Harvard University Initiative for Global Health Global Health Challenges Social Analysis 76: Lecture 9

Harvard University Initiative for Global Health Biology, Clinical Manifestations and Interventions Overview Plasmodium Life Cycle Clinical Malaria Acquired Resistance Preventive Interventions Treatment Interventions Global Distribution and Trends for Malaria Global Patterns of Malaria Distribution of Drug Resistance History of the Health System Response Challenges and Controversies

Harvard University Initiative for Global Health Malaria is a disease caused by a parasite of the genus Plasmodium. Clinical malaria is a major cause of childhood mortality and morbidity and also causes severe anaemia in pregnant women. Humans are infected through the bite of the anopheline mosquito. The parasite has a life cycle in the human involving the liver and red blood cells. Malaria

Harvard University Initiative for Global Health There are four types of human malaria falciparum, vivax, ovale, malariae. Two cause most human disease: Plasmodium falciparum and Plasmodium vivax. Malaria is a disease that requires the presence of a vector which in this case is the anopheline mosquito. Human Malaria

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Pathogenic species of Plasmodium cause acute febrile illnesses characterized by periodic febrile paroxysms occurring every 48 or 72 hours and a tendency to relapse of a period of months or even years. The severity of the attack is determined by the species and the strain, on age, genetic constitution, immunity, general health, nutritional status and use of antimalarial drugs. Clinical Malaria

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Thick and thin smears of blood can be used to detect Plasmodium. In developing countries, most malaria is diagnosed presumptively on the basis of fever and symptoms. False positives are common because in some endemic areas more than 50% of adults have parasites. Malaria Diagnosis

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Natural exposure to P falciparum gradually elicits, in human hosts, short-lived strain-specific malaria immunity: first to severe disease and death, and then to mild disease. Repeated infections are required to maintain immunity, which is both antibody and T-cell based. Acquisition of immunity in endemic areas explains why clinical episodes are often more severe in children in these communities. Impact of all intervention strategies requires long-term consideration of the consequences for acquired immunity. Acquired Immunity

Harvard University Initiative for Global Health 1) 1)Spraying air or surfaces (walls of homes) with insecticide that kills mosquitoes or their larvae. DDT was the main insecticide used until the 1970s. In the last month, WHO has again recommended domiciliary DDT spraying. 2) 2)Insecticide treated bednets (ITN) is a method of vector control that was developed in the early 90s which focuses vector control on the period when most anopheline bites occur. Vector Control

Harvard University Initiative for Global Health ITNs reduce under-5 mortality

Harvard University Initiative for Global Health Antimalarials can be used prophylactically to decrease the probability of developing infection or clinical episodes. These methods have been demonstrated to be effective in three target groups. Children – trials have shown substantial benefits in SSA. Some fear that prophylaxis for children may lead to increased mortality at older ages due to decreased acquired immunity. Pregnant women – the main benefits of even a limited number of doses of antimalarials are reduced incidence of severe anaemia and reduced low birth weight. Travellers Prophylaxis

Harvard University Initiative for Global Health The focus of most of this lecture is on malaria in endemic communities, endemic meaning where there is regular transmission each year. In some communities, malaria transmission may occur under unusual environmental circumstances (heavy rains) and inmigration of infected individuals. Individuals in these communities have not acquired immunity and are at high risk of severe malaria. Preventing the malaria epidemics requires surveillance and appropriate vector control and prophylactic interventions. Epidemic Malaria

Harvard University Initiative for Global Health Prompt treatment of clinical episodes decreases their duration and severity. In children, cerebral malaria requires extremely rapid treatment. The main strategy to avoid progression to cerebral malaria is to presumptively treat episodes early. Treatment has little or no effect on community transmission levels of malaria. Treatment

Harvard University Initiative for Global Health First antimalarial identified was the bark of the cinchona tree. Quinine was derived from this source. Chloroquine has been the mainstay of treatment for clinical episodes for the last 4 decades. Because of drug resistance it is no longer effective in many areas. Other agents such as SP have developed resistance rapidly. The most effective drug available today, artemisin, was developed from a Chinese traditional remedy. Artemisin based combination therapy (ACT) now recommended for many contexts. Antimalarials

Harvard University Initiative for Global Health Biology, Clinical Manifestations and Interventions Overview Plasmodium Life Cycle Clinical Malaria Acquired Resistance Preventive Interventions Treatment Interventions Global Distribution and Trends for Malaria Global Patterns of Malaria Distribution of Drug Resistance History of the Health System Response Challenges and Controversies

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Most of the malaria burden is from deaths in young children

Harvard University Initiative for Global Health In addition to being a major direct cause of death, exposure to malaria may increase risks of death and disability from other causes. Intervention trials and vector control historically have indicated larger reductions in mortality than simply expected on the basis of malaria deaths. The population prevalence of the Sickle-cell gene also implies higher mortality from malaria than direct deaths alone. Heterozygotes for the sickling form of hemoglobin have some malaria protection. Homozygotes have sickle cell anaemia. Direct and Indirect Effects

Harvard University Initiative for Global Health Because of the difficulty of measurement of malaria in a population, the trend for malaria is unclear. Parasitemia is not that helpful in monitoring trends. Perhaps, antibodies to merozoite surface protein can be used in the future? Some suspect it is worsening because of 1) the rise of drug resistance, 2) worsening vector control and declining national malaria program effectiveness, 3) limited verbal autopsy evidence from some surveillance sites. Malaria may be worsening or even if it is staying steady, as a relative share of the burden in children it will be increasing. What is the Trend of Malaria?

Harvard University Initiative for Global Health In vitro drug resistance is often higher than treatment failure rates. Treatment failure rates, however, have reached levels over 50% in many parts of Eastern and Southern Africa. SP resistance appears to be spreading rapidly. Artemisin and Artemisin combination therapy (ACT) appears to be the only major agent with little resistance at the population level. ACT costs times more than chloroquine. Chloroquine Resistance

Harvard University Initiative for Global Health Source: WHO Regional Office for Africa, Chloroquine treatment failure in Africa

Harvard University Initiative for Global Health Biology, Clinical Manifestations and Interventions Overview Plasmodium Life Cycle Clinical Malaria Acquired Resistance Preventive Interventions Treatment Interventions Global Distribution and Trends for Malaria Global Patterns of Malaria Distribution of Drug Resistance History of the Health System Response Challenges and Controversies

Harvard University Initiative for Global Health From late 19 th century through to WWII era, malaria control was primarily through environmental modification to decrease exposure to anopheline mosquitoes. Many high-income countries (including US, Italy) controlled malaria through these means. Resurgence of interest in such measures, but the natural potential of malaria transmission appears to be much greater in sub-Saharan Africa than Europe or North America. Pre-DDT Control

Harvard University Initiative for Global Health Residual spraying with DDT was extremely successful in the Caribbean, Sri Lanka, many parts of India and initially in sub-Saharan Africa. WHO launched a global eradication programme that was the centerpiece of global health in the 1960s. Rising DDT resistance, concerns about the environmental impact of DDT, difficulty of maintaining high levels of vector control in poor environments lead to the collapse of the program. Malaria control programs have been held up as the poster child of the ‘vertical’ disease control program. Global Malaria Eradication

Harvard University Initiative for Global Health In 1998, WHO launched the Roll-Back Malaria program. The central objective was to create an effective partnership of all actors (bilaterals, multilaterals, national governments and NGOs) to increase resources and political/managerial focus on malaria. RBM strategy: 1) Prompt effective treatment; 2) ITN; 3) Prophylaxis for pregnant women through antenatal clinics; 4) epidemic management. Roll-Back Malaria

Harvard University Initiative for Global Health During last 6 years, drug resistance has spread. Most countries are still using chloroquine as a first-line agent. Rising discussion in the academic literature on the need to switch to ACT. This switch is resisted because of the enormous cost implications. A further $500 million needed a year to fund switch. Responding to bad press, GFATM in July, 2004 announced all grantees must use ACT. World Bank has increased lending for malaria since April RBM: Prompt Treatment

Harvard University Initiative for Global Health Insecticide treated bednets (ITN) is the main component of the strategy that may have a major impact on the burden of malaria. ITN cost less than $5 a bednet which has a lifetime of 3-5 years. Uptake is related to cost as well as culture. Progress so far has been limited. Recent national campaigns for example in Togo, Uganda, Benin and Eritrea some linked to immunization programs appear to have been successful at more rapidly raising coverage. RBM: ITN

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2006 WHO endorsed the use of DDT for residual indoor spraying “Indoor spraying requires strong support from governments and the creation of a centralized infrastructure to properly train personnel, to educate communities, to coordinate spraying and to make sure that coverage is sufficient to make an impact. And, crucially, governments need to ensure that DDT is not diverted for use for agricultural purposes.” (Nature 2006) Ramifications for malaria control not yet clear – will there be a return to major residual indoor spraying? Return of DDT

Harvard University Initiative for Global Health Biology, Clinical Manifestations and Interventions Overview Plasmodium Life Cycle Clinical Malaria Acquired Resistance Preventive Interventions Treatment Interventions Global Distribution and Trends for Malaria Global Patterns of Malaria Distribution of Drug Resistance History of the Health System Response Challenges and Controversies

Harvard University Initiative for Global Health Several malaria vaccines have been tested in clinical trials. Recent candidates hold out promise but we are years from having a vaccine in general use. New interest in adding SP prophylaxis to childhood immunization programs. The long-term viability of this strategy is questioned because of drug resistance and the potential for raising mortality later in life. Global debate on subsidizing the production costs of ACT. New Strategies

Harvard University Initiative for Global Health Does ACT have a long enough shelf life to reach the rural dispensing networks? Does the high cost of ACT mean the saturation strategy used for chloroquine will be very wasteful? Why are we failing to be more aggressive about using ITN? It is vastly cheaper than ARVs but it is not getting as much attention. Why has RBM been a failure so far? Weak leadership, lack of resources, or inadequate technical strategy? Some Debates