IMPACT TANZANIA

 

“Interdisciplinary Monitoring Programme for Antimalarial Combination Therapy in Tanzania”

 

 

INFORMATION SHEET FOR

AN EVALUATION OF THE EFFECTIVENESS OF COMBINATION THERAPY FOR MALARIA IN INHIBITING DRUG RESISTANCE

 

EXECUTIVE SUMMARY

Antimalarial drug resistance is a growing threat worldwide.  In Africa, loss of currently available antimalarial drugs and the necessary reliance on very expensive alternatives that would follow, could make malaria treatment essentially unavailable to a large proportion of the population at risk.  Significant increases in treatment costs (from a current cost of approximately US$0.10 per adult treatment, to well over US$1.00 per adult treatment or even more) will challenge the economies of sub-Saharan Africa, many of which have annual per capita expenditures for all drugs below US$5.00^[1].  This has prompted many experts to rightfully warn of an impeding malaria disaster in Africa.

Because of multidrug resistant malaria, areas of Southeast Asia have been using combination therapy (the combination of an artemisinin antimalarial compound with a second, long half-life antimalarial, such as mefloquine) for about 6 years.  Experience in Southeast Asia has suggested that the use of this combination therapy approach has not only greatly improved the treatment success rate, but also has apparently halted progression of resistance intensification and reduced malaria transmission. 

These observations have led malaria experts and African governments to consider using a similar combination therapy approach in an attempt to halt drug resistance intensification in Africa.  Because of the urgency of the problem of drug resistance in Africa, these experts have called for the adoption and implementation of combination therapy in Africa without the usual studies and evaluations that would be expected prior to a major change in drug policy.      

In response to the local threat of drug resistance, the government of Tanzania is interested in piloting and evaluating the proposed new national policy [SP alone] in 3  districts in advance of expected national implementation.  Additionally, because of concerns about the durability of the efficacy of SP monotherapy, they are also considering  evaluating, at least on a pilot basis, combination therapy (sulfadoxine/ pyrimethamine [SP] + artesunate [AS]) in a fourth district.

Due to the large differences between sub-Saharan Africa and Southeast Asia in terms of malaria epidemiology, health seeking behaviors of people at risk, health infrastructure, and financial capacity, there is growing concern that this strategy may not work in Africa, and might, therefore, put a potentially significant strain on governments without allowing them to benefit from the promises of combination therapy.  The Tanzanian pilot implementation offers a unique opportunity to evaluate the appropriateness and effectiveness of a combination therapy approach in the context of Africa.  We propose to measure the effect of combination therapy on limiting intensification of resistance, reducing transmission, and improving general public health.  We are also proposing to investigate human behavior related to malaria and the costs (both to government and communities) associated with combination therapy.  Finally, we will  investigate the cost-effectiveness and policy-level implications of the strategy.

This evaluation should allow the Government of Tanzania, as well as other African governments and their international partners, to make much more highly informed decisions about whether or not combination therapy will avert a malaria disaster. 

IMPACT-Tanzania

Interdisciplinary Monitoring Project for Antimalarial Combination Therapy in Tanzania

 

The Problem:

Chloroquine was first synthesized during World War II.  Since then, its efficacy, low cost, and relative safety led to chloroquine becoming the backbone of malaria control, treatment, and prevention strategies all over the world.

  Since about 1960, however, Plasmodium falciparum (the parasite associated with nearly all severe malaria illness) has developed an ability to withstand the effects of chloroquine.  Resistance to chloroquine first appeared in Africa in the early 1980s and has spread and intensified rapidly since then.  Chloroquine resistance rates have increased to the point where some African nations have been forced to switch from chloroquine to sulfadoxine/ pyrimethamine (SP or Fansidar®) for the first-line treatment of all uncomplicated cases of malaria (Malawi was the first country to adopt a national policy of using SP for malaria treatment; other countries using SP include Botswana, South Africa, and Kenya). 

 An important question, however, is how long will SP efficacy last?  Already in eastern Africa, SP resistance has been identified, in some places at disturbingly high rates.  The Ministry of Health in Malawi, which has been using SP extensively since 1993, is approaching the point where it must begin to consider what strategy will follow SP when SP resistance intensifies beyond acceptable levels.  Other African countries are also very concerned about losing SP quickly once it is used widely, and in some countries, this concern has delayed critical decisions about how malaria should be treated. 

To delay a change from a poorly effective antimalarial drug to an effective drug, however, also has consequences.  Drug resistance has been associated with increased mortality rates, increased risk of anemia, epidemics, and expansion of malaria into areas previously free of malaria.

  One critical factor in deciding how to approach the problem of drug resistance is the cost of the available drugs that might replace SP in the future.  Currently, SP costs about the same per treatment dose as CQ (at 1999 world market prices, adult doses cost US$0.104 for CQ and US$0.102 for SP).  However, other currently available antimalarials cost much more (mefloquine, for example, would cost as much as US$3.14 per adult treatment at 25 mg/kg). 

  Clearly, strategies that are effective at prolonging the useful life of antimalarial drugs are urgently needed.   

  The Potential Solution:

Southeast Asia has, in many ways, been hardest hit with antimalarial drug resistance.  Thailand, for example, had to change treatment policy from CQ to SP in the mid-1970s, then from SP to mefloquine in 1984.  By 1989, cure rates after mefloquine treatment (15mg/kg) had declined to about 50%.  Increasing the dose of mefloquine to 25mg/kg only improved the situation briefly.  This growing mefloquine resistance necessitated a new approach, since patients were not reliably clearing their parasitemia with existing drugs.  Beginning in mid-1994, a strategy of combining mefloquine with artesunate was initiated in areas with a high risk of multi-drug resistance.  This strategy returned cure rates back above 90% to 95%.

  In addition to increased efficacy, using drugs in combination has 2 other, mostly hypothetical, advantages over using drugs singly.  First, the ease at which the malaria parasite can develop resistance to 2 drugs simultaneously is thought to be substantially less than to a single drug used alone.  If true, a combination therapy strategy could greatly prolong the useful lifespan of antimalarial drugs.  Combination therapy approaches are now standard for other important diseases, such as tuberculosis, Human Immunodeficiency Virus infections, and some forms of cancer and are increasingly common for malaria in Southeast Asia.  

  The second potential advantage is related to the rapidity with which parasites are cleared after treatment with artemisinin derivatives such as artesuante.  This rapid parasite clearance substantially reduces gametocyte carriage rates among treated patients which, in turn, may reduce the reservoir of infection and overall malaria transmission rates.

  The experience in Southeast Asia with combination therapy suggests that, at least in this epidemiologic setting, these additional theoretical benefits are being realized.  Monitoring of parasite response  to combination therapy has shown that efficacy rates have remained fairly stable since the introduction of this strategy.  Additionally, some studies have suggested that reductions in overall malaria transmission rates have in fact occurred. 

  The apparent success of combination therapy in Southeast Asia has led some malaria experts to call for the rapid and widespread adoption of a combination therapy approach as a way to avert the potentially disastrous impact of antimalarial drug resistance in Africa.  Toward that end, the World Health Organization is leading an effort to test the short-term efficacy and safety of combination therapy in multiple sites around Africa.  In these studies, the specific combination being tested is either artesuante + chloroquine/ amodiaquine (in areas where chloroquine resistance is currently fairly low, such as parts of West Africa) or artesunate + SP (in areas where chloroquine resistance is high, such as East Africa). 

  The Remaining Questions:

While this combination therapy approach offers a tremendous amount of promise for African countries facing the threat of drug resistant malaria, many challenges remain.  In particular, two questions need to be answered quickly: 

  Will combination therapy actually work in tropical Africa?  It is not clear whether the benefits reportedly seen in Southeast Asia can be realized in settings where malaria transmission is orders of magnitude more intense, where health care infrastructure is not as fully developed, and where the majority of people with malaria infections are asymptomatic.   Additionally, the added complexity of using combination therapy rather than a single drug may present problems with patient and provider adherence to, and acceptance of, recommended treatment regimens, potentially offsetting benefits expected from its use.

  Can African economies support combination therapy?  Combination therapy comes at a cost.  While still less expensive than mefloquine, current estimates of the costs of combination therapy show that such an approach will still cost far more than using either chloroquine or SP alone (treating with a combination of artesunate + SP would still be 17 times more expensive for  treating an adult with SP alone and over 30 times more expensive for treating a child).