ABSTRACT
Drug efficacy trials monitor the continued efficacy of front-line drugs against falciparum malaria. Overestimating efficacy results in a country retaining a failing drug as first-line treatment with associated increases in morbidity and mortality, while underestimating drug effectiveness leads to removal of an effective treatment with substantial practical and economic implications. Trials are challenging: they require long durations of follow-up to detect drug failures, and patients are frequently reinfected during that period. Molecular correction based on parasite genotypes distinguishes reinfections from drug failures to ensure the accuracy of failure rate estimates. Several molecular correction "algorithms" have been proposed, but which is most accurate and/or robust remains unknown. We used pharmacological modeling to simulate parasite dynamics and genetic signals that occur in patients enrolled in malaria drug clinical trials. We compared estimates of treatment failure obtained from a selection of proposed molecular correction algorithms against the known "true" failure rate in the model. Our findings are as follows. (i) Molecular correction is essential to avoid substantial overestimates of drug failure rates. (ii) The current WHO-recommended algorithm consistently underestimates the true failure rate. (iii) Newly proposed algorithms produce more accurate failure rate estimates; the most accurate algorithm depends on the choice of drug, trial follow-up length, and transmission intensity. (iv) Long durations of patient follow-up may be counterproductive; large numbers of new infections accumulate and may be misclassified, overestimating drug failure rate. (v) Our model was highly consistent with existing in vivo data. The current WHO-recommended method for molecular correction and analysis of clinical trials should be reevaluated and updated.
Subject(s)
Antigens, Protozoan/genetics , Antimalarials/pharmacology , Merozoite Surface Protein 1/genetics , Models, Statistical , Plasmodium falciparum/drug effects , Protozoan Proteins/genetics , Algorithms , Antigens, Protozoan/metabolism , Antimalarials/pharmacokinetics , Artemisinins/pharmacokinetics , Artemisinins/pharmacology , Biomarkers/metabolism , Clinical Trials as Topic , Gene Expression , Humans , Lumefantrine/pharmacokinetics , Lumefantrine/pharmacology , Malaria, Falciparum/drug therapy , Malaria, Falciparum/parasitology , Mefloquine/pharmacokinetics , Mefloquine/pharmacology , Merozoite Surface Protein 1/metabolism , Parasitic Sensitivity Tests , Plasmodium falciparum/genetics , Plasmodium falciparum/growth & development , Polymorphism, Restriction Fragment Length , Protozoan Proteins/metabolism , Quinolines/pharmacokinetics , Quinolines/pharmacology , Time Factors , Treatment OutcomeABSTRACT
We tested the efficacy and safety of chlorproguanil/dapsone co-administered with artesunate (CD+A) for the treatment of uncomplicated Plasmodium falciparum malaria in children compared with amodiaquine+sulfadoxine/pyrimethamine (AQ+SP) at two different sites in Rwanda. The trial was open label and 800 patients were randomly assigned to AQ+SP (n=400) or CD+A (n=400). Patients were hospitalised for 3 days and then followed-up weekly until Day 28 after treatment. Clinical and parasitological outcomes were recorded. Results showed that neither treatment was adequately efficacious. At one site, the adequate clinical and parasitological response (ACPR), PCR-adjusted, was 73.3% in the CD+A arm and 87.8% in the AQ+SP arm (P<0.001), and at the second site the ACPR, PCR-adjusted, was 70.5% in the CD+A arm and 38.1% in the AQ+SP arm (P<0.001). The combination CD+A is considered an alternative to, or replacement for, SP in Africa because CD has been shown to be effective in patients for whom SP treatment has failed and, with its short half-life, it is expected to exert less selection pressure for resistant parasites than SP. However, the results of this trial indicate that in an area of high SP resistance, CD+A may not be the best choice.
Subject(s)
Antimalarials/administration & dosage , Artemisinins/administration & dosage , Dapsone/administration & dosage , Malaria, Falciparum/drug therapy , Proguanil/analogs & derivatives , Animals , Antimalarials/adverse effects , Artemisinins/adverse effects , Artesunate , Child, Preschool , Dapsone/adverse effects , Drug Administration Schedule , Drug Therapy, Combination , Female , Genotype , Humans , Infant , Malaria, Falciparum/epidemiology , Male , Proguanil/administration & dosage , Proguanil/adverse effects , Rural Health , Rwanda/epidemiology , Treatment OutcomeABSTRACT
During a 3-month period, 131 cases of herpes zoster were diagnosed in Kigali, Rwanda. There were 46 female and 85 male patients. Mean age was 29 years (range 1-66). An unusually high proportion of patients presented with cranial and sacral nerve localisation of their cutaneous lesions. 55/131 patients (42%) had involvement of more than one dermatome. None of the patients had an underlying condition known to favour herpes zoster. 120/131 (92%) had antibodies to HIV detected by an immunoenzymatic assay (EIA) and indirect immunofluorescence. 92/125 adult patients (74%) had no sign or symptom related to HIV infection other than herpes zoster. This study suggests that herpes zoster in Central Africa is an early and readily detectable manifestation of HIV-induced immunosuppression.
Subject(s)
HIV Seropositivity/complications , Herpes Zoster/etiology , Adolescent , Adult , Age Factors , Aged , Child , Child, Preschool , Cranial Nerve Diseases/etiology , Female , Herpes Zoster/diagnosis , Humans , Infant , Male , Middle Aged , RwandaABSTRACT
PIP: The positive predictive values for HIV seropositivity are compared using WHO and US Centers for Disease Control (CDC) clinical case definitions of acquired immunodeficiency syndrome (AIDS), for cases in Rwanda, Africa. It is postulated that the article by Colebunders and co-workers should encourage clinicians and epidemiologists working in Africa to adopt the World Health Organization's provisional clinical case definition for AIDS. Although the predictive value for HIV seropositivity calculated in urban-based adults, as measured by the 2 different criteria, is comparable, (both criteria yield a 93% positive predictive value), this high % is not reached for cases of AIDS diagnosed for rural adults or urban-based children, using the WHO criteria. These data confirm the opinion of Colebunders and co-workers that regional variations in the prevalence of HIV infection can interfere with the positive predictive value for HIV seropositivity of this definition. Workers in other countries should test the validity of the WHO criteria in their own settings and evaluate the WHO case definition adapted to pediatric AIDS in Africa.^ieng