Antimalarial drug resistance

Resistance of P. falciparum to chloroquine appeared almost simultaneously in Colombia in 1960 and on the frontier between Thailand and Cambodia. In Asia, chloroquine-resistance was confined to Indochina until the 1970s, when it extended to the west and towards the neighbouring islands to the south and east. Today, only few countries in Central America north of the Panama Canal, including Haiti and Dominican Republic, do not report chloroquine-resistant falciparum malaria. Amodiaquine remains useful in areas where there is a moderate resistance to chloroquine, in spite of the results of some studies that suggest its low efficacy, perhaps because insufficient dosages were involved¹.

The sulfadoxine-pyrimethamine (S/P) fixed-dose combination ⁱ was used to replace chloroquine. At the beginning of the 1980s, that combination became almost totally ineffective in Thailand and neighbouring countries. Resistance to the drug combination spread rapidly in Central America. South Africa was the first country to replace chloroquine with SP in one Province and later Malawi was the first country to change its policy to sulfadoxine-pyrimethamine as the first line drug. Other African countries followed that example, but because of massive use of this product, resistance is already high in many parts of East Africa.

ⁱ SP is a synergistic fixed-dose combination, in which both components synergistically act on the the antifolate methabolic pathway of the parasite. Operationally, however, they are considered a single product in that neither of the individual components in itself can be given alone for antimalarial therapy.

Resistance to quinine and mefloquine is found mostly in Thailand and Cambodia. Sporadic cases of prophylactic failure of mefloquine in travellers and therapeutic failure with amino-alcohols have been reported in Africa, South America, and in other Asian countries. Several studies have noted a diminution in in vitro sensitivity to quinine throughout the world, and in West Africa, in vitro studies have shown strains presenting decreased sensitivity to mefloquine even before its therapeutic use.

The description of chloroquine-resistant P. vivax is more recent. In 1989, the first cases appeared in Papua New Guinea. Other cases of resistance or decreased sensitivity were reported from Irian Jaya and other Indonesian islands, Myanmar, the Solomon Islands, India and, more recently, Brazil and Guyana. The main problem in the evaluation of the sensitivity of P. vivax is the distinction between reappearance and relapse caused by the hypnozoites. As with P. falciparum, the measurement of the blood chloroquine level can give an individual confirmation that an effective concentration of the drug has been achieved. Chloroquine-resistant P. vivax infection could become a serious therapeutic problem since the sulfadoxine-pyrimethamine combination is not fully effective against this species.

So far, no resistance to artemisinin or artemisinin derivative has been reported, although some decrease in in vitro sensitivity has been reported in China. However, sensitivity testing as guided by WHO protocols² continues to be of paramount importance.

The effects of resistance

The appearance of resistance to antimalarials has increased the global cost of the disease. Therapeutic failure means that patients continue to consult health facilities for further diagnosis and treatment resulting in a loss of working days for adults and absence from school for children. Studies in East Africa have shown that ineffective treatment causes malaria-realted anaemia, which renders children’s health more fragile. In Central Africa, the appearance of chloroquine resistance led to an increase in hospital admissions because of the severe attacks of malaria. Other studies have shown increase in malaria case fatality rates and increasing mortality trends at the community level due to chloroquine resistance. The impact of drug resistance can also be illustrated by the changes in the proportion of P. falciparum relative to other species of malaria. For example, in India, P. falciparum now accounts for about 40% of the malaria cases after the advent of drug resistance, instead of the previously reported 15%³.

Use of antimalarials

Where are antimalarial medicines bought by the public?

A major proportion of cases is treated outside the formal health delivery system in many Sub-Saharan African countries. Self-treatment of malaria has been documented to range from a low of 19% in Guinea to a high of 94% in rural Ghana; the average of reviewed studies being about 66%. A review of 2 urban and 8 studies of paediatric cases of malaria in rural areas in African countries found a median of only 38% of malaria case being seen in government health centres. In Togo, 83% of reported fevers were treated at home with an antimalarial drug. In Kenya 60% of surveyed episodes of febrile illness were treated at home with locally purchased herbal remedies or medicines, and only 18% went for treatment to a health centre or hospital. A household survey in Burkina Faso concluded that only 13% of mild episodes and 54% of severe cases of fever were treated by ‘professional services’. Self-treatment with drugs from ordinary shops was commonly reported in a survey in Uganda^{4 5 6};

Appropriateness of self-medication with antimalarials

Appropriateness of self-administered treatments is often low. In Togo, the dosage of 70% of the treatments administered at home was found to be inadequate. A large fraction (24.6%) of caretakers in a Nigerian study used sub-curative doses of chloroquine to treat their children. Only 38% of adults in a Zambian study knew the correct dosage of malaria treatment for adults, and only 25% could state the correct dosage for children. A survey in Kenya estimated that only 4% of children given shop-bought chloroquine had received an adequate total dose, while fewer (2%) received chloroquine over the recommended 3-day period. These data demonstrate that self-medication practices have been severely inappropriate with the current antimalarials, and are likely to be inappropriate with future antimalarials, unless action is taken. The provision of FDCs may reduce this inappropriate use^{7 8 9}, by improving adherence to treatment and standardization of regimens.

The quality of antimalarial drugs in developing countries

An issue of serious concern is the high prevalence of substandard and counterfeit antimalarial products circulating in developing countries. Quality of antimalarial drugs differs greatly among countries, both in content and dissolution. Hence, an important cause of treatment failures may be actually due to drug quality problems.

Anti-infective products of poor quality may contribute to the emergence of resistance, as treatment with poor quality drugs may result in low bioavailability, which may result in drug under-dosage. This, in turn, may promote the selection and spread of resistance. Quality of antimalarials is rarely independently verified in most countries and local capacity for independent drug quality assurance is poorest where the disease burden is highest. Although malaria-endemic countries carry out drug resistance monitoring as per WHO protocols, the data are not linked to the overall proportion of treatment failures, which is due to many factors, including product quality.

Figure 1: The quality of anti-malarial products differs greatly among countries -both content and dissolution are problems

Cholorquine Tabs - % failure*

* Samples were judged to have “failed” if content was < 93% or >107%, and dissolution <80% in 45 minutes

Sulphdoxine/pyrimethamine Tabs - % failure*

* Samples were judged to have “failed” if content was <90% or >110%, and dissolution <65% in 30 minutes

In a recent survey of the quality of antimalarial drug products in eight African countries, significant quality problems were detected¹⁰. The study evaluated samples of chloroquine syrup, chloroquine tables and suphadoxine/pyrimethamine tablets. Findings included:

• active ingredient content failure rates averaged 57% for chloroquine syrup, and ranged from a high of 66%, to a low of 25%;

• active ingredient content failure for chloroquine tablets was very significant with highest levels being 66% and the lowest levels being 20%; and

• failure rates for SP tablets were most serious with regard to the dissolution of the pyrimethamine component. Average failure rates were 91.1%, and ranged between 75% to 100%.

It is recommended that definite action be taken at the country level to address this problem. Measures should include: promoting good procurement practices in the public sector; monitoring and supporting GMP compliance of manufacturers and suppliers; supporting the implementation of sound and effective drug quality control programmes within drug regulatory authorities to ensure safe use of good quality antimalarial products.