Pharmacokinetics and safety of coformulated bictegravir, emtricitabine, and tenofovir alafenamide in children aged 2 years and older with virologically suppressed HIV: a phase 2/3, open-label, single-arm study.

BACKGROUND: Coformulated bictegravir, emtricitabine, and tenofovir alafenamide is a single-tablet regimen and was efficacious and well tolerated in children and adolescents with HIV (aged 6 years to <18 years) in a 48-week phase 2/3 trial. In this study, we report data from children aged at least 2 years and weighing 14 kg to less than 25 kg. METHODS: We conducted this open-label, multicentre, multicohort, single-arm study in South Africa, Thailand, Uganda, and the USA. Participants were virologically suppressed children with HIV, aged at least 2 years, weighing 14 kg to less than 25 kg. Participants received bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) once daily, switching to bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) upon attaining a bodyweight of at least 25 kg. The study included pharmacokinetic evaluation at week 2 to confirm the dose of coformulated bictegravir, emtricitabine, and tenofovir alafenamide for this weight band by comparing with previous adult data. Primary outcomes were bictegravir area under the curve over the dosing interval (AUCtau) and concentration at the end of the dosing interval (Ctau) at week 2, and incidence of treatment-emergent adverse events and laboratory abnormalities until the end of week 24 in all participants who received at least one dose of bictegravir, emtricitabine, and tenofovir alafenamide. This study is registered with ClinicalTrials.gov, NCT02881320. FINDINGS: Overall, 22 participants were screened (from Nov 14, 2018, to Jan 11, 2020), completed treatment with bictegravir, emtricitabine, and tenofovir alafenamide (until week 48), and entered an extension phase. The geometric least squares mean (GLSM) ratio for AUCtau for bictegravir was 7·6% higher than adults (GLSM ratio 107·6%, 90% CI 96·7-119·7); Ctau was 34·6% lower than adults (65·4%, 49·1-87·2). Both parameters were within the target exposure range previously found in adults, children, or both". Grade 3-4 laboratory abnormalities occurred in four (18%) participants by the end week 24 and six (27%) by the end of week 48. Drug-related adverse events occurred in three participants (14%) by the end of week 24 and week 48; none were severe. No Grade 3-4 adverse events, serious adverse events, or adverse events leading to discontinuation occurred by the end of week 24 and week 48. INTERPRETATION: Data support the use of single-tablet coformulated bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) for treatment of HIV in children aged at least 2 years and weighing 14 kg to less than 25 kg. FUNDING: Gilead Sciences.

Improved survival and tumor control with Interleukin-2 is associated with the development of immune-related adverse events: data from the PROCLAIMSM registry.

BACKGROUND: Immune related adverse events (irAEs) are associated with immunotherapy for cancer and while results suggest improvement in tumor control and overall survival in those experiencing irAEs, the long-term impact is debated. We evaluated irAE reports related to high dose interleukin-2 therapy (IL-2) documented in the PROCLAIMSM registry data base from 2008 to 2016 (NCT01415167, August 9, 2011). METHODS: Reports on 1535 patients, including 623 with metastatic melanoma (mM) and 919 with metastatic renal cell cancer (mRCC) (7 patients had both diseases), were queried for irAEs. The timing of the event was categorized as occurring before, during or after IL-2 or related to any checkpoint inhibitor (CPI). mM patients and mRCC patients were analyzed separately. Tumor control [complete + partial response + stable disease (CR + PR + SD) was compared between those experiencing no irAE versus those with the development of irAEs. Survival was analyzed by tumor type related to timing of irAE and IL-2, and in those with or without exposure to CPI. RESULTS: Median follow-up was 3.5+ years (range 1-8+ years), 152 irAEs were reported in 130 patients (8.4% of all PROCLAIMSM patients): 99 (16%) in mM and 53 (5.8%) in mRCC patients. 31 irAEs occurred prior to IL-2, 24 during IL-2, and 97 after IL-2 therapy. 74 irAEs were attributed to IL-2 only (during/ after IL-2). Of the 97 post IL-2 irAEs, 24 were attributed to CPI, and 15 could not be distinguished as caused by IL-2 or CPI. Tumor control was 71% for those experiencing irAE, and 56% for those with no irAE (p = 0.0008). Overall survival was significantly greater for those experiencing irAEs during/ after IL-2 therapy, compared to those with no irAE or irAE before IL-2 therapy, in mM patients, median 48 months vs 18 months (p < 0.0001), and in mRCC patients, median 60 months vs 40 months (p = 0.0302), independent of CPI-related irAEs. IL-2-related irAEs were primarily vitiligo and thyroid dysfunction (70% of IL-2 related irAEs), with limited further impact. CONCLUSIONS: irAEs following IL-2 therapy are associated with improved tumor control and overall survival. IrAEs resulting from IL-2 and from CPIs are qualitatively different, and likely reflect different mechanisms of action of immune activation and response.

Vitamin d status and anthropometric indices of an omani study population.

OBJECTIVES: Serum 25-hydroxyvitamin D [25(OH)D] concentrations reflect vitamin D status, with deficiency implicated as causative of many diseases. This study assessed vitamin D status and anthropometric indices in a sample of healthy Omanis. METHODS: Serum 25(OH)D concentrations were measured by high performance liquid chromatography in 206 healthy Omanis, aged 18-55 years (mean age: men 31.1, women 26.8) in Muscat, Oman. Of this number, 95% indicated that they had never taken vitamin D supplements. Findings were compared with published values for populations domiciled in more northerly latitudes. Classical procedures were used to determine global obesity (body mass index [BMI]), and central obesity determined by waist circumference, waist-to-hip ratio (WHR), and waist-to-height ratio. RESULTS: Women, as compared to men, had markedly lower concentrations of 25(OH)D. Applying the cut-off point of serum 25(OH)D levels at 50 nmol/L, the prevalence of vitamin D deficiency in the study population was 87.5%; this was higher than the rates reported for the British, and European-, Hispanic-, and African-Americans. At a BMI cut-point of ≥30 kg/m(2), the prevalence of obesity was 14.6%; this was lower than the rates reported for European-, Hispanic-, and African-Americans. Levels of 25(OH) D increased relative to age and obesity. WHR was the main predictor of 25(OH)D levels. CONCLUSION: The striking vitamin D deficiency seen in the study population, relative to more northerly populations, may be linked to sun avoidance, inadequate dietary vitamin D, and virtual non-intake of supplemental vitamin D. Age and male-gender determined the status of vitamin D and of obesity.

Iron-fortified wheat flour and iron deficiency among women.

BACKGROUND: Iron deficiency is estimated to impact more than 1.6 billion individuals worldwide, affecting child, maternal, and perinatal mortality. Iron supplementation, fortification, and dietary diversification are strategies to reduce the prevalence of iron deficiency. However, there are relatively few studies demonstrating the effectiveness of iron-fortified wheat flour as an intervention. OBJECTIVE: To assess the relationship between average monthly per capita household consumption of iron-fortified wheat flour and iron deficiency among women of childbearing age in Oman. METHODS: Data were obtained from the National Micronutrient Status and Fortified Food Coverage Survey, 2004. Iron deficiency status was compared between women living in households with a monthly per capita consumption of iron-fortified wheat flour of 1 kg or more and women living in households with a monthly per capita consumption of iron-fortified wheat flour of less than 1 kg. The analyses excluded women with elevated or unknown levels of C-reactive protein and controlled for characteristics of the women and household demographics. RESULTS: Consumption of iron-fortified wheat flour was associated with a lower prevalence of iron deficiency among women in our sample (adjusted odds ratio, 0.60), after controlling for age, employment status, marital status, intake of iron or multivitamin supplements, self-reported presence of a blood disorder, household income, educational level of head of household, and family size. CONCLUSIONS: These results suggest that women in our study living in households with a greater consumption of iron-fortified wheat flour have a lower prevalence of iron deficiency; however, additional study is needed.

Ethanol-induced changes in lipid composition of intestinal microvillus membrane in rats fed different dietary fats.

BACKGROUND/METHOD: The effect of feeding ethanol for 5 weeks on the lipid composition of the intestinal microvillus membrane (MVM) was studied in rats fed a commercial rat pellet (RP) diet or purified diets containing 10% coconut oil (CCO), corn oil (CO) or fish oil (FO). RESULTS: A low cholesterol/phospholipid ratio and increased saturated fatty acid level were observed in MVM from the CCO or FO groups. Chronic administration of ethanol to RP- or CO-fed animals increased phospholipids, total and free cholesterol, and the triglyceride and ganglioside content of MVM. The free cholesterol and phospholipid content was reduced while the triglyceride level remained unaffected by ethanol treatment in the CCO or FO groups. Ethanol ingestion decreased 10:2 and 20:4 (n-6 fatty acids) but increased the saturated fatty acid content of MVM in all the dietary groups except in CCO-fed animals where the 18:2 level was not affected. An elevated 18:1, but decreased 22:6 percentage was observed in the ethanol-fed FO group. The fatty acid composition of MVM from the CCO-fed group was least affected by ethanol treatment. CONCLUSION: These observations suggest that the type of dietary fat modifies ethanol-mediated alterations in MVM lipid composition.