Decreased response to artemisinin combination therapy in falciparum malaria: A preliminary report from South India.

Sir,

Artemisinin based combination (ACTs) therapies are the current first line antimalarials in management of severe malaria, commonly caused by Plasmodium falciparum species. The failure to clear parasites by day 3 indicates a change in susceptibility of the parasites to artemisinin associated with loss of activity against the early ring stages and is probably the first stage of artemisinin resistance.[1] Resistance to artemisinin has been confirmed in the “Greater Mekong Region” in South East Asia, which is currently the epicenter for emergence and spread of drug resistant P. falciparum. We report the changing trends of response to ACT in patients with severe malaria, raising a suspicion of possible artemisinin resistance.

The study is a retrospective chart review conducted in Christian Medical College, Vellore, a Tertiary Care Institution in South India, which included patients admitted with severe malaria over a period of 1 year, from July 2010 to June 2011. An adult patient with the presence of asexual stages of falciparum species in peripheral blood smear as confirmed by microscopy was used as the study inclusion criteria. Diagnosis of malaria was made with the acridine orange (AO) – Quantitative buffy coat method, where the smears prepared from the centrifuged blood samples were stained with AO. This is a validated method for malaria diagnosis with higher sensitivity and specificity as compared to the conventional Giemsa staining.[234] The results were reported as parasitic index, which was the percentage of parasitized erythrocytes to the total red blood cell count. Therapeutic response was assessed using the parasite clearance and fever clearance time (FCT). FCT was defined as time (hours) taken for fever defervescence. Delayed parasitological response was defined as the presence of asexual parasitemia on day 3 of ACT. Definitions of treatment response were applied as per the WHO therapeutic efficacy monitoring protocol.[5] The primary outcome assessed was the proportion of patients with asexual parasitemia on day 3 of ACT and secondary outcome was the proportion of patients with delayed fever defervescence.

Over the study period of 1 year, 116 patients were hospitalized for malaria, of which 36 were excluded in the view of incomplete data at admission, and 12 had mono-infection with vivax species. Among 68 patients fulfilling the study inclusion criteria, 83.8% (n = 57) had mixed malarial infection and 16.1% (n = 11) had mono infection with P. falciparum. Smears to assess day 3 parasitemia were available in 57 patients; the remaining 23 were excluded from the analysis of primary outcomes.

Thrombocytopenia was a common complication, which occurred in 62 patients (77.5%) followed by acute renal failure (33.3%, n = 27) and hepatitis (34.5%, n = 28). Twenty one patients (26%) had more than 3 complications at admission. Majority of the patients (62.5%) received weight based regimens of artesunate with doxycycline followed by 37.5%, who received artesunate and lumefantrine, as per the WHO guidelines in management of malaria.[6]

The proportion of patients with day 3 parasitemia was found to be 59.6% (n = 34). Delayed fever defervescence time of more than 72 h was seen in 27 patients (47.3%). Univariate and multivariate logistic regression analysis revealed that the age, sex, parasitic index, and presence of complications (anemia, thrombocytopenia, renal failure, hepatic dysfunction, and coagulopathy) did not correlate with the treatment response.

Emergence of resistance to ACT was first reported in 2009 by Dondorp et al., showing delayed parasite clearance rates in Pailin, Western Cambodia. Resistance is now viewed as the sequelae of widespread use of this drug and the rates of spread are accentuated by the socioeconomic conditions in different geographic regions.[7] India shares a common border with these regions and the thick landscape might favor vector transmission and enable spread of resistance to India.

This is a preliminary report of decreased response to ACT in management of falciparum malaria in our population. Persistence of asexual parasitemia on day 3 suggests early treatment failure to ACT. Nosocomial and superadded bacterial infections were ruled out by a thorough clinical and laboratory evaluation among patients with delayed fever defervescence. Hence, a low grade parasitemia could have been a cause for the delayed fever clearance.

The major limitations are due to the retrospective study design with missing data and low numbers. Parasite density was not available to calculate the parasite clearance half-life, which is more specific than day 3 parasitemia rates. A structured systematically conducted observational study measuring body temperature till defervescence, parasite density at multiple time points to confirm delay in clearance is underway to tackle the limitations noted in the present study. This entity is under reported in malaria endemic countries such as India and Africa, in view of the lack of periodic therapeutic surveillance.[89] This assumes a great public health importance in view of our high malaria burden, and absence of an equipotent alternative therapeutic agent to artemisinin derivatives. This preliminary report shows the need for an emergent nationwide surveillance study assessing therapeutic response to ACT.

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Conflicts of interest

There are no conflicts of interest.