Journal Article > Meta-AnalysisFull Text
BMC Med. 2020 February 25; Volume 18 (Issue 1); 47.; DOI:10.1186/s12916-020-1494-3.
Bretscher MT, Dahal P, Griffin J, Stepniewska K, Bassat Q, et al.
BMC Med. 2020 February 25; Volume 18 (Issue 1); 47.; DOI:10.1186/s12916-020-1494-3.
BACKGROUND
The majority of Plasmodium falciparum malaria cases in Africa are treated with the artemisinin combination therapies artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ), with amodiaquine being also widely used as part of seasonal malaria chemoprevention programs combined with sulfadoxine-pyrimethamine. While artemisinin derivatives have a short half-life, lumefantrine and amodiaquine may give rise to differing durations of post-treatment prophylaxis, an important additional benefit to patients in higher transmission areas.
METHODS
We analyzed individual patient data from 8 clinical trials of AL versus AS-AQ in 12 sites in Africa (n = 4214 individuals). The time to PCR-confirmed reinfection after treatment was used to estimate the duration of post-treatment protection, accounting for variation in transmission intensity between settings using hidden semi-Markov models. Accelerated failure-time models were used to identify potential effects of covariates on the time to reinfection. The estimated duration of chemoprophylaxis was then used in a mathematical model of malaria transmission to determine the potential public health impact of each drug when used for first-line treatment.
RESULTS
We estimated a mean duration of post-treatment protection of 13.0 days (95% CI 10.7-15.7) for AL and 15.2 days (95% CI 12.8-18.4) for AS-AQ overall. However, the duration varied significantly between trial sites, from 8.7-18.6 days for AL and 10.2-18.7 days for AS-AQ. Significant predictors of time to reinfection in multivariable models were transmission intensity, age, drug, and parasite genotype. Where wild type pfmdr1 and pfcrt parasite genotypes predominated (<=20% 86Y and 76T mutants, respectively), AS-AQ provided ~ 2-fold longer protection than AL. Conversely, at a higher prevalence of 86Y and 76T mutant parasites (> 80%), AL provided up to 1.5-fold longer protection than AS-AQ. Our simulations found that these differences in the duration of protection could alter population-level clinical incidence of malaria by up to 14% in under-5-year-old children when the drugs were used as first-line treatments in areas with high, seasonal transmission.
CONCLUSION
Choosing a first-line treatment which provides optimal post-treatment prophylaxis given the local prevalence of resistance-associated markers could make a significant contribution to reducing malaria morbidity.
The majority of Plasmodium falciparum malaria cases in Africa are treated with the artemisinin combination therapies artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ), with amodiaquine being also widely used as part of seasonal malaria chemoprevention programs combined with sulfadoxine-pyrimethamine. While artemisinin derivatives have a short half-life, lumefantrine and amodiaquine may give rise to differing durations of post-treatment prophylaxis, an important additional benefit to patients in higher transmission areas.
METHODS
We analyzed individual patient data from 8 clinical trials of AL versus AS-AQ in 12 sites in Africa (n = 4214 individuals). The time to PCR-confirmed reinfection after treatment was used to estimate the duration of post-treatment protection, accounting for variation in transmission intensity between settings using hidden semi-Markov models. Accelerated failure-time models were used to identify potential effects of covariates on the time to reinfection. The estimated duration of chemoprophylaxis was then used in a mathematical model of malaria transmission to determine the potential public health impact of each drug when used for first-line treatment.
RESULTS
We estimated a mean duration of post-treatment protection of 13.0 days (95% CI 10.7-15.7) for AL and 15.2 days (95% CI 12.8-18.4) for AS-AQ overall. However, the duration varied significantly between trial sites, from 8.7-18.6 days for AL and 10.2-18.7 days for AS-AQ. Significant predictors of time to reinfection in multivariable models were transmission intensity, age, drug, and parasite genotype. Where wild type pfmdr1 and pfcrt parasite genotypes predominated (<=20% 86Y and 76T mutants, respectively), AS-AQ provided ~ 2-fold longer protection than AL. Conversely, at a higher prevalence of 86Y and 76T mutant parasites (> 80%), AL provided up to 1.5-fold longer protection than AS-AQ. Our simulations found that these differences in the duration of protection could alter population-level clinical incidence of malaria by up to 14% in under-5-year-old children when the drugs were used as first-line treatments in areas with high, seasonal transmission.
CONCLUSION
Choosing a first-line treatment which provides optimal post-treatment prophylaxis given the local prevalence of resistance-associated markers could make a significant contribution to reducing malaria morbidity.
Protocol > Research Study
de Wit MBK, Rao B, Lassovski M, Ouabo A, Badjo C, et al.
2018 July 1
Primary Objective: To measure the prevalence of molecular markers of SP resistant malaria in North and South Kivu, DRC.
Sulfadoxine/pyrimethamine (SP) forms the backbone of most malaria chemoprevention programmes in high endemicity settings, including intermittent preventative therapy in pregnancy and infants (IPTp and IPTi respectively) as well as seasonal malaria chemoprevention (SMC). P. falciparum parasite resistance to SP threatens recent triumphs preventing malaria infection in the most vulnerable risk groups. WHO guidance is that chemoprevention using SP may not be implemented when prevalence of the dhps K540E gene denoting SP resistance are greater than 50%. Simple, robust polymerase chain reaction (PCR) - based methods for molecular surveillance of resistance to SP have the potential to indicate whether SP-based chemoprevention programmes would be effective in areas where surveillance was conducted, but also to identify early stages of emerging resistance in order to advocate for alternative chemoprevention strategies.
A minimum of 750 samples will be collected per province. Three sites per province will provide 250 samples assuming an estimated prevalence of 50% prevalence of dhps K540E gene with 95% confidence and 5% precision. This is also sufficient for robust estimation of the prevalence of dhps 581, an alternative critical marker. This sample size is calculated to estimate regional prevalence, i.e. for both South Kivu and North Kivu, and hence this study requires samples from multiple MSF sites (including from different MSF Operating Centre missions) e.g. Baraka, Kimbi and Lulingu amongst others in South Kivu and Mweso, Rutsuru and Walikale in North Kivu with a minimum total of 750 per province. If estimating specific prevalence in only one limited site, a large sample size would be required.
Sulfadoxine/pyrimethamine (SP) forms the backbone of most malaria chemoprevention programmes in high endemicity settings, including intermittent preventative therapy in pregnancy and infants (IPTp and IPTi respectively) as well as seasonal malaria chemoprevention (SMC). P. falciparum parasite resistance to SP threatens recent triumphs preventing malaria infection in the most vulnerable risk groups. WHO guidance is that chemoprevention using SP may not be implemented when prevalence of the dhps K540E gene denoting SP resistance are greater than 50%. Simple, robust polymerase chain reaction (PCR) - based methods for molecular surveillance of resistance to SP have the potential to indicate whether SP-based chemoprevention programmes would be effective in areas where surveillance was conducted, but also to identify early stages of emerging resistance in order to advocate for alternative chemoprevention strategies.
A minimum of 750 samples will be collected per province. Three sites per province will provide 250 samples assuming an estimated prevalence of 50% prevalence of dhps K540E gene with 95% confidence and 5% precision. This is also sufficient for robust estimation of the prevalence of dhps 581, an alternative critical marker. This sample size is calculated to estimate regional prevalence, i.e. for both South Kivu and North Kivu, and hence this study requires samples from multiple MSF sites (including from different MSF Operating Centre missions) e.g. Baraka, Kimbi and Lulingu amongst others in South Kivu and Mweso, Rutsuru and Walikale in North Kivu with a minimum total of 750 per province. If estimating specific prevalence in only one limited site, a large sample size would be required.
Journal Article > ResearchFull Text
Malar J. 2019 December 18; Volume 18 (Issue 1); 430.; DOI:10.1186/s12936-019-3057-7
van Lenthe M, van der Meulen R, Lassovsky M, Ouabo A, Bakula E, et al.
Malar J. 2019 December 18; Volume 18 (Issue 1); 430.; DOI:10.1186/s12936-019-3057-7
BACKGROUND
Sulfadoxine–pyrimethamine (SP) is a cornerstone of malaria chemoprophylaxis and is considered for programmes in the Democratic Republic of Congo (DRC). However, SP efficacy is threatened by drug resistance, that is conferred by mutations in the dhfr and dhps genes. The World Health Organization has specified that intermittent preventive treatment for infants (IPTi) with SP should be implemented only if the prevalence of the dhps K540E mutation is under 50%. There are limited current data on the prevalence of resistance-conferring mutations available from Eastern DRC. The current study aimed to address this knowledge gap.
METHODS
Dried blood-spot samples were collected from clinically suspected malaria patients [outpatient department (OPD)] and pregnant women attending antenatal care (ANC) in four sites in North and South Kivu, DRC. Quantitative PCR (qPCR) was performed on samples from individuals with positive and with negative rapid diagnostic test (RDT) results. Dhps K450E and A581G and dhfr I164L were assessed by nested PCR followed by allele-specific primer extension and detection by multiplex bead-based assays.
RESULTS
Across populations, Plasmodium falciparum parasite prevalence was 47.9% (1160/2421) by RDT and 71.7 (1763/2421) by qPCR. Median parasite density measured by qPCR in RDT-negative qPCR-positive samples was very low with a median of 2.3 parasites/µL (IQR 0.5–25.2). Resistance genotyping was successfully performed in RDT-positive samples and RDT-negative/qPCR-positive samples with success rates of 86.2% (937/1086) and 55.5% (361/651), respectively. The presence of dhps K540E was high across sites (50.3–87.9%), with strong evidence for differences between sites (p < 0.001). Dhps A581G mutants were less prevalent (12.7–47.2%). The dhfr I164L mutation was found in one sample.
CONCLUSIONS
The prevalence of the SP resistance marker dhps K540E exceeds 50% in all four study sites in North and South Kivu, DRC. K540E mutations regularly co-occurred with mutations in dhps A581G but not with the dhfr I164L mutation. The current results do not support implementation of IPTi with SP in the study area.
Sulfadoxine–pyrimethamine (SP) is a cornerstone of malaria chemoprophylaxis and is considered for programmes in the Democratic Republic of Congo (DRC). However, SP efficacy is threatened by drug resistance, that is conferred by mutations in the dhfr and dhps genes. The World Health Organization has specified that intermittent preventive treatment for infants (IPTi) with SP should be implemented only if the prevalence of the dhps K540E mutation is under 50%. There are limited current data on the prevalence of resistance-conferring mutations available from Eastern DRC. The current study aimed to address this knowledge gap.
METHODS
Dried blood-spot samples were collected from clinically suspected malaria patients [outpatient department (OPD)] and pregnant women attending antenatal care (ANC) in four sites in North and South Kivu, DRC. Quantitative PCR (qPCR) was performed on samples from individuals with positive and with negative rapid diagnostic test (RDT) results. Dhps K450E and A581G and dhfr I164L were assessed by nested PCR followed by allele-specific primer extension and detection by multiplex bead-based assays.
RESULTS
Across populations, Plasmodium falciparum parasite prevalence was 47.9% (1160/2421) by RDT and 71.7 (1763/2421) by qPCR. Median parasite density measured by qPCR in RDT-negative qPCR-positive samples was very low with a median of 2.3 parasites/µL (IQR 0.5–25.2). Resistance genotyping was successfully performed in RDT-positive samples and RDT-negative/qPCR-positive samples with success rates of 86.2% (937/1086) and 55.5% (361/651), respectively. The presence of dhps K540E was high across sites (50.3–87.9%), with strong evidence for differences between sites (p < 0.001). Dhps A581G mutants were less prevalent (12.7–47.2%). The dhfr I164L mutation was found in one sample.
CONCLUSIONS
The prevalence of the SP resistance marker dhps K540E exceeds 50% in all four study sites in North and South Kivu, DRC. K540E mutations regularly co-occurred with mutations in dhps A581G but not with the dhfr I164L mutation. The current results do not support implementation of IPTi with SP in the study area.
Journal Article > LetterFull Text
Nat Med. 2020 August 7; Volume 26 (Issue 9); 1411–1416.; DOI:10.1038/s41591-020-1025-y
Sherrard Smith E, Hogan AB, Hamlet A, Watson OJ, Whittaker C, et al.
Nat Med. 2020 August 7; Volume 26 (Issue 9); 1411–1416.; DOI:10.1038/s41591-020-1025-y
The burden of malaria is heavily concentrated in sub-Saharan Africa (SSA) where cases and deaths associated with COVID-19 are rising. In response, countries are implementing societal measures aimed at curtailing transmission of SARS-CoV-2. Despite these measures, the COVID-19 epidemic could still result in millions of deaths as local health facilities become overwhelmed. Advances in malaria control this century have been largely due to distribution of long-lasting insecticidal nets (LLINs), with many SSA countries having planned campaigns for 2020. In the present study, we use COVID-19 and malaria transmission models to estimate the impact of disruption of malaria prevention activities and other core health services under four different COVID-19 epidemic scenarios. If activities are halted, the malaria burden in 2020 could be more than double that of 2019. In Nigeria alone, reducing case management for 6 months and delaying LLIN campaigns could result in 81,000 (44,000-119,000) additional deaths. Mitigating these negative impacts is achievable, and LLIN distributions in particular should be prioritized alongside access to antimalarial treatments to prevent substantial malaria epidemics.