A systematic approach to the development of a rational malaria treatment policy in Zambia

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1 Tropical Medicine and International Health volume 3 no 7 pp july 1998 A systematic approach to the development of a rational malaria treatment policy in Zambia Lawrence M. Barat 1, Benson Himonga 2, Simon Nkunika 2, Mary Ettling 3, Trenton K. Ruebush 1, Wamibinji Kapelwa 2 and Peter B. Bloland 1 1 Malaria Epidemiology Section, Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA 2 National Malaria Control Center, Ministry of Health, Lusaka, Zambia 3 US Agency for International Development, Environmental Health Project, Washington, DC, USA Summary Despite the spread of chloroquine-resistant Plasmodium falciparum throughout sub-saharan Africa, chloroquine (CQ) remains the first-line treatment for uncomplicated infection in most countries. To assess the efficacy of CQ and sulphadoxine-pyrimethamine (SP) in Zambia, studies using a standardized 14-day in vivo test were conducted at 6 geographically representative sites. Febrile children 5 years of age were treated with standard doses of CQ or SP and monitored for parasitological failure (using modified WHO criteria) and clinical failure (fever with parasitaemia after completion of therapy). RII/RIII (high to moderate level) parasitological failures were identified in 34% to 70% of CQ-treated children (total N 300) at the 6 sites and clinical failures in 31% to 48%. SP testing at 2 sites identified RII/RIII failures in 3% and 17% of children and only 1 clinical failure at each site. Because of the high levels of CQ resistance identified in these trials, the Ministry of Health of Zambia convened a national consensus meeting which recommended that Zambia s national malaria treatment policy be modified to make SP available at all health facilities for use in persons who fail initial therapy with CQ. In addition, selected sites, staff, and the methodology from these studies were used to implement a sentinel surveillance system for antimalarial drug efficacy. This systematic approach to antimalarial drug efficacy testing could be easily replicated in other countries seeking to reassess their malaria treatment policies. keywords malaria, drug resistance, treatment policy, chloroquine, sulphadoxine-pyremethamine, Zambia correspondence Lawrence Barat, Division of Parasitic Diseases, Centers for Disease Control and Prevention, 4770 Buford Highway, Mail Stop F22, Atlanta, GA , USA. LIB8@cdc.gov Introduction Many countries in sub-saharan Africa have experienced difficulties developing rational policy responses to the spread and intensification of chloroquine-resistant Plasmodium falciparum in part because of a lack of comparable drug efficacy data on which to base their decisions. Researchers conducting drug efficacy studies in the region have often used different methods, study populations, and outcome measures making it difficult to compare and interpret data from these studies. As a result, few countries have modified their national treatment policies and Malawi is the only country to have completely replaced chloroquine (CQ) with sulphadoxine-pyrimethamine (SP or Fansidar*) as their firstline antimalarial agent (Steketee et al. 1995). For many years, the standard method for assessing antimalarial drug efficacy was a 28-day in vivo test, in which subjects were administered standard doses of drug under observation and monitored under conditions that minimized the likelihood of reinfection (WHO 1973). Clearance of parasitaemia was the primary measure of response. Because of the high cost and logistic difficulties of 28-day tests, many investigators pursued development of a test with a shorter follow-up period. In 1973, the World Health Organization (WHO) recommended a 7-day test which incorporated *Use of trade names is for identification only and does not imply endorsement by the U.S. Public Health Service or by the Department of Health and Human Services Blackwell Science Ltd 535

2 clinical response into it s outcome measures (WHO 1973). Although simpler and less expensive to conduct, the major drawback of this procedure was that it did not assess clinical failures after Day 7, which some studies suggested also significantly contributed to malaria-related morbidity and mortality (Khoromana et al. 1986; Greenberg et al. 1989; Campbell 1991; Bloland et al. 1993). A 14-day follow-up study was proposed that permitted, with limited additional cost, a more complete assessment of clinical response. As in many countries in Africa, CQ efficacy trials conducted in Zambia between 1985 and 1995 used a variety of testing methods and outcome measures. CQ failure rates from these studies varied from 8% to 48% (unpublished observation). Faced with these conflicting data, Zambia s National Malaria Control Center (NMCC) requested assistance with the development of a plan to systematically assess the efficacy of CQ from WHO, the U.S. Agency for International Development (USAID), and the Centers for Disease Control and Prevention (CDC). The goal was to obtain comparable efficacy data from trials conducted with a consistent methodology at representative sites in a restricted period of time, which would enable NMCC to review and revise its malaria treatment policy. This report details the process by which NMCC planned and conducted CQ efficacy testing, used these data to revise their national drug policy, and developed a monitoring system for antimalarial drug efficacy. Materials and methods Site selection and study team One study site was selected in each of Zambia s nine provinces. Because of concerns that CQ resistance would be most intense along its eastern border with Malawi, two additional sites were designated in Eastern Province (Figure 1). Six sites are described in this report: Chipata, Lundazi, Choma, Chongwe, Mansa, and Isoka. Testing at four other sites using a similar methodology was conducted by a separate research team and will not be discussed, but yielded similar findings. Concurrent testing of SP at two sites in Eastern Province (Chipata and Lundazi) was carried out to determine whether resistance to this drug existed in the Malawi border area (where SP has been first-line treatment since 1993) and to assess the robustness of the study methodology for assessing the efficacy of antimalarial drugs other than CQ km ml ZAIRE Lake Mweru Lake Tanganyika Mpulungu TANZANIA Kasama Figure 1 Locations of the 11 sites selected for antimalarial drug efficacy testing (, ). One site was selected in each of Zambia s nine provinces, with two additional sites chosen in Eastern Province (near the Malawi border). The six sites for which results are presented in this paper are indicated by stars ( ). ANGOLA Solwezi Mufulira Kitwe Ndola Lake Bangweulu Chipata MALAWI Kabwe Mongu LUSAKA MOZAMBIQUE Zambezi NAMIBIA Lake Kariba Livingstone BOTSWANA ZIMBABWE Blackwell Science Ltd

3 The study team at each site consisted of a clinical officer, nurse, and laboratory technician selected from the staff of the participating health facility. This team was responsible for screening, enrolment, and follow-up procedures. Staff from NMCC and CDC conducted training and supervised the local staff in the daily testing procedures. Before initiation of testing, a 2-h training session was conducted to familiarize local staff and other interested parties with key features of the study. In-depth training on the study procedures was conducted during the screening and enrolment process. Study protocol The methods used for efficacy testing in Zambia were similar to a 28-day test used previously in Kenya and Malawi, with the follow-up period shortened to 14-days. (Bloland et al. 1993). All children 5 years of age seeking outpatient care at the study facilities with an axillary temperature 37.5 C underwent screening. A finger-prick thick blood slide was obtained, stained with 10% Giemsa for 15 min, and parasite density was estimated by scanning several oil immersion fields. Any child with a pure P. falciparum infection and one or more parasites for every four white blood cells ( 2000 parasites/ l) was eligible for enrolment. Children who had evidence of severe or complicated malaria or another serious infection, such as pneumonia, were excluded. A history of recent administration of CQ did not exclude children from enrolment. Informed consent was obtained from the caretaker. Demographic information, history of the current illness, and recent use of medications was obtained from the caretaker and a brief physical examination, including measurements of temperature, weight, and respiratory rate, was conducted. Repeat thick blood slides were obtained, stained with 2% Giemsa for 45 min, and parasite density was determined by counting the number of parasites and white blood cells (WBCs) until either 300 WBCs or 1000 parasites had been counted. Parasite density was calculated assuming a WBC count of /l of blood. At the 2 sites where SP was tested, assignment of treatment was by block assignment in Chipata and by flipping a coin in Lundazi. Since the enrolment period in Chipata was 19 days, during which climatic conditions were similar, bias should not have been introduced by a block assignment. Study drugs were obtained from a pharmaceutical manufacturer/supplier in Zambia and their quality confirmed through testing in CDC s biochemistry laboratory. CQ, 25 mg base/kg body weight, was administered orally over 3 days: 10 mg/kg on Day 0 and Day 1, and 5 mg/kg on Day 2. SP was given as a single oral dose on Day 0, based on the child s age: tablet for children 12 months of age, tablet for children months, and 1 tablet for children months (approximately 25 mg/kg body weight of sulphadoxine). All doses of study drug were administered directly by the study team. If a child vomited within 15 min of dosing, the medication was readministered. Children who vomited more than once on the same day were dropped from the study and treated with an alternative drug, because proper dosing could not be ensured. After completing treatment, the caretaker was asked to return with the child for follow-up visits on Days 3, 7, and 14. At each visit, the caretaker was administered a standard symptom inventory, the child s temperature and respiratory rate were measured, and two finger-prick thick blood slides were obtained. One blood slide was stained with 10% Giemsa for 15 min and a rapid determination of parasite density was carried out. This result was used to identify children who met criteria for clinical failure (Table 1) and would require alternative treatment. The second blood slide was later stained with 2% Giemsa for 45 min. The parasite Table 1 Parasitological and clinical outcome measures Parasitological endpoints RIII: Any of the following: 1. Day 2 parasite density 100% of Day 0 parasite density 2. Axillary temperature 37.5 C on Day 2 with a parasite density 25% of Day 0 3. Day 3 parasite density 25% of Day 0 parasite density 4. Axillary temperature 37.5 C and a positive blood film on Day 3 RII: Positive Day 3 blood film with a parasite density 25% of Day 0 and persistent parasitaemia through Day 7 RI/sensitive: Any child who did not meet criteria for RIII or RII resistance. Clinical endpoints Initial clinical response: Proportion of children with Day 3 axillary temperature 37.5 C Clinical failure: Either of the following: 1. Fever in the presence of any level of parasitaemia after Day 2 2. Any malaria-associated condition requiring a change in malaria therapy on or after Day 2 (including a Day 3 parasite denisty 25% of Day 0) Blackwell Science Ltd 537

4 count of this slide was used to determine the parasite density to be used for final analysis of parasitological response. Children treated with CQ also had a blood film examination performed on the day of their last treatment dose (Day 2). Children with parasitaemia but no fever or fever with no parasitaemia on the Day 7 visit were asked to return for an additional visit on Day 11 for clinical reassessment. A blood smear was only taken on Day 11 if a child had a temperature 37.5 C or other signs of clinical deterioration. Caretakers were encouraged to bring their child back on nonscheduled days if they had any concerns about the child s condition. Children that met criteria for clinical failure (Table 1) were treated with an alternative drug and removed from further follow-up. Children with documented parasitaemia but no fever after completion of therapy did not receive alternative treatment until either fever developed or the 14-day follow-up period had ended. To minimize the number of losses to follow-up, caretakers were given small incentives, including a bag of sugar, laundry soap, and a photograph of them with their child, when they returned for scheduled visits. If a child was not brought back on a scheduled follow-up day, they were visited at their home and assessed there. If a child was not brought for a critical follow-up day, could not be located, and had not already reached a parasitological endpoint, they were classified as a loss to follow-up. Children lost to follow-up after Day 7 (when a final determination of parasitological outcome could be made) were included in the analysis of parasitological endpoints, but excluded from the analysis of clinical response. Both parasitological and clinical endpoints were assessed (Table 1). Parasitological outcomes were based on modified 1973 WHO criteria (WHO 1994). Because recrudescent parasitaemia can occur up to several weeks after initial therapy, it is impossible to differentiate true sensitive responses from late recrudescences in a 14-day test. Therefore, RI and apparent sensitive responses were combined into a single category (RI/S). Two independent parameters were used to assess clinical response, initial clinical response and clinical failure. In instances where children had a Day 3 parasite density 25% of Day 0 but no fever they could be classified as both an initial clinical response and a clinical failure on that day. Because the study protocol was under development during testing in Chipata and did not initially include a Day 3 visit, 13 patients enrolled at that location could not be assessed for initial clinical response. Statistical analysis Data were recorded on standardized case report forms, reviewed daily for accuracy and completeness, and entered into an Epi Info 6.03 database (CDC 1994). Summary statistics were calculated using Epi Info Odds ratios, 95% confidence limits, and p-values were calculated to compare outcomes among study sites. Univariate analysis was carried out on selected patient characteristics (age, sex, prior CQ therapy, enrolment parasite density) to determine their effect on parasitological and clinical outcomes. Probability estimates for discrete variables were calculated using the Chi-square test, or Fisher s exact test when cell totals were less than five. Continuous indicator variables were compared by Analysis of Variance (anova) or Wilcoxon Two-Sample Test, if sample distributions had differing variances. Results Patient characteristics on screening and enrolment Characteristics of children with fever who underwent screening for enrolment in this study are shown in Table 2. Larger numbers of children were screened and enrolled at the Chipata and Lundazi sites because testing of both CQ and SP was conducted. The demographic characteristics of children enrolled were similar at the 6 sites, with a few exceptions (Table 3). The mean age of children in Lundazi, 14.8 months, was lower than that of children enrolled at all other sites, months (p anova 0.01), and more females were enrolled in Chongwe than Choma (P 0.04). CQ use before enrolment was reported in 11% to 26% of children. Geometric mean parasite densities on enrolment ranged from parasites/ l of blood in Mansa to parasites/ l in Isoka. Of 121 children enrolled in Chipata, 79 (65%) received CQ and 42 (35%) SP. In Lundazi, 51 (53%) of 97 children received CQ and 46 (47%), SP. Parasitological and clinical responses to chloroquine Of the 340 children treated with CQ, 41 (12%) were excluded from analysis. Reasons for exclusion included failure to complete treatment (n 18), administration of additional antimalarial drugs during follow-up (n 7), loss to follow-up (n 4), withdrawal (n 2), and hospitalization for another condition (n 2). Six children required hospitalization for either transfusion (n 3) or parenteral therapy for malaria (n 3), and two died before receiving the full course of CQ treatment (neither had signs of severe or complicated malaria on enrolment) and were also excluded from analysis. Nine children lost to follow-up after Day 7 were only included in the analysis for parasitological outcomes. RIII or RII resistance was identified in 34% to 70% of children at the six sites (Table 4). From 76% to 92% of children treated with CQ had a favourable initial clinical Blackwell Science Ltd

5 Table 2 Characteristics of febrile children who underwent screening for enrolment in antimalarial drug efficacy studies at six sites in Zambia Site Chipata Lundazi Choma Chongwe Mansa Isoka Number screened Mean age (months) * Female (number (%)) 135 (52) 182 (52) 97 (47) 68 (57) 42 (42) 61 (53) Smear positive (number (%)) 183 (70)* 280 (80) 169 (82) 83 (70)* 82 (82) 105 (91) 2000 parasites/ l (number (%)) 139 (53) 135 (39) 90 (44) 62 (52) 69 (69) 69 (60) Number enrolled (number (%)) 121 (46) 97 (28) 51 (25) 52 (44) 51 (51) 57 (49) *Significantly lower than other sites, P 0.05 Table 3 Characteristics of children with Plasmodium falciparum infection enrolled in antimalarial drug efficacy studies, Zambia Site Chipata Lundazi Choma Chongwe Mansa Isoka Enrolled Age (months, mean SD) 23.5 (13.6) 14.8 (11.7)* 24.9 (14.8) 25.5 (15.6) 21.5 (16.6) 22.0 (13.9) Female (number (%)) 67 (56) 51 (53) 24 (47) 35 (67) 25 (49) 28 (49) Prior CQ treatment (number (%)) 24 (20) 19 (20) 11 (22) 6 (12) 10 (20) 15 (26) Parasite density (geometric mean) 37,931 43,053 51,760 31,261 28,379 62,517 *Significantly lower than other sites (P 0.01); P 0.04 response by Day 3. However, 31% to 54% were classified as clinical failures during follow-up. Of those children who failed clinically, 25% to 66% failed by Day 3, 4% to 13% between Days 4 and 7, and 27% to 66% after Day 7. After completion of these studies, WHO published a revised 14-day in vivo protocol for areas of intense transmission with new outcome measures: early treatment failure (ETF), late treatment failure (LTF), and adequate clinical response (ACR) (WHO 1996). Children were classified as ETF if they developed danger signs or severe malaria on or before Day 3, had fever and a parasite density Day 0 on Day 2, had fever and parasitaemia on Day 3, or had a Day 3 parasite density 25% of Day 0. LTF was defined as parasitaemia after Day 3 with fever, danger signs, or severe malaria. All others were classified as ACR. Using these outcome measures, 8% to 22% of CQ-treated children would be classified as ETF, 14% to 32%, LTF, and 46% to 69%, ACR. Because of differences between the new WHO outcome measures and those used during this study 0% to 13% of patients could not be classified under the new WHO criteria. These were children who were classified as clinical failures on Day 2 because of fever and a Day 2 parasite density between 25% and 100% of Day 0. In the WHO protocol they would have continued to be monitored, but most would probably have been classified as treatment failures on a later day. The percentage of RII/RIII failures was significantly higher in Chipata than in Chongwe (OR 2.5, 95% CI 1.1, 5.8, P 0.02), Mansa (OR 4.8, 95% CI 1.9, 12.1, P 0.001), and Isoka (OR 2.6, 95% CI 1.2, 5.8, P 0.01). No other differences in the percentages of RII/RIII failures were identified. The number of clinical failures in Isoka was significantly higher than in Mansa (54% vs. 31%, OR 2.6, 95% CI 1.01, 7.02, P 0.03), but no other differences in clinical failure rates were noted. Univariate analysis demonstrated that the mean age of CQ-treated children in Mansa who exhibited RII/RIII resistance was significantly lower than that of children with RI/S responses (16.5 vs months, P anova 0.04). Mean age was not associated with parasitological outcome at the other sites. The child s sex, use of CQ before enrolment, and geometric mean parasite density on enrolment did not affect outcome. No statistically significant differences were identified in age, sex, prior CQ use, or geometric mean parasite density on enrolment in children who were diagnosed as clinical failures compared with those who were not. Parasitological and clinical response to sulphadoxinepyrimethamine Of the 88 children treated with SP, nine were excluded from analysis of SP efficacy, because of administration of additional antimalarial drugs during follow-up (n 5), withdrawal (n 1), hospitalization before Day 2 (n 2),and hospitalization for pneumonia (n 1) Blackwell Science Ltd 539

6 Table 4 Parasitological and clinical outcomes of children with malaria treated with chloroquine at six sites in Zambia Site Chipata Lundazi Choma Chongwe Mansa Isoka No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) Evaluable for parasitological outcomes RIII 18 (25) 10 (25) 10 (20) 12 (26) 3 (8) 11 (20) RII 32 (45) 12 (30) 17 (35) 11 (23) 10 (26) 15 (28) Total RII/RIII 50 (70)* 22 (55) 27 (55) 22 (49) 13 (34)* 26 (48) RI/S 21 (30) 18 (45) 22 (45) 24 (51) 26 (66) 28 (52) Evaluable for clinical outcomes Initial clinical response 48 (83)** 33 (89) 40 (85) 35 (76) 36 (92) 42 (84) Clinical failure 30 (42) 15 (41) 23 (49) 22 (48) 12 (31)* 27 (54)* Day of clinical failure Days (60) 10 (66) 10 (43) 12 (55) 3 (25) 11 (41) Days (13) 1 (7) 1 (4) 1 (5) 1 (8) 3 (11) Days (27) 4 (27) 12 (52) 9 (41) 8 (66) 13 (48) *Significantly different P 0.05; **n 58, 13 patients at Chipata did not have a Day 3 visit and therefore could not be assessed for initial clinical response. Note: Some patients who demonstrated an initial clinical response were also classified as clinical failures on day 3 because of unresponsive parasitaemia despite the absence of fever. Therefore, sum of initial clinical responses and clinical failures on days 2 3 may be greater than the total evaluable number. Table 5 Comparison of parasitological and clinical outcomes between children treated with CQ and SP in Chipata and Lundazi, Zambia Chipata Lundazi SP CQ SP CQ n 71 n 38 OR (95%CI) P-value n 40 n 41 OR (95%CI) P-value Total RII/RIII 50 (70) 1 (3) 88.1 (12.6, ) (55) 6 (17) 5.9 (1.9, 19.4) Evaluable Initial clinical response 48 (83)* 37 (97) 0.13 (0.0, 1.0) (87) 40 (98) 0.16 (0.0, 1.6) 0.1 Clinical failures 30 (42) 1 (3) 27.1 (4.0, ) (39) 1 (2) 26.1 (3.5, ) *n 58, 13 patients at Chipata did not have a Day 3 visit and therefore could not be assessed for initial clinical response. One (2%) of 41 children in Lundazi and none of 38 children in Chipata were classified as RIII failures. RII resistance was identified in six (15%) children in Lundazi and one (3%) in Chipata. Of note, six of the seven RII failures had parasite densities 200 parasites/ l on Day 7 and five of the six had negative blood smears on Day 14 without additional therapy. Thirty-seven (97%) children in Chipata and 40 (98%) in Lundazi demonstrated an initial clinical response. One child at each site was classified as a clinical failure (one ETF, one LTF). Comparison of parasitological and clinical outcomes to CQ and SP In Chipata, 70% of CQ-treated children demonstrated RII/RIII resistance compared with only 3% of SP-treated children (OR 88.1, 95% CI 12.6, , P 0.001) (Table 5). RII/ RIII resistance was also higher in CQ-treated children (55%) than in SP-treated children (17%) in Lundazi (OR 5.9, 95% CI 1.9, 19.4, P 0.001). Clinical failures were more likely to occur in CQ-treated children than SP-treated children in both Chipata (42% vs. 3%, OR 27.1, 95% CI 4.0, , P 0.001) and Lundazi (39% vs. 2%, OR 26.1, 95% CI 3.5, , P 0.001). Resources expended The cost for enrolment and follow-up of 50 children was approximately US$ 2000 per site. This included expenses incurred for personnel (excluding external consultants), supplies, equipment, drugs, incentives, and transportation Blackwell Science Ltd

7 Screening, enrolment, and completion of follow-up at one site took no more than 5 weeks. Discussion These studies provided NMCC with comparable data on drug efficacy from several sites within a one-year period and demonstrated moderate to high levels of resistance to CQ at all sites. RII/RIII failures to CQ ranged from 34% to 70% and clinical failures from 31% to 54%. Regional differences in CQ efficacy were noted, but these studies failed to show higher rates of resistance at sites near the Malawi border, as had been expected. In fact, parasitological and clinical failure rates were among the highest in Choma, the westernmost study site. Testing by another research team at four other sites in Copperbelt, Eastern, Western, and North-western Provinces yielded similar findings (unpublished observation). SP testing at two sites demonstrated its clear superiority to CQ. Only two children treated with SP were classified as clinical failures. Remarkably, six of seven RII failures to SP identified had parasite densities 200/ l on Day 7. Five of the six had no recurrence of fever and parasitaemia resolved by Day 14 without additional therapy. Ongoing surveillance of SP efficacy in Zambia will be necessary to determine whether these five cases are indications of a slow response to a drug with a long half-life or emerging resistance to SP. After testing had been completed, the Ministry of Health convened a consensus meeting in July 1996 which brought together ministry staff with local physicians, researchers, and representatives from CDC, WHO, USAID, and several nongovernmental organizations to review these efficacy data and revise national malaria treatment policy. It was recommended that CQ continue for now as the first-line drug for treatment of uncomplicated malaria, but that all health facilities would have SP available for treatment of persons with persistent or recurrent symptoms after treatment with CQ, regardless of whether or not the initial treatment had been prescribed by a health worker or came from another source. Previously, SP had only been available by physician prescription at referral hospitals. These studies were also the first step toward implementation of a sentinel surveillance system for antimalarial drug efficacy in Zambia, which uses the identical 14-day in vivo study methodology for testing of both CQ and SP at 4 of the established sites, two in Eastern Province and one each in the Copperbelt and Southern Provinces. Testing will be conducted at one site in each of the two regions on alternate years. Two national teams, consisting of a staff scientist and a laboratory technician from NMCC, will supervise testing at each site. Whenever possible, district-level staff that have already participated in these studies will be used to for these assessments. These studies will supply NMCC with comparable efficacy data over time, allowing periodic review of the national malaria treatment policy. A similar approach has proved very useful in Pakistan (Shah et al. 1997). The successful implementation of drug efficacy testing in Zambia has resulted in important advances for the rational assessment of antimalarial drug efficacy. By extending the follow-up period to 14 days, a more complete assessment of clinical response was possible. Had patients only been followed for 7 days, 27% to 66% of clinical failures would not have been identified. A 14-day test is also significantly simpler and less expensive than a 28-day test. Successful assessment of SP efficacy points to the robustness of this method for testing other antimalarial agents. Based in part on the experience in Zambia, WHO has adopted a modified version of this study as its standard protocol for assessing drug efficacy in areas with intense malaria transmission (WHO 1996). In the past, the lack of a systematic approach to assessing and responding to drug- resistant malaria in sub-saharan Africa has impeded the process of national drug policy development and, at times, prolonged the use of ineffective malaria treatment. As resistance to CQ continues to intensify in Africa, malaria control programs in other countries will find it necessary to assess the efficacy of drugs currently used for treatment of malaria and modify their national treatment policies. NMCC and its partners have developed a logical and comprehensive approach to addressing antimalarial drug resistance, which includes a systematic initial assessment of drug efficacy using standardized testing methodology at geographically representative sites, the use of this efficacy data in national drug policy review, and institution of ongoing sentinel surveillance for drug efficacy. This approach could be easily replicated in other countries in the region. Acknowledgements The authors would like to thank the following people for their assistance with the execution of these studies: Matias Lazao, Daka Nguluwe, National Malaria Control Center; Steven Wiersma, MD, MPH, Paul Hartenberger, USAID Mission to Zambia; Petra Wiersma, MD, University Teaching Hospital, University of Zambia; Remi Sogunro, MD, Michael McGunnigle, USAID Zambia Child Health Project; Modest Mulenga, MD, James Chipipa, Tropical Disease Research Center, Zambia; Kingsley Lapukeni, Chipata General Hospital; Delphine Kinkese, Chipata District Health Management Team; N. Charity Nalwambe, Lundazi District Health Management Team. This research was conducted with the financial support of the U.S. Agency for International Development, Washington, D.C Blackwell Science Ltd 541

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