Comparison of Bone and Renal Effects In HIV-infected Adults Switching to Abacavir or Tenofovir Based Therapy in a Randomized Trial

Our objective was to compare the bone and renal effects among HIV-infected patients randomized to abacavir or tenofovir-based combination anti-retroviral therapy.In an open-label randomized trial, HIV-infected patients were randomized to switch from zidovudine/lamivudine (AZT/3TC) to abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC). We measured bone mass density (BMD) and bone turnover biomarkers (osteocalcin, osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), alkaline phosphatase, type I collagen cross-linked C-telopeptide (CTx), and osteoprotegerin). We assessed renal function by estimated creatinine clearance, plasma cystatin C, and urinary levels of creatinine, albumin, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL). The changes from baseline in BMD and renal and bone biomarkers were compared across study arms.Of 40 included patients, 35 completed 48 weeks of randomized therapy and follow up. BMD was measured in 33, 26, and 27 patients at baseline, week 24, and week 48, respectively. In TDF/FTC-treated patients we observed significant reductions from baseline in hip and lumbar spine BMD at week 24 (-1.8% and -2.5%) and week 48 (-2.1% and -2.1%), whereas BMD was stable in patients in the ABC/3TC arm. The changes from baseline in BMD were significantly different between study arms. All bone turnover biomarkers except osteoprotegerin increased in the TDF/FTC arm compared with the ABC/3TC arm, but early changes did not predict subsequent loss of BMD. Renal function parameters were similar between study arms although a small increase in NGAL was detected among TDF-treated patients.Switching to TDF/FTC-based therapy led to decreases in BMD and increases in bone turnover markers compared with ABC/3TC-based treatment. No major difference in renal function was observed.Clinicaltrials.gov NCT00647244

Changes from baseline in hip and lumbar spine BMD.

<p>Percentage and absolute mean changes from baseline in lumbar spine (a, c) and hip (b, d) bone mass density as measured by dual energy x-ray absorptiometry (DXA). BMD = bone mass density; TDF/FTC = tenofovir/emtricitabine; ABC/3TC = abacavir/lamivudine. Error bars show 95% confidence intervals.</p

Baseline characteristics.

<p>BMI = body mass index; PI = protease inhibitor; HAART = highly active antiretroviral therapy; HIV = human immunodeficiency virus; BMD = bone mass density; P1NP = procollagen type 1 N-terminal propeptide; CTx = type I collagen cross-linked C-telopeptide; eCrCl = estimated creatinine clearance; NGAL = neutrophil gelatinase-associated lipocalin. Normally distributed data are presented as means with 95% confidence interval (95% CI) in parenthesis. Skewed data are presented as medians with interquartile range (IQR) in parenthesis.</p

Changes from baseline in markers of impaired renal function.

<p>Changes from baseline to the indicated time points in estimated creatinine clearance (a), levels of plasma cystatin C at baseline and week 48 (b), changes from baseline to week 48 in plasma cystatin C (c), and changes from baseline to the last measurement in ratios of urinary biomarkers relative to urine creatinine concentration (d, e, f). Changes in urinary biomarkers (d, e, f) were evaluated in 29 patients (15 in the TDF/FTC arm and 14 in the ABC/3TC arm); of these, 24 were followed from baseline to week 48. Error bars in (a) show 95% confidence intervals; the horizontal line in (c) represents the mean value, while the horizontal lines in (d, e, f) represent median values. eCrCl = estimated creatinine clearance; NGAL = neutrophil gelatinase-associated lipocalin TDF/FTC = tenofovir/emtricitabine; ABC/3TC = abacavir/lamivudine.</p

Flow chart of inclusion and follow up.

<p>Flow chart of inclusion and follow up.</p

Protocol Outlines for Parts 1 and 2 of the Prospective Endoscopy III Study for the Early Detection of Colorectal Cancer:Validation of a Concept Based on Blood Biomarkers

BACKGROUND: Programs for population screening of colorectal cancer (CRC) have been implemented in several countries with fecal immunochemical testing (FIT) as the preferred platform. However, the major obstacle for a feces-based testing method is the limited compliance that reduces the clinical sensitivity for detection of participants with non-symptomatic CRC. Therefore, research approaches have been initiated to develop screening concepts based on biomarkers in blood. Preliminary results show that protein, genetic, epigenetic, and metabolomic components may be valuable in blood-based screening concepts, particularly when combinations of the various components appear to lead to significant improvements. OBJECTIVES: The protocol described in this paper focuses on the validation of concepts based on biomarkers in blood in a major population screened by FIT. METHODS: In Part 1, participants will be identified and included through the Danish CRC Screening Program comprising initial FIT and subsequent colonoscopy to those with a positive result. Blood samples will be collected from 8000 FIT-positive participants, who are offered subsequent colonoscopy. Findings and interventions at colonoscopy together with personal data including co-morbidity will be recorded. Blood samples and data will also be collected from 6000 arbitrarily chosen participants with negative FIT. In Part 2, blood samples and data will be collected from 30,000 FIT-negative participants three times within 4 years. The blood samples will be analyzed using various in-house and commercially available manual and automated analysis platforms. RESULTS: We anticipate Part 1 to terminate late August 2016 and Part 2 to terminate late September 2022. The results from Parts 1 and 2 will be presented within 12 to 18 months from termination. CONCLUSIONS: The purpose of this study is to improve the efficacy of identifying participants with neoplastic bowel lesions, to identify false negative participants, to identify participants at risk of interval neoplastic lesions, to improve the compliance in screening sessions, and to establish guidelines for out-patient follow-up of at-risk participants based on combinations of blood-based biomarkers