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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 7. Uncomplicated P. falciparum malaria

A7.1 How do artemisinin combination therapies compare with non-artemisinin monotherapies?

Systematic review and meta-analysis of individual patient data from 16 randomized trials (total of 5948 people) that studied the effects of the addition of artesunate to monotherapy for falciparum malaria (1) (search date, September 2002). The analysis compared odds ratios (OR) of parasitological failure at days 14 and 28 (artesunate combination compared to monotherapy) and calculated combined summary ORs across trials using standard methods. Results comprise parasite failure including re-infections by day 28 in 14 trials (Figure A7.1), and parasite failure excluding re-infections in 11 trials (Figure A7.2).


Figure A7.1 Artemisinin derivatives administered in combination compared with monotherapy alone: total failures by day 28 (re-infections included); data from the International Artemisinin Study Group individual patient data meta-analysis (1)


Figure A7.2 Artemisinin derivatives administered in combination compared with monotherapy alone: total failures by day 28 (reinfections excluded); data from the International Artemisinin Study Group individual patient data meta-analysis (16)

A7.2 Are there any non-artemisinin combination therapies that provide an alternative to standard monotherapy?

A7.2.1 Sulfadoxine-pyrimethamine + chloroquine compared with sulfadoxine-pyrimethamine

Benefits

One systematic review (2) (search date 2001), which identified no randomized controlled trials (RCTs) meeting the criteria of at least a 28-day follow-up period for a clinical trial. No subsequent RCTs meeting the inclusion criteria but five with follow-up periods shorter than 28 days (3-7), which are described below.

The first subsequent RCT (160 children and adults, Colombia, 1999-2002), found a lower treatment failure rate at day 21 with the combination treatment than with sulfadoxine-pyrimethamine alone (11/64 (17%) with the combination, 19/79 (26%) with sulfadoxine-pyrimethamine alone, no statistical data reported) (3).

The second subsequent RCT (71 children, Uganda, 2001) found a lower treatment failure rate at day 14 with the combination treatment than with sulfadoxine-pyrimethamine alone (4/32 (13%) with the combination, 5/30 (17%) with sulfadoxine-pyrimethamine alone, no statistical data reported) (4).

The third subsequent RCT (52 children and adults, Lao People's Democratic Republic, 2001) found no significant difference in adequate clinical and parasitological responses at day 14 (20/24 with the combination, 23/28 with sulfadoxine-pyrimethamine alone; relative risk (RR): 1.01, 95% CI: 0.8-1.3) (5).

The fourth subsequent RCT (88 children and adults, Uganda, 2001) found no significant difference in adequate clinical response (27/27 with the combination, 29/29 with sulfadoxine-pyrimethamine alone) (6).

The fifth subsequent RCT (305 children and adults, Uganda, 2001-2002) found no significant difference in adequate clinical response (141/152 with the combination, 119/140 with sulfadoxine-pyrimethamine alone) (7).

Harms

Only one RCT reported on adverse events (7). It found that overall, the incidence of possible adverse events was higher in those receiving the combination therapy than in those receiving sulfadoxine-pyrimethamine monotherapy. This could be explained by the higher incidences of pruritus, nausea and vomiting in the combination group. When mild adverse events were excluded from the analysis, there was no significant difference between the groups. One severe adverse event was reported in the monotherapy group, namely an elevated alanine aminotransferase measurement on day 14 in a girl of 3 years of age. This event was not accompanied by symptoms and resolved within two weeks without medical intervention.

Comment

The systematic review (2) identified two RCTs comparing sulfadoxine-pyri-methamine + chloroquine to sulfadoxine-pyrimethamine alone (8, 9). However, neither trial met the WHO inclusion criteria.

The first RCT (85 children aged < 12 years, Papua New Guinea, 1980) compared combination treatment using sulfadoxine-pyrimethamine + an atypical single dose of chloroquine of 10 mg/kg daily to sulfadoxine-pyrimethamine alone (8).

The second RCT (405 children aged 1-10 years, The Gambia, 1995) had a high rate of loss to follow-up (30% in the sulfadoxine-pyrimethamine + chloroquine group, 26% in the monotherapy group) (9).

A7.2.2 Sulfadoxine-pyrimethamine + amodiaquine compared with sulfadoxine-pyrimethamine

Benefits

One systematic review (2) (search date 2001), which identified four RCTs, three in Africa (10-12) and one in China (13) (484 people). One subsequent RCT (14).

Three of the RCTs identified by the systematic review found slightly higher cure rates at day 28 with sulfadoxine-pyrimethamine + amodiaquine than with sulfadoxine-pyrimethamine alone, although the overall difference did not reach statistical significance (2). Similarly, two RCTs (one in Mozambique, and one in China, 1985-1986, 116 people) identified by the review found no significant difference in mean parasite clearance times between the two treatment groups (10, 13). However, the Chinese trial (69 people) found a significantly shorter mean fever clearance time with the combination treatment than with the monotherapy (13).

The subsequent RCT (191 children aged under 10 years, Cameroon, 2001) found a significantly higher adequate clinical response with a negative smear at day 28 with the combination treatment than with the monotherapy (14). Similarly, mean fever clearance time was significantly lower with the combination treatment than with the monotherapy.

Harms

The Chinese trial identified by the systematic review found no significant difference in the rate of adverse events between the two treatment groups (41.7% with the combination, 42.9% with the monotherapy); p value and absolute numbers not reported) (13). Sinus bradycardia and vomiting were the most frequent adverse events overall, and were also more frequent with the combination treatment than with sulfadoxine-pyrimethamine alone (no statistical data reported). However, abdominal pain, headache and dizziness were more common with the monotherapy (no statistical data reported). The Ugandan trial reported no serious adverse effects in either treatment group, whereas that conducted in Mozambique gave no information on adverse events (10, 11). The latter trial (400 people) measured haemoglobin and white blood cell count throughout the follow-up period and found no significant difference between the treatments (11).

The subsequent RCT found a significantly higher rate of fatigue, the most common adverse effect overall, with the combination treatment than with the monotherapy (59/62 (95%) with the combination, 47/62 (76%) with the monotherapy, p < 0.05). Similarly, there were higher rates of headache and vomiting with the combination treatment than with the monotherapy (headache: 4/62 (6%) with the combination, 0/62 (0%) with the monotherapy, p < 0.05; vomiting: 14/62 (23%) with the combination, 5/62 (8%) with the monotherapy, p < 0.05). There was also an increased rate of pruritus with the combination treatment than with sulfadoxine-pyrimethamine alone, although the difference did not reach statistical significance (9/62 (15%) with the combination, 3/62 (5%) with the monotherapy, p value not reported). One person receiving sulfadoxine-pyrimethamine monotherapy presented with purulent vesicles in the thoracic region (no further information provided) (14).

A7.2.3 Sulfadoxine-pyrimethamine + amodiaquine compared with amodiaquine

Benefits

One systematic review (2) (search date 2001), which identified three RCTs, one each in China, Mozambique and Uganda) (10, 11, 13). Three subsequent RCTs (14-16).

Two RCTs (150 people in China, 1985-1986 (13) and Mozambique, 1986 (10) identified by the review found higher parasitological cure rates at day 28 with the combination treatment than with amodiaquine alone. Owing to the apparent heterogeneity between individual study results, the combined relative risk as assessed by several methods did not reach significance (see comment below). These trials found a slightly shorter mean parasite clearance time with the combination treatment than with the monotherapy, although the difference did not reach significance. Similarly, the Chinese trial (97 people) found a shorter mean fever clearance time with the combination treatment than with the monotherapy, although the difference did not reach statistical significance (13). The Ugandan trial (11) only reported parasite outcomes at day 7.

The first subsequent RCT (159 children aged 0.5-10.0 years, Nigeria, 2000-2001) found no significant difference in cure rates at day 28 or in mean fever clearance times between the two treatment groups. However, mean parasite clearance time was significantly shorter with the combination treatment than with amodiaquine alone (15).

The second subsequent RCT (127 children aged under 10 years, Cameroon, 2001) found a significantly higher adequate clinical response with negative smear at day 28 with the combination treatment than with amodiaquine alone. However, there was no significant difference in mean fever clearance time between the two groups (14).

The third subsequent RCT (235 children aged 6-59 months, Uganda, 2001) found a lower parasitological failure rate at day 28 with combination treatment (16).

Harms

The Chinese RCT identified by the review reported a slightly higher rate of adverse events with the combination treatment than with amodiaquine alone (41.7% with the combination, 36% with the monotherapy, p value not reported) (13). Sinus bradycardia and vomiting were the most frequent adverse events overall and were also more frequent with the combination treatment than with the monotherapy (no statistical data reported). The Ugandan RCT reported no serious adverse effects in either treatment group, whereas that conducted in Mozambique gave no information on adverse events (10, 11).

The first subsequent RCT found three children with sleep disturbance secondary to pruritus but there was no significant difference between the treatments (2/75 with the combination, 1/82 with the monotherapy, p value not reported). All other adverse reactions were reported as mild (15).

The second subsequent RCT found no significant difference in fatigue between treatments (59/62 (95%) with the combination treatment, 54/61 (89%) with amodiaquine alone, p value not reported). Cutaneous reactions (dermatitis in the hip area in one person and diffuse urticaria at day 5 in one person) were recorded in two people receiving the monotherapy (0/62 (0%) with the combination, 2/61 (3%) with the monotherapy, p value not reported) (14).

The third subsequent RCT reported both treatments to be well tolerated and found no serious adverse effects (16).

Comment

The systematic review showed significant differences in parasitological cure rates at day 28 between the two RCTs (10, 13). However, the reviewers found no significant difference between treatments when using a random effects model, or worst and best case scenarios assuming that people lost to follow-up were either all treatment failures or successes (2).

A7.3. How do artemisinin combination therapies compare with non-artemisinin combinations?

A7.3.1 Artesunate + sulfadoxine-pyrimethamine

Benefits

No systematic review. One RCT (276 children aged 6-59 months, Uganda, 2001) comparing artesunate (3 days) + sulfadoxine-pyrimethamine with amodiaquine + sulfadoxine-pyrimethamine (16). It found that parasitological failure at day 28 was significantly increased in the group receiving artesunate (3 days) + sulfadoxine-pyrimethamine compared to that in the group receiving amodiaquine + sulfadoxine-pyrimethamine (PCR-unadjusted treatment failure at day 28: 42/144 (29%) with artesunate (3 days) + sulfadoxine-pyrimethamine, 22/132 (17%) with amodiaquine + sulfadoxine-pyrimethamine; OR: 0.49; 95% CI: 0.27-0.87). However, it found no significant difference in treatment failure rates at day 28 between the two groups once new infections had been excluded (PCR-adjusted treatment failure at day 28: 17/132 (13%) with arte-sunate (3 days) + sulfadoxine-pyrimethamine, 29/134 (22%) with amodiaquine + sulfadoxine-pyrimethamine; OR: 0.59; 95% CI: 0.29-1.18, p = 0.14).

Harms

The same RCT gave no information on adverse events (16).

A7.4 Which is the best artemisinin combination therapy?

A7.4.1 Artemether-lumefantrine (6 doses) compared with artemether-lumefantrine (4 doses)

Benefits

One RCT (17); the RCT (238 adults and children, Thailand, 1996-1997) found a significantly higher rate of cure at day 28 with the 6-dose regimen given over 3 days than with the 4-dose regimen also given over 3 days (PCR-unadjusted treatment cure rate for intention to treat population at day 28: 96/118 (81%); 95% CI: 73.1-87.9% with the 6-dose regimen, 85/120 (71%); 95% CI: 61.8-78.8% with the 4-dose regimen, p < 0.001; PCR-adjusted treatment cure rate for evaluable population: 93/96 (97%); 95% CI: 91.1-99.4% with the 6-dose regimen, 85/102 (83%); 95% CI: 74.7-90.0% with the 4-dose regimen, p < 0.001).

Harms

The RCT reported all adverse events to be mild or moderate in severity and possibly attributable to malaria (17). It found no adverse cardiovascular effects. It found four serious adverse events that the authors did not consider to be related to treatment. The trial found no changes in QRS duration and PR interval during treatment in 66 people who had regular electrocardiographic monitoring. Similarly, it found no differences in mean and median QTc values between treatment groups.

A7.4.2 Artemether-lumefantrine (6 doses) compared with artesunate (3 days) + mefloquine

Benefits

One systematic review (search date 2004, two RCTs, 419 people, Thailand, 1997-1998 and 1998-1999) (18).

The review found a higher proportion of people with parasitaemia at day 28 with artemether-lumefantrine treatment than with artesunate-mefloquine although the pooled difference did not reach statistical significance (PCR-unadjusted parasitaemia rate 11/289 (4%) with artemether-lumefantrine, 0/100 (0%) with artesunate-mefloquine, RR: 4.20; 95% CI: 0.55-31.93, p = 0.2; PCR-adjusted parasitaemia rate 9/289 (3%) with artemether-lumefantrine, 0/100 (0%) with artesunate-mefloquine, RR: 3.50; 95% CI: 0.45-27.03, p = 0.2; see comment below). The first RCT (219 adults and children aged over 12 years, Thailand, 1998-1999) identified by the review found no significant difference in median parasite clearance time between the two treatment groups (29 h; 95% CI: 29-32 h in 164 people receiving artemether-lumefantrine, 31 h; 95% CI: 26-31 h in 55 people receiving artesunate-mefloquine, p value not reported) (19). Similarly, it found no significant difference in median fever clearance time (29 h; 95% CI: 23-37 h in 76 people receiving artemether-lumefantrine, 23 h; 95% CI: 15-30 h in 29 people receiving artesunate-mefloquine, p value not reported) or in median gametocyte clearance time between treatments (72 h; 95% CI: 34-163 h in 26 people receiving artemether-lumefantrine, 85 h; 95% CI: 46-160 h in 10 people receiving artesunate-mefloquine, p value not reported). The systematic review did not report results for any other outcomes from the second RCT.

Harms

The systematic review found fewer mild to moderate adverse events with artemether-lumefantrine than with artesunate-mefloquine, although the differences did not reach statistical significance (nausea 4/150 (3%) with artemether-lumefantrine, 6/50 (12%) with artesunate-mefloquine; vomiting 4/150 (3%) compared to 5/50 (10%); sleep disorders: 2/150 (1%) compared to 8/50 (16%); dizziness: 8/150 (5%) compared to 18/50 (36%); p values not reported) (18). It found no significant difference in the proportion of people with severe adverse events between the two treatment groups (one person with each treatment).

A7.4.3 Artemether-lumefantrine (6 doses) compared with artesunate (3 days) + amodiaquine

Benefits

No RCTs with a 28-day follow-up period but one (295 children under 5 years of age, Burundi, 2001-2002) with a 14-day follow-up period (20). The trial found no significant difference in the proportion of people with adequate clinical and parasitological response at day 14 between the treatments (140/141 (99.3%); 95% CI: 97.9-100.0% with artemether-lumefantrine, 142/149 (95.3%); 95% CI: 91.9-98.7% with artesunate-amodiaquine, p value not reported).

Harms

The RCT found no significant difference in adverse events between the treatment groups other than vomiting, which was significantly less frequent on days 1 and 2 with artemether-lumefantrine than with artesunate-amodi-aquine (day 1, 5% with artemether-lumefantrine, 13% with artesunate-amodiaquine; day 2, 1% compared to 5%; p values not reported (20).

A7.5 References

1. Adjuik M et al. Artesunate combinations for treatment of malaria: meta-analysis. Lancet, 2004, 363:9-17 (search date 2003; primary sources, studies sponsored by the WHO/UNICEF/UNDP/World Bank Special Programme for Research and Training in Tropical Diseases, Medline, Cochrane Controlled Trials Register, and contact with investigators of published trials).

2. McIntosh HM. Chloroquine or amodiaquine combined with sulfadoxine-pyrimethamine for treating uncomplicated malaria. In: The Cochrane Library, Issue 4. Chichester, John Wiley & Sons, 2004. (Search date 2001. Primary sources: The Cochrane Infectious Diseases Group trials register, the Cochrane Controlled Trials Register, Medline, Embase, Science Citation Index, African Index Medicus and Lilacs, plus contact with experts in the field and pharmaceutical manufacturers).

3. Blair S et al. Eficacia terapeutica de tres esquemas de traitamiento de malaria no complicado por Plasmodium falciparum, Antioquia, Colombia, 2002. [Therapeutic efficacy of 3 treatment protocols for non-complicated Plasmodium falciparum malaria, Antioquia, Colombia, 2002.] Biomedica, 2003, 23:318-327

4. Ogwang S et al. Clinical and parasitological response of Plasmodium falciparum to chloroquine and sulfadoxine-pyrimethamine in rural Uganda. Wienerische Klinische Wochenschrift, 2003, 115(Suppl. 3):45-49.

5. Schwobel B et al. Therapeutic efficacy of chloroquine plus sulpha-doxine/pyrimethamine compared with monotherapy with either chloroquine or sulphadoxine/pyrimethamine in uncomplicated Plasmodium falciparum malaria in Laos. Tropical Medicine and International Health, 2003, 8:19-24.

6. Ndyomugyenyi R, Magnussen P, Clarke S. The efficacy of chloroquine, sulfadoxine-pyrimethamine and a combination of both for the treatment of uncomplicated Plasmodium falciparum malaria in an area of low transmission in western Uganda. Tropical Medicine and International Health, 2004, 9:47-52.

7. Gasasira AF et al. Comparative efficacy of aminoquinoline-antifolate combinations for the treatment of uncomplicated falciparum malaria in Kampala, Uganda. American Journal of Tropical Medicine and Hygiene, 2003, 68:127-132.

8. Darlow B et al. Sulfadoxine-pyrimethamine for the treatment of acute malaria in children in Papua New Guinea. I. Plasmodium falciparum. American Journal of Tropical Medicine and Hygiene, 1982, 31:1-9.

9. Bojang KA et al. A trial of Fansidar plus chloroquine or Fansidar alone for the treatment of uncomplicated malaria in Gambian children. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1998, 92:73-76.

10. Schapira A, Schwalbach J F. Evaluation of four therapeutic regimens for falciparum malaria in Mozambique, 1986. Bulletin of the World Health Organization, 1988, 66:219-226.

11. Staedke SG et al. Amodiaquine, sulfadoxine-pyrimethamine, and combination therapy for treatment of uncomplicated malaria in Kampala, Uganda: a randomised trial. Lancet, 2001, 358:368-374.

12. Dinis DV, Schapira A. Étude comparative de la sulfadoxine-pyrimethamine et de l'amodiaquine+sulfadoxine-pyrimethamine dans le traitement du paludisme à Plasmodium falciparum chloroquino-résistant à Maputo, Mozambique [Comparative study of sulfadoxine-pyrimethamine and amodiaquine + sulfadoxine-pyrimethamine for the treatment of malaria caused by chloroquine-resistant Plasmodium falciparum in Maputo, Mozambique.] Bulletin de la Societéé de Pathologie Exotique, 1990, 83:521-528.

13. Huang QL et al. [Efficacy of amodiaquine, Fansidar and their combination in the treatment of chloroquine resistant falciparum malaria.] Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi, 1988, 6:292-295 (in Chinese).

14. Basco LK et al. Therapeutic efficacy of sulfadoxine-pyrimethamine, amodiaquine and the sulfadoxine-pyrimethamine-amodiaquine combination against uncomplicated Plasmodium falciparum malaria in young children in Cameroon. Bulletin of the World Health Organization, 2002, 80:538-545.

15. Sowunmi A. A randomized comparison of chloroquine, amodiaquine and their combination with pyrimethamine-sulfadoxine in the treatment of acute, uncomplicated, Plasmodium falciparum malaria in children. Annals of Tropical Medicine and Parasitology, 2002, 96:227-238.

16. Rwagacondo CE et al. Efficacy of amodiaquine alone and combined with sulfadoxine-pyrimethamine and of sulfadoxine pyrimethamine combined with artesunate. American Journal of Tropical Medicine and Hygiene, 2003, 68:743-747.

17. van Vugt MV et al. Efficacy of six doses of artemether-lumefantrine (benflumetol) in multidrug-resistant Plasmodium falciparum malaria. American Journal of Tropical Medicine and Hygiene, 1999, 60:936-942.

18. Omari AA, Gamble C, Garner P. Artemether-lumefantrine for treating uncomplicated falciparum malaria. In: The Cochrane Library, Issue 4, 2004. Chichester, John Wiley & Sons (search date 2004, primary sources Cochrane Infectious Diseases Group trials register, the Cochrane Controlled Trials Register, Medline, Embase, Science Citation Index, African Index Medicus and Lilacs, plus contact with experts in the field and pharmaceutical manufacturers).

19. Lefevre G et al. A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand. American Journal of Tropical Medicine and Hygiene, 2001, 64:247-256.

20. Ndayiragije A et al. Efficacité de combinaisons thérapeutiques avec les dérivés de l'artémisinine dans le traitement de l'accès palustre non-compliqué au Burundi. [Efficacy of therapeutic combinations with artemisinin derivatives in the treatment of non complicated malaria in Burundi.] Tropical Medicine and International Health, 2004, 9:673-679.

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