Objectives
Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) is approved for pre‐exposure prophylaxis (PrEP) against HIV infection. Adherence is critical for the success of PrEP, but current ...adherence measurements are inadequate for real‐time adherence monitoring. We developed and validated a urine assay to measure tenofovir (TFV) to objectively monitor adherence to PrEP.
Methods
We developed a urine assay using high‐performance liquid chromatography coupled to tandem mass spectrometry with high sensitivity/specificity for TFV that allowed us to determine TFV concentrations in log10 categories between 0 and 10 000 ng/mL. We validated the assay in three cohorts: (1) HIV‐positive subjects with undetectable viral loads on a TDF/FTC‐based regimen, (2) healthy HIV‐negative subjects who received a single dose of TDF/FTC, and (3) HIV‐negative subjects receiving daily TDF/FTC as PrEP for 24 weeks.
Results
The urine assay detected TFV with greater sensitivity than plasma‐based measures and with a window of measurements within 7 days of the last TDF/FTC dose. Based on the urine log‐linear clearance after the last dose and its concordance with all detectable plasma levels, a urine TFV concentration > 1000 ng/mL was identified as highly predictive of the presence of TFV in plasma at > 10 ng/mL. The urine assay was able to distinguish high and low adherence patterns within the last 48 h (> 1000 ng/mL versus 10–1000 ng/mL), as well as nonadherence (< 10 ng/mL) extended over at least 1 week prior to measurement.
Conclusions
We provide proof of concept that a semiquantitative urine assay measuring levels of TFV could be further developed into a point‐of‐care test and be a useful tool to monitor adherence to PrEP.
Objectives
The aim of the study was to assess the validity of an easy‐to‐calculate chronic kidney disease (CKD) risk score developed by the Data Collection on Adverse Events of Anti‐HIV Drugs (D:A:D) ...group in a longitudinal observational study of people living with HIV (PLWH) in the USA.
Methods
PLWH (2002–2016) without prior exposure to potentially nephrotoxic antiretroviral agents and with at least three estimated glomerular filtration rate (eGFR) test results were identified in the Observational Pharmaco‐Epidemiology Research and Analysis (OPERA®) cohort. Three samples were drawn independently using the same eligibility criteria but each using a different eGFR equation, specifically the Cockcroft–Gault (C‐G), Modification of Diet in Renal Disease (MDRD) or Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) eGFR estimation method. Full and short D:A:D risk scores were applied. CKD was defined as a confirmed decrease in eGFR to < 60 mL/min/1.73 m2 (stages 3–5). Poisson models estimated the association between CKD incidence and a one‐point increase in the continuous risk score. The incidence rate ratio (IRR), adjusted IRR (aIRR), and Harrell's discrimination statistic were used to assess validity.
Results
There were 19 444, 22 727 and 22 748 PLWH in the OPERA C‐G, CKD‐EPI and MDRD samples, respectively. The median (minimum–maximum) follow‐up duration was 6.1 (0.3–9.1) years in the D:A:D cohort and ranged from 3.2 to 3.5 (0.2–15.5) years in the OPERA validation samples. The observation time for the majority of PLWH in the D:A:D cohort began prior to 2006, in stark contrast to the OPERA validation samples, where the majority of PLWH were observed after 2011. The CKD incidence ranged from 7.3 per 1000 person‐years 95% confidence interval (CI) 6.8, 7.9 per 1000 person‐years in OPERA C‐G to 11.0 (95% CI 10.4, 11.6 per 1000 person‐years) in OPERA MDRD. In OPERA samples, IRRs by risk group and adjusted IRRs (full risk score) were similar to those in the D:A:D derivation cohort (adjusted IRR 1.3; 95% CI 1.3, 1.3). Harrell's c‐statistic ranged from 0.87 to 0.92 in the OPERA samples, comparable to that in the derivation cohort (0.92). Results for short scores were similar.
Conclusions
The findings support the validity of the D:A:D risk scoring method for assessing CKD (stages 3–5) probability in an exclusively USA‐based sample regardless of eGFR method.
Summary
The impact of hepatitis C virus (HCV) RNA levels on immune status in chronically HCV mono‐infected when compared to HIV/HCV co‐infected on antiretroviral therapy (ART) remains poorly ...understood. A total of 78 African American subjects HCV viraemic/naïve to HCV treatment (33 HCV genotype 1 mono‐infected, 45 ART‐treated HIV/HCV genotype 1 co‐infected) were studied. Clinical and liver enzyme measurements were performed. Whole blood was analysed for immune subset changes by flow cytometry. Peripheral blood mononuclear cells (PBMC) were used for same‐day constitutive and in vitro Interferon (IFN)‐α‐induced signal transducer and activator of transcription (STAT) phosphorylation, K562 target cell lysis and K562 target cell recognition‐mediated IFN‐γ production. Statistical analysis was performed using R (2.5.1) or JMP Pro 11. While both groups did not differ in the level of liver enzymes, HIV/HCV had higher T‐cell activation/exhaustion, and constitutive STAT‐1 phosphorylation compared to HCV. In contrast, CD4+FoxP3+CD25+ frequency, IFN‐αR expression on NK cells, as well as constitutive and IFN‐α‐induced direct cytotoxicity were lower in HIV/HCV. Linear regression models further supported these results. Finally, increase in HCV viral load and CD4+ T‐cell count had an opposite effect between the two groups on NK cell activity and T‐cell activation, respectively. HCV viral load in ART‐treated HIV/HCV co‐infection was associated with greater immune activation/exhaustion and NK dysfunction than HCV viral load alone in HCV mono‐infection. The more pronounced immune modulation noted in ART‐treated HIV‐co‐infected/untreated HCV viraemic subjects may impact HCV disease progression and/or response to immunotherapy.
Antibiotic contamination in polluted rivers is well recognized as an environmental and public health challenge. In this study, the occurrence, distribution, and ecological risk assessment of three ...commonly used antibiotics (amoxicillin, ciprofloxacin, and azithromycin) were assessed in the Litani River, the most important and highly polluted river in Lebanon. Physicochemical and microbiological water quality parameters including the antibiotic-resistant ones were in parallel determined in the same sites. Water samples from five sites stretching across the river upper basin were analyzed for the antibiotics under study using high-performance liquid chromatography, with both fluorometric and UV detectors post-extraction using a solid-phase method with a hydrophilic-lipophilic balance cartridges. The disc diffusion method and standardized water quality methods were used for antibiotic-resistant bacteria and water quality assessment, respectively. Amoxicillin and ciprofloxacin were found at concentrations of 250 ng/L and 107.2 ng/L, while azithromycin was not detected in any of the sites under study. Varying levels of antibiotic resistance were detected with the isolated
Escher
ichia coli
(
E. coli
) and
Pseudomonas aeruginosa
(
P. aeruginosa
) while the total coliforms showed resistance to multiple antibiotics. COD, TP, PO43-, TN, NO3-, NH4 + ,
E. coli
, total coliform,
P. aeruginosa
, and Cd levels surpassed permissible levels. Correlation analysis with water quality parameters (COD, total phosphate, phosphate, total nitrogen, and cadmium) showed a significant positive correlation with ciprofloxacin (r > 0.5, p value < 0.05). Also, the resistant
P. aeruginosa
showed a significant positive correlation with cadmium (
r
> 0.5,
p
value < 0.05) while the resistant
E. coli was
positively correlated with total nitrogen, nitrate, and lead levels (
r
> 0.5,
p
value < 0.05). The ecological risk assessment revealed that all the tested antibiotics pose low risks (ecological risk quotient RQ < 0.1) except ciprofloxacin, which could pose a medium risk (0.1 < RQ < 1). Future research concerning the long-term assessment of antibiotics’ residues and the identification of resistance genes in the river is recommended.
Summary
Suppression of hepatitis B virus (HBV)‐DNA to undetectable levels is an important goal for HIV/HBV‐co‐infected patients receiving anti‐HBV‐active antiretroviral therapy (ART), and current ...guidelines recommend that this outcome should be reached by 1 year of treatment. However, the proportion of patients that fail to achieve an undetectable HBV DNA at this time point and its determinants remain unknown in clinical practice. The objective of this study was to determine the incidence and risk factors for incomplete HBV suppression following 1 year of tenofovir‐based ART. We performed a cohort study among tenofovir‐treated HIV/HBV‐co‐infected patients. Patients had HBV viraemia, initiated tenofovir‐based ART and had HBV DNA measured at 1 year of therapy. The primary outcome was incomplete HBV suppression (HBV DNA ≥2.6 log IU/mL) at 1 year. Logistic regression determined odds ratio (ORs) of incomplete HBV suppression for risk factors of interest. Among 133 patients, 54% (95% CI, 46–63%) had incomplete HBV suppression at 1 year. Incomplete suppression was associated with higher baseline HBV DNA (OR, 1.46 per log IU/mL increase; 95% CI, 1.1–1.94) and detectable HIV viraemia at 1 year (OR, 2.52; 95% CI, 1.19–5.32). Among 66 patients with suppressed HIV RNA at 1 year, 28 (42%) failed to achieve an undetectable HBV DNA. Failure to suppress HBV DNA by 1 year occurred in a sizeable proportion of tenofovir‐treated HIV/HBV‐co‐infected patients. Higher HBV DNA and detectable HIV viraemia were risk factors for incomplete HBV suppression.
Background. Stavudine is widely used in developing countries. Lipoatrophy and mitochondrial toxicity have been linked to stavudine use, but it is unclear whether switching to a lower dose can reduce ...these toxicities while maintaining human immunodeficiency virus (HIV) suppression. Methods. HIV-infected subjects receiving standard-dose stavudine with undetectable HIV type 1 RNA for ⩾6 months were randomized (ratio, 3:2) to receive one-half of the stavudine dose (switch arm) or to maintain the dose (continuation arm) while continuing to receive all other prescribed antiretrovirals. The following measurements were obtained at baseline and week 48: fasting lactate, pyruvate, and lipid levels; results of whole-body dual-energy x-ray absorptiometry; and mitochondrial DNA (mtDNA) measurements in fat and peripheral blood mononuclear cells. Change from baseline to week 48 was compared within and between groups. Results. Twenty-four patients (79% of whom were men and 79% of whom were African American; median age, 45 years) were enrolled in the study, 15 were enrolled in the switch arm, and 9 were enrolled in the continuation arm. The median duration of stavudine treatment was 55 months (range, 21–126 months). The median CD4 cell count was 558 cells/mm3 (range, 207–1698 cells/mm3). At baseline, the study arms had similar demographic characteristics and laboratory indices, except for body mass index, total lean body mass, and triglyceride levels (all of which were higher in the switch arm). Three patients (2 in the switch arm) discontinued the study because of study-unrelated reasons. CD4 cell counts remained unchanged. At 48 weeks, 6 patients (4 27% in the switch arm and 2 22% in the continuation arm) had detectable HIV RNA levels (median, 972 copies/mL; range, 60–49,400 copies/mL). All patients with detectable HIV RNA levels reported significant lapses in treatment adherence; none exhibited mutations in HIV genotype. After the treatment switch, significant changes from study entry to week 48 were noted only for lactate level (median change, −0.27 mmol/L; range, −1.2 to 0.25 mmol/L; P=.02) and fat mtDNA (median change, 40 copies/cell; range, −49 to 261 copies/cell; P=.02). In the continuation arm, a significant loss of bone mineral density was seen at week 48 (median change, −1.7%; range, −6.3% to 0.8%; P=.02). The only significant between-group difference was the change in bone mineral density from baseline (P=.003). Conclusions. Reducing stavudine dose by one-half increased fat mtDNA and decreased lactate levels, suggesting improvement in mitochondrial indices while preserving HIV suppression in subjects who maintained adherence. A significant loss of bone mineral density was seen in patients receiving standard-dose stavudine but not in those receiving low-dose stavudine. These results suggest that switching to low-dose stavudine may improve mitochondrial indices while maintaining virological suppression.
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