THE USE OF ANTIMALARIAL DRUGS
4. ANTIMALARIAL TREATMENT POLICIES

4.1 Definition

An antimalarial treatment policy is a set of recommendations and regulations concerning the availability and rational use of antimalarial drugs in a country (79). It should be part of the national essential drug policy and the national malaria control policy and in line with the overall national health policy.

4.2 Purpose

The primary purpose of an antimalarial treatment policy is to select and make accessible to the populations at risk of malaria safe, effective, good quality and affordable antimalarial drugs so that malaria disease can be promptly, effectively and safely treated. The definition of effective treatment may vary in different epidemiological situations as follows:

In areas of intense transmission: clinical cure, i.e. clinical remission including the prevention of clinical recrudescence (no appearance of signs and symptoms in the 14 days following treatment).

In areas of low transmission: parasitological or radical cure, i.e. elimination of all parasites from the body.

In areas of intense transmission and high population immunity, infected adults are often asymptomatic and clinical cure can be achieved without parasitological cure. In areas of low transmission and low population immunity, asymptomatic infections are rare and clinical cure can rarely be achieved without parasitological cure.

A second purpose is to prevent or delay the development of antimalarial drug resistance by correct diagnosis and rational drug use.

In certain countries and situations, a third purpose may be radical cure of all malarial infections with the objective of reducing transmission through the use of a gametocytocidal drug. Such an objective would be unrealistic in areas of intense transmission and high population immunity where asymptomatic infections are common, but may be realistic in areas of low transmission, if high treatment coverage can be achieved and/or vector control is carried out as a complementary measure.

An effective treatment policy should aim to:

4.3 Development

The categories for the treatment of malaria include drugs for first-line treatment (the treatment given to probable malaria, or confirmed malaria), second-and third-line treatment (given to treatment failures), severe malaria, pregnant women, presumptive treatment, self-treatment/over-the-counter treatment and mass treatment (recommended in epidemics). The antimalarial treatment policy must provide indications for all these treatment categories. However, the choice of first line treatment has the greatest economic implications and the greatest public health implications.

The essential components for developing and updating national treatment guidelines for antimalarial drugs include:

  • clear analysis of the technical, social and economic issues related to malaria control, anti-malarial drug resistance, potential interventions and the consequences of action or inaction,
  • analysis of the decision-making environment,
  • consensus-building among relevant stakeholders (policy-makers, researchers, control staff, donors, private providers, industry and user representatives),
  • a supervisory body to oversee the development, implementation and revision of the policy,
  • a regulatory body to ensure adherence to policy components.

    A critical starting point for developing or updating antimalarial treatment policy is an assessment of the status of antimalarial drug efficacy. Standardized approaches for assessing anti-malarial drug efficacy should be used to allow for trends to be monitored and comparisons made.

    4.4 Factors influencing antimalarial treatment policies

    Antimalarial drug resistance and policy-making are dynamic areas, and the situations in each country may vary depending on disease epidemiology, transmission, drug resistance patterns and political-economic contexts. In general, the policy process requires information from a variety of sources:

    Several factors may influence the selection of antimalarial therapies (see below); they are considered further below. Additional guidance on the selection of drugs for antimalarial treatment policies is given in Annex 2.

    Properties of antimalarial drugs that may influence their selection

  • Efficacy and half-life
  • Acceptability and adherence to treatment (including different formulations)
  • Effectiveness
  • Quality
  • Adverse effects
  • Drug interactions and contraindications
  • Use in special groups, e.g. pregnant women and infants
  • Capacity of health system to implement policy
  • Cost, cost-effectiveness, and affordability of various regimens
  • Reported resistance and/or cross-resistance
  • Useful therapeutic life

    Efficacy

    Drug efficacy is determined by the drug sensitivity of the Plasmodium species concerned, pharmacokinetics and the development of resistance as a function of time (influenced by the drug’s half-life). In developing or revising an antimalarial treatment policy, the efficacy of alternative regimens should also be taken into account.

    Acceptability and adherence to treatment

    Acceptability and adherence to treatment by patients are major components in the success of any public health system and are influenced by both behavioural and economic factors. They are determined by:

    Simple technology, like blister packaging of antimalarial drugs, may offer some solutions to the problem of incorrect use (78).

    Effectiveness

    Effectiveness is determined by efficacy and adherence to the treatment (see above).

    Quality

    Drug quality should be considered at all stages of the drug management cycle, including selection (80). Poor quality drugs decrease efficacy, affect the reputation of the drug and under-mine the treatment policy. Quality assurance is an important component of pre-registration and post-marketing surveillance.

    The WHO Model List of Essential Drugs

    Essential drugs are those drugs that satisfy the health care needs of the majority of the population; they should therefore be available at all times, at a price they and the community can afford, in adequate amounts and in appropriate dosage forms (81). In most countries, the selection of essential drugs is a two-step process. Firstly, market approval of a pharmaceutical product is usually granted on the basis of efficacy, safety and quality. Secondly, an evaluation is made on the basis of a comparison between various drug products for a given indication and their "value for money."

    The WHO Model List of Essential Drugs serves as a model for the second step in this selection process and for national and institutional essential drug lists, although inclusion of a new drug on the WHO Model List is not a regulatory decision and is not binding on national governments. The Model List currently includes 306 active compounds and is updated every two years. The list contains a section on antimalarial drugs (81). Selection of drugs for inclusion on this list is based on the following criteria:

    By the end of 1999, 146 Member States had official national lists of essential drugs, which serve as guides for the supply of drugs, including antimalarial drugs where appropriate, in the public sector in their respective countries.

    Registration and regulation

    Antimalarial drugs, like other medicines, are regulated by national drug regulatory authorities within ministries of health. The regulation and control of pharmaceutical products, including drug registration, quality assurance, and inspection of the distribution system, is in accordance with national pharmaceutical legislation and national drug policy. Supplementary legislation including regulations, norms, standards, specifications, guidelines and procedures is also taken into account. In developing countries, national drug regulatory authorities are at various stages of evolution. Their core functions include drug registration, overall quality assurance of pharmaceutical products, surveillance of drug distribution channels, and control of information and promotion.

    For registration of pharmaceutical products, the most frequently applied criteria are efficacy, safety and quality. National drug regulatory authorities approach overall quality assurance by combining quality assurance of pharmaceutical manufacturers (with regard to good manufacturing practices, GMP) with an effort to ensure that the pharmaceutical products available on the market meet the prescribed quality specifications.

    Assuring the quality of pharmaceutical products on the market is an expensive process in which a careful selection of products to be sampled and tested has to be made. Some countries have developed national regulatory laboratories specifically for this purpose, while others have chosen to contract with external laboratories for the necessary analyses. To ensure that registered products continue to comply with the regulatory requirements after they have been registered, a complement of well-trained pharmaceutical inspectors is needed for surveillance of pharmaceutical manufacturing plants, ensuring adherence with GMP as well as ensuring that the pharmaceutical products available on the market through the various drug distribution channels meet the prescribed quality specifications.

    The distribution of a product, within the marketing authorization granted, is linked to scheduling of drugs within the country, therapeutic category and specific indication(s) for the product, presentation of the product (dosage form), accompanying literature/information, ease of use of the product, and the expected level of training required to ensure safe use of the product.

    Cross-resistance

    Chemically related antimalarial drugs, e.g. chloroquine and amodiaquine, may give rise to similar patterns of resistance. However, the extent to which the degree of development of resistance to amodiaquine is due to resistance to chloroquine is unclear. Similarly, the extent to which the widespread use of sulfadoxine-pyrimethamine for malaria treatment or sulfamethoxazole-trimethoprim (cotrimoxazole) for bacterial infections may compromise the utility of other sulfa drugs, such as chlorproguanil-dapsone, is not known.

    Adverse effects

    Mild adverse effects, such as itching and gastrointestinal effects may influence adherence to treatment and choice of drug. The risk of severe adverse effects, such as neuropsychiatric effects or agranulocytosis, must be considered when deciding policy.

    Drug interactions

    Some drugs given concurrently or sequentially produce undesired effects. For example, folate supplementation can inhibit the action of sulfadoxine-pyrimethamine, increasing the likelihood of treatment failure. Quinine, mefloquine and halofantrine given close together are potentially cardiotoxic. Complementarity and potential synergistic effects must also be taken into consideration.

    Use in special groups

    Pregnancy is a contraindication for many antimalarial drugs (82). The risk to the mother and fetus must be carefully weighed against the risk of malaria. High-risk groups, such as non-immune refugee populations, may need a first-line drug that is different to that recommended in the national antimalarial treatment policy in hyper-and holoendemic areas. The full effects of HIV on the efficacy and adverse effects of antimalarial drugs are not yet known. Some preliminary data indicate a higher risk of adverse effects with sulfadoxine-pyrimethamine in HIV-positive patients with Plasmodium infections than in HIV-negative patients (83). The safety and effectiveness of some antimalarial drugs has not been established in infants, e.g. atovaquone-proguanil, artemether-lumefantrine, halofantrine and mefloquine. The tetracycline group of drugs is contraindicated in children under 8 years of age because of its effect bone growth and dental enamel. In additon, primaquine and sulfadoxine-pyrimethamine have age-specific contraindications in children.

    Health system capacity to implement the policy

    If an antimalarial treatment policy is to be successful, access to good quality essential drugs and health care is vital. Various national strategies exist to finance, distribute and dispense safe, effective and good quality drugs to those who need them. The health system requires political support and financial, managerial, technical and human resources to manage the drug supply and implement the policy effectively. These should be assessed in the context of health sector reform and decentralization. It is also essential to recognize that in many countries health care is sought outside formal health facilities. The role of the government in ensuring quality of service through the informal private sector should also be assessed.

    Cost, cost-effectiveness and affordability analysis

    To make decisions on whether or not to change the first-line therapy for malaria and what the change should be, policy-makers need information on the health outcomes, cost implications and cost-effectiveness of different regimens. Knowledge of the current and projected annual quantity of first-line and second-line treatments is also critical to the decision-making process. There is a wide spectrum of costs and health outcomes and the evolution of these costs and effects over time must be considered.

    Information on the prices of many generic drugs bought in bulk is available from the International Drug Price Indicator Guides produced by Management Sciences for Health, in collaboration with WHO. The average cost per treatment depends on the choice of drug and on the formulations used. The average cost per adult treatment with a range of antimalarial drugs and formulations is shown in Table 6.

    A cost-effectiveness analysis involves consideration of the incremental costs and health effects of implementing an intervention, compared with either the status quo, or a different intervention. For example, in considering the introduction of sulfadoxine-pyrimethamine as a new first-line drug, a comparison could be made with the costs and effects of continuing to use chloroquine or any other treatment. Alternatively the cost of changing immediately to sulfadoxine-pyrimethamine could be compared with changing after a delay of 3 or 5 years.

    The analysis must also take into account other costs involved in implementation, such as the need for consultation, consensus-building and policy formulation, revision and production of treatment guidelines, training of public and private sector health workers, and communication and publicity. The managerial capacity requirements and financial costs of these activities are significant. Country-specific costs will depend on the implementation activities selected. A retrospective analysis showed that the change from chloroquine to sulfadoxine-pyrimethamine as the first-line treatment in Malawi cost about US$ 612 000 or US$ 0.06 per capita. An estimated budget for the planned change in the United Republic of Tanzania indicated a total cost of US$ 424 000 over an 18-month period, equivalent to US$ 0.01 per capita, or 1% of the total annual Ministry of Health budget for 1998-1999 (84, 85).

    In addition to the direct benefits of reduced malaria mortality and morbidity, changing the first-line therapy to a more efficacious drug may bring other measurable improvements as a result of the reduction in the caseload of malarial illness. Firstly the quality of care may be improved, owing to reductions in the frequency of drug and laboratory supply stockouts, less pressure on staff and reduced patient waiting time. At the same time, more patients with other conditions may get access to care. Secondly, by avoiding return visits to formal health facilities and additional visits to other treatment sources, such as pharmacies, shops and traditional healers, patients will benefit from a reduction in direct expenditure and the time diverted from productive activities as well as the burden of anaemia and other consequences of disease progression. In addition, the use of transmission-blocking drugs such as artemisinin and its derivatives may reduce the incidence of new cases (9), especially in low-moderate transmission areas.

    Cost-effectiveness models are simplifications of reality, and the relevance of assumptions and parameter estimates to a particular setting must be carefully considered. Such analysis cannot provide definitive conclusions on the relative cost-effectiveness of different strategies, or resistance thresholds above which a change in first-line drug should definitely be made. However, it does provide a framework for consolidating information on epidemiological, cost and behavioural factors, and indicates ranges for the likely economic and health impacts of different strategies.

    The main properties of existing antimalarial drugs and those under development are presented in Annex 3. A summary of the characteristics of selected commonly used antimalarial drugs is provided in Table 6.

    4.5 Health-seeking behaviour

    The analysis of health-seeking behaviour is essential in developing and implementing a rational drug policy. For example, information on the factors that influence the recognition and interpretation of childhood fevers by consumers and providers, and subsequent choice of therapy will assist in the formulation of guidelines to improve adherence to treatment and treatment effectiveness. These in turn may influence the development of drug resistance. If a treatment does not produce the expected result, patients and care-givers may re-diagnose the cause of the fever (86). It is widely accepted that human behaviours leading to inadequate dosing, incomplete courses of therapy and indiscriminate and inappropriate drug use have contributed to the emergence and spread of resistant parasites (87). It must also be recognized that new treatment policies that replace long-familiar drugs and alter well-established patterns of care seeking and health care practice may fall short of the expectations of patients and care-givers.

    As most malaria treatment occurs in the home, changing the first-line drug in the public sector alone may not have a substantial impact. The role of the private sector is crucial in ensuring that drug distribution systems reflect public health policy and that the recommended treatment is available through all types of health care outlets used by the population. Household and community-level antimalarial drug use represents an important entry point for malaria control programmes in most African nations (88). In Africa, shops are the main source of antimalarial drugs (88-91). However, the course of treatment sold is often suboptimal (92-94).

    Operational research is needed to determine ways of improving prescribing practices, involving drug vendors and other informal sector providers, and achieving the successful replacement of one drug with another. This should be supported by careful documentation of programme experiences as new policies are implemented. Studies have shown that in-service training can improve the ability of health workers to diagnose and treat clinical malaria (95) and that treatment charts may result in more appropriate dosing of antimalarial medication (96).

    4.6 Criteria for changing treatment policy

    The primary indicator for changing antimalarial treatment policy is a high level of treatment failure with the currently used antimalarial drug. Conditions that signal a need for a reevaluation of the policy are:

    The current WHO standard protocol for the assessment of therapeutic efficacy of antimalarial drugs (29) focuses on the clinical efficacy of the drug, rather than the previously recommended parasitological responses. Treatment failure rate remains the cardinal parameter. It is the most easily measured indicator of efficacy, and its consequences are more or less understood and can be translated into economic terms. Incomplete parasitological cure may lead to anaemia or return of clinical illness which can progress to severe disease. An optimal antimalarial drug should therefore succeed in achieving clinical cure, and in clearing parasites and maintaining the parasite-free period for as long as possible.

    When to change

    There are no well-defined criteria for determining the level of clinical or parasitological failures with the current antimalarial therapy at which a first-line drug should be replaced. The decision to change is based on a range of factors including the prevalence and geographical distribution of documented treatment failures, the impact of treatment failures on mortality and severe morbidity, provider and/or user dissatisfaction, the political-economic context, and the availability of acceptable and affordable alternatives.

    A cut-off level of 25% treatment failures is a widely quoted but somewhat arbitrary figure. Several relatively rich countries in Asia and South America have decided not to accept a level higher than 25%, while in parts of Africa, where malaria is a neglected problem, changes in treatment policies have not occurred until the frequency of treatment failures had reached much higher levels. It has been proposed that the dynamic process of change should be analysed on the basis of the proportion of established clinical failures (14, 97). The various proportions of clinical failure rates have been classified as the grace period, alert period, action period and change period; policy-makers should be informed of the relevance of the available information at all stages.

    Grace period—Low levels of drug failures,

  • 5%. Countries can build consensus, conducting a wide range of research studies on the epidemiological, social and behavioural situation, and health systems analysis without urgency. Reliable mechanisms for malaria data collection and analysis can be established during this period. Baseline data and trends in drug efficacy should be determined.

    Alert period—Treatment failure rates of 6-15%. Mechanisms for the process of change should be set up and discussions on the rate of change of drug efficacy to the current first-line drug and the timing of any change in policy should be initiated. The expected adverse effects of increased drug resistance should be evaluated.

    Action period—Treatment failures of 16-24%. Activities to initiate change should commence in accordance with agreed strategies. Ascertainment of treatment failures, potential drug alternatives and channels of drug distribution should be evaluated. This will provide the information needed to prepare a plan for intervention when resistance to the first-line drug becomes intolerable.

    Change period—When the rate of treatment failure has reached 25% or above, consensus for change must already have been reached so that the change can be made within the shortest period of time possible. The actual cut-off point will depend on many factors as indicated above.

    Continuous monitoring and consensus-building is essential to the process leading to change. In vivo therapeutic efficacy studies should be conducted throughout the country in order to provide an indication of the geographical pattern of resistance. The tests should be carried out at regular intervals (18 months to 2 years) to provide a longitudinal perspective.

    4.7 Process of changing treatment policy: country examples

    Ethiopia

    In most areas in Ethiopia, 60-70% of cases are due to P. falciparum and 30-40% to
    P. vivax. Most of the population have no immunity to the parasite. Chloroquine resistance was first detected in 1986. Although in vivo studies conducted between 1991 and 1996 demonstrated increasing resistance to the drug, the methodology used was variable, making comparisons extremely difficult. Following the standardized WHO protocol, a series of in vivo studies was undertaken at 18 sites between 1997 and 1998. The total failure rate (ETF plus LTF) for chloroquine was 65%. Evaluation of sulfadoxine-pyrimethamine efficacy at four sites demonstrated an adequate clinical response rate of 92.3%.

    Following discussions at the regional and federal levels, the Ministry of Health established a technical working group to develop national guidelines for malaria control. Sulfadoxine- pyrimethamine was considered to be the most appropriate replacement for chloroquine for falciparum malaria; however, it has a low efficacy against P. vivax. In 1999 four options were considered by the technical working group for vivax malaria: (i) to leave the treatment of vivax malaria to sulfadoxine-pyrimethamine; (ii) to alternate the use of sulfadoxine-pyrimethamine and chloroquine (P. vivax dominates during the dry season, while P. falciparum occurs after the rains; (iii) to use a combination of chloroquine and sulfadoxine-pyrimethamine in situations where microscopy is not possible; and (iv) to change from chloroquine to amodiaquine. Option 3 was considered to have potential clinical advantages, although with possible increased adverse effects and costs. Option 4 was excluded as there was 35% resistance to amodiaquine in Ethiopia. It was decided that sulfadoxine-pyrimethamine, the current second-line treatment, should replace chloroquine for laboratory-confirmed cases of P. falciparum. Quinine was reserved for the treatment of severe malaria and for second-line treatment of P. falciparum, while chloroquine remained the first-line treatment for confirmed cases of P. vivax and primaquine would be used for antirelapse treatment of P. vivax and for its gametocytocidal activity during epidemics. The decision was also made to use a combination of chloroquine and sulfadoxine- pyrimethamine as the first-line treatment when laboratory diagnosis was not available. New treatment guidelines were prepared accordingly.

    The major challenges for implementation were dissemination of the new recommendations to health workers and ensuring acceptance of the new policy, given human resource and financial constraints. Other challenges were the lack of appropriate protocols for monitoring the therapeutic efficacy and safety of chloroquine + sulfadoxine-pyrimethamine. The main lessons learned in the process of policy change were the need for strong evidence to support the rationale for change, the need for early preparation for change in order to ensure the necessary resources, and the need to involve all stakeholders early in the process. Studies have been planned for measuring the efficacy of chloroquine against vivax malaria and to evaluate the adverse effects of the recommended treatments.

    Malawi

    Over 85% of the malaria infections in Malawi are due to P. falciparum, with P. ovale and P. malariae accounting for the remainder. In 1978 and 1980, WHO missions found no evidence of chloroquine resistance, but by 1983 clinicians noted increasing slide-confirmed chloroquine-resistant malaria with a rise in admissions for the disease. A malaria control programme was established in 1984 to study chloroquine resistance, identify alternative antimalarial drugs and formulate a rational antimalarial treatment policy. Six sentinel sites were established across the country, and the 7-day WHO in vivo efficacy test was used to evaluate chloroquine efficacy. By 1990, parasitological resistance to chloroquine had increased from between 10% and 40% to about 83% in children under 5 years of age. In addition, RIII resistance had increased from 8% in 1984 to 26% in 1990. From 1985 to 1991, the proportion of overall hospital deaths in children under 5 years increased from 10% to 20%.

    In December 1991, it was decided that chloroquine would be replaced with sulfadoxine- pyrimethamine as the first-line treatment for uncomplicated malaria in all age groups. At the same time, it was decided to introduce the use of a loading dose for quinine for the treatment of severe malaria and that sulfadoxine-pyrimethamine would be used for intermittent treatment in pregnant women. The new policy was officially launched in March 1993. Delays in implementation were attributed to the time taken for consensus-building and information dissemination among key groups, production of treatment guidelines and information, education and communication materials, and the procurement of adequate stocks of sulfadoxine- pyrimethamine (a challenge as it was more expensive than chloroquine). Antipyretics were used in conjunction with sulfadoxine-pyrimethamine, and chloroquine became a prescription-only drug. However, many people continued to buy branded chloroquine formulations, which remained on sale at pharmacies. Radio and poster messages emphasized that sulfadoxine- pyrimethamine was "stronger" than chloroquine and therefore that only a single dose was needed. As a result, some care-givers were reluctant to use sulfadoxine-pyrimethamine thinking that it may be too strong for young children. Attempts to correct these problems were made using health education including communication through musical and drama groups.

    Eight years on, some of these problems are still present. The sulfadoxine-pyrimethamine parasitological failure rate is now about 25% and the treatment failure rate (ETF + LTF) has increased from < 5% in 1991 to a national average of 13% (11-17%). Overall, the Ministry of Health has reported a reduction in deaths and hospital admissions due to malaria as a result of the drug change. Regular sulfadoxine-pyrimethamine efficacy monitoring is continuing.

    Peru

    Between 1990 and 1997, a major resurgence of malaria occurred in the two most highly endemic areas of Peru, the Northern Pacific Coast and the Amazon region. In response to this resurgence and to clinical evidence suggesting that chloroquine, the first-line treatment for
    P. falciparum, was no longer efficacious, a series of 14-day in vivo drug efficacy trials were carried out in both regions, beginning in 1998. These showed RII/RIII resistance levels of > 50% to both chloroquine and sulfadoxine-pyrimethamine at several sites in the Amazon region and > 50% to chloroquine but < 5% to sulfadoxine-pyrimethamine at three sites on the Northern coast. These findings were discussed at a national meeting in August 1999 and it was proposed that the national antimalarial treatment policy should be changed to combination therapy with sulfadoxine-pyrimethamine plus artesunate on the Northern coast and mefloquine-artesunate in the Amazon region, pending studies of the efficacy and safety of both combination therapy regimens. In the meantime, first-line therapy was changed to sulfadoxine-pyrimethamine monotherapy in the north and to a 7-day course of quinine plus tetracycline in the Amazon Basin.

    During 2000, 28-day in vivo trials comparing sulfadoxine-pyrimethamine monotherapy with sulfadoxine-pyrimethamine plus artesunate combination therapy and mefloquine (15 mg/kg) monotherapy with mefloquine-artesunate combination therapy were conducted. These trials showed efficacy of > 97% with sulfadoxine-pyrimethamine and > 99% with mefloquine mono-therapy and with both combination therapies. It is expected that the combination therapies with sulfadoxine-pyrimethamine plus artesunate and mefloquine- artesunate will be introduced as the new first-line treatment for uncomplicated P. falciparum malaria on the north coast and in the Amazon region, respectively, by mid-2001.

    Rwanda

    Antimalarial sensitivity testing was carried out in Rwanda between 1992 and 1997 to investigate complaints from clinicians about therapeutic failures with chloroquine. Although these initial studies showed high levels of chloroquine resistance, the methods used differed between studies and the sites were not thought to be nationally representative. It was decided, therefore, that further studies should be performed using standardized methodology. Rwanda became affiliated to the East African Network for Monitoring Antimalarial Treatment (EANMAT) and used its standardized network test methodology. Four sentinel sites were chosen to represent the ecological and epidemiological profile of the country, two sites in areas of holoendemic stable transmission and two sites in the epidemic-prone areas. The tests demonstrated a chloroquine clinical failure rate of 40% in some sites. It was decided that it was imperative to change the treatment policy. However, it was unclear which drug should replace chloroquine, as the efficacy of sulfadoxine-pyrimethamine in Rwanda was not known and reports from other EANMAT countries showed rapidly increasing resistance to this drug. The decision was therefore taken to test both sulfadoxine-pyrimethamine (at all four sites) and the chloroquine plus sulfadoxine- pyrimethamine combination (at two sites) during 2000. The results indicated that sulfadoxine- pyrimethamine was still efficacious. No significant difference was noted between the efficacy of sulfadoxine-pyrimethamine alone and in combination with chloroquine.

    These results suggested that changing to a combination of chloroquine plus sulfadoxine- pyrimethamine did not seem to be a viable option, although a possible justification for its use might be the theoretical reduction of selection pressure on sulfadoxine-pyrimethamine and prolongation of its useful therapeutic life. A review of the antimalarial treatment policy has been scheduled for February 2001. A National Technical Advisory Committee has been formed constituted with representatives from the Ministry of Health, the WHO country office, the National University, the Ministry of Finance and Economic Planning, the Prime Minister’s Office and the President’s Office, as well as representatives from the health regions to assist in the review.

    United Republic of Tanzania

    Chloroquine-resistant falciparum malaria has been recognized as a clinical problem in the United Republic of Tanzania since the early 1990s. Monitoring studies conducted at that time indicated the presence of chloroquine resistance. Although over 80% of Tanzanians live close to a source of chloroquine, most acute febrile illness deaths occur at home (48-88%). Of Tanzanians dying with suspected malaria in three districts, 56-80% attended formal health facilities during their final illness. Assuming that treatment guidelines were followed, most would have received chloroquine yet still died. In 1996, the Ministry of Health requested studies to document the level of chloroquine resistance and its geographical distribution. A national monitoring system was established, which became part of EANMAT in 1997.

    In 1999, the Tanzanian Task Force on Antimalarial Drug Policy concluded that the clinical treatment failure rate for chloroquine was 52% (range 28-72%), the total treatment failure rate for sulfadoxine-pryimethamine was 9.5% (6.4-34%) and the treatment failure rate for amodiaquine was 4.6% (3.5-6%), and that a change of antimalarial treatment policy was overdue. At present the choice has been: interim introduction of sulfadoxine-pyrimethamine as the first-line antimalarial, with amodiaquine as the second-line, and quinine as the third-line treatment (first choice in severe malaria), supported by a strategy to promote improved utilization of antimalarial drugs and other malaria control measures.

    National and subregional data have provided adequate evidence to support a change in first-line antimalarial drug from chloroquine to sulfadoxine-pyrimethamine as an interim measure, anticipating the availability of low-cost, generic combination therapy in the near future. It has been decided that continuous monitoring of treatment efficacy should be maintained and that new developments in potential alternative treatments should be followed carefully and communicated to the policy review group. This new policy will be implemented in 2001. Key lessons learned from the process are the importance of continuous dialogue and consensus-building between the research community, health providers (public and private), policy-and decisionmakers and the public.

    Viet Nam

    Some 40% of the population in Viet Nam live in areas endemic for malaria or with a risk of the disease. For areas with a predominance of P. vivax infections and levels of clinically resistant
    P. falciparum of < 50%, chloroquine is still used as the first-line treatment. For other areas, artemisinin or artesunate are used as the first-line treatment. Chloroquine-resistant P. falciparum, first detected in 1961, increased during 1980-1990 to 78.2% in vitro and 84.6% in vivo. Sulfadoxine-pyrimethamine was first used to treat malaria in 1980 but was ineffective by 1986-1990, with a resistance rate of 73.6%. Artemisinin was introduced by the national malaria control programme in 1992.

    Monitoring of P. falciparum drug susceptibility has been carried out continuously in the country, mainly using 7-, 14-, 21- and 28-day in vivo tests. First-line treatments are chosen according to the distribution of drug-resistant P. falciparum. In areas with evidence of clinical drug resistance of > 50%, the first-line treatment has been changed. In 1997, the Ministry of Health issued the current guidelines for first-line treatment of malaria for different areas and provincial and district hospitals on the basis of a new survey of the status of drug-resistant P. falciparum distribution (1992-1996) and following consultation with a wide range of stakeholders. The guidelines have been distributed to all localities and institutions, and appropriate training has been conducted.

    In 2001 it is planned to reconsider the new list of antimalarial drugs and guidelines. CV8, a new antimalarial drug combination containing dihydroartemisinin, piperaquine, trimethoprim and primaquine will be evaluated. There is evidence to suggest that susceptibility of P. falciparum to chloroquine may be returning. Further studies are needed to re-evaluate chloroquine in combination with other drugs. It is generally accepted that the antimalarial treatment policy requires reconsideration and possible revision every 3-5 years.

    4.8 Policy implementation and access to antimalarial drugs in endemic countries

    Implementation

    The key aspects of implementation of an antimalarial treatment policy are:

    While cost-effectiveness analysis is a useful tool to assist in the allocation of resources, the actual choice of strategy to be implemented is still mainly determined by the ability of individuals and communities to pay the absolute costs of a new drug, i.e. its affordability.

    Access


    The challenge for a national programme is to ensure that effective antimalarial drugs are easily accessible to the populations at risk of the disease (98). The World Bank African Development indicators define access to health services as the percentage of the population that can reach appropriate local health services (including antenatal care) by local means of transport within one hour. It is estimated that one-third of the population at risk in developing countries lacks access to therapy.

    Pharmaceutical "access" is the timely availability of good quality pharmaceuticals to those patients that need them. Many factors determine the level of access: appropriate use, supply management, infrastructure, economic issues, legislation and regulation, manufacturing, and research and development decisions. Access may be defined as:

    Expanding access to essential medicines requires an understanding of the local epidemiological, economic, regulatory and cultural context. It is a process that requires the participation and support of a range of stakeholders beginning with the government and extending to the private sector. Many access barriers originate in organizational or institutional problems, such as a lack of political will and poor governance, stagnant economic growth or a greater emphasis on secondary versus primary care. In most endemic countries, access of rural communities to health care is constrained by insufficient clinics, pharmacies and health personnel. Some government policy decisions may have a negative impact on pharmaceutical access.

    There are four key policy elements that can influence the level of access:

    These broader issues are critical to the development of rational policies and require extensive debate with a view to arriving at a consensus among all stakeholders on potential solutions. The process must begin with identification of the main factors limiting access and appraisal of potential interventions, the discussion of which is beyond the scope of this document.

    The Use of Antimalarial Drugs: Table of Contents