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close this bookGuidelines for the Treatment of Malaria (WHO; 2006; 266 pages) View the PDF document
View the documentGlossary
View the documentAbbreviations
open this folder and view contents1. Introduction
View the document2. The clinical disease
open this folder and view contents3. Treatment objectives
open this folder and view contents4. Diagnosis of malaria
open this folder and view contents5. Resistance to antimalarial medicines9
open this folder and view contents6. Antimalarial treatment policy
open this folder and view contents7. Treatment of uncomplicated P. Falciparum malaria10
open this folder and view contents8. Treatment of severe falciparum malaria14
open this folder and view contents9. Treatment of malaria caused by P. vivax, P. ovale or P. malariae19
View the document10. Mixed malaria infections
open this folder and view contents11. Complex emergencies and epidemics
close this folderAnnexes
View the documentAnnex 1. The guidelines development process
View the documentAnnex 2. Adaptation of WHO malaria treatment guidelines for use in countries
View the documentAnnex 3. Pharmacology of antimalarial drugs
View the documentAnnex 4. Antimalarials and malaria transmission
View the documentAnnex 5. Malaria diagnosis
View the documentAnnex 6. Resistance to antimalarials
View the documentAnnex 7. Uncomplicated P. falciparum malaria
View the documentAnnex 8. Malaria treatment and HIV/AIDS
View the documentAnnex 9. Treatment of severe P. falciparum malaria
View the documentAnnex 10. Treatment of P. vivax, P. ovale and P. malariae infections
 

Annex 4. Antimalarials and malaria transmission

A4.1 Principles of malaria transmission

Malaria is spread from person to person by mosquitoes belonging to the genus Anopheles. The female mosquito is infected by the sexual stages of the parasite, the gametocytes, when it bites a malaria-infected person to take a blood meal. The gametocytes undergo further development in the insect for a period of 6-12 days, after which they are capable of infecting a human, again through the bite of the mosquito.

The intensity of malaria transmission in an area is the rate at which people are inoculated with malaria parasites by mosquitoes. It is usually expressed as the annual entomological inoculation rate (EIR), i.e. the average number of infectious bites by malaria-infected mosquitoes delivered to an individual human resident in the area in the period of one year. It is the EIR that determines, to a large extent, the epidemiology of malaria and the pattern of clinical disease in that locality. The high end of the malaria transmission range is found in a few parts of tropical Africa, where EIRs of 500-1000 can be reached (1). At the low end of the range are EIRs of 0.01 or below, as found in the temperate climates of the Caucasus and Central Asia where malaria transmission is only barely sustained. Between these extremes are situations of unstable seasonal malaria such as in much of Asia and Latin America where EIRs lie below 10, and often around 1-2, and situations of stable but still seasonal malaria as in much of West Africa where the EIR is in the range 10-100.

The proportion of infected mosquitoes in a locality is itself related to the number of infected and infectious humans living there. Therefore, lowering of the infectivity of infected persons to the mosquito vector will contribute to lowering of malaria transmission, and eventually to reducing the prevalence of malaria and the incidence of disease in that locality. The relationship between the EIR and the prevalence of malaria is, however, complex and is affected by the nature of immunity to malaria, its acquisition and loss and to whether or not there is effective drug treatment. The hypothetical relationship represented in figure A4.1 assumes no drug treatment. In areas of low transmission, where EIRs are below 1 or 2, a reduction in the inoculation rates will result in an almost proportionate reduction in the prevalence (and incidence rate) of malaria. At EIRs in excess of 10, the reductions in transmission need to be increasingly large if they are to make a significant impact on malaria prevalence. In high-transmission settings where there is great redundancy in the infectious reservoir, the impact of reducing transmission on disease incidence is not at all obvious, and has been the subject of considerable debate. The experience with major interventions, such as the use of insecticide-treated nets, suggests, however, that effective transmission-reducing interventions will always be beneficial with respect to mortality (2, 3).


Figure A4.1 Relationship between inoculation rate and parasite prevalence (assumes that all infections are untreated)

A4.2 Effects of antimalarials on malaria transmission

Antimalarials can help bring about a reduction in malaria transmission by their effect on parasite infectivity. This can be a direct effect on the gametocytes, the infective stages found in human infections (gametocytocidal effect) or, when the drug is taken up in the blood meal of the mosquito, an effect on the parasite's development in the insect (sporonticidal effect) (Table A4.1; Figure A4.2). Chloroquine acts against young gametocytes but has no suppressive effects on mature infective forms (4). Chloroquine has even been shown to be capable of enhancing the infectivity of gametocytes to the mosquito (5). In contrast, sulfadoxine-pyrimethamine increases gametocyte carriage but, provided there is no resistance, reduces the infectivity of gametocytes to mosquitoes (5-7). Artemisinins are the most potent gametocytocidal drugs among those currently being used to treat an asexual blood infection (8-11). They destroy immature gametocytes, preventing new infective gametocytes from entering the circulation, but their effects on mature gametocytes are less and so they will not affect the infectivity of those already present in the circulation at the time a patient presents for treatment (11).

Table A4.1 Effects of some commonly used antimalarials on the infectivity of P. falciparum to the mosquito

 

Effect of treatment

 

Gametocytocidal

Sporonticidal

Drug

Viability of young sequestered gametocytes

Viability of mature circulating gametocytes

Infectivity of gametocytes to mosquitoes

Overall effect on suppressing infectivitya

Chloroquine

Reduces

No effect (4)

Enhances (5)

+

Sulfadoxine-pyrimethamine

No effect

Increases (5-7)

Suppresses (5-7)

+/-

Artemisinin derivatives

Reduces greatly (8-11)

Little effect (11)

Unknown

+++

Primaquine

Unknown

Reduces greatly (11)

Unknown

+++

Quinine (4)

No effect

No effect

No effect

None

 

a +/- no overall effect; + moderate effect; ++ high effect; +++ very high effect


Primaquine, an 8-aminoquinoline antimalarial that has been widely used as a hypnozoiticidal drug, is the only antimalarial medicine that had been deployed in the treatment of P. falciparum infections specifically for its effects on infectivity. It acts on mature infective gametocytes in the circulation and accelerates game-tocyte clearance (11), as opposed to artemisinins which mainly inhibit gametocyte development.

A4.3 The use of antimalarials to reduce infectivity

A4.3.1 Choice of drugs

Artemisinin derivatives, as indicated earlier, have specific and significant activity against gametocytes (Table A3.1). Effective treatment of a malaria blood infection with any antimalarial will, nevertheless, remove the source of new gametocytes by eliminating the asexual blood stages from which gametocytes derive. The faster the clearance of asexual blood parasites by a drug, the greater will be its impact on infectivity. In P. vivax, P. malariae and P. ovale infections, in which gametocytes have a short developmental period and are short-lived, effective treatment of the asexual blood infection alone (without the addition of gametocytocidal drugs) will be sufficient to abolish further infectivity to mosquitoes. P. falciparum is different because its gametocytes take longer to develop - about 12 days to mature from a young parasite (merozoite) - and the mature gametocytes may remain infective in the peripheral circulation for up to several weeks after the patient has been successfully treated for the asexual blood infection. In order to terminate infectivity o f P. falciparum, the infection needs to be treated with drugs that have specific activity against gametocytes, i.e. either ACTs that destroy immature gametocytes, or by the addition of primaquine to the treatment regime to eradicate mature gametocytes. It is not known whether the use of primaquine with ACTs would result in a further suppression of infectivity, although it appears possible in principle, given that the two drugs act on different developmental stages of gametocytes.


Figure A4.2 Transmission of Plasmodium falciparum and the effects of antimalarials

* When parasites are sensitive to the drug unless otherwise stated. Positive and negative arrows indicate the effect of the drug, enhancement (+) and suppression (-) respectively, on the parasite stage or its development.


A4.3.2 The effect on transmission of using transmission-blocking medicines

Situations of low to moderate transmission

The most direct consequences of lowering the infectivity of patients by the use of drugs are to be seen in areas of low transmission, where symptomatic patients constitute the majority of the infectious reservoir. Here, a strategy to shorten the period of infectivity of patients, if it could be achieved on a wide scale, would have a significant impact on the parasite reservoir of infection and, therefore, on malaria transmission. A reduction in transmission would, in these situations, result in an almost proportionate reduction in the prevalence of infection and incidence of disease.

In areas of low to moderate transmission, therefore, the provision of prompt and effective treatment to malaria patients is important both as a means of achieving the public health goal of reducing transmission, and attaining the therapeutic goal of reducing morbidity. Also important in these situations is the use of specific gametocytocidal drugs. There are anecdotal accounts from areas of low transmission with inadequate health services that offer little access to treatment, of patients presenting with extremely high parasite prevalence rates (>70%), approaching those found in areas of intense transmission (Figure A4.1). When treatment centres were established in such areas and early and effective malaria treatment was provided to patients, parasite prevalence and disease incidence rates decreased dramatically. One well-documented example is from the northwestern border of Thailand where high incidence rates of P. falciparum prevailed in the face of increasing resistance to mefloquine, the antimalarial in use at the time. There, the deployment of artesunate in combination with mefloquine led to a significant decline in the incidence of the disease (12).

Situations of intense transmission

In high-transmission settings, infected but asymptomatic persons constitute an important part of the infectious reservoir. Even though treated cases (mainly children) have higher densities of gametocytes, and effectiveness of transmission is positively related to gametocyte density, a treatment strategy to reduce infectivity of patients whose contribution to the reservoir of infection is only partial is not likely to have a major impact on transmission. This, together with the fact that a much greater reduction in transmission rates needs to be achieved in order to reduce parasite prevalence (and incidence of disease), makes the case for introducing an infectivity-suppressing component to the drug treatment of patients less compelling as a strategy for reducing the incidence of disease. However, the potentially important role of medication in reducing transmission must not be overlooked even in these situations. As intensified malaria control efforts deploying highly effective interventions, such as use of insecticide-treated mosquito nets and indoor residual spraying with insecticides, get under way, malaria inoculation rates could fall considerably (13). Transmission-reducing drug regimes will then have a greater role to play, and will complement other methods to achieve an impact on mortality and the incidence of malaria.

The use of antimalarial drugs to reduce infectivity:

is essential in low-transmission settings,
will be beneficial in high-transmission settings if used in conjunction with other effective transmission-blocking interventions.


A4.4 Dynamics of drug pressure and transmission of drug-resistant genes

A4.4.1 The continued use of a failing drug will confer a selective transmission advantage to resistant parasites

It has been shown that when resistance to a drug is prevalent in a locality, the continued use of that drug will confer a selective advantage to parasites carrying resistance genes, and will lead to higher rates of transmission of drug-resistant parasites. This will result in the rapid spread of the drug resistance through two mechanisms. First the use of the drug leads to higher numbers of circulating gametocytes in the resistant infections than in the sensitive ones (5, 6, 9, 10, 14, 15). The failing drug may reduce asexual para-sitaemias initially to an extent that they may be undetectable even by PCR, but it induces the production of detectable numbers of gametocytes carrying the resistant genes. Resistance is associated with recrudescence. The subsequent recrudescence is associated with higher rates of gametocyte carriage than the primary infection. The recrudescence with resistance parasites is also more likely to fail treatment and recrudesce again than the primary infection. Thus cumulatively the resistant infection generates more gametocytes than an infection with sensitive parasites. Secondly, gametocytes carrying resistant genes have been shown to be more infectious to mosquitoes. They produce higher densities of parasites (oocysts) in the mosquitoes, and infect a higher proportion of mosquitoes than those carrying sensitive genes (6, 7, 11). Molecular studies on the transmission of two P. falciparum genes linked to chloroquine resistance, pfcrt and pfmdr, showed that gametocytes carrying the former produced more oocysts and were also more infectious to mosquitoes than gametocytes of the sensitive genotype (15).

A4.4.2 Reversal of transmission advantage by artemisinins

The use of drugs in combination, specifically with artemisinin derivatives, will remove the survival advantage conferred on parasites resistant to a particular drug by the use of that drug as monotherapy (10, 15, 16). This is because artemisinins are very effective in clearing blood parasites and also in reducing gametocyte prevalence and density (10), and therefore infectivity. But high cure rates are needed to prevent recrudescence with its greater carriage, and so it is inadvisable to combine an artemisinin derivative with a failing partner drug. Artemisinins have a short in vivo half-life so that their gametocytocidal activity will soon cease, leaving the parasites exposed to the failing partner drug, which has a longer in vivo half-life. There is a high failure rate and transmission of resistance parasites is not prevented (9, 10, 15). The clear advantage of using artemisinins in combination with an effective partners drug is that it will delay the selection and spread of drug-resistant genes (10-12, 15, 16).

The implications are as follows.

• Once drug resistance has emerged in a locality, the continued use of the failing drug will result in:

- the rapid spread of drug resistance in the area because the use of the drug confers a transmission advantage to resistant parasites;

- the prevalence of infections in which only gametocytes may be present in the peripheral circulation; the continued use of the drug can lead to low-grade asexual parasitaemias with a high rate of differentiation to gametocytes; such infections must be considered as active drug-resistant infections and be treated with an effective second-line medicine.


• Early treatment of malaria patients with an effective antimalarial has the greatest chance of limiting the spread of drug-resistant parasites.

• The use of an artemisinin derivative with an effective partner drug will delay the selection and spread of drug resistance.


A4.5 The role of transmission-blocking interventions and antimalarials in curtailing the spread of drug resistance

A4.5.1 Transmission control

A reduction in transmission will curtail the spread of parasites of both sensitive and resistant strains. However, there is evidence to suggest that, in the absence of drug pressure, resistant parasites are at a survival disadvantage compared to sensitive strains, i.e. in the absence of selection by the drug to which they are resistant, drug-resistant parasites tend to be intrinsically less able to be transmitted than are drug-sensitive parasites (17, 18). These more stringent transmission conditions will, therefore, tend to selectively eliminate drug-resistant parasites (19). This expectation is supported by observations in Zimbabwe, where house spraying with insecticides to reduce malaria transmission was associated with reductions in the amount of drug resistance in the malaria parasites (20). Likewise, in low-transmission settings in India and Sri Lanka, the replacement of the failing chloroquine with an effective antimalarial, in combination with intense entomological transmission control, led to significant reductions, and in some instances even elimination, of chloroquine-resistant P. falciparum. In western Thailand where, in the 1990s, increasing levels of mefloquine resistance were associated with rising malaria incidence, the deployment of combination therapy for malaria treatment with mefloquine and artesunate was associated with an increased in vitro susceptibility of P. falciparum to mefloquine (12).

A4.5.2 Antimalarials

In contrast to transmission control methods, such as residual insecticide spraying and the use of insecticide-treated nets - which are constantly in effect against the entire parasite population through the killing of the vector mosquito and the prevention of biting - treatment with antimalarials affects only the parasites in an infected person at the time of treatment. In high-transmission situations, this is a relatively rare event because the proportion of persons who are ill among those who are infected is quite small, and applies only to a small fraction of the parasite population. Therefore, the impact of drug treatment as a means of curtailing the spread of resistant parasites may be small in comparison to that of vector control methods.

The implications are as follows:

The implementation of transmission control through vector control methods will help reduce the spread of drug resistance.

The use of infectivity-suppressing medicines will be synergistic with mosquito control methods.


A4.6 Conclusion

In situations of low malaria transmission, antimalarials have been and are being used for the specific purpose of reducing infectivity to mosquitoes - a notable example being the use of primaquine in the treatment of P. falciparum malaria. In areas of intense transmission, however, suppression of parasite infectivity has previously not been regarded as a significant goal of treatment. Now, the situation has changed. Artemisinin derivatives (which are gametocytocidal as well as destroying asexual stages of the parasite) are being widely deployed for the treatment of malarial disease, including in areas of intense transmission. This will allow the impact of anti-infective drugs on the reservoir of infection and transmission rates to be evaluated across the entire range of transmission intensities.

Reducing transmission is fundamental to the curtailment of drug resistance, and antimalarials can help achieve this, at least in some situations. This has implications for malaria treatment policy and also for drug development. The ability to suppress parasite infectivity should be included in the product profile of compounds that are being evaluated as potential new antimalarials.

A4.7 References

1. Hay SI et al. Annual Plasmodium falciparum entomological inoculation rates (EIR) across Africa: literature survey, Internet access and review. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2000, 94:113-127.

2. Lengeler C, Smith TA, Armstrong-Schellenberg J. Focus on the effect of bed nets on malaria morbidity and mortality. Parasitology Today, 1997, 13:123-124.

3. Molineaux L. Malaria and mortality: some epidemiological considerations. Annals of Tropical Medicine and Parasitology, 1997, 91:811-825.

4. Bruce-Chwatt L. Chemotherapy of malaria, 2nd ed. Geneva, World Health Organization, 1981:261.

5. Hogh B et al. The differing impact of chloroquine and pyrimethamine/sulfadoxine upon the infectivity of malaria species to the mosquito vector. American Journal of Tropical Medicine and Hygiene, 1998, 58:176-182.

6. Robert V et al. Gametocytemia and infectivity to mosquitoes of patients with uncomplicated, Plasmodium falciparum malaria attacks treated with chloroquine or sulfadoxine plus pyrimethamine. American Journal of Tropical Medicine and Hygiene, 2000, 62:210-216.

7. von Seidlein L et al. Risk factors for gametocyte carriage in Gambian children. American Journal of Tropical Medicine and Hygiene, 2001, 65:523-527.

8. von Seidlein L et al. A randomized controlled trial of artemether/benflumetol, a new antimalarial, and pyrimethamine/sulfadoxine in the treatment of uncomplicated falciparum malaria in African children. American Journal of Tropical Medicine and Hygiene, 1998, 58:638-644.

9. Targett G et al. Artesunate reduces but does not prevent post-treatment transmission of Plasmodium falciparum to Anopheles gambiae. Journal of Infectious Diseases, 2001, 183:1254-1259.

10. Drakeley CJ et al. Addition of artesunate to chloroquine for treatment of Plasmodium falciparum malaria in Gambian children causes a significant but short-lived reduction in infectiousness for mosquitoes. Tropical Medicine and International Health, 2004, 9:53-61.

11. Pukrittayakamee S et al. Activities of artesunate and primaquine against asexual- and sexual-stage parasites in falciparum malaria. Antimicrobial Agents and Chemotherapy, 2004, 48:1329-1334.

12. Nosten F et al. Effects of artesunate-mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: a prospective study. Lancet, 2000, 356:297-302.

13. Killeem G et al. The potential impact of integrated malaria transmission control on entomologic inoculation rate in highly endemic areas. American Journal of Tropical Medicine and Hygiene, 2000, 62:545-551.

14. Handunnetti SM et al. Features of recrudescent chloroquine-resistant Plasmodium falciparum infections confer a survival advantage on parasites, and have implications for disease control. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1996, 90:563-567.

15. Hallett RL et al. Combination therapy counteracts the enhanced transmission of drug-resistant malaria parasites to mosquitoes. Antimicrobial Agents and Chemotherapy, 2004, 48:3940-3943.

16. White NJ, Olliaro PL. Strategies for the prevention of antimalarial drug resistance: rationale for combination chemotherapy for malaria. Parasitology Today, 1996, 12:399-401.

17. De Roode JC et al. Competitive release of drug resistance following drug treatment of mixed Plasmodium chabaudi infections. Malaria Journal, 2004, 3:33-42.

18. De Roode JC et al. Host heterogeneity is a determinant of competitive exclusion or coexistence in genetically diverse malaria infections. Proceedings of the Royal Society of London B, Biological Sciences, 2004, 271:1073-1080.

19. Molyneux DH et al. Transmission control and drug resistance in malaria: a crucial interaction. Parasitology Today, 1999, 15:238-240.

20. Mharakurwa S et al. Association of house spraying with suppressed levels of drug resistance in Zimbabwe. Malaria Journal, 2004, 3:35.

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