Cell-Associated HIV-1 DNA and RNA Decay Dynamics During Early Combination Antiretroviral Therapy in HIV-1-Infected Infants.

BACKGROUND: The decay of human immunodeficiency virus type 1 (HIV-1)-infected cells during early combination antiretroviral therapy (cART) in infected infants is not defined. METHODS: HIV-1 DNA, including 2-long terminal repeat (2-LTR) circles, and multiply spliced (ms-) and unspliced (us-) HIV-1 RNA concentrations were measured at 0, 24, 48, and 96 weeks of cART in infants from the IMPAACT P1030 trial receiving lopinavir-ritonavir-based cART. The ratio of HIV-1 DNA concentrations to replication-competent genomes was also estimated. Linear mixed effects models with random intercept and linear splines were used to estimate patient-specific decay kinetics of HIV-1 DNA. RESULTS: The median HIV-1 DNA concentration before cART at a median age of 2 months was 3.2 log10 copies per million PBMC. With cART, the average estimated patient-specific change in HIV-1 DNA concentrations was -0.040 log10/week (95% confidence interval [CI], -.05, -.03) between 0 and 24 weeks and -0.017 log10/week between 24 and 48 weeks (95% CI, -.024, -.01). 2-LTR circles decreased with cART but remained detectable through 96 weeks. Pre-cART HIV-1 DNA concentration was correlated with time to undetectable plasma viral load and post-cART HIV-1 DNA at 96 weeks; although HIV-1 DNA concentrations exceeded replication-competent HIV-1 genomes by 148-fold. Almost all infants had ms- and usRNA detected pre-cART, with 75% having usRNA through 96 weeks of cART. CONCLUSIONS: By 2 months of age, a large pool of HIV-1-infected cells is established in perinatal infection, which influences time to undetectable viral load and reservoir size. This has implications for informing novel approaches aimed at early restriction of HIV-1 reservoirs to enable virologic remission and cure.

Sodium-Glucose Cotransporter 2 Inhibitors First Strategy Improve Decongestion in Patients with Symptomatic Heart Failure and Reduced Ejection Fraction When Compared to Angiotensin Receptor Neprilysin Inhibitor First Strategy.

BACKGROUND: Angiotensin receptor neprilysin inhibitor (ARNI) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) are emerging medical treatments for decompensated heart failure (HF) with reduced ejection fraction. In clinical practice, the combination of ARNI and SGLT2i cannot be administered owing to the poor hemodynamic status in patients with HF with reduced ejection fraction (HFrEF). This study aimed to compare different strategies of HF management for ARNI first or SGLT2i first in such a population. METHODS: From January 2016 to December 2021, 165 patients were diagnosed with HFrEF and New York Heart Association functional class ≥II and already received optimal medical treatment. Ninety-five patients received the ARNI-first strategy, and 70 patients received the SGLT2i-first strategy according to the physician's choice. Age, sex, hemodynamic condition, etiologies of HF, comorbidities, serum creatinine, N-terminal pro-B-type natriuretic peptide (NT-ProBNP), echocardiographic parameters, and clinical outcomes were compared between the ARNI and SGLT2i-first strategy groups. RESULTS: In the SGLT2i-first group, the median interval between the addition of the second medication was longer (ARNI-first vs. SGLT2i-first; 74 [49-100] days vs. 112 [86-138] days; p = 0.044). Improvement in left ventricular ejection fraction (LVEF), change in left atrial dimension, and change in left ventricular end-diastolic and end-systolic volume (LVESV) did not differ between the two groups. The incidence of HF hospitalization, cardiovascular mortality, and all-cause mortality did not differ between the two groups. A non-significant trend of lower NT-proBNP levels (ARNI-first vs. SGLT2i-first; 1383 [319-2507] pg/mL vs. 570 [206-1314] pg/mL; p = 0.055) and significantly higher discontinuation rate of diuretic agents (ARNI-first vs. SGLT2i- first; 6.8% vs. 17.5%; p = 0.039) were noted in the SGLT2i-first group. When early combination (≤14D) compared to late combination (>14D), better positive remodeling of LVESV presented significantly in early combination subgroups. CONCLUSIONS: In patients with symptomatic HFrEF, SGLT2i-first strategy may provide a higher possibility of discontinuing diuretic agents than the ARNI-first strategy. Changes in LV performance, progression of renal function, and clinical outcomes did not differ between the two groups. Early combination (≤14D) provided better LV remodeling.

Early Combination of Albumin With Crystalloid Administration Might Reduce Mortality in Patients With Cardiogenic Shock: An Over 10-Year Intensive Care Survey.

Background: In updated international guidelines, combined albumin resuscitation is recommended for septic shock patients who receive large volumes of crystalloids, but minimal data exist on albumin use and the optimal timing in those with cardiogenic shock (CS). The objective of this study was to evaluate the relationship between resuscitation with a combination of albumin within 24 h and 30-day mortality in CS patients. Methods: We screened patients with CS from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Multivariable Cox proportional hazards models and propensity score matching (PSM) were employed to explore associations between combined albumin resuscitation within 24 h and 30-day mortality in CS. Models adjusted for CS considered potential confounders. E-value analysis suggested for unmeasured confounding. Results: We categorized 1,332 and 254 patients into crystalloid-only and early albumin combination groups, respectively. Patients who received the albumin combination had decreased 30-day and 60-day mortality (21.7 vs. 32.4% and 25.2 vs. 34.2%, respectively, P < 0.001), and the results were robust after PSM (21.3 vs. 44.7% and 24.9 vs. 47.0%, respectively, P < 0.001) and following E-value. Stratified analysis showed that only ≥ 60 years old patients benefited from administration early albumin. In the early albumin combination group, the hazard ratios (HRs) of different adjusted covariates remained significant (HRs of 0.45-0.64, P < 0.05). Subgroup analysis showed that resuscitation with combination albumin was significantly associated with reduced 30-day mortality in patients with maximum sequential organ failure assessment score≥10, with acute myocardial infarction, without an Impella or intra-aortic balloon pump, and with or without furosemide and mechanical ventilation (HRs of 0.49, 0.58, 0.65, 0.40, 0.65 and 0.48, respectively; P < 0.001). Conclusion: This study found, compared with those given crystalloid-only, resuscitation with combination albumin within 24 h is associated with lower 30-day mortality of CS patients aged≥60. The results should be conducted to further assess in randomized controlled trials.

Exploring early combination strategy in Latin American patients with newly diagnosed type 2 diabetes: a sub-analysis of the VERIFY study.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) from Latin American countries face challenges in access to healthcare, leading to under-diagnosis, under-achievement of glycemic target, and long-term complications. Early diagnosis and treatment initiation are of paramount importance in this population due to the high prevalence of risk factors such as obesity and metabolic syndrome. The VERIFY study in patients with newly diagnosed T2DM (across 34 countries), assessed the normoglycemic durability (5 years), with early combination (EC) therapy approach versus the traditional stepwise approach of initiating treatment with metformin monotherapy (MET). Here we present the results from the VERIFY study for participants from eight countries in Latin America. METHODS: Newly diagnosed adult patients with T2DM, HbA1c 6.5-7.5% and body-mass index (BMI) of 22-40 kg/m2 were enrolled. The primary endpoint was time to initial treatment failure (TF; HbA1c ≥ 7.0% at two consecutive scheduled visits 13 weeks apart). Time to second TF was evaluated when patients in both groups were receiving and failing on the vildagliptin combination. Safety and tolerability were also assessed for both treatment approaches during the study. RESULTS: A total of 537 eligible patients (female, 58.8%) were randomly assigned to receive either EC (n = 266) or MET (n = 271). EC significantly reduced the relative risk of time to initial TF by 47% versus MET [HR (95% CI) 0.53 (0.4, 0.7) p < 0.0001]. Overall, 46.4% versus 66.3% of patients achieved the primary endpoint in the EC and MET groups, with a median [interquartile range (IQR)] time to TF of 59.8 (27.5, not evaluable) and 33.4 (12.2, 60.1) months, respectively. The risk for time to second TF was 31% lower with EC (p < 0.0092). A higher proportion of patients receiving EC maintained durable HbA1c < 7.0%, < 6.5%, and < 6.0%. Both treatment approaches were well tolerated, and only 3.2% of participants discontinued the study due to adverse events. All hypoglycemic events (EC: n = 7 and MET: n = 3) were single, mild episodes and did not lead to study discontinuation. CONCLUSION: Similar to the global population, long-term clinical benefits were achieved more frequently and without tolerability issues with EC versus standard-of-care MET in this Latin American sub-population. This study is registered with ClinicalTrials.gov, NCT01528254.

Evaluating the Evidence behind the Novel Strategy of Early Combination from Vision to Implementation.

Type 2 diabetes mellitus (T2DM) is a complex and progressive chronic disease characterised by elevating hyperglycaemia and associated need to gradually intensify therapy in order to achieve and maintain glycaemic control. Treating hyperglycaemia with sequential therapy is proposed to allow holistic assessment of the efficacy and risk-to-benefit ratio of each added component. However, there is an array of evidence supporting the scientific rationale for using synergistic, earlier, modern drug combinations to achieve glycaemic goals, delay the deterioration of glycaemic control, and, therefore, potentially preserve or slow down the declining ß-cell function. Additionally, implementation of early combination(s) may lead to opportunities to combat clinical inertia and other hurdles to optimised disease management outcomes. This review aims to discuss the latest empirical evidence for long-term clinical benefits of this novel strategy of early combination in people with newly diagnosed T2DM versus the current widely-implemented treatment paradigm, which focuses on control of hyperglycaemia using lifestyle interventions followed by sequentially intensified (mostly metformin-based) monotherapy. The recent reported Vildagliptin Efficacy in combination with metfoRmin For earlY treatment of T2DM (VERIFY) study results have provided significant new evidence confirming long-term glycaemic durability and tolerability of a specific early combination in the management of newly diagnosed, treatment-naïve patients worldwide. These results have also contributed to changes in clinical treatment guidelines and standards of care while clinical implementation and individualised treatment decisions based on VERIFY results might face barriers beyond the existing scientific evidence.

Strategies for Diabetes Management: Using Newer Oral Combination Therapies Early in the Disease.

INTRODUCTION: The duration of uncontrolled type 2 diabetes mellitus (T2DM) can adversely impact small and large vessels, eventually leading to microvascular and macrovascular complications. Failure of therapeutic lifestyle changes, monotherapy, and clinical inertia contribute to persistent hyperglycemia and disease progression. The aim was to review the complex pathophysiology of type 2 diabetes and how different oral agents can be used effectively as first-line therapy in combination with metformin, as well as in patients not achieving glycemic goals with metformin therapy. METHODS: For this review, a non-systematic literature search of PubMed, NCBI, and Google Scholar was conducted. RESULTS: New oral agents have made it possible to improve glycemic control to near-normal levels with a low risk of hypoglycemia and without weight gain, and sometimes with weight loss. Early combination therapy is effective and has been shown to have a favorable legacy effect. A number of agents are available in a single-pill combination (SPC) that provides fewer pills and better adherence. Compared with adding a sulfonylurea, still the most common oral combination used, empagliflozin has been shown to decrease cardiovascular (CV) events in a dedicated CV outcome study, and pioglitazone has been effective in reducing the risk of secondary CV endpoints, whereas sulfonylureas have been associated with an increased risk of CV disease. In those failing metformin, triple oral therapy by adding a non-metformin SPC such as empagliflozin/linagliptin or pioglitazone/alogliptin is a good option for reducing glycated hemoglobin (HbA1c) without significant hypoglycemia. CONCLUSION: Clinicians have a comprehensive armamentarium of medications to treat patients with T2DM. Clinical evidence has shown that dual or triple oral combination therapy is effective for glycemic control, and early treatment is effective in getting patients to goal more quickly. Use of SPCs is an option for double or triple oral combination therapy and may result in better adherence.