Ideally, every case of malaria should be followed up to ensure the completion of treatment and parasitological cure. Any evidence of treatment failure, despite full treatment, and no vomiting, is an indication to treat with second line drugs without further delay.
WHO has developed a revised protocol for assessment and monitoring of antimalarial drug efficacy in vivo, essentially for studies on drug resistance. This protocol requires the patient to be followed up for 14-28 days, depending on the drugs used and intensity of transmission, with the initiation of treatment considered as Day 0.[1]
WHO Definitions of Treatment Failure
Early-treatment failure
- Worsening of clinical condition: Development of danger signs or severe malaria any time during day 1–day 3, in the presence of parasitemia. Such patients must be referred immediately for management of severe malaria.
- Increase in parasitemia: Parasitemia on day 2 higher than day 0 count, irrespective of axillary temperature.
- Persistence of fever even after 72 hours: Parasitemia on day 3 with axillary temperature ≥37.5°C.
- Inadequate decrease in parasitemia: Parasitemia on day 3 ≥25% of count on day 0.
Late-treatment failure
Late clinical failure
- Late worsening: Development of danger signs or severe malaria after day 3 in the presence of parasitemia.
- Incomplete resolution/recurrence of parasitemia and fever: Presence of parasitemia and axillary temperature ≥37.5 °C (or history of fever) on any day from day 4 to day 28.
Late parasitological failure
- Failure to clear parasitemia: Presence of parasitemia on any day from day 7 to day 28 (day 14 in intense transmission areas) and axillary temperature <37.5°C. (In areas with intense transmission, recurrence of symptoms or parasitemia after 14 days may be due to reinfection).
Adequate clinical and parasitological response
- Absence of parasitemia on day 28 (day 14 in intense transmission areas) irrespective of axillary temperature. (In case of adequate clinical and parasitological clearance, the blood smear is usually negative after day 14 of treatment and in a low- to moderate-transmission area, it is expected to remain so on the 28th day too).
If the treatment is effective, the symptoms of malaria generally subside by day 3 and the parasitemia declines and disappears completely by day 7. If the symptoms persist on day 3 with inadequate decrease in parasitemia, the patient must be treated with second line treatment as recommended by the national guidelines. NVBDCP India recommends treatment with quinine and doxycycline (or clindamycin) and all such cases must be immediately reported to the authorities.[2]
It should be noted that the presence of gametocytes on the repeat smears does not suggest treatment failure. Similarly, a positive test on RDT does not suggest treatment failure as it can remain positive for weeks after successful treatment due to persistent antigenemia. In areas with intense transmission, recurrence of symptoms after 2 weeks may be due to reinfection, and it may not be possible to distinguish recrudescence due to treatment failure from reinfection. Recurrence of symptoms may also be due to mixed infection, either due to drug-resistant strains or due to activation of dormant tissue stages.[3,4]
Management of Treatment Failure
Treatment failures may result from drug resistance, poor adherence or inadequate drug exposure (from underdosing, vomiting or unusual pharmacokinetic properties in that individual) or substandard medicines.[5] Treatment failures are more common with chloroquine, Sulfa-Pyrimethamine or other monotherapies and most often seen in P. falciparum infections than nonfalciparum infections. With ACTs, treatment failure within 14 days is very unusual.[5]
Treatment failures within 14 days should be treated with a second-line antimalarial formulation. Since it is not practical to get PCR genotyping for all cases of recurrence after 14 days so as to differentiate recrudescence from reinfection, particularly in high transmission areas, all cases of treatment failure after 14 days should be considered as new infections and should be retreated with the first-line treatment. This should still be effective in most cases; if there is a further recurrence, second-line treatment can be considered. The second-line treatment can be the alternative ACT known to be effective in the region (such as artemether+lumefantrine) or quinine (10 mg salt/kg bw three times a day) + tetracycline (4 mg/kg bw four times a day) or doxycycline (3.5 mg/kg bw once a day) or clindamycin (10 mg/kg bw twice a day) for 7 days[5]
References
- Assessment and Monitoring of Antimalarial Drug Efficacy for the Treatment of Uncomplicated Falciparum Malaria. WHO/HTM/RBM/2003.50. World Health Organization. Geneva. 2003. Available at http://whqlibdoc.who.int/hq/2003/WHO_HTM_RBM_2003.50.pdf
- National Drug Policy on Malaria – 2013. Directorate of National Vector Borne Disease Control Programme. Govt. of India. New Delhi. 2013. Available at http://nvbdcp.gov.in/Doc/National-Drug-Policy-2013.pdf
- Snounou G, White NJ. The co-existence of Plasmodium: Sidelights from falciparum and vivax malaria in Thailand. Trends Parasitol. 2004;20(7):333–339.
- McKenzie FE, Smith DL, O’Meara WP, et al. Fever in patients with mixed-species malaria. Clin Infect Dis. 2006;42(12):1713–1718. doi: 10.1086/504330.
- Guidelines for the Treatment of Malaria. 2nd edn. WHO, Geneva, 2010. Available at http://whqlibdoc.who.int/publications/2010/9789241547925_eng.pdf
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