Name: Alifrangis, Michael
Home country: Denmark
Research country:
Project period: 1998-2001
Type: Ph.D. thesis

Title
The use of molecular markers to monitor malaria drug resistance

Abstract
The malaria parasite, Plasmodium falciparum has developed high levels of resistance to the first-line antimalarial drug, chloroquine (CQ) in almost all countries with endemic malaria. Thus, in recent years many countries have changed to sulfadoxin/pyrimethamin (S/P). Mutations In the P. falciparum genes dhfr and dhps, and Pfcrt results in S/P and CQ resistance respectively and monitoring these mutations could potentially be used as resistance markers as a support to rational pharmacotherapy.

The aim was to study if the resistance markers were able to predict the outcome of S/P or CQ treatment as well as investigate if the prevalence of mutations reflects resistance levels in vivo. PCR was used to identify the mutations, furthermore it was attempted to develop and ELISA-based method to detect the changes in the P. falciparum DHFR enzyme at the amino acid level.  

The ability of the gene mutations to predict the outcome of S/P or CQ treatment in children with uncomplicated malaria living in Tanzania was limited. However, a significant relationship between prevalence of mutations in the dhfr/dhps genes and S/P resistance was found by comparing four areas in East Africa with varying endemicity and level of resistance. It was furthermore shown that intervention with bed nets, by reducing the malaria transmission, had a positive effect on the prevalence of mutations and the implementation with bed nets may therefore facilitate restoration of susceptibility to antimalarial drugs.

Generally, the resistance markers have a limited value in areas with high levels of resistance. However, changes in sensitivity over time within an area with moderate levels of resistance may be revealed by longitudinal surveillance of the prevalence of locally defined resistance markers. 

Involved research institutions
The Ph.D. study was performed at the Panum Institute and Copenhagen University Hospital (Rigshospitalet), linked to Centre for Medical Parasitology.

Supervisor(s)
Anita M. Rønn, Department of Infectious Diseases, the National University Hospital, (Rigshospitalet)
Ib C. Bygbjerg, Department of International Health, Institute of Public Health, University of Copenhagen

Correspondence
Michael Alifrangis, Panum Institute, IMMI, Building 24.2, Blegdamsvej 3, DK-2200 København N
E-mail: Michael Alifrangis