From high to low malaria transmission in Zanzibar-challenges and opportunities to achieve elimination.

BACKGROUND: Substantial global progress in the control of malaria in recent years has led to increased commitment to its potential elimination. Whether this is possible in high transmission areas of sub-Saharan Africa remains unclear. Zanzibar represents a unique case study of such attempt, where modern tools and strategies for malaria treatment and vector control have been deployed since 2003. METHODS: We have studied temporal trends of comprehensive malariometric indices in two districts with over 100,000 inhabitants each. The analyses included triangulation of data from annual community-based cross-sectional surveys, health management information systems, vital registry and entomological sentinel surveys. RESULTS: The interventions, with sustained high-community uptake, were temporally associated with a major malaria decline, most pronounced between 2004 and 2007 and followed by a sustained state of low transmission. In 2015, the Plasmodium falciparum community prevalence of 0.43% (95% CI 0.23-0.73) by microscopy or rapid diagnostic test represented 96% reduction compared with that in 2003. The P. falciparum and P. malariae prevalence by PCR was 1.8% (95% CI 1.3-2.3), and the annual P. falciparum incidence was estimated to 8 infections including 2.8 clinical episodes per 1000 inhabitants. The total parasite load decreased over 1000-fold (99.9%) between 2003 and 2015. The incidence of symptomatic malaria at health facilities decreased by 94% with a trend towards relatively higher incidence in age groups > 5 years, a more pronounced seasonality and with reported travel history to/from Tanzania mainland as a higher risk factor. All-cause mortality among children < 5 years decreased by 72% between 2002 and 2007 mainly following the introduction of artemisinin-based combination therapies whereas the main reduction in malaria incidence followed upon the vector control interventions from 2006. Human biting rates decreased by 98% with a major shift towards outdoor biting by Anopheles arabiensis. CONCLUSIONS: Zanzibar provides new evidence of the feasibility of reaching uniquely significant and sustainable malaria reduction (pre-elimination) in a previously high endemic region in sub-Saharan Africa. The data highlight constraints of optimistic prognostic modelling studies. New challenges, mainly with outdoor transmission, a large asymptomatic parasite reservoir and imported infections, require novel tools and reoriented strategies to prevent a rebound effect and achieve elimination.

Cytochrome 1A1 and 1B1 gene diversity in the Zanzibar islands.

Amodiaquine (AQ) is a 4-aminoquinoline widely used in the treatment of malaria as part of the artemisinin combination therapy (ACT). AQ is metabolised towards its main metabolite desethylamodiaquine mainly by cytochrome P450 2C8 (CYP2C8). CYP1A1 and CYP1B1 play a minor role in the metabolism but they seem to be significantly involved in the formation of the short-lived quinine-imine. To complete the genetic variation picture of the main genes involved in AQ metabolism in the Zanzibar population, previously characterised for CYP2C8, we analysed in this study CYP1A1 and CYP1B1 main genetic polymorphisms. The results obtained show a low frequency of the CYP1A1*2B/C allele (2.4%) and a high frequency of CYP1B1*6 (approximately 42%) followed by CYP1B1*2 (approximately 27%) in Zanzibar islands. Genotype data for CYP1A1 and CYP1B1 show a low incidence of fast metabolisers, revealing a relatively safe genetic background in Zanzibar's population regarding the appearance of adverse effects.

CYP2C8 polymorphism frequencies among malaria patients in Zanzibar.

OBJECTIVE: The determination of the prevalence of the CYP2C8 main alleles in a typical set of malaria patients in Zanzibar, as these patients represent a typical population exposed to amodiaquine, an antimalarial mainly metabolized by CYP2C8. Also, to determine for the first time the frequencies of CYP2C8 alleles in native African populations. METHODS: Polymerase chain reaction-restriction fragment polymorphism for the identification of CYP2C8*1, CYP2C8*2, CYP2C8*3 and CYP2C8*4 on a random population of 165 unrelated malaria patients. RESULTS: The allele frequencies found were: CYP2C8*1 (wild type, 83.4%), CYP2C8*2 (13.9%), CYP2C8*3 (2.1%) and CYP2C8*4 (0.6%). In terms of genotypes, 70.4% of the patients showed the CYP2C8*1/ CYP2C8*1 genotypes, while heterozygous between the wild type and other minor alleles were seen in 26.0%. Finally, 3.6% of the patients were homozygous for slow metabolizer alleles. The frequencies observed are equivalent to those documented for African-Americans. CONCLUSIONS: CYP2C8 non-wild type alleles have a significant prevalence in the East African population studied. The consequent frequency of 3.6% of patients homozygous for slow metabolizer alleles represent a significant fraction of the population potentially in higher risk of adverse effects due to a less efficient metabolism of amodiaquine. As approximately 10(6) first-line treatments are currently performed in Zanzibar per year, this represents a non-negligible absolute number of amodiaquine exposures. This information constitutes a background for the pharmacovigilance programs presently being employed in Zanzibar.