Aus dem Institut für Medizinische Soziologie
der Heinrich-Heine-Universität
in Kooperation mit der Bayer Healthcare AG, Clinical Development, Wuppertal

The fight against Malaria in Malaria-Endemic Countries

Magisterarbeit

zur Erlangung des akademischen Grades

“Magistra des öffentlichen Gesundheitswesens (M.san.)”

vorgelegt von

Dr. Petra Heyen

Düsseldorf 2004

Table of Contents

0. TABLES AND FIGURES ... 3

1. LIST OF ABBREVIATIONS ... 4

2. INTRODUCTION ... 6
2.1 HUMAN MALARIA ... 7
2.1.1 Causative Parasites and their Life Cycle ... 7
2.1.2 Clinical Signs and Symptoms ... 10
2.1.2.1 General Clinical Features ... 10
2.1.2.2 Severe Falciparum Malaria ... 11
2.1.3 Diagnosis ... 12
2.1.4 Laboratory Findings ... 14
2.2 HISTORY ... 15
2.2.1 History of the Human Malaria Parasites ... 15
2.2.2 Geographical Malaria History ... 15
2.2.3 History of Malaria Handling ... 16
2.3 EPIDEMIOLOGY ... 17
2.3.1 Malaria Transmission ... 17
2.3.2 Prevalence and Incidence ... 18
2.3.3 Endemicity ... 19
2.3.3.1 Stable Endemic Malaria ... 20
2.3.3.2 Unstable and Epidemic Malaria ... 20
2.3.4 Epidemic preparedness, prediction and prevention of epidemics ... 21
2.3.5 Epidemiological information systems ... 21
2.3.6 Resistance Pattern ... 22
2.3.7 Travelers ... 25
2.4 MALARIA IN THE PEDIATRIC POPULATION AND PREGNANT WOMEN ... 25
2.4.1 Pediatric Population ... 26
2.4.2 Pregnant Women ... 27
2.5 MALARIA AS A DISEASE OF THE POOR ... 28

3. GLOBAL MALARIA CONTROL STRATEGIES ... 29
3.1 PREVENTIVE MEASURES ... 29
3.1.1 History of the Global Malaria Control Strategies ... 29
3.1.2 General preventative Measures ... 30
3.1.3 Vector Control ... 30
3.1.3.1 Insect repellents ... 30
3.1.3.2 Insecticide treated nets (ITNs) ... 31
3.1.3.3 Indoor Residual Spraying ... 32
3.1.3.4 Recommendations ... 32
3.1.4 Chemo-Prophylaxis ... 33
3.1.5 Vaccination ... 34
3.1.6 Other Preventive Measures ... 35
3.2 CURRENT TREATMENT APPROACHES ... 35
3.2.1 Benefits and Liabilities of Existing Anti-Malarial Drugs ... 36
3.2.1.1 Quinolines ... 36
3.2.1.2 Artemisinins ... 36
3.2.1.3 Antifolates ... 37
3.2.1.4 Antibiotics ... 38
3.2.2 Combination Therapy ... 38
3.3 TREATMENT POLICIES AND PRACTICES ... 39
3.4 MALARIA PREVENTION AND TREATMENT IN PREGNANT WOMEN ... 40

4. GLOBAL PUBLIC INITIATIVES – PUBLIC PRIVATE PARTNERSHIPS ... 43
4.1 WORLD HEALTH ORGANIZATION (WHO) ... 47
4.1.1 WHO Interactions with NGOs ... 48
4.1.2 WHO Essential Drugs ... 49
4.1.3 WHO and the Private Sector / Public Private Partnerships (PPPs) ... 49
4.2 SPECIAL PROGRAM FOR RESEARCH AND TRAINING IN TROPICAL DISEASES (TDR) ... 51
4.3 MEDICINES FOR MALARIA VENTURE (MMV) ... 56
4.4 ROLL BACK MALARIA (RBM) ... 58
4.5 GLOBAL ALLIANCE FOR VACCINES AND IMMUNIZATION (GAVI) ... 59
4.6 PROGRAM FOR APPROPRIATE TECHNOLOGY IN HEALTH (PATH) AND MALARIA VACCINE INITIATIVE (MVI) ... 60
4.7 WORLD BANK ... 62
4.8 BILL & MELINDA GATES FOUNDATION AS AN EXAMPLE FOR PRIVATE FOUNDATIONS ... 63
4.9 DONATION-DISTRIBUTION PARTNERSHIPS ... 64

5. HEALTH ECONOMY ... 66
5.1 MALARIA ASSOCIATED ECONOMIC MEASURES ... 66
5.2 COSTS OF ANTI-MALARIAL DRUGS ... 68
5.3 FINANCING OF ANTI-MALARIAL DRUGS ... 70
5.4 REGULATORY AGENCIES’ CONTRIBUTIONS ... 71
5.4.1 Orphan Drugs ... 71
5.4.2. Pediatric Laws ... 73
5.4.3 International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) ... 74
5.5 PHARMACEUTICAL INDUSTRY ... 75
5.5.1 Overview on Development of New Drugs ... 76
5.5.2 Development of New Anti-malarial Drugs ... 79
5.5.3 Glaxo Smith Kline (GSK) ... 82

6. DISCUSSION ... 84
6.1 THE CHALLENGE OF MALARIA IN ENDEMIC COUNTRIES ... 84
6.2 ROLE OF THE ENDEMIC COUNTRIES ... 86
6.3 PUBLIC-PRIVATE PARTNERSHIPS (PPPS) ... 88

7. CONCLUSION ... 90

8. REFERENCES ... 91

2. Introduction
Malaria is a life-threatening parasitic disease transmitted by mosquitoes. It was once thought that the disease came from fetid marshes, hence the name ‘mal aria,’ (bad air). In 1880, scientists discovered the real cause of malaria—a one-cell parasite called plasmodium. Later they discovered that the parasite is transmitted from person to person through the bite of a female Anopheles mosquito, which requires blood to nurture her eggs [84].

Malaria was eliminated from the United States and from most of Europe during the first half of the twentieth century as a result of changes in land use, agricultural practices, house construction and some targeted vector control. The development of the highly effective, residual insecticide Dichloro-Diphenyl-Trichlorethane (DDT) initiated a global eradication program in the 1950s and 1960s which was very successful in many countries such as India, Sri Lanka and the former Soviet Union. However, this success was not sustained because of the costs of the program, the resistance of many communities to repeated spraying of their houses and the emergence of resistance to DDT. Furthermore, with the exception of a few pilot schemes, no sustained effort was made to control malaria in sub-Saharan Africa, the main area of malaria endemicity in the world. The elimination of malaria from most of Europe and from North America and the failure of the global malaria eradication program led to a loss of interest in malaria for a period of about 25 years from the early 1970s to the late 1990s. Only 3 of 1,223 new drugs developed during the period 1975–1996 were anti-malarials [113]. Industry lost interest in the development of insecticides for public health use and support for research on malaria declined. Furthermore, in many malaria-endemic countries, national malaria control programs, established during the colonial period and sustained during the period when elimination of malaria was considered to be an achievable goal, collapsed. Thus, for many years, there was little change in mortality and morbidity from malaria, especially in Africa. Recently, the malaria situation has deteriorated and mortality from malaria is increasing in sub-Saharan Africa [37].

The past five years have seen a pronounced re-awakening of interest in malaria in the richer countries of the world. Statements on the need for greater efforts to control malaria have been made at a number of high-profile political meetings in Africa and in industrialized countries. Research scientists have had an important catalytic role in this process. In 1997, a meeting was held in Dakar, Senegal, attended by most of the small number of scientists undertaking malaria research in Africa and by their sponsors, which established priorities for a multidisciplinary program of research. [37].

At present, about 100 countries or territories in the world are considered malarious, almost half of which are in Africa, south of the Sahara. Although this number is considerably less than it was in the mid-1950s (140 countries or territories), more than 2,400 million of the world’s population are still at risk. The incidence of malaria worldwide is estimated to be 300–500 million clinical cases each year, with about 90% of these occurring in Africa — mostly caused by P. falciparum and secondly by P. vivax . The most important reason for the persistence of malaria in Africa is the presence of the vector Anopheles (A.) gambiae. A. gambiae feeds preferentially on humans and is long-lived, making it particularly effective at transmitting malaria from one person to the next. The entomological inoculation rate (EIR), a measure of the frequency with which an individual is bitten by an infectious mosquito, rarely exceeds 5 per year in Asia or South America. In contrast, EIRs of over 1,000 have been recorded in several parts of sub-Saharan Africa (“Hyperendemicity”). In savannah areas of West Africa, it is not unusual to collect in one room during the course of a single night several hundred mosquitoes of the A. gambiae complex, 1–5% of which are infectious. The task of interrupting transmission in such a situation is daunting [37]. Malaria is thought to kill between 1.1 and 2.7 million people worldwide each year, of whom about 1 million are children under the age of 5 years in Africa. These childhood deaths, resulting mainly from cerebral malaria and anemia, constitute nearly 25% of child mortality in Africa and take more than 2000 young lives every day in the world [1], [37], [99]. or one life every 30 seconds. Case fatality rates of 10–30% have been reported among children referred to hospital with severe malaria, although these rates are even higher in rural and remote areas where patients have restricted access to adequate treatment [94]. In endemic countries, one third of all clinic visits and at least a quarter of all hospital admissions are for malaria [1].

One of the biggest achievements in Public Health is the development of vaccines for polio and other diseases which has been funded publicly [56], and malaria should follow these examples.

Deaths from malaria in countries outside Africa occur principally in non-immune people who become infected with P. falciparum in areas where diagnosis and treatment are not available. One of the greatest challenges facing malaria control worldwide is the spread and intensification of parasite resistance to anti-malarial drugs. The limited number of such drugs has led to increasing difficulties in the development of anti-malarial drug policies and adequate disease management. The challenging task is to overcome resistance and develop safe and effective drugs as well as sustainable preventive measures mainly in young children and pregnant women [94]. As the disease mainly occurs in the poorest populations of the world the pharmaceutical industry in developed countries has little economic interest in the development of anti-malarial drugs (little chance of profits or only break-even point for investment). Therefore, a system of incentives has to be established in order to make drug development in this sector more attractive to the innovative pharmaceutical companies.

2.1 Human Malaria
2.1.1 Causative Parasites and their Life Cycle
Malaria is a protozoan disease transmitted by the bite of Anopheles mosquitoes.

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1 Africa Malaria Report 2003. World Health Organization/UNICEF 2003 . WHO/CDS/MAL/2003.1093 (http://www.rbm.who.int/amd2003/amr2003/amr_toc.htm)

37 Greenwood B., Mutabingwa T.: Malaria in 2002. Nature Vol 415, 670-672, 7 Februar 2002

56 Lob-Levyt J.: Round table discussion: a donor perspective. Bulletin of World Health Organization 79(8), 771-772, 2001

84 RBM Roll Back Malaria 2001–2010 United Nations Decade to Roll Back Malaria: What is malaria?

94 Ridley R.G.: Product R&D for neglected diseases. European Molecular Biology Organization, EBMO reports Vol 4, 543-5546, 2003

99 Sachs J., Malaney P.: The economic and social burden of malaria. Nature Vol 415, 680-685, 7 February 2002

113 Trouiller P., Olliaro P.I.: Drug development output from1975 to 1996: what proportion for tropical diseases? Int. J. Infect. Dis. 3, 61-63, 1998