Long-Term Benefits from Early Antiretroviral Therapy Initiation in HIV Infection.

Background: For people with HIV and CD4 counts >500 cells/mm, early initiation of antiretroviral therapy (ART) reduces serious AIDS and serious non-AIDS (SNA) risk compared with deferral of treatment until CD4 counts are <350 cells/mm. Whether excess risk of AIDS and SNA persists once ART is initiated for those who defer treatment is uncertain.

Methods: The Strategic Timing of AntiRetroviral Treatment (START) trial, as previously reported, randomly assigned 4684 ART-naive HIV-positive adults with CD4 counts .

ART in HIV-Positive Persons With Low Pretreatment Viremia: Results From the START Trial.

Background: The benefit of immediate antiretroviral therapy (ART) at CD4 >500 cells/μL was established in the Strategic Timing of Antiretroviral Treatment (START) study. The benefits and risks of immediate ART in participants with low pretreatment viremia, including virologic suppressors, were further assessed.

Setting: Randomized prospective international study.

Influence of and polymorphisms on atazanavir/r concentrations in Thai HIV-infected patients.

To evaluate the influence of genetic polymorphisms on plasma trough concentrations of atazanavir (ATV) and ritonavir (RTV). The concentration-to-dose ratios were compared between different genotype groups of , ,  and in 490 patients. Multiple regression analysis was used to examine the association between genetic and clinical factors and log-transformed concentration-to-dose ratio of ATV and RTV.

Risk Factors for Low CD4+ Count Recovery Despite Viral Suppression Among Participants Initiating Antiretroviral Treatment With CD4+ Counts > 500 Cells/mm3: Findings From the Strategic Timing of AntiRetroviral Therapy (START) Trial.

Background: Low CD4 recovery among HIV-positive individuals who achieve virologic suppression is common but has not been studied among individuals initiating treatment at CD4 counts of >500 cells/mm.

Setting: United States, Africa, Asia, Europe and Israel, Australia, Latin America.

Methods: Among participants randomized to immediate antiretroviral therapy (ART) in the Strategic Timing of AntiRetroviral Therapy trial, low CD4 recovery was defined as a CD4 increase of <50 cells/mm from baseline after 8 months despite viral load of ≤200 copies/mL.

In silico thrombin generation: Plasma composition imbalance and mortality in human immunodeficiency virus.

Background: Effective HIV treatment with antiretroviral therapy has prolonged survival and shifted causes of death to non-AIDS illnesses such as cardiovascular disease. We have shown that inflammation and HIV viral load associate with pro- and anticoagulant factor imbalances resulting in increased thrombin generation when mathematically modeled. We explore the hypothesis that factor compositional imbalance, corresponding to increased in silico thrombin generation, predicts mortality among HIV+ persons.

Benefit of Early versus Deferred Antiretroviral Therapy on Progression of Liver Fibrosis among People with HIV in the START Randomized Trial.

The role of antiretroviral therapy (ART) in reducing or contributing to liver fibrosis in persons with human immunodeficiency virus (HIV) is unclear. We evaluated participants in the Strategic Timing of AntiRetroviral Treatment (START) trial for liver fibrosis using the AST to Platelet Ratio Index (APRI) and Fibrosis-4 Index (FIB-4), and assessed for a benefit of early versus delayed ART on liver fibrosis progression. ART-naïve persons with high CD4 counts (>500 cells/µL) from 222 clinical sites in 35 countries were randomized to receive ART either at study enrollment (immediate treatment arm) or when their CD4 count fell below 350 cells/µL (deferred treatment arm).

Changes in plasma lipidome following initiation of antiretroviral therapy.

Introduction: HIV and antiretroviral therapy (ART) have been associated with increased cardiovascular disease and important changes in lipid metabolism. Advances in mass-spectrometry technology allow for the detailed assessment of individual lipid species which may illuminate the mechanisms underlying increased cardiovascular risk. We describe the change in plasma lipidome with initiation of antiretroviral therapy and compare these by regimen.

The Effect of Interrupted/Deferred Antiretroviral Therapy on Disease Risk: A SMART and START Combined Analysis.

Background: Pooled data from the SMART and START trials were used to compare deferred/intermittent versus immediate/continuous antiretroviral therapy (ART) on disease risk.

Methods: Endpoints assessed were AIDS, serious non-AIDS (SNA), cardiovascular disease (CVD), cancer, and death. Pooled (stratified by study) hazard ratios (HRs) from Cox models were obtained for deferred/intermittent ART versus immediate/continuous ART; analyses were conducted to assess consistency of HRs across baseline-defined subgroups.

Comparison of the Outcomes of Individuals With Medically Attended Influenza A and B Virus Infections Enrolled in 2 International Cohort Studies Over a 6-Year Period: 2009-2015.

Background: Outcome data from prospective follow-up studies comparing infections with different influenza virus types/subtypes are limited.

Methods: Demographic, clinical characteristics and follow-up outcomes for adults with laboratory-confirmed influenza A(H1N1)pdm09, A(H3N2), or B virus infections were compared in 2 prospective cohorts enrolled globally from 2009 through 2015. Logistic regression was used to compare outcomes among influenza virus type/subtypes.

Development of noviomimetics that modulate molecular chaperones and manifest neuroprotective effects.

Heat shock protein 90 (Hsp90) is a chaperone under investigation for the treatment of cancer and neurodegenerative diseases. Neuroprotective Hsp90 C-terminal inhibitors derived from novobiocin (novologues) include KU-32 and KU-596. These novologues modulate molecular chaperones and result in an induction of Heat Shock Protein 70 (Hsp70).

HIV dynamics linked to memory CD4+ T cell homeostasis.

The dynamics of latent HIV is linked to infection and clearance of resting memory CD4+ T cells. Infection also resides within activated, non-dividing memory cells and can be impacted by antigen-driven and homeostatic proliferation despite suppressive antiretroviral therapy (ART). We investigated whether plasma viral level (pVL) and HIV DNA dynamics could be explained by HIV's impact on memory CD4+ T cell homeostasis.

Comparison of Dried Blood Spots Versus Conventional Plasma Collection for the Characterization of Efavirenz Pharmacokinetics in a Large-Scale Global Clinical Trial-The ENCORE1 Study.

Background: The aim of this study was to determine the utility of dried blood spots (DBS) compared with conventional plasma collection methods for characterization of efavirenz pharmacokinetics, in the setting of a large-scale, global clinical trial (ENCORE1).

Methods: Six hundred thirty patients were recruited from 38 sites and had single matched whole blood DBS and plasma samples (mid-dose interval) taken at weeks 4 and 12 of treatment. In addition, a subgroup of patients underwent intensive DBS and plasma sampling (0-24 hours) to provide full-profile data for pharmacokinetic parameters.

Circulating miR-122 and miR-200a as biomarkers for fatal liver disease in ART-treated, HIV-1-infected individuals.

Liver disease is one of the main contributors to the increased levels of morbidity and mortality seen in the HIV-1-infected, ART-treated population. Circulating miRNAs, particularly those located inside extracellular vesicles, are seen as promising biomarkers for a number of human disease conditions, including liver-related diseases. Here, we show that serum levels of miR-122 and miR-200a are greater in HIV/HCV co-infected individuals compared to HIV-1 mono-infected individuals.

HIV-1 Env- and Vpu-Specific Antibody-Dependent Cellular Cytotoxicity Responses Associated with Elite Control of HIV.

Studying HIV-infected individuals who control HIV replication (elite controllers [ECs]) enables exploration of effective anti-HIV immunity. HIV Env-specific and non-Env-specific antibody-dependent cellular cytotoxicity (ADCC) may contribute to protection from progressive HIV infection, but the evidence is limited. We recruited 22 ECs and matched them with 44 viremic subjects.

Anti-HIV-1 ADCC Antibodies following Latency Reversal and Treatment Interruption.

There is growing interest in utilizing antibody-dependent cellular cytotoxicity (ADCC) to eliminate infected cells following reactivation from HIV-1 latency. A potential barrier is that HIV-1-specific ADCC antibodies decline in patients on long-term antiretroviral therapy (ART) and may not be sufficient to eliminate reactivated latently infected cells. It is not known whether reactivation from latency with latency-reversing agents (LRAs) could provide sufficient antigenic stimulus to boost HIV-1-specific ADCC.

Changes in Cardiovascular Disease Risk Factors With Immediate Versus Deferred Antiretroviral Therapy Initiation Among HIV-Positive Participants in the START (Strategic Timing of Antiretroviral Treatment) Trial.

Introduction: HIV infection and certain antiretroviral therapy (ART) medications increase atherosclerotic cardiovascular disease risk, mediated, in part, through traditional cardiovascular disease risk factors.

Methods And Results: We studied cardiovascular disease risk factor changes in the START (Strategic Timing of Antiretroviral Treatment) trial, a randomized study of immediate versus deferred ART initiation among HIV-positive persons with CD4 cell counts >500 cells/mm. Mean change from baseline in risk factors and the incidence of comorbid conditions were compared between groups.

Metabolic profiles of individuals switched to second-line antiretroviral therapy after failing standard first-line therapy for treatment of HIV-1 infection in a randomized, controlled trial.

Background: To investigate metabolic changes associated with second-line antiretroviral therapy (ART) following virological failure of first-line ART.

Methods: SECOND-LINE was an open-label randomized controlled trial. Participants were randomized 1:1 to receive ritonavir-boosted lopinavir (LPV/r) with 2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTI group) or raltegravir (RAL group).

Analysis of an ordinal endpoint for use in evaluating treatments for severe influenza requiring hospitalization.

Background/Aims A single best endpoint for evaluating treatments of severe influenza requiring hospitalization has not been identified. A novel six-category ordinal endpoint of patient status is being used in a randomized controlled trial (FLU-Intravenous Immunoglobulin - FLU-IVIG) of intravenous immunoglobulin. We systematically examine four factors regarding the use of this ordinal endpoint that may affect power from fitting a proportional odds model: (1) deviations from the proportional odds assumption which result in the same overall treatment effect as specified in the FLU-IVIG protocol and which result in a diminished overall treatment effect, (2) deviations from the distribution of the placebo group assumed in the FLU-IVIG design, (3) the effect of patient misclassification among the six categories, and (4) the number of categories of the ordinal endpoint.

Effect of Combination Antiretroviral Therapy on HIV-1-specific Antibody-Dependent Cellular Cytotoxicity Responses in Subtype B- and Subtype C-Infected Cohorts.

Background: There is growing interest in immune therapies to clear the latent HIV-1 after combination antiretroviral therapy (cART). There is limited information on the effect of cART on antibody-dependent cellular cytotoxicity (ADCC), and no studies have directly compared ADCC in HIV-1 subtype B- and subtype C-infected subjects. The effect of improving immunocompetence on ADCC to influenza also remains unexplored.

Improved quality of life with immediate versus deferred initiation of antiretroviral therapy in early asymptomatic HIV infection.

Objective: To determine if immediate compared to deferred initiation of antiretroviral therapy (ART) in healthy persons living with HIV had a more favorable impact on health-related quality of life (QOL), or self-assessed physical, mental, and overall health status.

Design: QOL was measured in the Strategic Timing of Antiretroviral Therapy study, which randomized healthy ART-naive persons living with HIV with CD4 cell counts above 500 cells/μl from 35 countries to immediate versus deferred ART.

Methods: At baseline, months 4 and 12, then annually, participants completed a visual analog scale (VAS) for 'perceived current health' and the Short-Form 12-Item Health Survey version 2 from which the following were computed: general health perception; physical component summary (PCS); and mental component summary (MCS); the VAS and general health were rated from 0 (lowest) to 100 (highest).

Early Antiretroviral Therapy at High CD4 Counts Does Not Improve Arterial Elasticity: A Substudy of the Strategic Timing of AntiRetroviral Treatment (START) Trial.

Background: Both human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) may increase cardiovascular disease (CVD) risk. Vascular function assessments can be used to study CVD pathogenesis. We compared the effect of immediate versus deferred ART initiation at CD4 counts >500 cells/mm on small arterial elasticity (SAE) and large artery elasticity (LAE).