ACT NOW by Médecins Sans Frontières (MSF) Australia

ACT NOW for all of the Asia Paciﬁc to get

malaria treatment that works Medécins Sans Frontières 2004

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Medécins Sans Frontières is an independent, international medical relief organisation that aids victims of armed conﬂict, epidemics, natural and man-made disasters, and others who lack health care due to geographic remoteness or ethnic marginalisation. Medécins Sans Frontières has been treating patients with malaria in its projects in Africa, Asia and Latin America since 1985. It currently runs malaria projects in nearly 40 countries treating over one million malaria patients every year. Medécins Sans Frontières won the Nobel Peace Prize in 1999.

© MSF 2004. Writing and research: Alyosha Jacobson Editorial Assistance and Advice: Kathryn Dinh, Christa Hook, Jean-Marie Kindermans, Margriet Den Boer, Nicolette Jackson, Daniel Berman Design: Motor Design agency, Darlinghurst, Sydney Australia & James Terry, Sydney Australia Additional thanks to MSF teams in the ﬁeld, and to Francois Nosten, Nicholas Anstey, Ric Price and Nick White Produced by The Access to Essential Medicines Campaign - MSF Australia Photo © Serge Sibert/Cosmos

Suite C, Level 1, 263 Broadway, Glebe NSW 2037, Australia Ph +61 2 9552 4933 Fax +61 2 9552 6539 www.msf.org.au Reasearched to August 2004. Published December 2004. Cover photo: © Stephan Gross Rüschkamp

Contents Glossary Executive Summary Why ACTs?

Page 2

Artemisinin use in the Asia Paciﬁc Supporting the production of artemisinins Accurate diagnosis Donor support What Medécins Sans Frontières believes needs to be done

4 4 4 5

The malaria problem Disease impact Malaria in the Asia Pacific Antimalarial drug resistance The consequences of drug resistance Unacceptable levels of treatment failure Malaria protocols in the Asia Pacific today Map: Therapeutic failure rates of commonly used antimalarials National malaria treatment protocols as of July 2004 What works What is Artemisinin? Artemisinin Combination Therapy (ACT) ACT use in the Asia Pacific may reduce cases of P falciparum malaria Artemisinin slows development of malaria drug resistance Avoiding a malaria disaster Choice of companion drug Accurate diagnosis is critical Making ACT a reality Implementation Urgent scaling-up of ACT production ACT financing Donor support for ACTs: how far does it go? Who is producing ACT now? The future of malaria treatment What Medécins Sans Frontières believes needs to be done Annex 1. Plasmodium vivax 2. Fake and Substandard Drugs 3. New FDCs 4. ACT blisters and FDCs for the future 5. Asia Pacific country-specific data on malaria drug resistance levels References

5 7 7 8 8 8 8 9 10 13 14 14 14 15 15 15 17 17 18 18 19 21 21 23 24 24 25 26 32

Photo © Olivier Bonnet

Glossary ACT AQ CQ In Vitro In Vivo Gametocytaemia Genotype Genotyping PCR Plasmodium falciparum Plasmodium vivax Parasitaemia RBM RDT Recrudescences Resistance: RI response RII response RIII response SEARO S- Sensitive Sensitivity Speciﬁcity WPRO

Artemisinin Combination Therapy Amodiaquine Chloroquine Measuring the effect of the infection and treatment in a laboratory test Measuring the effect of the infection and treatment on the person rather than in a laboratory Level of the infectious form of the parasite in the blood The genetic make-up of an organism A process of looking at the genetics of the particular organism found in an individual patient Polymerase Chain Reaction - a method of multiplying genetic material (eg of the malaria parasite in an individual) to the point where it is large enough to be closely examined The parasite causing the severe form of malaria. P falciparum is the only form of malaria that can lead to cerebral malaria and death The other common parasite causing malaria. Causes fever, shivering and anaemia but not death Levels of parasite in the blood Roll Back Malaria program established by WHO Rapid Diagnostic Test Recurrences of the original infection as a result of treatment failure Initial total removal of parasite from blood followed by recovery and reappearance of parasite more than 7 days after treatment Initial reduction in blood parasite levels but these recur prior to day 8 No signiﬁcant reduction of parasite in the blood whatsoever South-East Asian Regional Organisation of the WHO Subsequent to treatment, no parasites are seen in the blood from day 7 until the end of follow-up A measure of the degree to which a test is able to diagnose all positive cases A measure of the degree to which a test correctly rules out negative cases Western Paciﬁc Regional Organisation of the WHO

Photo © Ahmed Zouiten

Executive Summary This is a call to international donors and Asia Pacific governments to join in supporting World Health Organisation (WHO) treatment guidelines for malaria. On the advice of international experts, WHO recommends that Asia Pacific countries facing resistance to classical antimalarials introduce drug combinations containing artemisinin derivatives – artemisinin-based combination therapy, or ACT for short.1 Not only do Asia Pacific countries need encouragement to change their malaria protocols to ACTs but also support to meet the production demands for ACTs worldwide. Artemisinin derivatives have attributes that make them especially effective: they are highly potent, fast-acting (parasite reduction is fast and people recover quickly), very well tolerated and are slow to develop resistance.2 3 4 Implementation of new malaria recommendations is a matter of life and death in the Asia Pacific where - with an estimated 23 million cases per year – it remains a major cause of morbidity and mortality.*5 6 Over 46% of these cases, and rising, are from the deadliest form of malaria - Plasmodium falciparum (P falciparum).◆ 7 Also on the rise, and of serious concern, is the increasing resistance of P falciparum malaria to the most commonly used drugs to treat it: chloroquine (CQ), sulphadoxine-pyrimethamine (SP) and mefloquine. South East Asia has the most drug resistant malaria parasites in the world.8 Drug resistance levels are also of concern in the Western Pacific.9

Why is Médecins Sans Frontières so focused on changing malaria protocols to artemisinin derivatives? In Vietnam the introduction of artemisinin-based combination therapy (ACT) has contributed to a 98% drop in malaria mortality.10 11 Because they rapidly remove malaria parasites from the bloodstream, artemisinin derivatives can reduce the transmission of malaria, and so radically reduce the number of malaria cases. Following a change to ACTs in Thai refugee camps, P falciparum cases declined six-fold.12 ACTs also slow the development of drug resistance. Because the action of artemisinin derivatives in the bloodstream is so rapid and effective, malaria parasites are not exposed to low levels of drug, and hence are less susceptible to developing resistance. There is no clinically signiﬁcant resistance to artemisinin derivatives at present. Combined with another antimalarial, (as ACT), artemisinin derivatives may also help to prevent resistance developing to the other drug.13 This is crucial in the context of a resurgence in malaria worldwide and rising drug resistance, the focal point of which is in Asia.

* Calculation based on WHO estimates of 21 million cases in South East Asia and two million cases in the Western Paciﬁc annually. ◆ 44.9% of SEARO cases, 68% of WPRO cases, again based on WHO data.

Photo © Roger Job

Artemisinin use in the Asia Paciﬁc

Supporting the production of artemisinins

Artemisinin derivatives have been researched and widely used in Asian contexts. In 2004, Indonesia, Bangladesh, northeast India and Laos joined other Asian countries in opting for ACT as ﬁrst-line antimalarial treatment. These countries will need support in ACT procurement and national distribution. Countries will also need support in training health staff, ongoing monitoring of ACTs, quality control and drug regulation to prevent counterfeiting. The time from the initial change of protocol to availability of quality ACTs in all local health clinics in a country must be as short as possible.

An urgent scaling-up of production for artemisinins is needed. The WHO estimates that worldwide demand for ACTs by 2005 will be 131-219 million treatments annually. In April 2004 it was estimated that production capacity for 2004 was 25- 50 million treatments.14 While this is increasing, it is still far short of demand. Worldwide production, most of which occurs currently in Vietnam, China and India, desperately needs support with upgrading of production, quality assurance and advance funding for pooled orders.

However despite Asia having the world’s most resistant parasites, some Asia Pacific countries continue to treat malaria with relatively ineffective treatments. Five countries are still using non-artemisinin mono-therapy (single drug treatment) for P falciparum despite the WHO’s recommendations. These countries are India (except for north-east states), East Timor, Nepal, Sri lanka and Malaysia. Four other countries – the Philippines, Vanuatu, the Solomon Islands and Papua New Guinea – are currently using the combination CQ + SP as firstline treatment. With high drug resistance to CQ worldwide, and rising resistance to SP, this combination may not be effective, and is equivalent to using SP alone. Some countries, such as the Philippines and Papua New Guinea, are using ACTs as second-line treatment, in patients for whom first-line treatment has failed. However this risks lives by requiring ill patients to return to clinics that are often inaccessible for them, for a second treatment. The WHO recommends that once treatment failures using a particular drug reach 15%, (due to resistance), countries should change their treatment protocol. Studies throughout the Asia Pacific have shown resistance levels to CQ and SP of greater than 15% (see map page 9).

The plant from which artemisinin is derived, Artemisia annua, takes approximately one year from cultivation to finished product. Hence, pre-emptive bulk orders need to be made and financed, with donor support. Alternative ACT combinations need to be pre-qualified by the WHO, and technical assistance provided for manufacturers. Encouraging generic producers and competitors will help to stimulate the market and bring prices down.

Accurate Diagnosis Microscopy is the ideal test for malaria, but it requires expensive equipment and training. As a result, malaria is often diagnosed in peripheral health clinics according to clinical symptoms and signs, such as fever. Unfortunately fever is common to many illnesses and so the diagnosis is often missed or incorrect. Rapid diagnostic tests (RDTs) are simple pinprick blood tests that can be used in a basic clinic or by outreach teams, and can be performed accurately with minimal training. To improve the targeting of ACTs and reduce the development of drug resistance, accurate diagnosis should be a central part of the process. Further research into RDTs, and quality assurance by the WHO, is urgently needed.

Donor support There is now international consensus in support of ACTs, endorsed by Roll Back Malaria,15 USAID,16 UNICEF17 and the Global Fund to fight AIDS, Tuberculosis and Malaria.18 However ACTs cost US$0.50-$2.40 per treatment (depending on patient age and ACT type), compared with US$0.10 for the old drugs such as chloroquine. Despite the cost, donors have realised that it makes more sense to treat with a drug that is more expensive but works, than to waste money and allow people to die by funding ineffective treatments. These donors, wealthy governments and other agencies will now need to provide financial and technical support to malarious countries to assist them to change to ACTs. Although the consensus of experts is in support of ACTs, some donors, such as the United Kingdom’s Department for International Development (DFID) and the Australian Agency for International Development (AusAID), still have no specific drug recommendations in their funding of malaria programs. As a result they have inadvertently supported the old treatments. This may be through funding of the old drugs, or simply by not actively encouraging Asia Pacific countries to change their protocol to the WHO recommended ACTs. There is now compelling evidence in support of ACTs as the ‘gold standard’ treatment for P falciparum. ACTs are ideally suited for the Asia Pacific, where they have been extensively studied and have been shown to reduce morbidity and mortality from malaria.

It makes more sense to treat with a drug that is more expensive but works, than to waste money and allow people to die by funding ineffective treatments.

There is now compelling evidence in support of ACTs as the ‘gold standard’ treatment for P falciparum.

What Médecins Sans Frontières believes needs to be done All countries in the Asia Pacific should change to ACTs as first-line treatment for P falciparum. This requires: • The World Health Organisation to push for implementation of its own recommendation to switch to ACT • National governments to change their malaria protocols to ACTs for P falciparum, and support use of accurate diagnostics • Donors to proactively support ACTs and RDTs, financially and politically, instead of tacitly supporting the status quo, and wasting money by funding drugs that don’t work. Implementation of ACTs needs to occur quickly and to provide access to effective treatment for all. This requires: • Governments to match political commitment to change to ACTs with effective national implementation of the new malaria treatment protocols • International agencies and donors to provide technical and financial support to facilitate treatment implementation in the areas of: - Drug procurement - Education about ACTs and RDTs - Drug distribution - Continuing monitoring - Drug regulation - Widespread use of accurate diagnostics • Donors to support the additional costs of ACT treatment and diagnosis • ACTs to be provided free or at an affordable price for patients in public health facilities. Governments and donors should consider subsidising ACTs in the private sector. High quality artemisinin production must be scaled-up. This requires: • Donors to contribute to increasing output, competition and sustainability of production by assisting international and domestic drug suppliers to upgrade production standards. This can be achieved through technology transfer and technical assistance. • International donors, UNICEF, WHO procurement and the Global Fund to fight AIDS, Tuberculosis and Malaria to pool needs and make advance bulk orders of artemisinin in anticipation of rapidly increasing demand, and to bring down prices. • International and/or regional pre-qualification of malaria drugs by the WHO needs to be augmented to assist countries in identifying quality drug sources. In the future, the Global Fund will only support drugs that have been pre-qualified by the WHO. Research and Development must continue, to result in: • Cheaper and more effective RDTs to be developed and prequalified, with WHO support. • Sustained development of new malaria drugs especially in fixed-dose combinations. This report defines The Malaria Problem, looks at What Works in malaria treatment and outlines what needs to be done to Make ACT a Reality.

Photo ÂŠ Serge Sibert/Cosmos

The malaria problem Disease Impact: Malaria is the hidden global scourge. Where malaria thrives, people suffer and economies are drained. There are 300 to 500 million cases of malaria worldwide every year, 90% of which are in Sub-Saharan Africa. Malaria causes one to two million deaths annually, again mostly in Africa. 30 to 50% of all hospital admissions in Africa are for malaria.19 However malaria also has a significant impact in the Asia Pacific, with millions of infections and thousands of deaths annually. When a person is infected with malaria they become feverish, shiver, vomit and become drowsy. Children and pregnant women are especially susceptible to severe malaria. This can involve internal bleeding, kidney and liver failure, and can result in coma and death. Malaria leads to increased susceptibility to other diseases, as well as anaemia and poorer nutritional status.20 21 Studies have shown that measures which reduce malaria incidence also reduce mortality from other diseases, by up to 60%.22 23 Malaria can impact on children’s cognitive development and education.24 Pregnant women with malaria are more likely to deliver low birthweight babies, who are vulnerable to difficulties in school.25 26 High fertility rates in tropical, malaria-endemic areas may be a response to high infant mortality secondary to malaria. This in turn results in poor female education.27 Malaria impacts on adults’ ability to make a living and care for their families.28 At a country level, malaria affects trade, tourism and foreign direct investment.29 There is a significant correlation between malaria and poverty: average GDP in malarious countries is five times lower than in non-malarious countries.30

Malaria in the Asia Paciﬁc: 1. Malaria in the South- East Asia Region of the WHO (SEARO) (India, Bangladesh, Indonesia, Myanmar, Thailand, Sri Lanka, Democratic People’s Republic of Korea, Bhutan, Maldives, Nepal and East Timor) Malaria is a major problem in Asia. In the SEARO region, there are 21 million clinically suspected cases annually.31 An estimated 1.2 billion people or 85% of the total population of the South-East Asian region are at risk of malaria - with 30% of these in moderate to high risk regions. Transmission of malaria in Asia is ‘unstable’. This means that the average person is not infected on a regular basis, and infections are unpredictable. As a result the population, particularly children, do not have immunity, and there is a high risk that if the disease is contracted, it will be serious. The malaria incidence in the SEARO region has remained at a consistently high rate for at least the last ten years. In contrast, Thailand, the only SEARO country that changed to ACTs prior to 2004, and which has available data,* has had a steadily decreasing incidence of malaria since 1997 when ACTs were introduced.32 In 2004, Bangladesh and Indonesia announced they would change to ACTs, as did nine states of north-east India.

They will need donor support to translate this policy change into a practical reality. The rest of India, East Timor, Nepal and Sri Lanka all continue to use non-ACT antimalarials. The proportion of malaria cases caused by Plasmodium falciparum (P falciparum, the parasite causing the severe form of malaria) is rising in the South-East Asian region. In India, with an estimated 15 million cases annually, the percentage of P falciparum rose from 38% in 1997 to 48% in 2001,33 and in Bangladesh from 43% in 1993 to 71% in 2001. In 2001 the proportion of P falciparum in the overall SEARO region was 45%.35 A major reason for the rise in P falciparum, is its increasing resistance to commonly used drugs. P falciparum is potentially lethal, and is the main form of malaria that is treated by ACT. As in Africa, surveillance measures in the SEARO are inadequate. Only one in every eight suspected cases is reported. Deaths are estimated at 27,000 annually. The WHO admits that the wide gap between estimated and reported cases and deaths shows that a large percentage of cases are “out [of] reach of the malaria control programme or beyond the health service coverage”36 2. Malaria in the Western Pacific Region of the WHO (WPRO) (Vietnam, the Philippines, China, Cambodia, Rep. of Korea, Laos, Malaysia, Papua New Guinea, the Solomon Islands, Vanuatu) In most countries of the WPRO region, malaria significantly declined in the period 1992 to 2000. This may be attributable to improved control activities, including change in some countries to effective treatments. There is widespread consensus that the change to ACT in Vietnam was a significant factor in the 98% drop in malaria mortality between 1992 and 2002.37 38 Cambodia has also had a steady drop in malaria incidence and deaths since it changed to ACTs in 1999.39 The total number of confirmed cases reported in WPRO in 2000 was 404,000. 2.28 million cases of malaria are described as ‘probable’ or ‘suspected’, with over half of these occurring in Papua New Guinea.# In the WHO 2000 data, of those confirmed cases that specify the malaria parasite, 68% are P falciparum.• Using these estimates, P falciparum would account for 1,550,000 cases annually. Papua New Guinea, the Solomon Islands and Vanuatu have by far the greatest incidence of malaria per person in the Western Pacific region. As of June 2004, all of these countries continued to use CQ + SP as their first-line malaria protocol. Papua New Guinea is using ACT as second-line treatment. Malaria in Papua New Guinea has not declined over the last decade as it has in most other WPRO countries, and in Papua New Guinea the proportion of P falciparum is rising. Aside from the Republic of Korea and China (North of Yunnan province), where only P vivax malaria is endemic, in all the other malaria endemic countries of WPRO, P falciparum is the predominant parasite.40

Myanmar has also changed to ACTs but only in 2002 and there is no data on malaria morbidity subsequent to this. In this calculation, where both ‘probable’ and ‘suspected’ cases are available, ‘probable’ cases are used. ‘Suspected’ are used if there is no data for ‘probable’ cases. Conﬁrmed cases were used for those countries without an estimate of ‘suspected’ or ‘probable’. • Includes China, PNG, Philippines, Solomons, Vanuatu, Vietnam * #

Antimalarial Drug Resistance

Unacceptable levels of treatment failure

“South-East Asia has the most drug resistant malaria parasites in the world”.41 42

At a meeting in Harare in August 2003, the World Health Organisation stated that clinical failure rates above 15% are unacceptable and should lead to protocol change. By this recommendation, for countries noted in the map (following page), studies have demonstrated that there are (at the very least) many regions where change in protocol should occur. Other regions have poor data on resistance at this time. While further resistance studies are important to monitor trends and to choose a suitable ACT partner drug, waiting for more research should not otherwise slow a change to ACTs. The beneﬁts of ACTs in providing the most effective treatment, slowing drug resistance and potentially causing decreased rates of malaria warrant a change of national protocol to ACTs for P falciparum in all countries in the Asia Paciﬁc.

According to the WHO’s SEARO ofﬁce, antimalarial resistant strains now affect all countries of the region with P falciparum transmission. “The problem is becoming acute with the progression from mono to multi-drug resistance”, according to SEARO.43 South-East Asia’s high density population and large population movements across borders create a high risk for rapid spread of multi-drug resistance, into some of the world’s most populous nations. P falciparum resistance to CQ has been documented in SouthEast Asia since the 1960’s and 1970’s, to SP since the 1980’s, and to meﬂoquine in the 1990’s.44 There is evidence of the spread of multi-drug resistant P falciparum throughout Thailand, Myanmar and Bangladesh and further westwards.45 An estimated 140 million people in the region are at risk of multi-drug resistant malaria. In the WPRO region, according to the WHO, “the steadily increasing drug resistance of P falciparum is now an important dimension of the problem in all endemic countries…”.46 The WHO states that resistance levels are particularly high in Cambodia, Yunnan Province of China, Laos, Myanmar, Thailand, Vietnam, Sabah in Malaysia, and Mindanao and Palawan in the Southern Philippines.47

The consequences of drug resistance Ineffective drugs result in increased treatment failure. Studies have shown a direct correlation between chloroquine failure and a rise in infant mortality.48 49 Treatment failure increases the risk of severe malaria and anaemia and leads to greater malaria transmission. Partially treated infections produce four to eight times more gametocytes (the infective form of the parasite) compared to successfully treated infections.50 The therapeutic effect of a drug for malaria is very dependent on the existing immunity of the host. In other words, the antimalarial is more likely to work if an individual has been exposed to malaria many times before, as the drug works synergistically with an individual’s own immunity. In the Asia Paciﬁc region individuals are very susceptible to severe infections because they have little immunity.51 Children are the most susceptible to death from malaria, because they have no immunity to support failing drugs.

“the steadily increasing drug resistance of P falciparum is now an important dimension of the problem in all endemic countries…”. 46 WHO Western Paciﬁc Region

Malaria protocols in the Asia Pacific today Asia Pacific countries can be divided into four groups based on their national malaria protocol. The first group are those who are now using ACTs as first-line treatment for P falciparum - these are Bhutan, Thailand, Myanmar, Cambodia, China and Vietnam. Group two are those who are considering changing their protocol to ACTs or are in the process of changing. These are the nine states of North-East India, Bangladesh, Indonesia, Laos and Papua New Guinea. These countries need support from the international community in ACT implementation. Despite recognition by the international community that ACTs are the treatment of choice for P falciparum, and despite rising P falciparum and drug resistance, many countries in the Asia Pacific still use less effective treatments. Group three countries are currently using a combination of drugs as first-line treatment for P falciparum, but this is a combination of medications with questionable efficacy. These are the Philippines, the Solomon Islands and Vanuatu, as well as Papua New Guinea at this time. Group four countries are using non-artemisinin monotherapy for P falciparum. These are the rest of India, East Timor, Nepal, Sri Lanka and Malaysia. All Asia Pacific countries with P falciparum need encouragement from the international community to move to ACTs as first-line treatment. Some countries such as the Philippines and Papua New Guinea, do use ACTs in patients for whom first-line treatment has failed. However this presupposes that ill patients, for whom first-line treatment has not worked, will be able to visit the clinic again for second-line treatment. This is not the reality in areas that are often remote, with poor, often uneducated patients and understaffed clinics.

“In poor countries like ours, children have only one chance. They struggle just to visit a health service, and if they get the wrong drug the first time, they are then found dead.” Dr. Fred Binka, Professor of Epidemiology, University of Ghana.* “Empirical treatment with first-line anti-malarials [CQ or SP] alters the clinical profile of resistant P falciparum, making it milder temporarily, delays in confirming the diagnosis and leads to high mortality”. Mehta 199852

Quoted in Donald G. McNeil Jr., New Drug for Malaria Pits U.S. Against Africa. New Yok Times May 28, 2002

Therapeutic failure rates of commonly used anti-malarials (also see Annex 5.)

India: CQ 64 - 94%, SP 38 - 57%

Bangladesh: CQ + SP 38%, SP + Qu failure 13%, Mef + Art failure 3.5%

Laos: CQ 36 - 45%, SP 25% Philippines: CQ 25 - 75%, SP 25% PNG: CQ 73 - 84%, AQ 22 - 24%

Solomon Islands: CQ 20 - 50%

Sri Lanka: Known CQ resistance Vanuatu: CQ 28% Irian Jaya/West Papua: CQ 75 - 95%, SP 15 - 63%

Malaysia: CQ 63.3%, SP 47.4%

East Timor: CQ 58%

Indonesia: CQ 47%, SP 22% Sources (See Annex 5 for details) : Bangladesh: Chittagong, MSF 2003, East Timor: Ezard 2003, India: Assam, MSF 2001, Indonesia; Central Java, Maguire 2002, Irian Jaya: Baird 1995, 1997,2002, Hadya 2001, Iwa 2003, Taylor 2001, Tjitra 2001, Laos: Mayxay 2003, Schwbel 2003, Malaysia:Lokman Hakim 1996, Philippines: WPRO, PNG: WPRO, Solomon Islands: WPRO, Sri Lanka: WPRO, Vanuatu: WPRO

National Malaria Treatment Protocols in the Asia Paciﬁc, as of July 200453 ◆ Group 1: Countries using ACTs as ﬁrst-line for P falciparum Country

Malaria species

National Protocol Clinical malaria

Conﬁrmed P falciparum

Treatment failure

Conﬁrmed P vivax

Bhutan

Pf, Pv

Coartem

Q (7d)

Thailand

Pf, Pv

Art (3d) + Mef

Q+Tet (7d)

CQ+PQ

Myanmar

Pf, Pv

Art+Mef

Art(3d)+Mef

Q (7d)

CQ+PQ

Cambodia

Pf, Pv

Art (3d) +Mef

Q+Tet (7d)

China,Yunnan, Hainan

Pf, Pv

CQ/Artm (5d)

Artm/Art (5d)

Art/Artm (7d)

CQ+PQ (5d)

Vietnam (Nth)

Pf, Pv

Art (5d) +PQ / CV8 + PQ#

Art (3d) +Mef

CQ +PQ (5d)

Vietnam (other)

Pf, Pv

Art (5d)

Art (3d)+Mef

Q+Tet (5d)

CQ+PQ (5d)

Group 2 Countries considering changing or in the process of changing protocol to ACTs (June 2004)* Malaria Species

Clinical Malaria (old protocol)

Conﬁrmed P falcip(old protocol)

Treatment failure(old protocol)

P falcip (New protocol)

Bangladesh

Pf, Pv

Coartem

India (9 Nth East states)†

Pf, Pv

CQ + PQ

Art + SP

Indonesia

Pf, Pv

Art+ AQ

Laos

Pf, Pv

CQ or SP

CQ + SP

SP/Q (7d)/ Art (5d)

Art+ Mef

PNG

Pf, Pv

CQ or AQ (<5yo) + SP

CQ/AQ + SP

Art (7d) + SP

Country

Conﬁrmd P vivax

CQ + PQ

CQ + PQ (14d) CQ + PQ (14d)

Photo © Roger Job

Group 3 Countries that are using a non-ACT combination as ﬁrst-line treatment for P falciparum Country

Malaria species

Philippines

Pf, Pv

Solomon Isl

Pf, Pv

Vanuatu

Pf, Pv

National Protocol Clinical malaria

Conﬁrmed P falciparum

Treatmnt failure

Conﬁrmed P vivax

CQ + SP + PQ

Coartem

CQ + PQ (14d)

CQ + SP

Q (3d) + SP

CQ + PQ (14d)

CQ + SP

Q (7d)

CQ + PQ (14d)

CQ + SP

Group 4 Countries that are using non-artemisinin single-drug treatment as ﬁrst-line for P falciparum Country

Malaria species

National Protocol Clinical malaria

Conﬁrmed P falciparum

Treatmnt failure

Conﬁrmed P vivax

East Timor

Pf, Pv

CQ + SP

Q (7d)

CQ + PQ

India (general)

Pf, Pv

CQ + PQ

Nepal

Pf (7%),Pv

Sri Lanka

Pf, Pv

CQ + PQ

Malaysia

Pf, Pv

CQ + PQ (day3)

Q(7d) + T (7d)

CQ + PQ (14d)

Note ‘Clinical’ malaria is malaria that is diagnosed based on signs and symptoms without the use of a biological test. ‘Confirmed’ malaria is diagnosed based on microscopy or rapid diagnostic test. ‘d’ (eg 5d) refers to number of days of treatment Pf- P falciparum, Pv- P vivax, PQ - Primaquine, AQ – Amodiaquine, Q – Quinine, Art – Artemisinin/Artesunate, ArtmArtemether, Mef- Mefloquine, T- Tetracycline, Coartem™ - Art + Lumefantrine. CV8- combination dihydroartemisinin, piperaquine, trimethoprim. See Annex 1 for details about P vivax, and P vivax resistance in the Asia Pacific Note these protocols are rapidly changing. Some spaces are left where the author was unable to confirm the current protocol. It is uncertain which of these protocols Vietnam is using. * Note, at this time it is unknown where ACTs will fit into the national protocol, whether for clinical or confirmed treatment, whether first-line or second-line. † These are Arunachal Pradesh, Nagaland, Manipur, Mizoram, Tripura, Meghalaya, Assam, West Bengal and Orissa ◆ #

Photo ÂŠ Sebastian Bolesch

What works “WHO, on the advice of international experts, recommends the introduction of combinations of drugs to replace single drugs (monotherapy) in the treatment of malaria…. WHO recommends in particular, the use of drug combinations containing artemisinin compounds — artemisinin-based combination therapy — ACT for short.” World Health Organization, Statement, February 2002 54

What is artemisinin? Artemisia annua is a Chinese herb from which artemisinin is extracted and chemically converted to diverse derivatives. Artemisinin derivatives have been in widespread use for malaria treatment in South East Asia for the past decade, and have been extensively studied. Used in combination with another antimalarial they have been shown to cause a faster clinical and parasitological cure than any other antimalarial treatment. Studies in Asia and elsewhere have shown a clear beneﬁt in terms of the reduction of risk of treatment failure, superior pharmacodynamic action (reduction in parasites and fever) and reduction in gametocytes (the infectious form of the parasite).55 56 57 58

‘Artemisinin and its derivatives.. are the most potent and rapidly acting of the antimalarial drugs’ Nick White, 199959 # Artemisinin and its derivatives have several characteristics that make them excellent malaria medicines. 1. It reduces parasitaemia faster than any other antimalarial drug, ten times faster than quinine. It reduces the total parasite count 10,000 fold in 48 hours compared with 100-1000 fold for other antimalarials.60 2. Used for three days in combination with another antimalarial, it substantially reduces the risk of treatment failure (by 75%), and of progression from uncomplicated to severe malaria.61 62 3. It relieves fever faster than any other antimalarial (generally in one day). Patients feel better and return to work and school sooner. #

4. It reduces gametocytes more rapidly and to a greater extent than any other antimalarial. Gametocytes are the infective form of the malaria parasite. They are ingested from the infected person’s blood by the mosquito and enable malaria to be transmitted to other people. Artemisinin derivatives cause a roughly 90% reduction in gametocytes,63 where many other antimalarials do not reduce or even, in the case of SP, increase gametocyte carriage.64 65 66 5. Artemisinin derivatives in tablet form are well absorbed by mouth and are not unpleasant to take. They can also be given by intravenous or intramuscular injection, in a oncedaily administration. In combination with another effective antimalarial, treatment is only for three days, similar to other treatments. 6. It has few side effects. 7. There are no reports of severe toxicity in humans. The artemisinin derivatives have been given to millions of people and studied in thousands. Some artesunate combinations have been studied widely (such as with meﬂoquine and lumefantrine), and others to varying degrees, but generally they are all considered safe.67 68 69 However, there is still not enough evidence to allow their use in the ﬁrst trimester of pregnancy. 8. There is no known clinical resistance to artemisinin and its derivatives, despite the fact that it has been used extensively for the last decade in South East Asia, and previously for centuries in China.

Nick White is Professor of the Wellcome-Mahidol University Oxford Tropical Medicine Research Programme and a world expert in malaria treatment

Photo © Stephan Gross Rüschkamp/MSF

Artemisinin derivatives slow development of drug resistance Artemisinins act rapidly on parasites and the drugs do not remain in the bloodstream for long. Most parasites are therefore destroyed before drug concentrations drop to sub-therapeutic levels, reducing the chances that parasites will be exposed to low, less effective levels of the drug. In this way resistance to artemisinin is limited.74 75 When artemisinin derivatives are combined with an additional effective antimalarial, the remaining parasites are then killed by therapeutic concentrations of the co-drug.

‘There are compelling reasons to believe that resistance to the available antimalarial drugs would be slowed or prevented by the addition of artemisinin or one of its derivatives’ Nick White, 1999 76 #

Artemisinin Combination Therapy (ACT) It is now generally accepted that malaria treatment, like treatment of TB and HIV, should be through a combination of drugs, each effective, each with an independent mode of action and each acting on a different biochemical site. This is not only a more effective treatment, but also vastly reduces the likelihood of resistance developing. Both drugs must have low rates of resistance, otherwise the protective effect of having two drugs will be lost.

ACT use in the Asia Paciﬁc may reduce the number of cases of P falciparum malaria Most parts of the Asia Paciﬁc have low rates of malaria transmission. Consequently the population has low immunity and, therefore, individuals are generally symptomatic if they are infected with malaria. This is the ideal situation in which to treat with ACTs. With most patients symptomatic when they are ill, a high percentage of those infected can be treated, reducing the pool of gametocytes which can infect the community.

In Thai refugee camps, documented mefloquine resistance was reversed after several years of treatment with ACT (artesunate + mefloquine).77 Fast-acting artesunate eliminates the main biomass of parasites rapidly, leaving only 0.000001% of the parasite to be exposed to mefloquine alone. Hence the partner drug can easily overwhelm the remaining parasite and resistance does not develop.78 Once again, this process is most likely to occur in contexts of low malaria transmission, such as the Asia Pacific region. Parasites resistant to mefloquine die out as they are not transmitted enough. There is no evidence at this time, however, that this will occur with other companion drugs. The reduction in gametocyte production by ACTs is a further explanation for reduced development of resistance. Studies have demonstrated that treatment failures with other antimalarials (such as SP) are associated with increased production of gametocytes. This increase in infectivity is a powerful means by which resistant strains spread. Artemisinin derivatives, however, decrease gametocyte carriage by over 90%.79 80

Large trials in Thai refugee camps showed a six-fold decline in P falciparum cases after ACT was introduced.70 In Kwazulu Natal, South Africa, after ACTs were introduced along with new vector control measures, cases of P falciparum malaria dropped from 41,000 to 9,000 in one year, hospital admissions were cut by 82% and deaths by 87%.71 In Vietnam, the introduction of ACT as the malaria treatment protocol has contributed to a drop in malaria mortality from 2,600 in 1992 to 50 in 2002.72 73

Nick White is Professor of the Wellcome- Mahidol University Oxford Tropical Medicine Research Programme and a world expert in malaria treatment

Photo © Stephan Gross Rüschkamp

Malaria epidemiology, including patterns of transmission, drug resistance and mosquito behaviour, varies widely from country to country. Choice of treatment must be adapted to the speciﬁc setting.

Avoiding a malaria disaster ‘The evolution of resistance in P falciparum seems to be outstripping the development of new drugs’ Nick White Worldwide, and particularly in Asia, resistance to other antimalarials has developed rapidly. In north-west Thailand, significant resistance to mefloquine developed over four years, prior to introduction of ACTs.81 Even with a new highly effective treatment – artemisinin, if there are no effective drugs to combine it with, there will be no available treatment. This is a potential malaria disaster. Hence, ACTs should be deployed before there is resistance to the partner drug, so as to delay resistance to this drug, and to preserve the efficacy of artemisinin itself.

Choice of companion drug The following are the therapeutic options currently recommended by WHO: 1. artemether plus lumefantrine 2. artesunate plus amodiaquine 3. artesunate plus sulfadoxine/pyrimethamine (in areas where SP efficacy remains high) 4. artesunate plus mefloquine(for areas of low transmission) 5. amodiaquine plus sulfadoxine/pyrimethamine (only an option for areas where efficacy of both amodiaquine and SP remains high - almost entirely confined to West Africa) November 2003, ‘Position of WHO’s Roll Back Malaria Department on malaria treatment policy’82

Accurate diagnosis is critical A crucial element of effective treatment of malaria is proper diagnosis of the disease. In most of the Asia Pacific, diagnosing malaria based on symptoms alone is normal practice. This clinical diagnosis was actively promoted when malaria treatments were cheap, safe, and easy to use, and biological diagnosis was considered too complex and expensive. However clinical diagnosis is very inaccurate as symptoms of malaria are non-specific and may indicate the presence of other infectious diseases.83 Even with a doctor’s expertise, clinical diagnosis of malaria may be incorrect in over 60% of cases.84 Clinical diagnosis can therefore needlessly increase treatment costs. It may also play a role in the development of resistance. Accurate diagnosis of malaria using biological tests should be encouraged and supported as part of ACT implementation. Biological diagnosis can be done through microscopic examination or rapid tests. Microscopy is the ‘gold standard’. However it is time intensive and the equipment is costly, requiring skilled technicians. Rapid diagnostic tests (RDTs) using a simple “dipstick”, on which is placed a pinprick of the patient’s blood, can greatly facilitate diagnosis of malaria. They can be read in minutes, are simple to interpret, and are easy to use in areas where medical and laboratory facilities are minimal or non-existent. Sensitivity and specificity in tests such as ‘Paracheck’ are comparable to microscopy in the field setting, with some limitations. See “The future of malaria treatment”, pg 21

The WHO estimates worldwide demand for ACTs to be 131 -219 million treatments by 2005… Current production capacity was estimated (in April 2004) at 25- 50 million treatments for 2004…86

Photo © Olivier Bonnet

Making ACT a reality ‘Expanding access to ACT is increasingly a matter of life and death for people at risk of malaria ..[we are] committed to discontinuing support for the use of ineffective medicines and actively working toward the implementation of ACT as quickly as possible’ “ACT Now” malaria symposium Joint Statement. Implementation

Urgent scaling-up of ACT production

In 2004, Bangladesh, Indonesia, Laos and nine states of northeast India all changed their national malaria protocol to ACTs. Papua New Guinea is also considering ACTs at this time. These countries will all need support to implement this change as quickly as possible.

Demand for ACTs by the ﬁrst countries that have changed their national protocol is already stretching the limits of global supplies. The WHO estimates worldwide demand by 2005 to be 131 -219 million treatments, depending on whether only public health systems are stocked, or if all malaria cases are counted (public + private).85 Current production capacity was estimated (in April 2004) at 25- 50 million treatments for 2004.86 This capacity is rapidly rising, however it is nevertheless not keeping up with demand. An urgent scaling-up of cultivation of the Artemisia annua plant (for planting in late 2004) and of extraction facilities will be needed to meet this demand. Cultivation of Artemisia annua can occur if the climate is appropriate. Most of the worldwide production of ACTs today occurs in South East Asia - particularly China, India and Vietnam.

Technical support is needed to determine which ACT to use. Health workers at all levels need to be trained in the appropriate use of ACTs, including dosages for children, safe use during pregnancy and the use of artemether for severe malaria. Health workers will also need to be educated about the beneﬁt of using accurate biological diagnostic tests as opposed to clinical signs and symptoms to diagnose malaria. The community needs to be educated about ACTs, particularly the importance of being accurately diagnosed and taking the full course of treatment. The distribution and storage of ACTs and RDTs depends on factors such as the shelf lives of the drugs and monitoring tools as well as their temperature requirements. The shelf lives of ACTs are 2-3 years compared with 3-5 years for CQ and SP, and many RDTs are heat and moisture sensitive. Therefore, distribution of drugs and RDTs to peripheral health centres must be appropriate and match demand. Increased drug regulation and packaging that hinders counterfeiting will be required, as this is already a major problem in Myanmar, Cambodia, Vietnam, Laos and Thailand (See Annex 2). Clearly health systems and distribution will require support from donors. Asia Paciﬁc countries will need donor support to pay for ACTs and diagnostic tests. Continual monitoring is essential. Country studies are required to monitor adherence of patients to the full treatment, and to check for rare side effects of drugs. Although some ACT combinations have been extensively studied, (such as Coartem™ and amodiaquine-artesunate), for others there has been relatively little research, so monitoring needs to be ongoing. Use of artemisinins in pregnancy is still unclear, as is suitability of antimalarials for prophylaxis in pregnancy in different malaria settings.

Donors can support quality drug production at a national and international level. Cultivation of Artemisia annua needs to be increased quickly as cultivating and processing of the raw material takes almost a year. While many Asian manufacturers comply with international standards and are already exporting ACTs, other manufacturers will need support to improve production standards and quality control. Producers need financial support to upgrade the capacity of extraction and processing of the raw material, and technical support in order to meet international quality standards for raw materials. Financial and technical support is also required for the production of ACTs in tablets in combined blister packs or coformulated tablets. Donors need to support drug producers by pooling orders and providing start-up funds, so that producers can meet the upcoming global demand without taking large financial risks. For example, in Vietnam, farmers are willing to plant additional acreage of this cash crop if they can be assured of demand.ß (See pages 19 and 20 for more on challenges for ACT producers). Pooled orders and secure finance will help to establish a viable market for local producers. UNICEF has committed to making an estimate of likely future global needs and leading a strategy to avoid shortages. An international procurement strategy, led by UNICEF, the Global Fund and Roll Back Malaria can ensure lowest prices and maximise availability. However, it will take political will, financial support and expressed commitment from donors to support this.

* Personal communication with MSF pharmacist Margriet den Boer, observation from MSF ﬁeld trip to Vietnam March 2003 ß Daniel Berman. Observations from MSF ﬁeld trip to Vietnam, March 2003.

Photo © Leila Kramis

be subsidised. MSF estimates that provision of ACT drugs (based on accurate diagnosis) for all Asia Pacific countries that need it today would cost about US$10.7 million a year at current drug prices.◆◆ Cost of rapid diagnostic tests is difficult to estimate, as their use would depend on clinical suspicion. Today RDTs are available for US$0.50 each. To put this in perspective, the United States’ aid budget is US$8.5 billion.87 The 2003/2004 Australian aid budget was AUD$1.89 billion.88 Use of ACTs will quickly pay for itself. Introduction of Coartem™, an ACT which is particularly expensive, in Kwazulu Natal, South Africa, has resulted in significant savings as a result of reduced cases of uncomplicated malaria and severe malaria requiring hospitalisation.89

Donor support for ACTs: how far does it go?

Donors can encourage producers to become more proactive in obtaining WHO drug pre-qualification for their antimalarials. This is a process whereby drug producers and their products are assessed and certified if their standards are satisfactory. According to its policy, the Global Fund aims to finance only WHO prequalified products from 2005, or drugs registered in ICH or PIC countries.◆ However, at present only one fixed-dose combination ACT (Coartem™ made by Novartis), and one single artesunate preparation (Arsumax made by Sanofi), have been pre-qualified by the WHO. The WHO pre-qualification process has made a call for “expressions of interest” to producers of ACTs, and products and facilities are currently undergoing WHO examination. The process is, however, slow as some producers do not meet the required standards for their products and progress is being jeopardised by a lack of human, financial and technical resources within the WHO prequalification project. Better resourcing of the WHO prequalification project is urgently needed.

ACT ﬁnancing The cost of ACTs is currently much higher than the previous “gold standard” treatments, such as chloroquine monotherapy. The lowest quotes to humanitarian and government organisations for combination therapy artesunate-amodiaquine have been about US$1.50 per adult treatment,# compared with US$0.10 for CQ or SP. While at this time the price of ACTs has risen due to shortages, MSF estimates that the price of the artesunate-amodiaquine combination will decrease in the future, as production increases. ACTs need to be available to the people that need them. This means that they need to be free or highly subsidised, and available in poor rural communities. Otherwise, patients will buy substandard treatments or partial treatments from private pharmacies which are less likely to work and will encourage counterfeiting and drug resistance. In areas where there are no public health facilities and many patients access their medicines from the private sector, privately sold ACTs need to

The Global Fund to Fight AIDS, Tuberculosis and Malaria, established in 2001, is now the largest financer of ACTs. From the first three rounds of grants, US$41 million has been committed for ACTs worldwide•, enough to fund six million treatments per year. The Global Fund is actively supporting the move of many countries to ACTs as first-line treatment, including countries that received funding for non-ACT drugs in Rounds one to three. These countries are encouraged to review the efficacy of the initial drugs, and are supported to change protocol if there is significant resistance in that country. Over four rounds, the Global Fund has committed to spend US$280 million for malaria in total in east and south Asia and the Pacific.91 Global Fund ACT funding has jumped in Round four, with an additional 123 million ACT treatments to be funded over five years. Today, of a total of 144.9 million ACT treatments to be funded by the Global Fund (over all rounds, over 5 years), 140.7 million are earmarked for Sub-Saharan Africa.† On paper at least, there is now a consensus in support for ACTs. At a 2004 malaria conference in New York, UNICEF and the WHO stated: ‘Expanding access to ACT is increasingly a matter of life and death for people at risk of malaria ..[we are] committed to discontinuing support for the use of ineffective medicines and actively working toward the implementation of ACT as quickly as possible’92 USAID states on its website that to meet the challenge of growing antimalarial drug resistance it “recommends artemesinin based combination therapy (ACT) for treatment of falciparum malaria”.93

ICH: International Conference on Harmonisation. PIC: Pharmaceutical Inspection Convention # Price quoted to WHO and MSF at various times in 2002-2003 by several producers. ◆◆ MSF estimate, based on 10,810,000 P falciparum cases (45% of 21 million cases in SEARO, 68% of two million cases in WPRO), 35% cases under 5: 1/4 dose, 15% cases 5-15: 1/2 dose, 50% cases adult. Cost US$1.50/adult. This calculation assumes a direct correlation between proportion of adult dose and proportion of adult price. * Chairman, Wellcome Trust Southeast Asian Tropical Medicine Research Units and Professor of Tropical Medicine, Mahidol and Oxford Universities • Data on ACT spending from Round 4 is not available. Note additional money for ACTs will come from re-allocating funds from Rounds 1-3 for non-ACT antimalarials † Round 4 slides for press, powerpoint. Provided by Global Fund External Relations advisor, Tim Clark. ◆

Photo © Olivier Bonnet

However in 2003, UNICEF spent a total of only US$1 million on ACTs,94 and, with USAID funding, has in the past few years spent large sums of money on chloroquine and SP. The UK and Australian aid agencies, DFID and AusAID, have no official policy on which type of malaria treatment they endorse, instead supporting the malaria protocol as chosen by the recipient country. Unfortunately this approach in the past has meant tacit support for cheaper, less effective treatments. The Global Fund has announced that it will re-program money towards ACTs and accelerate disbursement so that countries can meet treatment needs. Grantees are encouraged to apply for more funding if needed. For re-programmed Rounds 1-3 this has meant funds for five years of non-ACT antimalarials have been accelerated to pay for two years of ACT treatment. There is a funding shortfall. An initial estimate of the worldwide cost for ACTs is US$1.2 billion over five years, with US$400 million required over the first two years.* Only 4.2 million ACT treatments have been earmarked for all developing countries outside of Sub- Saharan Africa over the next five years. Reducing malaria morbidity and mortality, in the Asia Pacific and worldwide, will require further significant political will and financial assistance from donors.

Who is producing ACT now?† The main challenge today to increased production is the limited supply of raw materials. Increasing quantities of raw materials and scaling-up production of artemisinin-based combinations is technically possible. What is needed is political will. Below is a list of some the major producers of artesunate tablets and combination treatment.

ASIAN PRODUCERS Indian producers Cipla produces artesunate tablets and an artesunate (AS) + amodiaquine (AQ) blister. Cipla also has an AS + SP blister pack in development. Ipca produces amodiaquine-artesunate blisters and artesunate tablets. Both Cipla and IPCA are under evaluation for pre-qualiﬁcation of their antimalarial drugs by the WHO and are close to meeting those quality standards. Challenges for Indian producers are to: 1) Meet WHO prequaliﬁcation and quality requirements 2) Scale-up production of artesunate and ACT combinations

“People keep bringing up the fact that ACTs are expensive, as if it were a reason not to start using them. But what would you rather do - waste money on old cheap drugs that you don`t know work or fund a more expensive tratment that will save lives?” Nick White** ** Chairman, Wellcome Trust Southeast Asian Tropical Medicine Research Units and Professor of Tropical Medicine, Mahidol and Oxford Universities. * ‘ACT NOW’ malaria symposium Key Points. New York 2004. Internal MSF document, Daniel Berman † Information from MSF malaria pharmacist Margriet Den Boer July 2004

VIETNAMESE AND CHINESE PRODUCERS

EUROPEAN PRODUCERS

Along with the Chinese, the Vietnamese are currently the leading cultivators of Artemisia annua and also extract and synthesize artemisinin derivatives. In Vietnam, several of these raw material producers, such as Hanoi College of Pharmacy and Saokim Vietnam, are investing in meeting international standards for the manufacture of tablets and are likely to offer cheaper ﬁnished products in the near future.

Novartis (Switzerland), sells a ﬁxed-dose ACT combination (artemether/lumefantrine) produced in China under the name Coartem™. This is now pre-qualiﬁed by the WHO and is on the WHO essential drug list. The discounted price to the WHO and NGOs is US$2.40 per adult dose. Coartem™ is sold at about US$12 in private pharmacies in developing countries.

In China, the Guilin factory produces 50mg artesunate tablets for Sanofi. These have been WHO pre-qualified. Guilin produces the same artesunate (under their own name for the Asia-Pacific market) which is registered in China, India, Pakistan, Thailand, Burma, Vietnam, Laos, Cambodia and Papua New Guinea. Sanofi distributes the product in African countries. Chongqing Holley (Holleykin), a Chinese pharmaceutical company, is the present supplier of artesunate-amodiaquine for Indonesia and cultivates Artemisia annua on a very large scale. Holleykin is also collaborating with the Medicines for Malaria Venture (MMV) on the development of a dihydroartemisinin/ piperaquine fixeddose combination (Artekin).

The challenges for Novartis are to: 1) Simplify the WHO process for obtaining access to discounted Coartem™. 2) Reduce the “public” and private prices of Coartem™ for developing countries 3) Increase Coartem™ production Sanoﬁ-Synthélabo, based in France, have produced an artesunate-amodiaquine blister. The artesunate component is WHO pre-qualiﬁed.

Challenges for Chinese and Vietnamese production are to:

The challenges for Sanoﬁ- Synthélabo are to:

1) Rapidly scale-up cultivation of Artemisia annua and subsequent production of quality approved, cheap raw materials

1) Stop aggressively marketing the stand-alone artesunate product; and

2) Produce ﬁnished products that meet WHO pre-qualiﬁcation requirements

2) Begin marketing the combination blister in needed quantities at an affordable price

3) International agencies and donors to make accurate estimates of future needs, and pool funds so that the necessary investments to upgrade production can occur without ﬁnancial risks to the producers.

Mepha, based in Switzerland, also produces artesunate tablets. Mepha has developed a combination blister of artesunate and meﬂoquine for the Asian market and for the African market (different dosages) as well as a rectal artesunate formulation

AFRICAN PRODUCERS African producers will also be part of the solution. For example, several Kenyan pharmaceutical companies have started production of artesunate tablets and the Artemisia annua plant is now being grown in Kenya and Tanzania. Other African companies are likely to follow suit in the near future.

Photo © Serge Sibert/Cosmos

The future of malaria treatment 1. Accurate and affordable diagnostics

What Médecins Sans Frontières believes needs to be done

Presently, the main rapid diagnostic test (RDT) used by MSF in the field is ‘Paracheck’, produced by Orchid (India). Recent alterations to ‘Parahit’, a similar type of test produced by Span (India), have made the two tests equivalent in efficacy and ease of use. While there are many different tests, there are some common limitations that need to be overcome: - RDTs may still give positive results for up to three weeks after effective treatment - There are no RDTs today that are able to pick up both P falciparum and P vivax, each with a high degree of sensitivity and specificity. This is necessary in a context where different species of malaria exist (such as the Asia Pacific). - The current ‘dipstick’ RDT tests are vulnerable to degradation by heat and moisture, which can occur particularly in peripheral health facilities where protective storage facilities are limited.95 It is likely that two different types of tests will be needed. The first must be able to reliably say whether or not malaria is present, regardless of species. ‘Pan pLDH’ tests, which test for enzymes made by malaria parasites fill this role, but require further research and development work. The second type of test specifically checks for P falciparum. ‘Paracheck’ (an ‘HRP2’ test) is one of these. In the Asia Pacific context, a combination of the most useful features of both tests is required. There is a need for quality assurance and pre-qualification of RDTs by the WHO, so that advice can be provided to developing countries about which test to use. There is an urgent need for research and development into new rapid diagnostic tests with improved performance in varying contexts. The price of RDTs, which today is US$0.50 per test, could be reduced by competition and bulk purchasing. 2. New Fixed-dose Combinations Artemisinin derivatives are already widely available as single drugs (not as part of combinations) in private pharmacies in many parts of the Asia Pacific for people who can afford them. This availability in monotherapy invites the development of resistance, although non has yet been reported. Hence, ACTs should be dispensed ideally as combined tablets (fixeddose combinations (FDCs)) or in blister packs. This creates a treatment standard, makes complete treatment easier for patients and delays resistance. (See the above section on presently available combination ACTs and Annex 3). From past lessons learnt in the malaria field, we know that no drug lasts forever, and increased levels of research are urgently needed to develop brand-new drugs for malaria treatment. Unfortunately, few major multinational pharmaceutical companies have ongoing malaria drug development projects, and the non-profit sector has so far been handicapped by insufficient funding. A public private partnership, Medicines for Malaria Venture (MMV), claims that the biggest limiting factor for its work is lack of funds. As a result, no new chemical entities against malaria seem likely to become available in the next ten years. More political and financial support for research and development of antimalarial drugs is therefore critical.

Information from Christa Hook, malaria specialist, MSF July 2004

All countries in the Asia Pacific should change to ACTs as first-line treatment for P falciparum. This requires: • The World Health Organisation to push for implementation of its own recommendation to switch to ACT • National governments to change their malaria protocols to ACTs for P falciparum, and support use of accurate diagnostics • Donors to proactively support ACTs and RDTs, financially and politically, instead of tacitly supporting the status quo, and wasting money by funding drugs that don’t work. Implementation of ACTs needs to occur quickly and to provide access to effective treatment for all. This requires: • Governments to match political commitment to change to ACTs with effective national implementation of the new malaria treatment protocols • International agencies and donors to provide technical and financial support to facilitate treatment implementation in the areas of: - Drug procurement - Education about ACTs and RDTs - Drug distribution - Continuing monitoring - Drug regulation - Widespread use of accurate diagnostics • Donors to support the additional costs of ACT treatment and diagnosis • ACTs to be provided free or at an affordable price for patients in public health facilities. Governments and donors should consider subsidising ACTs in the private sector. High quality artemisinin production must be scaled-up. This requires: • Donors to contribute to increasing output, competition and sustainability of production by assisting international and domestic drug suppliers to upgrade production standards. This can be achieved through financial support, technology transfer and technical assistance. • International donors, UNICEF, WHO procurement and the Global Fund to fight AIDS, Tuberculosis and Malaria to pool needs and make advance bulk orders of artemisinin in anticipation of rapidly increasing demand, and to bring down prices. • International and/or regional pre-qualification of malaria drugs by the WHO needs to be augmented to assist countries in identifying quality drug sources. In the future, the Global Fund will only support drugs that have been pre-qualified by the WHO. Research and Development must continue, to result in: • Cheaper and more effective RDTs to be developed and prequalified, with WHO support. • Sustained development of new malaria drugs especially in fixed-dose combinations.

Photo ÂŠ Catrinus Van Der Veen

Annex 1 Plasmodium Vivax Many countries in the Asia Pacific region have two different strains of malaria - the less serious type, Plasmodium vivax (P vivax), as well as Plasmodium falciparum. While P vivax is not lethal , it causes a huge, often unrecognised morbidity in the Asia Pacific. Treatment is different for these two types of malaria. Ideally accurate diagnosis is used to distinguish between them so that appropriate medicines are used as well as to delay development of drug resistance. For confirmed cases of P vivax, where drug resistance is minimal, MSF uses chloroquine (CQ). CQ + primaquine (PQ) is used in areas where there are low rates of infection. Primaquine is used to clear the liver of dormant P vivax infection, which CQ is unable to do. However PQ requires 14 days of treatment. In places where rapid re-infection with P vivax is very likely, it is debatable whether the repeated use of primaquine is a viable option.

It is impossible to differentiate clinically between P falciparum and P vivax, especially at the early phase. Moreover, many patients are infected with both parasites. Hence, where diagnosis is clinical only, and it is a region where both P vivax and P falciparum are present, ACTs should be used in case the infection is P falciparum.† Unpublished data from Thailand and Indonesia strongly point to the efﬁcacy of CoartemTM, as well as amodiaquine-artesunate for P vivax. Chinese data suggests that piperaquine-artesunate is also effective.

Photo © Steve Sandford

P vivax chloroquine resistance has appeared in a patchy distribution in India, Indonesia, Myanmar, Papua New Guinea and the Solomon Islands.96 It is likely that the burden of P vivax chloroquine resistance is at this time not fully realised. P vivax is ‘relatively resistant to primaquine in Indonesia and in Oceania’. For an alternative treatment for P vivax, sulfadoxinepyrimethamine (SP) has not been as effective as chloroquine. P vivax has intrinsic resistance to sulphadoxine.98 99 Even if P vivax is sensitive to pyrimethamine, SP leads to slow parasite and fever elimination.100 In those areas where there is CQ/ PQ resistance, Professor Nick White* of the Shoklo Institute in Thailand recommends amodiaquine, artesunate + meﬂoquine or Coartem™.

Personal correspondance with Professor Nick White * Nick White is Professor of the Wellcome- Mahidol University Oxford Tropical Medicine Research Programme and a world expert in malaria treatment †

Annex 2

Annex 3

Fake and substandard drugs

New Fixed-Dose Combinations

The WHO estimates that 10% of global pharmaceutical commerce is in counterfeit drugs.101 This has not received significant attention, with drug companies hesitant to publicise the problem and erode market confidence. Confidence in the health system by patients is eroded however when they do not benefit from their treatment.

MSF is supporting the Drugs for Neglected Diseases Initiative (DNDi) in developing FDCs of artesunate/amodiaquine and artesunate/meﬂoquine, which should become available in 2006. The WHO, Bordeaux University and Pharmaguinhos Brazil are collaborating on these projects, along with many other partners. Cipla is also producing an artesunate-amodiaquine FDC which should be registered and available by 2006.

Fake antimalarial drugs are a significant concern in Asia. Studies have shown high levels of fake artesunate in Myanmar, Cambodia, Vietnam, Laos and Thailand, where 38% of shop bought tablets contained no artesunate whatsoever.102 A study in Cambodia of 133 drug vendors and pharmacies in 12 market places revealed that 71% sold fake artesunate and 60% sold fake mefloquine.103 Informal health providers are typical sources of first-line treatment for most patients in remote Cambodian communities, with the fake drugs often preferred over the genuine drugs as they are cheaper. In a recent study in Southern Laos, 19 of 22 pharmacies offered only counterfeit drugs.104 In a survey of pharmacies in the Philippines, 8% of drugs bought were fake.105 While there are no large surveys assessing the degree of this problem, from these papers and informal MSF staff accounts, substandard drugs are clearly widespread, and are likely to lead to loss of life. Cambodia has responded with a public education campaign, which has ‘driven the sale of counterfeit antimalarials underground’.106 New counterfeits however include fake holograms and are virtually indistinguishable to the eye from the originals. A study done by the WHO in 1999 in Vietnam and Myanmar suggested that the prevalence of substandard drugs was a more significant problem than that of counterfeit medicine, with 11% of 500 samples failing a quality test.107 A 1998 WHO Vietnam study demonstrated major weaknesses in the capacity of Hanoi regulators to pick up deficiencies in the quality of the drugs sold.108

MMV and GlaxoSmithKline have been collaborating on the development of artesunate/LapDap™ (chorproguanil/dapsone), which should be available in 2007. The Korean company Shin Poong and TDR* are also expected to make available a ﬁxed-dose combination of artesunate/ pyronaridine in 2007. Synthetic versions of artemisinin derivatives are also an important element of ACT development, as they will eliminate the labour-intensive process of plant cultivation and extraction. They are likely to make up a major part of the next phase of antimalarial drug development. For example, the MMV is developing synthetic peroxides with a group of university researchers, and a semi-synthetic product - artemisone - with the pharmaceutical company Bayer. These products could become available by the end of the decade.

Photo © Andrew Schechtman/MSF

These studies show a clear need for further large surveys of the prevalence of fake and substandard drugs, their public health impact, and identification of effective countermeasures.109 Awareness must be followed up by action. Solutions will require monitoring, improvement in regulation of drug supply and distribution, and development of simple, cheap and effective methods to identify fakes. A number of tests have already been developed.110 111 Public education is essential, and prices of the genuine drug should be lowered as much as possible to reduce the benefits of counterfeiting. There needs to be international cooperation and legal controls must be enforced.112 113 These are areas in which the experience and expertise of donor governments and international organisations could have a significant impact.

Chongqing Holley (a Chinese pharmaceutical company), Sigma Tau (Italian), Oxford University and a public private partnership, Medicines for Malaria Venture (MMV), are collaborating on a dihydroartemisinin/piperaquine ﬁxed-dose combination (also known as Artekin®) which should be available by 2006.

* UNICEF, UNDP, World Bank, WHO Special Program for Research and Training in Tropical diseases

Annex 4 ACT blisters and FDCs for the Future AS + SP blister Dafra (Belgium)

AS + AQ blister Dafra

Artemisone (semi-synthetic endoperoxide) Bayer + MMV

Art: artemether, AS: artesunate, AQ: amodiaquine, DHA: dihydroartemisinin, LUM: lumefantrine, MQ: meďŹ&#x201A;oquine, LapDap: chlorproguanil/dapsone, PPQ: piperaquine, SP: sulphadoxine/pyrimethamine. FDC: Fixed Dose Combination, GSK: GlaxoSmithKline, MMV: Medicines for Malaria Venture, TDR: WHO Programme for Research and Training in Tropical diseases *DHA/PPQ is already being used in China and Vietnam

Annex 5 Country Specific Data on Resistance Levels The following is malaria resistance data on countries in the Asia Pacific which have not yet, or only recently changed to ACTs as their first-line treatment. Note all trials are of uncomplicated Plasmodium falciparum unless stated otherwise. See tables on pages 10 and 11 for information on national protocols for each country.

Bangladesh According to the WHO there is P falciparum resistance to CQ and SP in north-east and south-east Bangladesh (data from 1993).114 These areas border India and Myanmar. The proportion of cases caused by P falciparum is rising – up to 71% in 2001. P falciparum has increased 2.5 fold over the last 10 years.115 According to WHO, ‘malaria cases are grossly underreported’.116 90% of malaria in Bangladesh occurs in the east, in Chittagong Division (CHT), an area with 7% of the total population. Conﬁrmed malaria cases make up 30% of patients seen in MSF clinics in the Khagrachari district of this division. For example, there were 9,000 conﬁrmed cases seen in ten months prior to October 2003. In this region 85% of malaria is P falciparum and 15% P vivax. Malaria in this region is of moderate endemicity.

According to Van Den Broek (2004) ”Drug resistant strains are reported from the three Chittagong Districts and adjoining areas of the eastern border”.117 In September 2003, MSF completed a three-armed trial in Khagrachari, Chittagong division. The therapeutic failure rates were: CQ+SP – 38.5%, Meﬂoquine +Art - 3.5%, Art + Lumefantrine (Coartem™) – 7.6%. The two artemisinin treatments had under 4% gametocytaemia (level of the infectious form of the parasite in the blood), compared with greater than 40% gametocytaemia for CQ + SP.118 Studies done in 1996-1998 for P falciparum in Cox’s Bazaar indicated drug resistance to CQ alone (56%), to CQ + SP (21%) and a resistance of 13-16% to Quinine 3 days (Q3) + SP.119 120 121 Rahman (2001) assumes that the RI failures (resistance level 1, where the parasite is initially totally cleared from the blood but then reappears after 7 days of treatment), are all re-infections. In other words Rahman assumes that these cases are new infections as opposed to recurrences of the original infection as a result of treatment failure (recrudescences). If these cases were recrudescences, the rate of resistance to CQ was 77%, and to Q3 + SP was 34%.122 Note that several other studies using PCR (a method of multiplying genetic material to the point where it can be closely examined) have shown that a high percentage of recrudescences – late treatment failures, occur after day 14, and hence are missed by many studies.123

Photo © Yuki Asada

East Timor A 28-day study of SP + Quinine by MSF in 2002, in the Khagrachari district (CHT) found 12.9% treatment failure after being checked by PCR. This study found a high frequency of CQ and SP resistant genotypes. In other words the genetic make-up of the parasites was no longer typical and had become resistant to CQ and SP.124 According to several studies with strong evidence of high parasite resistance from in vitro (drug effectiveness in the lab) and in vivo (measuring the effect of the infection and treatment on the person rather than in a laboratory) studies, CQ should be removed from the malaria national protocol.125 126 SP is also likely to be increasingly ineffective. Unpublished data from the Bangladesh Government prior to 1993 showed 59% treatment failure rates for CQ, 44% for SP.127 MSF genotyping showed changes to the genetic make-up of the malaria parasite which confer resistance to SP.128 Three-day treatment with quinine is concerning as quinine is slow acting, and may be unable to eliminate all SP resistant parasites in this time. A recent in vitro study at Cox’s Bazaar found a surprisingly high level of meﬂoquine resistance, surpassing the level found in Myanmar.129

In the three year period since reporting started from Oct 1999 to Sept 2002, there were 300,000 suspected malaria cases. This accounted for 15% of all consultations. Malaria is responsible for over 40% of deaths in East Timor. P falciparum is 50-70% of cases. There were 134,000 cases of malaria in 2000/2001. Surveillance systems in East Timor are very poor, and there is incomplete coverage by the health system, so true ﬁgures are likely to be much higher.130 According to the Round two Global Fund application, P falciparum is resistant to CQ in East Timor, and there are indications of resistance to pyrimethamine. A 2000 study demonstrated 58% CQ treatment failure (28 out of 48 patients). Patients with CQ treatment failure were given SP and this successfully treated all at day 14.131 Note, as discussed previously, a 14-day study may miss treatment failures that occur between day 14 and day 28. The Global Fund application also describes a very limited technical capacity in the Department of Communicable Diseases.132 In Round two, East Timor received $3 million over ﬁve years from the Global Fund. None of this money has been earmarked for ACTs.133

India Malaria was nearly eradicated from India in the early 1960’s but the disease has since re-emerged as a major public health problem. According to the WHO there is P falciparum resistance to CQ and SP in northern and central India, with epicentres of infection in the north-east states bordering Myanmar, such as Assam and in other states such as Orissa. Orissa alone contributes 15-20% of malaria cases to the national total. The WHO also describes foci of resistance to mefloquine and to quinine. North-east India shares a long border with Myanmar, which has very high malaria drug resistance. Epidemics or outbreaks of malaria became more common in the late 1990’s (1997-2001),134 though the overall number of cases annually has not changed significantly over the last few years. P falciparum comprises 40% of an estimated 15 million cases nationally (in 2000) and is a rising fraction of all cases. A 1997 report by the Indian National Anti-Malaria program (NAMP) partly attributed the increase in malaria mortality during the 1990’s to CQ resistance.135 Long term surveillance by the Indian Malaria Control Program, supported by RBM, of over 15,000 P falciparum cases nationwide, showed 23% resistance to chloroquine, ranging from RI response (initial total removal of parasite from blood followed by recovery and reappearance of parasite more than 7 days after treatment) to RIII response (no significant reduction of parasite in the blood whatsoever). 51% of cases had an indeterminate response to chloroquine. In these cases it could not be determined whether they were sensitive to the drug, or that they were RI cases.136 Another study estimated cumulative resistance of 24% to CQ in the entire country.137

A number of reports documenting CQ resistance are available. A recent in-vivo study in Arunachal Pradesh (bordering Myanmar) found 83% therapeutic failure to CQ and 44% therapeutic failure to CQ + SP. Reduction of parasites and fever were slowest with CQ. The study concluded that CQ and SP resistance was increasing in the Indo-Myanmar border areas.138 Studies in Mumbai have shown a rising resistance to CQ (from 15% in 1993 to 54% in 1996) and 13% to CQ +SP.139 140 Kshirsagar (Mumbai, 2000), showed a 95% 28-day cure rate for ACT (artemether plus lumefantrine: Coartem™) compared to a 19.7% cure rate for chloroquine. He noted the need for new effective anti-malarial drugs.141 Studies in Rajasthan and Orissa looking at in-vitro tests have also shown P falciparum resistance levels to CQ of 51%-95%.142 143 Worryingly, SP resistance is also growing, but there have been few studies. Ahmed (2004), found that “the mutations associated with SP resistance continue to be progressively increasing”.144 SP resistance has developed within 5 years when used in monotherapy elsewhere.145 An unpublished MSF four-armed sensitivity study in Assam 2001 of CQ, SP, meﬂoquine and meﬂoquine+artesunate found 94% CQ treatment failure, 57% SP treatment failure (in Sontipur) and 64% and 38% treatment failure for CQ and SP respectively (in Karbi Anglong) after 42 days follow-up.*

* Drug Sensitivity of falciparum malaria: A clinical study in Assam state. Dr Patricia Campbell. Accessed from Jean Paul Guthmann, Epicentre, Paris.

Indonesia There were an estimated 3.1 million cases of malaria in Indonesia in 2001, 42% of which were P falciparum. Most cases occur in the eastern outer islands.147 While Indonesia changed protocol to ACT in 2004, because of its highly decentralised health system, this change may require significant support for the provinces, who are responsible for drug procurement and implementation. There are foci of chronic hypoendemicity in central Java. As prevention measures such as residual spraying have declined and with rising drug resistance, these areas ‘threaten to seed the reintroduction of endemic malaria on Java’.148 In 2000 an epidemic occurred in one district of the Menoreh Hills in central Java. The annual parasite incidence rose from an average of 5/1,000 residents per year (1986-1995) to 44.5/1,000.149 There is a high therapeutic failure rate in this region for both P falciparum and P vivax to both CQ and SP. In 28-day studies, using PCR confirmation of diagnosis and measuring whole blood drug concentrations, the therapeutic failure rate for P falciparum was 47% to CQ and 22% to SP. For P vivax, CQ failed in 18% of cases, and SP in 67%.150 Chloroquine is no longer adequately clinically effective for treatment of P falciparum in Eastern Indonesia, according to Tjitra (2001).151 The movement of non-immune migrants into areas of higher endemicity puts them at high risk of infection, which may be also more severe.152 A 1998 study in Nias Island, off the north-west coast of Sumatra, found 83% P falciparum resistance to SP at day 28, and 21% P vivax resistance to CQ.153 There are well-defined foci of chloroquine resistant P vivax in Sumatra. P vivax is also ‘relatively resistant to primaquine in Indonesia’.154

Irian Jaya/West Papua According to the WHO, north-east Irian Jaya is an area of moderate transmission. Difference in study results may partly reﬂect different levels of immunity within the population, which occur due to resettlement from other areas of Indonesia. Low immunity to malaria as a result of little previous exposure, results in a higher risk of treatment failure. In three trials in north-east Irian Jaya, CQ therapeutic failure rates for P falciparum ranged from 80-95%.155 156 157 158 Three studies of CQ for P vivax showed therapeutic failure rates of 22%, 70% and 84%.159 160 161 A 2002 randomised controlled trial also in north-east Irian Jaya comparing SP alone with SP + artesunate, found treatment failure of 15% with SP alone versus 4% with artesunate+SP. This study had a 28-day follow up as well as genotyping to establish whether cases were re-infections or a result of recrudescence. There were signiﬁcantly less gametocytes in patients after treatment with the artesunate combination than in the SP alone group.162 Two studies in north-west Irian Jaya found CQ failure rates for P falciparum of 89% and 75%.163 164 A further 63% failed subsequent treatment with SP.165

In Indonesia, according to the WHO, “drug resistant falciparum malaria is spreading.. Emergence of mono and multi-drug resistance in P falciparum and chloroquine resistance in P vivax may have contributed to this rise in malaria”.146 Photo © Serge Sibert/Cosmos

Laos

Malaysia

Laos has a signiﬁcant malaria problem, especially along border areas. WPRO describes 40,000 laboratory conﬁrmed cases annually. Surveys during malaria months have found high percentages of the population are P falciparum positive, 90% of whom are children.

According to WPRO, malaria has declined in incidence in Malaysia over the past decade, from 52,000 conﬁrmed cases in 1996 to 11,000 in 2002.

P falciparum is responsible for 95% of malaria infections in Laos. According to WPRO, in Vientiane (bordering Thailand) RII/RIII failure rates to chloroquine were 35%, 75% and 46% in 1995, 1998 and 2000 respectively. SP RII/RIII failure rates in Vientiane were 17% in 1995, 43% in 1998 and 15% in 2000.166 MSF supports the main hospital of Sekong province in Southern Laos, abutting Vietnam. In 1999 malaria represented 18% of outpatient cases and 32% of cases hospitalised. In a study of CQ for uncomplicated P falciparum in Sekong province (with 28day follow up and PCR analysis), MSF found 32-39% treatment failure.167 Other data indicates significant resistance to CQ. Two recent studies in southern Laos, Mayxay (2003) and Schwobel (2003), found 36% and 45% treatment failure respectively to CQ, and both found 18% treatment failure to SP.168 169 The latter study had only a 14-day follow up so may have underestimated failure rates. Both studies found a far higher proportion of failure rates in children, who lack immunity. This was up to five times higher than adult failure rates. Hence studies with both adults and children are likely to underestimate the risk of treatment failure in children, and their subsequent severe illness. A high proportion of the treatment failures in Laos are high grade failures, in other words treatment failures that respond minimally to treatment and have a significant risk of progression to severe disease.170 171 172 The Schwobel study found a 16% therapeutic failure rate at 14 days for SP + CQ - no significant advantage over SP alone. The Mayxay study concurred, stating “combined CQ and SP treatment, if it were effective, would be likely to have a short period of usefulness in Laos, because resistance to both drugs is well established”.173 Generally, chloroquine resistance appears to be widespread and of homogeneous severity throughout Laos. In its projects in Laos, MSF recommends SP or mefloquine in combination with artemesinin.

However malaria remains an important public health issue in remote areas of Malaysia - particularly in the provinces of Sabah and Sarawak. Signiﬁcant drug resistance levels are found in both east and peninsular Malaysia.174 A 1996 study in peninsular Malaysia found chloroquine resistance was 63% and SP resistance 47%. The large majority of treatment failures had high grade resistance (ie treatment had little if any impact on the progression of the disease).175 Despite the fall in malaria incidence, malaria related deaths have increased, which may be partly explained by failing drugs.

Papua New Guinea According to WHO, 75% of malaria cases in Papua New Guinea are caused by P falciparum. In 2000 there were 81,000 confirmed cases of malaria, but 1.36 million ‘probable’ malaria cases, in a total population of 5.2 million. There were 617 deaths in Papua New Guinea as a result of malaria in 2000. Malaria is the second leading cause of death and second leading cause of hospital admissions in Papua New Guinea .176 There has been a minor improvement in the incidence of malaria since the early 1990’s, but a slight rise in death rate, though with fluctuating levels of surveillance it is difficult to compare. The microscopy service is poor. Laboratory diagnosis is available in only 25% of health facilities, so diagnosis of malaria is usually clinical.177 Malaria is endemic in the coastal lowland areas. As a result of population movements and man-made sites of stagnant water, malaria has spread into Papua New Guinea’s most populated regions - the highland fringe areas above 1,200 meters, where it causes epidemics with high mortality because of low immunity in the population.178

Studies in the 1990’s showed resistance of 73-84% for CQ and 22-24% for amodiaquine (AQ) in Madang province.179 A 1996 study in Madang found 69% of cases had treatment failure to CQ and to amodiaquine by day 21.180 An in-vitro study in Central Province in 1995 found all of 30 samples were resistant to chloroquine.181 With this high CQ resistance, SP is effectively acting alone in treating malaria, and cannot be expected to remain highly effective for long. Moreover SP is unsuitable for epidemics as it causes an increase in gametocytes and hence increased malaria infectivity. Amodiaquine and chloroquine are similar compounds, and cross-resistance between AQ and CQ has been reported. There are well-defined foci of CQ resistant P vivax in northern Papua New Guinea. PNG has received malaria funding from the Global Fund of over 20 million dollars over five years. Only US$300,000 has been allocated for ACTs in the first two years, money after this has not yet been allocated.182 Most funding is going towards RDTs, bednets and improved surveillance.183 The WHO is planning to conduct a three-armed study (CQ + SP, Artemisinin + SP and Artekin), the results of which will be ready by the end of 2005.184

The Philippines

The Solomon Islands The Solomon Islands have the highest malaria incidence per capita in the Asia Pacific, one of the highest in the world: 176 cases/1,000 people annually in 2001. There are 68,000 confirmed cases of malaria per year, of which 68% are P falciparum. In 2001 there were 76,000 cases, 2000 of which were severe malaria.186 There have been few resistance studies, but the WHO describes CQ resistance of 20-32% in the outer islands and 50% in Guadalcanal. As a result of recent social unrest leading to large population movements there are concerns that malaria may rise (in 1991 there were 400 cases/1,000 annually). Subsequent to the economic collapse (in 1999), the Solomon Islands` government funding for the malaria program has been severely curtailed. The 2002 Global Fund application by The Solomon Islands states “there are no funds for field operations or supplies”. Donors have also significantly reduced their support for the malaria program. A Global Fund grant was awarded for malaria in the Solomon Islands and Vanuatu, of USD $4.9 million over five years. This will go towards combination treatment CQ + SP, malaria diagnostics, nets and increased community education. AusAID has been a significant funder of antimalarial drugs in the Solomon Islands.187

In 2000, the Philippines reported 36,000 confirmed cases and 334,000 suspected cases of malaria, with 536 deaths. A WHO source claims that ACT is often used as first-line treatment, though according to the protocol it is officially used for secondline treatment.

Sri Lanka

There is little data on in vivo drug resistance. According to WPRO, a study in Mindanao has shown CQ resistance above 25% and SP resistance at 25%. In Palawan in vitro tests have shown a rise in drug resistance from 14% in 1992 to 45% in 1996, and in vivo failure rates from 39% to 75%.185

As a result of large population movements and disrupted health systems caused by ongoing conflict, there have been significant epidemics over the past decade. In 2000, there were 210,000 reported cases of malaria and 290,000 predicted cases in Sri Lanka, with 28% of cases P falciparum. However the number of cases dropped significantly in 2001 to 66,000 cases, of which 16% were P falciparum. According to SEARO, there is known P falciparum resistance to CQ.188

According to SEARO, malaria in Sri Lanka has wide variations in transmission. In some places it is hyperendemic, in other regions it is unstable and epidemic.

Vanuatu The incidence of malaria has been rising since 2001, with 14,000 cases recorded in 2002. A study of 153 cases of P falciparum between 1988 and 1991 found 28% resistance to chloroquine.189

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Fund, Geneva Portfolio of grants in Papua New Guinea, Round three, malaria http:// www.theglobalfund.org/search/docs/3PNGM_702_0_full.pdf [Accessed 1 Sept, 2004] Personal communication with Dr Luo Dapeng, WPRO Papua New Guinea http://www.wpro.who.int/themes_focuses/theme1/focus2/t1f2phil.asp [Accessed on 30 April 2004] Portfolio of grants in Multi-country Western Paciﬁc, Round two, malaria http://www.theglobalfund.org/search/docs/2MWPM_19_124_full.pdf [Accessed 1 Sept 2004] Ibid http://w3.whosea.org/malaria/malaria.sea.htm [Accessed on 30 April, 2004] http://www.wpro.who.int/themes_focuses/theme1/focus2/t1f2vanuatu. asp [Accessed May 20, 2004]