Validation of the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) chronic kidney disease risk score in HIV-infected patients in the USA.

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.

HCV viraemia associates with NK cell activation and dysfunction in antiretroviral therapy-treated HIV/HCV-co-infected subjects.

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.

Urine assay for tenofovir to monitor adherence in real time to tenofovir disoproxil fumarate/emtricitabine as pre-exposure prophylaxis.

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.

Incidence and risk factors for incomplete HBV DNA suppression in HIV/HBV-co-infected patients initiating tenofovir-based therapy.

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.

Prediction based classification for longitudinal biomarkers.

Assessment of circulating CD4 count change over time in HIV-infected subjects on antiretroviral therapy (ART) is a central component of disease monitoring. The increasing number of HIV-infected subjects starting therapy and the limited capacity to support CD4 count testing within resource-limited settings have fueled interest in identifying correlates of CD4 count change such as total lymphocyte count, among others. The application of modeling techniques will be essential to this endeavor due to the typically non-linear CD4 trajectory over time and the multiple input variables necessary for capturing CD4 variability. We propose a prediction based classification approach that involves first stage modeling and subsequent classification based on clinically meaningful thresholds. This approach draws on existing analytical methods described in the receiver operating characteristic curve literature while presenting an extension for handling a continuous outcome. Application of this method to an independent test sample results in greater than 98% positive predictive value for CD4 count change. The prediction algorithm is derived based on a cohort of n = 270 HIV-1 infected individuals from the Royal Free Hospital, London who were followed for up to three years from initiation of ART. A test sample comprised of n = 72 individuals from Philadelphia and followed for a similar length of time is used for validation. Results suggest that this approach may be a useful tool for prioritizing limited laboratory resources for CD4 testing after subjects start antiretroviral therapy.

Effect of reducing the dose of stavudine on body composition, bone density, and markers of mitochondrial toxicity in HIV-infected subjects: a randomized, controlled study.

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 > or =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/mm(3) (range, 207-1698 cells/mm(3)). 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.

Relationship of admission plasma gelsolin levels to clinical outcomes in patients after major trauma.

Actin-scavenging proteins, e.g., plasma gelsolin, counteract the pathophysiological consequences of actin leaked into the circulation from dying cells, but the capacity of this defense system can be overwhelmed by massive tissue injury. We examined the prognostic implications of plasma gelsolin levels obtained near the time of admission to our level I Trauma Unit on the subsequent clinical course in a group of patients with severe traumatic injuries. Blood samples were obtained from 13 patients shortly after major trauma and 11 healthy volunteers who served as the control group. Plasma gelsolin levels were assayed by quantitative Western blotting. Duration of mechanical ventilation, stay in the Trauma Intensive Care Unit, and development of acute respiratory distress syndrome (ARDS) were measured as clinical outcomes reflecting the complexity of the hospital course. Subsequently, we evaluated an additional 52 patients after major and minor trauma to extend our earlier observations. Plasma gelsolin concentrations were significantly lower in our 13 original patients compared with healthy controls. Levels below 250 mg/L (> 2 standard deviations below the mean of the control group) were associated with prolonged mechanical ventilation and a stay in the intensive care unit >/= 13 days. Both patients whose gelsolin level was < 100 mg/L in this first series developed ARDS. Including all 65 patients, 6 of the 10 patients who developed ARDS had admission gelsolin levels less than 250 mg/L, compared with only 7 of the 55 patients without ARDS (p = 0.0028). The mean gelsolin levels were 193 and 400 mg/L in patients with and without ARDS, respectively (p < 0.0001) and 398 mg/L in survivors versus 259 mg/L for patients who expired (p < 0.0001). Ten of the 13 patients (77%) with gelsolin levels at the time of admission more than 2 SD below the control mean had "bad outcomes," defined as mechanical ventilation for >/= 13 days in the Trauma Intensive Unit, ARDS, and/or death. Plasma gelsolin levels appear to be an early prognostic marker in patients experiencing major trauma. Whether circulating gelsolin serves a biologically vital function or is simply depleted after massive trauma cannot be determined from our study. The potential therapeutic benefits of infusions of recombinant human plasma gelsolin for patients in whom multiorgan dysfunction commonly follows a serious but self-limited insult have not yet been investigated.

Prophylactic use of antibiotics and vaccines in patients with rheumatologic disorders.

In patients with serious underlying medical conditions, preventive interventions are a prudent, cost-effective, but underused strategy that could lessen morbidity and even mortality. In particular, immunization status should be assessed in all patients with rheumatologic disorders. Tuberculin reactivity is optimally documented before initiation of steroid therapy. It is often easier (and wiser) to prevent an infection than to treat it in a compromised host.