Intramuscular AZD7442 (Tixagevimab-Cilgavimab) for Prevention of Covid-19.

BACKGROUND: The monoclonal-antibody combination AZD7442 is composed of tixagevimab and cilgavimab, two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that have an extended half-life and have been shown to have prophylactic and therapeutic effects in animal models. Pharmacokinetic data in humans indicate that AZD7442 has an extended half-life of approximately 90 days. METHODS: In an ongoing phase 3 trial, we enrolled adults (≥18 years of age) who had an increased risk of an inadequate response to vaccination against coronavirus disease 2019 (Covid-19), an increased risk of exposure to SARS-CoV-2, or both. Participants were randomly assigned in a 2:1 ratio to receive a single dose (two consecutive intramuscular injections, one containing tixagevimab and the other containing cilgavimab) of either 300 mg of AZD7442 or saline placebo, and they were followed for up to 183 days in the primary analysis. The primary safety end point was the incidence of adverse events after a single dose of AZD7442. The primary efficacy end point was symptomatic Covid-19 (SARS-CoV-2 infection confirmed by means of reverse-transcriptase-polymerase-chain-reaction assay) occurring after administration of AZD7442 or placebo and on or before day 183. RESULTS: A total of 5197 participants underwent randomization and received one dose of AZD7442 or placebo (3460 in the AZD7442 group and 1737 in the placebo group). The primary analysis was conducted after 30% of the participants had become aware of their randomized assignment. In total, 1221 of 3461 participants (35.3%) in the AZD7442 group and 593 of 1736 participants (34.2%) in the placebo group reported having at least one adverse event, most of which were mild or moderate in severity. Symptomatic Covid-19 occurred in 8 of 3441 participants (0.2%) in the AZD7442 group and in 17 of 1731 participants (1.0%) in the placebo group (relative risk reduction, 76.7%; 95% confidence interval [CI], 46.0 to 90.0; P<0.001); extended follow-up at a median of 6 months showed a relative risk reduction of 82.8% (95% CI, 65.8 to 91.4). Five cases of severe or critical Covid-19 and two Covid-19-related deaths occurred, all in the placebo group. CONCLUSIONS: A single dose of AZD7442 had efficacy for the prevention of Covid-19, without evident safety concerns. (Funded by AstraZeneca and the U.S. government; PROVENT ClinicalTrials.gov number, NCT04625725.).

Methaemoglobin as a surrogate marker of primaquine antihypnozoite activity in Plasmodium vivax malaria: A systematic review and individual patient data meta-analysis.

BACKGROUND: The 8-aminoquinolines, primaquine and tafenoquine, are the only available drugs for the radical cure of Plasmodium vivax hypnozoites. Previous evidence suggests that there is dose-dependent 8-aminoquinoline induced methaemoglobinaemia and that higher methaemoglobin concentrations are associated with a lower risk of P. vivax recurrence. We undertook a systematic review and individual patient data meta-analysis to examine the utility of methaemoglobin as a population-level surrogate endpoint for 8-aminoquinoline antihypnozoite activity to prevent P. vivax recurrence. METHODS AND FINDINGS: We conducted a systematic search of Medline, Embase, Web of Science, and the Cochrane Library, from 1 January 2000 to 29 September 2022, inclusive, of prospective clinical efficacy studies of acute, uncomplicated P. vivax malaria mono-infections treated with radical curative doses of primaquine. The day 7 methaemoglobin concentration was the primary surrogate outcome of interest. The primary clinical outcome was the time to first P. vivax recurrence between day 7 and day 120 after enrolment. We used multivariable Cox proportional-hazards regression with site random-effects to characterise the time to first recurrence as a function of the day 7 methaemoglobin percentage (log base 2 transformed), adjusted for the partner schizonticidal drug, the primaquine regimen duration as a proxy for the total primaquine dose (mg base/kg), the daily primaquine dose (mg/kg), and other factors. The systematic review protocol was registered with PROSPERO (CRD42023345956). We identified 219 P. vivax efficacy studies, of which 8 provided relevant individual-level data from patients treated with primaquine; all were randomised, parallel arm clinical trials assessed as having low or moderate risk of bias. In the primary analysis data set, there were 1,747 patients with normal glucose-6-phosphate dehydrogenase (G6PD) activity enrolled from 24 study sites across 8 different countries (Indonesia, Brazil, Vietnam, Thailand, Peru, Colombia, Ethiopia, and India). We observed an increasing dose-response relationship between the daily weight-adjusted primaquine dose and day 7 methaemoglobin level. For a given primaquine dose regimen, an observed doubling in day 7 methaemoglobin percentage was associated with an estimated 30% reduction in the risk of P. vivax recurrence (adjusted hazard ratio = 0.70; 95% confidence interval [CI] [0.57, 0.86]; p = 0.0005). These pooled estimates were largely consistent across the study sites. Using day 7 methaemoglobin as a surrogate endpoint for recurrence would reduce required sample sizes by approximately 40%. Study limitations include the inability to distinguish between recrudescence, reinfection, and relapse in P. vivax recurrences. CONCLUSIONS: For a given primaquine regimen, higher methaemoglobin on day 7 was associated with a reduced risk of P. vivax recurrence. Under our proposed causal model, this justifies the use of methaemoglobin as a population-level surrogate endpoint for primaquine antihypnozoite activity in patients with P. vivax malaria who have normal G6PD activity.

AZD7442 (Tixagevimab/Cilgavimab) for Post-Exposure Prophylaxis of Symptomatic Coronavirus Disease 2019.

BACKGROUND: This phase 3 trial assessed AZD7442 (tixagevimab/cilgavimab) for post-exposure prophylaxis against symptomatic coronavirus disease 2019 (COVID-19). METHODS: Adults without prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or COVID-19 vaccination were enrolled within 8 days of exposure to a SARS-CoV-2-infected individual and randomized 2:1 to a single 300-mg AZD7442 dose (one 1.5-mL intramuscular injection each of tixagevimab and cilgavimab) or placebo. Primary end points were safety and first post-dose SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR)-positive symptomatic COVID-19 event before day 183. RESULTS: A total of 1121 participants were randomized and dosed (AZD7442, n = 749; placebo, n = 372). Median (range) follow-up was 49 (5-115) and 48 (20-113) days for AZD7442 and placebo, respectively. Adverse events occurred in 162 of 749 (21.6%) and 111 of 372 (29.8%) participants with AZD7442 and placebo, respectively, mostly mild/moderate. RT-PCR-positive symptomatic COVID-19 occurred in 23 of 749 (3.1%) and 17 of 372 (4.6%) AZD7442- and placebo-treated participants, respectively (relative risk reduction, 33.3%; 95% confidence interval [CI], -25.9 to 64.7; P = .21). In predefined subgroup analyses of 1073 (96%) participants who were SARS-CoV-2 RT-PCR-negative (n = 974, 87%) or missing an RT-PCR result (n = 99, 9%) at baseline, AZD7442 reduced RT-PCR-positive symptomatic COVID-19 by 73.2% (95% CI, 27.1 to 90.1) vs placebo. CONCLUSIONS: This study did not meet the primary efficacy end point of post-exposure prevention of symptomatic COVID-19. However, analysis of participants who were SARS-CoV-2 RT-PCR-negative or missing an RT-PCR result at baseline support a role for AZD7442 in preventing symptomatic COVID-19. Clinical Trials Registration. NCT04625972.

Tafenoquine versus Primaquine to Prevent Relapse of Plasmodium vivax Malaria.

BACKGROUND: Tafenoquine, a single-dose therapy for Plasmodium vivax malaria, has been associated with relapse prevention through the clearance of P. vivax parasitemia and hypnozoites, termed "radical cure." METHODS: We performed a phase 3, prospective, double-blind, double-dummy, randomized, controlled trial to compare tafenoquine with primaquine in terms of safety and efficacy. The trial was conducted at seven hospitals or clinics in Peru, Brazil, Colombia, Vietnam, and Thailand and involved patients with normal glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and female patients with moderate G6PD enzyme deficiency; all patients had confirmed P. vivax parasitemia. The patients were randomly assigned, in a 2:1 ratio, to receive a single 300-mg dose of tafenoquine or 15 mg of primaquine once daily for 14 days (administered under supervision); all patients received a 3-day course of chloroquine and were followed for 180 days. The primary safety outcome was a protocol-defined decrease in the hemoglobin level (>3.0 g per deciliter or ≥30% from baseline or to a level of <6.0 g per deciliter). Freedom from recurrence of P. vivax parasitemia at 6 months was the primary efficacy outcome in a planned patient-level meta-analysis of the current trial and another phase 3 trial of tafenoquine and primaquine (per-protocol populations), and an odds ratio for recurrence of 1.45 (tafenoquine vs. primaquine) was used as a noninferiority margin. RESULTS: A protocol-defined decrease in the hemoglobin level occurred in 4 of 166 patients (2.4%; 95% confidence interval [CI], 0.9 to 6.0) in the tafenoquine group and in 1 of 85 patients (1.2%; 95% CI, 0.2 to 6.4) in the primaquine group, for a between-group difference of 1.2 percentage points (95% CI, -4.2 to 5.0). In the patient-level meta-analysis, the percentage of patients who were free from recurrence at 6 months was 67.0% (95% CI, 61.0 to 72.3) among the 426 patients in the tafenoquine group and 72.8% (95% CI, 65.6 to 78.8) among the 214 patients in the primaquine group. The efficacy of tafenoquine was not shown to be noninferior to that of primaquine (odds ratio for recurrence, 1.81; 95% CI, 0.82 to 3.96). CONCLUSIONS: Among patients with normal G6PD enzyme activity, the decline in hemoglobin level with tafenoquine did not differ significantly from that with primaquine. Tafenoquine showed efficacy for the radical cure of P. vivax malaria, although tafenoquine was not shown to be noninferior to primaquine. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; GATHER ClinicalTrials.gov number, NCT02216123 .).

Single-Dose Tafenoquine to Prevent Relapse of Plasmodium vivax Malaria.

BACKGROUND: Treatment of Plasmodium vivax malaria requires the clearing of asexual parasites, but relapse can be prevented only if dormant hypnozoites are cleared from the liver (a treatment termed "radical cure"). Tafenoquine is a single-dose 8-aminoquinoline that has recently been registered for the radical cure of P. vivax. METHODS: This multicenter, double-blind, double-dummy, parallel group, randomized, placebo-controlled trial was conducted in Ethiopia, Peru, Brazil, Cambodia, Thailand, and the Philippines. We enrolled 522 patients with microscopically confirmed P. vivax infection (>100 to <100,000 parasites per microliter) and normal glucose-6-phosphate dehydrogenase (G6PD) activity (with normal activity defined as ≥70% of the median value determined at each trial site among 36 healthy male volunteers who were otherwise not involved in the trial). All patients received a 3-day course of chloroquine (total dose of 1500 mg). In addition, patients were assigned to receive a single 300-mg dose of tafenoquine on day 1 or 2 (260 patients), placebo (133 patients), or a 15-mg dose of primaquine once daily for 14 days (129 patients). The primary outcome was the Kaplan-Meier estimated percentage of patients who were free from recurrence at 6 months, defined as P. vivax clearance without recurrent parasitemia. RESULTS: In the intention-to-treat population, the percentage of patients who were free from recurrence at 6 months was 62.4% in the tafenoquine group (95% confidence interval [CI], 54.9 to 69.0), 27.7% in the placebo group (95% CI, 19.6 to 36.6), and 69.6% in the primaquine group (95% CI, 60.2 to 77.1). The hazard ratio for the risk of recurrence was 0.30 (95% CI, 0.22 to 0.40) with tafenoquine as compared with placebo (P<0.001) and 0.26 (95% CI, 0.18 to 0.39) with primaquine as compared with placebo (P<0.001). Tafenoquine was associated with asymptomatic declines in hemoglobin levels, which resolved without intervention. CONCLUSIONS: Single-dose tafenoquine resulted in a significantly lower risk of P. vivax recurrence than placebo in patients with phenotypically normal G6PD activity. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; DETECTIVE ClinicalTrials.gov number, NCT01376167 .).

Living with tuberculosis: a qualitative study of patients' experiences with disease and treatment.

BACKGROUND: Although tuberculosis (TB) is a curable disease, treatment is complex and prolonged, requiring considerable commitment from patients. This study aimed to understand the common perspectives of TB patients across Brazil, Russia, India, China, and South Africa throughout their disease journey, including the emotional, psychological, and practical challenges that patients and their families face. METHODS: This qualitative market research study was conducted between July 2020 and February 2021. Eight TB patients from each country (n = 40) completed health questionnaires, video/telephone interviews, and diaries regarding their experiences of TB. Additionally, 52 household members were interviewed. Patients at different stages of their TB treatment journey, from a range of socioeconomic groups, with or without TB risk factors were sought. Anonymized data underwent triangulation and thematic analysis by iterative coding of statements. RESULTS: The sample included 23 men and 17 women aged 13-60 years old, with risk factors for TB reported by 23/40 patients. Although patients were from different countries and cultural backgrounds, experiencing diverse health system contexts, five themes emerged as common across the sample. 1) Economic hardship from loss of income and medical/travel expenses. 2) Widespread stigma, delaying presentation and deeply affecting patients' emotional wellbeing. 3) TB and HIV co-infection was particularly challenging, but increased TB awareness and accelerated diagnosis. 4) Disruption to family life strained relationships and increased patients' feelings of isolation and loneliness. 5) The COVID-19 pandemic made it easier for TB patients to keep their condition private, but disrupted access to services. CONCLUSIONS: Despite disparate cultural, socio-economic, and systemic contexts across countries, TB patients experience common challenges. A robust examination of the needs of individual patients and their families is required to improve the patient experience, encourage adherence, and promote cure, given the limitations of current treatment.

Pharmacogenetic assessment of tafenoquine efficacy in patients with Plasmodium vivax malaria.

Plasmodium vivax has the largest geographic range of human malaria species and is challenging to manage and eradicate due to its ability to establish a dormant liver stage, the hypnozoite, which can reactivate leading to relapse. Until recently, the only treatment approved to kill hypnozoites was the 8-aminoquinoline, primaquine, requiring daily treatment for 14 days. Tafenoquine, an 8-aminoquinoline single-dose treatment with activity against P. vivax hypnozoites, has recently been approved by the US Food and Drug Administration and Australian Therapeutic Goods Administration for the radical cure of P. vivax malaria in patients 16 years and older. We conducted an exploratory pharmacogenetic analysis (GSK Study 208099) to assess the role of host genome-wide variation on tafenoquine efficacy in patients with P. vivax malaria using data from three GSK clinical trials, GATHER and DETECTIVE Part 1 and Part 2. Recurrence-free efficacy at 6 and 4 months and time to recurrence up to 6 months postdosing were analyzed in 438 P. vivax malaria patients treated with tafenoquine. Among the approximately 10.6 million host genetic variants analyzed, two signals reached genome-wide significance (P value ≤ 5 × 10). rs62103056, and variants in a chromosome 12 intergenic region, were associated with recurrence-free efficacy at 6 and 4 months, respectively. Neither of the signals has an obvious biological rationale and would need replication in an independent population. This is the first genome-wide association study to evaluate genetic influence on response to tafenoquine in P. vivax malaria.

Thrombocytopenia Impairs Host Defense Against Burkholderia pseudomallei (Melioidosis).

Background: Infection with the gram-negative bacillus Burkholderia pseudomallei (melioidosis) is an important cause of pneumosepsis in Southeast Asia and has a mortality of up to 40%. We aimed to assess the role of platelets in the host response against B. pseudomallei infection. Methods: Association between platelet counts and mortality was determined in 1160 patients with culture-proven melioidosis. Mice treated with (low- or high-dose) platelet-depleting antibody were inoculated intranasally with B. pseudomallei and killed. Additional studies using functional glycoprotein Ibα-deficient mice were conducted. Results: Thrombocytopenia was present in 31% of patients at admission and predicted mortality in melioidosis patients even after adjustment for confounders. In our murine-melioidosis model, platelet counts decreased, and mice treated with a platelet-depleting antibody showed enhanced mortality and higher bacterial loads compared to mice with normal platelet counts. Low platelet counts had a modest impact on early-pulmonary neutrophil influx. Reminiscent of their role in hemostasis, platelet depletion impaired vascular integrity, resulting in early lung bleeding. Glycoprotein Ibα-deficient mice had reduced platelet counts during B. pseudomallei infection together with an impaired local host defense in the lung. Conclusions: Thrombocytopenia predicts mortality in melioidosis patients and, during experimental melioidosis, platelets play a protective role in both innate immunity and vascular integrity.

Role of Toll-Like Receptor 5 (TLR5) in Experimental Melioidosis.

The Gram-negative intracellular pathogen Burkholderia pseudomallei is the causative agent of melioidosis, an important cause of sepsis in Southeast Asia. Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) is essential for an appropriate immune response during pathogen invasion. In patients with melioidosis, TLR5 is the most abundantly expressed TLR, and a hypofunctional TLR5 variant has been associated with improved survival. Here, we studied the functional role of TLR5 and its ligand flagellin in experimental melioidosis. First, we observed differential TLR5 expression in the pulmonary and hepatic compartments upon infection with B. pseudomallei Next, we found that B. pseudomallei-challenged TLR5-deficient (Tlr5-/- ) mice were more susceptible to infection than wild-type (WT) mice, as demonstrated by higher systemic bacterial loads, increased organ injury, and impaired survival. Lung bacterial loads were not different between the two groups. The phenotype was flagellin independent; no difference in in vivo virulence was observed for the flagellin-lacking mutant MM36 compared to the wild-type B. pseudomallei strain 1026b. Tlr5-/- mice showed a similar impaired antibacterial defense when infected with MM36 or 1026b. Ex vivo experiments showed that TLR5-deficient macrophages display markedly impaired phagocytosis of B. pseudomallei In conclusion, these data suggest that TLR5 deficiency has a detrimental flagellin-independent effect on the host response against pulmonary B. pseudomallei infection.

Population Pharmacokinetics of Tafenoquine, a Novel Antimalarial.

Tafenoquine is a novel 8-aminoquinoline antimalarial drug recently approved by the U.S. Food and Drug Administration (FDA) for the radical cure of acute Plasmodium vivax malaria, which is the first new treatment in almost 60 years. A population pharmacokinetic (POP PK) analysis was conducted with tafenoquine exposure data obtained following oral administration from 6 clinical studies in phase 1 through phase 3 with a nonlinear mixed effects modeling approach. The impacts of patient demographics, baseline characteristics, and extrinsic factors, such as formulation, were evaluated. Model performance was assessed using techniques such as bootstrapping, visual predictive checks, and external data validation from a phase 3 study not used in model fitting and parameter estimation. Based on the analysis, the systemic pharmacokinetics of tafenoquine were adequately described using a two-compartment model. The final POP PK model included body weight (allometric scaling) on apparent oral and intercompartmental clearance (CL/F and Q/F, respectively), apparent volume of distribution for central and peripheral compartments (V2/F and V3/F, respectively), formulation on systemic bioavailability (F1) and absorption rate constant (Ka ), and health status on apparent volume of distribution. The key tafenoquine population parameter estimates were 2.96 liters/h for CL/F and 915 liters for V2/F in P. vivax-infected subjects. Additionally, the analyses demonstrated no clinically relevant difference in relative bioavailability across the capsule and tablet formulations administered in these clinical studies. In conclusion, a POP PK model for tafenoquine was developed. Clinical trial simulations based on this model supported bridging the exposures across two different formulations. This POP PK model can be applied to aid and perform clinical trial simulations in other scenarios and populations, such as pediatric populations.

Comparing the Efficacy of Drug Regimens for Pulmonary Tuberculosis: Meta-analysis of Endpoints in Early-Phase Clinical Trials.

Background: A systematic review of early clinical outcomes in tuberculosis was undertaken to determine ranking of efficacy of drugs and combinations, define variability of these measures on different endpoints, and to establish the relationships between them. Methods: Studies were identified by searching PubMed, Medline, Embase, LILACS (Latin American and Caribbean Health Sciences Literature), and reference lists of included studies. Outcomes were early bactericidal activity results over 2, 7, and 14 days, and the proportion of patients with negative culture at 8 weeks. Results: One hundred thirty-three trials reporting phase 2A (early bactericidal activity) and phase 2B (culture conversion at 2 months) outcomes were identified. Only 9 drug combinations were assessed on >1 phase 2A endpoint and only 3 were assessed in both phase 2A and 2B trials. Conclusions: The existing evidence base supporting phase 2 methodology in tuberculosis is highly incomplete. In future, a broader range of drugs and combinations should be more consistently studied across a greater range of phase 2 endpoints.

Pharmacokinetic Interactions between Tafenoquine and Dihydroartemisinin-Piperaquine or Artemether-Lumefantrine in Healthy Adult Subjects.

Tafenoquine is in development as a single-dose treatment for relapse prevention in individuals with Plasmodium vivax malaria. Tafenoquine must be coadministered with a blood schizonticide, either chloroquine or artemisinin-based combination therapy (ACT). This open-label, randomized, parallel-group study evaluated potential drug interactions between tafenoquine and two ACTs: dihydroartemisinin-piperaquine and artemether-lumefantrine. Healthy volunteers of either sex aged 18 to 65 years without glucose-6-phosphate dehydrogenase deficiency were randomized into five cohorts (n = 24 per cohort) to receive tafenoquine on day 1 (300 mg) plus once-daily dihydroartemisinin-piperaquine on days 1, 2, and 3 (120 mg/960 mg for 36 to <75 kg of body weight and 160 mg/1,280 mg for ≥75 to 100 kg of body weight), or plus artemether-lumefantrine (80 mg/480 mg) in two doses 8 h apart on day 1 and then twice daily on days 2 and 3, or each drug alone. The pharmacokinetic parameters of tafenoquine, piperaquine, lumefantrine, artemether, and dihydroartemisinin were determined by using noncompartmental methods. Point estimates and 90% confidence intervals were calculated for area under the concentration-time curve (AUC) and maximum observed plasma concentration (Cmax) comparisons of tafenoquine plus ACT versus tafenoquine or ACT. All subjects receiving dihydroartemisinin-piperaquine experienced QTc prolongation (a known risk with this drug), but tafenoquine coadministration had no clinically relevant additional effect. Tafenoquine coadministration had no clinically relevant effects on dihydroartemisinin, piperaquine, artemether, or lumefantrine pharmacokinetics. Dihydroartemisinin-piperaquine coadministration increased the tafenoquine Cmax by 38% (90% confidence interval, 25 to 52%), the AUC from time zero to infinity (AUC0-∞) by 12% (1 to 26%), and the half-life (t1/2) by 29% (19 to 40%), with no effect on the AUC from time zero to the time of the last nonzero concentration (AUC0-last). Artemether-lumefantrine coadministration had no effect on tafenoquine pharmacokinetics. Tafenoquine can be coadministered with dihydroartemisinin-piperaquine or artemether-lumefantrine without dose adjustment for any of these compounds. (This study has been registered at ClinicalTrials.gov under registration no. NCT02184637.).

Tafenoquine treatment of Plasmodium vivax malaria: suggestive evidence that CYP2D6 reduced metabolism is not associated with relapse in the Phase 2b DETECTIVE trial.

BACKGROUND: Tafenoquine (TQ) and primaquine (PQ) are 8-aminoquinolines (8-AQ) with anti-hypnozoite activity against vivax malaria. PQ is the only FDA-approved medicine for preventing relapsing Plasmodium vivax infection and TQ is currently in phase 3 clinical trials for the same indication. Recent studies have provided evidence that cytochrome P450 (CYP) metabolism via CYP2D6 plays a role in PQ efficacy against P. vivax and have suggested that this effect may extend to other 8-AQs, including TQ. Here, a retrospective pharmacogenetic (PGx) investigation was performed to assess the impact of CYP2D6 metabolism on TQ and PQ efficacy in the treatment of P. vivax in the DETECTIVE study (TAF112582), a recently completed, randomized, phase 2b dose-ranging clinical trial. The impact of CYP2D6 on TQ pharmacokinetics (PK) was also investigated in TAF112582 TQ-treated subjects and in vitro CYP metabolism of TQ was explored. A limitation of the current study is that TAF112582 was not designed to be well powered for PGx, thus our findings are based on TQ or PQ efficacy in CYP2D6 intermediate metabolizers (IM), as there were insufficient poor metabolizers (PM) to draw any conclusion on the impact of the PM phenotype on efficacy. METHODS: The impact of genetically-predicted CYP2D6 reduced metabolism on relapse-free efficacy six months post-dosing of TQ or PQ, both administered in conjunction with chloroquine (CQ), was assessed using exact statistical methods in 198 P. vivax-infected study participants comparing IM to extensive metabolizers (EM). The influence of CYP2D6 metabolizer phenotypes on TQ PK was assessed comparing median TQ area under the curve (AUC). In vitro metabolism of TQ was investigated using recombinant, over-expressed human CYP enzymes and human hepatocytes. Metabolite identification experiments were performed using liquid chromatography-mass spectrometry. RESULTS: Reduction of CYP2D6 activity was not associated with an increase in relapse-rate in TQ-treated subjects (p = 0.57). In contrast, and in accordance with recent literature, CYP2D6 IMs were more common (p = 0.05) in PQ-treated subjects who relapsed (50 %) than in subjects who remained relapse-free (17 %). Further, CYP2D6 metabolizer phenotypes had no significant effect on TQ AUC, and only minimal metabolism of TQ could be detected in hepatic in vitro systems. CONCLUSION: Together, these data provide preliminary evidence that in CYP2D6 IMs, TQ efficacy in P. vivax-infected individuals is not diminished to the same extent as PQ. As there were no PMs in either the TQ or PQ treatment arms of TAF112582, no conclusions could be drawn on potential differences in PMs. These findings suggest that differential effects of CYP2D6 metabolism on TQ and PQ efficacy could be a differentiation factor between these 8-AQs, but results remain to be confirmed prospectively in the ongoing phase 3 studies.

Time-to-detection in culture predicts risk of Mycobacterium tuberculosis transmission: a cohort study.

BACKGROUND: Contact screening is an essential component of all tuberculosis control strategies. We hypothesize that time-to-detection (TTD) in liquid culture of spontaneously produced sputum samples may help identify index cases at high risk of transmission. METHODS: We studied retrospectively a cohort of patients with pulmonary tuberculosis in Birmingham, United Kingdom (January 2010-December 2012). We studied the correlation of TTD with the risk of transmission of infection from index cases to contacts and compared this with sputum microscopy. Chest radiographs (CXRs) were graded from 0 to 6 (0, no radiographic evidence of disease; 5, bilateral cavitation; and 6, miliary disease). RESULTS: Of the 184 cases of pulmonary tuberculosis reported during the study period, 111 were included in the final study, and these generated 825 contacts. A transmission event (new latent or active tuberculosis) was identified in 165 contacts (transmission rate 0.20). Short TTD (<9 days) was associated with an increased risk of transmission (odds ratio, 2.56; P < .001), and this relationship persisted after adjusting for potential confounders. A 1-point increase in CXR grade correlated with a 3.2-day decrease in TTD (P < .001), and this correlation persisted after adjustment for potential confounders. CONCLUSIONS: TTD < 9 days identifies patients at high risk of transmitting tuberculosis and is superior to sputum smear. CXR grade at diagnosis predicts patients with short TTD. Our findings have the potential to guide the organization and prioritization of contact investigations in similar settings.

Limited role for ASC and NLRP3 during in vivo Salmonella Typhimurium infection.

BACKGROUND: The inflammasome is an intracellular protein complex triggered by exposure to intracellular pathogens, its components or other endogenous proteins. It leads to the activation of and subsequent release of proinflammatory cytokines such as IL-1ß and IL-18. S. Typhimurium is a Gram-negative intracellular bacterium, which is known to trigger inflammasome assembly via recognition by the cytosolic receptors, NLRP3 and NLRC4 (which act via the adaptor protein, ASC) to induce cell death and cytokine release. We sought to characterize the role of ASC and NLRP3 in two different murine models (typhoid and colitis) of systemic Salmonella infection. RESULTS: Release of the inflammasome cytokine IL-18 was hampered in Asc-/- but not Nlrp3-/- mice (background C57BL/6) during S. Typhimurium infection. Unexpectedly, neither ASC nor NLRP3 played a significant role in host defense against S. Typhimurium infection, as reflected by equal bacterial counts in WT, Asc-/- and Nlrp3-/- mice at all time points, in both the typhoid and colitis models. Proinflammatory cytokine levels (TNF-α, IL-6) and the extent of hepatic and splenic pathology did not differ between groups in the typhoid model. In the colitis model small differences were seen with regard to splenic and hepatic inflammation, although this was IL-18 independent. CONCLUSIONS: IL-18 release was reduced in Asc-/- but not Nlrp3-/- mice during S. Typhimurium infection. Despite this reduction, bacterial counts, cytokine levels and histological inflammation did not differ between wild-type and knockout mice in either model. Our results reveal a limited role for ASC and NLRP3 during in vivo S. Typhimurium infection despite its role in cytokine maturation.

Response to comment on 'The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis'.

In our recent paper on the clinical pharmacology of tafenoquine (Watson et al., 2022), we used all available individual patient pharmacometric data from the tafenoquine pre-registration clinical efficacy trials to characterise the determinants of anti-relapse efficacy in tropical vivax malaria. We concluded that the currently recommended dose of tafenoquine (300 mg in adults, average dose of 5 mg/kg) is insufficient for cure in all adults, and a 50% increase to 450 mg (7.5 mg/kg) would halve the risk of vivax recurrence by four months. We recommended that clinical trials of higher doses should be carried out to assess their safety and tolerability. Sharma and colleagues at the pharmaceutical company GSK defend the currently recommended adult dose of 300 mg as the optimum balance between radical curative efficacy and haemolytic toxicity (Sharma et al., 2024). We contend that the relative haemolytic risks of the 300 mg and 450 mg doses have not been sufficiently well characterised to justify this opinion. In contrast, we provided evidence that the currently recommended 300 mg dose results in sub-maximal efficacy, and that prospective clinical trials of higher doses are warranted to assess their risks and benefits.

A first-in-class leucyl-tRNA synthetase inhibitor, ganfeborole, for rifampicin-susceptible tuberculosis: a phase 2a open-label, randomized trial.

New tuberculosis treatments are needed to address drug resistance, lengthy treatment duration and adverse reactions of available agents. GSK3036656 (ganfeborole) is a first-in-class benzoxaborole inhibiting the Mycobacterium tuberculosis leucyl-tRNA synthetase. Here, in this phase 2a, single-center, open-label, randomized trial, we assessed early bactericidal activity (primary objective) and safety and pharmacokinetics (secondary objectives) of ganfeborole in participants with untreated, rifampicin-susceptible pulmonary tuberculosis. Overall, 75 males were treated with ganfeborole (1/5/15/30 mg) or standard of care (Rifafour e-275 or generic alternative) once daily for 14 days. We observed numerical reductions in daily sputum-derived colony-forming units from baseline in participants receiving 5, 15 and 30 mg once daily but not those receiving 1 mg ganfeborole. Adverse event rates were comparable across groups; all events were grade 1 or 2. In a participant subset, post hoc exploratory computational analysis of 18F-fluorodeoxyglucose positron emission tomography/computed tomography findings showed measurable treatment responses across several lesion types in those receiving ganfeborole 30 mg at day 14. Analysis of whole-blood transcriptional treatment response to ganfeborole 30 mg at day 14 revealed a strong association with neutrophil-dominated transcriptional modules. The demonstrated bactericidal activity and acceptable safety profile suggest that ganfeborole is a potential candidate for combination treatment of pulmonary tuberculosis.ClinicalTrials.gov identifier: NCT03557281 .

Lineage-informative microhaplotypes for recurrence classification and spatio-temporal surveillance of Plasmodium vivax malaria parasites.

Challenges in classifying recurrent Plasmodium vivax infections constrain surveillance of antimalarial efficacy and transmission. Recurrent infections may arise from activation of dormant liver stages (relapse), blood-stage treatment failure (recrudescence) or reinfection. Molecular inference of familial relatedness (identity-by-descent or IBD) can help resolve the probable origin of recurrences. As whole genome sequencing of P. vivax remains challenging, targeted genotyping methods are needed for scalability. We describe a P. vivax marker discovery framework to identify and select panels of microhaplotypes (multi-allelic markers within small, amplifiable segments of the genome) that can accurately capture IBD. We evaluate panels of 50-250 microhaplotypes discovered in a global set of 615 P. vivax genomes. A candidate global 100-microhaplotype panel exhibits high marker diversity in the Asia-Pacific, Latin America and horn of Africa (median HE = 0.70-0.81) and identifies 89% of the polyclonal infections detected with genome-wide datasets. Data simulations reveal lower error in estimating pairwise IBD using microhaplotypes relative to traditional biallelic SNP barcodes. The candidate global panel also exhibits high accuracy in predicting geographic origin and captures local infection outbreak and bottlenecking events. Our framework is open-source enabling customised microhaplotype discovery and selection, with potential for porting to other species or data resources.

Outpatient Treatment with AZD7442 (Tixagevimab/Cilgavimab) Prevented COVID-19 Hospitalizations over 6 Months and Reduced Symptom Progression in the TACKLE Randomized Trial.

INTRODUCTION: We assessed effects of AZD7442 (tixagevimab/cilgavimab) on deaths from any cause or hospitalizations due to coronavirus disease 2019 (COVID-19) and symptom severity and longer-term safety in the TACKLE adult outpatient treatment study. METHODS: Participants received 600 mg AZD7442 (n = 452) or placebo (n = 451) ≤ 7 days of COVID-19 symptom onset. RESULTS: Death from any cause or hospitalization for COVID-19 complications or sequelae through day 169 (key secondary endpoint) occurred in 20/399 (5.0%) participants receiving AZD7442 versus 40/407 (9.8%) receiving placebo [relative risk reduction (RRR) 49.1%; 95% confidence interval (CI) 14.5, 69.7; p = 0.009] or 50.7% (95% CI 17.5, 70.5; p = 0.006) after excluding participants unblinded before day 169 for consideration of vaccination). AZD7442 reduced progression of COVID-19 symptoms versus placebo through to day 29 (RRR 12.5%; 95% CI 0.5, 23.0) and improved most symptoms within 1-2 weeks. Over median safety follow-up of 170 days, adverse events occurred in 174 (38.5%) and 196 (43.5%) participants receiving AZD7442 or placebo, respectively. Cardiac serious adverse events occurred in two (0.4%) and three (0.7%) participants receiving AZD7442 or placebo, respectively. CONCLUSIONS: AZD7442 was well tolerated and reduced hospitalization and mortality through 6 months, and symptom burden through 29 days, in outpatients with mild-to-moderate COVID-19. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT04723394. ( https://beta. CLINICALTRIALS: gov/study/NCT04723394 ).

Antibodies are proteins produced by the body's immune system to specifically combat foreign substances, such as viruses. Tixagevimab and cilgavimab are a pair of antibodies that bind to a specific part of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19). When they bind to the virus, they reduce its ability to cause disease. These antibodies were tested in a clinical trial to see if they could prevent people with COVID-19 from being hospitalized or dying. Around 900 adults took part in this clinical trial. These people all had COVID-19 but were not sick enough to be in hospital. Half of this group were treated with a dose of tixagevimab and cilgavimab, given as two injections. The other half received a placebo (injections that look exactly like the tixagevimab and cilgavimab injections but contain no medicine). The study found that, over 6 months, people with COVID-19 who received tixagevimab and cilgavimab were less likely to need to go to hospital than people who received the placebo. They were also less likely to die of COVID-19. Tixagevimab and cilgavimab also helped to improve COVID-19 symptoms. People who received the antibodies saw their symptoms improve faster than people who received the placebo. They were also less likely to have symptoms that got worse. Most people felt better within 1­2 weeks of getting treatment. No safety issues were found with tixagevimab and cilgavimab compared with placebo.