Abuaku et al. Malar J (2019) 18:206 https://doi.org/10.1186/s12936-019-2848-1 Malaria Journal RESEARCH Open Access Therapeutic efficacy of artesunate– amodiaquine and artemether–lumefantrine combinations for uncomplicated malaria in 10 sentinel sites across Ghana: 2015–2017 Benjamin Abuaku1* , Nancy O. Duah‑Quashie1, Lydia Quaye1, Sena A. Matrevi1, Neils Quashie1,2, Akosua Gyasi3, Felicia Owusu‑Antwi4, Keziah Malm3 and Kwadwo Koram1 Abstract Background: Routine surveillance on the therapeutic efficacy of artemisinin‑based combination therapy (ACT) has been ongoing in Ghana since 2005. The sixth round of surveillance was conducted between 2015 and 2017 to deter‑ mine the therapeutic efficacy of artesunate–amodiaquine (AS–AQ) and artemether–lumefantrine (AL) in 10 sentinel sites across the country. Methods: The study was a one‑arm, prospective, evaluation of the clinical, parasitological, and haematological responses to directly observed treatment with AS–AQ and AL among children 6 months to 9 years old with uncompli‑ cated falciparum malaria. The WHO 2009 protocol on surveillance of anti‑malaria drug efficacy was used for the study with primary outcomes as prevalence of day 3 parasitaemia and clinical and parasitological cure rates on day 28. Secondary outcomes assessed included patterns of fever and parasite clearance as well as changes in haemoglobin concentration. Results: Day 3 parasitaemia was absent in all sites following treatment with AS–AQ whilst only one person (0.2%) was parasitaemic on day 3 following treatment with AL. Day 28 PCR‑corrected cure rates following treatment with AS–AQ ranged between 96.7% (95% CI 88.5–99.6) and 100%, yielding a national rate of 99.2% (95% CI 97.7–99.7). Day 28 PCR‑corrected cure rates following treatment with AL ranged between 91.3% (95% CI 79.2–97.6) and 100%, yielding a national rate of 96% (95% CI 93.5–97.6). Prevalence of fever declined by 88.4 and 80.4% after first day of treatment with AS–AQ and AL, respectively, whilst prevalence of parasitaemia on day 2 was 2.1% for AS–AQ and 1.5% for AL. Gametocytaemia was maintained at low levels (< 5%) during the 3 days of treatment. Post‑treatment mean haemoglobin concentration was significantly higher than pre‑treatment concentration following treatment with either AS–AQ or AL. Conclusions: The therapeutic efficacy of AS–AQ and AL is over 90% in sentinel sites across Ghana. The two anti‑ malarial drugs therefore remain efficacious in the treatment of uncomplicated malaria in the country and continue to achieve rapid fever and parasite clearance as well as low gametocyte carriage rates and improved post‑treatment mean haemoglobin concentration. Keywords: Therapeutic efficacy, Artesunate–amodiaquine, Artemether–lumefantrine, Uncomplicated malaria, Sentinel sites, Ghana *Correspondence: babuaku@noguchi.ug.edu.gh 1 Epidemiology Department, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, P. O. Box LG581, Legon, Accra, Ghana Full list of author information is available at the end of the article © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licens es/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Abuaku et al. Malar J (2019) 18:206 Page 2 of 12 Background to directly observed therapy for uncomplicated malaria Malaria control efforts in Ghana have, over the years, among children aged 6 months to 9 years in 10 sentinel yielded some positive results. The national parasite prev- sites across Ghana. Primary objectives were to assess alence among children aged 6–59  months decreased prevalence of day 3 parasitaemia as well as the clinical from 27.5% in 2011 to 20.4% in 2016 [1, 2]. The propor- and parasitological cure rates on day 28 following treat- tion of out-patients suspected to have malaria decreased ment with AS–AQ and AL. Secondary objectives were from 44% in 2013 to 34% in 2017 [3, 4]. Malaria parasite to assess the patterns of fever and parasite clearance, positivity rates among febrile cases in 30 sentinel sites changes in haemoglobin concentration, gametocyte car- have also shown a significant decline from 23.7% in 2014 riage rates, and prevalence of adverse events. Five of the to 16.7% in 2017 (unpublished data). The proportion of 10 sentinel sites were scheduled to first study AS–AQ deaths that were attributable to malaria declined from followed by AL whilst the other five were scheduled to 19.5% in 2010 to 2.1% in 2017 [4, 5]. Despite the gains first study AL followed by AS–AQ. made in control efforts, malaria remains a major public health problem in Ghana accounting for an annual eco- Study sites nomic loss of approximately US$6.6 million among busi- The study was conducted in all 10 sentinel sites for anti- nesses in the country [6]. malarial drug efficacy monitoring in Ghana (Fig. 1). The Currently, case management remains one of the main sites were Navrongo War Memorial Hospital (NWMH), malaria interventions in Ghana. There are three first-line Yendi Municipal Hospital (YMH) and Wa regional Hos- anti-malarial drugs for treating uncomplicated malaria pital (WRH), located within the northern savannah zone in the country. These are artesunate–amodiaquine (AS– of the country; Sunyani Municipal Hospital (SMH), Bek- AQ) combination, artemether–lumefantrine (AL) com- wai Municipal Hospital (BMH), Begoro Government bination, and dihydroartemisinin–piperaquine (DHAP) Hospital (BGH), Hohoe Municipal Hospital (HMH), combination [7]. AL or DHAP is the drug of choice for and Tarkwa Apinto Government Hospital (TAGH), confirmed uncomplicated malaria following seasonal located within the forest zone of the country; and, Led- malaria chemoprevention (SMC), which has been piloted zokuku Krowor Municipal Hospital (LEKMH) and Ewim and scaled up in the northern savannah zone of the coun- Polyclinic (EWP) located, within the coastal zone of the try using amodiaquine–sulfadoxine/pyrimethamine country. Malaria transmission in the northern savannah (AQ–SP) combination [7, 8]. The emergence and spread zone is perennial with marked seasonal variation and of both artemisinin and partner drug resistance threatens estimated annual entomological inoculation rate (EIR) the efficacy of artemisinin-based combination therapy of up to 1132 infective bites per person per year [16–18]. (ACT) and subsequently undermines the clinical objec- Malaria transmission in the forest zone is intense and tive of treating uncomplicated malaria, which is to elimi- perennial with estimated annual EIR of up to 866 infec- nate all parasites from the body and prevent progression tive bites per person per year [17, 19, 20]. Malaria trans- to severe disease [9, 10]. It is, therefore, necessary to pro- mission in the coastal zone is perennial but not intense vide continuous data on the therapeutic efficacy of first- with estimated annual EIR of fewer than 50 infective bites line ACT to ensure real-time evidence-based review of per person per year [21]. national treatment policies as and when necessary. Since Seven sites (NWMH, SMH, HMH, BMH, BGH, TAGH, the introduction of ACT in Ghana in 2005, there have EWP) were able to study both AS–AQ and AL during the been five rounds of national surveillance on therapeutic study period whilst WRH and LEKMH studied only AS– efficacy [11–14]. This paper presents data on the thera- AQ, and YMH studied only AL. peutic efficacy of AS–AQ and AL combinations from the sixth round of surveillance conducted between August Study population 2015 and December 2017 in 10 sentinel sites across the The study population was made up of febrile children country using the 2009 WHO protocol for surveillance aged 6  months to 9  years suspected to have malaria. of anti-malarial drug efficacy [15]. Efficacy of DHAP was Inclusion criteria were axillary temperature ≥ 37.5  °C or not studied during this round of surveillance because it history of fever during the past 24 h, mono-infection with was cost-effective focusing on the widely supplied and Plasmodium falciparum, parasite count ranging between used ACT (AS–AQ and AL) in the country [4]. 1000 and 250,000/µl, haemoglobin level > 5  g/dl, paren- tal consent, ability and willingness to comply with study Methods protocol, absence of signs/symptoms of severe malaria, Study design absence of severe malnutrition, absence of other causes The study was a one-arm, prospective, evaluation of the of fever such as pneumonia, otitis media, gastroenteritis, clinical, parasitological and haematological responses measles, and urinary tract infection, absence of chronic Abuaku et al. Malar J (2019) 18:206 Page 3 of 12 Fig. 1 Map of Ghana showing sentinel sites for monitoring antimalarial drug efficacy and corresponding PCR‑uncorrected and PCR‑corrected cure rates for AS–AQ and AL disease such as cardiac, renal and hepatic, and, history of product daily for 3 days; (ii) 9 to < 18 kg received a tab- allergy to test medicine. let of the 50/135  mg product daily for 3  days; and, (iii) 18 to < 36 kg received a tablet of the 100/270 mg product Treatment daily for 3 days. The administration of AL (20/120 mg), All anti-malarials used in the study were fixed-dose which was also by weight, was at 0, 8, 24, 36, 48, and 60 h. combinations, and were supplied by WHO, Geneva. Treatment doses were as follows: children weighing: (i) 5 The AS–AQ used were from Sanofi Aventis whilst the to < 15 kg received one tablet per treatment hour; (ii) 15 AL used were from Ipca Laboratories Ltd, India. Treat- to < 25  kg received two tablets per treatment hour; and, ment doses for AS–AQ were as follows: children weigh- (iii) 25 to < 35  kg received three tablets per treatment ing: (i) 4.5 to < 9  kg received a tablet of the 25/67.5  mg hour. All treatments were given under direct observation Abuaku et al. Malar J (2019) 18:206 Page 4 of 12 of a study nurse after satisfying himself/herself that the Data analysis child had eaten. The child was then observed for 30 min A minimum sample size of 50 was computed for each to ascertain retention of anti-malarial. Children who sentinel site based on an estimated treatment failure vomited during the observation period were re-treated rate of 5% at 95% confidence level, 10% precision, and with the same dose of anti-malarial and observed for an 20% loss to follow-up. Data were captured using WHO additional 30 min. Children with repeated vomiting were Microsoft Excel® template for therapeutic efficacy tests withdrawn from the study and treated as severe malaria [15]. Primary treatment outcomes analysed for each ACT according to national standard treatment guidelines were prevalence of day 3 parasitaemia and day 28 PCR- using the following options: (i) intravenous artesunate uncorrected and PCR-corrected outcomes as per WHO (2.4  mg and 3.0  mg/kg body weight for children weigh- criteria: early treatment failure (ETF), late parasitologi- ing ≥ 20 kg and < 20 kg, respectively, on admission, then cal failure (LPF), late clinical failure (LCF), and adequate at 12, 24 h, and daily until patient was able to swallow); clinical and parasitological response (ACPR) [15]. Day or, (ii) intramuscular artemether (3.2 mg/kg body weight 28 treatment outcomes were analysed per protocol and as loading dose and 1.6  mg/kg body weight once daily Kaplan–Meier. Briefly, PCR-uncorrected per protocol until patient was able to swallow). Parenteral treatment analysis excluded children lost to follow-up and with- of severe malaria cases was given for a minimum of 24 h. drawn whilst Kaplan–Meier analysis censored last day A full 3-day course of oral ACT was given when child was of follow-up for such children. PCR-corrected per pro- able to swallow oral medication [7]. All children in the tocol analysis excluded children lost to follow-up, with- study were allowed use of antipyretics (acetaminophen). drawn, with falciparum re-infection, and undetermined PCR whilst Kaplan–Meier analysis censored last day Patient follow‑up of follow-up for those lost to follow-up as well as those All children enrolled were scheduled to visit the outpa- withdrawn or with falciparum re-infection. Children with tient clinic on days 1, 2, 3, 7, 14, 21, and 28 (day 0 being undetermined PCR were also excluded in the Kaplan– the day treatment was started). Enrolled children were Meier analysis [15]. Secondary treatment outcomes ana- clinically examined by the study physician any time they lysed were patterns of fever (i.e. temperature ≥ 37.5  °C) visited the clinic. Asexual parasite densities and presence and parasite clearance during the first week of follow-up, of gametocytes were assessed on days 2, 3, 7, 14, 21, 28, mean differences between pre- (day 0) and post-treat- and any unscheduled visit within the 28 days of follow-up. ment (day 28) haemoglobin concentration, and preva- lence of adverse events. Chi-square and Fisher’s exact Laboratory procedures tests were used to compare proportions whilst Student’s Thick and thin blood smears prepared on the days of para- t-test was used to compare means (significant at p < 0.05). sitological assessment were stained with 3% Giemsa for 30–45  min. Asexual parasites were counted against 200 Results white blood cells using a hand tally counter whilst the Baseline characteristics presence of gametocytes was noted. Parasite densities were Out of a total of 1463 children screened in nine facili- finally expressed per µl blood assuming white blood cell ties to receive AS–AQ, 492 met the inclusion criteria and count of 8000/µl blood. A blood smear was declared nega- were enrolled  (Additional file  1). Apart from one facil- tive after examination of 100 thick-film fields. All blood ity (LEKMA), male/female ratio for those treated with slides were read by two qualified independent micros- AS–AQ was approximately 1:1 with majority of the chil- copists, and discordant readings (in terms of presence or dren (283/492 or 57.5%) under 5 years old. Mean weight absence of parasites: asexual or sexual, species identifi- ranged between 14.4  kg (± 5.3) in WRH and 17.9  kg cation, and day 0 count meeting the inclusion criterion (± 6.0) in NWMH, yielding an overall mean of 16.1  kg of 1000–250,000/µl blood) were re-examined by a third (± 5.5). Mean axillary temperature ranged between qualified independent microscopist, whose reading was 37.7  °C (± 0.9) in SMH and 38.7  °C (± 0.8) in NWMH, considered final. Filter paper blots were obtained on day yielding an overall mean of 38.1  °C (± 1.1). Geomet- 0 and at recurrence of parasitaemia for PCR genotyping ric mean parasitaemia ranged between 9039/µl blood using merozoite surface protein 2 (MSP2)-specific prim- in TAGH and 53,5441/µl blood in NMWH, yielding an ers: FC 27 and 3D7 to distinguish between recrudescence overall mean of 31,119/µl blood. Gametocytaemia was and re-infection [22, 23]. Samples were classified as recru- prevalent in four facilities. Mean haemoglobin concentra- descence when pre-treatment and post-treatment alleles tion ranged between 8.8 g/dl (± 1.8) in WRH and 10.8 g/ had the same band sizes (base pairs). Haemoglobin levels dl (± 1.9) in BGH, yielding an overall mean of 10.1 g/dl were assessed for all study children on days 0 and 28 using (± 1.8) (Table 1). an automated haematology analyzer (Sysmex KX-21N™). Abuaku et al. Malar J (2019) 18:206 Page 5 of 12 Table 1 Demographic, clinical, parasitological, and haematological characteristics of patients treated with AS–AQ at baseline Characteristic NWMH WRH SMH BMH BGH HMH TAGH LEKMH EWP TOTAL n = 55 n = 51 n = 54 n = 63 n = 62 n = 61 n = 61 n = 23 n = 62 N = 492 Male/female 24/31 27/24 28/26 30/33 25/37 33/28 38/23 7/16 32/30 244/248 Age group < 5 years (%) 21 (38.2) 37 (72.5) 35 (64.8) 44 (69.8) 32 (51.6) 37 (60.7) 34 (55.7) 14 (60.9) 29 (46.8) 283 (57.5) 5–9 years 34 14 19 19 30 24 27 9 33 209 Weight (kg) Mean weight (sd) 17.9 (6.0) 14.4 (5.3) 16.1 (5.1) 14.7 (4.9) 16.0 (6.1) 15.5 (4.6) 16.0 (5.4) 17.6 (5.5) 17.2 (6.0) 16.1 (5.5) Range (min, max) 8.0, 30.0 7.1, 27.0 7.0, 27.0 6.6, 35.0 6.1, 32.3 8.0, 27.0 7.2, 29.0 9.0, 29.4 6.7, 30.0 6.1, 35.0 Axillary temperature in °C Mean temperature (sd) 38.7 (0.8) 37.9 (1.0) 37.7 (0.9) 38.2 (1.1) 37.7 (1.1) 38.0 (1.0) 38.6 (1.1) 38.1 (1.2) 38.2 (1.1) 38.1 (1.1) Range (min, max) 37.5, 40.4 36.0, 39.8 36.0, 39.8 35.4, 40.3 35.2, 39.7 36.2, 40.1 36.0, 40.4 35.9, 39.7 35.8, 40.5 35.2, 40.5 Asexual parasitaemia/µl Geometric mean 53,441 42,754 31,815 39,961 29,423 36,917 9039 18,747 41,089 31,119 Range (min, max) 3200, 217,182 1200, 247,040 1391, 208,000 2365, 246,227 1822, 146,686 1747, 206,502 1000, 163,343 3248, 101,423 1340, 229,410 1000, 247,040 Gametocytaemia (%) 0.0 2.0 0.0 0.0 0.0 1.6 1.6 0.0 3.2 1.0 Haemoglobin level in g/dl Mean (sd) 9.6 (1.6) 8.8 (1.8) 10.0 (1.7) 10.3 (2.0) 10.8 (1.9) 10.1 (1.4) 10.5 (1.6) 9.9 (1.7) 10.8 (1.4) 10.1 (1.8) Range (min, max) 6.0, 12.7 5.4, 12.8 6.0, 12.9 6.4, 16.0 5.1, 13.9 6.5, 13.3 6.1, 13.1 7.1, 12.2 7.2, 13.9 5.1, 16.0 sd standard deviation, NWMH Navrongo War Memorial Hospital, WRH Wa Regional Hospital, SMH Sunyani Municipal Hospital, BMH Bekwai Municipal Hospital, BGH Begoro Government Hospital, HMH Hohoe Municipal Hospital, TAGH Tarkwa Apinto Government Hospital, LEKMH Ledzokuku-Krowor Municipal Hospital, EWP Ewim Polyclinic Abuaku et al. Malar J (2019) 18:206 Page 6 of 12 Out of a total of 1068 children screened in eight facili- of 2.3% (1/43), yielding a national rate of 0.2% (1/462). ties to receive AL, 472 met the inclusion criteria and were ETF was reported in three sites: one site after treat- enrolled. Male/female ratio for those treated with AL was ment with AS–AQ and two sites after treatment with AL approximately 1:1 in all sites with majority of the chil- (Table 3), yielding a national rate of 0.2% (1/492) for AS– dren (267/472 or 56.6%) under 5 years old. Mean weight AQ and 0.6% (3/472) for AL (p = 0.634) (Table 3). Nature ranged between 14.0  kg (± 6.0) in YMH and 17.8  kg of the ETF associated with AS–AQ treatment was para- (± 5.3) in HMH, yielding an overall mean of 16.0  kg sitaemia on day 2 higher than day 0 whilst nature of the (± 5.7). Mean axillary temperature ranged between three ETF associated with AL treatment was parasitae- 37.1  °C (± 0.8) in SMH and 38.5  °C (± 0.8) in NWMH, mia on day 3 with axillary temperature > 37.5 °C (1 child) yielding an overall mean of 38.0  °C (± 1.1). Geometric and day 2 parasitaemia higher than day 0 (2 children). mean parasitaemia ranged between 2941/µl blood in Per protocol analysis of treatment outcomes for 473 TAGH and 54,373/µl blood in BGH, yielding an overall and 446 evaluable children who received AS–AQ and AL, mean of 23,534/µl blood. Gametocytaemia was preva- respectively, showed day 28 PCR-uncorrected cure rates lent in only one facility (BMH). Mean haemoglobin con- ranging between 93.5% (95% CI 84.3–98.2) and 100% for centration ranged between 9.0 g/dl (± 1.5) in YMH and AS–AQ (national average of 98.5%; 95% CI 96.8–99.4) 10.9  g/dl (± 1.8) in TAGH, yielding an overall mean of and between 75% (95% CI 61.6–85.6) and 100% for AL 10.1 g/dl (± 1.6) (Table 2). (national average of 90.8%; 95% CI 87.6–93.3). PCR-cor- rected cure rates ranged between 96.7% (95% CI 88.5– Primary outcomes 99.6) and 100% for AS–AQ and between 91.3% (95% CI For all sites that tested AS–AQ, there was no child with 79.2–97.6) and 100% for AL (Fig. 1). The PCR-corrected parasitaemia on day 3. For sites that tested AL, day 3 par- national cure rates were 99.2% (95% CI 97.7–99.7) for asitaemia was prevalent in only one site (SMH) at a rate AS–AQ and 96% (95% CI 93.5–97.6) for AL (p = 0.003). Table 2 Demographic, clinical, parasitological, and haematological characteristics of patients treated with AL at baseline Characteristic NWMH YMH SMH BMH BGH HMH TAGH EWP TOTAL n = 58 n = 60 n = 43 n = 63 n = 63 n = 60 n = 58 n = 67 N = 472 Male/female 29/29 32/28 20/23 34/29 32/31 33/27 32/26 37/30 249/223 Age group < 5 years (%) 33 (56.9) 33 (55.0) 32 (74.4) 45 (71.4) 34 (54.0) 19 (31.7) 37 (63.8) 34 (50.7) 267 (56.6) 5–9 years 25 27 11 18 29 41 21 33 205 Weight (kg) Mean weight 15.9 (5.2) 14.0 (6.0) 15.4 (4.7) 14.1 (4.3) 17.3 (6.9) 17.8 (5.3) 16.2 (5.9) 17.1 (5.8) 16.0 (5.7) (sd) Range (min, 8.0, 29.0 5.0, 35.0 8.0, 30.0 8.0, 26.0 7.0, 35.0 7.8, 32.0 6.2, 33.0 7.0, 40.0 5.0, 40.0 max) Axillary temperature in °C Mean tem‑ 38.5 (1.2) 37.6 (0.9) 37.1 (0.8) 38.3 (1.2) 38.0 (1.3) 38.2 (0.9) 38.3 (1.0) 38.0 (1.1) 38.0 (1.1) perature (sd) Range (min, 36.1, 40.5 36.0, 39.5 35.5, 39.8 35.7, 41.5 35.8, 40.8 37.0, 40.8 35.7, 40.2 36.1, 40.7 35.5, 41.5 max) Asexual parasitaemia/µl Geometric 14,454 36,433 23,957 21,975 54,373 40,198 2941 44,238 23,534 mean Range (min, 2200, 183,680 1035, 218,877 1040, 211,400 2528, 215,615 5963, 226,615 5040, 24,783 1120, 65,800 1200, 249,960 1035, 249,960 max) Gametocytae‑ 0.0 0.0 0.0 1.6 0.0 0.0 0.0 0.0 0.2 mia (%) Haemoglobin level in g/dl Mean (sd) 9.5 (1.6) 9.0 (1.5) 10.4 (1.2) 9.7 (1.3) 10.4 (1.4) 10.2 (1.1) 10.9 (1.8) 10.8 (1.7) 10.1 (1.6) Range (min, 6.2, 11.9 5.4, 13.4 7.3, 12.5 6.4, 13.0 7.2, 13.8 7.1, 12.3 7.7, 15.2 6.5, 16.6 5.4, 16.6 max) sd standard deviation, NWMH Navrongo War Memorial Hospital, YMH Yendi Municipal Hospital, SMH Sunyani Municipal Hospital, BMH Bekwai Municipal Hospital, BGH Begoro Government Hospital, HMH Hohoe Municipal Hospital, TAGH Tarkwa Apinto Government Hospital, EWP Ewim Polyclinic Abuaku et al. Malar J (2019) 18:206 Page 7 of 12 Table 3 Day 28 PCR-uncorrected study endpoints for children enrolled Antimalarial drug Treatment Sentinel site Total outcome WRH NWMH YMH SMH BMH BGH HMH TAGH LEKMH EWP AS–AQ n = 51 n = 55 n = 0 n = 54 n = 63 n = 62 n = 61 n = 61 n = 23 n = 62 N = 492 ETF 0 1 – 0 0 0 0 0 0 0 1 LCF 0 0 – 0 0 0 0 0 0 0 0 LPF 0 0 – 0 1 1 0 0 0 4 6 ACPR 45 54 – 51 62 58 58 60 20 58 466 LFU 5 0 – 3 0 3 3 1 3 0 18 WTH 1 0 – 0 0 0 0 0 0 0 1 Antimalarial drug Treatment Sentinel site Total outcome WRH NWMH YMH SMH BMH BGH HMH TAGH LEKMH EWP AL n = 0 n = 58 n = 60 n = 43 n = 63 n = 63 n = 60 n = 58 n = 0 n = 67 N = 472 ETF – 0 0 1 0 0 0 2 – 0 3 LCF – 0 0 0 1 1 0 0 – 0 2 LPF – 5 3 3 3 1 0 12 – 9 36 ACPR – 53 54 39 59 57 47 42 – 54 405 LFU – 0 0 0 0 2 13 2 – 1 18 WTH – 0 3 0 0 2 0 0 – 3 8 WRH Wa Regional Hospital, NWMH Navrongo War Memorial Hospital, YMH Yendi Municipal Hospital, SMH Sunyani Municipal Hospital, BMH Bekwai Municipal Hospital, BGH Begoro Government Hospital, HMH Hohoe Municipal Hospital, TAGH Tarkwa Apinto Government Hospital, LEKMH Ledzokuku-Krowor Municipal Hospital, EWP Ewim Polyclinic, ETF early treatment failure, LCF late clinical failure, LPF late parasitological failure, ACPR adequate clinical and parasitological response, LFU loss to follow-up, WTH withdrawn Site-specific cure rates for sites that studied both AS– The overall proportion of children with parasitaemia AQ and AL showed no significant differences between on day 2 following treatment with AS–AQ was not sig- the two drugs: NWMH (98.2% vs. 98.1%; p = 0.502); nificantly different from children treated with AL (2.1% SMH (100% vs. 92.9%; p = 0.179); BMH (100% vs. 96.7%; vs. 1.5%; p = 0.655) (Fig. 3). This pattern was observed in p = 0.464); BGH (98.3% vs. 100%; p = 0.989); HMH (100% all sites that studied both AS–AQ and AL. Subsequently, vs. 100%); TAGH (100% vs. 91.3%; p = 0.070); and EWP the proportion of children with parasitaemia on day 3 (96.7% vs. 91.5%; p = 0.415). Day 28 cumulative cure rates and day 7 following treatment with AS–AQ was not sig- per Kaplan–Meier analysis showed similar rates as per nificantly different from children treated with AL (0.0% protocol analysis (Table 4). vs. 0.2%; p = 0.956 for day 3 and 0.0% vs. 0.2%; p = 0.947 for day 7) (Fig. 3). Although pre-treatment (day 0) game- tocytaemia was prevalent among children in the two Secondary outcomes treatment groups, there was no evidence of gametocytae- The overall proportion of children with axillary tempera- mia in either group by day 7 post-treatment (Fig. 4). ture ≥ 37.5  °C significantly declined after the first day of The overall mean haemoglobin concentration signifi- treatment with either AS–AQ (from 72.2%; 95% CI 68.0– cantly increased on day 28 compared with day 0 following 76.1 to 8.4%; 95% CI 6.1–11.4; p < 0.001) or AL (from treatment with either AS–AQ (10.1 g/dl ± 1.8 vs. 11.1 g/ 70.3%; 95% CI 65.9–74.4 to 13.8%; 95% CI 10.9–17.4; dl ± 1.5; p < 0.001) or AL (10.1 g/dl ± 1.6 vs. 10.9 g/dl ± 1.2; p < 0.001) (Fig. 2). The significant decline was observed in p < 0.001. There was only one site, NWMH, located in the all sites. However, the overall proportion of children with savannah zone with no significant increase in haemo- axillary temperature ≥ 37.5 °C after first day of treatment globin concentration following treatment with AS–AQ was significantly higher among those who received AL whilst two sites (TAGH, located in the forest zone and compared with those who received AS–AQ (13.8%; 95% EWP, located in the coastal zone) showed no significant CI 10.9–17.4 vs. 8.4%; 95% CI 6.1–11.4; p = 0.011). By day increase following treatment with AL (Table 5). 7 there was no significant difference between AS–AQ The main adverse event reported was vomiting. Prev- and AL in terms of proportion of children with axillary alence of vomiting during the three days of treatment temperature ≥ 37.5 °C (0.7% vs. 1.1%; p = 0.778) (Fig. 2). declined with day for both AS–AQ and AL from day 0 Abuaku et al. Malar J (2019) 18:206 Page 8 of 12 Table 4 Site-specific day 28 PCR-uncorrected and PCR-corrected cure rates (per protocol and Kaplan–Meier) Site PCR‑uncorrected PCR‑corrected AS–AQ AL AS–AQ AL PP KM PP KM PP KM PP KM n % (95% CI) n % (95% CI) n % (95% CI) n % (95% CI) n % (95% CI) n % (95% CI) n % (95% CI) n % (95% CI) NWMH 55 98.2 (90.3–100.0) 55 98.2 (87.8–99.7) 58 91.4 (81.0–97.1) 58 91.4 (80.5–96.3) 55 98.2 (90.3–100.0) 55 98.2 (87.8–99.7) 54 98.1 (90.1–100.0) 54 98.1 (87.6–99.7) WRH 45 100.0 (92.1–) 51 100.0 (n/a) – – – – 45 100.0 (92.1–) 51 100.0 (n/a) – – – – YMH – – – – 57 94.7 (85.4–98.9) 60 94.7 (84.6–98.3) – – – – 56 96.4 (87.7–99.6) 59 96.4 (86.5–99.1) SMH 51 100.0 (93.0–) 54 100.0 (n/a) 43 90.7 (77.9–97.4) 43 90.7 (77.1–96.4) 51 100.0 (93.0–) 54 100.0 (n/a) 42 92.9 (80.5–98.5) 42 92.9 (79.5–97.6) BMH 63 98.4 (91.5–100.0) 63 98.4 (89.3–99.8) 63 93.7 (84.5–98.2) 63 93.7 (84.0–97.6) 62 100.0 (94.2–) 63 100.0 (n/a) 61 96.7 (88.7–99.6) 61 96.7 (87.5–99.2) BGH 59 98.3 (90.9–100.0) 62 98.3 (88.6–99.8) 59 96.6 (88.3–99.6) 63 96.6 (87.1–99.1) 59 98.3 (90.0–100.0) 62 98.3 (88.6–99.8) 57 100.0 (93.7–) 61 100.0 (n/a) HMH 58 100.0 (93.8–) 61 100.0 (n/a) 47 100.0 (92.5–) 60 100.0 (n/a) 58 100.0 (93.8–) 61 100.0 (n/a) 47 100.0 (92.5–) 60 100.0 (n/a) TAGH 60 100.0 (94.0–) 61 100.00 (n/a) 56 75.0 (61.6–85.6) 58 75.4 (62.0–84.6) 60 100.0 (94.0–) 61 100.0 (n/a) 46 91.3 (79.2–97.6) 53 92.2 (80.4–97.0) LEKMH 20 100.0 (83.2–) 23 100.0 (n/a) – – – – 20 100.0 (83.2–) 23 100.0 (n/a) – – – – EWP 62 93.5 (84.3–98.2) 62 93.5 (83.7–97.5) 63 85.7 (74.6–93.3) 67 85.7 (74.3–92.3) 60 96.7 (88.5–99.6) 62 96.8 (87.7–99.2) 59 91.5 (81.3–97.2) 65 91.7 (81.2–96.5) Overall 473 98.5 (96.8–99.3) 492 98.5 (96.9–99.3) 446 90.8 (87.6–93.2) 472 90.9 (87.9–93.2) 470 99.2 (97.7–99.7) 492 99.2 (97.8–99.7) 422 96.0 (93.5–97.6) 455 96.1 (93.8–97.5) PP per protocol, KM Kaplan–Meier, WRH Wa Regional Hospital, NWMH Navrongo War Memorial Hospital, YMH Yendi Municipal Hospital, SMH Sunyani Municipal Hospital, BMH Bekwai Municipal Hospital, BGH Begoro Government Hospital, HMH Hohoe Municipal Hospital, TAGH Tarkwa Apinto Government Hospital, LEKMH Ledzokuku-Krowor Municipal Hospital, EWP Ewim Polyclinic, n/a not applicable Abuaku et al. Malar J (2019) 18:206 Page 9 of 12 Table 5 Changes in  mean haemoglobin levels after  treatment with  AS–AQ and  AL in  sentinel sites in Ghana Antimalarial drug Site Mean Hb (sd) p‑value Day 0 Day 28 AS–AQ WRH 8.8 (1.8) 9.6 (1.2) 0.015 NWMH 9.6 (1.6) 9.9 (1.2) 0.268 SMH 10.0 (1.7) 11.0 (1.0) 0.008 BMH 10.3 (2.0) 11.1 (1.6) 0.015 BGH 10.9 (1.9) 11.7 (1.1) 0.006 HMH 10.1 (1.4) 11.5 (0.9) < 0.001 TAGH 10.5 (1.6) 11.2 (1.2) 0.015 Fig. 2 Proportion of children with measured fever LEKMH 9.9 (1.7) 11.5 (0.8) < 0.001 (temperature ≥ 37.5 °C) during first week of follow‑up EWP 10.8 (1.4) 12.1 (1.7) < 0.001 Overall 10.1 (1.8) 11.1 (1.5) < 0.001 AL NWMH 9.5 (1.6) 10.6 (1.2) 0.001 YMH 9.0 (1.5) 10.4 (1.5) < 0.001 SMH 10.5 (1.2) 11.3 (0.8) 0.001 BMH 9.7 (1.3) 10.8 (0.8) < 0.001 BGH 10.4 (1.4) 11.4 (1.1) < 0.001 HMH 10.2 (1.1) 10.9 (0.9) 0.001 TAGH 10.9 (1.8) 11.4 (1.4) 0.103 EWP 10.8 (1.7) 10.9 (1.1) 0.693 Overall 10.1 (1.6) 10.9 (1.2) < 0.001 WRH Wa Regional Hospital, NWMH Navrongo War Memorial Hospital, YMH Yendi Municipal Hospital, SMH Sunyani Municipal Hospital, BMH Bekwai Municipal Hospital, BGH Begoro Government Hospital, HMH Hohoe Municipal Hospital, TAGH Tarkwa Apinto Government Hospital, LEKMH Ledzokuku-Krowor Municipal Hospital, EWP Ewim Polyclinic Fig. 3 Proportion of children with parasites during first week of follow‑up vs. 0.4% on day 2 (p < 0.001). No serious adverse event was reported. Discussion Routine surveillance on the therapeutic efficacy of anti- malarials in sentinel sites across Ghana has been ongoing since the introduction of ACT in 2005. For five rounds of surveillance conducted between 2005 and 2013, each of the 10 sites representing the 10 regions of the coun- try were scheduled to study either AS–AQ or AL. For the purpose of obtaining site-specific efficacy data for both AS–AQ and AL in one round of surveillance, each sen- tinel site was scheduled to test both anti-malarials dur- ing the 2015–2017 round of surveillance. Seven of the Fig. 4 Proportion of children with gametocytaemia during first 10 sites successfully tested both AS–AQ and AL whilst week of follow‑up. Dark blue line represents AS–AQ and dark red line represents AL two sites tested only AS–AQ and another site tested only AL. The primary outcomes assessed were: (i) prev- alence of day 3 parasitaemia, which is an indicator of to day 2. The proportions were, however, significantly suspected artemisinin (partial) resistance; and, (ii) a day higher among children who received AS–AQ compared 28 treatment outcome, which is an indicator of partner with those who received AL: 17.3% vs. 10.9% on day 0 drug resistance [24]. Secondary outcomes assessed were (p = 0.001); 8.2% vs. 1.5% on day 1 (p < 0.001); and 6.5% Abuaku et al. Malar J (2019) 18:206 Page 10 of 12 patterns of fever and parasite clearance as well as changes A commonly reported adverse event following in haemoglobin levels and prevalence of adverse events. treatment with either AS–AQ or AL was vomiting. The study showed no presence of parasitaemia on day Prevalence of vomiting on each day of treatment was 3 following treatment with AS–AQ in all sites whilst only significantly higher among children treated with AS– one person (0.2%) was parasitaemic on day 3 following AQ compared with those treated with AL. This finding treatment with AL. This finding is far below the WHO suggests that AL may be more tolerable than AS–AQ threshold of 10%, and therefore suggests that artemisinin influencing patient preference and use as reported by (partial) resistance following ACT treatment of falcipa- Chatio and colleagues [33]. rum malaria is not a problem in Ghana [24]. The main limitation of this study is the lack of phar- The overall day 28 cure rates were 99.2% for AS–AQ macokinetic data to better explain the recrudescence and 96.0% for AL, yielding ACT treatment failure rates observed. The cure rates for AS–AQ and AL may there- of between 0.8 and 4.0%. The ACT treatment failure rates fore be higher than the rates observed. Furthermore, in observed are below the WHO threshold of 10%, and view of the fact that this study was not a randomized therefore suggest that amodiaquine and lumefantrine are trial, it cannot be concluded that AS–AQ is superior not failing as partner drugs in ACT use in Ghana [24]. to AL even though its overall cure rate appeared to be The high ACT cure rates compare well with other find- higher than that of AL. ings in previous studies in the country and other parts of Africa [9, 11–14, 25–32]. Although this study was not a comparative one, it was observed that in the seven sites Conclusions that studied both AS–AQ and AL there were no statisti- The therapeutic efficacy of AS–AQ and AL are over cally significant differences in cure rates even though the 90% in sentinel sites across Ghana. The two anti-malar- overall cure rate for AS–AQ was significantly higher than ial drugs therefore remain efficacious in the treatment that of AL (99.2% vs. 96.0%; p = 0.003). This observation of uncomplicated malaria in the country achieving of seemingly significant difference between the overall rapid fever and parasite clearance as well as low game- cure rates of AS–AQ and AL when site-specific rates did tocyte carriage rates and improved post-treatment not show such significant difference, raises the need to mean haemoglobin concentration. consider site-specific efficacy data in national anti-malar- ial drug policy reviews. Both AS–AQ and AL showed rapid fever and parasite Additional file clearance during the first week of follow-up in all sites. Overall prevalence of fever declined by 88.4 and 80.4% Additional file 1. Participant flow showing number screened, enrolled after first day of treatment with AS–AQ and AL, respec- and included in the per‑protocol population. tively, whilst prevalence of parasitaemia on day 2 was 2.1% for AS–AQ and 1.5% for AL. Gametocytaemia was Abbreviations absent on day 7 following treatment with either AS–AQ ACT: artemisinin‑based combination therapy; AS–AQ: artesunate–amodi‑ or AL. These findings suggest that ACT remains effec- aquine; AL: artemether–lumefantrine; DHAP: dihydroartemisinin–piperaquine; PCR: polymerase chain reaction; WHO: World Health Organization; NMWH: tive in rapidly clearing fever and asexual parasites as well Navrongo War Memorial Hospital; WRH: Wa Regional Hospital; YMH: Yendi as reducing gametocyte carriage rates in Ghana [12–14, Municipal Hospital; SMH: Sunyani Municipal Hospital; BMH: Bekwai Municipal 25–32]. Hospital; BGH: Begoro Government Hospital; HMH: Hohoe Municipal Hospital; TAGH: Tarkwa Apinto Government Hospital; LEKMH: Ledzokuku‑Krowor Generally, post-treatment mean haemoglobin concen- Municipal Hospital; EWP: Ewim Polyclinic; ETF: early treatment failure; LPF: late tration following treatment with either AS–AQ or AL parasitological failure; LCF: late clinical failure; ACPR: adequate clinical and was higher than pre-treatment concentration. Only one parasitological response; IRB: Institutional Review Board; GHS: Ghana Health Service; NMIMR: Noguchi Memorial Institute for Medical Research. of the nine sites that studied AS–AQ and two of the eight sites that studied AL did not show a significant increase Acknowledgements in post-treatment haemoglobin concentration. It is worth The authors wish to acknowledge the contributions of Dr. Jackson Sillah (WHO‑AFRO), Dr. Marian Warsame (WHO, Geneva), Dr. Pascal Ringwald (WHO, noting that all the three sites that did not show significant Geneva) and study teams in the 10 sentinel sites. We also wish to thank increase in post-treatment haemoglobin concentration Messrs. Abdul Haruna (NMIMR, Accra), Charles Attiogbe (NMIMR, Accra) and following treatment with either AS–AQ or AL showed Roger Tagoe (GHS, Koforidua) for their technical assistance. increases of between 0.1 and 0.5  g/dl, suggesting that Authors’ contributions ACT treatment has a positive impact on post-treatment BA, KM, AG, FOA and KK conceived and designed the study. NDQ, SAM and haemoglobin levels as shown in previous studies [11, NQ carried out molecular genetic studies to distinguish between re‑infection and recrudescence. BA, KM, AG and LQ coordinated the study. BA and KK 25–32]. participated in the data analysis. BA drafted the manuscript. All authors read and approved the final manuscript. Abuaku et al. Malar J (2019) 18:206 Page 11 of 12 Funding 12. Abuaku B, Duah N, Quaye L, Quashie N, Koram K. Therapeutic efficacy of The study received financial support from the Global Fund to fight AIDS, artemether–lumefantrine combination in the treatment of uncompli‑ Tuberculosis and Malaria (GFATM), through the Ghana National Malaria Control cated malaria among children under five years of age in three ecological Programme. zones in Ghana. Malar J. 2012;11:388. 13. Abuaku B, Quaye L, Quashie N, Quashie N, Koram KA. Managing antima‑ Availability of data and materials larial drug resistance in Ghana: the importance of surveillance. In: Koram Data supporting the conclusions of this article are included within the article. KA, Ahorlu CSK, Wilson MD, Yeboah Manu D, Bosompem KM, editors. The datasets analyzed are available upon reasonable request to the cor‑ Towards effective disease control in Ghana: research and policy implica‑ responding author. tions, vol. 1. Accra: University of Ghana reader series; 2014. p. 7–18. https ://books .googl e.com.gh/books ?isbn=99886 47506 . Ethics approval and consent to participate 14. Abuaku B, Duah N, Quaye L, Quashie N, Malm K, Bart‑Plange C, et al. The study received approval from the Institutional Review Board (IRB) of the Therapeutic efficacy of artesunate–amodiaquine and artemether–lume‑ Noguchi Memorial Institute for Medical Research, University of Ghana. Written fantrine combinations in the treatment of uncomplicated malaria in two informed consent was obtained from each parent/guardian at the start of the ecological zones in Ghana. Malar J. 2016;15:6. study. Each parent/guardian was informed of the objectives, methods, antici‑ 15. WHO. Methods for surveillance of antimalarial drug efficacy. Geneva: pated benefits and potential hazards of the study. They were also informed World Health Organization; 2009. that they were at liberty to withdraw their children from the study at any time 16. Kasasa S, Asoala V, Gosoniu L, Anto F, Adjuik M, Tindana C, et al. Spatio‑ without penalty. temporal malaria transmission patterns in Navrongo demographic surveillance site, northern Ghana. Malar J. 2013;12:63. Consent for publication 17. Asare EO, Amekudzi LK. Assessing climate driven malaria variability in Not applicable. Ghana using a regional scale dynamical model. Climate. 2017. https ://doi. org/10.3390/cli50 10020 . Competing interests 18. Appawu M, Owusu‑Agyei S, Dadzie S, Asoala V, Anto F, Koram K, Rogers The authors declare that they have no competing interests. W, Nkrumah F, Hoffman SL, Fryauff DJ. Malaria transmission dynamics at a site in northern Ghana proposed for testing malaria vaccines. 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Efficacy of artesunate plus amodiaquine versus that of artemether–lumefantrine for the treatment of uncomplicated childhood Publisher’s Note Plasmodium falciparum malaria in Zanzibar, Tanzania. Clin Infect Dis. Springer Nature remains neutral with regard to jurisdictional claims in pub‑ 2005;41:1079–86. lished maps and institutional affiliations. Ready to submit your research ? Choose BMC and benefit from: • fast, convenient online submission • thorough peer review by experienced rese archers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations • maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions