RAVREDA-AMI: Amazon Network for the Surveillance of Antimalarial Drug Resistance (RAVREDA) / Amazon Malaria Initiative (AMI)

RAVREDA/AMI Thematic Area:

Resistance to Antimalarials

Surveillance of Antimalarial Drug Resistance:
RAVREDA/AMI Sentinel Sites for Efficacy Studies, 2002–2004

At the end of 1990s, countries in the Amazon region did not had a surveillance system that could routinely evaluate the efficacy of antimalarial treatments. Reliable and standardized malaria information was not available for decision-making. For this reason, the Network's first step was devoted to developing a surveillance system for antimalarial drug resistance in the Amazon countries, with the goal of generating reliable, evidence-based, and standardized drug efficacy information:

• Generic Protocols and Flow Diagram for in vivo Antimalarial Drug-Efficacy Studies in the Americas
• Instrument and Exercise for in vivo Antimalarial Drug-Efficacy Studies (WHO, 2004)
• Practical Guide for in vivo Antimalarial Drug-Efficacy Studies in the Americas
• Assessment and Monitoring of Antimalarial Drug Efficacy for the Treatment of Uncomplicated falciparum Malaria (WHO)

The surveillance system of RAVREDA/AMI consists of the evaluation of the therapeutic effectiveness of antimalarials through the application of a standardized protocol, based on WHO recommendations, to a sample of patients looking for facilities in their health system that provide malaria diagnostic and care services, identified as sentinel sites (SC). Some minor adjustments were made based on previous experiences with efficacy studies in the Region:

The countries first evaluate the drugs and official therapeutic regimens and subsequently the most advisable therapeutic alternatives.

By first semester 2007, more than 88 drug efficacy evaluations had been concluded in the eight countries making up the Amazon Basin. Resistance is being mapped across the region and all countries have evaluated one or more ACT regimens:

• Antimalarial Drug Efficacy Studies, 2002–2005
  (Excel table)

In the four years of its operation, the network has generated information on therapeutic effectiveness and has guided changes in therapeutic regimens. Since 2001, Peru and Bolivia have introduced the use of artemisinin-based therapeutic combinations for the treatment of P. falciparum. By the end of 2005, artemisinin-based therapeutic combinations were already being used as first-line regimens in Venezuela, Suriname, Guyana, and Ecuador; and its use has already been recommended in Brazil and Colombia. Training human resources from the health services and strengthening ties between research institutions and control programs is yet another product of the network, as is the generation of greater venues for analyzing problems within Malaria Control Programs.

The results of monitoring therapeutic response to antimalarials through RAVREDA-AMI were particularly important for the region due to their number, geographical and temporal coverage, standardization, and involvement of control program in their execution. The findings map both the spatial and temporal aspects of resistance, which provided a legitimate scientific basis for the process of treatment change towards more efficacious combinations.

Antimalarials Efficacy in P. vivax Infections

Although the priority of the Network has always been P. falciparum infections, P. vivax accounts for more than 70% of all cases of malaria in the Americas; and CQ-resistant strains have been reported in the region. Seventeen studies have been carried out to evaluate the efficacy of CQ (25 mg/kg) against P. vivax have been conducted by RAVREDA in Bolivia, Brazil, Colombia, Peru, and Venezuela. Four of these studies (Bolivia, Colombia and Venezuela) have demonstrated 100% chloroquine efficacy. In the other 13, therapeutic failure was verified in a range of 1.5–25%. In the failures, CQ drug levels in the blood was measured, but only in some of the studies carried out in Brazil and Peru. Three studies carried out in Venezuela evaluated the entire scheme (chloroquine + primaquine), with a 100% clinical and parasitological cure.

The measurement of serum chloroquine levels in the evaluation of the therapeutic response of P. vivax to chloroquine therapy has special importance in the confirmation of treatment failure. Determination of serum levels of chloroquine and desetilchloroquine is being included by RAVREDA in monitoring P. vivax therapeutic response to chloroquine.

• Workshop on Measuring Antimalarial Serum Levels
  (Belém, Brasil, 29 May – 2 June 2006) (draft executive summary in Portuguese)

Recognizing the irreplaceable role of in vivo effectiveness evaluations in providing guidance for the adjustment of antimalarial policies, other methods of surveillance are needed to complement the system:

1. in vitro susceptibility evaluations, and
2. detection of molecular markers of resistance.

Over the last two years, RAVREDA-AMI has made progress in standardizing the methodology for the use of ELISA-based tests in monitoring temporal and spatial variations in drug susceptibility:

• Utilization of in vitro Susceptibility Tests in RAVREDA-AMI the for Surveillance of Resistance to Antimalarials: Guidelines Proposed at a Technical Meeting on Standardizing the Use of in vitro Tests in RAVREDA-AMI (Bogotá, 25–28 April 2004) (draft in Spanish)

The implementation of a systematic monitoring of such variations will enable early detection of resistance to the new drugs used in the Region (derivatives of Artemisinins and Mefloquine).

• RAVREDA/AMI: Summary of Field Assays Using in vitro Tests for P. falciparum Sensitivity to Antimalarials (Fresh Isolates)