APPENDIX B
Methodology for Efficacy Assessment of In Vivo Malaria Therapy

INTRODUCTION

A standardized protocol for assessing antimalarial drug efficacy in vivo is available from the World Health Organization (1996c, 2002b) and should be used wherever possible. The following is a brief description of the protocol.

METHODS

Patients presenting to a health clinic with fever or history of fever suggestive of malaria are evaluated with thick blood smears for inclusion. In areas where malaria is highly endemic and acquired immunity is likely to be high, patients should be limited to those in the highest-risk groups (i.e., children less than 5 years of age). In areas where malaria is less intensely transmitted and acquired immunity is likely to be low, all age groups are at risk of clinical illness and are appropriate participants. Those who have a parasite density above a defined level are treated with a standard dose of antimalarial drug under supervision to ensure compliance. Follow-up thick blood smears are typically obtained on days 2 and 3, 7 days after initiation of treatment, and then once every 7 days for the duration of follow-up. The duration of posttreatment follow-up depends on the malaria transmission level (and therefore the probability that reappearance of malaria parasites could be due to reinfection instead of drug failure), the drug being



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Malaria Control During Mass Population Movements and Natural Disasters APPENDIX B Methodology for Efficacy Assessment of In Vivo Malaria Therapy INTRODUCTION A standardized protocol for assessing antimalarial drug efficacy in vivo is available from the World Health Organization (1996c, 2002b) and should be used wherever possible. The following is a brief description of the protocol. METHODS Patients presenting to a health clinic with fever or history of fever suggestive of malaria are evaluated with thick blood smears for inclusion. In areas where malaria is highly endemic and acquired immunity is likely to be high, patients should be limited to those in the highest-risk groups (i.e., children less than 5 years of age). In areas where malaria is less intensely transmitted and acquired immunity is likely to be low, all age groups are at risk of clinical illness and are appropriate participants. Those who have a parasite density above a defined level are treated with a standard dose of antimalarial drug under supervision to ensure compliance. Follow-up thick blood smears are typically obtained on days 2 and 3, 7 days after initiation of treatment, and then once every 7 days for the duration of follow-up. The duration of posttreatment follow-up depends on the malaria transmission level (and therefore the probability that reappearance of malaria parasites could be due to reinfection instead of drug failure), the drug being

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Malaria Control During Mass Population Movements and Natural Disasters used, and the likelihood of good follow-up success. In sub-Saharan Africa, 14 days of follow-up is recommended in most situations. In areas with low transmission, a follow-up period of 28 days or longer might be more appropriate. In some cases a 7-day follow-up period has been used, although this would likely underestimate failure rates, perhaps substantially. Patients are always encouraged to return to the clinic should symptoms recur between regularly scheduled visits. Every effort should be made to find patients not returning for scheduled visits. Failure to do this may seriously bias the results. INTERPRETATION Drug efficacy is best measured using both parasitological failure and clinical failure as outcomes. The World Health Organization has defined standard definitions for both parasitological failure and clinical failure. The definitions differ somewhat for areas with high transmission, with differences in the protocol highlighted for areas of low/moderate transmission. The definitions below are the ones applied to areas of high malaria transmission. Classification of Response to Treatment These are outcome measures based on changes in the patient’s clinical condition in response to a standard dose of an antimalarial drug: Early treatment failure (ETF) Development of danger signs or severe malaria on Day 1, Day 2, or Day 3, in the presence of parasitemia OR Parasitemia on Day 3 with axillary temperature greater than or equal to (=) 37.5ºC OR Parasitemia on Day 2 higher than Day 0 count Parasitemia on Day 3 greater than or equal to (=) 25% of count on Day 0. NOTE: No differences for areas of low/moderate transmission. Late treatment failure (LTF) b1. Late clinical failure: Development of danger signs or severe malaria after Day 3 in the presence of parasitemia, without previously meeting any of the criteria of ETF OR

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Malaria Control During Mass Population Movements and Natural Disasters Presence of parasitemia and axillary temperature greater than or equal to (=) 37.5º on any day from Day 4 to Day 14,1 without previously meeting any of the criteria for ETF. b2. Late parasitologic failure: Presence of parasitemia on Day 142 AND axillary temperature less than (<) 37.5ºC, without previously meeting any of the criteria of ETF or late clinical failure. Adequate clinical and parasitological response (ACPR): An absence of parasitemia on Day 14,3 irrespective of axillary temperature, without previously meeting any of the criteria of early treatment failure or late clinical or parasitological failure. NOTE Parasitological Response Parasitological response refers to the change in parasite density in response to a standard dose of an antimalarial drug. The parasitological response is categorized below. There have been previous versions of the current recommended in vivo protocol and some readers may be more familiar with the definitions formally used to describe parasitological response. The terms RIII, RII, Early RI and Sensitive/Late RI are described below.4 1   Day 4 to Day 28 in areas of low/moderate transmission. 2   On any day from Day 7 to Day 28 in areas of low/moderate transmission. 3   Absence of parasitemia on Day 28 in areas of low/moderate transmission. 4   Previous versions of WHO (World Health Organization, 1996c) recommended in vivo methods used the “R system” to classify parasitological response. RIII denotes a severely resistant response in which little or no decline in parasite densities is observed within the first 48 to 72 hours posttreatment. RII denotes a moderately resistant response in which substantial declines in parasite density are observed within the first 48 to 72 hours posttreatment, but actual clearance does not occur and the patient continues to remain parasitemic through day 7 posttreatment. RI denotes a mildly resistant response in which parasitemia declines substantially within the first 48 to 72 hours posttreatment, is apparently cleared on subsequent examinations, but recrudesces sometime during follow-up. S denotes a fully sensitive response in which parasites are cleared and patients remain parasite free for the duration of follow-up. These tests and classification schemes were originally designed for follow-ups of at least 28 days. Studies using shorter follow-up periods (such as 14 days) are incapable of distinguishing an S response from a late RI response (i.e., parasites recrudesce between Day 14 and Day 28), so patients who remain parasite free for the 14-day follow-up period are often classified as S/RI. Actual definitions can be found in Bloland et al. (1993) as well as many other references.

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Malaria Control During Mass Population Movements and Natural Disasters RIII: a Day 2 parasite density that is greater than (>25) percent of the day 0 parasite density. RII: a positive Day 2 blood smear with a parasite density that is less than or equal to (=) 25 percent of the Day 0 density and a positive Day 7 blood smear. Early RI: EITHER Negative Day 2 blood smear with a positive blood smear on any day between Day 3 and Day 14, OR Positive Day 2 blood smear with a parasite density that is less than (<) 25 percent of Day 0, Negative Day 7 blood smear, Positive blood smear on any day between Day 8 and Day 14. Sensitive/Late RI A Day 2 parasite density that is less than (<) 25 percent of the Day 0 density AND negative blood smears on every follow-up examination between Day 7 and Day 14. With follow-up periods of 14 days, it is not possible to distinguish sensitive responses from late recrudescences, and these responses are combined in the RI/S category. For follow-up periods longer than 14 days, the “late RI” definition is applied to any reappearance of parasites between Day 14 and the end of follow-up. “Sensitive” responses are reserved for those patients not experiencing reappearance of parasites for the duration of follow-up.