Surveillance of Antimalarial Drug Resistance: RAVREDA/AMI Sentinel Sites for Efficacy Studies. At the end of 1990s, countries in the Amazon subregion did not have 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.
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:
Differences in protocol used by RAVREDA network with respect to
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:
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:
in vitro susceptibility evaluations, and
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.
Practical Guide for in vivo Antimalarial Drug-Efficacy Studies in the Americas
(RAVREDA-AMI, revised version, October 2003*)
Resistance of Plasmodium falciparum to antimalarial drugs is one of the most serious challenges facing national malaria control programs in the Americas. At present, P. falciparum is resistant to both chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) throughout the Amazon Basin and to CQ alone on the Pacific Coast of South America.
Additionally, in recent years several investigators have reported cases of P. vivax therapeutic failure to CQ. In response to the public-health threat of drug resistance, several ministries of health in the region have begun studies to map the distribution and intensity of P. falciparum and P. vivax resistance to antimalarial drugs within their borders. Peru and Bolivia have finished their baseline studies and have already changed their first-line treatments for uncomplicated P. falciparum infections. These countries are also establishing surveillance systems for drug resistance at sentinel sites throughout the country.
Although a variety of methods have been used by ministries of health to evaluate antimalarial drug resistance, in vivo drug-efficacy studies are generally considered the method of choice because their results correlate best with the clinical response of patient to these drugs. The World Health Organization (WHO) has published guidelines for in vivo drug-efficacy studies, originally intended for use in settings with intense transmission, such as Africa, but more recently with modifications appropriate for areas of low to moderate transmission, such us the Americas. In South America, most of the changes in national malaria treatment policies that have been made during the last 3-4 years have been based on the results of these in vivo studies.
While in vivo drug efficacy studies do not require sophisticated technology, they are not simple to conduct correctly. They require a well-trained and experienced clinical and laboratory team that closely follows the study protocol. Because of the low levels of malaria transmission in the Americas, it may be a challenge to meet the required sample sizes, particularly for P. falciparum infections. Also, in regions such as the Amazon Basin, where the population is widely dispersed and highly mobile, it may be extremely difficult to limit the number of patients lost to follow-up to no more than 10-15% of enrolled patients, as recommended by the WHO.
Even though most in vivo studies carried out in the Americas during the last 3-4 years have made use of standardized study protocols based on the WHO guidelines, those recommendations do not describe in detail how to carry out a study or how to avoid the pitfalls that can be encountered when working in the field. The purpose of the recommendations in this guide, which is based on recent experiences with antimalarial drug efficacy studies in South America, was to complement to the WHO guidelines and standardized protocols. It is hoped that this guide, together with the generic protocols, will contribute to the successful implementation of in vivo studies and a surveillance system for antimalarial drug resistance in the Americas.
* Date of original version: January 2003.
Generic Protocols and Flow Diagram for in vivo Antimalarial Drug-Efficacy Studies in the Americas
The Amazon Network for the Surveillance of Antimalarial Drug Resistance (RAVREDA) es a joint effort on the part of eight countries of the Amazon region with the Pan American Health Organization (PAHO) and the US Agency for International Development's (USAID's) Amazon Malaria Initiative (AMI), with technical support from the Centers for Disease Control and Prevention (CDC). The main area of work of RAVREDA/AMI is regional consolidation of a network of sentinel sites to evaluate the therapeutic efficacy of treatment schemes currently in use and of antimalarial drugs that could be introduced into the Region. The results of efficacy evaluations that have been carried out within the framework of RAVREDA since 2002 have already permitted countries to improve their policies on antimalarials. In September 2003-in a meeting held in Iquitos, Peru, involving eight countries of the region, PAHO, USAID, and CDC-an evaluation was carried out on the protocols used by RAVREDA to evaluate therapeutic effectiveness in treating uncomplicated Plasmodium falciparum and Plasmodium vivax malaria. Modifications were introduced based on the latest WHO recommendations on how to carry out this type of studies in areas of low transmission (WHO/CDS/CSR/EPH/2002.17).
:: Global Plan for Artemisinin Resistance containment (En Inglés)
Researchers from the Region have developed a guide with instructions and practical recommendations to facilitate the efficacy protocols, taking into account the peculariarities of the Amazon region. This guide can be very helpful in organizing and planning study execution and in guaranteeing strict compliance with the methodology established in the protocols.
Project Descriptions (with links to protocols and flow diagram)
1. Title: Efficacy of Chloroquine and Sulfadoxine-Pyrimethamine for the Treatment of Uncomplicated Plasmodium falciparum Malaria
Objective: Assess the efficacy of chloroquine and sulfadoxine-pyrimethamine for the treatment of uncomplicated P. falciparum infections.
Methods: This concerns an in vivo antimalarial drug-efficacy trial. Subjects > 6 months of age with parasitologically-confirmed, uncomplicated P. falciparum infections. Patients will be treated with either chloroquine (25 mg/kg over three days) or with sulfadoxine/pyrimethamine (25 mg/kg of the sulfadoxine component in a single dose). (For comparative studies: Patients will be randomly assigned one of the two drugs regimens). Clinical and parasitologic parameters will be monitored over a (14/28)-day follow-up period to evaluate drug efficacy. Results from this study will be used to assist the Ministry of Health in assessing their national malaria treatment policy for P. falciparum malaria. Protocol
2. Title: Efficacy and Safety of Mefloquine and Mefloquine-Artesunate Combination Therapy for the Treatment of Uncomplicated Plasmodium falciparum Malaria
:: Assess the efficacy and safety of mefloquine alone and mefloquine-artesunate combination therapy for the treatment of uncomplicated P. falciparum infections.
:: Evaluate the impact of mefloquine alone and mefloquine-artesunate therapy on gametocytemia.
Methods: This concerns an in vivo antimalarial drug-efficacy trial. Subjects > 6 months of age with parasitologically-confirmed, uncomplicated P. falciparum infections will be assigned at random to be treated with either mefloquine (25 mg/kg in two divided doses) or mefloquine (25 mg/kg in two divided doses) plus artesunate (12 mg/kg over 3 days). Clinical and parasitologic parameters will be monitored over a 28-day follow-up period to evaluate drug efficacy and safety. Results from this study will be used to assist the Ministry of Health in assessing their national malaria treatment policy for P. falciparum malaria.
3. Title: Efficacy of Chloroquine for the Treatment of Plasmodium vivax Malaria
Objective: Assess the efficacy of chloroquine for the treatment of P. vivax infections.
Methods: This concerns an in vivo drug-efficacy study. Subjects > 6 months of age with parasitologically-confirmed P. vivax infections will be treated under supervision with chloroquine, 25 mg/kg over three days. Clinical and parasitologic parameters will be monitored over a 28-day follow-up period to evaluate drug efficacy. Blood samples will be taken to measure the CQ level in blood and to genotype parasites that appear after Day 3. Results from this drug efficacy study will be used to assist the Ministry of Health in assessing their national malaria treatment policy for P. vivax malaria. Protocol
Instrument and Exercise for in vivo Antimalarial Drug-Efficacy Studies (WHO, 2004)
An instrument for analyzing the results of the evaluations of antimalarial drug efficacy has been made available to the teams carrying out this type of study within the framework of PAHO's Amazon Network for the Surveillance of Antimalarial Drug Resistance (RAVREDA, from its name in Spanish Red de Vigilancia de la Resistencia a las Drogas Antimaláricas) and USAID's Amazon Malaria Initiative (AMI).
Assessment and Monitoring of Antimalarial Drug Efficacy for the Treatment of Uncomplicated falciparum Malaria
Antimalarial drug resistance has emerged as a leading threat to ongoing malaria control efforts. As resistance to one or more antimalarial drugs occurs more frequently, malaria control programmes and other concerned institutions need to be able to evaluate antimalarial drug efficacy in a way that provides timely, relevant, reliable, and understandable information.
The primary goal of this protocol is to provide guidance in obtaining the minimum essential information about the clinical and parasitological response to antimalarial drugs among populations at greatest risk of severe morbidity or mortality due to malaria. The intended use of this protocol, therefore, is primarily as a tool for the collection of clinically relevant information for developing evidence-based antimalarial treatment policy. It is not intended for use as a more traditional biomedical research protocol and is not intended to replace welldesigned clinical trials conducted under Good Clinical Practice (GCP) guidelines, as should be done when investigating new treatment lacking an adequate history of safe clinical use.
Considerable emphasis has been placed on maintaining as much simplicity and practicality as possible. Using this protocol, programmes lacking access to substantial financial resources or to state-of-the-art laboratory analysis-most often obtained through collaborative links with medical research institutions-should nonetheless be able to produce the information needed to ensure the best malaria treatment for the people living in their country. Programmes that do have adequate resources and expertise are encouraged to collect any additional information that they feel is relevant. However, they are also encouraged to at least collect this minimal data set in a way that is consistent with this protocol. Only through such standardization will it be possible to compare and interpret results over time and within or between regions.