Stavudine-associated peripheral neuropathy in zidovudine-naïve patients: effect of stavudine exposure and antiretroviral experience

A post hoc analysis of safety data from study protocol NZT40012 assessed the incidence of conditions defined by the Centers for Disease Control and Prevention in 86 zidovudine-na?ve, antiretroviral-experienced patients with HIV-1 infection who responded poorly (plasma HIV-1 RNA > 1000 copies/mL) despite at least 4 months' treatment with stavudine-containing regimens. Peripheral neuropathy occurred in 21%; other conditions were seen less frequently (candidiasis [13%], herpes zoster [12%], diarrhea lasting > 1 month [9%], Pneumocystis carinii pneumonia [9%], and wasting syndrome [8%]). The incidence of peripheral neuropathy rose significantly with the number of drugs comprising treatment regimens (> or = 4 vs 1-3; P = .013) and tended to be higher in patients with longer exposure to stavudine (29% with > or = 24 months' exposure vs 13% with < 24 months). Because peripheral neuropathy was observed with such high frequency, vigilance for signs and symptoms of this condition appears warranted if stavudine-containing regimens are to be continued.     

Relationships among brain metabolites,cognitive function,and viral loads in antiretroviral-naïve HIV patients

This study aims to determine the relationship among cerebral metabolite concentrations (on proton magnetic resonance spectroscopy or (1)H MRS), cognitive function, and clinical variables (CD4, plasma and CSF viral loads, and lipids) in antiretroviral medication-nai;ve HIV patients. We hypothesized that the probable glial markers myo-inositol [MI] and choline compounds [CHO] would correlate with cognitive function, CD4 count, and viral loads, but not with serum lipids. Forty-five antiretroviral-drug-nai;ve HIV patients and 25 control subjects were evaluated. Frontal lobe [MI], [CHO], and total creatine [CR] were elevated, while basal ganglia [CR] were decreased, with increasing dementia severity. As a group, HIV patients showed slowing on fine motor (Grooved Pegboard) and psychomotor function (Trails A & B), and deficits on executive function (Stroop tasks). Lower CD4 counts and elevated plasma viral loads were associated with elevated frontal white matter [MI], which in turn correlated with the Stroop tasks. These findings suggest that systemic factors (resulting from suppressed immune function and higher plasma viral load) may lead to glial proliferation (elevated [MI], [CHO], and [CR]) in the frontal white matter, which in turn may contribute to deficits on executive function in HIV. Studying antiretroviral-nai;ve patients minimized the confounding effects of antiretroviral treatment on the clinical, MRS, and neuropsychological variables, and allowed for a more accurate assessment of the relationships among these measurements. Metabolite concentrations, rather than metabolite ratios, should be measured since [CR], a commonly used reference for metabolite ratios, varies with disease severity in both frontal lobe and basal ganglia.     

Postmarketing study of nateglinide in Japan: treatment of medication-naïve patients with type 2 diabetes

Nateglinide is an oral antidiabetic medication (OAD) that acts through rapid, short-term stimulation of insulin production. This study was conducted to identify the nature of any adverse effects associated with nateglinide and to evaluate its clinical efficacy in patients with type 2 diabetes, with particular attention to hypoglycemia. Patients with type 2 diabetes who were OAD naïve (n=547), whose fasting blood glucose levels were 150 mg/dL or lower, and who had started to take nateglinide alone were recruited from 139 centers in Japan with a 12-week observation period. The incidence of adverse reactions was 7.62%. Hypoglycemia accompanied by hypoglycemic symptoms was the most prevalent adverse event (2.10%; 11/525). Nine of 11 episodes required no therapeutic intervention. Severe hypoglycemia was recognized in only 1 case of diabetes complicated by serious renal dysfunction, for which nateglinide has been contraindicated in Japan. No subject experienced symptoms of nocturnal or prolonged hypoglycemia. After 12 weeks of nateglinide treatment, decreases were noted in hemoglobin A_1c (0.82%), postprandial glucose (reduced by 59.4 mg/dL to 158.0 mg/dL), and fasting glucose (reduced by 11.7 mg/dL to 122.4 mg/dL). Nateglinide, which demonstrates limited risk of hypoglycemia and effectively controls blood glucose level, is regarded as a useful drug for the treatment of patients with type 2 diabetes.     

A randomised comparison of safety and efficacy of nevirapine vs. atazanavir/ritonavir combined with tenofovir/emtricitabine in treatment-naïve patients

Background: We report data from NEWART, a randomised phase 4 clinical trial comparing virologic efficacy and safety of nevirapine (NVP) vs. ritonavir‐boosted atazanavir (ATV/r) on a background of tenofovir/emtricitabine (TDF/FTC) in HIV‐1‐infected treatment‐naïve patients. This study enrolled patients according to CD4‐based initiation criteria for NVP (<250 cells/mm³ for women and <400 cells/mm³ for men), to reduce the likelihood of symptomatic hepatic events. NEWART was designed to support and confirm results from ARTEN, an international trial with similar design and study endpoints. Methods: A total of 152 patients were randomised 1 : 1 to open‐label NVP 200 mg twice daily or ATV/r (300/100 mg) once daily, plus once daily TDF/FTC (300/200 mg). All participants met CD4⁺ guidelines at entry. The primary endpoint for non‐inferiority was virologic response prior to and at week 48 (confirmed HIV plasma viral load <50 copies/ml, without rebound or change in ARVs). Safety data, including plasma lipids, were recorded throughout the study. Results: The primary endpoint was achieved in 46/75 (61.3%) and 50/77 (64.9%) of patients taking NVP and ATV/r, respectively. Frequency of adverse events (AEs) was similar between arms, with 88.0% of NVP‐treated patients and 94.8% of ATV/r‐treated patients experiencing at least one AE. Nine patients (12%) in each arm experienced an AE that led to discontinuation. At week 48, a significantly greater increase was seen in mean plasma HDL cholesterol (HDL‐C) in the NVP arm (9.6 mg/dl) vs. the ATV/r arm (3.5 mg/dl); p = 0.016. Also, total cholesterol (TC):HDL‐C ratio on‐treatment was ?0.38 and ?0.02 for the NVP and ATV/r arms, respectively (p = 0.038). Conclusions: Efficacy results were consistent with the ARTEN study demonstrating that NVP was non‐inferior to ATV/r when taken in combination with TDF/FTC. Rates of AEs were similar between the two arms, whereas HDL‐C increased and TC:HDL‐C decreased significantly more in patients taking NVP than ATV/r.     

Trichophyton rubrum isolated from aids and human immunodeficiency virus-infected patients in São Paulo, Brazil: antifungal susceptibility and extracellular enzyme production

BACKGROUND: In order to identify intraspecific variations in Trichophyton rubrum and to correlate them to the immunological status of the host, sixty strains isolated from AIDS, HIV-positive and HIV-negative patients were compared for the production of extracellular enzymes and for their susceptibility to several antifungal drugs. METHODS: The isolates were tested for their ability to secrete keratinases, proteinases, phospholipases, lipases and DNases. Likewise, we investigated their susceptibility to amphotericin B, ketoconazole, ciclopiroxolamine, griseofulvin, miconazole and tolnaftate. RESULTS: Variations in the Minimal Inhibitory Concentration (MIC80)) values were observed for all antifungals tested, but they were similarly distributed among the three clinical groups. Griseofulvin showed the most prominent differences among the three groups of isolates. Regarding enzyme secretion, all samples secreted keratinases and DNases, while none secreted phospholipases. Proteinases and lipases were secreted by some of them. CONCLUSIONS: The differences among isolates of the three groups were not statistically significant and therefore could not be ascribed to a given clinical status. Intraspecific variations similarly occurred in each group, irrespective of the immunological status of the patients.     

Efficacy and safety of sitagliptin and the fixed-dose combination of sitagliptin and metformin vs. pioglitazone in drug-naïve patients with type 2 diabetes

Aim: The efficacy and safety of sitagliptin (SITA) monotherapy and SITA/metformin (MET) vs. pioglitazone (PIO) were assessed in patients with type 2 diabetes and moderate‐to‐severe hyperglycaemia (A1C = 7.5–12.0%). Methods: In an initial 12‐week phase (Phase A), 492 patients were randomised 1 : 1 in a double‐blind fashion to SITA (100 mg qd) or PIO (15 mg qd, up‐titrated to 30 mg after 6 weeks). In Phase B (28 additional weeks), the SITA group was switched to SITA/MET (up‐titrated to 50/1000 mg bid over 4 weeks) and the PIO group was up‐titrated to 45 mg qd Results: At the end of Phase A, mean changes from baseline were ?1.0% and ?0.9% for A1C; ?26.6 mg/dl and ?28.0 mg/dl for fasting plasma glucose; and ?52.8 mg/dl and ?50.1 mg/dl for 2‐h post‐meal glucose for SITA and PIO, respectively. At the end of Phase B, improvements in glycaemic parameters were greater with SITA/MET vs. PIO: ?1.7% vs. ?1.4% for A1C (p = 0.002); ?45.8 mg/dl vs. ?37.6 mg/dl for fasting plasma glucose (p = 0.03); ?90.3 mg/dl vs. ?69.1 mg/dl for 2‐h postmeal glucose (p = 0.001); and 55.0% vs. 40.5% for patients with A1C < 7% (p = 0.004). A numerically higher incidence of gastrointestinal adverse events and a significantly lower incidence of oedema were observed with SITA/MET vs. PIO. The incidence of hypoglycaemia was similarly low in both groups. Body weight decreased with SITA/MET and increased with PIO (?1.1 kg vs. 3.4 kg; p < 0.001). Conclusion: Improvements in glycaemic control were greater with SITA/MET vs. PIO, with weight loss vs. weight gain. Both treatments were generally well tolerated.     

Pharmacokinetics and pharmacodynamics of TBR-652, a novel CCR5 antagonist, in HIV-1-infected, antiretroviral treatment-experienced, CCR5 antagonist-naïve patients

TBR-652 is a novel CCR5 antagonist with potent in vitro anti-HIV activity. The objective of this study was to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of TBR-652 in HIV-1-infected, antiretroviral treatment-experienced, CCR5 antagonist-naïve patients. A double-blind, placebo-controlled, randomized, dose-escalating study of TBR-652 monotherapy given once daily orally for 10 days was performed, followed by a 40-day follow-up period. Approximately 10 patients/dose level received 25, 50, 75, 100, and 150 mg TBR-652 or placebo (4:1). Blood was collected at different intervals for PK and HIV-1 RNA assessments. PK analysis of TBR-652 was performed using noncompartmental methods. PK/PD was modeled using a maximum inhibitory effect model (E_max) and 50% inhibitory concentrations (IC₅₀). TBR-652 was well absorbed in the systemic circulation. TBR-652 concentration levels declined slowly, with mean elimination half-lives ranging from 22.5 to 47.62 h across dose levels. TBR-652 treatment resulted in potent, dose-dependent decreases in viral load, with statistically significant decreases in nadir HIV-1 RNA compared to baseline for all dose levels. Suppression of HIV-1 RNA persisted over the 40-day follow-up period. A steep exposure-effect relationship was observed, with an E_max of −1.43 log₁₀ copies/ml and IC₅₀ of 13.1 ng/ml. TBR-652 was generally safe and well tolerated at all dose levels studied. Short-term monotherapy treatments of TBR-652 in HIV-1-infected patients resulted in promising PK and PD results, with a clear exposure-response relationship at the current dose levels studied. Data from this study support further development of TBR-652 in HIV-infected patients.     

Polymerase ε1 mutation in a human syndrome with facial dysmorphism,immunodeficiency, livedo,and short stature (“FILS syndrome”)

DNA polymerase ε (Polε) is a large, four-subunit polymerase that is conserved throughout the eukaryotes. Its primary function is to synthesize DNA at the leading strand during replication. It is also involved in a wide variety of fundamental cellular processes, including cell cycle progression and DNA repair/recombination. Here, we report that a homozygous single base pair substitution in POLE1 (polymerase ε 1), encoding the catalytic subunit of Polε, caused facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”) in a large, consanguineous family. The mutation resulted in alternative splicing in the conserved region of intron 34, which strongly decreased protein expression of Polε1 and also to a lesser extent the Polε2 subunit. We observed impairment in proliferation and G1- to S-phase progression in patients’ T lymphocytes. Polε1 depletion also impaired G1- to S-phase progression in B lymphocytes, chondrocytes, and osteoblasts. Our results evidence the developmental impact of a Polε catalytic subunit deficiency in humans and its causal relationship with a newly recognized, inherited disorder.DNA polymerases are required for DNA synthesis. Mutations in DNA polymerases or changes in their expression could be manifested by alterations in DNA replication, in cell cycle progression, and most prominently, in mutagenesis (Loeb and Monnat, 2008). Several different human diseases might present opportunities to identify disease-associated polymerase mutations and clarify their specific role and mechanisms. Mutations that have a strong effect on function of the canonical DNA polymerases would probably lead to early embryonal or fetal lethality. In contrast, partial loss of function or haploinsufficiency might lead to either multisystem, organ-specific, or cell lineage–specific developmental defects or to the early exhaustion of continuously replicating cell lineages.In this study, we describe a large, consanguineous family in which mild facial dysmorphism, immunodeficiency, livedo, and short stature were associated in 11 affected subjects with genomic mutation in POLE1 (polymerase ε 1), resulting in haploinsufficiency. Of note, patients did not exhibit cancer susceptibility. The findings indicate that Polε is primarily required for cell proliferation and early phase of cell cycle progression.     

Comparison of efficacy for erectile function and lower urinary tract symptoms of tadalafil 20 mg on-demand and 5 mg once daily in patients with erectile dysfunction

Aim: To compare the improvement in erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) as well as safety of tadalafil dosed at 20 mg on‐demand and 5 mg once daily among ED patients. Materials and methods: A total of 194 ED patients visited between March 2010 and June 2011 were recruited. Out of 194 individuals, 168 (86.6%) met inclusion criteria after completing the two‐week screening period (V0). The Patients were randomly allocated into two groups: (i) 20 mg of tadalafil as needed (Group 1: n = 84, 50.0%) and (ii) 5 mg of tadalafil once daily (Group 2: n = 84, 50.0%). Blood pressure (BP), heart rate (HR) and the five‐item version of the International Index of Erectile Function (IIEF‐5) were assessed immediately before initiation of treatment (V1) and after four (V2) and twelve weeks of treatment (V3). In men with an IPSS of ≥ 8 at V1, IPSS, maximal flow rate (Qmax) and post‐void residual volume (PVR) were also assessed. Results: Of the 168 patients, 134 (79.8%; Group 1: n = 68, 81.0%; Group 2: n = 66, 78.6%) patients completed the trial. IIEF‐5 improved in both groups, and the mean change was larger in Group 2 at V3 (4.9 ± 4.2 vs. 6.5 ± 4.5; p = 0.032) Similarly, though IPSS (with ≥ 8, n = 88, 65.7%; Group 1: n = 44, 64.7%; Group 2: n = 44, 66.7%) improved in both groups, the mean change was larger in Group 2 at V3 (?2.8 ± 4.3 vs. ?4.8 ± 4.1; p = 0.026). Qmax and PVR did not differ significantly in either group. Conclusions: Once daily tadalafil was more efficacious in treating both ED and LUTS than on‐demand dosing. However, no differences were observed between the two dosing schedules with regard to the improvement in LUTS when stratified by improvement in ED. The side effects were insignificant for both dosing schedules.     

Efficacy and safety of the seven-day buprenorphine transdermal system in opioid-naïve patients with moderate to severe chronic low back pain: an enriched, randomized, double-blind, placebo-controlled study

Context

This article presents the results of a pivotal Phase 3 study that assesses a new treatment for the management of chronic low back pain: a transdermal patch containing the opioid buprenorphine. In this randomized, placebo-controlled study with an enriched enrollment design, the buprenorphine transdermal system (BTDS) was found to be efficacious and generally well tolerated.

Objectives

This enriched, multicenter, randomized, double-blind study evaluated the efficacy, tolerability, and safety of BTDS in opioid-naïve patients who had moderate to severe chronic low back pain.

Methods

Patients who tolerated and responded to BTDS (10 or 20 mcg/hour) during an open-label run-in period were randomized to continue BTDS 10 or 20 mcg/hour or receive matching placebo. The primary outcome was “average pain over the last 24 hours” at the end of the 12-week double-blind phase, collected on an 11-point scale (0 = no pain, 10 = pain as bad as you can imagine). Sleep disturbance (Medical Outcomes Study subscale) and total number of supplemental analgesic tablets used were secondary efficacy variables.

Results

Fifty-three percent of patients receiving open-label BTDS (541 of 1024) were randomized to receive BTDS (n = 257) or placebo (n = 284). Patients receiving BTDS reported statistically significantly lower pain scores at Week 12 compared with placebo (least square mean treatment difference: −0.58, P = 0.010). Sensitivity analyses of the primary efficacy variable and results of the analysis of secondary efficacy variables supported the efficacy of BTDS relative to placebo. During the double-blind phase, the incidence of treatment-emergent adverse events was 55% for the BTDS treatment group and 52% for the placebo treatment group. Laboratory, vital sign, and electrocardiogram evaluations did not reveal unanticipated safety findings.

Conclusion

BTDS was efficacious in the treatment of opioid-naïve patients with moderate to severe chronic low back pain. Most treatment-emergent adverse events observed were consistent with those associated with the use of opioid agonists and transdermal patches.     

Is cardiovascular disease in patients with diabetes associated with serum levels of MMP-2, LOX,and the elastin degradation products ELM and ELM-2?

Background: Diabetes mellitus type 2 (T2DM) is a significant risk factor for the development of cardiovascular diseases (CVDs). In a previous microarray study of internal mammary arteries from patients with and without T2DM, we observed several elastin-related genes with altered mRNA-expression in diabetic patients, namely matrix metalloproteinase 2 (MMP-2), lysyl oxidase (LOX) and elastin itself. In this study we investigate whether the serum concentrations of elastin-related proteins correlate to signs of CVD in patients with T2DM.

Methods: Blood samples from 302 type 2 diabetic patients were analysed for MMP-2, LOX, and the elastin degradation products ELM and ELM2. The results were investigated for correlations to signs of CVD in different vascular territories, as determined by myocardial perfusion scintigraphy, carotid artery thickness and ankle-brachial blood pressure index.

Results: T2DM patients with peripheral arterial disease (low ankle-brachial index) (PAD) display higher levels of MMP-2 and ELM compared to patients without PAD. However, none of the proteins or degradation products correlated with myocardial ischemia or a combined measure of CVD-signs, including myocardial ischemia, increased carotid thickness and decreased ankle-brachial blood pressure.

Conclusions: Our results suggest that the diabetic environment affects the circulating amounts of MMP-2 and ELM in patients with PAD. However, the same connection could not be seen in diabetic patients with CVD broadly identified in three vascular territories. LOX and ELM-2 did not correlate to any type of CVD. Overall, serum levels of elastin-related molecules are only remotely related to CVD in type 2 diabetes.     

Achieve control: a pragmatic clinical trial of insulin glargine 300 U/mL versus other basal insulins in insulin-naïve patients with type 2 diabetes

Objective: This study aims to compare the effectiveness of insulin glargine 300 U/mL (Gla-300) with its accompanying patient support program with that of other basal insulin and available patient support programs in patients with type 2 diabetes (T2D) in a real-world setting in terms of achieving HEDIS (Healthcare Effectiveness Data and Information Set) individualized glycemic targets without documented symptomatic hypoglycemia.

Methods: Achieve Control is a US-based, multicenter, randomized, open-label, active-controlled, parallel group pragmatic Phase IV trial in insulin-naïve patients with T2D uncontrolled on ≥2 oral antidiabetes drugs (OAD) and/or glucagon-like peptide-1 receptor antagonists (GLP-1 RA). Inclusion criteria include a diagnosis of T2D, age ≥18 years, and glycated hemoglobin (HbA1c) between 8.0% and 11.0%. Patients will be assigned to either the Gla-300 or other basal insulin group. The primary end point is the proportion of patients achieving HEDIS HbA1c targets (<8.0% [64 mmol/mol] in patients with comorbidities or aged ≥65 years; <7.0% [58 mmol/mol] in all other patients) without occurrence of symptomatic hypoglycemia (blood glucose ≤70 mg/dL) from baseline to 6 months. Secondary end points include rates of documented symptomatic nocturnal hypoglycemia and severe hypoglycemia; change from baseline in HbA1c, fasting glucose, and body weight; treatment persistence; patient-reported outcomes; and healthcare resource utilization. Planned enrollment is 3270 patients across approximately 400 clinical sites.

Conclusion: Pragmatic clinical trials offer the potential to assess comparative effectiveness in broadly based patient populations receiving care (with or without a corresponding educational support program) in real-world clinical settings. The results of Achieve Control should elucidate the benefits of management of T2D with Gla-300 versus other basal insulins in terms of patient outcomes, experiences, and perceptions, and its impact on healthcare resource utilization and cost.

Clinical trial registration: www.clinicaltrials.gov identifier is NCT02451137.     

Early diagnosis of candidemia in intensive care unit patients with sepsis: a prospective comparison of (1→3)-β-D-glucan assay, Candida score, and colonization index

Introduction  

The culture-independent serum (1→3)-β-D-glucan (BG) detection test may allow early diagnosis of invasive fungal disease, but its clinical usefulness needs to be firmly established. A prospective single-center observational study was conducted to compare the diagnostic value of BG assay, Candida score (CS), and colonization index in intensive care unit (ICU) patients at risk for Candida sepsis.