RESUMEN
Painful HIV-associated neuropathy (HIV-SN) is a prevalent co-morbidity of HIV infection. Sensory phenotyping, using quantitative sensory testing (QST) could allow for improved stratification to guide personalized treatment. However, previous methods of QST interpretation have demonstrated limited association with self-reported pain measures. This study sought to identify differences in self-reported pain measures between composite QST-derived sensory phenotypes, and to examine any differences in participants reporting multi-site, multi-etiology chronic pain. In this cross-sectional observational study of participants with HIV (n = 133), individuals were allocated to neuropathy and neuropathic pain groups through clinical assessment and nerve conduction testing. They completed symptom-based questionnaires and underwent standardized QST. Participants were assigned, by pre-determined algorithm, to a QST-derived sensory phenotype. Symptoms were compared between sensory phenotypes. Symptom characteristics and Neuropathic Pain Symptom Inventory scores differed between QST-derived sensory phenotypes: 'sensory loss' was associated with more paroxysmal and paraesthetic symptoms compared to 'thermal hyperalgesia' and 'healthy' phenotypes (P = .023-0.001). Those with painful HIV-SN and additional chronic pain diagnoses were more frequently allocated to the 'mechanical hyperalgesia' phenotype compared to those with painful HIV-SN alone (P = .006). This study describes heterogeneous sensory phenotypes in people living with HIV. Differences in self-reported pain outcomes between sensory phenotypes has the potential to guide future stratified trials and eventually more targeted therapy. PERSPECTIVE: This article presents quantitative sensory testing derived phenotypes, thought to reflect differing pathophysiological pain mechanisms and relates them to self-reported pain measures in people with HIV infection. This could help clinicians stratify patients to individualize analgesic interventions more effectively.
Asunto(s)
Dolor Crónico , Infecciones por VIH , Neuralgia , Humanos , Hiperalgesia , Autoinforme , Infecciones por VIH/complicaciones , Dimensión del Dolor/métodos , Estudios Transversales , Fenotipo , Umbral del Dolor/fisiologíaRESUMEN
BACKGROUND: Drug choice and metabolic changes with antiretroviral therapy contribute to cardiovascular risk in persons with HIV-1 infection. METHODS: A randomized, 12 week, open-label, comparative study of the impact on lipids of continuation of abacavir/lamivudine (ABC/3TC) plus efavirenz (EFV) or replacement with the single tablet regimen of EFV/emtricitabine/tenofovir DF (EFV/FTC/TDF) in hypercholesterolaemic subjects on successful antiretroviral therapy, with a 12-week extension with all subjects on EFV/FTC/TDF. RESULTS: 157 subjects received study drug, 79 switched to EFV/FTC/TDF and 78 subjects continued ABC/3TC+EFV. At Week 12, 73 subjects on ABC/3TC+EFV switched to EFV/FTC/TDF. The switch was well tolerated and no subject experienced viral rebound. Median baseline fasting total cholesterol was 6.32 mmol/L. 12 weeks following switch, the difference in the means (LSM) between treatment groups (EFV/FTC/TDF minus ABC/3TC+EFV) in total cholesterol change from baseline was -0.74 mmol/l (95% CI -1.00, -0.47, p < 0.001). The median change from baseline in total cholesterol following switch in the EFV/FTC/TDF arm was -0.86 mmol/l (p < 0.001) compared with +0.01 mmol/l (p = 0.45) in the continuation arm at Week 12. Significant (p < 0.001) differences between treatment groups following switch were seen for all lipid fractions from baseline to Week 12: LDL cholesterol (-0.47 mmol/L [-0.70, -0.25]), HDL cholesterol (-0.15 mmol/L [-0.21, -0.08]), triglycerides (-0.43 mmol/L [-0.75, -0.11]), and non HDL cholesterol (-0.56 mmol/L [-0.80, -0.31]). In the extension phase, similar declines in total cholesterol were observed with a median change from Week 12 to Week 24 of -0.73 mmol/L (p < 0.001). CONCLUSIONS: Switching from ABC/3TC+EFV to EFV/FTC/TDF in persons with hypercholesterolemia maintains virological control and significantly improves key lipid parameters. TRIAL REGISTRATION: ClinicalTrials.gov NCT00615810.
Asunto(s)
Benzoxazinas/administración & dosificación , Didesoxinucleósidos/administración & dosificación , Emtricitabina/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Hipercolesterolemia/tratamiento farmacológico , Lamivudine/administración & dosificación , Tenofovir/administración & dosificación , Adulto , Alquinos , Benzoxazinas/efectos adversos , Colesterol/sangre , Ciclopropanos , Didesoxinucleósidos/efectos adversos , Combinación de Medicamentos , Emtricitabina/efectos adversos , Femenino , Estudios de Seguimiento , Infecciones por VIH/sangre , Infecciones por VIH/complicaciones , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/complicaciones , Lamivudine/efectos adversos , Masculino , Persona de Mediana Edad , Tenofovir/efectos adversosRESUMEN
: Antiretroviral therapy initiation is associated with declines in bone mineral density (BMD), which seem greatest with tenofovir disoproxil fumarate (DF)-containing regimens. Data comparing protease inhibitors are limited. This CASTLE substudy compared paired baseline with week 96 BMD in patients initiating tenofovir DF/emtricitabine plus atazanavir/ritonavir (n = 106) vs lopinavir/ritonavir (n = 70). In both groups, week 96 BMD declined significantly in arm, leg, trunk, and total body regions. Atazanavir/ritonavir was associated with smaller 96-week trunk and total body BMD declines compared with lopinavir/ritonavir [multivariate-adjusted least squares mean difference +2.00% (95% confidence interval: 0.52 to 3.45; P = 0.008) and +1.24% (95% confidence interval: 0.13 to 2.35; P = 0.029), respectively]. In addition, low baseline CD4 cell count (<50 cells per microliter) and increasing age were associated with larger declines in BMD.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Composición Corporal , Densidad Ósea , Infecciones por VIH/tratamiento farmacológico , Absorciometría de Fotón , Fármacos Anti-VIH/efectos adversos , Sulfato de Atazanavir , Infecciones por VIH/fisiopatología , VIH-1 , Humanos , Lopinavir/administración & dosificación , Lopinavir/uso terapéutico , Análisis Multivariante , Oligopéptidos/administración & dosificación , Oligopéptidos/uso terapéutico , Piridinas/administración & dosificación , Piridinas/uso terapéutico , Ritonavir/administración & dosificación , Ritonavir/uso terapéuticoRESUMEN
BACKGROUND AND OBJECTIVE: Antiretroviral drug regimen choice may influence changes in body composition. The objective of this study was to compare changes in body composition between ritonavir-boosted atazanavir (ATV/r) and ritonavir-boosted lopinavir (LPV/r) over 96 weeks using data from a substudy of CASTLE, which compared once-daily ATV/r with twice-daily LPV/r, both in combination with tenofovir disoproxil fumarate/emtricitabine in treatment-naïve patients with HIV-1 infection. METHODS: We examined 224 patients (125 on ATV/r; 99 on LPV/r) at baseline, 48 and 96 weeks using dual-energy X-ray absorptiometry and computerised tomography. RESULTS: In the lowest baseline body mass index (BMI) group, there were significantly greater gains at week 96 for ATV/r than for LPV/r in subcutaneous adipose tissue and in visceral adipose tissue (VAT). By week 96, patients with lowest baseline CD4 cell counts on ATV/r had 28 % increases in VAT versus 14 % reductions for patients receiving LPV/r. Those with the lowest baseline BMI on ATV/r had 19 % increases in VAT versus reductions of 5 % for patients on LPV/r. In the highest baseline BMI group, the mean increase in triglycerides was 6 and 70 % in the ATV/r and LPV/r arms, respectively. Compared with baseline, an increase in proportion of patients with high waist circumference (WC)/high triglycerides at 96 weeks was noted in both treatment arms, but this increase was numerically greater with LVP/r (18 %) than with ATV/r (11 %). CONCLUSION: Truncal fat gains on ATV/r primarily led to increases in WC, which may reflect return to health, while on LPV/r increases in WC and triglycerides occurred. Changes in body composition with antiretroviral therapy are influenced by treatment choice and baseline characteristics.
Asunto(s)
Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Composición Corporal/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Ritonavir/farmacología , Absorciometría de Fotón , Adenina/administración & dosificación , Adenina/análogos & derivados , Adenina/farmacología , Adenina/uso terapéutico , Adulto , Sulfato de Atazanavir , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Combinación de Medicamentos , Quimioterapia Combinada , Emtricitabina , Femenino , Humanos , Lopinavir/administración & dosificación , Lopinavir/farmacología , Lopinavir/uso terapéutico , Masculino , Oligopéptidos/administración & dosificación , Oligopéptidos/farmacología , Oligopéptidos/uso terapéutico , Organofosfonatos/administración & dosificación , Organofosfonatos/farmacología , Organofosfonatos/uso terapéutico , Piridinas/administración & dosificación , Piridinas/farmacología , Piridinas/uso terapéutico , Ritonavir/administración & dosificación , Ritonavir/uso terapéutico , Tenofovir , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
BACKGROUND: Abacavir/lamivudine (ABC/3TC) and tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) are widely used as first-line antiretroviral therapies. However, there are limited data comparing the safety of these therapies with long-term use. The objective of this study was to assess the long-term safety of these commonly used first-line nucleoside/nucleotide combinations each administered with efavirenz (EFV). METHODS: This open-label, 96-week, randomized study compared the safety (renal, bone and metabolic) and efficacy of ABC/3TC and TDF/FTC plus EFV in HLA-B*5701-negative antiretroviral-naive adults. RESULTS: A total of 385 subjects were enrolled, and 249 (65%) subjects completed the study. The difference in changes from baseline in estimated glomerular filtration rate (calculated by the Modified Diet in Renal Disease equation) between treatment arms was not significant. There was a significant difference between the arms (P < 0.0001) for markers of tubular dysfunction (retinol-binding protein and ß-2 microglobulin) favouring ABC/3TC. Hip bone mineral density decreased from baseline in both arms, with a significantly greater decline with TDF/FTC (ABC/3TC -2.2% and TDF/FTC -3.5%; P < 0.001 at week 96). Subjects in the ABC/3TC arm had greater increases from baseline in median total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides. Adverse events were similar between arms. The virological failure rate was low in both arms. CONCLUSIONS: ABC/3TC and TDF/FTC in combination with EFV minimally affected estimated glomerular filtration rate over 96 weeks. TDF/FTC was associated with greater increases in tubular dysfunction and bone turnover marker levels, greater decreases in hip bone mineral density, and smaller increases in serum lipid levels.
Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/uso terapéutico , Benzoxazinas/uso terapéutico , Desoxicitidina/análogos & derivados , Didesoxinucleósidos/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Lamivudine/uso terapéutico , Organofosfonatos/uso terapéutico , Adenina/uso terapéutico , Alquinos , Terapia Antirretroviral Altamente Activa/efectos adversos , Densidad Ósea , Huesos/efectos de los fármacos , Huesos/patología , Ciclopropanos , Desoxicitidina/uso terapéutico , Combinación de Medicamentos , Emtricitabina , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Infecciones por VIH/virología , VIH-1 , Humanos , Riñón/efectos de los fármacos , Riñón/fisiopatología , Masculino , Tenofovir , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Abdominal adiposity in HIV-1 patients initiating antiretroviral therapy may be part of a restoration-to-health phenomenon. Lipoatrophy is associated with long-term thymidine analogue therapy. Individual protease inhibitors (PIs) differ in their effects on lipids and insulin resistance. METHODS: A randomized open-label multicentre 96-week trial compared changes in fat distribution in patients with suppressed HIV-1 RNA and abdominal adiposity, who either continued on their current twice-daily ritonavir-boosted PI (PI/r) or switched to once-daily boosted atazanavir (ATV/r). Treatment with two nucleoside reverse transcriptase inhibitors was unchanged. Body composition was assessed by dual-energy x-ray absorptiometry (DEXA) and abdominal computerized tomography (CT) scanning. RESULTS: In total, 201 patients were randomized; 131 switched to ATV/r. Viral suppression (<50 copies/ml) was similarly maintained (93% ATV/r versus 89% PI/r). Mean changes from baseline in trunk-to-limb fat ratio were similar; difference estimates 0.03 (95% CI -0.06, 0.12; P=0.48 at week 48) and 0.02 (95% CI -0.10, 0.14; P=0.73 at week 96). More patients in the PI/r arm had a decrease of ≥20% in limb fat from baseline at week 96. Significantly greater reductions in proatherogenic lipids occurred following switch to ATV/r. Both treatment regimens were generally well-tolerated; the incidence of grade 3-4 treatment-related clinical adverse events was 34% among ATV/r recipients versus 4% of PI/r-treated patients. CONCLUSIONS: Switching to ATV/r had no demonstrable benefit on abdominal adiposity. Maintenance of efficacy, less limb fat loss and marked reduction in proatherogenic lipids was observed with ATV/r compared with continuing a PI/r regimen.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Oligopéptidos/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Piridinas/uso terapéutico , Grasa Abdominal , Adulto , Anciano , Fármacos Anti-VIH/administración & dosificación , Sulfato de Atazanavir , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oligopéptidos/administración & dosificación , Inhibidores de Proteasas/administración & dosificación , Piridinas/administración & dosificación , Adulto JovenRESUMEN
Adherence may be facilitated by reducing perceptual and practical barriers to antiretroviral therapy (ART). Practical barriers include the complexity of daily dosing, while perceptual barriers include perceptions of the need for treatment and concerns about adverse effects. The study aim was to assess the effect of switching zidovudine plus lamivudine twice-daily (Combivir, CBV) to once-daily tenofovir DF plus emtricitabine (Truvada, TVD), each plus efavirenz (EFZ), on adherence, beliefs about ART and quality of life (QoL). Subjects stable on CBV + EFV were randomised 1:1 to continue this regimen or switch to TVD + EFV. Adherence was measured using the Medication Adherence Self-Report Inventory at 4, 12, 24 and 48 weeks. Beliefs about ART (perceptions of necessity and concerns about adverse effects), treatment intrusiveness and QoL were measured by questionnaire at baseline 4, 12, 24 and 48 weeks. Viral load was assessed at each visit. Two hundred and thirty-four subjects initiated treatment. At week 48, the proportion of subjects reporting high adherence (≥95% taken as prescribed) was significantly greater in the TVD arm (p=0.049). Low adherence (reporting taking <95% as prescribed, discontinuing the study or having missing data) was associated with doubts about necessity (p=0.020), stronger concerns about adverse effects (p=0.010), greater treatment intrusiveness (p=0.010) and poorer mental health related QoL (p=0.008). At week 48, both concerns about ART (p=0.038) and treatment intrusiveness (p=0.004) were lower among those who switched to TVD. Furthermore, there was a decline in both concerns about ART (p=0.007) and treatment intrusiveness (p=0.057) over the 48 weeks among those who switched to TVD. There were no significant differences in necessity beliefs, QoL or viral load between randomised groups. Switching from CBV to TVD may improve patient reported outcomes including slightly better adherence, a greater reduction in concerns about adverse effects and less treatment intrusiveness.
Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Cumplimiento de la Medicación/psicología , Calidad de Vida/psicología , Adenina/administración & dosificación , Adenina/análogos & derivados , Adulto , Anciano , Alquinos , Terapia Antirretroviral Altamente Activa/psicología , Benzoxazinas/administración & dosificación , Ciclopropanos , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Combinación de Medicamentos , Sustitución de Medicamentos/psicología , Quimioterapia Combinada/métodos , Emtricitabina , Femenino , Infecciones por VIH/psicología , Conocimientos, Actitudes y Práctica en Salud , Humanos , Lamivudine/administración & dosificación , Masculino , Persona de Mediana Edad , Organofosfonatos/administración & dosificación , Tenofovir , Resultado del Tratamiento , Adulto Joven , Zidovudina/administración & dosificaciónRESUMEN
BACKGROUND: Antiretroviral therapy is associated with metabolic complications, including dyslipidaemia, body fat changes and insulin resistance. Healthy volunteer studies have demonstrated a decrease in glucose disposal associated with dosing with specific antiretrovirals. METHODS: HIV-type-1-positive male participants were randomized to receive tenofovir disoproxil fumarate and lamivudine, with either fosamprenavir (FPV)/ritonavir or lopinavir (LPV)/ritonavir twice daily. A hyperinsulinaemic euglycaemic clamp was performed at baseline and at 2 weeks after commencing treatment. The homeostasis model assessment index for insulin resistance (HOMA-IR) was also calculated at these time points. Changes in lipids and lipoprotein subfractions (by nuclear magnetic resonance spectroscopy) were assessed. A pharmacokinetic assessment was undertaken at week 2. RESULTS: A total of 27 participants were enrolled. There was no significant change in whole-body insulin sensitivity or HOMA-IR from baseline or between groups. Total cholesterol increased significantly, by 6.6% with FPV and 10.9% with LPV. The changes in lipids and lipoprotein subfractions were similar between groups with increases in triglycerides, very low-density lipoprotein (VLDL) and chylomicrons, and low-density lipoprotein (LDL) particles. Although the total high-density lipoprotein (HDL) particles were not significantly altered, a decrease in small HDL particles was seen. Changes in VLDL and chylomicron particles in both groups and triglycerides and small HDL particles in the LPV group were statistically significant. CONCLUSIONS: In HIV-type-1-positive men initiating antiretroviral therapy with FPV- or LPV-based regimens, there were no significant changes in whole-body insulin sensitivity after 2 weeks. A proatherogenic lipid profile characterized by increases in triglycerides, VLDL and chylomicron particles and LDL particles, and a decrease in small HDL particles, was observed in both groups.
Asunto(s)
Fármacos Anti-VIH/efectos adversos , Carbamatos/farmacocinética , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Resistencia a la Insulina , Lípidos/sangre , Organofosfatos/farmacocinética , Sulfonamidas/farmacocinética , Adenina/efectos adversos , Adenina/análogos & derivados , Adenina/farmacocinética , Adenina/uso terapéutico , Tejido Adiposo/efectos de los fármacos , Adulto , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Carbamatos/efectos adversos , Carbamatos/uso terapéutico , Intervalos de Confianza , Esquema de Medicación , Combinación de Medicamentos , Dislipidemias/inducido químicamente , Furanos , Infecciones por VIH/complicaciones , Infecciones por VIH/metabolismo , Humanos , Insulina/sangre , Resistencia a la Insulina/fisiología , Lamivudine/efectos adversos , Lamivudine/farmacocinética , Lamivudine/uso terapéutico , Lopinavir , Masculino , Organofosfatos/efectos adversos , Organofosfatos/uso terapéutico , Organofosfonatos/efectos adversos , Organofosfonatos/farmacocinética , Organofosfonatos/uso terapéutico , Pirimidinonas/efectos adversos , Pirimidinonas/farmacocinética , Pirimidinonas/uso terapéutico , Ritonavir/efectos adversos , Ritonavir/farmacocinética , Ritonavir/uso terapéutico , Sulfonamidas/efectos adversos , Sulfonamidas/uso terapéutico , TenofovirRESUMEN
BACKGROUND: Abacavir/lamivudine and tenofovir/emtricitabine fixed-dose combinations are commonly used first-line antiretroviral therapies, yet few studies have comprehensively compared their safety profiles. METHODS: Forty-eight-week data are presented from this multicenter, randomized, open-label study comparing the safety profiles of abacavir/lamivudine and tenofovir/emtricitabine, both administered with efavirenz, in HLA-B*5701-negative HIV-1-infected adults. RESULTS: Three hundred eighty-five subjects were enrolled in the study. The overall rate of withdrawal was high (28%). Changes in estimated glomerular filtration rate from baseline were similar between arms [difference 0.953 mL.min.1.73 m (95% confidence interval: -1.445 to 3.351), P = 0.435]. Urinary excretion of retinol-binding protein and beta-2 microglobulin increased significantly more in the tenofovir/emtricitabine arm (+50%; +24%) compared with the abacavir/lamivudine arm (no change; -47%) (P < 0.0001). A lower proportion achieved viral load <50 copies per milliliter in the abacavir/lamivudine arm (114 of 192, 59%) compared with the tenofovir/emtricitabine arm (137 of 193, 71%) [difference 11.6% (95% confidence interval: 2.2 to 21.1)]. The overall virological failure rate was low. The adverse event rate was similar between arms (except drug hypersensitivity, reported more in the abacavir/lamivudine arm). CONCLUSIONS: The study showed no difference in estimated glomerular filtration rate between the arms, however, increases in markers of tubular dysfunction were observed in the tenofovir/emtricitabine arm, the long-term consequence of which is unclear. A significant difference in efficacy favoring tenofovir/emtricitabine was observed.
Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/efectos adversos , Benzoxazinas/efectos adversos , Desoxicitidina/análogos & derivados , Didesoxinucleósidos/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Riñón/efectos de los fármacos , Lamivudine/efectos adversos , Organofosfonatos/efectos adversos , Adenina/administración & dosificación , Adenina/efectos adversos , Adolescente , Adulto , Anciano , Alquinos , Fármacos Anti-VIH/administración & dosificación , Benzoxazinas/administración & dosificación , Ciclopropanos , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Didesoxinucleósidos/administración & dosificación , Combinación de Medicamentos , Emtricitabina , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , VIH-1/aislamiento & purificación , Humanos , Lamivudine/administración & dosificación , Masculino , Persona de Mediana Edad , Organofosfonatos/administración & dosificación , Proteínas de Unión al Retinol/orina , Tenofovir , Resultado del Tratamiento , Carga Viral , Adulto Joven , Microglobulina beta-2/orinaRESUMEN
BACKGROUND: Certain antiretrovirals are known to affect lipid and glucose homeostasis. The aim of this study was to assess the effect on insulin sensitivity (determined by peripheral glucose uptake using a hyperinsulinaemic euglycaemic clamp) of tenofovir disoproxil fumarate (TDF) administration compared with placebo for 2 weeks in HIV-1-seronegative healthy male volunteers. Changes in lipids, adiponectin, leptin, plasminogen activator inhibitor 1 (PAI-1) and the adhesion molecules E-selectin and P-selectin were also assessed. METHODS: This was a single-centre, randomized, double-blinded, placebo-controlled study that used a two-sequence, two-period cross-over design. A total of 19 HIV-negative males were recruited to the study and randomized 1:1 to receive either 2 weeks of TDF (300 mg once daily) followed by 2 weeks of placebo or placebo initially followed by tenofovir. Clamps were performed at baseline, after 2 weeks and after 4 weeks. RESULTS: All three clamps were completed by 16 participants. During the euglycaemic clamp, there were no significant changes in insulin sensitivity after 2 weeks of TDF administration compared with placebo or baseline. There was a significant reduction in the mean total cholesterol (9.4%) and low-density lipoprotein (LDL; 8.1%) cholesterol following 2 weeks of TDF compared with placebo. Levels of adiponectin, leptin, PAI-1, P-selectin and E-selectin were not significantly altered. CONCLUSIONS: TDF use for 2 weeks does not affect insulin sensitivity, as assessed by the hyperinsulinaemic euglycaemic clamp in HIV-negative male volunteers. TDF use resulted in modest, but statistically significant, reductions in total and LDL cholesterol.
Asunto(s)
Adenina/análogos & derivados , Adipoquinas/metabolismo , Fármacos Anti-VIH/administración & dosificación , Seronegatividad para VIH/efectos de los fármacos , Insulina/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Organofosfonatos/administración & dosificación , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Adenina/administración & dosificación , Adenina/farmacología , Adulto , Fármacos Anti-VIH/farmacología , Colesterol/metabolismo , LDL-Colesterol/efectos de los fármacos , LDL-Colesterol/metabolismo , Estudios Cruzados , Esquema de Medicación , Técnica de Clampeo de la Glucosa , Humanos , Resistencia a la Insulina , Masculino , Organofosfonatos/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Tenofovir , Resultado del Tratamiento , Adulto JovenRESUMEN
Mechanisms underlying the lipodystrophy syndrome associated with antiretroviral therapy (ART) for HIV infection are not completely understood. We investigated the effect of ART on blood lipid concentrations in the fasting state and after consumption of a meal containing [1-13C]palmitic acid in HIV-positive men receiving nucleoside reverse transcriptase inhibitors (NRTI, n 7), NRTI combined with protease inhibitors (PI; NRTIPI, n 6), in HIV-positive but therapy-naïve men (noART, n 5) and in HIV-seronegative men (controls, n 6). HIV-positive subjects had higher fasting TAG concentrations and resting energy expenditure than controls. Subjects receiving NRTIPI therapy had higher fasting NEFA concentrations than the other groups. There were no significant differences in postprandial lipid metabolism between noART subjects and controls. NRTI therapy impaired hydrolysis of meal-derived TAG, most evidently when combined with PI (the NRTIPI group). Accumulation of 13C-label in the NEFA fraction was not different between groups. In the NRTIPI group, fasting and postprandial NEFA concentrations were significantly higher than other groups. Postprandial glucose and insulin responses in HIV-positive subjects did not differ from controls. These findings suggest that ART dyslipidaemia is associated with impaired postprandial TAG clearance, which is exacerbated by NRTIPI therapy. If dyslipidaemia is to be minimised in ART, the specific adverse effects of particular combinations during the fed state should be considered.
Asunto(s)
Fármacos Anti-VIH/efectos adversos , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Hipertrigliceridemia/inducido químicamente , Adulto , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa/efectos adversos , Terapia Antirretroviral Altamente Activa/métodos , Glucemia/metabolismo , Metabolismo Energético/efectos de los fármacos , Infecciones por VIH/sangre , Inhibidores de la Proteasa del VIH/efectos adversos , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Hidrólisis/efectos de los fármacos , Hipertrigliceridemia/sangre , Insulina/sangre , Masculino , Persona de Mediana Edad , Oxidación-Reducción/efectos de los fármacos , Periodo Posprandial/fisiología , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Triglicéridos/sangre , Adulto JovenRESUMEN
BACKGROUND: Long-term antiretroviral therapy dramatically reduces HIV-related morbidity and mortality but is also associated with metabolic and morphological changes and requires high levels of adherence. METHODS: A randomized, 48-week, open-label, comparative study of continuation of twice-daily zidovudine/lamivudine or replacement with once-daily tenofovir disoproxil fumarate/emtricitabine in individuals on successful efavirenz-based antiretroviral therapy. Limb fat mass was assessed by dual x-ray absorptiometry in a subset of participants through week 48. RESULTS: Two hundred thirty-four individuals were randomized and treated (117 each to continue or switch) with 206 subjects completing 48 weeks of study. Five percent subjects in the continue group and 3% subjects in the switch group discontinued due to adverse events. By intent-to-treat, missing = failure analysis, no differences in virological efficacy were observed at any time point (week 48 <50 copies/mL continue 85%, switch 88%). At week 24, switching was associated with significant increases in hemoglobin (mean difference 0.37 g/dL, 95% confidence interval: 0.15 to 0.58 g/dL, P < 0.001) and significant declines in total cholesterol and triglycerides. In the dual x-ray absorptiometry substudy (n = 100), fat was preserved or increased in the switch group but declined in the continue group (mean difference 448 g, 95% confidence interval: 57 to 839 g, P = 0.025). Individuals with longer exposure to zidovudine and lower baseline limb fat experienced less limb fat increase after switching. No differences in renal adverse events were observed between groups. CONCLUSIONS: Switching from zidovudine/lamivudine to tenofovir disoproxil fumarate/emtricitabine in persons on efavirenz therapy maintains virological control, establishes a once-daily regimen, results in improvements in hemoglobin and key lipid parameters, and preserves and restores limb fat relative to continuation of zidovudine/lamivudine.
Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Adenina/administración & dosificación , Adenina/análogos & derivados , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/patología , Adulto , Anciano , Alquinos , Fármacos Anti-VIH/efectos adversos , Benzoxazinas/administración & dosificación , Ciclopropanos , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Emtricitabina , Extremidades , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/patología , Infecciones por VIH/virología , Síndrome de Lipodistrofia Asociada a VIH/etiología , Síndrome de Lipodistrofia Asociada a VIH/metabolismo , Síndrome de Lipodistrofia Asociada a VIH/patología , Humanos , Lamivudine/administración & dosificación , Lípidos/sangre , Masculino , Persona de Mediana Edad , Organofosfonatos/administración & dosificación , Tenofovir , Adulto Joven , Zidovudina/administración & dosificaciónAsunto(s)
Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa/métodos , Infecciones por VIH/tratamiento farmacológico , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Sulfato de Atazanavir , Enfermedades Cardiovasculares/inducido químicamente , Didesoxinucleósidos/efectos adversos , Interacciones Farmacológicas , Humanos , Interleucina-2/administración & dosificación , Interleucina-2/uso terapéutico , Oligopéptidos/farmacocinética , Piridinas/farmacocinética , Pirrolidinonas/farmacocinética , Raltegravir PotásicoAsunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Terapia Antirretroviral Altamente Activa/efectos adversos , Terapia Antirretroviral Altamente Activa/métodos , Terapia Antirretroviral Altamente Activa/normas , Combinación de Medicamentos , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
BACKGROUND: Efficacious immune-based therapy in treated chronic HIV-1 infection requires the induction of virus-specific CD4+ T cells and subsequent maturation and maintenance of specific memory CD8+ T cells. Concomitant daily administration of recombinant human growth hormone (rhGH) with highly active antiretroviral therapy (HAART) was used in chronically infected patients with lipodystrophy in an attempt to reconstitute these virus-specific T-cell responses. METHODS: Individuals with chronic HIV-1 infection on HAART were enrolled on a randomized, double-blinded, placebo-controlled study to receive rhGH therapy. We assessed HIV-1-specific proliferative CD4+ and interferon-gamma (IFN-gamma)-producing CD8+ T-cell responses, quantified thymic output and proviral HIV-1 DNA at the following time points: baseline; after 12 weeks of rhGH therapy; at 24 weeks, after randomization into three groups [placebo weeks 12-24 (Group A), alternate-day dosing weeks 12-24 (Group B), and twice-per-week dosing weeks 12-24 (Group C)]; and at 48 weeks after all patients had received HAART alone for the final 24 weeks. RESULTS: We found significant increases in both proliferative CD4+ and IFN-gamma-producing CD8+ HIV-1-specific T-cell responses after daily administration of rhGH. This increase was focused on HIV-1 Gag-specific T-cell responses. Following subsequent randomisation into different dosing regimens, HIV-1-specific proliferative CD4+ T-cell responses declined in patients receiving less frequent dosing of rhGH, while virus-specific IFN-gamma-producing CD8+ T-cell responses were maintained for longer periods of time. There was no significant change in thymic output and the cell-associated HIV-1 DNA remained stable in most patients. An increased anti-HIV-1 Nef-specific CD4+ T-cell proliferative response was correlated to a decrease in proviral load, and an increased HIV-1 Gag-specific IFN-gamma-producing CD8+ T-cell response correlated with an increase in proviral load. CONCLUSION: The implication of these data is that daily dosing of rhGH with HAART, in addition to improving HIV-1-associated lipodystrophy, may reverse some of the T-lymphocyte dysfunction seen in most treated HIV-1-positive patients, in a dose-dependent manner. Such immune-based therapeutic strategies used in treated, chronic HIV-1 infection may enable the induction of virus-specific CD4+ T cells essential for the subsequent 'kick-start' and expansion of virus-specific CD8+ T cells. TRIAL REGISTRATION: GH in Lipoatrophy IMP22350.
RESUMEN
PURPOSE: Treatment options for HIV-associated lipodystrophy syndrome (HALS) remain limited. The objective of this randomized open-label study was to compare three emerging therapies, rosiglitazone, pravastatin, and growth hormone alone and together, in men and women with HALS. METHOD: Sixty-four subjects received daily rosiglitazone (4 mg, n = 14), pravastatin (40 mg, n = 11), or rosiglitazone plus pravastatin (n = 13) for 48 weeks or recombinant human growth hormone (rhGH; Serostim 2 mg, 12 weeks, n = 13) alone or combined with rosiglitazone (n = 13). Primary endpoint was body composition change by dual X-ray absorptiometry (DXA) and computed tomography (CT). RESULTS: Rosiglitazone resulted in slow accrual of limb fat detected by DXA (+444 +/- 186 g; p < .05) but not CT. Pravastatin had no consistent significant effects on body composition, although it reduced total and LDL cholesterol. Negative interactions were observed between pravastatin and rosiglitazone. rhGH reduced abdominal fat by CT (-31 +/- 15 cm2, 26%; p < .05) and DXA (-1597 +/- 383 g, 27%; p < .05) and increased trunk and limb lean mass (+10% and +12%, respectively). However, effects largely disappeared within 12 weeks post treatment. rhGH alone impaired insulin sensitivity but not when combined with rosiglitazone. CONCLUSION: Prolonged rosiglitazone treatment slowly improves lipoatrophy. rhGH rapidly and selectively reduces visceral fat, although effects are short-lived; co-administered rosiglitazone abrogates rhGH-related insulin resistance.