collected in 2006–2007 from Hainan and Yunnan provinces, China. Nested PCR-sequencing assays were applied to analyse the SNPs in four genes: P. falciparum chloroquine resistance transporter ( pfcrt ) gene, multi-drug resistance 1 ( pfmdr1 ) gene, dihydrofolate reductase ( dhfr ) gene and dihydropteroate synthetase ( dhps ) gene.
Results  We found the widespread presence of point mutations in the dhfr and dhps genes which are associated with SP treatment failure. The molecular analyses also showed the fairly high prevalence of point mutation in the pfcrt gene which is linked to CQ resistance.
Conclusion  The results of the present study indicate that CQ and SP should not be reintroduced for falciparum malaria treatment in the near future in China.     

Sulphadoxine/pyrimethamine: an appropriate first-line alternative for the treatment of uncomplicated falciparum malaria in Ghanaian children under 5 years of age

OBJECTIVE: To assess whether chloroquine (CQ) still is an appropriate first-line drug for the treatment of uncomplicated falciparum malaria in Ghana and whether sulphadoxine/pyrimethamine (SP) could be a good alternative. METHOD: The parasitological, clinical and haematological responses to CQ and SP were studied in children < 5 years of age according to a modified WHO 28-day in vivo protocol. A total of 142 children attending the outpatients department meeting the inclusion criteria were randomly assigned to the CQ (n=72) or SP (n=70) group. RESULTS: In the CQ group, 15 children (20.8%) exhibited early clinical failure (within 3 days) compared with only 1 (1.4%) in the SP group (P < 0.01). The clinical failure rate before day 14 (early treatment failure plus late treatment failure before day 14) also showed a marked advantage in favour of the SP group (1.4 against 29.2%). The median time to clinical failure was 11.5 days in the CQ group and 26 days in the SP group (P < 0.01). Of the 72 children treated with CQ, 9 (12.5%) had RIII resistance and 19 (26.4%) had RII resistance. A total of 36 (50.0%) were sensitive to CQ. From the 70 children treated with SP, none had RIII or RII resistance. There was no difference in haematological response between the two treatment groups. CONCLUSION: Although there is little concordance on when to change treatment policy, the high resistance to CQ in this study supports the change to another first-line drug for children under 5 years of age. SP seems to be a good alternative, although a high RII and RIII resistance against this drug has already been reported in the coastal zones of Ghana.     

Formulation of malaria treatment policy for children in C?te d'Ivoire as chloroquine resistant Plasmodium falciparum spreads into west Africa

To develop a malaria treatment policy for children with Plasmodium falciparum, an in vivo and in vitro chloroquine (CQ) sensitivity study was conducted in C?te d'Ivoire in September 1986. The efficacy of a single dose of CQ (10 mg base kg-1, C10) was tested with assessment of subjects on Days 2 and 7 after treatment; 108 (99%) of 109 children were aparasitaemic on Day 7. Of 33 isolates of P. falciparum tested in vitro, two (6%) were resistant to CQ. Although C10 appeared effective clinically and parasitologically in C?te d'Ivoire, a treatment dose of 25 mg of CQ base kg-1 (C25), over three days, was recommended as first-line therapy for malaria. This was because in vivo CQ-resistance will soon spread into other West African countries including C?te d'Ivoire, the C25 dose still retains clinical effectiveness in most partially-immune persons living in areas with low-level chloroquine resistance, and alternate drugs are more expensive.     

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.     

Changes in genotypes of Plasmodium falciparum human malaria parasite following withdrawal of chloroquine in Tiwi, Kenya

Chloroquine (CQ) drug was withdrawn in 1998 as a first-line treatment of uncomplicated malaria in Kenya. This was in response to resistance to the drug in Plasmodium falciparum malaria parasite. Investigations were conducted to determine prevalence of CQ resistance genotypes in the parasites in Tiwi, a malaria endemic town in Kenya, before and about a decade after the withdrawal of the drug. Blood samples were collected and spotted on filter papers in 1999 and 2008 from 75 and 77 out-patients respectively with uncomplicated malaria. The sampling was conducted using finger pricking technique. DNA was extracted from individual spots in the papers and screened for the presence of P. falciparum chloroquine resistance transporter (Pfcrt) and multi drug resistance (Pfmdr-1) markers using nested PCR. Nature of mutations (haplotypes) in the Pfcrt and Pfmdr-1 markers in the samples were confirmed using dot blot hybridization technique. Changes in pattern of CQ resistance in the parasite samples in 1999 and 2008 were assessed by Chi Square test. There was a significant (P<0.05) reduction in CQ resistant genotypes of the parasite between 1999 and 2008. Pfmdr and Pfcrt CQ resistant genotypes in 2008 reduced to 54.10 and 63.64% respectively, from 75.39 and 88.0% respectively in 1999. This reduction was accompanied by emergence of Pfcrt specific CQ sensitive (IEK) and intermediate/partially CQ resistant (MET) haplotypes. Results suggest significant reversal of the phenotype of the parasite from chloroquine resistant to wild/sensitive type. The novel haplotypes indicates transitional phase of the parasite to the wild type. Current prevalence of chloroquine resistant genotype is definitely above the threshold for efficacious re-introduction of chloroquine for treatment of malaria in Tiwi.     

Confirmed vivax resistance to chloroquine and effectiveness of artemether-lumefantrine for the treatment of vivax malaria in Ethiopia

Chloroquine (CQ) is still the drug of choice for the treatment of vivax malaria in Ethiopia, whereas artemether-lumefantrine (AL) is for falciparum malaria. In this setting, clinical malaria cases are treated with AL. This necessitated the need to assess the effectiveness of AL for the treatment of Plasmodium vivax with CQ as a comparator. A total of 57 (80.3%) and 75 (85.2%) cases treated with CQ or AL, respectively, completed the study in an outpatient setting. At the end of the follow-up period of 28 days, a cumulative incidence of treatment failure of 7.5% (95% confidence interval [CI] = 2.9-18.9%) for CQ and 19% (95% CI = 11-31.6%) for AL was detected. CQ resistance was confirmed in three of five CQ treatment failures cases. The effectiveness of AL seems lower than CQ; however, the findings were not conclusive, because the AL evening doses were not supervised.     

Association of pfcrt but not pfmdr1 alleles with chloroquine resistance in Iranian isolates of Plasmodium falciparum

This study was designed to analyze the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) mutations as markers of chloroquine (CQ) resistance in 200 blood samples collected from malaria patients in south-eastern Iran during 2002-2005. Among these, 25 (post-treatment) fulfilled the 28-day follow-up study. A high number of Iranian P. falciparum (97%) strains harbored quadruple mutations at codons 76T, 220S, 326D, and 356L. All post-treatment isolates harbored the mutant allele 76T, but low rates of the mutant allele 86Y (44%) of the pfmdr1 gene were detected. No wild haplotype of pfcrt (72-CVMNKAQNIR-371) was found in post-treatment samples; however, 56% of clinical "failure" samples carried the wild type of pfmdr1 (NYSND). The present results suggest a strong association between pfcrt 76T, but not pfmdr1 86Y mutation and in vivo CQ resistance. Furthermore, we found the CQ resistance-associated SVMNT haplotype, which previously had been seen in South American isolates. Although Iran is located more proximally to Southeast Asia than to South America, no CQ resistance-associated CVIET haplotye has been observed in this region. Therefore, these results were not consistent with the earlier presumed spread of CQR parasites from Southeast Asia to Africa via the Indian subcontinent. In conclusion, P. falciparum mutations associated with resistance to CQ are abundant in south-eastern Iran and this finding strongly supports that CQ as the first line drug is inadequate for treatment of uncomplicated falciparum malaria in Iran.     

Chloroquine-treatment failure in northern Ghana: roles of pfcrt T76 and pfmdr1 Y86

Although chloroquine (CQ) monotherapy is now generally inadequate for the treatment of Plasmodium falciparum malaria in northern Ghana--recently, 58% of 225 children failed treatment by day 14--use of the drug continues because of its low cost and wide availability. The risk factors associated with CQ-treatment failure in this region of Africa, including the T76 mutation in the chloroquine resistance transporter (pfcrt) gene and the Y86 mutation in the multidrug resistance (pfmdr1) gene of P. falciparum, have now been investigated, and genotype-failure indices (GFI) have been calculated.Treatment failure was found to be associated with young age, poor nutritional status, pfcrt T76 and pfmdr1 Y86, and early treatment failure (ETF) was also associated with high parasitaemia. The presence and concentration of 'residual' CQ in the blood of patients immediately before they were treated with CQ for the present study appeared to have no effect on outcome. Presence at recruitment of pfcrt T76 or pfmdr1 Y86 or both mutations increased the risk of treatment failure by 3.2-, 2.4- and 4.5-fold, and the risk of ETF by 9.8-, 2.7- and 10.2-fold, respectively. The pfcrt T76 GFI for clinical and all treatment failures were 2.8 and 1.4, respectively. These indices were relatively low in the younger children, those with malnutrition, and those with high parasitaemias when treated. Residual CQ did not affect the GFI substantially.Both pfcrt T76 and, to a lesser extent, pfmdr1 Y86 would be useful tools for the surveillance of CQ resistance in northern Ghana. In the current transition phase to alternative first-line treatment for P. falciparum malaria, it should be possible to provide estimates of the level of CQ resistance by monitoring the prevalences of these mutations.     

Inhibitory activity of ferroquine, versus chloroquine, against western Kenya Plasmodium falciparum field isolates determined by a SYBR Green I in vitro assay

Ferroquine (FQ), a chloroquine (CQ) analog, is being developed to treat persons with Plasmodium falciparum malaria. In 146 P. falciparum field isolates from western Kenya, we measured 50% inhibitory concentrations (IC(50); nM) of CQ and FQ by a SYBR Green I in vitro assay. Reference clones included W2 (CQ resistant) and D6 (CQ sensitive). Mutation analysis was done for P. falciparum CQ-resistance transporter gene (Pfcrt K76T). Median IC(50) values for FQ were lower than CQ for field isolates and the W2 clone (both P < 0.05). The Pfcrt mutation (76T), which was detected in > 80% of isolates, conferred higher CQ IC(50) values (P < 0.05) and modestly lower FQ IC(50) values (P < 0.05), versus Pfcrt wild type (K76). FQ is more potent than CQ against CQ-resistant P. falciparum field isolates and the W2 clone, and is less affected by Pfcrt 76T. These findings support the notion that FQ could be useful in treating persons with P. falciparum malaria.     

Molecular markers for chloroquine-resistant Plasmodium falciparum malaria in Thailand and Laos.

Chloroquine-resistant Plasmodium falciparum is well documented in Thailand. Laos, however, continues to use chloroquine (CQ) as the first-line therapy for the treatment of P. falciparum malaria. The objective of the present study was to determine the prevalence, in these two areas, of the cg2, pfmdr1 and pfcrt allelic types that have previously been associated with CQ resistance. Isolates of P. falciparum were collected from participants in ongoing treatment studies conducted in Thailand (near the Thai-Cambodian border) and in Laos (Vang Vieng district). The pfmdr1 and pfcrt alleles were characterized by PCR-RFLP and mutations in cg2 were characterized by PCR and single-stranded-conformation-polymorphism (SSCP) electrophoresis. Eight (32%) of the 25 Laotian isolates but only one (4%) of the 25 Thai isolates were found to contain the pfmdr1 mutation N86Y (P = 0.02). In contrast, the cg2 polymorphisms previously associated with CQ resistance were present in only 10 of the isolates from Laos but 24 of those from Thailand (40% v. 96%; P < 0.001). All the samples from both countries contained the pfcrt K76T mutant allele reported to confer resistance to CQ. The results may indicate that drug pressure for the maintenance of the pfmdr1 and cg2 alleles varies in intensity in the Thai and Laotian study areas, probably reflecting differences in the national malaria-treatment policies of Thailand and Laos.     

Chloroquine efficacy in the treatment of uncomplicated malaria at three sentinel sites in northern Togo

In Togo, chloroquine (CQ) remains the first-line drug for the treatment of uncomplicated, Plasmodium falciparum malaria. In the absence of recent data on the level of parasite resistance to antimalarial drugs, Togo's National Malaria Control Programme (NMCP) decided to assess the current efficacy of CQ in the treatment of uncomplicated, P. falciparum malaria at three sentinel sites in the north of the country. Between the September and November of 2001, the World Health Organization's standard 14-day protocol was used to investigate 153 malarious children aged 6-59 months old (46 from Sokode, 54 from Niamtougou and 53 from Dapaong). Of the subjects from Sokode, Niamtougou and Dapaong, early treatment failure was observed in 0%, 7% and 12%, late treatment failure in 0%, 11% and 17%, and overall parasitological failure in 0%, 45% [with a 95% confidence interval (CI) of 39%-51%] and 62% (CI=54%-70%), respectively. Even within northern Togo, there is clearly considerable geographical variation in the level of resistance to CQ. Before an efficient antimalarial-drug policy can be developed, there is an urgent need to develop and use the national surveillance system further, to collect relevant data on the efficacies of CQ and other antimalarial drugs, such as amodiaquine and sulfadoxine-pyrimethamine.     

Evaluation of chloroquine (CQ) and sulphadoxine/pyrimethamine (SP) therapy in uncomplicated falciparum malaria in Indo-Myanmar border areas

Chloroquine (CQ) and sulphadoxine/pyrimethamine (SP) are two first-line antimalarials used under the existing Indian National Drug Policy in the north-eastern region of India bordering several countries including Myanmar. Although widespread resistance to antimalarials in Plasmodium falciparum has been reported from western Myanmar, information from the Indian side of the border is scarce. We studied the therapeutic response to CQ and SP at four sites in Changlang and Lohit, two administrative districts of Arunachal Pradesh bordering Myanmar. We monitored uncomplicated falciparum malaria patients after treatment with standard regimens of CQ and SP for 28 days following the revised in-vivo protocol of the World Health Organization. A total of 236 patients, 95 in the CQ group and 141 in the SP group, participated. We recorded 23.8% early treatment failures to CQ and 14.1% to SP; late clinical failures of 14.3 and 12.6%; late parasitological failures of 10.7 and 8.1% and adequate clinical and parasitological responses of 51.2 and 65.2%, respectively. The significantly different treatment failure rates seen in Chowkham (furthest from Indo-Myanmar border) and Jairampur/Nampong (nearest to Indo-Myanmar border) for chloroquine (Cox proportion hazard ratio 9.1, P<0.0001) and SP (Cox proportion hazard ratio 7.35, P=0.001) denote a non-response gradient to the two antimalarials extending from the international border. The gradient is probably indicative of the direction of movement of the drug-resistant P. falciparum parasite. The utility of chloroquine as the first-line drug under the present National Drug Policy in these areas needs reconsideration.     

Evidence for a reduced effect of chloroquine against Plasmodium falciparum in alpha-thalassaemic children

Alpha-thalassaemia is common in malaria-endemic regions and is considered to confer protection from clinical disease due to infection with Plasmodium falciparum. In vitro, sensitivity to chloroquine (CQ) of P. falciparum infecting alpha-thalassaemic erythrocytes is reduced. We examined, in a cross-sectional study of 405 Nigerian children, associations between alpha-globin genotypes, blood concentrations of CQ, and P. falciparum parasitaemia. Of the children, 44% were alpha+-thalassaemic (36.8% heterozygous, 7.6% homozygous). CQ in blood and P. falciparum-infection were observed in 52 and 80%, respectively. CQ was more frequently found in homozygous alpha+-thalassaemic (71%) than in non-thalassaemic children (50%; odds ratio, 2.42; 95% confidence interval, 1.01-5.8). Among children with CQ in blood and despite similar drug concentrations, alpha+-thalassaemic individuals had fewer infections below the threshold of microscopy which were detectable by PCR only, and they had a higher prevalence of elevated parasitaemia than non-thalassaemic children. No such differences were discernible among drug-free children. CQ displays a lowered efficacy in the suppression of P. falciparum parasitaemia in alpha+-thalassaemic children; hence protection against malaria due to alpha+-thalassaemia may be obscured in areas of intense CQ usage. Moreover, alpha+-thalassaemia may contribute to the expansion of CQ resistance.     

Randomized comparison of chloroquine and amodiaquine in the treatment of acute, uncomplicated, Plasmodium falciparum malaria in children.

The increasing resistance of Plasmodium falciparum to chloroquine (CQ) has created an urgent need for the evaluation of alternative, effective, safe, cheap, readily available and affordable antimalarial treatments. In the present study, the efficacy of amodiaquine (AQ) in the treatment of acute, symptomatic, uncomplicated, P. falciparum malaria was compared with that of CQ, each drug being given at 10 mg/kg per day for 3 days (days 0, 1 and 2). The 210 subjects (104 given AQ and 106 CQ) were Nigerian children aged 5 months-12 years. Fever-clearance times (FCT), parasite densities on days 1-4 and parasite-clearance times (PCT) were all significantly lower with AQ than with CQ. Mean (S.D.) PCT, for example, were 2.6 (0.8) days with AQ and 3.0 (1.0) days with CQ (P = 0.001). The cure rates obtained on days 14, 21 and 28 - 98.1% v. 79.3% (P =0.000), 97.1% v. 64.2% (P = 0.00001) and 95.2% v. 58.5% (P = 0.0000000) with AQ and CQ, respectively - were all also significantly higher with AQ. All but two of the 20 subjects who were considered CQ-treatment failures by day 14 (i.e. two RIII, two RII and 16 RI) responded to subsequent treatment with AQ, with PCT (but not FCT) significantly shorter than during their initial treatment with CQ. In siblings in whom there was clustering of infections, the cure rates were 100% with AQ (N =12) and 63.6% with CQ (N = 11; P = 0.03). Adverse reactions to CQ and AQ were similar and tolerable: pruritus in 10 and 11 children in the AQ and CQ groups, respectively, and gastro-intestinal disturbances which occurred in three children from each group. Haematological parameters were not adversely affected by either drug. At least in the setting of the present study, AQ appears more effective than CQ, effective against CQ-resistant infections, and well tolerated by children with acute, uncomplicated, P. falciparum malaria. It may therefore be useful as an alternative to CQ in areas of CQ resistance.