ISBN-10:
0309092183
ISBN-13:
9780309092180
Pub. Date:
09/09/2004
Publisher:
National Academies Press
Saving Lives, Buying Time:: Economics of Malaria Drugs in an Age of Resistance

Saving Lives, Buying Time:: Economics of Malaria Drugs in an Age of Resistance

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ISBN-13: 9780309092180
Publisher: National Academies Press
Publication date: 09/09/2004
Pages: 384
Product dimensions: 6.00(w) x 9.00(h) x 1.00(d)

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SAVING LIVES, BUYING TIME

Economics of Malaria Drugs in an Age of Resistance


NATIONAL ACADEMIES PRESS

Copyright © 2004 National Academy of Sciences
All right reserved.

ISBN: 978-0-309-09218-0



Chapter One

Executive Summary

INTRODUCTION For more than 50 years, chloroquine silently saved millions of lives and cured billions of debilitating episodes of malaria. Falciparum malaria has always been a major cause of death and disability-particularly in Africa-but chloroquine offered a measure of control even in the worst-affected regions. At roughly 10 cents a course and readily available from drug peddlers, shops, and clinics, it reached even those who had little contact with formal health care.

Now chloroquine is increasingly impotent against falciparum malaria, and malaria's death toll is rising. Yet desperate patients still turn to chloroquine and other failing, low-cost malaria medicines because they lack the few dollars needed to buy new, potentially life-saving treatments. Chief among these new treatments are the "artemisinins," paradoxically both an ancient and a modern class of drug that can still cure any form of human malaria. If falciparum malaria sufferers had the same broad access to artemisinins that currently exists for chloroquine, the rising burden of malaria in the world today would halt or reverse.

The crisis is both economic andbiomedical. On the economic side, to state the obvious, the era of cheap and effective antimalarial treatment may have ended, but poverty in sub-Saharan Africa and malarious countries elsewhere, has not. Thus, although artemisinins at a dollar or two per course are both inexpensive by U.S. or European standards and highly cost-effective by any norm, neither national governments nor consumers in most malaria-endemic countries can afford them in quantities that remotely approach the world's current consumption of chloroquine-roughly 300-500 million courses of treatment per year.

Biomedically, today's malaria situation also is precarious. The artemisinins are the only first-line antimalarial drugs appropriate for widespread use that still work against all chloroquine-resistant malaria parasites. If resistance to artemisinins is allowed to develop and spread before replacement drugs are at hand, malaria's toll could rise even higher.

The challenge, therefore, is twofold: to facilitate widespread use of artemisinins while, at the same time, to preserve their effectiveness for as long as possible. The central recommendation of this report-a sustained global subsidy of artemisinins coformulated with other antimalarial drugs-is the most economically and biomedically sound means to meet this challenge.

Two caveats must accompany this report and its recommendations. Even in the best of times when chloroquine was still effective, it did not reach everyone. As a result, at least one million people died each year from malaria, most of whom could have been saved by adequate treatment. Merely substituting artemisinin combination therapies (ACTs) for chloroquine is not the whole answer. Expanded access to effective treatment will also be needed if we are to gain ground against malaria.

Second, malaria control requires a suite of interventions to prevent disease: insecticide-treated bednets, environmental measures to limit mosquito breeding, and intermittent preventive treatment of high-risk asymptomatic individuals (eventually, malaria vaccines will join the armamentarium). If proven preventive interventions are combined with ACTs, we can expect even greater progress generally, while, in some areas, good drugs plus good control can actually reduce malaria transmission to near zero. Commitments of international funding substantially greater than the sums needed for an antimalarial drug subsidy but still modest in terms of their return on investment are therefore needed to advance malaria control overall.

However, this report does not address malaria control comprehensively; that is a task for others. This committee was asked to recommend economic mechanisms to make effective antimalarial drugs widely accessible in order to stem the deaths from drug-resistant malaria that now occur day in, day out. When it comes to saving lives, effective drugs will always be a mainstay while malaria continues to threaten humankind.

THE CURRENT MALARIA SITUATION

Although malaria was once a global scourge, by the mid-20th century it was eliminated as a major health problem in much of the world. The hard core remained, however, and in many parts of sub-Saharan Africa, malaria still is the largest contributor to the burden of disease and premature death. To a lesser degree, malaria also remains an important health problem in parts of south Asia, South America and other tropical regions of the world.

Chloroquine began losing its effectiveness against falciparum malaria in Asia during the 1960s and 1970s. Looking back, we know that mutant parasite strains with genetically-mediated chloroquine resistance initially arose in areas of low malaria transmission (Asia and South America) and reached east Africa by the 1980s. Over the next 2 decades, sub-Saharan Africa-where real malaria control had never been achieved, yet chloroquine was effectively treating illness and preventing deaths, especially among children-was hard hit. After declining from post-World War II through the mid-1990s, death rates from malaria are now increasing in Africa. The failure of chloroquine, followed by the waning efficacy of other low-cost drugs such as sulfadoxine-pyrimethamine (SP), appears to be the main cause.

It was the original emergence of drug resistance in Asia that inspired development of the artemisinins, an extraordinarily effective family of antimalarials derived from a traditional Chinese medicinal herb. Although they are nonproprietary, artemisinin compounds still cost more to produce than chloroquine because plants must first be cultivated and harvested and the drugs then extracted and processed rather than simply synthesized from inexpensive chemicals.

Over the past 2 decades, the use of artemisinins in Asia has grown continuously, but demand in Africa has remained negligible. At first the reason was that chloroquine and SP were still effective in Africa, but now the reason is strictly economic: artemisinins cost about 20 times more than chloroquine, and African countries and their citizens cannot afford their higher price tag. The lack of global demand for artemisinins has, in turn, led to a desultory pace of production and impeded the economies of scale and improved production methods that would substantially reduce prices, were larger markets and competition in place.

This is the crux of the current crisis: African countries are increasingly adopting artemisinin combination therapies (ACTs) for first-line treatment of uncomplicated malaria; however, without external funding neither governments nor consumers-who bear most of the cost-can afford them.

The IOM committee took these realities into account in devising a concrete plan for reversing the trend of increased malaria morbidity and mortality while preserving effective drugs for the future. To understand the reasoning behind the recommendations of the committee, it is important to appreciate certain biological aspects of malaria, particularly as they relate to the development and spread of drug resistance.

DRUG RESISTANCE AND THE NEED FOR COMBINATION THERAPY FOR MALARIA

The evolution of drug resistance is an inevitable consequence of genetics and natural selection when drugs are used against microbial pathogens, including the protozoan parasites that cause malaria. As effective and robust as the artemisinin drugs are today, it is only a matter of time before genetically resistant strains emerge and spread. However, practical steps can be taken to push that day further into the future. The logic is as follows.

In the case of any antimalarial drug, the new development of drug resistance is a rare event: a chance genetic change in a single parasite in a single patient. But once that single malaria parasite generates multiple descendants, the math changes. Now, mosquitoes can acquire resistant parasites from a single individual and transmit them to other people. The subsequent spread of a robust, resistant clone would be similar to the spread of any malaria strain.

The way around this dismal scenario derives from the fact that a nascent resistant parasite will not survive and proliferate in an infected person's bloodstream if a second effective antimalarial drug with a different mechanism of action is simultaneously present. The key, therefore, to preserving the artemisinins is to eliminate their routine use as "monotherapies," and to treat patients with uncomplicated malaria (the vast majority of cases) with "artemisinin-based combination therapies" (ACTs) instead. ACTs equal an artemisinin derivative plus another unrelated antimalarial drug, ideally coformulated in a single pill so that individual drugs cannot be knowingly or inadvertently used as monotherapies. Combining drugs in this way-already an accepted practice in the treatment of tuberculosis and HIV/AIDS infection-minimizes the likelihood that a single parasite with drug resistance will propagate and spread. Since all drug-resistant microbes are capable of crossing national borders, delaying the development of resistance through this strategy creates a benefit, otherwise known as a "global public good," for people living both within and beyond malaria-endemic areas.

Although still relatively new to malaria, combination therapy is no longer controversial: within just the past few years, it has been endorsed by the World Health Organization, the Global Fund to Fight AIDS, Tuberculosis and Malaria, and by malaria experts worldwide. In addition, combinations are not only good for preventing resistance, they also confer advantages to patients. In the case of the artemisinins, the treatment regimen is shortened from 7 days using monotherapy to 3 days using a combination.

In order for antimalarial combination treatment to keep drug resistance at bay over the long term, however, it must be used as first-line treatment for uncomplicated falciparum malaria as widely as possible. Should monotherapies persist in some locales and drug resistance result, there would be no way to contain the resistant parasites to one country or continent. Artemisinin monotherapy is, in fact, widely used in Asia today in the same areas where resistance to chloroquine and SP originally surfaced not that long ago. There is an urgent need for Asian-based production of artemisinin monotherapy to convert to ACT production, aided by a global subsidy. The window of opportunity to create a global public good-years of extended effective antimalarial drug life-is open now, but it may not remain open very long.

The equal urgency for change in Asia and Africa may seem counterintuitive but antimalarial drug resistance historically has emerged in areas of low transmission-mainly Southeast Asia and South America-and then spread to high-transmission areas, mainly Africa. This pattern fits with current understanding of the biology of drug resistance in low- and high-transmission areas. As a practical matter, it is therefore essential that ACTs quickly dominate the market in low-transmission areas in Asia and Africa, as well as penetrate Africa's most endemic locales.

"Market penetration" will occur in a meaningful way only if the brunt of the increased cost of the drug is not borne by consumers-many of whom earn less than $1 per day. As the most practicable way to achieve this end, this report recommends a large subsidy near the top of the distribution chain, which will lower the price to consumers at all points of sale.

THE ECONOMICS OF ARTEMISININS AND ACTs

By Western standards, artemisinin derivatives are already inexpensive. They also are well within the bounds of what is internationally acknowledged as cost effective for health care interventions in low-income countries. With the incentive of a secure and large market, producers already are promising that wholesale prices for a course of ACTs will fall to US$ .50-1.00 (or possibly lower) within 2 years. However, that projected price is still 5 to 10 times higher than the price of chloroquine or SP in Africa, making artemisinins essentially unaffordable for most sub-Saharan governments and individuals, especially the poor, rural families whose children are most likely to die from malaria.

Without substantial and sustained subsidies, in some countries well over half of all malaria patients needing treatment-including most who currently are able to acquire chloroquine and SP-will not have access to artemisinin-based drugs. Children will die and many more will suffer.

Priming the Market for ACTs

Once scaled up, the additional cost of ACTs versus currently failing drugs for the world is expected be US$ 300-500 million per year (a closer approximation is difficult because estimates of malaria cases-or fevers assumed to be malaria-are imprecise). This cost estimate assumes that ACTs will be used to treat up to half a billion episodes per year, which roughly equals the number currently treated by chloroquine or SP. The estimate also assumes a competitive market in which ACT prices fall over time.

In the meantime, there is a chicken-and-egg dilemma surrounding ACT supply and demand. Without an assured market, potential manufacturers will not commit to adequate ACT production, nor will farmers expand the cultivation of Artemisia annua, the source plant. There is a critical need to jump-start ACT production. To do this, the global community must provide sufficient funds to encourage investments by manufacturers, guarantee purchases of ACTs and generally stimulate a robust world market. This must be done through a visible, centralized mechanism, ideally using existing national and international organizations (e.g., UNICEF, WHO), which can quickly take on the task.

THE CASE FOR A GLOBAL SUBSIDY FOR ANTIMALARIAL DRUGS: THE CORE RECOMMENDATION OF THIS REPORT

The global community can take definitive action by subsidizing the difference in cost between inexpensive but ineffective antimalarials, and effective ACTs. For ACTs to reach most consumers, the subsidy must first bring the price of ACTs down to about the price of chloroquine (even at those prices, the poorest in society will need assistance to make them affordable). Then the subsidy must be sustained, at least over the medium term, until either economic conditions improve in the endemic countries, or the price of effective antimalarials comes down significantly. Furthermore, for consumers to preferentially choose ACTs over monotherapies, they must cost no more than the least expensive monotherapy available (whether an artemisinin or another drug). Otherwise, simple economics will dictate that a vulnerable monotherapy will be chosen over an ACT, and the global benefits of combination treatment in countering the emergence of resistance will not be achieved. (This report recommends specific measures to keep unneeded monotherapies off the market, as well.)

The subsidy must be applied in a way that does not diminish access to antimalarials. The routes through which people obtain antimalarials vary from place to place, but overall in Africa, upwards of 70 percent of these drugs reach consumers through the private sector, particularly small pharmacies, street side drug peddlers, and general store kiosks.

The importance of drug availability "close to home" cannot be overemphasized: if not treated, malaria can kill a small child within 24 hours of the onset of fever. Delayed consultations and referrals and correspondingly slow access to treatment can work for chronic infectious diseases such as tuberculosis, but not for malaria. Of course, public sector and nongovernmental organizations are important sources of health care, especially where they do reach populations as the village level, but frequently they are restricted to towns and cities.

(Continues...)



Excerpted from SAVING LIVES, BUYING TIME Copyright © 2004 by National Academy of Sciences. Excerpted by permission.
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Table of Contents

Contents

Executive Summary....................1
PART 1 A RESPONSE TO THE CURRENT CRISIS 1 Malaria Today....................19
2 The Cost and Cost-Effectiveness of Antimalarial Drugs....................61
3 The Case for a Global Subsidy of Antimalarial Drugs....................79
4 An International System for Procuring Antimalarial Drugs....................112
PART 2 MALARIA BASICS 5 A Brief History of Malaria....................125
6 The Parasite, the Mosquito, and the Disease....................136
7 The Human and Economic Burden of Malaria....................168
8 Malaria Control....................197
9 Antimalarial Drugs and Drug Resistance....................252
PART 3 ADVANCING TOWARD BETTER MALARIA CONTROL 10 Research and Development for New Antimalarial Drugs....................301
11 Maximizing the Effective Use of Antimalarial Drugs....................312
Acronyms and Abbreviations....................329
Glossary....................334
Index....................347

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