Malaria--change in therapeutic policy.
Article Type: Letter to the editor
Authors: Kar, P.K.
Bhatt, R.M.
Anvikar, Anup
Dua, V.K.
Pub Date: 02/01/2009
Publication: Name: Indian Journal of Medical Research Publisher: Indian Council of Medical Research Audience: Academic Format: Magazine/Journal Subject: Biological sciences; Health Copyright: COPYRIGHT 2009 Indian Council of Medical Research ISSN: 0971-5916
Issue: Date: Feb, 2009 Source Volume: 129 Source Issue: 2
Accession Number: 197413821
Full Text: Sir,

Chloroquine: Novel uses & manifestations by Cooper and Magawere (1) was an excellent review on chloroquine for therapeutic purposes.

In the last paragraph of the article, the use of chloroquine as a miracle drug in Malawi has been amply justified on the basis of its clinical response in the study population. In this reference, certain aspects of the study need to be carefully ascertained to justify change over to a monotherapy (2). There is evidence of the use of a combination therapy (2,3) which is also to be determined for the prospects of a switch over therapeutic policy treating resistance falciparum malaria cases in Malawi where the level of resistance is even lower than East Africa. The work of Plowe et al (4) has been corroborated further for clinical efficacy of sulphadoxine-pyrimethamine (S-P) as first line drug treatment in Malawi, for switching over to a new regimen schedule. In vitro and in vivo studies for nine months from January-September 2001 with the asymptomatic adults accompanying sick children with genetic markers as a tool to validate the identification of mutation-specific resistance in the transmission area were conducted (5). We would like to point out that the level of sulphadoxiaepyrimethamine (S-P) resistance in India is also low inspite of the fact that the drug is extensively used by the private practitioners and Government agencies for over three decades supporting the view of Greenwoods (2). Recently, S-P combination with artesunate therapy has been introduced in India in chloroquine resistant areas to limit the development of S-P resistance (personal communication: National Vector Borne Disease Control Programme, Delhi). In children with Plasmodium falciparum infection, the clinical and parasitological failures rates after post-regimen follow up of day 28 were 20 and 70 per cent respectively, with developing clinical attack which is interpreted as an unusual phenomenon (2). Studies have identified parasites as genuinely recrudescent by genotyping those in the original and subsequent parasitaemia (6). If post-treatment parasite samples carry identical alleles to those of original infection, they represent genuine recrudescence of resistant forms (7). As such, the analyses defined failures at any time with positive parasitaemia i.e., detectable on blood smears, and were compared with failures at day 7, 14, 28, 42, and 63 days. Failure on or before day 7 should not be genotyped as derived from the initial symptomatic infections (8).

Over a period of four years, with a large number of children studied (5), trial arm could have been divided into five follow up pre-scheduled dates on days 7, 14, 28, 42 and day 63. Similarly, PCR-adjusted treatment failure rate should have been considered as the reference time failure because recrudescence after this date (i.e., day 63) was unlikely (8). Studies on Malawi did not mention the number of recorded children common to a 4-yr follow up period for assessing critically the PCR-adjusted corrected failure rate and to establish the relationship on genotype-resistance index (GRI) and genotype-failure index (GFI) as reported during the study period (9). It has been postulated that in the absence of chloroquine drug pressure, wild type Pfcrt parasites will be selected at the cost of chloroquine resistance-conferring Pfcrt mutation in the absence of pre-scheduled day 42 and day 63 follow up period in condition of high drop-out rates which is the usual picture of the study (8). This is in contrast to asymptomatic infections and early acquisition of immunity in children as reported earlier (2) while in Thailand, East African countries and in India, a moderate level of resistance with sulphadoxinepyrimethamine (S-P) could be sustained over several years (2). However, without adopting the trial arm with 5-day pre-scheduled follow up period, children with much higher vs lower transmission intensities or highly seasoned vs year-round transmission might yield very different results which are to be compromised to exploit the molecular mechanism of resistance for providing chemotherapy and prophylaxis policies in a country intending to change drug policy. It was noticed that the blood samples were collected from children with severe infection from December to March 1992-1996 while the same was also done with uncomplicated malaria from 1998-2000 where categorization of predicted failure rate could not be done on the basis of PCR-adjusted linear relationship with corrected failures rate between day 28 and day 63 assessment (8). Similarly, the categorization of antimalarial treatment group by terminal elimination half-life could have been worked out, had it been done on data obtained from only in low transmission areas. However, it was noted that the result obtained only in low-transmission areas could not be extrapolated to areas of higher malaria transmission once it was known the progressive fall of clinical efficacy of chloroquine before being switching to sulphadoxinepyrimethamine combination when the level of resistance was sustained for several years (4,8).

As per records, a day 14 PCR-genotype correlated maximum failure rates of 25 per cent has been suggested as the threshold for antimalarial drug policy change which is in accordance with the support of a combination therapy being switching from monotherapy on the basis of trial arm as already been pointed out by Stepniewska et al (8).

Competing interests: None declared.

P.K. Kar *, R.M. Bhatt (#) Anup Anvikar ** & V. K. Dua * (+)

* National Institute of Malaria Research Field Unit, BHEL, Ranipur Hardwar 249 403, Uttarakhand

** National Institute of Malaria Research Delhi & (#) National Institute of Malaria Research Field Unit, Chhattisgarh, India

(+) For correspondence: vkdua51 @gmail.com

References

(1.) Cooper RG, Magwere T. Chloroquine: novel uses & manifestations. Indian J Med Res 2008; 127: 305-16.

(2.) Treating malaria in Africa. BMJ 2004; 328 : 534-5.

(3.) Nosten F, Brasscur P. Combination therapy for malaria: the way forward? Drugs 2002; 62 : 1315-29.

(4.) Plowe CV, Kublin JG, Dzinjalamala FK, Kamwendo DS, Mukadam RA, Chimpeni P, et al. Sustained clinical efficacy of sulfadoxine-pyrimethamine for uncomplicated falciparum malaria after 10 years as first line treatment: five year prospective study. BMJ 2004; 328 : 545.

(5.) Kublin JG, Cortese JF, Njunju EM, Mukadam RA, Wirima JJ, Kazembe PN, et al. Reemergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi. JInfect Dis 2003; 187 : 1870-5.

(6.) Babiker H, Ranford-Cartwright L, Sultan A, Satti G, Walliker D. Genetic evidence that RI chloroquine resistence of Plasmodium falciparum is caused by recrudescence of resistant parasites. Trans R Soc Trop Med Hyg 1994; 88 : 328-31.

(7.) Ranford-Cartwright LC, Taylor J, Umasunthar T, Taylor LH, Babikar HA, Lell B, et al. Molecular analysis of recrudescent parasites in a Plasmodium falciparum drug efficacy trial in Gabon. Trans R Soc Trop Med Hyg 1997; 91 : 719-24.

(8.) Stepniewska K, Taylor WR, Mayxay M, Price R, Smithuis F, Guthmann JP, et al. In vivo assessment of drug efficacy against Plasmodium falciparum malaria: duration of follow-up. Antimicrob Agents Chemother 2004; 48 : 4271-80.

(9.) Plowe CV. Monitoring antimalarial drug resistance: making the most of the tools at hand. J Exp Biol 2003; 206 : 3745-52.
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