In vivo efficacy and safety of artemether-lumefantrine and amodiaquine-artesunate for uncomplicated Plasmodium falciparum malaria in Mozambique, 2018.

BACKGROUND: Artemisinin-based combination therapy (ACT) has been the recommended first-line treatment for uncomplicated malaria in Mozambique since 2006, with artemether-lumefantrine (AL) and amodiaquine-artesunate (AS-AQ) as the first choice. To assess efficacy of currently used ACT, an in vivo therapeutic efficacy study was conducted. METHODS: The study was conducted in four sentinel sites: Montepuez, Moatize, Mopeia and Massinga. Patients between 6 and 59 months old with uncomplicated Plasmodium falciparum malaria (2000-200,000 parasites/µl) were enrolled between February and September of 2018, assigned to either an AL or AS-AQ treatment arm, and monitored for 28 days. A Bayesian algorithm was applied to differentiate recrudescence from new infection using genotyping data of seven neutral microsatellites. Uncorrected and PCR-corrected efficacy results at day 28 were calculated. RESULTS: Totals of 368 and 273 patients were enrolled in the AL and AS-AQ arms, respectively. Of these, 9.5% (35/368) and 5.1% (14/273) were lost to follow-up in the AL and AS-AQ arms, respectively. There were 48 and 3 recurrent malaria infections (late clinical and late parasitological failures) in the AL and AS-AQ arms, respectively. The day 28 uncorrected efficacy was 85.6% (95% confidence interval (CI) 81.3-89.2%) for AL and 98.8% (95% CI 96.7-99.8%) for AS-AQ, whereas day 28 PCR-corrected efficacy was 97.9% (95% CI 95.6-99.2%) for AL and 99.6% (95% CI 97.9-100%) for AS-AQ. Molecular testing confirmed that 87.4% (42/48) and 33.3% (1/3) of participants with a recurrent malaria infection in the AL and AS-AQ arms were new infections; an expected finding in a high malaria transmission area. Adverse events were documented in less than 2% of participants for both drugs. CONCLUSION: Both AL and AS-AQ have therapeutic efficacies well above the 90% WHO recommended threshold and remain well-tolerated in Mozambique. Routine monitoring of therapeutic efficacy should continue to ensure the treatments remain efficacious. Trial registration Clinicaltrials.gov: NCT04370977.

Quality of antimalarial drugs and antibiotics in Papua New Guinea: a survey of the health facility supply chain.

BACKGROUND: Poor-quality life-saving medicines are a major public health threat, particularly in settings with a weak regulatory environment. Insufficient amounts of active pharmaceutical ingredients (API) endanger patient safety and may contribute to the development of drug resistance. In the case of malaria, concerns relate to implications for the efficacy of artemisinin-based combination therapies (ACT). In Papua New Guinea (PNG), Plasmodium falciparum and P. vivax are both endemic and health facilities are the main source of treatment. ACT has been introduced as first-line treatment but other drugs, such as primaquine for the treatment of P. vivax hypnozoites, are widely available. This study investigated the quality of antimalarial drugs and selected antibiotics at all levels of the health facility supply chain in PNG. METHODS AND FINDINGS: Medicines were obtained from randomly sampled health facilities and selected warehouses and hospitals across PNG and analysed for API content using validated high performance liquid chromatography (HPLC). Of 360 tablet/capsule samples from 60 providers, 9.7% (95% CI 6.9, 13.3) contained less, and 0.6% more, API than pharmacopoeial reference ranges, including 29/37 (78.4%) primaquine, 3/70 (4.3%) amodiaquine, and one sample each of quinine, artemether, sulphadoxine-pyrimethamine and amoxicillin. According to the package label, 86.5% of poor-quality samples originated from India. Poor-quality medicines were found in 48.3% of providers at all levels of the supply chain. Drug quality was unrelated to storage conditions. CONCLUSIONS: This study documents the presence of poor-quality medicines, particularly primaquine, throughout PNG. Primaquine is the only available transmission-blocking antimalarial, likely to become important to prevent the spread of artemisinin-resistant P. falciparum and eliminating P. vivax hypnozoites. The availability of poor-quality medicines reflects the lack of adequate quality control and regulatory mechanisms. Measures to stop the availability of poor-quality medicines should include limiting procurement to WHO prequalified products and implementing routine quality testing.

Substandard artemisinin-based antimalarial medicines in licensed retail pharmaceutical outlets in Ghana.

BACKGROUND & OBJECTIVES: The artemisinin-based antimalarial medicines are first line medicines in the treatment of severe and uncomplicated falciparum malaria. Numerous brands of these medicines manufactured in various countries are available in the Ghanaian market. The study was aimed at evaluating the authenticity and quality of selected brands of artemisinin-based antimalarial medicines marketed in Ghana. METHODS: In all, 14 artemisinin-based antimalarial medicines were purchased from pharmacies (P) and licensed chemical shops (LCSs) in the Kumasi metropolis, Ghana. Simple field tests based on colorimetry and thin layer chromatography were employed in determining the authenticity of the samples. Important quality assessment tests, namely uniformity of mass, crushing strength, disintegration time, and the percentage content of active pharmaceutical ingredients (APIs) were determined. RESULTS: All the brands tested contained the stipulated APIs. Artesunate tablet AT2 failed the uniformity of mass test while artesunate tablets AT3 & AT4 as well as amodiaquine tablets AM4 & AM6 failed the crushing strength test. All the six artemether-lumefantrine tablet brands passed the uniformity of mass, crushing strength and disintegration tests. Only artemether-lumefantrine tablet brand AL1 contained the correct amount of the drugs. The other 13 artemisinin products contained either a lower (underdose) or higher (overdose) amount of the specified drug. Artesunate monotherapy tablets were readily available in pharmacies and licensed chemical shops. INTERPRETATION & CONCLUSION: All the artemisinin-based medicines tested (except AL1) were of substandard quality. The results demonstrate the need for continuous monitoring and evaluation of the quality of artemisininbased antimalarials in the Ghanaian market. Also, the practice of artemisinin antimalarial monotherapy is prevalent in Ghana. Determined efforts should, therefore, be made to eradicate the practice to prevent the development of resistance to the artemisinins.

The quality of sulphadoxine-pyrimethamine and amodiaquine products in the Kenyan retail sector.

BACKGROUND AND OBJECTIVE: Malaria is a disease of major public health importance in Kenya killing 26,000 children under 5 years of age annually. This paper seeks to assess the quality of sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) products available over-the-counter to communities in Kenya as most malaria fevers are self-medicated using drugs from the informal retail sector. METHODS: A retail audit of 880 retail outlets was carried in 2002 in four districts in Kenya, in which antimalarial drug stocks and their primary wholesale sources were noted. In addition, the expiry dates on audited products and the basic storage conditions were recorded on a proforma. The most commonly stocked SP and AQ products were then sampled from the top 10 wholesalers in each district and samples subjected to standard United States Pharmacopoeia (USP) tests of content and dissolution. RESULTS AND DISCUSSION: SP and AQ were the most frequently stocked antimalarial drugs, accounting for approximately 75% of all the antimalarial drugs stocked in the four districts. Of 116 SP and AQ samples analysed, 47 (40.5%) did not meet the USP specifications for content and/or dissolution. Overall, approximately 45.3% of SP and 33.0% of AQ samples were found to be sub-standard. Of the sub-standard SP products, 55.2% were suspensions while 61.1% of the substandard AQ products were tablets. Most SP failures were because of the pyrimethamine component. CONCLUSION: There is a need to strengthen post-marketing surveillance systems to protect patients from being treated with sub-standard and counterfeit antimalarial drugs in Kenya.

Evaluation of the quality of amodiaquine and sulphadoxine/pyrimethamine tablets sold by private wholesale pharmacies in Dar Es Salaam Tanzania.

OBJECTIVE: There are several independent reports in Tanzania of treatment failures with commercially available sulphadoxine/pyrimethamine (SP) and amodiaquine (AQ) brands. The aim of this work was to assess the quality of SP and AQ tablets marketed by wholesale pharmacies in Dar Es Salaam, Tanzania. METHODS: All eight wholesale pharmacies authorized to import medicines and located in Dar Es Salaam were included in the study. From each pharmacy, samples of all SP and AQ brands available at the time of sampling were bought, provided they had a shelf-life of at least 1 year. A sample was either an intact box of 100 tablets or a sealed tin of 100 tablets. To ensure blinding, 30 tablets of each sample were removed from their original containers, coded and sent to the quality control laboratory for analysis. The name, strength, batch number, manufacturer and the expiry dates of the tablets were recorded. In total 15 AQ and 18 SP samples were collected. Identity, assay for content of active ingredients and dissolution assay were performed as described in the United States Pharmacopoeia (USP). RESULTS: All samples passed the identity test. Among the AQ samples collected, two of 15 (13%) failed the dissolution test but all passed the assay for content, whereas two of 18 (11%) and eight of 18 (44%) SP samples failed the assay for content and dissolution tests, respectively. None of the pharmacies stocked all AQ and SP brands. CONCLUSION: This work reveals the availability of poor quality antimalarial drugs on the Tanzanian market. Use of substandard drugs could have serious clinical consequences to patients. The results support the need for continuous monitoring of the quality of marketed drugs to ensure safety and efficacy of these products in the treatment of malaria in endemic areas.