Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 WHO Library Cataloguing in Publication Data Review of the malaria drug efficacy situation in 10 countries of the WHO Western Pacific Region, 1987-2003. 1.Malaria -- drug therapy. 2. Antimalaria -- pharmacology. 3. Drug resistance. ISBN 92 9061 198 7 (NLM Classification: WC 750) World Health Organization 2005 All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The World Health Organization does not warrant that the information contained in this publication is complete and correct and shall not be liable for any damages incurred as a result of its use. Publications of the World Health Organization can be obtained from Marketing and Dissemination, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel: +41 22 791 2476; fax: +41 22 791 4857; email: bookorders@who.int). Requests for permission to reproduce WHO publications, in part or in whole, or to translate them whether for sale or for noncommercial distribution should be addressed to Publications, at the above address (fax: +41 22 791 4806; email: permissions@who.int). For WHO Western Pacific Regional Publications, request for permission to reproduce should be addressed to Publications Office, World Health Organization, Regional Office for the Western Pacific, P.O. Box 2932, 1000, Manila, Philippines, Fax. No. (632) 521-1036, email: publications@wpro.who.int ii

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 Abbreviations ACR ACPR ACT adequate clinical response adequate clinical and parasitological response artemisinin-based combination therapy AL artemether-lumefantrine (Coartem TM ) AQ ART ASU ATM CQ CV8 TM DHA dhfr dhps ETF G-6-PD IC50 LTF MEF MSP msp amodiaquine artemisinin artesunate artemether chloroquine combination of dihydroartemisinin, piperaquine, trimethoprim and primaquine dihydroartemisinin dihydrofolate reductase dihydropteroate synthase early treatment failure glucose-6-phospate dehydrogenase inhibitory drug concentration yielding a 50% reduction in parasite growth compared to zero drug concentration in an in vitro test late treatment failure mefloquine combination of mefloquine, sulfadoxine, pyrimethamine merozoite surface protein P. Plasmodium iii

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 PCR Pf pfcrt PIP PQ Pv PYR QN RI RII RIII S S/RI SP TCN TRI polymerase chain reaction Plasmodium falciparum Plasmodium falciparum chloroquine resistance transporter gene piperaquine primaquine Plasmodium vivax pyronaridine quinine resistance at RI level according to the old in vivo test classification: recrudescence following parasite clearance (at least 2 consecutive days with no detectable asexual parasites within 7 days after start of treatment) resistance at RII level according to the old in vivo test classification: no clearance (see above) and asexual parasitaemia below 25% of initial parasitemia 48 hours after start of treatment resistance at RIII level according to the old in vivo test classification: no clearance (see above) and asexual parasitaemia above 25% of initial parasitemia 48 hours after start of treatment sensitive according to the old in vivo classification: parasite clearance and norecrudescence within 28 days after start of treatment clearance and no recrudescence in in vivo test within 28 days sulfadoxine-pyrimethamine tetracycline trimethoprim iv

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 Table of Contents Acknowledgements... viii Preface...1 Executive summary...3 Introduction...5 Methodology...7 Regional overview...9 Country situation... 21 Cambodia... 23 China... 29 The Lao People s Democratic Republic... 35 Malaysia... 39 Papua New Guinea... 43 The Philippines... 49 The Republic of Korea... 53 Solomon Islands... 57 Vanuatu... 61 Viet Nam... 65 References... 73 CD-ROM: Western Pacific Regional Database of Antimalarial Drug Efficacy Studies, 1987-2003 Annex 1 Western Pacific Regional Database: P. falciparum in vivo Annex 2 Western Pacific Regional Database: P. falciparum in vitro Annex 3 Western Pacific Regional Database: P. vivax v

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 List of Tables Table 1. Number of antimalarial drug efficacy reports and publications from selected countries in the WHO Western Pacific Region... 9 Table 2. Antimalarial drug status of countries in the Mekong region... 17 Table 3. Antimalarial drug status of Mekong Plus countries... 18 Table 4. Antimalarial drug status of selected Pacific island countries... 19 Table 5. Malaria treatment policies in the Western Pacific Region, 2004 (dosage for adults)... 20 Table 6. In vitro data on artesunate sensitivity against P. falciparum in Hainan and Yunnan provinces, China... 30 Table 7. In vitro resistance trend of chloroquine against P. falciparum in Hainan, China... 31 Table 8. In vivo variation in chloroquine efficacy against P. falciparum in Hainan, China... 32 vi

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 List of Maps Map 1. Status of chloroquine, sulfadoxine-pyrimethamine and mefloquine efficacy in Cambodia, 1995-1999... 27 Map 2. Status of artesunate and artemisinin-based combination therapy efficacy in Cambodia, 1997-2003... 28 Map 3. Therapeutic efficacy of antimalarial drugs against P. falciparum in China, 1995-2002... 34 Map 4. Status of chloroquine, sulfadoxine-pyrimethamine, mefloquine, chloroquine + sulfadoxine-pyrimethamine and artemisinin-based combination therapy efficacy in the Lao People s Democratic Republic, 1997-2003... 37 Map 5. Status of chloroquine, sulfadoxine-pyrimethamine, mefloquine and chloroquine + sulfadoxine-pyrimethamine efficacy in Peninsular and East Malaysia, 1994-2003... 41 Map 6. Status of chloroquine, sulfadoxine-pyrimethamine and chloroquine + sulfadoxine-pyrimethamine efficacy in Papua New Guinea, 1991-1998... 47 Map 7. Status of chloroquine, sulfadoxine-pyrimethamine, chloroquine + sulfadoxine-pyrimethamine and artemether-lumefantrine in the Philippines, 1995-2003...52 Map 8. Chloroquine efficacy in vivax malaria in the Republic of Korea, 1996-1999... 54 Map 9. Status of chloroquine, sulfadoxine-pyrimethamine and chloroquine + sulfadoxine-pyrimethamine efficacy in Solomon Islands, 1994-2001...59 Map 10. Status of chloroquine, sulfadoxine-pyrimethamine and chloroquine + sulfadoxine-pyrimethamine efficacy in Vanuatu, 1994-2001... 63 Map 11. Status of chloroquine, sulfadoxine-pyrimethamine and mefloquine efficacy in Viet Nam, 1996-2001...68 Map 12. Status of artemisinin derivatives and artemisinin-based combination therapy efficacy in Viet Nam, 1999-2003... 69 vii

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 Acknowledgements The Malaria, Other Vectorborne and Parasitic Diseases unit of the WHO Regional Office for the Western Pacific wishes to acknowledge with gratitude the significant support from the United States Agency for International Development (USAID) for the creation of the database and this report. This review is the product of cooperation between ministries of health, national malaria control programmes and WHO. We express our gratitude to all country malaria control programme managers for providing drug-resistance data, validating the database and reviewing this report. This document was prepared by Ma. Dorina G. Bustos, MD, PhD; Eva Maria Christophel, MD and Carolyn L. Bautista. Cover photo by Pricha Petlueng. Contact details: christophele@wpro.who.int World Health Organization Regional Office for the Western Pacific PO Box 2931, Ermita 1000, Manila, Philippines Tel no: (632) 528 8001 Fax no: (632) 521 1036. viii

Preface Drug-resistant malaria was first identified in the Thai-Cambodian border areas in the late 1960s. Resistance to common antimalarial drugs then quickly developed and spread to most malaria-endemic countries of the WHO Western Pacific Region. The Region now has the most serious multidrug-resistant malaria situation in the world. The herbal drug qinghaosu has been used for centuries in China. But it became available internationally only after the scientific evaluation of its active ingredient, artemisinin, and its derivates in the late 1980s. Artemisinin has significantly contributed to the decline of malaria deaths and of the malaria disease burden in the Region. Since 2003, WHO has been recommending the use of artemisinin-based combination therapy for drug-resistant malaria. However, malaria continues to be a major health problem in the Region. In this context, it is heartening to note that most countries have either recently changed their first-line malaria treatment recommendations and are using in vivo studies to monitor efficacy prospectively, or are evaluating current treatment recommendations as a step towards potential drug policy change. While data on treatment efficacy represent only one element in a wide array of information needed to develop evidence-based antimalaria policy, the results of in vivo and in vitro studies conducted using WHO standard protocols and standardized tests are vital. This review looks at antimalarial drug efficacy data and trends during the past 15 years in the malaria-endemic countries of the Region. It is hoped that it will facilitate changes in drug policies and contribute to the harmonization of treatment. The varying geographic conditions and evolving drug policies of the countries and areas in the Region necessitate for periodic assessment of antimalarial drug efficacy through sentinel site monitoring, sharing of data and closer intercountry collaboration. 1

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 WHO, together with its Roll Back Malaria partners, strongly supports national control programmes and research institutions in their continuing efforts to implement therapeutic efficacy surveillance and to establish regional networks for cooperation and the exchange of information. These measures will be vital in the battle to halt the spread of multidrug-resistant malaria. Shigeru Omi, MD, Ph.D. Regional Director 2

Executive summary In order to address the need for a continuous evaluation of the efficacy of antimalarial drugs, the WHO Regional Office for the Western Pacific conducted a systematic inventory of in vivo and in vitro drug efficacy studies from the past 15 years. The studies were gathered from four countries in the Mekong region (Cambodia, China, the Lao People s Democratic Republic and Viet Nam), Malaysia, the Philippines and the Republic of Korea, as well as from the Pacific island countries of Papua New Guinea, Solomon Islands and Vanuatu, which are endemic for malaria. A database was created to facilitate analysis and tracking of drug efficacy. The main objectives of the initiative were: (1) to create a database of drug efficacy studies in the WHO Western Pacific Region; (2) to present a report on Plasmodium falciparum and Plasmodium vivax drug resistance in the Region; and (3) to review each country s drug policy and how it has evolved over time. Numerous studies have been conducted in the Mekong region using a network of sentinel sites where there are high levels of P. falciparum multidrug resistance. All countries in the Mekong region have now changed their national malaria drug policies to include artemisinin-based combination therapy. Since 2000, Cambodia and Viet Nam have been reporting rates of 95%-100% adequate clinical and parasitological response (ACPR) to artemisinin-based combination therapies such as mefloquine + artesunate, the combination of dihydroartemisinin, piperaquine, trimethoprim and primaquine (CV8 TM ), and piperaquine + dihydroartemisinin (Artekin TM ). North-west Cambodia is the exception, with mefloquine + artesunate cure rates averaging as low as 86% in some studies. Viet Nam additionally uses artemisinin monotherapy as a first-line treatment, which has yielded an ACPR rate of 82%-96% over the last three years. China, which documented a failure rate of more than 60% for chloroquine treatment in the mid-1970s, shifted its national drug policy first to using piperaquine or pyronaridine until 1985, and then to using artemisinin derivatives, either as monotherapy or in combination with piperaquine or pyronaridine. The artemisinin derivatives and artemisinin-based combination therapy treatment regimens have yielded over 95% efficacy rates, according to studies from Hainan and Yunnan provinces. The Lao People s Democratic Republic is currently pilot implementing the artemisinin-based combination therapy artemether-lumefantrine before finalizing its new malaria drug policy. 3

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 Malaysia and the Philippines still use chloroquine and sulfadoxine-pyrimethamine, despite reports of greater than 30% resistance to the treatment over the last decade. In 2002, the Philippines changed its malaria drug policy to include chloroquine + sulfadoxine-pyrimethamine as the first-line treatment and artemether-lumefantrine (Coartem TM ) as the second-line treatment. Malaysia has yet to change its national policy despite high treatment failures, especially in the high transmission provinces of Sabah and Sarawak, which are now reporting failure rates of 50% or higher to chloroquine and sulfadoxine-pyrimethamine, both when administered alone or in combination. Fewer studies are available from the Pacific islands, which bear the highest disease burden in the Western Pacific Region. Those countries have treated malaria with a combination of chloroquine + sulfadoxine-pyrimethamine since the mid-1990s, but current assessments of efficacy are insufficient. It is necessary to begin regular monitoring in sentinel sites in the Pacific, especially with the recent introduction of treatment regimens using artemisinin derivatives in the private sector. For treatment of vivax malaria, the efficacy of chloroquine and primaquine also varies across countries. In China, which has a predominance of P. vivax cases, it is necessary to further assess the response to those treatments. In the Republic of Korea, which has seen a resurgence of vivax malaria since 1994, there is no report indicating P. vivax resistance to chloroquine and primaquine. Similarly, the Philippines has not reported any chloroquine treatment failures for P. vivax over the last five years. Although one study in Viet Nam reported a 16% chloroquine failure rate in 2000 in Binh Thuan province, a recent study of 277 P. vivax patients, conducted by the National Institute of Malariology, Parasitology and Entomology, documented 100% efficacy of chloroquine. The Pacific islands have reported P. vivax chloroquine treatment failures since the early 1990s, with rates of 1% in Vanuatu, 9% in Papua New Guinea, and 30% in Solomon Islands. In summary, the database initiative has shown that the malaria drug resistance situation in the Western Pacific Region is dynamic. The varying geographies and drug policies of the countries in the Region, as well as the high degree of mobility of its populations, support the need for periodic assessment of antimalarial drug efficacy through continuation of sentinel site monitoring, sharing of efficacy surveillance data and intercountry collaboration. These data will be the basis for regular periodic reviews of national malaria treatment guidelines. 4

Introduction This report summarizes the findings of the WHO Western Pacific Region malaria drug-efficacy database, which consists of studies from the past 15 years conducted in the malaria-endemic countries of the Region, specifically the Mekong countries of Cambodia, China, the Lao People s Democratic Republic and Viet Nam; the Mekong Plus countries of Malaysia and the Philippines; the Republic of Korea; and the Pacific island countries of Papua New Guinea, Solomon Islands and Vanuatu, (enclosed CD-ROM). The objective of this report is to provide an overview of the malaria drug-efficacy situation as it impacts on the whole Region, and to review in vitro and in vivo data on the development of resistance of both P. falciparum and P. vivax to currently used antimalarials, as defined by each country s malaria drug policy. The database will be publicly available through the Mekong Malaria Documentation Center website and will be continuously updated. Information presented includes: (1) the historical and current context for the development and spread of drug resistance in terms of geography and time; (2) country-level malaria policy decisions with respect to drug treatments; and (3) gaps and issues in malaria drug resistance to be addressed at both the individual country level and the regional level. 5

6 Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003

Methodology AMicrosoft Excel-based database was created using published and unpublished in vivo and in vitro studies of P. falciparum and P. vivax responses to antimalarials over the last 15 years. Published studies were identified through Medline searches, and unpublished studies were provided to the WHO Western Pacific Regional Office in response to a request made to each country s malaria control programme. The studies were individually reviewed and technical information was entered into the database using a format designed at WHO Headquarters. Following the completion of data entry, each country s ministry of health received their individual country s database for validation, review and confirmation. All available English language in vitro and 14-day or 28-day in vivo studies were included in the database. The report relies predominantly on the major published studies, supplemented by a few unpublished reports provided by ministries of health. The database is made available in Annexes 1, 2 and 3 on the CD-ROM included in this report. In vivo results are presented using either the previous drug resistance classification RI, II and III (WHO, 1976) or the more recent therapeutic efficacy classification (WHO, 2003). In vitro results are presented in IC50 per drug (if available). A regional overview and individual country reports, with maps, were prepared, detailing the status of resistance to various antimalarial drugs as well as each country s current drug policy. These reports were also sent to the ministries of health for review and confirmation. 7

8 Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003

Regional overview FINDINGS A total of 202 in vivo and 74 in vitro studies were ascertained, entered and reviewed, 104 of which were published articles (Table 1). The database can be found in Annexes 1, 2 and 3 on the CD-ROM included in this report. Table 1. Number of antimalarial drug efficacy reports and publications from selected countries in the WHO Western Pacific Region Countries In vivo studies Published a In vivo studies In vitro studies Published In vitro studies Cambodia 71 2 12 2 China 11 5 18 2 (English) The Lao People's Democratic Republic 22 4 NA NA Malaysia Papua New Guinea 10 17 2 12 1 14 1 6 The Philippines 27 4 1 The Republic of Korea Solomon Islands 3 9 3 1 1 1 Vanuatu 10 4 2 2 a Viet Nam 77 35 24 TOTAL 202 76 74 NA Studies published in English language or abstracts available in English No available data 17 31 The first reports of chloroquine-resistant falciparum malaria in south-east Asia (Thailand) and South America (Colombia) were in 1959. By the late 1970s, countries in the Mekong region (Cambodia, China, the Lao People s Democratic Republic and Viet Nam in the WHO Western Pacific Region; and Myanmar and Thailand in the WHO South-East Asia Region) began reporting chloroquine resistance of more than 25% in falciparum malaria (Table 2). By the mid-1980s, other countries in the Western Pacific Region had reported similar findings (Table 3 and 4). Initial reports revolved around clinical observations, which were subsequently documented with parasitological 14-day or 28-day in vivo and in vitro drug efficacy studies conducted in endemic areas with larger populations. Some countries, such as Viet Nam, responded to the chloroquine resistance problem by administering sulfadoxine-pyrimethamine monotherapy. By 1980-1990, most countries in the Mekong region were reporting very high levels of sulfadoxine-pyrimethamine treatment failures reaching 70%-100% in the south and central provinces of Viet Nam and the western side of Cambodia, bordering Thailand. The spread and severity of 9

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 chloroquine and sulfadoxine-pyrimethamine resistance was attributed to the in- and out-migration of non-immune workers from the gem mines on the Cambodian-Thai border and the unstable sociopolitical situation along the border of Thailand and Myanmar, both areas with intense malaria transmission. China abandoned the use of chloroquine in 1979 and moved to piperaquine or pyronaridine monotherapy as the first-line treatment. In 1985, following in vitro and in vivo reports of resistance to those drugs in the provinces of Yunnan and Hainan, China shifted to pyronaridine + sulfadoxine-pyrimethamine and some artemisinin derivatives. By 1991, longitudinal in vitro monitoring in Hainan showed that sensitivity to chloroquine was again on the increase, with only 18% in vivo failures, compared with the 84% in vivo failures documented in 1981. China s current policy includes the use of several different regimens of artemisinin derivatives as mono- or combination therapy and pyronaridine + sulfadoxine-pyrimethamine to treat chloroquine-resistant falciparum malaria. From 1991 to 1999, reports from north-east Cambodia put S/RI levels to mefloquine at 91%-100% and to artesunate + mefloquine at 100%. In north-west Cambodia, however, the levels were much lower, with S/RI to mefloquine at 60%-97% and a 70%-100% ACPR rate for artesunate + mefloquine. Cambodia changed from using quinine + tetracyline to mefloquine monotherapy in 1993. Since the introduction of the artesunate + mefloquine combination as the first-line therapy in 2000, the country has reported increasing treatment failures to that antimalarial drug combination. However, these have so far been reported mainly from the west and do not exceed 14% at present. Quinine efficacy, which was as low as 10%-19% S/RI in 1991 when it was the country s first-line treatment before mefloquine was introduced, increased to 100% S/RI in the late 1990s. In 2002, artemether-lumefantrine was tested as a potential future artemisinin-based combination therapy, but its efficacy was only 71%. Viet Nam has been using artesunate or artemisinin monotherapies and artemisinin + mefloquine or artesunate + mefloquine combinations for the last 10 years. The country recently tested the efficacy of CV8 TM (combination dihydro-artemisinin + piperaquine + trimethoprim + primaquine) and introduced it. These drugs have all remained highly effective when appropriate doses are given for the appropriate duration. Chloroquine was used until 2001 in the Lao People s Democratic Republic. The country is currently implementing an interim chloroquine + sulfadoxine-pyrimethamine regimen, which studies in 2001-2002 in the south showed sufficiently effective (83% ACPR in Attapeu, 92% ACPR in Savannakhet province), while evaluating different artemisinin-based combination therapies to determine the best suitable future artemisinin-based first-line treatment. Pilot implementation of artemether-lumefantrine has started in some provinces. 10

Although Malaysia still uses chloroquine for falciparum malaria, it has embarked on an extensive surveillance programme to monitor the efficacy of chloroquine and sulfadoxine-pyrimethamine monotherapies, and the chloroquine + sulfadoxinepyrimethamine combination therapy in the endemic provinces of Peninsular Malaysia, Sarawak and Sabah. Recent preliminary data point to high failure rates for chloroquine (45%), sulfadoxine-pyrimethamine (13-29%) and chloroquine + sulfadoxinepyrimethamine (43-63%) in both east and west Malaysia. In addition, resistance markers for chloroquine (pfcrt) and sulfadoxine-pyrimethamine (dhfr and dhps) have been found in P. falciparum parasite isolates. On the other hand, mefloquine and artesunate monotherapies have shown good efficacy, with ACPR rates of 100% and 83%, respectively. The Philippines changed its chloroquine treatment policy in 2002, designating chloroquine + sulfadoxine-pyrimethamine as the first-line treatment, and artemether-lumefantrine as the second-line treatment. During an outbreak in 2002, one province documented a 70% ACPR rate with the chloroquine + sulfadoxinepyrimethamine combination. Better results of 94% efficacy have been observed in therapeutic efficacy monitoring studies in two sentinel sites in the northern Philippines in 2003-2004. These sites are in high transmission non-outbreak areas, which saw sulfadoxine-pyrimethamine cure rates of >90% before the drug policy change. Artemether-lumefantrine has been a highly successful treatment, with a 99-100% ACPR rate in both the northern and southern parts of the country. The Pacific islands began replacing chloroquine for treatment of falciparum malaria with chloroquine + sulfadoxine-pyrimethamine combination in the mid-1990s, with Vanuatu adopting the regimen in 1994, Papua New Guinea in 1997 and Solomon Islands in 2001. The chloroquine + sulfadoxine-pyrimethamine combination therapy yielded ACPR rates of 99% in Papua New Guinea in 1998, 92% in Solomon Islands in 2001, and 84%-95% in Vanuatu in 2001. Despite the resurgence of vivax malaria in the Republic of Korea in 1993, there have been no documented failures of P. vivax for the standard three-day chloroquine and the 14-day primaquine regimens. Unfortunately, the Pacific island countries have not had the same experience and have documented chloroquine failures for P. vivax treatment, with failure rates of 1% in Vanuatu in 1991, 9% in Papua New Guinea, and 30% failure rates in Solomon Islands in 1995. More recent reports have shown refractoriness to the 14-day regimen of primaquine 15 mg/kg/day against the hepatic stage of vivax malaria in cases coming from these countries. There is no indication of chloroquine resistance in other Western Pacific Region countries that periodically monitor P. vivax resistance to chloroquine. 11

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 Table 5 lists the updated malaria treatment policies, as provided by each country. Until recently, sentinel sites for drug resistance tests were chosen arbitrarily. The selection of such sites was systematized in the Mekong region in October 2000, with 36 strategic sentinel sites planned in the network, including Thailand and Myanmar. The Philippines has three sentinel sites in the north, south and west of the country, Malaysia has several sites in the east and west, and the Pacific island countries are currently designating sentinel sites. The first- and second-line national malaria policy treatments usually are tested in each site at least every two years. Some countries have collaborated with research institutions to conduct studies on molecular markers for drug resistance, and likewise genotyping studies using msp1 and msp2 markers in conjunction with in vivo drug efficacy trials, to differentiate recrudescence from reinfection. It is evident that there is a predominance and fixation of the pfcrt K76T point mutation associated with, but not uniquely responsible for, chloroquine resistance in malaria-endemic areas. Studies have shown that parasite isolates from some countries, such as Malaysia and Papua New Guinea, have already acquired the dhps and dhfr markers for sulfadoxine-pyrimethamine resistance, indicating the foreseeable loss of efficacy of either the chloroquine + sulfadoxine-pyrimethamine combination or sulfadoxinepyrimethamine monotherapy regimens. CONCLUSIONS The database-generated reviews of the situation in each country show that the quality and quantity of available data are generally insufficient. Inconsistent methodologies have been used in assessing in vivo response, with 7-day, 14-day, 28-day or 42-day follow-ups, leading to varying interpretations in measuring drug efficacy. In some countries, only the adult population has been studied, which may have led to underestimations of resistance. There have been inconsistencies also with methodology and interpretation of in vitro test results, with some using the WHO micro-test system and others the radioisotope micro-dilution method. 12

Follow-up periods of 28 days may not be sufficient to assess the efficacy of drugs with long half-lives (i.e. mefloquine); 14-day tests may have underestimated the true levels of resistance in some countries. Countries are now aware of the importance of maintaining drug efficacy surveillance systems using the standardized 28-day protocol in strategic sentinel sites, which can be integrated into national control programmes. Sentinel site drug resistance monitoring network exists in the Mekong region, and are also currently established in the other countries, including Malaysia and the Philippines, all actively monitoring treatment efficacy. However, the Pacific island countries have a higher disease burden for P. falciparum than the Mekong countries, but very few corresponding drug efficacy studies. Surveillance studies on P. vivax resistance have been minimal or absent in some countries. P. vivax is predominant in China and the Republic of Korea, but problems with chloroquine efficacy and refractoriness to primaquine exist, specially in the Pacific islands. Collaboration with research institutions to conduct studies on molecular markers for drug resistance and genotyping exist in some countries. These studies have construed that parasite isolates from some countries have already acquired sulfadoxinepyrimethamine resistance, aside from chloroquine resistance, indicating the foreseeable loss of efficacy of either the chloroquine + sulfadoxine-pyrimethamine combination or sulfadoxine-pyrimethamine monotherapy regimens. Longitudinal data with molecular markers are useful in predicting the longevity of treatment regimens and developing rational drug policies. From the review, it is evident that in the past, anti-malaria efficacy studies are traditionally regarded as part of drug research and development, rather than part of a country s routine surveillance programme for treatment efficacy. The threat of multi-drug resistance affecting several countries in the last 15 years has created the urgency for countries to closely monitor their treatment recommendations, and at the same time conduct trials for new drugs. By monitoring trends in the development of resistance, timely malaria treatment policy decisions can be made. Unfortunately, even with such available information, malaria drug policy changes in some countries continue to take too long. 13

14 Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003

RECOMMENDATIONS (1) Ministries of health and international funding agencies should make a commitment to fund antimalarial drug efficacy monitoring in sentinel sites as part of a country s national malaria control programme. WHO could provide technical support and assistance as countries make timely and rational decisions once all valid evidence for drug resistance and alternative regimens are available. (2) Sentinel sites should be established at strategic geographical locations within countries, and surveillance of the efficacy of first- and second-line malaria drugs should be conducted, including options for replacement, every two years if possible, giving due consideration to financial sustainability and operational constraints. It is necessary to limit the number of sentinel sites in the Mekong region to strategically important areas to ensure long-term sustainability, and to establish additional sentinel sites in the Pacific islands. (3) It is recommended that malaria programmes adhere to WHO standard in vivo protocols (including the use of sample sizes appropriate to prevalence rates, inclusion criteria, study-drug quality control, slide examination processes and patient follow-up). However, in areas with very low numbers of cases, alternatives need to be explored. (4) Standardized in vitro tests should be used as an early warning tool for resistance development and for baseline information on new drugs. (5) In the event of a policy change, national and regional efforts should be made to allocate and mobilize funds for the more costly new regimens, to ensure re-training of health workers and effective implementation of the new treatment policy, to ensure patient compliance, and to monitor the overall impact on the malaria disease burden. (6) An increased focus on the situation in the Pacific island countries is necessary, covering both malaria control and drug efficacy monitoring. 15

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 (7) All countries with P. vivax cases should conduct periodic drug efficacy monitoring. Other P. vivax issues to address include: (a) the variety of chloroquine and primaquine treatment regimens being used and tested in different countries; (b) the duration of follow-up; and (c) the need for genotyping studies to differentiate between relapse and reinfection. (8) Molecular markers and genotyping studies are tools that should be fully explored to assist national control programmes in assessing the efficacy of current drug policies, particularly in areas where malaria prevalence is decreasing to an extent that there are not enough study patients for conventional in vivo studies. Collaborations between control programmes and research institutions should be strengthened. 16

Table 2. Antimalarial drug status of countries in the Mekong region Countries Study site(s) in last 5-10 years CQ failures SP failures Status of Mefloquine Drug policy change (Year) Current firstand second-line Tx Current status of first-line Year % Year % Year % Failures Year % Failures China Yunnan, Hainan (1) Late 70s >50% NA NA NA NA 1979, 1985 and 2001 1st: CQ, PIP 2nd: PYR, ART, ASU, DHA, PYR+SP, AL 2001-02 (2) DHA: 3% DHA+PYR: 0% Viet Nam Lao People's Democratic Republic Cambodia North South and central provinces (3) Vientiane province, Attapeu, Savannakhet West: Battambang East: Rattanakiri, Kratie 1992-1995 1986-1990 1976 1991 1990s 48% (9) 65% 42% (5) 97% 3-34% 27-76% 1992-1995 1986-1990 2000 2001 1991 1990s 29% 70% 23% (6) 18% (7) 100% 3-45% 20-43% 1991 (10) 1993 (4) 2001 1990s (8) 1990s (8) 9% 34% 0% (7) 3-40% 0-9% 0-13% 1993 1993 in process 1991 QT: 1993-2000 MEF: 2000 ASU+MEF TM 1st: CQ, ASU5-7, CV8 2nd: ART or ASU+MEF 1st: CQ, ASU5-7, CV8 2nd: ASU + MEF 1st: chloroquine + sulfadoxinepyrimethamine (interim policy) 1st: ASU + MEF 2nd: Q+T TM 2000 2000 (3) 2001 2001-2002 (8) ASU+MEF: 0% ASU+MEF: 2% (3) CQ+SP: 17% (7) 4-14% 0-3% NA: no available data (1) Tang Lin-Hua, 2003. Unpublished report, Ministry of Health report, Shanghai, China (2) Liu Dequan et al. Manuscript submitted to Bulletin of the World Health Organization, 2003. (3) Le Dinh Cong, 2000: Nong Thi Tien, 2003. Unpublished report. Ministry of Health, Hanoi, Viet Nam (4) Le Nguc Hung et al. Transactions of the Royal Society for Tropical Medicine and Hygiene, 1997, 91: 191-194. (5) Tawil NA. Southeast Asian Journal of Tropical Medicine and Public Health, 1978, 9: 409-13. (6) Mayxay M et al. Clinical Infectious Diseases, 2003, 37 (8):1021-8. (7) Schwöbel B et al. Tropical Medicine and International Health, 2003, 8 (1): 19-24. (8) Unpublished report, 2003. National Malaria Centre, Ministry of Health, Phnom Penh, Cambodia. (9) Morillon et al. Medecine Tropicale, 1996, 56: 197-200. (10) Nguyen TA. Bulletin de la Societe de Patholologie Exotique et de ses Filiales, 1993, 86: 494-499. Sentinel site monitoring 2 sites: Yunnan? sites: Hainan 2 sites 8 sites 9 sites 8 sites 17

Table 3. Antimalarial drug status of Mekong Plus countries Countries Study site(s) in last 5-10 years CQ failures >25% SP failures Other drugs tested Drug policy change (Year) Current firstand second-line Tx Current status of first-line Year % Year % Year % Failure Sentinel site monitoring Philippines North: Kalinga- Apayao (2) South: Mindanao (2), Palawan (3,4) 2000 1995 35% 40-69% 2000 2000 9% 43% chloroquine + sulfadoxinepyrimethamine artemether lumefantrine 2002 1st: chloroquine + sulfadoxinepyrimethamine 2nd: artemetherlumefantrine 2002 (outbreak) (5) 2001 (6) CQ + SP 30% (8/27) CQ + SP 15% (11/74) 2 sites 2 sites Malaysia Peninsular Malaysia (7) East Malaysia (8) 1994 NA 64% NA 1994 1996 47% 29% artesunate mono mefloquine mono NA 1st: chloroquine and chloroquine + sulfadoxinepyrimethamine in Peninsular Malaysia, SP in Sabah 2nd: quinine 7 days 2001 (8) 1999-2000 (9) CQ 77% SP 30% CQ + SP 43% Yes 2 sites in Sarawak, 4 sites in Sabah Republic of Korea Capital AF Gen Hospital, Seoul; Soldiers fr Paju, Kyunggi, Pochon, Yonchon, Chonwon (1) - - - - - P. vivax: chloroquine + primaquine14 days 1996 3% NA NA: no available data (1) Lim CS et al. Annals of Tropical Medicine and Parasitology, 1999, 93 (6): 565-68 (2) Bustos MDG et al, 2002. Unpublished Report, RITM-Department of Health, Manila (3) Baird JK et al. Transactions of the Royal Soc Tropical Medicine and Hygiene, 1996, 90:413-414. (4) Bustos MDG et al. Journal of Infectious Diseases, 1999, 179:1587-1590. (5) Aumentado C et al, 2002. Unpublished Report, NEC-Department of Health, Manila (6) Espino F et al, 2001. Unpublished Report, RITM-Department of Health, Manila (7) Hakim SL et al. Transactions of the Royal Soc Tropical Medicine and Hygiene, 1996, 90: 294-297. (8) Unpublished Report, 2003. VBDC Ministry of Health, Kuala Lumpur, Malaysia (9) Cox-Singh J et al. International Journal for Parasitology, 2003; 33 (13): 1545-52 18

Table 4. Antimalarial drug status of selected Pacific island countries Countries Study site(s) in last 5-10 years CQ failure rate SP failure rate Other drugs tested Drug policy change (Year) Current firstand second-line Tx Current status of first-line Sentinel site monitoring P. vivax malaria chloroquine3: 25mg/kg Year % Year % Year % Failure Year % Failure Papua New Guinea East & West Sepik, Madang, Island provinces (1) (2) 1980 46-51% NA NA Halofantrine 1997 chloroquine + sulfadoxinepyrimethamine; quinine + sulfadoxinepyrimethamine 1998 (14-day test) 1% (3/402) 2 sites 1991 9% Solomon Islands Western, Choiseul, Temotu, Isabel, Malaita, Central, Makira- Ulawa, Guadalcanal, Honaiara & Central Hospital (3) 1998 28% NA NA 2001 chloroquine + sulfadoxinepyrimethamine; quinine + sulfadoxinepyrimethamine 2001 8.4% (6) 7 sites currently being established 2001 30% Vanuatu Banks, Santo in North: Maewo, Pentecost in East; Malakula, Ambrym in C. North; Epi, Tongoa, Efate in C.South; Tanna, Anatom in South (4) (5) 1989 31% 1991 5% Proguanil 1994 chloroquine + sulfadoxinepyrimethamine; quinine 7 days 2001 16% (8/50)? Sites 1991 1% NA: no available data (1) Cattani JA et al. American Journal Tropical Medicine and Hygiene, 1986, 35:3-15. (2) Dulay I et al. Papua New Guinea Medical Journal, 1987, 30 (4): 281-190. (3) Velayudahn R et al, 2002. Presentation: Drug Resistance Conference, Honiara, Solomon Islands (4) Reeve PA et al. Papua New Guinea Medical Journal, 1994, 37 (3); 181-8. (5) Kaneko A et al. Japanese Journal of Parasitology, 1994, 43: 371-383. (6) Boaz L, 2005. MScPH Thesis (submitted). University of the Philippines, College of Public Health, Manila, Philippines 19

Table 5. Malaria treatment policies in the Western Pacific Region, 2004 (dosage for adults) P. falciparum P. vivax Countries Species Uncomplicated malaria Unconfirmed Lab-confirmed Treatment failure**** Severe malaria Pregnancy Treatment Prevention Chloroquine Treatment Failure Cambodia F, V ASU+M ASU+M Q+T ATM (IM)+M Q or ASU+M None 25mg/kg 3days NA China F, V not recommended CQ3; or PIP3 total 1.5g; + PQ2 22.5mg/day ASU5 total 600 mg, or ATM5 total 600 mg; or DHA7 total 640 mg; or PYR3 total 1.2g or 1.6g; or AL3; or PYR+SP; or ATM+PM; or DHA/ATM/ASU+PYR; + PQ2 ATM or PYR or ASU No recommendation No recommendation CQ3 NA Lao People's Democratic Republic F, V CQ or SP CQ + SP*** SP or Q7 or ASU Q7 or ASU chloroquine + sulfadoxinepyrimethamine CQ 10 mg/kg/wk or intermittent SP CQ3 NA Malaysia F, V not recommended CQ3+PQ3 and CQ3 + SP: SP in Sabah Q7 Q CQ3; or Q2:3 x 650 mg/day +SPday3 CQ 300 mg/week; or 400 mg 2-weekly CQ3 NA Papua New Guinea F, V chloroquine + sulfadoxinepyrimethamine or AQ+SP CQ+SP ASU/ATM + SP: Q3 + SP ASU/ATM + SP Q7 CQ 5 mg/kg/wk CQ 25 mg/kg CQ3 +SP Philippines F, V CQ3+SP+PQ CQ3+SP+PQ AL3-24 tab + PQ I/V inf. Q: loading 20 mg/kg + 10 mg/kg 8hrly + T Q7 CQ weekly CQ3 NA Republic of Korea Vivax only NA NA NA NA NA NA CQ3 25 mg/kg NA Solomon Islands F,V CQ3+SP QN3 +SP I/V inf. QN : loading 20 mg/kg + 10 mg/kg 8hrly. Switch to oral QN when appropriate CQ3+SP CQ weekly CQ3 CQ3 +SP Vanuatu F,V CQ 15 mg/kg CQ+SP Q7 Inj. Q 10 mg/kg chloroquine + sulfadoxinepyrimethamine CQ CQ 15 mg/kg Q7 Viet Nam F,V CQ3, AS5-7 or ASU5-7 AS+PQorM**; orasu+pqor M** on day 4 or CV8 TM AS/ASU + M ASU inj or AS or Q inj 1st trimester: Q7; 2-3rd trimester: CQ3 or AS5-7 or ASU5-7 CQ CQ3 NA AL = artesunate/lumefantrine (Coartem) AS = artemisinin ASU = artesunate AQ = amodiaquine ATE = arteether ATM = artemether CQ = chloroquine (25 mg/kg over 3 days) DHA = dihydroartemisinin M = mefloquine PIP = piperaquine PM = pyrimethamine * G6PD deficiency **M - mefloquine as gametocidal drug ***in The Lao PDR, this was introduced in 2002 as an interim regimen until the national drug policy is formally changed (before: CQ or SP or Q) ****for China, the information contained in this column is the antimalarial treatment for areas with drug resistance >30% NA = not applicable PQ = primaquine (45 mg, single dose or 15 mg/d) PYR = pyronaridine Q = quinine SP = sulfadoxine + pyrimethamine T = tetracycline Primaquine Not recommended* PQ8days, 22.5 mg/day PQ 14 days PQ 14 days PQ 14 days PQ 14 days PQ 14 days 0.25 mg/kg/day 14 days No PQ* PQ 10 Days 20

Country Situation 21

Cambodia CAMBODIA Background In Cambodia, there are significant variations in malaria endemicity and drug resistance patterns between the country s western border with Thailand, the south-eastern region bordering Viet Nam, the north-eastern border with the Lao People s Democratic Republic, and the south central parts of the country. In 2003, Cambodia reported 89% falciparum malaria out of 71 258 confirmed malaria cases. Since 1991, the Cambodia National Malaria Centre has conducted drug efficacy monitoring every year in several sentinel sites, specifically in the provinces bordering the Lao People s Democratic Republic, Thailand and Viet Nam. Monitoring has primarily consisted of 14-day tests, which may have resulted in an underestimation of mefloquine resistance rates. In 2001, Cambodia adopted the standard WHO 28-day protocol for monitoring. However, as only children six years of age or older were included, it is possible that drug resistance was underestimated. The eight sentinel provinces for drug efficacy surveillance designated by the country are: (1) Oddar Mean Chay (north-west,thai border); (2) Battambang (north-west,thai border); (3) Pursat (north-west,thai border); (4) Pailin (north-west,thai border); (5) Preah Vihear (north-west,thai and Lao border); (6) Rattanikiri (north-east,viet Nam and Lao border); (7) Kratie (south east,viet Nam border); and (8) Kampong Speu (south central). 23

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 Drug policy and status of resistance to first-line drugs Cambodia used chloroquine as the first-line treatment for uncomplicated falciparum malaria until 1991. In 1993, the national treatment guidelines adopted mefloquine monotherapy as the first-line treatment and quinine+tetracycline for seven days as the second-line treatment in provinces in the north-west of the country. In the other parts of the country, chloroquine remained the first-line treatment until 2000. Due to high recrudescence rates with mefloquine monotherapy, the combination artesunate (or artemether) + mefloquine therapy became the first-line treatment nationwide in 2000. To improve compliance with the combination regimen, the Malaria Control Programme has provided blister co-packaged artesunate +mefloquine since May 2000. Currently, the first-line treatment is artesunate 600 mg over three to five days + mefloquine 1000 mg over 2 days. With this regimen, studies conducted over the past two years show a 100% ACPR rate in the eastern areas of Rattanakiri, Snoul and Prea Vhear. In the west of the country, the ACPR rate is 96% in Battambang, 86% in Pailin, and 94% in Pursat 1. Studies of alternative artemisinin-based therapies, such as piperaquine +dihydroartemisinin (Artekin TM ), piperaquine+dihydroartemisinin+trimethoprim (Artecom TM ), and artemether+lumefantrine (Coartem TM ), have been conducted since 1999. Artecom TM showed 94% S/RI in Kratie and 100% S/RI in Battambang in 1999; piperaquine+dihydroartemisinin yielded a 94% ACPR rate in Oddar Meanchey and 98% in Snoul in 2001-2002; and artemether+lumefantrine achieved a 71% ACPR rate in a study in Battambang in 2002 2 (Map 2). A 1999 study assessed pfcrt polymorphism in isolates from different parts of the country with varying rates of chloroquine resistance. Results showed pfcrt genetic clustering of parasites circulating in the highly resistant western border area, even after 20 years without chloroquine pressure 3. 24

Cambodia P. falciparum resistance to antimalarial drugs Since the early 1990s, provinces in the west of Cambodia have reported very high levels of resistance for chloroquine (97%) and sulfadoxine-pyrimethamine (100%), and greater than 80% RII-RIII levels for both drugs (Annex 1, Map 1). Resistance to mefloquine exceeded 25% (RI-RIII) in the mid-1990s, but recent studies have shown that those levels have not increased. This is perhaps due to the increase in the dose of mefloquine and the introduction of artemisinin derivatives and artemisinin-based combination therapy. These findings are corroborated by reports from neighbouring Thailand, where the Thai Malaria Control Programme documented a rapid drop in mefloquine sensitivity by 1990. The Cambodian-Thai border has been identified as the epicentre of multidrug-resistant malaria in the Region 4. In studies conducted since the 1990s, therapeutic efficacy results display higher sensitivity in the north-east of the country than the north-west. Treatment cure rates in the north-east were 70% S/RI for chloroquine, 79% S/RI for sulfadoxine-pyrimethamine and 100% S/RI for mefloquine, while in the north-west chloroquine efficacy had fallen to 3%S/RI, sulfadoxine-pyrimethamine was 0% S/RI and mefloquine was 74%. Mefloquine sensitivity had remained at 100% in the central Cambodian provinces. In the south central parts of Cambodia, fewer studies were carried out. In 1991, monitoring for quinine+tetracycline sensitivity showed a 10%-19% treatment failure rate. The most recent studies from the late 1990s show a 100% S/RI to the quinine+tetracycline combination seven-day therapy in 14-day tests. In vitro data are consistent with the in vivo observations that P. falciparum isolates from the north-east were mostly sensitive to chloroquine, while 88% of P. falciparum isolates from the west and south-east were in vitro chloroquine-resistant 5 6 (Annex 2). The results of in vitro sensitivity of 352 Plasmodium falciparum isolates collected in 2001 and 2002 to chloroquine, mefloquine, quinine and artesunate are consistent with the in vivo observations. Chloroquine-resistant phenotypes were highly prevalent in Cambodia. Similarly, a high proportion of isolates displayed elevated IC50 to mefloquine. In contrast, only 1% of isolates presented with decreased susceptibility to quinine and 2% to artesunate. Isolates with decreased susceptibility to chloroquine and mefloquine were common along the border with Thailand, while most of the isolates from the east of Cambodia were susceptible to those compounds. Isolates collected along the western and eastern borders did not respond differently to artesunate 7. 25

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 P. vivax There are no available treatment efficacy studies on vivax malaria. Conclusions and recommendations Compared with other countries in the Region, Cambodia s western border has displayed a high level of resistance to several antimalarials. Over the last 15 years, it has been considered a focus of multidrug resistance. Recent evidence showed that artesunate+mefloquine is starting to fail in the western part of the country. The widespread uncontrolled use of drugs in the private sector, where 80% of patients seek treatment, and the proliferation of counterfeit drugs in the market may have contributed to the multidrug-resistance situation in Cambodia. In addition, antimalarial drug quality in the private sector is a problem. While antimalarial drug quality control is under development in all areas where drug efficacy is being monitored, advocacy for judicious use of antimalarials is needed by both the private and public sectors. Additional recommendations include: close monitoring along the Thai-Cambodian border of current and potential future ACTs; monitoring of molecular markers of resistance specially for mefloquine in different parts of the country. inclusion of children younger than six years of age in therapeutic efficacy monitoring; monitoring chloroquine efficacy for P. vivax in areas with high vivax malaria prevalence; 26

Cambodia Map 1. Status of chloroquine, sulfadoxine-pyrimethamine and mefloquine efficacy in Cambodia,1995-1999 (results based on 14-day tests) 27

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 Map 2. Status of artesunate and artemisinin-based combination therapy efficacy in Cambodia, 1997-2003 *using ASU+MEF blister packs 28

China CHINA Background In China, the two main malaria-endemic areas for both falciparum and vivax malaria are the provinces of Hainan and Yunnan. Cases of P. vivax are reported in at least six other provinces in central, south and south-west China. In 2003, P. vivax accounted for 88% of the 40 681 confirmed malaria cases in China; it was responsible for most of the local outbreaks that occurred in the provinces of Anhui, Henan, Jiangsu, Hubei, Guangdong and Guangxi. Falciparum malaria is close to elimination in Hainan province. This overview focuses only on P. falciparum resistance to antimalarials, based on English-language studies. Drug policy changes and status of resistance Yunnan first reported chloroquine resistance in falciparum malaria in 1973, followed one year later by Hainan. In 1979, the Government discontinued the use of chloroquine in provinces that had in vitro results showing 85% to 98% resistance to the drug and shifted to piperaquine or pyronaridine monotherapy until 1985. Chloroquine was only used in areas with vivax malaria. In 1985, the first-line treatment was the sulfadoxinepyrimethamine+pyronaridine combination therapy, and the second-line treatment for drug resistant falciparum malaria was set as artemisinin derivative monotherapy 8. Since 2001, the official antimalarial drug policy in China has recommended chloroquine or piperaquine as the first-line drug for sensitive P. falciparum. The following second-line regimens were set for drug-resistant malaria (published in June 2002): 29

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 (1) 5-7-day artesunate monotherapy (2) 5-7-day artemether monotherapy (3) 7-day dihydroartemisinin monotherapy (4) 3-day pyronaridine monotherapy (5) artemether-lumefantrine (Coartem TM ) (6) pyronaridine+sulfadoxine-pyrimethamine+primaquine (7) artemether+pyrimethamine (8) pyronaridine+ any of the artemisinin derivatives. Parenteral (intravenous and intramuscular) preparations of the above artemisinin derivatives are used to treat severe malaria. In vitro monitoring of artesunate in both provinces from 1986 to 2002 showed a pronounced increase in mean ICs in P. falciparum isolates from Hainan, which was less apparent in Yunnan province (Annex 2, Table 6). However, the in vitro susceptibility of P. falciparum isolates from patients in the south and west of Yunnan, bordering Myanmar, were lower than those from central and south-east Yunnan, bordering the Lao People s Democratic Republic, possibly indicating more resistant strains in the former area 9. Table 6. In vitro data on artesunate sensitivity against P. falciparum in Hainan and Yunnan provinces, China Year 1986 1989 1991 1997 2002 1988 1992 1999 2002 No. of Cases HAINAN Province 18 30 Source: Ministry of Health Report 2003 45 72 32 YUNNAN Province 24 33 18 22 Concentration of inhibition (nmol/l) 28 44 62 130 135 38 46 74 54 30

China Limited in vivo studies on the use of artemisinin derivatives, artemisinin monotherapy or artemisinin in combination with other schizontocidal antimalarials, are available (Annex 1, Map 3). A single 1995 study from Hainan showed a 96% cure rate with a regimen of 16 tablets of artemether+lumefantrine given for three days 10. A seven-day course of dihydroartemisinin showed a cure rate of 97%, while the rate for the five-day course was 80% 11. Liu and colleagues reported a 100% cure rate with the dihydroartemisinin+pyronaridine combination therapy in 82 patients from Ledong county in Hainan 12. There are no in vivo data on the artemisinin derivatives or artemisinin-based combination therapy from Yunnan, a province with higher transmission, more drug pressure, and possibly more drug resistance problems. Yunnan has established sentinel sites for drug efficacy monitoring in Mengla county, bordering the Lao People s Democratic Republic and Myanmar, and in Ruili county, on the Myanmar border. P. falciparum resistance in Hainan and Yunnan Hainan Longitudinal in vitro studies of isolates from Hainan show an improvement in chloroquine susceptibility from 98% resistance in 1981 to 27% resistance in 1997. The mean chloroquine concentration for schizont inhibition was 10.4 pmol/µl in 1981, decreasing to 3.0 pmol/µl in 1991 and 1.6 pmol/µl in 1997 (Table 7) 13. Limited in vivo studies show a decrease in failure rates in the last 12 years, when chloroquine was not used, from 84% in 1981 to 18% in 1991 (Table 8). Table 7. In vitro resistance trend of chloroquine against P. falciparum in Hainan Year 1981 1983 1989 1991 1996 1997 No. of Cases 48 45 77 46 26 45 Source: Ministry of Health Report 2003 Resistance rates (%) 98 91 81 61 31 27 Concentration (p/ul) 10.4 +/- 7.1 6.1 +/- 5.1 3.8 +/- 3.0 3.0 +/- 2.9 2.5 +/- 2.0 1.6 +/- 1.5 Rates of cases (%) < 1.6.p/ul > 6.4 p/l 4.2 18.2 48.1 60.8 69.2 73.3 83.3 62.2 37.6 17.4 7.7 6.7 31

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 Table 8. In vivo variation in chloroquine efficacy against P. falciparum in Hainan Year 1981 1982-1983 1986-1989 1991 No. of Cases 38 32 20 38 Source: Ministry of Health Report 2003 Failure rates (%) 84 84 40 18 Parasite clearance time (hrs) 72.0 74.2 58.9 50.7 Failure Rates (%) RI RII RIII 41 59 63 57 6 26 13 29 53 15 24 14 The efficacy of piperaquine monotherapy was compromised soon after the start of its use in 1985. In vitro resistance rates increased from 16% in 1985 to 51% in 1991 and 73% in 1997. Mean ICs of in vitro tests increased from 9.7 pmol/µl in 1985 to 47.9 pmol/µl in 1997 (Annex 2). In vivo assays likewise showed resistance rates increasing from 17% (11/64) in 1984 to 50% (21/42) in 1997, with mostly RIII resistance (70%) (Annex 1, Map 3). Pyronaridine mean ICs also increased from 0.08 pmol/µl in 1986 to 1.36 pmol/µl in 1997, but showed improvement to 0.37 pmol/µl in 2002. A study in 2001-2002 documented a 100% ACPR rate in 72 patients who received the drug 14. Yunnan Unlike Hainan, chloroquine in vitro resistance rates in Yunnan province have remained elevated over the last 20 years. The 97%-100% rates documented from 1981 to 1984 improved slightly to 70% in 2002, with mean ICs decreasing from 17.4 pmol/µl in 1981 to 4.0 pmol/µl in 2002. Two in vivo studies reported a 91% chloroquine treatment failure rate in 1996, and 40% in 2000 15 16 (Annexes 1 and 2). From 1990 to 1993, piperaquine in vitro resistance rates increased from 21% to 73%, with mean ICs increasing from 19 to 38 pmol/µl. Pyronaridine mean ICs increased from 0.14 to 0.54 pmol/µl in 1988 to 1995. There are no documented in vivo studies on pyronaridine treatment response in Yunnan. The in vitro results show higher levels of resistance to pyronaridine and piperaquine in Yunnan than in Hainan in the early 1990s, probably related to the higher malaria transmission and more intense drug pressure in Yunnan 17 18. There are no available molecular drug resistance and genotyping studies from China. 32

China P. vivax There are no available studies of P. vivax resistance to chloroquine in the country, Conclusions and recommendations China and Viet Nam are the only countries in the Region that have continuously monitored chloroquine sensitivity through longitudinal in vitro and limited in vivo studies over the last 20 years. In the long term, especially given the improving sensitivities of chloroquine, their results may prove to be useful. Despite the fact that there is indication of emerging in vitro resistance against the artemisinin derivatives, these continue to be used as monotherapy by the private sector. It may be wise to streamline the use of those drugs and limit the number of regimens available in the current drug policy. Currently, a change in malaria treatment policy towards ACT is underway in China. Other areas that also need to be addressed include: establishing drug efficacy monitoring sentinel sites in Hainan and other parts of China, especially areas with re-emerging vivax malaria; conducting in vivo therapeutic efficacy studies on artemisinin derivatives and especially ACTs, particularly in the high transmission border areas of Yunnan; conducting in vivo studies to assess treatment response of P. vivax to chloroquine and primaquine, since there is a predominance of such cases in Yunnan and Hainan, as well as in the six central provinces of China where outbreaks have been reported in recent years; analysing molecular markers of resistance, especially for sulfadoxine-pyrimethamine, because it is still widely used for prophylactic treatment; and reviewing in vitro techniques and interpreting results and cut-off thresholds with reference according to WHO standards. 33

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 Map 3. Therapeutic efficacy of antimalarial drugs against P. falciparum in China, 1995-2002 34

The Lao People s Democratic Republic The LAO PEOPLE S DEMOCRATIC REPUBLIC Background In the Lao People s Democratic Republic, P. falciparum accounts for 90-95% of all malaria cases and P. vivax for the remainder. All available studies of antimalarial drug efficacy focus on P. falciparum. The country s malaria mortality rates is among the highest in the Mekong region, although it has shown significant improvement, from 12.2/100 000 in 1996 to 3.3/100 000 population in 2003. Drug policy and status of resistance to interim first-line drugs The Lao current national drug policy for uncomplicated falciparum malaria recommends chloroquine as the first-line treatment, sulfadoxine-pyrimethamine as the second-line, and quinine for severe malaria. Following documented reports of high chloroquine and sulfadoxine-pyrimethamine treatment failures in the last five years, the National Malaria Control Programme has launched pilot studies of artemisinin-based combination therapy in areas with high transmission. The drug policy is expected to shift when the results of the pilot studies are received, but until then an interim policy of chloroquine +sulfadoxinepyrimethamine combination therapy was put in place to treat uncomplicated falciparum malaria. 35

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 A 2001 study in southern Savannakhet showed a 92% ACPR rate for the chloroquine+sulfadoxine-pyrimethamine combination, while the highly endemic south eastern Attapeu province documented 83% ACPR, and a 100% cure rate in 26 patients with 14-day follow-up for mefloquine monotherapy 19. More studies are underway to validate the efficacy of the chloroquine+sulfadoxine-pyrimethamine combination therapy, although it may not be suitable for a longer term first-line treatment given that resistance to both drugs as monotherapy is well established. Several artemisinin-based combination regimens tested recently showed a 100% ACPR to artesunate+mefloquine and 94% ACPR to artemether-lumefantrine in Luangnamtha in 2003, and a 100% ACPR to artesunate+mefloquine and 97% ACPR to artemether-lumefantrine in Savannakhet in 2003 (Annex 1, Map 4). P. falciparum resistance to antimalarial drugs Chloroquine While chloroquine resistance was initially reported in the mid-1960s, the first formal study documenting the trend did not appear until 1976. That study documented a 42% chloroquine treatment failure rate in 48 patients from the Nam Ngum dam site in Vientiane province, broken down into 21%RI, 17%RII and 4% RIII 20 (Annex 1). In the subsequent decade, several in vivo tests conducted around the country showed increasing S/RI resistance up to 54%, 15% RII and 3% RIII. It is important to note that the in vivo studies from that period used seven-day or 14-day follow-ups, which may have led to an underestimation of treatment failure rates. Despite that limitation, chloroquine treatment failure rates classified as RII or RIII ranged between 12% and 43% from 1980 to 1997. Subsequent studies conducted from 2000 to 2002 by the Centre for Malariology, Parasitology, and Entomology and others used either 14-day or 28-day in vivo tests and showed higher chloroquine treatment failure rates, ranging from 33% to 78% 21 22 (Annex 1, Map 4). It must also be noted that, as early as 1980-1988, in vitro studies using the WHO macrotest and microtest methods had already documented a greater than 75% chloroquine resistance rate 23 (Annex 2). Those in vitro studies took place in the west of the country, bordering Thailand. In vivo studies showed greater than 20% resistance to chloroquine (RII and RIII) in 1976, a figure that increased over time to greater than 50% in 1999-2001 (RII and RIII). Only after the mid-1990s were in vivo studies also conducted in the east and south-east of the country, bordering Cambodia and Viet Nam, showing chloroquine failure rates ranging from 22% to 45% and leading to the observation that, unlike Cambodia, the Lao People s Democratic Republic had a more homogenous geographical distribution of chloroquine resistance. 36

The Lao People s Democratic Republic Sulfadoxine-pyrimethamine The 1992 Pholsena report 24 (Annex 1) documented 5% RI and 11% RII treatment failures with sulfadoxine- pyrimethamine in 56 patients from 1980 to 1988. Other studies showed less than 10% failure rates in the late 1990s, which increased to 17% in 2001 and 23% in the most recent 28-day in vivo studies from 2002-2003 (Annex 1, Map 4), indicating that the severity of sulfadoxine-pyrimethamine resistance is much less than chloroquine resistance. There were no recent in vitro studies. Map 4. Status of chloroquine, sulfadoxine-pyrimethamine, mefloquine, chloroquine +sulfadoxine-pyrimethamine and artemisinin-based combination therapy efficacy in the Lao People s Democratic Republic, 1997-2003. 37

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 P. vivax There are no treatment efficacy studies on vivax malaria. Conclusions and recommendations Resistance to chloroquine and sulfadoxine-pyrimethamine developed more gradually in the Lao People s Democratic Republic than in other countries in the Mekong region, possibly due to lower access to drugs and sparse population distribution in the transmission areas. Until 2001, the country s national drug policy recommended using chloroquine as the first-line treatment and sulfadoxine-pyrimethamine as the secondline drug 25. Since then, an interim treatment policy of the combination of both drugs is in place. Recently, with the opening up of the country through development of road networks with neighbouring countries, the possibility of an influx of drugs, migrants and counterfeit drugs has increased. Any delay in finalizing the malaria drug policy change may put the Lao People s Democratic Republic in a precarious drug-resistance situation similar to its neighbour countries. In the long term, it will be necessary to: continue to monitor and assess whatever new treatment policy is instituted in the country with therapeutic efficacy studies using 28-day follow-up; assess the treatment response of P. vivax to chloroquine; establish a nationwide drug quality control system to prevent the entry and proliferation of counterfeit drugs; and consider re-establishing in vitro testing. 38

Malaysia MALAYSIA Background Malaria in Peninsular Malaysia is confined to some foci in the deep hinterland, while most reported cases come from the Sabah and Sarawak provinces of East Malaysia, on the island of Kalimantan (Malaysian Borneo). P. vivax acounted for 50% of 5477 confirmed malaria cases in 2003. Drug Policy According to the official drug policy for falciparum malaria, the first-line treatment in Peninsular Malaysia and Sarawak is chloroquine monotherpy, and sulfadoxinepyrimethamine monotherapy in Sabah. Some states, however, use the combination chloroquine+sulfadoxine-pyrimethamine 26. A seven-day regimen of quinine is the official second-line drug as well as the treatment for severe malaria. The recommended treatment for vivax malaria is chloroquine for three days + primaquine for 14 days. 39

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 P. falciparum resistance to antimalarial drugs P. vivax West Malaysia In 1963, Montgomery and Eyles first reported 29% treatment failures to chloroquine, which increased to greater than 60% by the mid-1990s 27 28. The same study documented a 47% sulfadoxine-pyrimethamine failure rate for the first time in the country. No further reports are available until 2000-2001, when two 28-day in vivo studies on chloroquine+sulfadoxine-pyrimethamine combination therapy reported a 51% (19/37) treatment failure rate in Kemaman, Terengganu State, and 63% (15/24) in Air Bah, Perak State. Surveillance at 10 sentinel sites in West Malaysia began in early 2003 to monitor the treatment responses to chloroquine and sulfadoxine-pyrimethamine monotherapies and chloroquine+sulfadoxine-pyrimethamine combination therapy 29 (Annex 1, Map 5). East Malaysia It was only in 2003 that studies on chloroquine resistance in Sarawak became available, showing a treatment failure rate of around 45% in an ongoing efficacy surveillance programme 30 (Annex 1, Map 5). In 1996, in Sabah, the Ministry of Health reported a 29% sulfadoxine-pyrimethamine treatment failure rate in a 28-day in vivo study. The same study reported 100% sensitivity to mefloquine and quinine, and a 17% (2/12) failure rate for artesunate 20 mg/kg for six days 31. A study in 1999-2000 in Sarawak documented a 43% failure rate for the chloroquine+sulfadoxine-pyrimethamine combination 32. Sarawak has two and Sabah four sentinel sites for surveillance as part of the Ministry of Health and Institute of Medical Research national malaria drug efficacy surveillance programme that started in early 2003. A molecular marker study in 1996 and 1997 detected the dhfr gene with triple-point mutation alleles in 87% of isolates from Peninsular Malaysia, where clinical failures to sulfadoxine-pyrimethamine had been reported, while 100% of the isolates from Sabah had dhfr alleles with 2 or less point mutations. These are important results coming from two geographically distinct parts of the country 33. In Sarawak, a 1999-2000 allelic typing study detected 100% prevalence of the pfcrt K76T marker associated with chloroquine resistance, and 78% prevalence of the pfdhfr NRNL haplotype associated with sulfadoxine-pyrimethamine treatment failure. The high prevalence of these 2 markers for resistance adds to the available evidence which calls into question the use of chloroquine and sulfadoxine-pyrimethamine in both monotherapy and combination treatment. There are no recent falciparum in vitro studies. There are no treatment efficacy studies on vivax malaria. 40

Malaysia Conclusions and recommendations It may be necessary to standardize drug policy across Malaysia, as recent reports indicate similar drug resistance levels in the eastern and western parts of the country. There are high levels of chloroquine and sulfadoxine-pyrimethamine treatment failures, and results of initial studies on the chloroquine+sulfadoxine-pyrimethamine combination and molecular marker results are not encouraging. Recommendations for Malaysia are: begin baseline studies of artemisinin-based combination therapies as alternative regimens, especially in light of increasing reports of chloroquine+sulfadoxinepyrimethamine resistance and supporting molecular marker studies; monitor and assess the treatment response of P. vivax to chloroquine in both parts of Malaysia; re-establish in vitro studies in both parts of Malaysia. Map 5. Status of antimalarial drug efficacy in Peninsular and East Malaysia, 1994-2003 41

Papua New Guinea PAPUA NEW GUINEA Background Papua New Guinea has intense malaria transmission, with the Highlands very prone to epidemics. In 2003, 21% of confirmed malaria cases were vivax malaria. Papua New Guinea is one of the few countries in the world where chloroquine resistance of both falciparum and vivax malaria is prevalent. Drug policy and status of resistance to antimalarial drugs P. falciparum resistance to chloroquine was first reported in 1976 from the North Fly region of Western Province 34 35. In 1989, P. vivax resistance was reported in the same area 36 37. Numerous reports published in the 1980s document an increase in P. falciparum chloroquine treatment failures, rising from 20% to 40% in the mid-1980s (mainly at the RI level) to 50% or more by the 1990s 38 (Annex 1, Map 6). In the past decade, there have been very limited studies on any antimalarial regimen used, partly due to the deteriorating sociopolitical and security condition in the country. Chloroquine resistance was highest in the New Guinea Island regions, the Highlands and the southeastern tip of mainland Papua New Guinea. 43

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 In vitro studies from the 1980s to the mid-1990s, mainly carried out by the Institute of Medical Research and the Malaria Control Programme, all demonstrated 50%-90% resistance rates to chloroquine and amodiaquine in over 300 isolates from different parts of the country (Annex 2). In 1997, the Government changed the drug policy to the combination chloroquine or amodiaquine+sulfadoxine-pyrimethamine for uncomplicated falciparum malaria. One year later, in 1998, a study using a 14-day follow up for treatment response of over 400 patients from different parts of the country showed that the chloroquine+sulfadoxine-pyrimethamine or amodiaquine+sulfadoxine-pyrimethamine combination had yielded a cure rate of 95% 39 (Annex 1, Map 6). No baseline studies had been conducted, however, to document the treatment response to sulfadoxinepyrimethamine monotherapy before it became part of the combination therapy. Sulfadoxine-pyrimethamine is also used as a single dose in combination with a threeday course of quinine (10 mg/kg/day), mainly for patients failing chloroquine treatment. A current ongoing study shows failure rates of 24% for the chloroquine+sulfadoxinepyrimethamine combination regimen using 14-day follow-up 40. There have been several studies using molecular markers and genotyping for drug resistance in P. falciparum. The high prevalence and fixed levels of pfcrt and pfmdr1 polymorphisms are consistent with the increasing levels of resistance to the 4-aminoquinolines observed in the country since the 1980s. There are high levels of dhfr polymorphism and a complete absence of dhps polymorphisms, possibly attributable to pyrimethamine combined with chloroquine having been used in mass drug administration campaigns in the eradication eras of the 1960s and early 1970s 41. Earlier studies in the mid-1990s 42 did not reveal the presence of dhps gene polymorphisms, implying that it is the sulfadoxine component that is providing the therapeutic protection in the combination in association with acquired immunity. Continued use of sulfadoxinepyrimethamine will create selective pressure on the dhps gene, leading to the development of resistance polymorphisms. Another study in Madang province in 1997 revealed that recurring P. falciparum isolates typed for allelic variants of msp1 and msp2 are true recrudescing parasites and not new infections, indicating confirmed resistance to the 4-aminoquinolines 43. The investigators reported extensive polymorphism of the msp1 and msp2 alleles from the same study site. These studies indicate widespread chloroquine and sulfadoxine-pyrimethamine resistance. 44

Papua New Guinea P. vivax P. vivax resistance to chloroquine is widespread in the country, with the most active geographical focus in Madang on mainland New Guinea, and the New Guinea island region 44 (Annex 3, Map 6). The same author reported treatment failures of less than 10% in a seven-day follow-up of 375 vivax cases given chloroquine 10 mg/kg + sulfadoxinepyrimethamine single dose on day 7. In more recent years, reports of chloroquine-resistant P. vivax and refractoriness to a 14-day course of primaquine 15 mg/day have come from Australian soldiers treated at the Australian Army Malaria Institute 45, and other individual case reports from several authors. 45

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 Conclusions and recommendations There is indication that the current chloroquine+sulfadoxine-pyrimethamine regimen needs to be phased out soon. Recommendations for Papua New Guinea include: establish sentinel sites for the monitoring and assessment of the treatment response to the first-line chloroquine+sulfadoxine-pyrimethamine combination treatment; consider the available baseline data on sulfadoxine-pyrimethamine molecular markers (dhfr and dhps) before recommendations are made to use it in combination with other drugs; assess artemisinin-based combination regimens as alternative first-line treatment (artesunate or artemether+sulfadoxine-pyrimethamine; artemether-lumefantrine or piperaquine+dihydroartemisinin); currently such a trial is underway; use the modified in vivo therapeutic efficacy protocol for high transmission areas, enrolling only children < 5 years of age; conduct surveillance studies for vivax malaria to assess efficacy of chloroquine plus 14-days primaquine; use genotyping studies to differentiate resistance from reinfection. 46

Papua New Guinea Map 6. Status of chloroquine, sulfadoxine-pyrimethamine and chloroquine+sulfadoxine-pyrimethamine efficacy in Papua New Guinea, 1991-1998 47

Review of the Malaria Drug The Efficacy Philippines Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 The PHILIPPINES Background Falciparum malaria accounts for 70% of all malaria cases in the Philippines and P. vivax for the remaining 30%. In 2003, the country reported 47 677 confirmed cases, giving an incidence rate of 0.55/1000 population. The main disease foci are in remote rural areas of 25 endemic provinces (out of a total of 65 provinces). Drug policy and status of efficacy of antimalarial drugs Starting in the 1950s, the 4-aminoquinolines amodiaquine and chloroquine were the country s first-line drugs. In response to reports of resistance in the early 1970s, sulfadoxine-pyrimethamine was introduced as the second-line treatment in the mid-1980s. Quinine monotherapy was the third-line drug for severe malaria. Despite increasing reports of resistance to chloroquine and sulfadoxine-pyrimethamine, those drugs remained the Philippines first-line and second-line treatments for falciparum malaria until the 2002 change in drug policy. In August 2002, the Philippines New National Drug Policy was signed, designating chloroquine+sulfadoxinepyrimethamine combination therapy as the first-line drug, artemether-lumefantrine (Coartem TM ) as the second-line treatment, and quinine+antibiotic (tetracycline, clindamycin or doxycycline) as the treatment regimen for severe malaria. 49

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 P. falciparum resistance to antimalarial drugs From the 1970s to the 1980s several studies evaluated chloroquine in vitro, showing resistance rates ranging from 5% to 80% in different parts of the country 46 47. Systematic in vivo studies of chloroquine and sulfadoxine-pyrimethamine for treatment of falciparum malaria have been conducted by the Malaria Control Service and the Research Institute for Tropical Medicine Malaria Study Group from 1995 to 2003. The studies show chloroquine treatment failure rates as high as 42% to 65% in the provinces of Palawan in the west, Kalinga-Apayao in the north, and Agusan del Sur, Davao Norte and Compostela Valley in the south. Most of the failures were late treatment failures or resistance at the RI level. Sulfadoxine-pyrimethamine treatment failures ranged from 9% to 19% in Palawan and Kalinga-Apayao, to as high as 45% to 68% in Davao Norte, Agusan del Sur and Compostela Valley in Mindanao 48 49 50 (Annex 1, Map 7). Since the 2002 policy change, treatment failure rates with chloroquine+ sulfadoxine-pyrimethamine ranged between 6% and 15% in different parts of the country, with a tendency towards higher failure rates in the south. During a malaria outbreak in Bulacan province north of Manila in 2002, a 30% (8/27) failure rate was reported 51. A 2003-2004 study to assess treatment responses in two sites in the north indicated a 99-100% cure rate for artemether-lumefantrine (Coartem TM ) and 94% for chloroquine+sulfadoxine-pyrimethamine 52. Two more sentinel sites will be established in Palawan and in Mindanao in 2005 for malaria drug efficacy monitoring and surveillance of the chloroquine+sulfadoxine-pyrimethamine combination and artemether-lumefantrine. In 2000, genotyping studies detected the pfcrt K76T mutation in all but one isolate (158/159) in six study sites in the north and south of the Philippines, although 48% (76/159) were in vivo sensitive to chloroquine. Triple or 2-point mutations at positions 51, 59 and 108 in dhfr codons and positions 436 and 437 on the dhps gene were also detected in all 154 isolates, despite 66% adequate in vivo treatment response to sulfadoxine-pyrimethamine (101/154) 53. P. vivax One study in Palawan 54 assessed the treatment response of P. vivax to 3-day chloroquine in 1995, and later two studies in 2000 in the north and south of the country 55 used the 3-day chloroquine + 14-day primaquine with follow-up for 28 days (Annex 3). All three studies reported 100% cure rates and the regimen chloroquine+primaquine remains the main treatment for vivax malaria. 50

Review of the Malaria Drug The Efficacy Philippines Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 Conclusions and recommendations Since the chloroquine+sulfadoxine-pyrimethamine combination is achieving a >85% ACPR rate in most studies so far, except in a malaria outbreak situation, it is likely to remain the interim drug policy for the time being. However, there are many indications (including results from molecular studies) that its lifespan as a first-line drug regimen is nearing its end. Recommendations for the Philippines are: continue monitoring efficacy of first-line and second-line drugs nationwide, and explore options for other artemisinin-based combination regimens (aside from artemether-lumefantrine) to replace the current chloroquine+sulfadoxinepyrimethamine first-line regimen; in the Philippine s decentralized system, institutionalize drug efficacy monitoring at the local level as part of Malaria Control Programme activities in designated sentinel sites, with technical supervision by research institutions; organize a consultation on using artemether-lumefantrine as the first-line drug, and consider and plan for the resulting budgetary requirements; establish in vitro monitoring for falciparum malaria; continue monitoring the efficacy of chloroquine and primaquine for vivax malaria. 51

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 Map 7. Status of chloroquine, sulfadoxine-pyrimethamine, chloroquine+sulfadoxinepyrimethamine and artemether-lumefantrine in the Philippines, 1995-2003 52

The Republic of Korea The REPUBLIC OF KOREA Background By 1984, malaria had been eliminated from the Republic of Korea due to the intensive control efforts of the Malaria Eradication Programme from the 1960s to the 1980s. However, in mid-july 1993, the first case in what has become a re-emergence of vivax malaria was confirmed in a soldier working near the Demilitarized Zone (DMZ). In the succeeding months and years, more cases were reported from the same area. Outbreaks have occurred since 1995, spreading south and east from the northern part of the DMZ, and secondary transmission has occurred in the civilian population in several sites 56. A unique feature of this re-emergence of vivax malaria is its prolonged incubation period. The course of illness is relatively mild and, according to available literature, no mortality has been reported. In 2003, there was a marked reduction in the number of cases following major control efforts in the country. 53

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 Status of currently used drugs for P. vivax To date, there has been no indication of chloroquine resistance in this re-emerging vivax malaria situation 57 58 59 (Annex 3, Map 8). Only one study in 1996 60 reported two treatment failures out of 81 P. vivax cases (3%) among Korean soldiers confined at the Capital Armed Forces General Hospital in Seoul and given the standard chloroquine for 3 days + primaquine for 14 days. Still parasitemic by day 14, both patients responded to a second course of the same regimen, although one had a relapse eight months later. There are no molecular studies available. Map 8. Chloroquine efficacy in vivax malaria in the Republic of Korea, 1996-1999. 54

The Republic of Korea Conclusions and recommendations The National Control Programme has effectively tracked and halted the spread of cases from the DMZ and the re-emergence of vivax malaria in the Republic of Korea in the last 10 years. It may become necessary to use close monitoring and extended follow-up in treating relapsing vivax malaria, especially in the civilian population coming from known endemic areas. Recommendations for the Republic of Korea include: continue monitoring the treatment response of P. vivax to chloroquine alone to determine true chloroquine resistance; monitor and assess for refractoriness to 14-day primaquine treatment at 15 mg/ day; conduct studies with long follow-up periods to assess the efficacy of the chloroquine three-day + primaquine 14-day regimen as terminal prophylaxis; molecular studies are needed in relapsing vivax malaria because of the long incubation period. 55

Solomon Islands SOLOMON ISLANDS Background Solomon Islands, with a population of approximately 430 000, had a reported malaria incidence of 190 confirmed cases/1000 population in 2003, of which 33% were vivax malaria. It is one of the least developed countries and has the highest incidence of confirmed malaria cases in the Western Pacific Region. Drug policy and status of resistance to antimalarial drugs Chloroquine-resistant falciparum and vivax malaria are prevalent in Solomon Islands. The resistance of P. falciparum to chloroquine has been recorded in the country since 1980, initially in the Western, Central, Guadalcanal and Malaita provinces, and gradually spreading all over the country in subsequent years. A systematic monitoring for resistance was conducted throughout the country from 1994 to 2001, using the WHO modified seven-day in vivo test (Annex 1, Map 9). Chloroquine treatment failure rates were 17% and 28% 61 62. A single in vitro study in 1995-1996 confirmed this level of chloroquine resistance (Annex 2). By 2001, chloroquine treatment failures had significantly increased to 67% based on the 28-day in vivo test. Solomon Islands has unique experience in using selected microscopists to conduct such studies in sentinel sites, and helping the programme monitor the level of therapeutic efficacy of the first-line drug on a longitudinal basis. However, no baseline studies on treatment responses to sulfadoxinepyrimethamine monotherapy are available. The current antimalarial drug policy was approved in 2001 and implemented in 2002. It recommends chloroquine+sulfadoxine-pyrimethamine as the first-line treatment for uncomplicated falciparum malaria. The latest available therapeutic efficacy assessment of the combination documented 90% cure rates using a 14-day test 63. The second-line treatment is a combination of quinine for three days + a single dose of 57

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 sulfadoxine-pyrimethamine. An artemisinin-based combination therapy, artesunate+sulfadoxine-pyrimethamine, is recommended as the third-line treatment. In recent years, the artemisinin derivatives have been introduced and used mainly by the private sector. Currently, a study is underway comparing chloroquine+sulfadoxinepyrimethamine and artesunate+sulfadoxine-pyrimethamine, and will include molecular marker studies on sulfadoxine-pyrimethamine. P. vivax Until 1991, the standard treatment for P. vivax was chloroquine and primaquine (45 mg). Primaquine was removed from the treatment schedule following reports of haemolysis in some patients. A single study in 1995 documented the reappearance of parasitaemia in 14 of 46 P. vivax patients (30%) followed up for 28 days (Annex 3, Map 9). Chloroquine levels showed that 7 out of 14 patients still had adequate chloroquine in their blood at the time of reappearance of parasites, and as such were considered resistant. The remaining seven had zero levels of chloroquine in their blood, indicating a relapse or reinfection. This study showed an overall 15% P. vivax chloroquine treatment failures 64. Recently, the 14-day course of primaquine was reintroduced in the drug policy as an antirelapse agent, since relapsing vivax malaria is becoming an increasing problem. The lower dose of 15 mg (adult) primaquine taken for 14 days for the elimination of hypnozoite stages from the liver may not cause haemolysis as indicated by the above 1995 study. In 2001, a study showed 84% cure with chloroquine + primaquine in 231 vivax cases in Western province using 14-day follow-up 65. Conclusions and recommendations Both P. vivax and P. falciparum resistance are present in the Solomon Isalnds. Since the 2001 change in drug policy, a single efficacy study has been conducted on the current first-line treatment of chloroquine+sulfadoxine-pyrimethamine. Recommendations for the Solomon Islands include: assess regularly the efficacy of the current first line chloroquine+sulfadoxinepyrimethamine regimen; evaluate the efficacy of sulfadoxine-pyrimethamine before its further use in combination with other drugs such as the artemisinin derivatives; for vivax malaria, conduct studies on the efficacy of chloroquine and 14-day primaquine in areas where reinfection can be ruled out, coupled with surveillance for G-6-PD deficiency prevalence in the country; use genotyping studies to differentiate reinfections from resistance; regulate antimalarial drug use, especially in the private sector. 58

Solomon Islands Map 9. Status of chloroquine, sulfadoxine-pyrimethamine and chloroquine +sulfadoxine-pyrimethamine efficacy in Solomon Islands, 1994-2001 59

Vanuatu VANUATU Background Vanuatu, consisting of 80 islands in Melanesia, had an estimated malaria-endemic population of 206 000 in 2003 (out of a total population of 212 000). The incidence of confirmed cases was 72/1000 population, 45% of which were vivax malaria, the highest proportion of vivax cases in the Pacific. Drug policy and status of resistance to antimalarial drugs In 1991, following reports of chloroquine treatment failures for P. falciparum increasing to 28%, especially in children less than five years of age, first-line treatment was changed from chloroquine to sulfadoxine-pyrimethamine (Annex 1, Map 10). However, another in vivo study in 1994 documented that one third of failures were due to inadequate chloroquine blood levels in children, hence true chloroquine treatment failures was only 7% 66. A 1991 study also documented a 5% failure rate for sulfadoxine-pyrimethamine, mostly at the RI level 67. A review of the historical evolution and distribution of drug resistance from in-house documents and publications can be found in a report by Hazel Clothier 68. In 1994, Vanuatu officially issued its revised malaria treatment guidelines, with the chloroquine+sulfadoxine-pyrimethamine combination set as the first-line treatment for uncomplicated malaria, oral quinine for seven days as the second-line, and parenteral quinine 10 mg/kg as the third-line drug. 61

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 Only one study has evaluated the treatment response to chloroquine +sulfadoxinepyrimethamine. This was carried out in January-March 2001 at three sites according to the 28-day WHO protocol. Results showed a 16% (8/50) treatment failure rate, with 14% (7/50) late treatment failures and 2% (1/50) early treatment failures (Annex 1, Map 10). To date, this is the only study that has documented the treatment efficacy of currently recommended drugs in Vanuatu. It appears that the chloroquine+sulfadoxine-pyrimethamine combination had maintained its efficacy against falciparum malaria for 7 years. Currently, a new study is underway to reassess the efficacy of chloroquine+sulfadoxine-pyrimethamine. There are no recent in vitro studies, although earlier studies done from 1984 to 1991 showed >47% chloroquine in vitro resistance (Annex 2). P. vivax For vivax malaria, there has only been one study in 1991 which documented a treatment response rate of 99% (101/102 subjects) to chloroquine and 81% to sulfadoxinepyrimethamine 69 (Annex 3, Map 10). Conclusions and recommendations The chloroquine+sulfadoxine-pyrimethamine combination has been in place for more than 10 years and still seems to work reasonably. Recommendations for Vanuatu include: establish sentinel sites and conduct in vivo drug efficacy monitoring studies; reassess chloroquine+sulfadoxine-pyrimethamine and alternative artemisininbased combination therapy drugs for P. falciparum; re-establish in vitro drug resistance studies; monitor the efficacy of chloroquine, and chloroquine + primaquine for 14 days against P. vivax. 62

Vanuatu Map 10. Status of chloroquine, sulfadoxine-pyrimethamine and chloroquine +sulfadoxine-pyrimethamine efficacy in Vanuatu, 1994-2001 63

Viet Nam VIET NAM Background Viet Nam was very successful in rolling back malaria. In 2003, the incidence rate of confirmed malaria was 0.46/1000 countrywide. P. falciparum accounts for 79% of malaria cases and P. vivax for 21%. In different provinces, the ratio of P. falciparum to P. vivax cases varies from 1:1 to 1:2. Drug policy and status of efficacy of first-line and second-line drugs The current drug policy in Viet Nam recommends the use of chloroquine or artesunate for seven days as the first-line treatment for probable malaria, and artesunate for seven days or dihydro-artemisinin+piperaquine+trimethoprim+primaquine (CV8 TM ) for confirmed falciparum malaria. The second-line treatment is artesunate 8 mg/kg for three days+mefloquine 15 mg/kg on day 3. Mefloquine was introduced in the early 90s. Parenteral or suppository artesunate or parenteral quinine is given for severe malaria. South and central Viet Nam have demonstrated higher chloroquine resistance than north Viet Nam, reflecting the country s stratified treatment regimen in the 1990s. But recent policy changes recommend artesunate or CV8 TM for all cases of confirmed falciparum malaria nationwide, and mefloquine+artesunate for drug-resistant falciparum malaria (June 2003). Despite the official malaria drug policy, the injudicious use and non-adherence to the 7-day artemisinin monotherapy especially by the private sector may contribute to the development of resistance. 65

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 Since 1990, artemisinin or artesunate monotherapy has been used as the main treatment for complicated and severe falciparum malaria, especially in the North. It is regarded as one of the important factors for the reduction of malaria mortality and morbidity in Viet Nam since the early 90s. While there are no documented reports of artemisinin derivative resistance in vitro, in vivo studies indicate emerging resistance, with 17% failures in DakLak, 18% in Binh Thuan and 8-50% in Binh Phuoc (Annex 1, Map 11). High recrudescence rates have been observed from the start, especially with low-dose short-course regimens, owing to the drug s short half-life. Artesunate+mefloquine is a mutually protective combination and remains highly effective in Viet Nam. Most in vivo studies from the last four years have shown high cure rates at 99%-100% ACPR. Recorded failures have been attributed to a single or short-dose artemisinin component, or a low-dose mefloquine component. CV8 is a new anti-malarial combination produced in Viet Nam, a fixed combination tablet composed of dihydroartemisinin 32 mg, piperaquine 320 mg, trimethoprim 90 mg and primaquine 5 mg, in a total of eight tablets given over three days (adult dose). Local studies in 1999-2000 using 28-day tests have shown 99%-100% cure rates. Molecular studies in 1998 showed that the T76 in pfcrt gene and mutations in the pfmdr1 gene were tightly linked to chloroquine resistance, and that the dhfr and dhps genes were also present in south Viet Nam. The same study documented increased IC50 of mefloquine in secondary isolates after artemisinin treatment, and amplification of the wild-type pfmdr1 gene. The investigators suggested monitoring for artemisinin resistance 70. 66

Viet Nam P. falciparum resistance to antimalarial drugs The first clinical reports of chloroquine treatment failures from South Viet Nam appeared in 1961. Local studies conducted in the 1980s and early 1990s showed an increase in failure rates to 65% for chloroquine and 70% for sulfadoxine-pyrimethamine and 15% for quinine 71 72. Resistance spread further from the mid-1990s to 2001, according to in vivo studies in the provinces of central and south Viet Nam, which showed 22%-72% failure rates for chloroquine and 13%-87% for sulfadoxine-pyrimethamine (Annex 1, Map 12). In 1992, areas with focal malaria transmission in north Viet Nam reported 10%-81% chloroquine failure rates (RII-RIII) and 15%-52% sulfadoxinepyrimethamine failure rates (RII-RIII). A single study in 1999 in Lao Cai and Son La, north Viet Nam, revealed 50% resistance to chloroquine and 70% to sulfadoxinepyrimethamine, although the sample size was small since this is a low transmission area with 50% P. vivax infections 73. With the introduction of artemisinin derivatives in 1990 for uncomplicated and severe malaria, the use of chloroquine, sulfadoxine-pyrimethamine, and quinine was reduced. While chloroquine remains the first-line treatment for vivax malaria, it has not been used officially for falciparum malaria for over 10 years. As in China, chloroquine in vitro sensitivity has improved dramatically, presumably due to the reduction in drug pressure. In 1986, 83%of 496 isolates tested in vitro were resistant to chloroquine, with an IC99 of 900 nmol/l, as opposed to 17% resistance with an IC99 of 359 nmol/l in 1998 74 (Annex 2). Mefloquine In the early years of mefloquine use as a monotherapy, there were reports of a 34% treatment failure rate in south Viet Nam 75 (Annex 1). Subsequently, mefloquine was only used in combination with artemisinin derivatives in drug-resistant cases. It gained wider use as a combination for all P. falciparum cases in 1995. Mefloquine efficacy stabilized when it started being combined with artemisinin derivatives (mefloquine 15 mg/kg single dose+artesunate 8 mg/kg for three days, 28-day followup), with in vitro studies from 1995-1999 showing 97%-100% sensitivity to mefloquine 76 (Annex 2). As such, mefloquine has remained a fully effective antimalarial drug in endemic areas of Viet Nam after more than a decade of use, partly due to its concomitant use with artemisinin derivatives (Map 12). 67

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 Quinine Two studies in 1993 and 1997 documented 18% and 16% treatment failure rates, respectively, to seven-day quinine in uncomplicated malaria 77 78 (Annex 1). Quinine, however, remains effective for severe malaria, as shown in a large-scale comparative clinical trial of artemether versus quinine in 561 patients from 1991 to 1996 79. In vitro tests conducted from 1995 to 1999 in several parts of south and central Viet Nam further confirmed the efficacy of quinine (Annex 2). Map 11. Status of artemisinin derivatives and artemisinin-based combination therapy efficacy in Viet Nam, 1999-2003 68

Viet Nam P. vivax P. vivax accounts for approximately 20% of malaria cases in Viet Nam. Four studies conducted between 1994 and 2000 showed that the standard three-day course of chloroquine yielded better cure rates than a three-day course of artemisinin 40 mg/kg, with a 23% treatment failure rate; CV8 TM with a 4% failure rate; or halofantrine 8 mg/kg three doses with a 13% failure rate 80 81 (Annex 3). Although a 28-day study documented a 16% chloroquine failure rate in 111 P. vivax cases in Binh Thuan province in 2000 82, a more recent study of 277 P. vivax cases, conducted by the National Institute of Malariology, Parasitology and Entomology, documented 100% efficacy of the 3-day dose of chloroquine. Map 12. Status of chloroquine, sulfadoxine-pyrimethamine and mefloquine efficacy in Viet Nam, 1996-2001 69

Review of the Malaria Drug Efficacy Situation in 10 Countries of the WHO Western Pacific Region 1987-2003 Conclusions and recommendations Despite the official drug policy, there are many drug regimens available and in use in Viet Nam. Especially, artemisinin drugs are available in different monotherapy packages as they are locally produced. Not surprisingly, there is indication of emerging drug resistance to artemisinin derivatives. Artesunate 8 mg/kg for 3 days in combination with mefloquine 15 mg/kg on day 3, however, remains a highly effective antimalarial regimen in Viet Nam; for this combination to be fully effective, higher doses of longer therapy with artemisinin or artesunate mefloquine may be needed to prevent recrudescence and emergence of drug-resistant P. falciparum strains. The malaria epidemics in several parts of Viet Nam in the early 1990s led to strong political support for investment in local production of the artemisinin plant and compounds, which made access to artemisinin derivatives easier for both the public and private sectors. Better access to effective antimalarials, improvements in the health infrastructure and health care delivery, and early introduction of the artemisinin derivatives as well as effective vector control measures have all contributed to the significant decline in malaria morbidity and mortality in Viet Nam in the ensuing years 83. However, there is a current regulatory need to ensure the quality of these drugs, especially since counterfeit drugs are known to exist in the south. CV8 TM (combination of dihydroartemisinin, piperaquine, trimethoprim and primaquine) is currently used as 1 st -line regimen, but contains an unnecessary compound (trimethoprim). Artesunate monotherapy (7 days) is still part of the guidelines, but the compliance to a 7-day regimen may not be sufficient. Recommendations for Viet Nam include: review current malaria treatment policy especially the use of CV8 and artemisinin derivatives monotherapy; continue in vivo and in vitro antimalarial drug efficacy studies, following WHO standard protocols; 70

Viet Nam conduct more efficacy studies in the north, where malaria prevalence is decreasing but treatment response to the currently recommended regimen needs monitoring; closely monitor the efficacy of artemisinin derivatives monotherapy and combination therapy to be able to detect and counteract emerging artemisinin resistance; conduct therapeutic efficacy testing of chloroquine and primaquine against P. vivax in endemic areas; advocate for judicious use of artemisinin derivatives monotherapy (or cease using it as monotherapy), especially in the private sector where treatment response is not monitored; establish antimalarial drug quality monitoring in strategic sites. 71