Second-line Treatments For Uncomplicated Malaria Research Articles

Health workers’ adherence to malaria case management protocols in Northern Sudan: a qualitative study

BackgroundNonadherence to national standards for malaria diagnosis and treatment has been reported in Sudan. In this study, qualitative research examined the clinical domains of nonadherence, factors influencing nonadherent practices and health workers’ views on how to improve adherence.MethodsIn September 2023, five Focus Group Discussions (FGDs) were undertaken with 104 health workers from 42 health facilities in Sudan’s Northern State. The participants included medical assistants, doctors, nurses, laboratory personnel, pharmacists and public health officers. The FGDs followed a semi-structured guide reflecting the national malaria case management protocol. Qualitative thematic analysis was performed.ResultsNonadherent practices included disregarding parasitological test results, suboptimal paediatric artemether–lumefantrine (AL) dosing, lack of counselling, use of prohibited artemether injections for uncomplicated and severe malaria, artesunate dose approximations and suboptimal preparations, lack of AL follow on treatment for severe malaria; and rare use of primaquine for radical Plasmodium vivax treatment and dihydroartemisinin-piperaquine as the second-line treatment for uncomplicated malaria. Factors influencing nonadherence included stock-outs of anti-malarials and RDTs; staff shortages; lack of training, job aids and supervision; malpractice by specialists; distrust of malaria microscopy and RDTs; and patient pressure for diagnosis and treatment. Health workers recommended strengthening the supply chain; hiring personnel; providing in-service protocol training including specialists; establishing external quality assurance for malaria diagnosis; and providing onsite supportive supervision and public health campaigns.ConclusionsThis study revealed a broad spectrum of behavioural and systemic challenges in malaria management among frontline health workers in Northern Sudan, including nonadherence to protocols due to resource shortages, training gaps, a lack of supportive supervision and patient pressure. These insights, including health workers’ views about improvements, will inform evidence-based interventions by Sudan’s National Malaria Control Programme to improve health systems readiness and the quality of malaria case management.

Efficacy of artemether\u2013lumefantrine and dihydroartemisinin\u2013piperaquine for the treatment of uncomplicated malaria in Papua New Guinea

BackgroundIn 2009, the Papua New Guinea (PNG) Department of Health adopted artemether–lumefantrine (AL) and dihydroartemisinin–piperaquine (DHA-PPQ) as the first- and second-line treatments for uncomplicated malaria, respectively. This study was conducted to assess the efficacy of both drugs following adoption of the new policy.MethodsBetween June 2012 and September 2014, a therapeutic efficacy study was conducted in East Sepik and Milne Bay Provinces of PNG in accordance with the standard World Health Organization (WHO) protocol for surveillance of anti-malarial drug efficacy. Patients ≥ 6 months of age with microscopy confirmed Plasmodium falciparum or Plasmodium vivax mono-infections were enrolled, treated with AL or DHA-PPQ, and followed up for 42 days. Study endpoints were adequate clinical and parasitological response (ACPR) on days 28 and 42. The in vitro efficacy of anti-malarials and the prevalence of selected molecular markers of resistance were also determined.ResultsA total of 274 P. falciparum and 70 P. vivax cases were enrolled. The day-42 PCR-corrected ACPR for P. falciparum was 98.1% (104/106) for AL and 100% (135/135) for DHA-PPQ. The day-42 PCR-corrected ACPR for P. vivax was 79.0% (15/19) for AL and 92.3% (36/39) for DHA-PPQ. Day 3 parasite clearance of P. falciparum was 99.2% with AL and 100% with DHA-PPQ. In vitro testing of 96 samples revealed low susceptibility to chloroquine (34% of samples above IC50 threshold) but not to lumefantrine (0%). Molecular markers assessed in a sub-set of the study population indicated high rates of chloroquine resistance in P. falciparum (pfcrt SVMNT: 94.2%, n = 104) and in P. vivax (pvmdr1 Y976F: 64.8%, n = 54).ConclusionsAL and DHA-PPQ were efficacious as first- and second-line treatments for uncomplicated malaria in PNG. Continued in vivo efficacy monitoring is warranted considering the threat of resistance to artemisinin and partner drugs in the region and scale-up of artemisinin-based combination therapy in PNG.

Efficacy of artemisinin-based combination therapies and prevalence of molecular markers associated with artemisinin, piperaquine and sulfadoxine-pyrimethamine resistance in Sierra Leone

Currently, the national malaria control programme (NMCP) of Sierra Leone recommends artesunate–amodiaquine (ASAQ) and artemether–lumefantrine (AL) as first- and second-line treatment for uncomplicated malaria, respectively, and artesunate + sulfadoxine–pyrimethamine (SP) for intermittent preventive treatment during pregnancy and for infants. In 2016, the NMCP conducted a study to assess the clinical and parasitological responses of children under five years to ASAQ, AL and dihydroartemisinin–piperaquine (DHA/PPQ) according to the WHO protocol. Day-0 samples were tested for mutations in the Kelch 13 gene (pfk13) and dihydrofolate reductase/dihydropteroate synthase (pfdhfr/pfdhps) genes associated with artemisinin and SP resistance, respectively, and amplification in the pfplasmepsin2 gene for piperaquine resistance. A total of 295 (ASAQ = 128, AL = 64 and DHA/PPQ = 103) eligible children were enrolled at three sites. PCR-corrected 100% adequate clinical and parasitological response and no parasitaemia on day-3 were observed for all patients in each treatment group. Of the 278 samples with interpretable molecular data, only 2.2% carried non-synonymous pfk13 mutants (A578S, I646T), which are not associated with artemisinin resistance. None of the 103 day-0 samples from the DAH/PPQ group had pfplasmepsin2 gene amplification, confirming the absence of piperaquine resistance. The prevalence of the triple pfdhfr mutant (N51I/C59R/S108N) was close to or reached fixation (97.4–100%). For combined pfdhfr/pfdhps mutation, 55–71% carried the quadruple (N51I/C59R/S108N+A437G) mutant and about 10% the quintuple mutant N51I/C59R/S108N+A437G/K540E. Our findings confirm that ASAQ, AL and DHA/PPQ were highly effective for the treatment of uncomplicated malaria in the study areas, and neither pfk13 validated mutations nor pfplasmepsin2 multiple copies were found. The very low prevalence of the quintuple mutant in this study supports the NMCP’s decision to introduce intermittent preventive treatment for infants with SP in the districts with high malaria transmission.

Co-nanoencapsulation of antimalarial drugs increases their in vitro efficacy against Plasmodium falciparum and decreases their toxicity to Caenorhabditis elegans

Drugs used for the treatment and prevention of malaria have resistance-related problems, making them ineffective for monotherapy. If properly associated, many of these antimalarial drugs may find their way back to the treatment regimen. Among the therapeutic arsenal, quinine (QN) is a second-line treatment for uncomplicated malaria but has side effects that limit its use. Curcumin (CR) is a natural compound with anti-plasmodial activities and low bioavailability. In this context, the aim of this work was to develop and characterize co-encapsulated QN + CR-loaded polysorbate-coated polymeric nanocapsules (NC-QC) to evaluate their activity on Plasmodium falciparum and the safety of the nanoformulations for Caenorhabditis elegans. NC-QC displayed a diameter of approximately 200 nm, a negative zeta potential and a slightly basic pH. The drugs are homogeneously distributed in the NCs in the amorphous form. Co-encapsulated NCs exhibited a significant reduction in P. falciparum parasitemia, better than QN/CR. The worms exposed to NC-QC showed higher survival and longevity and no decrease in their reproductive capacity compared to free and associated drugs. It was possible to prove that the NCs were absorbed orally by the worms using fluorescence microscopy. Co-encapsulation of QN and CR was effective against P. falciparum, minimizing the toxic effects caused by chronic exposure of the free drugs in C. elegans.

In vivo efficacy of artemether-lumefantrine and artesunate-amodiaquine for uncomplicated Plasmodium falciparum malaria in Malawi, 2014.

BackgroundMalaria causes significant morbidity in Malawi, with an estimated 5 million cases in 2014. Artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) are the first- and second-line treatments for uncomplicated malaria, respectively, but emerging resistance threatens their efficacy. In order to understand whether AL and ASAQ remain efficacious for the treatment of uncomplicated Plasmodium falciparum malaria in Malawi, a therapeutic efficacy trial was conducted.MethodsDuring March–July 2014, febrile children aged 6–59 months with microscopy-confirmed uncomplicated P. falciparum malaria (1000–200,000 parasites/μL) were enrolled in a 28-day randomized in vivo efficacy trial at three sites: one each in northern (Karonga), central (Nkhotakota) and southern (Machinga) Malawi. The study was powered to estimate site-specific efficacy for AL and overall efficacy for ASAQ, with 3:1 randomization to AL or ASAQ. Blood was collected for malaria microscopy and molecular testing on days 0–3, 7, 14, 21, and 28. Recrudescence and reinfection were differentiated using polymerase chain reaction (PCR) genotyping of merozoite surface protein. The primary outcome was the PCR-corrected day 28 Kaplan–Meier cumulative success rate.ResultsA total of 452 children were enrolled; 303/338 (89 %) and 98/114 (86 %) reached a study endpoint in AL and ASAQ arms, respectively. All treatment failures occurred after day 3. The day 28 uncorrected cumulative success rate was 97.1 % (95 % confidence interval [CI]: 93.9–100 %) for ASAQ and 76.8 % (95 % CI 72.1–81.5 %) for AL, with 82.5 % (95 % CI 75.4–89.7 %), 69 % (95 % CI 59.9–78.1 %), and 78.2 % (95 % CI 70.2–86.3 %) success in the northern, central, and southern regions, respectively. The day 28 PCR-corrected cumulative success rate was 99 % (95 % CI 97.2–100 %) in the ASAQ arm and 99.3 % (95 % CI 98.3–100 %) in the AL arm, with 98–100 % efficacy in each site.ConclusionsAs evidenced by the day 28 PCR-corrected cumulative success rates, both AL and ASAQ remain efficacious treatments for uncomplicated malaria in Malawi. The lower uncorrected efficacy in the AL arm compared to ASAQ may be explained by the shorter half-life of lumefantrine (3–6 days) compared to amodiaquine (9–18 days). The high reinfection rate suggests that there is a continued need to scale-up effective malaria prevention interventions.

Polymorphisms in Pfmdr1, Pfcrt, and Pfnhe1 genes are associated with reduced in vitro activities of quinine in Plasmodium falciparum isolates from western Kenya.

In combination with antibiotics, quinine is recommended as the second-line treatment for uncomplicated malaria, an alternative first-line treatment for severe malaria, and for treatment of malaria in the first trimester of pregnancy. Quinine has been shown to have frequent clinical failures, and yet the mechanisms of action and resistance have not been fully elucidated. However, resistance is linked to polymorphisms in multiple genes, including multidrug resistance 1 (Pfmdr1), the chloroquine resistance transporter (Pfcrt), and the sodium/hydrogen exchanger gene (Pfnhe1). Here, we investigated the association between in vitro quinine susceptibility and genetic polymorphisms in Pfmdr1codons 86 and 184, Pfcrt codon 76, and Pfnhe1 ms4760 in 88 field isolates from western Kenya. In vitro activity was assessed based on the drug concentration that inhibited 50% of parasite growth (the IC50), and parasite genetic polymorphisms were determined from DNA sequencing. Data revealed there were significant associations between polymorphism in Pfmdr1-86Y, Pfmdr1-184F, or Pfcrt-76T and quinine susceptibility (P < 0.0001 for all three associations). Eighty-two percent of parasites resistant to quinine carried mutant alleles at these codons (Pfmdr1-86Y, Pfmdr1-184F, and Pfcrt-76T), whereas 74% of parasites susceptible to quinine carried the wild-type allele (Pfmdr1-N86, Pfmdr1-Y184, and Pfcrt-K76, respectively). In addition, quinine IC50 values for parasites with Pfnhe1 ms4760 3 DNNND repeats were significantly higher than for those with 1 or 2 repeats (P = 0.033 and P = 0.0043, respectively). Clinical efficacy studies are now required to confirm the validity of these markers and the importance of parasite genetic background.

Antimalarial resistance and DHFR/DHPS genotypes of Plasmodium falciparum three years after introduction of sulfadoxine–pyrimethamine and amodiaquine in rural Tanzania

We assessed the efficacy of sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) and DHFR/DHPS genotypes of Plasmodium falciparum in rural Tanzania, 3 years after their introduction as first- and second-line treatments for uncomplicated malaria, respectively. Under five children with uncomplicated malaria were given standard treatments of either SP (n=66) or AQ (n=30) and treatment outcomes after 14 and 28 days were determined. Total treatment failure of 18 and 42.5% was observed for SP on days 14 and 28, respectively. For AQ, total treatment failure of 27 and 53% was found on day 14 and 28, respectively. On day 14, significantly lower SP total treatment failures were observed in 2004 compared with results from a study conducted in 1999 in the same location. No relationship was detected between clinical outcome and DHFR/DHPS genotypes, but the point mutation prevalence in parasites was higher than in 1999. Pre-treatment blood levels of SP were detected in a quarter of the study children: less than expected. We report unacceptably high levels of total treatment failures, both for first- and second-line treatments for uncomplicated malaria in Tanzania 3 years after their introduction, supporting the decision to replace them with artemisinin-based combination therapy.

Chloroquine or sulfadoxine-pyrimethamine for the treatment of uncomplicated, Plasmodium falciparum malaria during an epidemic in Central Java, Indonesia.

A recent malaria epidemic in the Menoreh Hills of Central Java has increased concern about the re-emergence of endemic malaria on Java, which threatens the island's 120 million residents. A 28-day, in-vivo test of the efficacy of treatment of malaria with antimalarial drugs was conducted among 167 villagers in the Menoreh Hills. The treatments investigated, chloroquine (CQ) and sulfadoxine-pyrimethamine (SP), constitute, respectively, the first- and second-line treatments for uncomplicated malaria in Indonesia. The prevalence of malaria among 1389 residents screened prior to enrollment was 33%. Treatment outcomes were assessed by microscopical diagnoses, PCR-based confirmation of the diagnoses, measurement of the whole-blood concentrations of CQ and desethylchloroquine (DCQ), and identification of the Plasmodium falciparum genotypes. The 28-day cumulative incidences of therapeutic failure for CQ and SP were, respectively, 47% (N = 36) and 22% (N = 50) in the treatment of P. falciparum, and 18% (N = 77) and 67% (N = 6) in the treatment of P. vivax. Chloroquine was thus an ineffective therapy for P. falciparum malaria, and the presence of CQ-resistant P. vivax and SP-resistant P. falciparum will further compromise efforts to control resurgent malaria on Java.