Artemisinin resistance containment project in Thailand. II: responses to mefloquine-artesunate combination therapy among falciparum malaria patients in provinces bordering Cambodia

Abstract Background Artemisinin-based combination therapy (ACT) was deployed in 2005 as an alternative to chloroquine and is considered the most efficacious treatment currently available for uncomplicated falciparum malaria. While widespread artemisinin resistance has not been reported to date in Africa, recent studies have reported partial resistance in Rwanda. The purpose of this study is to provide a current systematic review and meta-analysis on ACT at Mali study sites, where falciparum malaria is highly endemic. Methods A systematic review of the literature maintained in the bibliographic databases accessible through the PubMed, ScienceDirect and Web of Science search engines was performed to identify research studies on ACT occurring at Mali study sites. Selected studies included trials occurring at Mali study sites with reported polymerase chain reaction (PCR)-corrected adequate clinical and parasite response rates (ACPRcs) at 28 days. Data were stratified by treatment arm (artemether–lumefantrine (AL), the first-line treatment for falciparum malaria in Mali and non-AL arms) and analysed using random-effects, meta-analysis approaches. Results A total of 11 studies met the inclusion criteria, and a risk of bias assessment carried out by two independent reviewers determined low risk of bias among all assessed criteria. The ACPRc for the first-line AL at Mali sites was 99.0% (95% CI (98.3%, 99.8%)), while the ACPRc among non-AL treatment arms was 98.9% (95% CI (98.3%, 99.5%)). The difference in ACPRcs between non-AL treatment arms and AL treatment arms was not statistically significant (p = .752), suggesting that there are potential treatment alternatives beyond the first-line of AL in Mali. Conclusions ACT remains highly efficacious in treating uncomplicated falciparum malaria in Mali. Country-specific meta-analyses on ACT are needed on an ongoing basis for monitoring and evaluating drug efficacy patterns to guide local malaria treatment policies, particularly in the wake of observed artemisinin resistance in Southeast Asia and partial resistance in Rwanda.

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Faculty Opinions recommendation of Azithromycin combination therapy with artesunate or quinine for the treatment of uncomplicated Plasmodium falciparum malaria in adults: a randomized, phase 2 clinical trial in Thailand.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1047842.497861 ◽

2006 ◽

Author(s):

David Sullivan

Keyword(s):

Clinical Trial ◽

Plasmodium Falciparum ◽

Combination Therapy ◽

Falciparum Malaria ◽

Plasmodium Falciparum Malaria ◽

Phase 2 ◽

Phase 2 Clinical Trial ◽

Uncomplicated Plasmodium Falciparum Malaria ◽

Randomized Phase 2

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Predictors of treatment failures of plasmodium falciparum malaria in Vietnam: a 4-year single‐centre retrospective study

Malaria Journal ◽

10.1186/s12936-021-03720-3 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Minh Cuong Duong ◽

Oanh Kieu Nguyet Pham ◽

Phong Thanh Nguyen ◽

Van Vinh Chau Nguyen ◽

Phu Hoan Nguyen

Keyword(s):

Plasmodium Falciparum ◽

Treatment Failure ◽

Severe Malaria ◽

Falciparum Malaria ◽

Control Strategies ◽

Artemisinin Resistance ◽

Plasmodium Falciparum Malaria ◽

Molecular Technique ◽

Drug Resistant ◽

Public Health Burden

Abstract Background Drug-resistant falciparum malaria is an increasing public health burden. This study examined the magnitude of Plasmodium falciparum infection and the patterns and predictors of treatment failure in Vietnam. Methods Medical records of all 443 patients with malaria infection admitted to the Hospital for Tropical Diseases between January 2015 and December 2018 were used to extract information on demographics, risk factors, symptoms, laboratory tests, treatment, and outcome. Results More than half (59.8%, 265/443, CI 55.1–64.4%) of patients acquired Plasmodium falciparum infection of whom 21.9% (58/265, CI 17.1–27.4%) had severe malaria, while 7.2% (19/265, CI 4.6–10.9%) and 19.2% (51/265, CI 14.7–24.5%) developed early treatment failure (ETF) and late treatment failure (LTF) respectively. Among 58 patients with severe malaria, 14 (24.1%) acquired infection in regions where artemisinin resistance has been documented including Binh Phuoc (11 patients), Dak Nong (2 patients) and Gia Lai (1 patient). Under treatment with intravenous artesunate, the median (IQR) parasite half-life of 11 patients coming from Binh Phuoc was 3 h (2.3 to 8.3 h), two patients coming from Dak Nong was 2.8 and 5.7 h, and a patient coming from Gia Lai was 6.5 h. Most patients (98.5%, 261/265) recovered completely. Four patients with severe malaria died. Severe malaria was statistically associated with receiving treatment at previous hospitals (P < 0.001), hepatomegaly (P < 0.001) and number of inpatient days (P < 0.001). Having severe malaria was a predictor of ETF (AOR 6.96, CI 2.55–19.02, P < 0.001). No predictor of LTF was identified. Conclusions Plasmodium falciparum remains the prevalent malaria parasite. Despite low mortality rate, severe malaria is not rare and is a significant predictor of ETF. To reduce the risk for ETF, studies are needed to examine the effectiveness of combination therapy including parenteral artesunate and a parenteral partner drug for severe malaria. The study alerts the possibility of drug-resistant malaria in Africa and other areas in Vietnam, which are known as non-endemic areas of anti-malarial drug resistance. A more comprehensive study using molecular technique in these regions is required to completely understand the magnitude of drug-resistant malaria and to design appropriate control strategies.

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Epidemic of Plasmodium falciparum malaria in Central India, an area where chloroquine has been replaced by artemisinin-based combination therapy

Transactions of the Royal Society of Tropical Medicine and Hygiene ◽

10.1016/j.trstmh.2010.11.002 ◽

2011 ◽

Vol 105 (3) ◽

pp. 133-139 ◽

Cited By ~ 10

Author(s):

Neeru Singh ◽

Man M. Shukla ◽

Gyan Chand ◽

Praveen K. Bharti ◽

Mrigendra P. Singh ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Combination Therapy ◽

Falciparum Malaria ◽

Central India ◽

Plasmodium Falciparum Malaria

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A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria

Nature ◽

10.1038/nature14412 ◽

2015 ◽

Vol 520 (7549) ◽

pp. 683-687 ◽

Cited By ~ 320

Author(s):

Alassane Mbengue ◽

Souvik Bhattacharjee ◽

Trupti Pandharkar ◽

Haining Liu ◽

Guillermina Estiu ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Molecular Mechanism ◽

Falciparum Malaria ◽

Artemisinin Resistance ◽

Plasmodium Falciparum Malaria

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The neurological assessment in young children treated with artesunate monotherapy or artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria

Malaria Journal ◽

10.1186/1475-2875-8-207 ◽

2009 ◽

Vol 8 (1) ◽

pp. 207 ◽

Cited By ~ 8

Author(s):

Michael T Ambler ◽

Lilly M Dubowitz ◽

Ratree Arunjerdja ◽

Eh Hla ◽

Kyaw Thwai ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Young Children ◽

Combination Therapy ◽

Falciparum Malaria ◽

Plasmodium Falciparum Malaria ◽

Neurological Assessment ◽

Uncomplicated Plasmodium Falciparum Malaria

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Treatment of Uncomplicated Falciparum Malaria with Artesunate-Amodiaquine Combination Therapy (ACT) in a Rural Fishing Community in Sierra Leone

Sierra Leone Journal of Biomedical Research ◽

10.4314/sljbr.v1i2.53342 ◽

2010 ◽

Vol 1 (2) ◽

Author(s):

F Sahr ◽

M Gevao ◽

A Bockarie ◽

E Ibrahim-Sayo ◽

S Sevalie ◽

...

Keyword(s):

Combination Therapy ◽

Sierra Leone ◽

Falciparum Malaria ◽

Uncomplicated Falciparum Malaria ◽

Fishing Community

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Efficacy of dihydroartemisinin/piperaquine and artesunate monotherapy for the treatment of uncomplicated Plasmodium falciparum malaria in Central Vietnam

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa172 ◽

2020 ◽

Author(s):

Eduard Rovira-Vallbona ◽

Nguyen Van Hong ◽

Johanna H Kattenberg ◽

Ro Mah Huan ◽

Nguyen Thi Thu Hien ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Falciparum Malaria ◽

Ex Vivo ◽

Survival Rates ◽

Artemisinin Resistance ◽

Plasmodium Falciparum Malaria ◽

Parasite Clearance ◽

Resistance Mutations ◽

Malaria Burden ◽

Central Vietnam

Abstract Background Artemisinin-based combination therapies (ACTs) have significantly contributed to reduce Plasmodium falciparum malaria burden in Vietnam, but their efficacy is challenged by treatment failure of dihydroartemisinin/piperaquine ACT in Southern provinces. Objectives To assess the efficacy of dihydroartemisinin/piperaquine for uncomplicated P. falciparum malaria in Gia Lai, Central Vietnam, and determine parasite resistance to artemisinin (ClinicalTrials.gov identifier NCT02604966). Methods Sixty patients received either dihydroartemisinin/piperaquine (4 mg/kg/day, 3 days; n = 33) or artesunate monotherapy (4 mg/kg/day, 3 days; n = 27) followed by dihydroartemisinin/piperaquine (AS + DHA/PPQ). Clinical phenotypes were determined during a 42 day follow-up and analysed together with ex vivo susceptibility to antimalarials and molecular markers of drug resistance. Results Day 3 positivity rate was significantly higher in the AS + DHA/PPQ arm compared with dihydroartemisinin/piperaquine (70.4% versus 39.4%, P = 0.016). Parasite clearance time was 95.2 h (AS + DHA/PPQ) versus 71.9 h (dihydroartemisinin/piperaquine, P = 0.063) and parasite clearance half-life was 7.4 h (AS + DHA/PPQ) versus 7.0 h (dihydroartemisinin/piperaquine, P = 0.140). Adequate clinical and parasitological response at Day 42 was 100% in both arms. By RT–qPCR, 36% (19/53) patients remained positive until Day 7. No recurrences were detected. kelch13 artemisinin resistance mutations were found in 87% (39/45) of isolates and 50% (20/40) were KEL1/C580Y. The piperaquine resistance marker plasmepsin-2 was duplicated in 10.4% (5/48). Isolates from Day 3-positive patients (n = 18) had higher ex vivo survival rates to artemisinin compounds (P < 0.048) and prevalence of kelch13 mutations (P = 0.005) than Day 3-negative patients (n = 5). The WHO definition of artemisinin resistance was fulfilled in 60% (24/40) of cases. Conclusions Although dihydroartemisinin/piperaquine remained effective to treat P. falciparum, the high Day 3 positivity rate and prevalence of KEL1 strains calls for continuous monitoring of dihydroartemisinin/piperaquine efficacy in Central Vietnam.

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Host immunity to Plasmodium falciparum and the assessment of emerging artemisinin resistance in a multinational cohort

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1615875114 ◽

2017 ◽

Vol 114 (13) ◽

pp. 3515-3520 ◽

Cited By ~ 41

Author(s):

Ricardo Ataide ◽

Elizabeth A. Ashley ◽

Rosanna Powell ◽

Jo-Anne Chan ◽

Michael J. Malloy ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Confidence Interval ◽

Falciparum Malaria ◽

Artemisinin Resistance ◽

Parasite Clearance ◽

Host Immunity ◽

Mean Difference ◽

Acquired Immunity ◽

Wild Type ◽

Transmission Potential

Artemisinin-resistant falciparum malaria, defined by a slow-clearance phenotype and the presence of kelch13 mutants, has emerged in the Greater Mekong Subregion. Naturally acquired immunity to malaria clears parasites independent of antimalarial drugs. We hypothesized that between- and within-population variations in host immunity influence parasite clearance after artemisinin treatment and the interpretation of emerging artemisinin resistance. Antibodies specific to 12 Plasmodium falciparum sporozoite and blood-stage antigens were determined in 959 patients (from 11 sites in Southeast Asia) participating in a multinational cohort study assessing parasite clearance half-life (PCt1/2) after artesunate treatment and kelch13 mutations. Linear mixed-effects modeling of pooled individual patient data assessed the association between antibody responses and PCt1/2.P. falciparum antibodies were lowest in areas where the prevalence of kelch13 mutations and slow PCt1/2 were highest [Spearman ρ = −0.90 (95% confidence interval, −0.97, −0.65), and Spearman ρ = −0.94 (95% confidence interval, −0.98, −0.77), respectively]. P. falciparum antibodies were associated with faster PCt1/2 (mean difference in PCt1/2 according to seropositivity, −0.16 to −0.65 h, depending on antigen); antibodies have a greater effect on the clearance of kelch13 mutant compared with wild-type parasites (mean difference in PCt1/2 according to seropositivity, −0.22 to −0.61 h faster in kelch13 mutants compared with wild-type parasites). Naturally acquired immunity accelerates the clearance of artemisinin-resistant parasites in patients with falciparum malaria and may confound the current working definition of artemisinin resistance. Immunity may also play an important role in the emergence and transmission potential of artemisinin-resistant parasites.

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