ABSTRACT
Heavily treatment-experienced (HTE) persons with HIV have limited options for antiretroviral therapy and face many challenges, complicating their disease management. There is an ongoing need for new antiretrovirals and treatment strategies for this population. We reviewed the study designs, baseline characteristics, and results of clinical trials that enrolled HTE persons with HIV. A PubMed literature search retrieved articles published between 1995 and 2020, which were grouped by trial start date (1995-2009, N = 89; 2010-2014, N = 3; 2015-2020, N = 2). Clinical trials in HTE participants markedly declined post-2010. Participant characteristics and study designs showed changes in trends over time. As treatment strategies for HTE persons with HIV progress, we must look beyond virologic suppression to consider the broader needs of this complex heterogeneous population.
Subject(s)
Anti-HIV Agents , HIV Infections , Humans , Anti-HIV Agents/therapeutic use , HIV Infections/drug therapy , Anti-Retroviral Agents/therapeutic use , Viral LoadABSTRACT
Background: Older adults living with HIV (OALWH) are a growing population facing unique challenges to successful antiretroviral therapy.Objective: To assess efficacy and safety profiles of antiretroviral regimens, including those containing dolutegravir, in OALWH.Methods: Combined data from 6 phase III/IIIb trials in treatment-naive (ARIA, FLAMINGO, SINGLE, SPRING-2; N = 2634) and treatment-experienced (DAWNING, SAILING; N = 1339) participants receiving dolutegravir- or non-dolutegravir-based regimens were analyzed by age (<50, ≥50 to <65, and ≥65 years). Baseline data included comorbidities and numbers of concomitant medications. Week 48 efficacy outcomes included virologic response (HIV-1 RNA <50 copies/mL) and CD4+ cell count change from baseline. Safety outcomes included incidence of adverse events (AEs), serious AEs, and AE-related withdrawals.Results: Use of ≥5 concomitant medications was more frequently reported among treatment-naive and treatment-experienced participants aged ≥50 to <65 (30% [90/296] and 25% [57/227], respectively) and ≥65 years (43% [10/23] and 29% [4/14]) than among those aged <50 years (13% [310/2315] and 11% [118/1098]). Comorbidities were more prevalent in the older age groups. For dolutegravir-based regimens, Week 48 rates of virologic response and change in CD4+ cell count were similar across age groups (treatment naive, 80-87% and 234-251 cells/mm3; treatment experienced, 70-100% and 105-156 cells/mm3, respectively). There were no major differences in safety outcomes in each age group.Conclusions: In these analyses of combined phase III/IIIb trial data, efficacy and safety of dolutegravir-based regimens were generally similar across age groups in treatment-naive or treatment-experienced participants. Polypharmacy and comorbidities were more common among OALWH than those aged <50 years.
Subject(s)
HIV Infections , HIV-1 , Aged , Aging , HIV Infections/drug therapy , Heterocyclic Compounds, 3-Ring , Humans , Oxazines , Piperazines , PyridonesABSTRACT
The oral prodrug fostemsavir (GSK3684394, formerly BMS-663068) is an antiretroviral treatment for HIV-1. Fostemsavir is metabolized to its active moiety, temsavir, a first-in-class HIV-1 attachment inhibitor that binds to the viral envelope glycoprotein 120. Long-term antiretroviral therapy, the resulting longer life expectancy, and/or certain coinfections can increase the risk of chronic liver and kidney disease in HIV-1-infected individuals. Two studies were conducted to collectively evaluate the impact of renal and hepatic impairment on temsavir pharmacokinetics (PK) and safety following a single dose of a 600-mg extended-release fostemsavir tablet. There was no clinically meaningful effect of renal or hepatic impairment on temsavir PK, although renal clearance decreased with increasing renal impairment from moderate to severe, and exposure (maximum concentration and area under the plasma concentration-time curve from time 0 to infinity) tended to increase with increasing severity of hepatic impairment. No clinically meaningful effect of hemodialysis on temsavir PK parameters was observed. Fostemsavir was generally safe and well tolerated by treated subjects. Most adverse events (AEs) were mild, with the exception of 1 patient in the renal impairment study who discontinued due to 2 serious AEs unrelated to the study drug. No other treatment-emergent serious AEs occurred, and no other AEs leading to discontinuation were reported. Overall, these results suggest that fostemsavir can be used without dose modification in subjects with mild to severe renal impairment, including those with end-stage renal disease on hemodialysis, and in subjects with mild to severe hepatic impairment.
Subject(s)
Anti-HIV Agents/pharmacokinetics , Hepatic Insufficiency/epidemiology , Organophosphates/pharmacokinetics , Piperazines/pharmacokinetics , Renal Insufficiency/epidemiology , Adult , Age Factors , Aged , Anti-HIV Agents/therapeutic use , Body Mass Index , Creatinine/blood , Female , Glomerular Filtration Rate , HIV Infections/drug therapy , Hepatic Insufficiency/metabolism , Humans , Liver Function Tests , Male , Middle Aged , Organophosphates/therapeutic use , Patient Acuity , Piperazines/therapeutic use , Prodrugs , Racial Groups , Renal Insufficiency/metabolism , Sex FactorsABSTRACT
Advanced colon cancer is extremely difficult to cure, underscoring the need to develop novel therapeutic agents. Prenylated curcumins that are semisynthetic curcumin derivatives with significant anti-cancer potential have been studied herein to assess their therapeutic potential for colon cancer and tested to this aim in vitro for their growth inhibitory properties against 5-fluorouracil + oxaliplatin resistant human colon cancer CR-HT29 and HCT-116 cells. The resulting most active product, gercumin (mono-O-geranylcurcumin), has been further tested for its synergistic effects with FOLFOX (a combination of 5-fluorouracil and oxaliplatin) on the same cell lines. Activity of this combination on colonosphere formation was also investigated. Gercumin was able to suppress the growth of cancer cells with a potency similar to that of curcumin. A synergistic effect of this compound and FOLFOX was also observed. doses tested for synergy in the colonosphere assays did not show greater suppression of colonosphere formation than independent treatment with either reagent alone. Only one of the combinations was shown to be more effective at suppressing colonosphere formation [gercumin 5 µM + FOLFOX (2x)]. Thus, the growth inhibitory effects of curcumin against human cancer cells can be modulated and enhanced by the introduction of hydrophobic chains, normally found in several natural compounds, like the geranyl one. Such compounds are also able to synergize with known chemotherapeutics.
Subject(s)
Antineoplastic Agents/pharmacology , Colonic Neoplasms/pathology , Curcumin/pharmacology , Drug Resistance, Neoplasm , Fluorouracil/pharmacology , Oxaliplatin/pharmacology , Antineoplastic Combined Chemotherapy Protocols , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Colonic Neoplasms/drug therapy , Drug Screening Assays, Antitumor , Drug Synergism , HCT116 Cells , HT29 Cells , Humans , Organoplatinum Compounds/pharmacologyABSTRACT
Extracellular stresses influence transcription factor (TF) expression and therefore lineage identity in the peri-implantation mouse embryo and its stem cells. This potentially affects pregnancy outcome. To understand the effects of stress signaling during this critical period of pregnancy, we exposed cultured murine embryonic stem cells (mESCs) to hyperosmotic stress. We then measured stress-enzyme-dependent regulation of key pluripotency and lineage TFs. Hyperosmotic stress slowed mESC accumulation due to slowing of the cell cycle over 72 h, after a small apoptotic response within 12 h. Phosphoinositide 3-kinase (PI3K) enzymatic signaling was responsible for stem cell survival under stressed conditions. Stress initially triggered mESC differentiation after 4 h through MEK1, c-Jun N-terminal kinase (JNK), and PI3K enzymatic signaling, which led to proteasomal degradation of Oct4, Nanog, Sox2, and Rex1 TF proteins. Concurrent with this post-transcriptional effect was the decreased accumulation of potency TF mRNA transcripts. After 12-24 h of stress, cells adapted, cell cycle resumed, and Oct4 and Nanog mRNA and protein expression returned to approximately normal levels. The TF protein recovery was mediated by p38MAPK and PI3K signaling, as well as by MEK2 and/or MEK1. However, due to JNK signaling, Rex1 expression did not recover. Probing for downstream lineages revealed that although mESCs did not differentiate morphologically during 24 h of stress, they were primed to differentiate by upregulating markers of the first lineage differentiating from mESCs, extraembryonic endoderm. Thus, although two to three TFs that mark pluripotency recover expression by 24 h of stress, there is nonetheless sustained Rex1 suppression and a priming of mESCs for differentiation to the earliest lineage.
Subject(s)
Cell Differentiation , Embryonic Stem Cells/cytology , MAP Kinase Signaling System , Osmotic Pressure , Phosphatidylinositol 3-Kinases/metabolism , Pluripotent Stem Cells/cytology , Animals , Cell Line , Embryonic Stem Cells/metabolism , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Mice , Nanog Homeobox Protein , Octamer Transcription Factor-3/genetics , Octamer Transcription Factor-3/metabolism , Pluripotent Stem Cells/metabolism , SOXB1 Transcription Factors/genetics , SOXB1 Transcription Factors/metabolismABSTRACT
OBJECTIVE: This post hoc analysis sought to assess the efficacy, safety, and tolerability of saxagliptin in patients with type 2 diabetes mellitus and cardiovascular (CV) risk factors or disease (CVD). METHODS: Data from 5 randomized controlled trials were pooled to compare saxagliptin 5 mg with placebo: 2 studies of saxagliptin as monotherapy in drug-naïve patients and 1 each of saxagliptin as add-on therapy to metformin, glyburide, or a thiazolidinedione. Analysis was performed according to the following baseline/trial entry criteria: 1) history/no history of CVD; 2) ≥ 2 versus 0 to 1 CV risk factors; 3) statin use versus no statin use; and 4) hypertension versus no hypertension. Change from baseline glycated hemoglobin (HbA1c), fasting plasma glucose, and postprandial glucose levels; and the proportion of patients achieving an HbA1c level < 7% were analyzed (week 24). Safety was assessed by adverse events, hypoglycemia, and body weight. RESULTS: In total, 882 patients received saxagliptin 5 mg and 799 received placebo. Differences in adjusted mean change from baseline HbA1c (95% CI) were greater with saxagliptin compared with placebo in patients with a history of CVD (-0.64% [-0.90 to -0.38]) and no history of CVD (-0.68% [-0.78 to -0.58]); with ≥ 2 CV risk factors (-0.73% [-0.85 to -0.60]) and 0 to 1 CV risk factor (-0.62% [-0.75 to -0.48]); with statin use (-0.70% [-0.89 to -0.52]) and no statin use (-0.66% [-0.77 to -0.56]); and with hypertension (-0.69% [-0.82 to -0.57]) and no hypertension (-0.66% [-0.80 to -0.52]). Saxagliptin was well tolerated, with similar adverse event rates and types compared with placebo. There was a < 1% rate of confirmed hypoglycemia in all groups except in patients with CV history who received placebo (2.1%). CONCLUSION: Saxagliptin improved glycemic measures, resulted in low rates of confirmed hypoglycemia, and was well tolerated in patients with or without CVD and CV risk factors.
Subject(s)
Adamantane/analogs & derivatives , Cardiovascular Diseases/complications , Diabetes Mellitus, Type 2/drug therapy , Dipeptides/therapeutic use , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Adamantane/administration & dosage , Adamantane/adverse effects , Adamantane/therapeutic use , Cardiovascular Diseases/prevention & control , Diabetes Mellitus, Type 2/complications , Dipeptides/administration & dosage , Dipeptides/adverse effects , Dipeptidyl-Peptidase IV Inhibitors/adverse effects , Drug Therapy, Combination , Glyburide/administration & dosage , Glyburide/therapeutic use , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/therapeutic use , Metformin/administration & dosage , Metformin/therapeutic use , Risk Factors , Thiazolidinediones/administration & dosage , Thiazolidinediones/therapeutic useABSTRACT
This hypothesis and review introduces rules of stem cell stress responses that provide biomarkers and alternative testing that replaces or reduces gestational tests using whole animals. These rules for the stress responses of cultured stem cells validate the organismal strategy of the stress response and show that it emulates what must happen if the conceptus implants during a response to stress in vivo. Specifically there is a profound threshold during a stress dose response where stem cell accumulation is significantly reduced. Below this threshold stress enzymes manage the stress response by converting anabolic to catabolic processes and by suppressing apoptosis, without affecting differentiation. However above this threshold the stem cell survival response converts to an organismal survival response where stress enzymes switch to new substrates and mediate loss of potency factors, gain of early essential differentiated lineages, and suppression of later essential lineages. Stressed stem cells 'compensate' for lower accumulation rates by differentiating a higher fraction of cells, and the organismal survival response further enhances adaptation by prioritizing the differentiation of early essential lineages. Thus compensatory and prioritized differentiation and the sets of markers produced are part of a response of cultured embryos and stem cells that emulate what must happen during implantation of a stressed gestation. Knowledge of these markers and use of stressed stem cell assays in culture should replace or reduce the number of animals needed for developmental toxicity and should produce biomarkers for stressed development in vitro and in vivo.
Subject(s)
Animal Testing Alternatives , Cell Differentiation/drug effects , Developmental Biology/methods , Stem Cells/drug effects , Stress, Physiological/drug effects , Toxicity Tests/methods , Animals , Biomarkers, Pharmacological/metabolism , Cell Lineage/drug effects , Cell Survival/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Embryonic Development/drug effects , Humans , Models, Animal , Risk Assessment , Stem Cells/metabolism , Time FactorsABSTRACT
Benzo(a)pyrene (BaP), a cigarette smoke component, is metabolized to diol esters (BPDE) that bind to DNA and form mutagenic BPDE-DNA adducts. BaP activates stress enzymes including stress-activated protein kinase/jun kinase (MAPK8/9) in embryos, AMP-activated protein kinase alpha1/2 subunits (PRKAA1/2) in somatic cells, and inhibits the proliferation of trophoblast cell lineages. The loss of transcription factor inhibitor of differentiation (ID)2 is required for the initial differentiation of mouse trophoblast stem cells (TSC) in implanting mouse embryo to produce the first placental hormone, chorionic sommatomammotropin (CSH)1. Here we demonstrate that BaP activates PRKAA1/2 and causes ID2 protein loss in TSC in a time- and dose-dependent manner. Although PRKAA1/2 was activated at low BaP doses, PRKAA1/2-dependent ID2 protein loss occurred at a dose that was similar to the threshold that results in a significant decrease in TSC accumulation and decreased fraction of proliferating TSC. This suggests a possible relationship between stress-induced declines in cell accumulation and stem cell differentiation when BaP levels are high. The threshold BaP dose that induces significant ID2 loss is in the range of a 2-3 pack/day habit, suggesting that this mechanism may be involved with implantation failure in smoking women.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Benzo(a)pyrene/toxicity , Inhibitor of Differentiation Protein 2/metabolism , Protein Subunits/metabolism , Stem Cells/drug effects , Trophoblasts/metabolism , AMP-Activated Protein Kinases/genetics , Animals , Benzo(a)pyrene/metabolism , Cells, Cultured , Enzyme Activation , Female , Humans , Mice , Pregnancy , Protein Subunits/genetics , Smoking/adverse effects , Stem Cells/cytology , Stem Cells/metabolism , Nicotiana/chemistry , Trophoblasts/cytology , Trophoblasts/drug effectsABSTRACT
Students have specific learning style preferences, and these preferences may be different between male and female students. Understanding a student's learning style preference is an important consideration when designing classroom instruction. Therefore, we administered the visual, auditory, reading/writing, kinesthetic (VARK) learning preferences questionnaire to our first-year medical students; 38.8% (97 of 250 students) of the students returned the completed questionnaire. Both male (56.1%) and female (56.7%) students preferred multiple modes of information presentation, and the numbers and types of modality combinations were not significantly different between genders. Although not significantly different, the female student population tended to be more diverse than the male population, encompassing a broader range of sensory modality combinations within their preference profiles. Instructors need to be cognizant of these differences and broaden their range of presentation styles accordingly.