A randomized control trial of high-dose micronutrient-antioxidant supplementation in healthy persons with untreated HIV infection.

BACKGROUND: Although micronutrient and antioxidant supplementation are widely used by persons with human immunodeficiency virus (HIV), a therapeutic role beyond recommended daily allowances (RDA) remains unproven. An oral high-dose micronutrient and antioxidant supplement (Treatment) was compared to an RDA supplement (Control) for time to progressive immunodeficiency or initiation of antiretroviral therapy (ART) in people living with HIV (PLWH). METHODS: This study was a randomized, double-blind, placebo-controlled multicenter clinical trial. PLWH were recruited from Canadian HIV Trials Network sites, and followed quarterly for two years. Eligible participants were asymptomatic, antiretroviral treatment (ART)-naïve, HIV-seropositive adults with a CD4 T lymphocyte count (CD4 count) between 375-750 cells/µL. Participants were randomly allocated 1:1 to receive Treatment or Control supplements. The primary outcome was a composite of time-to-first of confirmed CD4 count below 350 cells/µL, initiation of ART, AIDS-defining illness or death. Primary analysis was by intention-to-treat. Secondary outcomes included CD4 count trajectory from baseline to ART initiation or two years. A Data and Safety Monitoring Board reviewed the study for safety, recruitment and protocol adherence every six months. RESULTS: Of 171 enrolled participants: 66 (38.6%) experienced a primary outcome: 27 reached a CD4 count below 350 cells/µL, and 57 started ART. There was no significant difference in time-to-first outcome between groups (Hazard Ratio = 1.05; 95%CI: 0.65, 1.70), or in time to any component outcome. Using intent-to-treat censoring, mean annualized rates of CD4 count decline were -42.703 cells/µL and -79.763 cells/µL for Treatment and Control groups, with no statistical difference in the mean change between groups (-37.06 cells/µL/52 weeks, 95%CI: (-93.59, 19.47); p = 0.1993). Accrual was stopped at 171 of the 212 intended participants after an interim analysis for futility, although participant follow-up was completed. CONCLUSIONS: In ART-naïve PLWH, high-dose antioxidant, micronutrient supplementation compared to RDA supplementation had no significant effect on disease progression or ART initiation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00798772.

Vedolizumab treatment across antiretroviral treatment interruption in chronic HIV infection: the HAVARTI protocol for a pilot dose-ranging clinical trial to assess safety, tolerance, immunological and virological activity.

INTRODUCTION: Continuous antiretroviral therapy (ART) suppresses HIV plasma viral load (pVL) to very low levels, which allows for some immune recovery. Discontinuation of ART leads to pVL rebound from reservoirs of persistence and latency, and progressive immunodeficiency. One promising but controversial strategy targeting CD4+ T lymphocytes with a monoclonal antibody (mAb) against α4ß7 integrin has shown promise through sustained virological remission of pVL (SVR) in SIV239-infected rhesus macaques. We propose to assess the safety and tolerability of vedolizumab, a licensed humanised mAb against human α4ß7 integrin, in healthy HIV-infected adults on ART. This study will also assess, by analytical treatment interruption (ATI), whether vedolizumab treatment can induce SVR beyond ART and vedolizumab treatment. METHODS AND ANALYSIS: The HIV-ART-vedolizumab-ATI (HAVARTI) trial is a single-arm, dose-ranging pilot trial in healthy HIV-positive adult volunteers receiving ART. Twelve consenting persons will be enrolled in sequential groups of 4 to each serial dosing vedolizumab regimen (300 mg, 150 mg, 75 mg). The primary outcomes are: (1) to assess the safety and tolerability of seven serial infusions of vedolizumab at each of three doses; (2) to identify the immunovirological measures, including pVL and T-cell kinetics, that characterise HIV/ART cases before, during, after vedolizumab treatment and ATI; and (3) to seek SVR of pVL after ATI. Secondary outcomes will include immune reconstitution and pVL suppression as well as immune reconstitution and long-term safety following re-initiation of ART in the absence of SVR. ETHICS AND DISSEMINATION: The study protocol was approved by the Ottawa Health Science Network-REB and by the Health Canada Therapeutic Products Directorate. A Data Safety Monitor will review safety information at regular intervals. The final manuscript will be submitted to an open access journal within a year of study completion. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03147859; https://clinicaltrials.gov/ct2/show/NCT03147859.

Micronutrient deficiency and treatment adherence in a randomized controlled trial of micronutrient supplementation in ART-naïve persons with HIV.

INTRODUCTION: The MAINTAIN study is an on-going RCT comparing high-dose micronutrient and anti-oxidant supplementation versus recommended daily allowance (RDA) vitamins in slowing HIV immune deficiency progression in ART-naïve people with HIV infection. OBJECTIVE: We planned analysis of the first 127 participants to determine the baseline prevalence of serum micronutrient deficiencies and correlates, as well as tolerance and adherence to study interventions. METHODS: Participants receive eight capsules twice daily of 1) high-dose or 2) RDA supplements for two years and are followed-up quarterly for measures of immune deficiency progression, safety and tolerability. Regression analysis was used to identify correlates of micronutrient levels at baseline. Adherence was measured by residual pill count, self-report using the General Treatment Scale (GTS) and short-term recall HIV Adherence Treatment Scale (HATS). RESULTS: Prior micronutrient supplementation (within 30 days) was 27% at screening and 10% of study population, and was not correlated with baseline micronutrient levels. Low levels were frequent for carotene (24%<1 nmol/L), vitamin D (24%<40 nmol/L) and serum folate (20%<15 nmol/L). The proportion with B12 deficiency (<133 pmol/L) was 2.4%. Lower baseline levels of B12 correlated lower baseline CD4 count (r = 0.21, p = 0.02) with a 21 pmol/L reduction in B12 per 100 cells/µL CD4. Vitamin D levels were higher in men (p<0.001). After a median follow-up of 1.63 years, there were 19 (15%) early withdrawals from the study treatment. Mean treatment adherence using pill count was 88%. Subjective adherence by the GTS was 81% and was moderately but significantly correlated with pill count (r = 0.29, p<0.001). Adherence based on short-term recall (HATS) was >80% in 75% of participants. CONCLUSION: Micronutrient levels in asymptomatic HIV+ persons are in keeping with population norms, but micronutrient deficiencies are frequent. Adherence levels are high, and will permit a valid evaluation of treatment effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT00798772.

From clinical sites to biorepositories: effectiveness in blood sample management.

Today's biobanks must work to take full advantage of collected samples, while maximizing sample quality and minimizing costs to sustain operations for a long period of time. This is a tall order that will require collaboration and compromise for both end-users and collection sites. This article discusses the efforts of the Génome Québec-Centre Hospitalier Affilié Universitaire Régional de Chicoutimi Biobank to fractionate blood samples for the simultaneous preservation of plasma and DNA-containing layers while minimizing resources required for shipping and transport. This article also describes methods for successful reproducible application of the plasma-depleted blood sample to GenPlates (GenVault, Carlsbad, CA).

Association study between candidate genes and obesity-related phenotypes using a sample of lumberjacks.

INTRODUCTION: Complex traits such as obesity are modulated by genetic and environmental factors and lead to varied clinical presentations.The aim of this study was to investigate associations between candidate genes and obesity-related phenotypes using a sample of 252 lumberjacks issued from a founder population and sharing a common and circumscribed environment. METHODS: Thirty-seven variants in 18 genes were genotyped. The restriction fragment length polymorphism method and the template-directed dye-terminator incorporation assay with fluorescence polarization detection were employed for the genotyping assays. Multivariate logistic regression models were built in order to calculate the relative odds of exhibiting obesity-related phenotypes associated with the presence of the studied polymorphism. Among them, 21 single nucleotide polymorphisms were tested for associations with obesity phenotypes. RESULTS: Significant associations were found between carriers of the minor alleles of APOE-epsilon2, FABP2-A54T, UCP1-L229M, LPL-HindIII, LPL-S447X and LPL-T1973C, patients bearing a combination of LPL-D9N, LPL-N291S and LPL-P207L and obesity-related phenotypes. CONCLUSION: The present results suggest that a particular population such as lumberjacks, sharing the same environment, could help target genes involved in complex traits.

Systematic services audit of consecutive suicides in New Brunswick: the case for coordinating specialist mental health and addiction services.

OBJECTIVE: To weight the potential of promotion, prevention, and treatment programs to help establish priorities in multipronged suicide prevention strategies. METHODS: Psychological autopsy methods served to collect information on consecutive suicides over 14 months in New Brunswick (n = 102). A panel of researchers, clinicians, provincial planners, and consumers reviewed the cases and applied a systematic needs assessment procedure to establish interventions and services received, unmet needs at the individual level, and programmatic and systemic shortcomings. RESULTS: More than two-thirds of the individuals suffered from a depressive disorder and a similar proportion from substance (essentially alcohol) abuse or dependence; one-half also presented a personality disorder. In the last year, more than one-half had been in contact with a mental health services specialist, but less than 5% had contact with addiction services, though one-third had previous contact in their lifetime. In one-third of the cases, service gaps called for greater coordination and integration of mental health specialists and addiction services within the health care system. In one-half of the cases, system needs were found to be unmet for public awareness efforts aimed at encouraging individuals to consult health and social services professionals, and in terms of training efforts geared to improving detection, treatment, and referral for mental illness, substance-related problems, and suicidal behaviour by primary medical, social, and specialist services. CONCLUSION: This study supports multipronged suicide prevention strategies that should include integrated public promotion, professional development campaigns, and better program coordination. Authorities in New Brunswick have opted to favour the latter strategy component, whose development and application must be evaluated to determine its impact on suicide rates.

Life trajectories and burden of adversity: mapping the developmental profiles of suicide mortality.

BACKGROUND: Little is known about differential suicide profiles across the life trajectory. This study introduces the life-course method in suicide research with the aim of refining the longitudinal and cumulative assessment of psychosocial factors by quantifying accumulation of burden over time in order to delineate distinctive pathways of completed suicide. METHOD: The psychological autopsy method was used to obtain third-party information on consecutive suicides. Life-history calendar analysis served to arrive at an adversity score per 5-year segment that was then cluster-analysed and correlated to define victim profiles. RESULTS: Two distinct life trajectories emerged: (1) individuals who experienced childhood traumas, developmental adversity and little protection were more likely to present concurrent psychiatric and Axis II disorders; and (2) individuals who experienced less adversity but seemed more reactive to later major difficulties. CONCLUSIONS: The life calendar approach presented here in suicide research adds to the identification of life events, distal and recent, previously associated with suicide. It also quantifies the burden of adversity over the life course, defining two distinct profiles that could benefit from distinct targeted preventive intervention.