Treatment of children with Plasmodium falciparum malaria with chloroquine in Guinea-Bissau.

Self Cite

High chloroquine doses are commonly prescribed in Guinea-Bissau. Double-dose chloroquine has been shown to be more efficacious (92% efficacy) than the standard dose (80% efficacy). However, chloroquine is toxic when overdosed, and it was not known if the high doses prescribed in Guinea-Bissau were taken or whether they caused adverse effects. We aimed to determine the dosage of chloroquine commonly prescribed, the doses commonly taken, and whether concentration-dependent adverse events occurred in routine practice. Chloroquine prescriptions by eight physicians and chloroquine intake by 102 children were recorded. Chloroquine intake and adverse events were assessed by questioning. Chloroquine concentrations in whole blood were measured. The median total chloroquine dose prescribed and that reportedly taken were 81 and 77 mg kg ؊1 , respectively. The total dose was usually split into two to three daily doses of 6.6 mg kg ؊1 each. These were taken unsupervised for a median of 5 days. Forty percent of the study children had chloroquine concentrations in the same range as those found in a previous study in which double the normal dose (50 mg kg ؊1 ) of chloroquine was taken. Only 3/102 children had Plasmodium falciparum in the blood at the time of diagnosis and treatment. No severe adverse events were reported. No adverse events were associated with higher chloroquine concentrations. High doses of chloroquine are commonly taken and well tolerated in Guinea-Bissau. Malaria diagnostics are poor, and chloroquine is commonly prescribed to children without parasitemia. Use of highdose chloroquine is concurrent with an exceptionally low prevalence of chloroquine-resistant P. falciparum.Chloroquine-resistant (CQR) Plasmodium falciparum spread through Africa during the '80s and '90s and was first described in Guinea-Bissau in 1990 (5). Until June 2008, chloroquine (CQ) remained by far the most commonly used antimalarial in the country. In Guinea-Bissau, as in most other areas of Africa, CQR is associated with a mutation in the CQR transporter (pfcrt K76T) (22,25). Despite the presence of the pfcrt K76T mutation and continued CQ use, which should select CQR P. falciparum, the prevalence of CQR P. falciparum is exceptionally low and unchanged in Guinea-Bissau (23).In Guinea-Bissau, treatment with the standard total CQ dose of 25 mg kg Ϫ1 of body weight given over 3 days had an efficacy of 80% (8). Treatment with 50 mg kg Ϫ1 of CQ in two divided daily doses over 3 days resulted in a 92% PCR-corrected efficacy at day 28 (8). When 50 mg kg Ϫ1 was used, 78% of infections with P. falciparum carrying the CQR-associated genetic marker (pfcrt 76T) were successfully treated, while only 34% were successfully treated with 25 mg kg Ϫ1 (22). The WHO recommendation that an antimalarial drug should have a minimum 90% efficacy was therefore still attained with CQ in .CQ is rapidly and almost completely absorbed. The peak concentration is obtained 1 to 3 h after oral intake, and 50 to 65% is protein bound in plasma. The concentration in whole ...

Section: Vol 53 2009 High-dose Chloroquine In Guinea-bissau 183supporting

confidence: 92%

“…We have previously reported that high CQ doses are commonly prescribed in one health center in Guinea Bissau (23) and that higher doses are more efficacious (6)(7)(8). The primary objectives of this observational study were therefore to monitor CQ prescription practices by clinicians and reported CQ consumption by children.…”

mentioning

confidence: 99%

Chloroquine Is Grossly Overdosed and Overused but Well Tolerated in Guinea-Bissau

Ursing

Kofoed

Rodrigues

et al. 2009

Self Cite

“…We identified a further 21 treatment arms comprising a total of 3,259 patients where both day 14 and day 28 failure rates were reported (11,12,18,19,38,40,51,55,56); 9 treatment arms were with drugs in the There were only five trials with Ͼ42 days of follow-up, and in these the day 14 assessment detected a median of 33% (0 to 62%), and the day 28 assessment was 70% (0 to 88%) of the overall failures. This is comparable with the results from the studies with genotyping: for day 14 assessment, 14% (0 to 80%) and for day 28 assessment, 82% (0 to 100%).…”

Section: (Iii) Studies With 28-day Follow-up (58 Trial Arms)mentioning

confidence: 99%

In Vivo Assessment of Drug Efficacy against Plasmodium falciparum Malaria: Duration of Follow-Up

Stepniewska

Taylor

Mayxay

et al. 2004

To determine the optimum duration of follow-up for the assessment of drug efficacy against Plasmodium falciparum malaria, 96 trial arms from randomized controlled trials (RCTs) with follow-up of 28 days or longer that were conducted between 1990 and 2003 were analyzed. These trials enrolled 13,772 patients, and participating patients comprised 23% of all patients enrolled in RCTs over the past 40 years; 61 (64%) trial arms were conducted in areas where the rate of malaria transmission was low, and 58 (50%) trial arms were supported by parasite genotyping to distinguish true recrudescences from reinfections. The median overall failure rate reported was 10% (range, 0 to 47%). The widely used day 14 assessment had a sensitivity of between 0 and 37% in identifying treatment failures and had no predictive value. Assessment at day 28 had a sensitivity of 66% overall (28 to 100% in individual trials) but could be used to predict the true failure rate if either parasite genotyping was performed (r 2 ‫؍‬ 0.94) or if the entomological inoculation rate was known. In the assessment of drug efficacy against falciparum malaria, 28 days should be the minimum period of follow-up.

“…(ii) Calibrating the CQ model with IC 50 values typical of resistant parasites gave high treatment failure rates. Doubling the CQ dosage (as was done in GuineaBissau [27,35,63]) restored the efficacy of CQ against these "resistant" parasites (data not shown). (iii) Artemisinin monotherapies over 3 days are unable to clear infection, but extending the treatment time to 7 days does reliably clear parasites (1).…”

mentioning

confidence: 95%

“…We investigated four drugs, chloroquine (CQ), lumefantrine (LF), MQ, and piperaquine (PQ), given as monotherapies and as components of artemisinin-containing combination therapies (ACTs) with artesunate (AS), artemether (AR), or dihydroartemisinin (DHA) as appropriate. Chloroquine is no longer officially deployed through the formal health sector for treatment of Plasmodium falciparum (with the interesting exception of Guinea-Bissau [27,35,63]). It is included here for historical comparison and because it results in higher failure rates (see below) than the ACTs, allowing us to compare the different dynamics of drug failure.…”

mentioning

confidence: 99%

Development, Evaluation, and Application of an In Silico Model for Antimalarial Drug Treatment and Failure

Winter

Hastings

2011

129

Pharmacological mechanism-based modeling was refined and used to develop an in silico model of antimalarial drug treatment validated against clinical and field data. We used this approach to investigate key features of antimalarial drug action and effectiveness, with emphasis on the current generation of artemisinin combination therapies. We made the following conclusions. (i) The development of artemisinin tolerance and resistance will, unless checked, have an immediate, large impact on the protection afforded to its partner drug and on the likely clinical efficacy of artemisinin combination therapies. (ii) Long follow-up periods are required in clinical trials to detect all drug failures; the follow-up periods of 28 days recommended by the World Health Organization are likely to miss at least 50% of drug failures, and we confirmed recent suggestions that 63 days would be a more appropriate follow-up period. (iii) Day 7 serum drug concentrations are a significant risk factor of failure, although, paradoxically, receiver operating characteristic curve analysis revealed that their predictive power is relatively poor. (iv) The pharmacokinetic properties of the partner drugs in artemisinincontaining combination therapies are the most important determinants of treatment outcome, particularly the maximum killing rate. We discuss the assumptions made in such modeling approaches and how similar approaches may be refined in future work.