Drug Resistant P. falciparum in Pakistan

Development and spread of drug resistant Plasmodium falciparum poses major threat to malaria control. In Pakistan, incidence of malaria has markedly increased during the last decade. Increasing resistance to commonly used antimalarial drugs might have also contributed to this rise.

Chloroquine resistance was first reported from Pakistan in 1984 and was followed by several reports confirming it in Punjab, Afghan refugee camps and areas bordering Afghanistan.1 Similarly resistance to sulphadoxine-pyrimethamine monotherapy has been reported from western Pakistan.

In 2008, Pakistan had adopted artemisinin-based combination therapy (ACT) for treatment of uncomplicated P. falciparum malaria with artesunate plus sulphadoxine-pyrimethamine as first-line treatment. However, the use of this combination is of concern as efficacy studies conducted in Baluchistan (2001-2005) reported 56 % treatment failure with sulphadoxine-pyrimethamine monotherapy.2

Chloroquine (CQ) and the antifolates sulfadoxinepyrimethamine (SP) being the key antimalarial drugs used in the western Pakistan, largely as monotherapies. 3  Although Pakistan joined the Roll Back Malaria (RBM) initiative in 2001 with the formulation of a 5-year RBM strategy, several of her regions, such as the North West Frontier Province (NWFP), were unable to implement the strategy because of lack of resources, to the effect that, by the end of 2005, there was no evidence of monotherapies being replaced by combination therapies, contrary to RMB recommendations. 3  The monotherapeutic use of CQ and SP is expected to trigger drug resistance .

In addition to conventional in vitro and in vivo efficacy studies, analyses of mutations in drug resistance associated genes are valuable tool for surveillance of antimalarial drug resistance and provide in depth information on spread of resistance. The K76T amino acid substitution in the chloroquine resistance transporter gene (pfcrt)has been shown to be predictive of chloroquine and amodiaquine treatment failure. Single nucleotide polymorphisms (SNPs) in the P. falciparumdihydrofolate reductase gene(pfdhfr) and dihydroptereoate synthetase gene(pfdhps) are well established determinants of pyrimethamine and sulphadoxine resistance.

A recent analysis of mutations in pfcrt gene from Pakistan indicates high levels of in vivochloroquine resistance. The reported high prevalence of polymorphisms in the pfdhfr indicates that decreased susceptibility to sulphadoxine-pyrimethamine is also widespread.3

Continued antimalarials drug resistance surveillance is essential to assess the efficacy of current treatment option. With use of modern molecular tools, malaria resistance can be mapped using known markers for drug resistance in this region and this can provide basis for developing a rationale drug policy to reduce the level of resistance.

Moreover, monotherapies are still being used in NWFP. 3 The continued use of monotherapies will likely hasten the dangerous development of high levels of antifolate resistance by both species. The enforcement of lucid drug use to minimize drug pressure, and the use of antifolates, together with artemisinin, would therefore be a highly desirable therapeutic policy for this area.

1. Fox E, Khaliq AA, Sarwar M, Strickland GT: Chloroquine-resistant Plasmodium falciparum:  now in Pakistani Punjab. Lancet 1985, 1:1432-1435.
2. WHO: Division of communicable disease control newsletter. 2005, 6:1-4.

   1. Ghanchi NK, Ursing J, Beg MA, Veiga MI, Jafri S, Martensson A: Prevalence of resistance associated polymorphisms in Plasmodium falciparum field isolates from southern Pakistan. Malaria Journal. 2011 Jan 28;10(1):18.