There is a renewed commitment to pursue malaria eradication. Access to effective therapy is an essential component of this effort. With emerging concerns of artemisinin resistance in Asia [50, 51] and the possibility that drugs previously compromised by resistance can regain efficacy, it is important that we elucidate the effect of drug use on the dynamics of anti-malarial resistance. A review of the most recent data on chloroquine and SP use patterns in Africa and the first multi-country analysis of the relationship between anti-malarial drug use and the prevalence of resistant infections is presented here. This review of DHS and MICS survey data reveals that, as of 2006--2007, the estimated proportion of chloroquine and SP use in many African countries remained high. Furthermore, the descriptive comparisons of reported chloroquine use to patterns in pfcrt supports the hypothesis that in Africa widespread chloroquine use is associated with the persistence of chloroquine-resistant parasites, while a decrease chloroquine use is associated with a decline in the resistance.
Limitations of the DHS and MICS data include inaccuracies inherent to information derived from surveys and from selection bias, arising from non-random factors influencing when and where surveys are conducted and successfully completed. Molecular marker data may also be affected by selection bias introduced in choosing study sites and by publication bias. More dense spatial representation may better estimate prevalence on a national scale, particularly because local variation in the prevalence of chloroquine resistance within the same country has been documented [33, 52]. Finally, there are varying strategies to estimate haplotype frequencies within parasites causing human infection . The selected method was limited to reviewing previously collected data without precise measurements of allelic frequency. Despite these limitations, the analysis presented here uses data derived from the most comprehensive sources available at this time.
Chloroquine use and drug resistance
Longitudinal trends in pfcrt 76T prevalence in Malawi, Kenya and Tanzania, the three countries with historically high but recently low chloroquine use, support the hypothesis that a decline in chloroquine resistance occurs with the withdrawal of drug pressure. In Malawi, chloroquine use was negligible by 2000 and chloroquine resistance had disappeared by 2003. Tanzania appears to follow a similar pattern, with a significant downward trend in the prevalence of pfcrt 76T. Chloroquine resistance is declining in Kenya as well, as previously demonstrated in Kilifi , although more gradually than in Tanzania and Malawi. The slower rate may be a result of amodiaquine use , which was reported to have been taken by 9.6% of sampled children treated for fever in the 2003 DHS survey in Kenya . However, reported chloroquine use was also high in Kenya until at least 2000, and the full effect of decreased chloroquine use may not become evident for several years.
The four countries with sustained reported chloroquine use at moderate to high levels exhibited no change or even slight increases in the prevalence of pfcrt 76T. In Uganda, almost all infections were chloroquine-resistant, while in Burkina Faso and Mali half to three quarters of the infections were chloroquine-resistant. Prevalence of pfcrt 76T in Guinea Bissau was lower than Uganda, Burkina Faso and Mali, but remained stable around 20%. The reason for these differences in prevalence is unclear. Seasonality of the transmission patterns in East versus West Africa could be a contributing factor. In Uganda, malaria transmission is perennial, characterized by year-round infections with peaks during rainy seasons. As a result, treatment occurs throughout the year, subjecting parasites to constant selective pressure. In contrast, the more seasonal transmission of the West African Sahel, including Burkina Faso and Mali, may lead to prolonged periods of lower anti-malarial use. The prevalence of chloroquine-resistant alleles was shown to increase over the transmission season and decrease between seasons in a study conducted in The Gambia, suggesting that the transient decrease in drug pressure is enough to allow for the resurgence of susceptible parasites .
Differences in access to anti-malarial treatment are also a possible contributor to the varying levels of pfcrt 76T in Guinea-Bissau, Burkina Faso, Mali, and Uganda. If a large proportion of children with fever go untreated, even when chloroquine is the most commonly used anti-malarial, a large proportion of the parasite population is not subjected to chloroquine selective pressure. This may contribute to the high level of resistant parasites in Uganda, which has among the highest anti-malarial coverage for the treatment of fever, likely due to the use of home based therapies. However, this does not adequately address the differences in pfcrt 76T levels seen in West Africa, where Guinea Bissau, Mali, and Burkina Faso had similar anti-malarial coverage for febrile and convulsive children, ranging from 33-46%. A wide range of factors including environmental conditions, access to medication, host immunity, duration of drug pressure and others likely contribute to the differing baseline levels of resistant alleles.
This study demonstrates that as of 2006-2007, reported anti-malarial use did not reflect national policy in several countries. The analysis does suggest that in Africa, changes in prevalence of pfcrt 76T are related to estimates of drug use. This relationship raises the possibility that the level of resistance could be used as an indicator of continuing drug use. However, the lack of correlation between the most recent point estimates of drug use and prevalence of pfcrt 76T indicates that chloroquine resistance is not always related to current levels of drug pressure. This point is exemplified by Kenya, where reported use in 2003 was 4% but pfcrt 76T prevalence was 80% as of 2007. Rather, it appears that chloroquine resistance declines only under sustained conditions of very low or near-absent use, as demonstrated by the cases of Malawi and Tanzania. The level of resistance maintained by high drug pressure may vary by country and epidemiological situation, as seen by comparing Uganda and Guinea-Bissau. Additionally, while pfcrt 76T has declined in some African countries, the resistant genotype remains fixed in some regions of Southeast Asia and Latin America after decades of little to no chloroquine use for P. falciparum infection [64–66]. This may be due to reduced parasite diversity in low compared to high transmission settings, leading to decreased opportunities for recombination and the fixation of alleles in the population. As ACT uptake increases and transmission decreases in Africa, it will be informative to examine the dynamics of chloroquine susceptibility within the parasite populations in different settings. The return of chloroquine sensitivity in Malawi has been attributed to the re-expansion of sensitive parasites that survived in the population despite drug pressure rather than reversion of resistant parasites . The return of chloroquine sensitivity to other countries is likely to depend on the availability of circulating chloroquine-susceptible parasites to out-compete the resistant population in the absence of drug pressure.
The wealth of standardized information collected in DHS and MICS surveys along with published information on the prevalence of chloroquine resistance has allowed us to take a step toward understanding the relationship between estimates of drug pressure and the dynamics of drug-resistant malaria. As an increasing amount of data on molecular markers, in vitro and clinical estimates of resistance are made available via initiatives such as the WorldWide Antimalarial Resistance Network (WWARN), our ability to characterize the level of resistance in different geographic areas will become more comprehensive and precise. This knowledge will inform targeted, rational approaches to the study of drug resistance and the design of more efficient and cost effective programs to curb resistance.