Background
From quinine to chloroquine resistance
In vivo drug resistance
Trials supporting the use of ACT
Recent suspicions of in vivo lumefantrine (LUM) resistance
Resistance to artemisinin derivatives
Reference | Location | Drug therapy | Follow up | Results (between baseline and follow up) | ||
---|---|---|---|---|---|---|
Cambournac et al. [8] | Province: Huambo Type of study: efficacy, case-control (placebo), probably partially randomized. Bind to the patient Sampling date: 1953 Participants: 200, mainly < 515 year old. | Pyrimethamine | 24 weeks | All treated subjects were parasite free after the completion of the trial. 5.4 % of the participants in the control group (placebo) carried parasites at endpoint | ||
Suleimanov SD [62] | Province: Type of study: ex vivo survey Sampling date: 1991–1992 Participants: 105 | CQ Fansidar Quinine-tetracycline | Resistance CQ: 61 % showed resistance Fansidar: 40 % showed resistance Quinine-tetracycline: 56 % were successfully cured Quinine-Delayed elimination of the parasites within 7 days of initiation of the therapy | |||
Guthmann et al. [19] | Provinces: Huambo and Bié Type of study: efficacy, partial randomization, with “absence of allocation concealment” Sampling date: 2002–2003 Participants: 619 children (240 Huambo and 379 Bié) | CQ-Huambo AQ-Huambo and Bié SP-Huambo and Bié AQAS-Bié SPAS-Bié | 28 days | Failure rates CQ-84 % AQ-17 % in Huambo and 22 % in Bié SP: 25 % in Huambo and 39 % in Bié AQAS-1.2 % SPAS-1.2 % | Decreased anemia AQ-86 to 45 % SP–85 to 66 % in Huambo and 93 to 66 % in Bié AQAS–83 to 39 % SPAS-90 to 37 % | |
Guthmann et al. [18] | Provinces: Huambo and Bié Type of study: randomized efficacy trial Sampling date: 2004 Participants: 137 children (6–59 months) | AL ASAQ | 28 days | Reinfection AL-3.2 % ASAQ: 6.2 % | Decreased anemia AL: 54 to 13 % ASAQ: 53 to 16 % | Cure rates AL and ASAQ: 100 % |
Kiaco et al. [29] | Province: Luanda Type of study: Interventional prospective cohort Sampling dates: 2011, 2012 and 2013 Participants 103 children and adults (6 months to 56 years; 37 from 2011, 33 from 2012 and 33 from 2013) | AL | 28 days | Adequate clinical and Parasitological response: 90 % Global failure rate (before PCR correction): 9.7 % Samples With pfmdr1 increased copy number + adequate clinical and Parasitological response: 92 % | Cure rate: 91 % | |
Plucinski et al. [23] | Province: Uíge and Zaire Type of study: open-label, nonrandomized Sampling date: 2013 Participants: 320 children (6–108 months) | AL DHA-PPQ | 28 days | Treatment failure AL-7.5 % DHA-PPQ-0.3 % Adequate clinical and parasitological response AL: Zaire-88 % and Uíge-97 % DHA-PPQ: Zaire-100 % and Uíge-100 % |
Molecular markers of drug resistance
Reference | Study design | Gene | Main results | |||||
---|---|---|---|---|---|---|---|---|
Pinheiro et al. [55] | Province: Luanda Sampling data: unknown Number of participants: 15 Population: Travelers from Luanda (age unknown) |
Pfmdr1
|
Pfmdr1
86: T-73 %* 1246: 0 % | |||||
Pinheiro et al. [55] | Province: unknown Sampling data: unknown Number of participants: 9 from Angola Population: unknown |
pfdhfr
|
Pfdhfr
108: S-11 %, N-11 % 108/51: NI-44 % 108/59: NR-11 % 108/51/59: NIR-22 % | |||||
Kryger et al. [37] | Province: Bengo (Kifangondo) Sampling data: 1999 Number of participants: 168 (59 analyzed) Population: unknown |
pfcrt
|
pfcrt
76:T-98 % | |||||
Pimentel et al. [70] | Province: Luanda Sampling data: 2013/2014 Number of participants: 249 Population: Under 12 years |
pfcytb
|
Pfcytb
268: 0 % of mutations associated to atovaquone-proguanil treatment failure | |||||
Figueiredo et al. [39] | Province: Luanda Sampling data: unknown Number of participants: 245 Population: children between 1–16 years |
pfcrt
pfmdr1
pfdhfr
pfdhps
|
pfcrt
76: T-94 %, K-5.7 % KT-0.4 % |
pfmdr1
86: Y-61 % N-29 % NY-10 % |
pfdhfr
59: C-61 % R-21 % CR-19 % |
pfdhps
540: K-88.3 % E-6.3 % KE-5.4 % |
Pfdhfr/pfdhps
(51/59/108)/ (437/540) Quintuple mutant: IRNGE-9 % | |
Menegon et al. [38] | Province-Úíge Sampling data-2004 Number of participants-66 Population-Children |
pfcrt
pfmdr1
pfdhfr
pfdhps
pfATPase6
|
pfcrt
72/74–76: CIET-94 % CMNK-6 % SMNT-0 % |
pfmdr1
86 Y-36 % N-32 % NY-32 % |
pfdhfr
50C-100 % 51I-95 % 59R-36 % 108N-97 % |
pfdhps
436A-52 % 437G-92 % 540K-100 % 581A-100 % 613A-100 % |
pfATPase6
243Y-3 % 431K-24 % 402/771: VE-3 % 263/623/769: LAS-100 % |
Pfcrt 76/ pfmdr186/ pfdhfr 51,59,108/
Pfdhps436, 437 haplotypes: Sixfold mutated: 36 % Fivefold mutated: 33 % Sevenfold mutated: 14 % |
Gama et al. [40] | Province: Luanda Sampling data: 2007 Number of participants: 114 Population: >18 years |
Pfcrt
Pfmdr1
|
Pfcrt 72-76: CVIET-13 % StctVMNT-57 % CVMNT-3.9 % CVMDT-2.9 % | Pfmdr1 86, 130, 184, 1034, 1042, 1109 and 1246: YEYSNVD-61 % NEFSNVD-11 % NEYSNVD-21 % | ||||
Fortes et al. [64] | Provinces: Huambo, Cabinda, Uíge, Kwanza Norte and Malanje. Sampling data: unknown Number of participants: 452 Population: under five children |
pfdhfr
pfdhps
|
pfdhfr
Total 51: I-90 %, NI-7.5 % 59: C-51 %, R-20 %, CR-29 % 108: N-99 % 51/59/108: IRN-25 %, ICN-72 % Malange 51: N-3.4 %, I-83 %, NI-14 %, 59: C-63 %, R-5.9 %, CR-32 %, 108: S-1.5 %, N-98 %, SN-0.5 % 51/59/108: IRN-3.9 %, ICN-91 % Kuanza Norte 51: N-2.1 %, I-95 %, NI-3 % 59: C-50 %, R-27 %, CR-24 % 108: S-0 %, N-100 %, SN-0 % 51/59/108: IRN-32 %, ICN-65 % Cabinda 51: N-0 %, I-99 %, NI-1.4 % 59: C-28 %, R-48 %, CR-24 %, 108: S-0 %, N-100 %, SN-0 % 51/59/108: IRN-64 %, ICN-36 % Úige 51: N-1.9 %, I-96 %, NI-1.9 % 59: C-36 %, R-28 %, CR-36 % 108: S-0 %, N-100 %, SN-0 % 51/59/108: IRN-41 %, ICN-56 % Huambo 51: N-0 %, I-96 %, NI-4.4 % 59: C-46 %, R-27 %, CR-27 % 108: S-0 %, N-100 %, SN-0 % 51/59/108: IRN-17 %, ICN-83 % |
pfdhps
Total 437: G-83 %, AG-11 % 540: K-87 % 437/540: GK-91 %, GE-3.2 %, AK-5.6 % Malange 437: A-7.7 %, G-75 %, AG-16 % 540: K-91 %, E-2.4 %, KE-6.3 % 437/540: GK-89 %, GE-3.1 %, AK-7.5 % Kuanza Norte 437: A-0 %, G-97 %, AG-3.1 % 540: K-96 %, E-2.1 %, KE-7.5 % 437/540: GK-95 %, GE-2.1 %, AK-3.2 % Cabinda 437: A-12 %, G-86 %, AG-1.5 % 540: K-83 %, E-4.5 %, KE-12 % 437/540: GK-88 %, GE-5.3 %, AK-7.0 % Úige 437: A-0 %, G-96 %, AG-3.7 % 540: K-98 %, E-1.9 %, KE-0 % 437/540: GK-98 %, GE-1.9 %, AK-0 % Huambo 437: A-13 %, G-38 %, AG-50 % 540: K-61 %, E-5.6 %, KE-33 % 437/540: GK-63 %, GE-13 %, AK-25 % |
pfdhfr/pfdhps mix: Total ICN/GK-63 % IRN/GK-25 % Malange ICN/GK-81 % IRN/GK-3.9 % Kuanza-Norte ICN/GK-60 % IRN/GK-29 %) Cabinda ICN/GK-28 % IRN/GK-61 % Uíge ICN/GK-55 %, IRN/GK-45 % Huambo ICN/GK-25.0 % IRN/GK-25.0 % | |||
Fancony et al. [46] | Province: Bengo Sampling data: 2010 Number of participants: 541 Population: children and adult their caretakers |
Pfcrt
Pfmdr1
|
Pfcrt
72–76: CVIET-38 % CVMNK-37 % SVMNK-0 % CVMNK/CVIET-25 % |
Pfmdr1
86: N-68 %, Y-17 %, NY-15 % 184:Y-61 %, F-27 %, YF-12 % 1034, 1042 and 1246: SND-100 % 86/184/1034/1042/1246: YYSND-18 %, NFSND-34 %, NYSND-48 % | ||||
Kaingona [65] | Province: Huíla Sampling data: unknown Number of participants: 110 Population: children and adult their caretakers |
pfdhfr
pfdhps
|
pfdhfr
Total 108: N-98 % 59: R-65 % 51: I-47 % 164: L-2 % Single 108N-2 % Double mutations: 59/108: RN-48 % 51/108: IN-29 % Triple mutations 51/59/108: IRN-17 % 50/51/108 RIN-2 % 59/108/164: RNL-2 % |
pfdhps Total 437: G-96 % , A-4 % Single 437: G-88 % Double mutations 437/540: GE-8.3 % 436/437: A/F+G-4.2 % Triple mutations 436/437/540 SGK-88 % SGE-8 % AGK-4.5 % | ||||
Ngane et al. [47] | Province: Benguela Sampling data: 2010/2011 Number of participants: 60 Population: under 15 years old |
pfcrt
pfmdr1
pfdhfr
pfdhps
|
pfcrt
72-76: CVMNK-11 % CVIET-89 % |
pfmdr1
86, 184, 1034, 1042, 1246: NYSND-35 %, YYSND-48 % NFSND-11 % YFSND-3.7 % YYSNY-1.8 % |
pfdhfr
16, 51, 59, 108, 164 ANCSI-3.4 % ANCNI-1.7 % AICNI-69 % ANRNI-5.2 % AIRNI-21 %. |
pfdhps
436, 437, 540, 581, 613: SAKAA-13 % SAKAA-13 % SGKAA-60 % AGKAA-27 % | ||
Plucinski et al. [23] | Province: Zaire and Uíge Sampling data: 2013 Number of participants: 25 Population: children |
pfmdr1
Chr 10
Chr 13
pfk 13 propeller
|
pfmdr1
86/184/1246: Uíge NFD-17 % NYD-50 % YYD/NFD-17 % YFD/YYD-17 % Zaire NFD-26 % NYD-32 % YYD-5.2 % YYD/NFD-5.2 % YFD/YYD-5.2 % NFD/YYD-5.2 % YYY/NYD-11 % NFY/NYD-5.2 % NYD/NFD-5.2 % | Chr 10 688956: Wild-type-100 % | Chr 13 1718319 Wild-type-100 % |
K13
Wild-type-100 % | ||
Escobar et al. [73] | Province: Luanda, Malange and Kwanza Norte Sampling data: 2003–2010 Number of participants: 100 Population: unknown |
pfk13-propeller
|
K13
471, 493, 539, 543, 575, 580 Total R471R-2 % R575R-1 % 493/539/543/580: HTTY-0 % Malange R471R-1 % R575R-1 % Kwanza Norte-0 % Luanda-R471R-1 % | |||||
Kiaco et al. [29] | Province: Luanda Sampling dates: 2011, 2012 and 2013 Number of participants: 103 (37 from 2011, 33 from 2012 and 33 from 2013) Population: 6 months to 56 years old |
pfmdr1
pfatp6
pfk13-propeller |
pfmdr186: N-73.4 % (68 % in 2011, 69.7 % in 2012 and 82 % in 2013) Y-18.1 % (21 % in 2011, 18 % in 2012 and 15 % in 2013) NY-8.5 % (11 % in 2011, 12 % in 2012 and 3 % in 2013) 1246 D-99 % (100 % in 2011, 97 % in 2012 and 100 % in 2013) Y-1 % (0 % in 2011, 3 % in 2012 and 0 % in 2013) |
pfatp6
769 S-100 % |
K13 493, 539, 543 and 580: Wild-type (YRIC)-100 % |