| THE USE OF ANTIMALARIAL DRUGS |
| Annex 2 |
GUIDANCE ON THE SELECTION OF DRUGS FOR NATIONAL ANTIMALARIAL TREATMENT POLICIES
Introduction
This Annex uses the information summarized in earlier sections to provide guidance on the selection of drugs for use in national antimalarial treatment policies. It considers drugs for first-and second-line treatment of uncomplicated malaria and for severe malaria in infants, children under 5 years, older children, adults and pregnant women. Each possible drug is assessed according to its efficacy, dosage regimen (which influences adherence), cost and adverse effects. Key considerations for the choice of drugs and how best to use them are described. Six scenarios covering some of the major epidemiological and socioeconomic settings and drug resistance patterns are discussed. They do not cover every possible setting, but provide examples of the process of selecting options. Final decisions are the responsibility of policy-makers at country level.
Before introducing artemisinin-derivative combination therapy, a strategy needs to be developed. Decisions on which drugs to combine may follow the principle of selecting a combination of two short half-life drugs in areas of high transmission and a combination of a drug with a short half-life with one with a either a short or long half-life in areas with low transmission.
Drug developers should be encouraged to develop fixed and slow-release formulations of short half-life drugs with the aim of providing single-dose treatments.
In all the scenarios, monitoring of drug efficacy at least every two years is essential. When new polices are formulated, it is necessary to plan for their integration into existing health programmes, to liaise with the Integrated Management of Childhood Illness Programme and to institute training programmes at all levels of the health care system. Home treatment is fundamental to the success of an antimalarial treatment policy, and efforts aimed at improving compliance and reducing cost must be made. Health and diagnostic services must be strengthened to allow rational implementation of the policy and rational use of the recommended drugs.
Affordability is a major consideration for countries in choosing which drugs to recommend. In the absence of adequate resources, the best possible drugs sometimes have to be passed over for cheaper, possibly less effective drugs. This Annex therefore considers the selection of drugs in the face of economic constraints and how the choice would be influenced if increased funding was available.
Scenario 1
Current situation: the currently recommended first-and second-line treatments are chloroquine and sulfadoxine-pyrimethamine respectively. The frequency of clinical failures following chloroquine treatment has become unacceptable. Neighbouring countries have an increasing incidence of sulfadoxine-pyrimethamine failures after a short period of use. There are reports of amodiaquine toxicity. The available affordable treatments are chloroquine, amodiaquine, sulfadoxine-pyrimethamine and quinine. Artemisinin and derivatives, mefloquine and halofantrine are all available in the private sector. Quinine is used in the district hospital to treat malaria cases in pregnant women. The Malarone ® Donation Program is active. HIV prevalence at antenatal clinics is 20-30% in urban centres and 6-25% in rural areas.
This scenario is typical of several African countries in 2000. Actual levels of chloroquine resistance vary from country to country and even within countries. Resistance tends to be higher in East and southern African countries than in West Africa, but there is resistance in many West African countries. All countries need to collect efficacy data and review options continuously to ensure the best treatment. The scenario is also relevant to some other countries in Asia and South America. The antimalarial drug options are summarized in Table A2.1 and proposed treatments are set out in Table A2.2
First-line treatment
Sulfadoxine-pyrimethamine alone is less desirable for first-line treatment, as widespread use in areas with existing resistance may compromise future antifolate combinations. Given the high prevalence of HIV infections, if large-scale use of prophylactic cotrimoxazole will be implemented, there is theoretical risk that this may contribute to shortening the useful therapeutic life of sulfadoxine-pyrimethamine and other antifolates for malaria treatment. These patients need a different first-line antimalarial treatment, other than SP.
The combination of chloroquine and sulfadoxine-pyrimethamine is a possible consideration as first-line treatment, as the regimen requires the addition of a second drug, which changes health messages only slightly from the traditional chloroquine messages. Furthermore, chloroquine may alleviate initial clinical symptoms while sulfadoxine-pyrimethamine may clear parasites and give a sustained response. The combination may be given during pregnancy for treatment of malaria cases. It is important to note, however, that there is little evidence on the efficacy of this combination, so data collection should be a priority. This option cannot be administered to infants < 3 months.
Other indications
Amodiaquine may be considered as an option for second-line treatment, but again data on efficacy are needed. Quinine may be considered as the third-line drug for treatment of uncomplicated malaria and for treatment of severe malaria. Rectal artesunate is an option as an emergency pre-referral treatment and for improving community management of severe malaria, but its use must be accompanied by community education on the recognition of severe malaria symptoms.
The choice for intermittent treatment in pregnancy is sulfadoxine-pyrimethamine.
For all options, drug efficacy must be monitored closely and compared with drugs currently in use before and after the policy is implemented. The efficacy of chloroquine plus sulfadoxine- pyrimethamine, sulfadoxine-pyrimethamine alone, and amodiaquine must be determined as a priority using standard methods.
With increased funding
If financial constraints were removed, the options would be different. The options available are the co-formulated combination of artemether and lumefantrine, atovaquone-proguanil and mefloquine. Mefloquine has a long half-life, which may produce a rapid selection of resistant parasites if used as a monotherapy. Under the definitions of the current donation programme, the use of atovaquone-proguanil (Malarone®) is restricted to third-line treatments of uncomplicated malaria. Artemether-lumefantrine may be considered as a suitable option for second-line treatment, but, before incorporation into treatment policy, it must be pilot tested under local conditions. A combination of artesunate with an existing drug may be an option for first-line therapy. Partner drugs may be sulfadoxine-pyrimethamine or amodiaquine. As above, quinine or artemether or artesunate may be used for severe malaria, with artesunate rectal suppositories for community pre-referral treatment of severe disease.
Health system
If more expensive drugs are introduced, it will be essential to strengthen health services to ensure adequate control of drugs, and to promote administration on the basis of confirmatory laboratory diagnosis to limit unnecessary use.
West Africa
In areas of West Africa where chloroquine resistance is emerging but resistance levels do not indicate that immediate change is required, close vigilance is necessary to ensure that treatment policy can be adapted rapidly if mortality due to ineffective treatment rises. Several options may be available in this case:
Africa suggests that the latter has a limited useful therapeutic life.
Scenario 2
Current situation: The currently recommended first-and second-line treatments are chloroquine and sulfadoxine-pyrimethamine respectively. The frequency of clinical failures following chloroquine treatment has become unacceptable. Data from resistance monitoring sites also indicate unacceptable rates of clinical failure with sulfadoxine-pyrimethamine. Efficacy varies in different parts of the country. The available affordable treatments are chloroquine, amodiaquine, sulfadoxine-pyrimethamine and quinine.
This is the scenario facing many countries in East and southern Africa, where chloroquine can no longer be used, and there are reservations about changing to sulfadoxine-pyrimethamine because of emerging resistance. The antimalarial drug options are summarized in Table A2.3 and proposed treatments are set out in Table A2.4.
First-line treatment
This scenario highlights the problem of countries that need to change immediately but do not have adequate data on alternatives. It also raises the question of whether it is advisable to have different recommendations in different parts of a country on the basis of the different levels of resistance recorded. The functioning and level of decentralization of the health services influences this decision.
One option would be to use sulfadoxine-pyrimethamine as an interim measure where chloroquine resistance is known to be high, while data on alternatives are collected. However, the costs of introducing a new drug (for guidelines, training, drug supply and distribution) are high and may not be justified unless the drug is going to be used for some years.
Amodiaquine is a favoured option, but there are a number of points to consider:
Artemether-lumefantrine has not completed phase IV trials and there are limited data about its use in children. Its use will need to be re-evaluated when more data are available.
Health system
The emergency action (interim policy) can be used as an opportunity for assessing attitudes and practices and to develop an essential package for malaria treatment. Antenatal care should be improved. HIV infections in pregnant women are likely to be high, and insecticide-treated mosquito nets should be made accessible to this risk group.
Scenario 3
Following a coup in the neighbouring country, refugees have flooded across the border into an area of chronic-phase emergency. Many of the incoming refugees are from highland areas, where malaria transmission is low, while others come from lowland high-transmission areas.
About 50% of malaria infections are P. falciparum and 50% P. vivax. Within 2 weeks there is a sharp rise in severe illness in all the camps, especially among pregnant women and children under 5 years of age, and this is thought to be due to malaria. The local district hospital sends its staff to try to help, but has limited supplies of chloroquine, their first-line drug. Limited testing shows that P. falciparum is resistant to chloroquine, sulfadoxine-pyrimethamine and decreased susceptibility to quinine. No microscopic species diagnosis is possible, since laboratory facilities are poor, but tented laboratories are planned as soon as practicable.
The United Nations and five nongovernmental organizations arrive to set up health services in the camps. One nongovernmental organization brings artesunate and sulfadoxine-pyrimethamine for combination treatment, another brings sulfadoxine-pyrimethamine, believing that a 3-day treatment with artesunate will not be feasible, another follows the local protocol of chloroquine, and a fourth brings a new drug to test. The national malaria control programme manager calls a meeting to consider whether there is a need for a special protocol in view of the difficult circumstances. The government has already stated that it cannot afford to provide expensive combinations to all the regions and is reluctant to recommend combination therapy as the national first-line treatment.
Malaria in complex emergencies contributes significantly to the global malaria burden, and raises many issues, as reflected in this scenario. The antimalarial drug options are summarized in Table A2.5 and proposed treatments are set out in Table A2.6.
First-line treatment
The choice of first-line treatment is based on availability of drugs (no amodiaquine), problems of follow up for primaquine, lack of confirmed diagnosis, possibilities of drug resistance and the proportion of P. vivax infections.
Other indications
For severe disease, intramuscular quinine is recommended (unless there are other reasons for needing infusion) because quinine resistance is unlikely, and, even if there is some resistance, quinine will work as initial rescue therapy. Susceptibilit to quinine should be checked. Quinine is easily available, nongovernmental organization physicians will be familiar with it, and it is in line with national policy.
For second-line treatment, quinine and an antibiotic are suggested because of reported decrease in susceptibility to quinine. Tetracycline should not be used in pregnant women and children under 8 years of age.
Health system
The first step is to establish whether the increase in cases is a malaria
problem. Diagnosis for case management will initially be clinical, but, when
tented laboratories are in place, thick films can be used. Dipsticks may have a
limited role, as it is only possible to distinguish between
P. vivax
and P. falciparum with more expensive products.
Coordination is essential, in particular someone is needed to coordinate activities among agencies and the Ministry of Health of the country. All agencies should follow a common policy. New experimental drugs should not be tested on refugees.
Chemoprophylaxis for expatriates
If there is intense transmission, chemoprophylaxis is recommended for international travellers in combination wih mosquito bites prevention. Options include doxycycline, mefloquine, atovaquone-proguanil and primaquine (United States Food and Drug Administration approval has not yet been granted for this).
Impact on local community
Should the policy be different for local and refugee populations? This could lead to huge influx of local inhabitants seeking treatment, could exert selection pressure, which will affect the local population, and may not be sustainable in chronic emergencies. However, the national policy may be appropriate for a semi-immune local population, but not for non-immune refugees, and special measures may be needed to contain potential epidemics. Decisions should be made in dialogue with the national government and the malaria programme manager.
Monitoring is important and should include in vivo resistance testing and rapid assessment of treatment-seeking behaviour, leading to development of an information, education and communication intervention to promote early diagnosis and treatment.
Scenario 4
P. vivax is responsible for 70% of all malaria infections. The currently recommended first-line treatment for uncomplicated malaria is chloroquine. Results in the northern region of the country showed no resistance to chloroquine, which was interpreted as no need to change the national first-line antimalarial treatment policy. However, there is dissatisfaction with chloroquine and a reluctance to use sulfadoxine-pyrimethamine owing to resistance to this drug in the neighbouring country. The neighbouring country reported falciparum malaria resistant to chloroquine and sulfadoxine- pyrimethamine 5 years ago and resistance to amodiaquine of 44% 2 years ago. The neighbouring country is now using mefloquine.
A village less than 5 km from the border area, with settlers from a non-malarious part of the country has a gold mining facility relatively nearby. Intense population movement is present in the region between the two countries. The frequency of clinical failures following chloroquine treatment has become unacceptable in this village and two deaths have been reported recently.
The epidemiological situation in this country requires assessment and microscopic diagnosis needs to be introduced. In vivo tests are needed to assess the efficacy of chloroquine and amodiaquine against P. vivax and chloroquine, amodiaquine and sulfadoxine-pyrimethamine against P. falciparum. Several options exist. Sulfadoxine-pyrimethamine is ineffective against P. vivax but can be used to treat confirmed P. falciparum infections, while chloroquine can be retained as the treatment of choice for P. vivax infections as an interim policy while awaiting results of in vivo tests. A combination of mefloquine plus artesunate, amodiaquine plus artesunate or artemether-lumefantrine may be considered as immediate options for treatment, although they are significantly more expensive than the current treatment policy of chloroquine. Without cost constraints these combinations would be more suitable. Quinine or artemether or artesunate can be used for severe malaria.
Scenario 5
The currently recommended first-and second-line treatments are mefloquine 15 mg/kg and quinine plus tetracycline respectively. The recommended first-line treatment for pregnant women and infants is quinine for 7 days. The frequency of mefloquine failures in the north-eastern part of the country has become unacceptable. The rate of emergence of mefloquine resistance has been alarmingly fast; 10-40% of patients treated with 15 mg/kg mefloquine in these regions show true recrudescence within 2 months. Pilot studies by a group of scientists using a combination of mefloquine plus artesunate in this region indicate 100% effectiveness. Sulfadoxine-pyrimethamine efficacy is high in the southern part of the country, and in these districts is the first-line therapy. However, patients in this region complain that sulfadoxine-pyrimethamine does not work, but guidelines still advise the use of this drug. The district health manager from the mefloquine district is concerned that patients from the south-east will travel to his clinics for better drugs. While there is microscopic diagnosis in the district hospital, and two health centres are using dipsticks, the health posts just use clinical classification.
This scenario is characteristic of some countries in South-East Asia, where there is high level multidrug resistance but also considerable variability in levels of resistance in different areas. The antimalarial drug options are summarized in Table A2.9 and proposed treatments are set out in Table A2.10.
First-line treatment
Changes would increase the cost per treatment, but fewer drugs would be needed since the treatment would be effective. If P. vivax is present, the treatment policy will need to take this into account.
Health system
Scenario 6
A country that has achieved major successes in malaria control is now facing an increasing malaria problem. Transmission intensity is moderate to low. P. vivax has been the dominant malaria parasite in the past, but the incidence and proportion of P. falciparum has steadily increased, and in some districts now constitutes up to 80% of malaria infections. In these districts up to 70% of infections have been found to be resistant to chloroquine, and a few treatment failures with sulfadoxine-pyrimethamine are reported. Chloroquine is still the first line of treatment for both species in the public sector, and sulfadoxine-pyrimethamine is used only for microscopically confirmed treatment failures. However, private practitioners prescribe sulfadoxine-pyrimethamine and even mefloquine. Deaths due to malaria, which have not been experienced for many decades, are increasing in all age groups. This has brought public pressure to bear on politicians to contain malaria.
The malaria control programme manager wants to launch a major attack in the malaria transmission foci against P. falciparum; she is convinced that P. falciparum is persisting and spreading because of drug resistance and the continued use of ineffective drugs, leading to large reservoirs of this species. Given the effects of artemisinin derivatives on gametocytes and the successful Thai-Myanmar border experience with artesunate-containing drug combinations in decreasing P. falciparum incidence, the proposal is to deploy artemether-lumefantrine together with intensive vector control activities as a crisis intervention measure to reduce drastically the reservoir of P. falciparum.
The antimalarial drug options are summarized in Table A2.11 and proposed treatments are set out in Table A2.12.
First-line treatment
Although artemether-lumefantrine may be an option for this scenario, and could potentially reduce transmission, as most infections will be symptomatic and thus treated, there are no safety or adherence data available with this drug in this region. This combination has the advantage of being co-formulated as well as having limited previous use in the private sector.
An alternative is mefloquine combined with primaquine or artesunate. The combination of mefloquine and primaquine is inexpensive, it is a shorter treatment already registered, it is effective against P. vivax. The addition of artesunate to mefloquine would give rapid action and recduce gametocyte carriage rate. Mefloquine-artesunate compared to the six-dose adult artemether-lumefantrine treatment, is a shorter treatment, is already registered, is effective against vivax malaria, and can be used in pregnancy, after the first trimester.
The suggestion to use chloroquine plus sulfadoxine-pyrimethamine in the rest of the country is based on the likelihood of significant chloroquine resistance elsewhere, and the need to treat P. vivax as well as P. falciparum. When the crisis is over this new first-line treatment could be adopted for use in foci. It is less expensive than artemether-lumefantrine or mefloquine plus artesunate, but there may be problems of acceptability. However, if affordable, it would be better to continue with mefloquine plus artesunate or artemether-lumefantrine in the whole country.
Useful information to be gathered would include:
Vector control and distribution of insecticide-impregnated bednets should also be implemented. Rapid dipsticks can also be introduced. However, they are expensive and may not be affordable in areas with financial constraints.
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