Dianne J Terlouw

Use of weight-for-age-data to optimize tablet strength and dosing regimens for a new fixed-dose artesunate-amodiaquine combination for treating falciparum malaria

OBJECTIVEnTo test a novel methodology to define age-based dosing regimens for the treatment of malaria with a new, user-friendly, blister-packaged fixed-dose combination of artesunate and amodiaquine.nnnMETHODSnA weight-for-age reference database of 88 054 individuals from sub-Saharan Africa was compiled using data from Demographic Health Surveys, observational and intervention studies, and standardized for sex, age and malaria risk. We then determined the optimal tablet strength (milligram (mg) per tablet) and age-dose categories for the combination of artesunate and amodiaquine. The proportions of patients predicted to receive doses within newly defined therapeutic ranges for amodiaquine (7-15 mg/kg/day) and artesunate (2-10 mg/kg/day), were estimated for different age categories and mg tablet strengths using models based on the weight-for-age reference database.nnnFINDINGSnThe optimal paediatric (p) and adult (a) strength tablets contained 25/67.5 and 100/270 mg artesunate/amodiaquine, respectively. A regimen with five age categories: 0-1 months (1/2 p), 2-11 months (1 p), 1-5 years (2 p), 6-13 years (1 a), and > 14 years (2 a) had an overall dosing accuracy of 83.4% and 99.9% for amodiaquine and artesunate, respectively.nnnCONCLUSIONnThe proposed method to use weight-for-age reference data from countries where malaria is endemic is a useful tool for designing age-based dosing regimens for antimalarial drugs for drug registration and field use.

Impact of mass distribution of free long-lasting insecticidal nets on childhood malaria morbidity: The Togo National Integrated Child Health Campaign

BackgroundAn evaluation of the short-term impact on childhood malaria morbidity of mass distribution of free long-lasting insecticidal nets (LLINs) to households with children aged 9-59 months as part of the Togo National Integrated Child Health Campaign.MethodsThe prevalence of anaemia and malaria in children aged zero to 59 months was measured during two cross-sectional household cluster-sample surveys conducted during the peak malaria transmission, three months before (Sept 2004, n = 2521) and nine months after the campaign (Sept 2005, n = 2813) in three districts representative of Togos three epidemiological malaria transmission regions: southern tropical coastal plains (Yoto), central fertile highlands (Ogou) and northern semi-arid savannah (Tone).ResultsIn households with children <5 years of age, insecticide-treated net (ITN) ownership increased from <1% to >65% in all 3 districts. Reported ITN use by children during the previous night was 35.9%, 43.8% and 80.6% in Yoto, Ogou and Tone, respectively. Rainfall patterns were comparable in both years. The overall prevalence of moderate to severe anaemia (Hb < 8.0 g/dL) was reduced by 28% (prevalence ratio [PR] 0.72, 95% CI 0.62-0.84) and mean haemoglobin was increased by 0.35 g/dL (95% CI 0.25-0.45).The effect was predominantly seen in children aged 18-59 months and in the two southern districts: PR (95% CI) for moderate to severe anaemia and clinical malaria: Yoto 0.62 (0.44-0.88) and 0.49 (0.35-0.75); Ogou 0.54 (0.37-0.79) and 0.85 (0.57-1.27), respectively. Similar reductions occurred in children <18 months in Ogou, but not in Yoto. No effect was seen in the semi-arid northern district despite a high malaria burden and ITN coverage.ConclusionsA marked reduction in childhood malaria associated morbidity was observed in the year following mass distribution of free LLINs in two of the three districts in Togo. Sub-national level impact evaluations will contribute to a better understanding of the impact of expanding national malaria control efforts.

Azithromycin for treating uncomplicated malaria

BACKGROUNDnTo prevent the development of drug resistance, the World Health Organization (WHO) recommends treating malaria with combination therapy. Azithromycin, an antibiotic with antimalarial properties, may be a useful additional option for antimalarial therapy.nnnOBJECTIVESnTo compare the use of azithromycin alone or in combination with other antimalarial drugs with the use of alternative antimalarial drugs for treating uncomplicated malaria caused by Plasmodium falciparum or Plasmodium vivax.nnnSEARCH STRATEGYnWe searched the Cochrane Infectious Diseases Group Specialized Register (August 2010); CENTRAL (The Cochrane Library Issue 3, 2010); MEDLINE (1966 to August 2010); EMBASE (1974 to August 2010); LILACS (August 2010); the metaRegister of Controlled Trials (mRCT, August 2010); conference proceedings; and reference lists. We also contacted researchers and a pharmaceutical company.nnnSELECTION CRITERIAnRandomized controlled trials comparing azithromycin, either alone or combined with another antimalarial drug, with another antimalarial drug used alone or combined with another antimalarial drug, or with azithromycin combined with another antimalarial drug if different combinations or doses of azithromycin were used. The primary outcome was treatment failure by day 28, defined as parasitological or clinical evidence of treatment failure between the start of treatment and day 28. Secondary outcomes included treatment failure by day 28 corrected for new infections confirmed by polymerase chain reaction (PCR), fever and parasite clearance time, and adverse events.nnnDATA COLLECTION AND ANALYSISnTwo people independently applied the inclusion criteria, extracted data and assessed methodological quality. We used risk ratio (RR) and 95% confidence intervals (CI).nnnMAIN RESULTSnFifteen trials met the inclusion criteria (2284 participants, 69% males, 16% children). They were conducted in disparate malaria endemic areas, with the earlier studies conducted in Thailand (five) and India (two), and the more recent studies (eight) spread across three continents (South America, Africa, Asia). The 15 studies involved 41 treatment arms, 12 different drugs, and 28 different treatment regimens. Two studies examined P. vivax.Three-day azithromycin (AZ) monotherapy did not perform well for P. vivax or P. falciparum (Thailand: P. vivax failure rate 0.5 g daily, 56%, 95% CI 31 to 78. India: P. vivax failure rate 1 g daily,12%, 95% CI 7 to 21; P. falciparum failure rate 1 g daily, 64%, 95% CI 36 to 86.) A 1 g azithromycin and 0.6 g chloroquine combination daily for three days for uncomplicated P. falciparum infections was associated with increased treatment failure in India and Indonesia compared with the combination of sulphadoxine-pyrimethamine and chloroquine (pooled RR 2.66, 95% CI 1.25 to 5.67), and compared with the combination atovaquone-proguanil in a multicentre trial in Columbia and Surinam (RR 24.72, 95% CI 6.16 to 99.20). No increased risk of treatment failure was seen in two studies in Africa with mefloquine as the comparator drug (pooled RR 2.02, 95% CI 0.51 to 7.96, P = 0.3); the pooled RR for PCR-corrected data for the combination versus mefloquine was 1.01, 95% CI 0.18 to 5.84 (P = 1.0). An increased treatment failure risk was seen when comparing azithromycin in a dose of 1.2 to 1.5 mg in combination with artesunate (200 mg per day for three days) with artemether-lumefantrine (pooled RR 3.08, 95% CI 2.09 to 4.55; PCR-corrected pooled RR 3.63, 95% CI 2.02 to 6.52).Serious adverse events and treatment discontinuation were similar across treatment arms. More adverse events were reported when comparing the 1 g azithromycin/ 0.6 g chloroquine combination with mefloquine (pooled RR 1.20, 95% CI 1.06 to 1.36) or atovaquone-proguanil (RR 1.41, 95% CI 1.09 to1.83).nnnAUTHORS CONCLUSIONSnCurrently, there is no evidence for the superiority or equivalence of azithromycin monotherapy or combination therapy for the treatment of P. falciparum or P. vivax compared with other antimalarials or with the current first-line antimalarial combinations. The available evidence suggests that azithromycin is a weak antimalarial with some appealing safety characteristics. Unless the ongoing dose, formulation and product optimisation process results in a universally efficacious product, or a specific niche application is identified that is complementary to the current scala of more efficacious antimalarial combinations, azithromycins future for the treatment of malaria does not look promising.

Polymorphisms in genes of interleukin 12 and its receptors and their association with protection against severe malarial anaemia in children in western Kenya

BackgroundMalarial anaemia is characterized by destruction of malaria infected red blood cells and suppression of erythropoiesis. Interleukin 12 (IL12) significantly boosts erythropoietic responses in murine models of malarial anaemia and decreased IL12 levels are associated with severe malarial anaemia (SMA) in children. Based on the biological relevance of IL12 in malaria anaemia, the relationship between genetic polymorphisms of IL12 and its receptors and SMA was examined.MethodsFifty-five tagging single nucleotide polymorphisms covering genes encoding two IL12 subunits, IL12A and IL12B, and its receptors, IL12RB1 and IL12RB2, were examined in a cohort of 913 children residing in Asembo Bay region of western Kenya.ResultsAn increasing copy number of minor variant (C) in IL12A (rs2243140) was significantly associated with a decreased risk of SMA (P = 0.006; risk ratio, 0.52 for carrying one copy of allele C and 0.28 for two copies). Individuals possessing two copies of a rare variant (C) in IL12RB1 (rs429774) also appeared to be strongly protective against SMA (P = 0.00005; risk ratio, 0.18). In addition, children homozygous for another rare allele (T) in IL12A (rs22431348) were associated with reduced risk of severe anaemia (SA) (P = 0.004; risk ratio, 0.69) and of severe anaemia with any parasitaemia (SAP) (P = 0.004; risk ratio, 0.66). In contrast, AG genotype for another variant in IL12RB1 (rs383483) was associated with susceptibility to high-density parasitaemia (HDP) (P = 0.003; risk ratio, 1.21).ConclusionsThis study has shown strong associations between polymorphisms in the genes of IL12A and IL12RB1 and protection from SMA in Kenyan children, suggesting that human genetic variants of IL12 related genes may significantly contribute to the development of anaemia in malaria patients.

Malaria in infants below six months of age: retrospective surveillance of hospital admission records in Blantyre, Malawi

BackgroundInformation on the burden of malaria in early infancy is scarce. Young infants are relatively protected against clinical malaria during the first six months of life due to the presence of maternal antibodies and foetal haemoglobin, and have received relatively little attention with respect to research and treatment guidelines. The World Health Organization provides treatment guidelines for children from six months onwards, without specific treatment guidelines for the younger infants. A number of recent reports however suggest that the burden in this young age group may be underestimated.MethodsA retrospective review of paediatric hospital records at the Queen Elizabeth Central Hospital in Blantyre from 1998 to 2008 from three data sources was carried out. The number of admitted infants <6 months and ≤ 15 years was obtained from the registry books of the Paediatric-Nursery-Department and the Malaria Research Laboratory. For the period 2001 - 2004, more detailed malaria related admission information was available as part of an ongoing study on severe malaria, allowing a calculation of the proportion of infants < 6 months of age among admissions in children < 5 years.ResultsRetrospective analysis of hospital records showed that over the course of these years, the average annual proportion of paediatric admissions in children ≤ 15 years with confirmed malaria aged <6 months was 4.8% and ranged between 2.8%-6.7%. This proportion was stable throughout the seasons. Between 2001-2004, 9.9% of admissions with confirmed malaria in children <5 years occurred in infants <6 months, with numbers increasing steadily during the first six months of life.ConclusionsThese findings are consistent with recent reports suggesting that the burden of malaria during the six first months of life may be substantial, and highlight that more research is needed on dose-optimization, safety and efficacy of anti-malarials that are currently used off-label in this vulnerable patient group.

Schistosomiasis in pre-school-age children and their mothers in Chikhwawa district, Malawi with notes on characterization of schistosomes and snails

BackgroundTo complement ongoing schistosomiasis control within national control programmes (NCPs) that administer praziquantel to school-age children, assessing the risk and extent of schistosomiasis in pre-school-age children (PSAC) is important.MethodsIn June 2012, schistosomiasis in Chikhwawa district, Malawi was assessed across 12 villages examining pre-school-age children (PSAC) and their mothers by serological and parasitological diagnosis, as supplemented with urine-antigen and questionnaire-interview methods. Urinary tract morbidity was inferred by haematuria and albuminuria assays.ResultsIn total, 49.5% (CI95 42.6-56.4) of 208 PSAC and 94.5% (CI95 90.9-98.1) of 165 mothers were seropositive for schistosomiasis, in 2 villages seroprevalence exceeded 75% in PSAC. Egg-patent urogenital and intestinal schistosomiasis was observed; 17.7% (CI95 12.4-23.2) of PSAC and 45.1% (CI95 37.4-52.8) of mothers having active schistosomiasis by parasitological and urine-antigen testing combined. PSAC often had extensive daily water contact and many (~25%) had haematuria and albuminuria. As eggs with an atypical morphology of Schistosoma haematobium were observed, a general selection of schistosome eggs was characterized by DNA barcoding, finding Group I S. haematobium and Group IV and V S. mansoni. Malacological surveys encountered several populations of Bulinus globosus but failed to find Biomphalaria.ConclusionsBoth PSAC and their mothers appear to be at significant risk of schistosomiasis and should be considered for treatment within the NCP of Malawi.

Effects of transmission reduction by insecticide- treated bed nets (ITNs) on parasite genetics population structure: I. The genetic diversity of Plasmodium falciparum parasites by microsatellite markers in western Kenya

BackgroundInsecticide-treated bed nets (ITNs) reduce malaria transmission and are an important prevention tool. However, there are still information gaps on how the reduction in malaria transmission by ITNs affects parasite genetics population structure. This study examined the relationship between transmission reduction from ITN use and the population genetic diversity of Plasmodium falciparum in an area of high ITN coverage in western Kenya.MethodsParasite genetic diversity was assessed by scoring eight single copy neutral multilocus microsatellite (MS) markers in samples collected from P. falciparum- infected children (< five years) before introduction of ITNs (1996, baseline, n = 69) and five years after intervention (2001, follow-up, n = 74).ResultsThere were no significant changes in overall high mixed infections and unbiased expected heterozygosity between baseline (%MA = 94% and He = 0.75) and follow up (%MA = 95% and He = 0.79) years. However, locus specific analysis detected significant differences for some individual loci between the two time points. Pfg377 loci, a gametocyte-specific MS marker showed significant increase in mixed infections and He in the follow up survey (%MA = 53% and He = 0.57) compared to the baseline (%MA = 30% and He = 0.29). An opposite trend was observed in the erythrocyte binding protein (EBP) MS marker. There was moderate genetic differentiation at the Pfg377 and TAA60 loci (FST = 0.117 and 0.137 respectively) between the baseline and post-ITN parasite populations. Further analysis revealed linkage disequilibrium (LD) of the microsatellites in the baseline (14 significant pair-wise tests and ISA = 0.016) that was broken in the follow up parasite population (6 significant pairs and ISA = 0.0003). The locus specific change in He, the moderate population differentiation and break in LD between the baseline and follow up years suggest an underlying change in population sub-structure despite the stability in the overall genetic diversity and multiple infection levels.ConclusionsThe results from this study suggest that although P. falciparum population maintained an overall stability in genetic diversity after five years of high ITN coverage, there was significant locus specific change associated with gametocytes, marking these for further investigation.

Estimating regional centile curves from mixed data sources and countries

Regional or national growth distributions can provide vital information on the health status of populations. In most resource poor countries, however, the required anthropometric data from purpose-designed growth surveys are not readily available. We propose a practical method for estimating regional (multi-country) age-conditional weight distributions based on existing survey data from different countries. We developed a two-step method by which one is able to model data with widely different age ranges and sample sizes. The method produces references both at the country level and at the regional (multi-country) level. The first step models country-specific centile curves by Box-Cox t and Box-Cox power exponential distributions implemented in generalized additive model for location, scale and shape through a common model. Individual countries may vary in location and spread. The second step defines the regional reference from a finite mixture of the country distributions, weighted by population size. To demonstrate the method we fitted the weight-for-age distribution of 12 countries in South East Asia and the Western Pacific, based on 273 270 observations. We modeled both the raw body weight and the corresponding Z score, and obtained a good fit between the final models and the original data for both solutions. We briefly discuss an application of the generated regional references to obtain appropriate, region specific, age-based dosing regimens of drugs used in the tropics. The method is an affordable and efficient strategy to estimate regional growth distributions where the standard costly alternatives are not an option.

Combining data from multiple spatially-referenced prevalence surveys using generalized linear geostatistical models

type=main xml:id=rssa12069-abs-0001> Data from multiple prevalence surveys can provide information on common parameters of interest, which can therefore be estimated more precisely in a joint analysis than by separate analyses of the data from each survey. However, fitting a single model to the combined data from multiple surveys is inadvisable without testing the implicit assumption that all of the surveys are directed at the same inferential target. We propose a multivariate generalized linear geostatistical model that accommodates two sources of heterogeneity across surveys to correct for spatially structured bias in non-randomized surveys and to allow for temporal variation in the underlying prevalence surface between consecutive survey periods. We describe a Monte Carlo maximum likelihood procedure for parameter estimation and show through simulation experiments how accounting for the different sources of heterogeneity among surveys in a joint model leads to more precise inferences. We describe an application to multiple surveys of the prevalence of malaria conducted in Chikhwawa District, Southern Malawi, and discuss how this approach could inform hybrid sampling strategies that combine data from randomized and non-randomized surveys to make the most efficient use of all available data.

Optimizing the programmatic deployment of the anti-malarials artemether-lumefantrine and dihydroartemisinin-piperaquine using pharmacological modelling

BackgroundSuccessful programmatic use of anti-malarials faces challenges that are not covered by standard drug development processes. The development of appropriate pragmatic dosing regimens for low-resource settings or community-based use is not formally regulated, even though these may alter factors which can substantially affect individual patient and population level outcome, such as drug exposure, patient adherence and the spread of drug resistance and can affect a drug’s reputation and its eventual therapeutic lifespan.MethodsAn in silico pharmacological model of anti-malarial drug treatment with the pharmacokinetic/pharmacodynamic profiles of artemether-lumefantrine (AM-LF, Coartem®) and dihydroartemisinin-piperaquine (DHA-PPQ, Eurartesim®) was constructed to assess the potential impact of programmatic factors, including regionally optimized, age-based dosing regimens, poor patient adherence, food effects and drug resistance on treatment outcome at population level, and compared both drugs’ susceptibility to these factors.ResultsCompared with DHA-PPQ, therapeutic effectiveness of AM-LF seems more robust to factors affecting drug exposure, such as age- instead of weight-based dosing or poor adherence. The model highlights the sub-optimally low ratio of DHA:PPQ which, in combination with the narrow therapeutic dose range of PPQ compared to DHA that drives the weight or age cut-offs, leaves DHA at a high risk of under-dosing.ConclusionPharmacological modelling of real-life scenarios can provide valuable supportive data and highlight modifiable determinants of therapeutic effectiveness that can help optimize the deployment of anti-malarials in control programmes.