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Drugs and resistance

Source: TropIKA

Title of the session: Drugs and resistance

Date: 05 November 2009

Agenda item: Scientific Session 26

Session theme: Drugs and resistance

Meeting room: Tsavo Ballroom 1

Chair(s): Dr. Alexis Nzila Kemri/Wellcome Trust Laboratories

Presenters:

• Ms. Amani Kheir, Uppsala University
• Ms. Leah Mwai, KEMRI
• Ass. Prof. Marielle Bouyou-akotet, Department of parasitology
• Mr.Sompob Saralamba, Mahidol-Oxford Tropical Medicine Research Unit
• Dr. Bakri Nour, Blue Nile National Institute for Communicable Diseases -University of Gezira
• Prof. Stephane Picot, University Lyon1
• Prof. Wilfred Mbacham, The Laboratory for Public Health Biotechnlogy
• Shannon Takala, University of Maryland School of Medicine

TropIKA rapporteur: Beatrice Irungu

Major topics:

• Transmission of Plasmodium falciparum dhfr Haplotypes in the Gambia
• Towards understanding the mechanisms of Lumefantrine resistance
• Prevalence of sulfadoxine-pyrimethamine resistant alleles of Plasmodium falciparum isolates from pregnant women after introduction of iptp-sp in Gabon
• Intra-host model of malaria infection: characterizing artesunate resistance
• Molecular monitoring of Plasmodium falciparum drug resistance
• A systematic review and meta-analysis of evidence for correlation between molecular markers of parasite resistance and treatment outcome in falciparum malaria
• Il-22 snp implications in clearance of drug resistant P. falciparum in Cameroon
• The search for molecular markers of artemisinin resistance: implications for Africa

Keywords:

• Resistance
• Plasmodium falciparum

Scope: Scope was narrow. Session covered identification of molecular markers and use of molecular markers in monitoring drug resistance.

REPORT ON ORIGINAL SESSION

Overview

Drug resistance is a major problem in the fight against malaria. In this session, molecur markers (MM) as a tool for monitoring drug resistance were emphasized. A study was carried out in Gabon to find out prevalence of suphadoxine/pyrimethamine resistance alleles, SP is used for IPTPp in Gabon. In Sudan, molecular monitoring was carried out to monitor Plasmodium falciparum drug resistance in Central and Eastern Sudan. Understanding mechanism of resistance of antimalarial drug lumefantrine (LM) and identifying it MM was also discussed. Lumefantrine/artemether is now the recommended first line drug for treatment of malaria in endemic regions. There is no base line data on LM activity. A study was carried out with the main objective of identifying LM molecular markers that could be used to monitor its efficacy.

MM could provide key information for the deployment of an effective national drug policy

CONTEXT AND ISSUE

No baseline data on LM activity which is currently being used in combination with artemether (coartem) in many countries as a first line treatment for malaria. There is need to understand its mechanisms of resistance and identify molecular markers of resistance.

Can molecular markers be used as anti-malarial efficacy assessment method?

Which markers are useful for monitoring drug resistance?

Key facts and figures

Drug resistance is a major problem in the fight against malaria. Molecular markers can be a used as a tool for monitoring drug resistance. It can provide useful data that can be used in drawing national drug policies.

Initiatives on the ground; experience/s derived

Isolates were collected and adapted to the laboratory settings. They were tested for their susceptibility towards different antimalarial drugs. To understand resistance parasites were genotyped.

Research Findings

In vitro data revealed that lumefantrine and chloroquine have an inverse relationship. This implies that use of coartem (lumefantrine/artemether) may lead to selection of chloroquine sensitive parasites. Hence continuous monitoring of coartem resistance is very important.

A study in Gabon revealed that use of sulphadoxine pyrimethamine in IPTp could soon be compromised due to presence of mutant parasites from samples analyzed from pregnant women. Hence, evaluation of alternative drugs in Gabon for IPTp is urgently required.

A study carried out in Eastern and central Sudan on molecular monitoring of P. falciparum drug resistance demonstrated that molecular marker studies could provide key information for the deployment of an effective national drug policy. Genes associated with artemisinin resistance were detected in this study.

There is need to extend tests for artesunate outside of Asia to find out how far the resistance has spread.

IL-22 is a pro-inflammatory cytokine, by whatever mechanism maybe needed by people in Cameroon to clear drug resistant parasites.

Which markers are useful for monitoring drug resistance? The best marker not yet related to clinical failure. The most needed is artemisinin resistance Pfmdr1 N86Y most tested.

Sompob Saralamba from Mahidol-Oxford Tropical Medicine Research Unit Faculty of Tropical Medicine, Mahidol University, Thailand presented an Intra-host model of malaria infection that can be used for characterizing artesunate resistance. Data obtained from this model is reproducible and support the hypothesis that increasing of parasite clearance time results from reduced efficacy of the drug at the ring stage of parasite life-cycle. It can also be used for designing alternative dosing regimens.

Lessons learned

No validated molecular marker for artemisinin yet

Future plans

Need to identify artemisinin and its derivatives molecular markers and their partner drug

Need to understand artemisinin mechanism of resistance

FINDINGS AND CONCLUSIONS

From formal presentations

Policy Impact

Pressure of lumefantrine could lead to selection of chloroquine resistance parasites. This implies that resistance to lumefantrine will lead to reversal of chloroquine resistance. This data was in a laboratory setting. If were to happens in the field then we may see a return of chloroquine soon.

Knowledge gap created

Molecular markers are an important tool for monitoring drug resistance and should be incorporated in malaria surveillance studies.

From open discussions/debates

The study in Gabon: Prevalence of SP-resistant alleles of P. falciparum isolates from pregnant women after induction of IPTp-sp in Gabon. It is too early to draw conclusion that SP will be compromised shortly from the data obtained.

Which markers are useful for monitoring drug resistance?

How initial age of the parasite was estimated in the Intra-host model of malaria infection? Was it assumed that the movement of parasites through the stages is fixed? Is there any evidence of the hypothesized resting stage where parasite is not affected by artesunate and is it fitted in the model?

Identified conclusions

Molecular marker is an important tool for monitoring drug resistance and it should be incorporated in malaria surveillance studies.

Recommendations

• Incorporate molecular markers in malaria surveillance studies.

• Use raw data to correlate marker failure

• ALWAYS compare data from previous similar study

Personal observations from rapporteur

Antimalarial drug resistance is a major problem. Studies to indentify MM are important. These molecular markers will be a useful tool for monitoring drug resistance.

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