Novartis Sweeps Access Index but KLU156 and Newborn Data Remain Unproven

Limited access and affordability of quality-assured ACT in the private sector: Less than a third, 27.7% (309/1114) of private drug outlet clients obtained a QAACT for management of malaria symptoms. Of participants who obtained QAACT, more than half 56.9% (173/309) reported finding the medicine expensive, and individuals who did not find artemisinin-based combinations to be expensive were more likely to obtain a QAACT anti-malarial (aPR = 1.24; 95%CI 1.03, 1.49). Additional predictors included type of drug outlet visited (aPR = 0.74; 95%CI 0.6, 0.91), not obtaining full dose (3-day treatment) of ACT (aPR = 0.49; 95%CI 0.33, 0.73), post-primary education (aPR = 1.29; 95%CI 1.07,1.56), business occupation (aPR = 1.24; 95%CI 1.02,1.50) and not having a prescription (aPR = 0.76; 95%CI 0.63, 0.92), with 77.9% (868/1114) obtaining anti-malarial agents without a prescription.

High burden of substandard and falsified medicines: Overall, 17.9% (95% CI 13.6-22.7) of tested medicines failed quality standards across 36,069 medicine samples. Substandard medicines accounted for most poor-quality products (pooled prevalence 12.8%), while falsified medicines were less common (1.2%), with antimalarials among classes ranging from 15-20% failure.

Artemisinin and partner-drug resistance: Artemisinin resistance, defined as a delayed time to parasite clearance following administration of artemisinin, is associated with mutations in the propeller domain of the Kelch family protein K13. Day-3 positive parasites featuring reduced sensitivity occurred without pfkelch13 mutation, with two new Pfcoronin SNVs (I68G and L173F) in addition to the P76S earlier reported identified in a recrudescent isolate. Resistance to partner drugs involves point mutations in PfCRT and PfMDR1 and amplification of pfmdr1 and plasmepsin 2 and 3, with the quintuple mutant genotype from dhfr triple mutant (51I/59R/108N) with dhps double mutant 436A/437G detected at 30% in Benin samples.

G6PD-related safety restrictions for 8-aminoquinoline radical cure: Both primaquine and tafenoquine can cause acute haemolytic anaemia in individuals with G6PD deficiency, and tafenoquine should only be given to those with G6PD activity >70% of the local population median. G6PD deficiency screening is usually unavailable at point of care, radical cure is greatly underused, and long courses of 7 or 14 days may result in poor adherence and low treatment efficacy. Both drugs are currently considered contraindicated in pregnant and lactating women, and impaired CYP2D6 metabolism has been associated with primaquine treatment failure with 88.9% of patients with impaired CYP2D6 activity relapsing with related parasite.

Severe and cerebral malaria management gaps: Cerebral malaria remains a critical condition with a mortality rate of 15-25% and long-term neurological sequelae in survivors. Intravenous artesunate is the first-line drug, with no proven benefit for adjunctive therapies in routine care, and neuromonitoring strategies are critical yet underutilized in adults with CM. Patients with cerebral malaria are unable to take oral medication due to impaired consciousness and vomiting, presently there is no intravenous formulation available for combination therapy, and rectal artesunate shows variable absorption.

Diagnostic limitations affecting treatment decisions: Plasmodium falciparum can sequester in the placenta resulting in low density peripheral parasitemia and false negative microscopy, while persistent HRP2 after successful treatment leads to false positive results and hrp2 and hrp3 deletions result in false-negative rapid diagnostic tests.

Evaluation of the immune response to RTS,S/AS01 and RTS,S/AS02 adjuvanted vaccines: randomized, double-blind study in malaria-naïve adults — Interventions were RTS,S/AS01, RTS,S/AS02, or RTS,S/saline at months 0, 1, and 2. One month after the third vaccine dose, RTS,S/AS01 (160.3 EU/mL [95%CI: 114.1-225.4]) and RTS,S/AS02 (77.4 EU/mL (95%CI: 47.3-126.7)) recipients had significantly higher anti-CS antibody geometric mean titers (GMTs) than recipients of RTS,S/saline (12.2 EU/mL (95%CI: 4.8-30.7); P < 0.0001 and P = 0.0011, respectively), and the anti-CS antibody GMT was significantly higher with RTS,S/AS01 than with RTS,S/AS02 (P = 0.0135). CS- and HBs-specific CD4(+) T cell responses were greater for both RTS,S/AS groups than for the RTS,S/saline group, and anti-CS antibody avidity was in the same range in all groups. Reactogenicity was in general higher for RTS,S/AS compared with RTS,S/saline, most grade 3 solicited adverse events (AEs) were of short duration and grade 3 solicited general AEs were infrequent in the 3 groups, and no serious adverse events were reported.

Declining Efficacy of Artemisinin Combination Therapy Against P. Falciparum Malaria on the Thai-Myanmar Border (2003-2013): The Role of Parasite Genetic Factors — Intervention was mefloquine-artesunate (MAS3) in 1005 patients with uncomplicated P. falciparum malaria. Polymerase chain reaction (PCR)-adjusted cure rates declined from 100% in 2003 to 81.1% in 2013 as proportions of isolates with multiple Pfmdr1 copies doubled from 32.4% to 64.7% and those with K13 mutations increased from 6.7% to 83.4%. The PCR-adjusted cure rate was 57.8% (95% confidence interval [CI], 45.4, 68.3) compared with 97.8% (95% CI, 93.3, 99.3) in patients with K13 wild type and Pfmdr1 single copy, those infected with both multiple Pfmdr1 copy number and a K13 propeller mutation were 14 times more likely to fail treatment, and the combined population attributable fraction of recrudescence associated with K13 mutation and Pfmdr1 amplification was 82%.

Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated malaria in the setting of three different chemopreventive regimens — Interventions were no chemoprevention, monthly sulphadoxine-pyrimethamine (SP), daily trimethoprim-sulphamethoxazole (TS), or monthly dihydroartemisinin-piperaquine (DP), with episodes of uncomplicated malaria treated with artemether-lumefantrine (AL). Early response to therapy with AL was excellent with 96.5% fever clearance and 99.4% parasite clearance by day 3, however, over 50% of AL treatments were followed by recurrent parasitaemia within 28 days. Compared to the no chemoprevention arm, the cumulative risk of recurrent malaria within 84 days following treatment with AL was significantly lower in the DP arm (HR = 0.77, 95% CI 0.63-0.95, p = 0.01) but not the SP or TS arms, and none of the chemopreventive regimens were associated with an increased risk of adverse events following treatment of malaria with AL.

Randomized controlled trial of RTS,S/AS02D and RTS,S/AS01E malaria candidate vaccines given according to different schedules in Ghanaian children — Interventions were RTS,S/AS01(E) or RTS,S/AS02(D) given by 0,1-, 0,1,2- or 0,1,7-months schedules in infants and young children 5-17 months of age. Both candidate vaccines were highly immunogenic for anti-circumsporozoite and anti-Hepatitis B Virus surface antigen antibodies, recipients of RTS,S/AS01(E) compared to RTS,S/AS02(D) had higher peak anti-circumsporozoite antibody responses for all 3 schedules, and three dose schedules were more immunogenic than 2 dose schedules. The number of serious adverse events reported across groups was balanced, one child had a simple febrile convulsion, which evolved favourably without sequelae, considered to be related to RTS,S/AS01(E) vaccination, low grade reactions occurred slightly more frequently in recipients of RTS,S/AS than rabies vaccines, grade 3 reactions were infrequent, and less local reactogenicity occurred with RTS,S/AS01(E) than RTS,S/AS02(D).

Young children and pediatric populations in endemic regions — including children under 5 years, children aged 5-36 months, and children aged 5-15 years, with emphasis on durable, population-level protection, booster strategies, long-term effectiveness monitoring, and extrapolation to pediatric populations by incorporating developmental physiology, protein turnover, and FcRn-mediated recycling.

Pregnant women and individuals in seasonal transmission settings — including intermittent preventive treatment in pregnancy and infancy and seasonal chemoprevention, and complementary combination strategies leveraging broad, durable immunity from vaccines and immediate, predictable protection from antibodies, particularly during seasonal peaks or in high-risk groups.

Plasmodium vivax relapse populations requiring radical cure — with prevention of P. vivax malaria recurrence essential for malaria elimination in Brazil, Cambodia, and Thailand, using chloroquine (25 mg/kg over 3 days) plus point-of-care quantitative glucose-6-phosphate dehydrogenase (G6PD) testing followed by single-dose tafenoquine 300 mg, 7-day primaquine 0.5 mg/kg per day, primaquine 0.75 mg/kg per week for 8 weeks, or 14-day primaquine targeting dormant hypnozoites in the liver to prevent relapse.

Subclinical and asymptomatic infection reservoirs sustaining transmission — with parasite prevalence of 57.1% by qPCR, 40.9% by RDT, and 8.4% by microscopy in three districts in Ghana, 33.8% (219/647) of infections sub-patent, and 22% (1,136/5,134) mRDT-negative but qPCR-positive in Bagamoyo District, predominantly because of low-density parasitemia (92% had <100 p/µL by qPCR).

Severe and cerebral malaria in resource-limited African settings — predominantly affecting children and pregnant women in Sub-Saharan Africa, associated with high mortality rates (15%-30%) and significant long-term neurological sequelae among survivors (10%-30%), compounded by widespread misdiagnosis (up to 23% of clinically diagnosed CM cases may not meet strict diagnostic criteria), delayed presentation, and limited access to specialized neurological rehabilitation services.

Migrant and imported-case populations and drug- and diagnostic-resistance threats — including Afghan nationals comprising 80.8% of infections and imported cases representing 80.8% of the total burden in Isfahan Province, Iran, Plasmodium falciparum kelch13 (K13) propeller-domain mutations reaching 32% in Rwanda with K13-561H (23.5% 20/85) and K13-675V (6.4%, 6/94 infections), and hrp2/hrp3 deletions assessed by qPCR and digital PCR (dPCR).