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.

Cardiovascular and thermal responses to repeated head-up tilts following exercise-induced heat stress.

BACKGROUND: We evaluated the acute cardiovascular and thermoregulatory responses to repeated 70 degrees head-up tilts (HUT) performed following exercise-induced hyperthermia. METHODS: Eight male subjects underwent intermittent episodes of 70 degrees HUT in either a non-exercise/ non-heat stress state (NH) or an exercise-induced hyperthermic state (EIH). Subjects remained supine for 30 min in a thermoneutral environment (22 degrees C) and were subsequently exposed to three successive 6-min 70 degrees head-up tilts (HUT1, HUT2, HUT3), each separated by 10 min of supine resting. During EIH, subjects were rendered hyperthermic by exercise in the heat (core temperature of approximately 40.0 degrees C) and were then transferred to an ambient temperature of 22 degrees C. We evaluated the relative change in hemodynamic and thermal responses from the last minute in the supine position preceding the HUT to the final minute in HUT. RESULTS: While we measured a difference in the relative change in heart rate between conditions for all HUTs, no differences were observed in mean arterial pressure (MAP), total peripheral resistance, or cardiac output. A reduced change in baroreceptor sensitivity was measured in EIH for HUT1 only (-2 +/- 1 ms x mmHg(-1) following EIH compared to -13 +/- 3 ms x mmHg(-1) during NH). A significant transient reduction in cutaneous vascular conductance (CVC) occurred during HUT1 and HUT2 following EIH (-20 +/- 5% CVCmax and -9 +/- 3 %CVCmax, respectively), despite significant elevations in core temperature above resting levels (i.e., 1.4 degrees C and 0.9 degrees C for HUT1 and HUT2). CONCLUSION: We conclude that the maintenance of MAP following exercise in the heat is mitigated by reductions in skin perfusion despite significant elevations in core temperature.

Influence of nonthermal baroreceptor modulation of heat loss responses during uncompensable heat stress.

We evaluated the hypothesis that with increasing levels of hyperthermia, thermal influences would predominate over nonthermal baroreceptor control of cutaneous vascular conductance (CVC) and local sweat rate (LSR). On separate days, eight male participants were positioned in either an upright seated posture (URS) or a 15 degrees head-down tilt (HDT) posture in a thermoneutral condition and during passive heating, until mean body temperature (T(body)) increased by 1.5 degrees C. Hemodynamic [heart rate (HR), cardiac output, mean arterial pressure (MAP)] and thermal responses [T(re), CVC, LSR] were measured continuously. MAP showed a gradual decrease in the early- to mid-stages of heating for both HDT and URS. At a T(body) > 0.6 degrees C, MAP achieved a stable, albeit reduced level from baseline resting for the duration of the heating, whereas MAP decreased significantly throughout the heating period in the URS position (p < 0.001). CVC increased rapidly in the early stages of heating and achieved a stable elevated level in both HDT and URS at the mid-stage of heating (T(body) increase

Challenges in initiating antiretroviral therapy in 2010.

Many clinical trials have shown that initiating antiretroviral therapy (ART) at higher rather than lower CD4 T cell-positive counts results in survival benefit. Early treatment can help prevent end-organ damage associated with HIV replication and can decrease infectivity. The mainstay of treatment is either a non-nucleoside reverse transcriptase inhibitor or a ritonavir-boosted protease inhibitor in combination with two nucleoside reverse transcriptase inhibitors. While effective at combating HIV, ART can produce adverse alterations of lipid parameters, with some studies suggesting a relationship between some anti-retroviral agents and cardiovascular disease. As the HIV-positive population ages, issues such as hypertension and diabetes must be taken into account when initiating ART. Adhering to ART can be difficult; however, nonoptimal adherence to ART can result in the development of resistance; thus, drug characteristics and the patient's preparedness to begin therapy must be considered. Reducing the pill burden through the use of fixed-dose antiretroviral drug combinations can facilitate adherence.

De nombreux essais cliniques ont montré que l'instauration d'un traitement antirétroviral à partir d'un seuil de CD4 T supérieur plutôt qu'inférieur produit un avantage sur la survie. Un traitement précoce peut aider à prévenir l'atteinte des organes cibles associée à la réplication du VIH et réduire l'infectivité. Le traitement repose principalement soit sur un inhibiteur non nucléosidique de la transcriptase inverse, soit sur un inhibiteur de la protéase rehaussé par ritonavir en association avec deux inhibiteurs nucléosidiques de la transcriptase inverse. Bien qu'efficaces pour combattre le VIH, les antirétroviraux peuvent avoir une influence négative sur les paramètres lipidiques, des études ayant fait état d'un lien entre certains antirétroviraux et la maladie cardiovasculaire. À mesure que la population VIH-positive vieillit, il faut tenir compte de problèmes comme l'hypertension et le diabète au moment d'amorcer des antirétroviraux. La fidélité aux antirétroviraux pose parfois problème. Toutefois, une piètre observance thérapeutique peut contribuer à la résistance. Il faut donc prendre en compte les caractéristiques des patients et leur volonté de démarrer le traitement. On peut réduire le nombre de comprimés en utilisant des antirétroviraux d'association à dose fixe afin de promouvoir l'observance thérapeutique.

Menstrual cycle and oral contraceptive use do not modify postexercise heat loss responses.

It is unknown whether menstrual cycle or oral contraceptive (OC) use influences nonthermal control of postexercise heat loss responses. We evaluated the effect of menstrual cycle and OC use on the activation of heat loss responses during a passive heating protocol performed pre- and postexercise. Women without OC (n = 8) underwent pre- and postexercise passive heating during the early follicular phase (FP) and midluteal phase (LP). Women with OC (n = 8) underwent testing during the active pill consumption (high exogenous hormone phase, HH) and placebo (low exogenous hormone phase, LH) weeks. After a 60-min habituation at 26 degrees C, subjects donned a liquid conditioned suit. Mean skin temperature was clamped at approximately 32.5 degrees C for approximately 15 min and then gradually increased, and the absolute esophageal temperature at which the onset of forearm vasodilation (Th(vd)) and upper back sweating (Th(sw)) were noted. Subjects then cycled for 30 min at 75% Vo(2 peak) followed by a 15-min seated recovery. A second passive heating was then performed to establish postexercise values for Th(vd) and Th(sw). Between 2 and 15 min postexercise, mean arterial pressure (MAP) remained significantly below baseline (P < 0.05) by 10 +/- 1 and 11 +/- 1 mmHg for the FP/LH and LP/HH, respectively. MAP was not different between cycle phases. During LP/HH, Th(vd) was 0.16 +/- 0.24 degrees C greater than FP/LH preexercise (P = 0.020) and 0.15 +/- 0.23 degrees C greater than FP/LH postexercise (P = 0.017). During LP/HH, Th(sw) was 0.17 +/- 0.23 degrees C greater than FP/LH preexercise (P = 0.016) and 0.18 +/- 0.16 degrees C greater than FP/LH postexercise (P = 0.001). Postexercise thresholds were significantly greater (P < or = 0.001) than preexercise during both FP/LH (Th(vd), 0.22 +/- 0.03 degrees C; Th(sw), 0.13 +/- 0.03 degrees C) and LP/HH (Th(vd), 0.21 +/- 0.03 degrees C; Th(sw), 0.14 +/- 0.03 degrees C); however, the effect of exercise was similar between LP/HH and FP/LH. No effect of OC use was observed. We conclude that neither menstrual cycle nor OC use modifies the magnitude of the postexercise elevation in Th(vd) and Th(sw).