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Higher iron stores and the HFE 187C>G variant delay onset of peripheral neuropathy during combination antiretroviral therapy.
Kallianpur, AR, Wen, W, Erwin, AL, Clifford, DB, Hulgan, T, Robbins, GK
PloS one. 2020;(10):e0239758
Abstract
OBJECTIVE People with HIV (PWH) continue to experience sensory neuropathy and neuropathic pain in the combination antiretroviral therapy (cART) era for unclear reasons. This study evaluated the role of iron in a previously reported association of iron-loading hemochromatosis (HFE) gene variants with reduced risk of neuropathy in PWH who received more neurotoxic cART, since an iron-related mechanism also might be relevant to neuropathic symptoms in PWH living in low-resource settings today. DESIGN This time-to-event analysis addressed the impact of systemic iron levels on the rapidity of neuropathy onset in PWH who initiated cART. METHODS Soluble transferrin receptor (sTFR), the sTFR-ferritin index of iron stores, and high-sensitivity C-reactive protein (hsCRP) levels were determined in stored baseline sera from participants of known HFE genotype from AIDS Clinical Trials Group (ACTG) Study 384, a multicenter randomized clinical trial that evaluated cART strategies. Associations with incident neuropathy were evaluated in proportional-hazards, time-to-event regression models, adjusting for potential confounders. RESULTS Of 151 eligible participants with stored serum who were included in the original genetic study, 43 had cART-associated neuropathy; 108 had sufficient serum for analysis, including 30 neuropathy cases. Carriers of HFE variants had higher systemic iron (lower sTFR and sTFR-ferritin index) and lower hsCRP levels than non-carriers (all p<0.05). Higher sTFR or iron stores, the HFE 187C>G variant, and lower baseline hsCRP were associated with significantly delayed neuropathy in self-reported whites (n = 28; all p-values<0.05), independent of age, CD4+ T-cell count, plasma HIV RNA, and cART regimen. CONCLUSIONS Higher iron stores, the HFE 187C>G variant, and lower hsCRP predicted delayed onset of neuropathy among self-reported white individuals initating cART. These findings require confirmation but may have implications for cART in HIV+ populations in areas with high endemic iron deficiency, especially those PWH in whom older, more neurotoxic antiretroviral drugs are occasionally still used.
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Vitamin D and Calcium Supplement Attenuate Bone Loss among HIVInfected Patients Receiving Tenofovir Disoproxil Fumarate/Emtricitabine/ Efavirenz: An Open-Label, Randomized Controlled Trial.
Boontanondha, P, Nimitphong, H, Musikarat, S, Ragkho, A, Kiertiburanakul, S
Current HIV research. 2020;(1):52-62
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BACKGROUND Antiretroviral therapy (ART), especially with tenofovir disoproxil fumarate (TDF), has been associated with accelerated bone turnover and leads to significant bone loss. OBJECTIVE We aimed to determine the effect of vitamin D2 and calcium on bone mineral density (BMD) in HIV-infected patients receiving TDF/emtricitabine (FTC)/efavirenz (EFV). METHODS A prospective, open-label, randomized controlled study was conducted. Eligible patients were ART naïve HIV individuals who initiated TDF/FTC/EFV. The study group received supplementation with vitamin D2 and calcium carbonate, whereas the control group was administered only ART. The primary outcome was the percentage change in total hip BMD at week 24 compared with baseline. RESULTS A total of 18 patients were randomized (9 in each group). The mean (standard deviation; SD) total hip BMD significantly decreased from baseline in both groups, from 0.96 (0.14) g/cm2 to 0.93 (0.13) g/cm2 in the study group (p = 0.006) and from 0.87 (0.11) g/cm2 to 0.84 (0.11) g/cm2 in the control group (p = 0.004). The mean (SD) lumbar spine BMD significantly decreased from baseline in both groups, from 1.00 (0.13) g/cm2 to 0.97 (0.13) g/cm2 (p = 0.004) in the study group and from 0.90 (0.09) g/cm3 to 0.86 (0.08) g/cm2 in the control group (p = 0.006). At week 24, the mean (SD) lumbar spine BMD was significantly greater in the study group than in the control group (p = 0.042). However, there were no significant differences in the percentage change of total hip, lumbar spine, and femoral neck BMD between both groups. No adverse events were reported. In conclusion, as early as 24 weeks after TDF initiation, a significant decline in BMD was detected. CONCLUSION Vitamin D2 and calcium supplements should be considered for HIV-infected patients receiving TDF/FTC/EFV in a resource-limited setting where there are limited ART options (Clinicaltrials. gov NCT0287643).
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Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate is Non-inferior to Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-naive Adults With Human Immunodeficiency Virus-1 Infection: Week 48 Results of the DRIVE-AHEAD Trial.
Orkin, C, Squires, KE, Molina, JM, Sax, PE, Wong, WW, Sussmann, O, Kaplan, R, Lupinacci, L, Rodgers, A, Xu, X, et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2019;(4):535-544
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BACKGROUND Doravirine (DOR), a novel non-nucleoside reverse-transcriptase inhibitor (NNRTI), is active against wild-type Human Immunodeficiency Virus (HIV)-1 and the most common NNRTI-resistant variants, and has a favorable and unique in vitro resistance profile. METHODS DRIVE-AHEAD is a phase 3, double-blind, non-inferiority trial. Antiretroviral treatment-naive adults with ≥1000 HIV-1 RNA copies/mL were randomized (1:1) to once-daily, fixed-dose DOR at 100 mg, lamivudine at 300 mg, and tenofovir disoproxil fumarate (TDF) at 300 mg (DOR/3TC/TDF) or to efavirenz at 600 mg, emtricitabine at 200 mg, and TDF at 300 mg (EFV/FTC/TDF) for 96 weeks. The primary efficacy endpoint was the proportion of participants with <50 HIV-1 RNA copies/mL at week 48 (Food and Drug Administration snapshot approach; non-inferiority margin 10%). RESULTS Of the 734 participants randomized, 728 were treated (364 per group) and included in the analyses. At week 48, 84.3% (307/364) of DOR/3TC/TDF recipients and 80.8% (294/364) of EFV/FTC/TDF recipients achieved <50 HIV-1 RNA copies/mL (difference 3.5%, 95% CI, -2.0, 9.0). DOR/3TC/TDF recipients had significantly lower rates of dizziness (8.8% vs 37.1%), sleep disorders/disturbances (12.1% vs 25.2%), and altered sensorium (4.4% vs 8.2%) than EFV/FTC/TDF recipients. Mean changes in fasting low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) were significantly different between DOR/3TC/TDF and EFV/FTC/TDF (-1.6 vs +8.7 mg/dL and -3.8 vs +13.3 mg/dL, respectively). CONCLUSIONS In HIV-1 treatment-naive adults, DOR/3TC/TDF demonstrated non-inferior efficacy to EFV/FTC/TDF at week 48 and was well tolerated, with significantly fewer neuropsychiatric events and minimal changes in LDL-C and non-HDL-C compared with EFV/FTC/TDF. CLINICAL TRIALS REGISTRATION NCT02403674.
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The Effectiveness of a Bioactive Food Compound in the Lipid Control of Individuals with HIV/AIDS.
Dos Santos Ferreira, R, de Cássia Avellaneda Guimarães, R, Jardim Cury Pontes, ER, Aragão do Nascimento, V, Aiko Hiane, P
Nutrients. 2016;(10)
Abstract
Cardiovascular events due to decompensated lipid metabolism are commonly found in Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) patients using anti-retroviral therapy (HAART). Thus, the aim of this study was to identify the effect of a bioactive food compound (BFC) containing functional foods on individuals with HIV undergoing HAART. Particularly, this study aims to verify the clinical outcome in the change of the lipid profile due to the use of this compound. This study includes 115 individuals with HIV on HAART. All patients received dietary guidelines; however, sixty-one consumed BFC while fifty-one did not (NO BFC). Biochemical examinations and socio-demographic and clinical profiles were evaluated. As result, in patients using hypolipidemic and/or hypoglycemic drugs, there was 28.6% decrease in triglyceride levels (p < 0.001) in the NO BFC group, and 18.3% reduction in low density lipoprotein cholesterol (LDL-C) (p < 0.001) in the BFC group. In patients who did not use hypolipidemic and/or hypoglycemic drugs in the NO BFC group, there was 30.6% increase in triglycerides, 11.3% total cholesterol and 15.3% LDL-C levels (p < 0.001) while for the BFC group there was 4.5% reduction in total cholesterol (p < 0.001). In conclusion, this study evidenced that the dietary intervention containing BFC positively affected in lipid control, since these HIV/AIDS patients using HAART are more vulnerable to lipid disorders.
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A prospective, randomized clinical trial of antiretroviral therapies on carotid wall thickness.
Stein, JH, Ribaudo, HJ, Hodis, HN, Brown, TT, Tran, TT, Yan, M, Brodell, EL, Kelesidis, T, McComsey, GA, Dube, MP, et al
AIDS (London, England). 2015;(14):1775-83
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OBJECTIVE This article compares the effects of initiating three contemporary antiretroviral therapy (ART) regimens on progression of carotid artery intima-media thickness (IMT) over 3 years. DESIGN Randomized clinical trial. SETTING Multicenter (26 institutions). PATIENTS ART-naive HIV-infected individuals (n = 328) without known cardiovascular disease or diabetes mellitus. INTERVENTION Random assignment to tenofovir/emtricitabine along with atazanavir/ritonavir (ATV/r), darunavir/ritonavir (DRV/r), or raltegravir (RAL). MAIN OUTCOME MEASURES Right-sided carotid IMT was evaluated by B-mode ultrasonography before ART initiation, and then after 48, 96, and 144 weeks. Comparisons of yearly rates of change in carotid IMT used mixed-effects linear regression models that permitted not only evaluation of the effects of ART on carotid IMT progression but also how ART-associated changes in traditional risk factors, bilirubin, and markers of HIV infection were associated carotid IMT progression. RESULTS HIV-1 RNA suppression rates were high in all arms (>85%) over 144 weeks. Modest increases in triglycerides and non-high-density lipoprotein cholesterol levels were observed in the protease inhibitor-containing arms compared with decreases with RAL. In contrast, carotid IMT progressed more slowly on ATV/r [8.2, 95% confidence interval (5.6, 10.8) μm/year] than DRV/r [12.9 (10.3, 15.5) μm/year, P = 0.013]; changes with RAL were intermediate [10.7 (9.2, 12.2) μm/year, P = 0.15 vs. ATV/r; P = 0.31 vs. DRV/r]. Bilirubin and non-high-density lipoprotein cholesterol levels appeared to influence carotid IMT progression rates. CONCLUSION In ART-naive HIV-infected individuals at low cardiovascular disease risk, carotid IMT progressed more slowly in participants initiating ATV/r than those initiating DRV/r, with intermediate changes associated with RAL. This effect may be due, in part, to hyperbilirubinemia.
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Vitamin D3 supplementation in HIV infection: effectiveness and associations with antiretroviral therapy.
Coelho, L, Cardoso, SW, Luz, PM, Hoffman, RM, Mendonça, L, Veloso, VG, Currier, JS, Grinsztejn, B, Lake, JE
Nutrition journal. 2015;:81
Abstract
BACKGROUND HIV infection and antiretroviral therapy (ART) may create unique risk factors for vitamin D insufficiency, including alterations of vitamin D metabolism by ART. We prospectively compared demographic and clinical parameters between vitamin D sufficient and insufficient HIV-infected (HIV+) adults, and assessed changes in these parameters among insufficient participants following standardized vitamin D supplementation. METHODS HIV+ adults (≥ 18 years old) with HIV-1 RNA <50 copies/mL on ART were enrolled. Vitamin D sufficiency and insufficiency were defined as 25-hydroxyvitamin D (25(OH)D) ≥ 30 or <30 ng/mL, respectively. Insufficient participants received open-label vitamin D3 50,000 IU twice weekly for 5 weeks, then 8000 IU twice weekly to complete 24 weeks. The primary endpoint was success or failure to achieve 25(OH)D ≥ 30 ng/mL at week 24. RESULTS Ninety-seven participants enrolled (34 vitamin D sufficient, 63 insufficient); 32% female, 47% non-White, median age 46 years, ART duration 5 years, CD4+ T lymphocyte count (CD4) 673 cells/mm(3). 25(OH)D repletion was 83% (95% CI 71%-90%) successful. 25(OH)D levels correlated with both CD4 (r = 0.44, p = 0.01) and time on protease inhibitor (r = -0.35, p = 0.01). After adjusting for age, sex, race, nadir CD4 and baseline 25(OH)D: 1) current use of efavirenz exposure was associated with a 21.1 ng/mL higher week 24 25(OH)D level (p = 0.007), 2) per year use of zidovudine was associated with 7.1 ng/mL reduction in week 24 serum 25(OH)D (p = 0.05) and 3) every 1 ng/mL 25(OH)D increase was associated with a 3.3 cell/mm(3) CD4 increase (p = 0.06). CONCLUSION Vitamin D3 supplementation was effective in repleting 25(OH)D levels after 24 weeks. Current efavirenz use was positively associated with post-repletion 25(OH)D levels, while greater time on zidovudine was associated with lower post-repletion 25(OH)D levels. The association between improved CD4 recovery and vitamin D repletion suggests a potential benefit of vitamin D supplementation on immunologic recovery during HIV treatment. TRIAL REGISTRATION This trial is registered at The Brazilian Clinical Trials Registry (U1111-1165-2537).
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Hypercholesterolemia is associated with the apolipoprotein C-III (APOC3) genotype in children receiving HAART: an eight-year retrospective study.
Rocco, CA, Mecikovsky, D, Aulicino, P, Bologna, R, Sen, L, Mangano, A
PloS one. 2012;(7):e39678
Abstract
Polymorphisms in apolipoprotein genes have shown to be predictors of plasma lipid levels in adult cohorts receiving highly active antiretroviral therapy (HAART). Our objective was to confirm the association between the APOC3 genotype and plasma lipid levels in an HIV-1-infected pediatric cohort exposed to HAART. A total of 130 HIV-1-infected children/adolescents that attended a reference center in Argentina were selected for an 8-year longitudinal study with retrospective data collection. Longitudinal measurements of plasma triglycerides, total cholesterol, HDL-C and LDL-C were analyzed under linear or generalized linear mixed models. The contribution of the APOC3 genotype at sites -482, -455 and 3238 to plasma lipid levels prediction was tested after adjusting for potential confounders. Four major APOC3 haplotypes were observed for sites -482/-455/3238, with estimated frequencies of 0.60 (C/T/C), 0.14 (T/C/C), 0.11 (C/C/C), and 0.11 (T/C/G). The APOC3 genotype showed a significant effect only for the prediction of total cholesterol levels (p<0.0001). However, the magnitude of the differences observed was dependent on the drug combination (p = 0.0007) and the drug exposure duration at the time of the plasma lipid measurement (p = 0.0002). A lower risk of hypercholesterolemia was predicted for double and triple heterozygous individuals, mainly at the first few months after the initiation of Ritonavir-boosted protease inhibitor-based regimens. We report for the first time a significant contribution of the genotype to total cholesterol levels in a pediatric cohort under HAART. The genetic determination of APOC3 might have an impact on a large portion of HIV-1-infected children at the time of choosing the treatment regimens or on the counter-measures against the adverse effects of drugs.
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Use of acyclovir for suppression of human immunodeficiency virus infection is not associated with genotypic evidence of herpes simplex virus type 2 resistance to acyclovir: analysis of specimens from three phase III trials.
Watson-Jones, D, Wald, A, Celum, C, Lingappa, J, Weiss, HA, Changalucha, J, Baisley, K, Tanton, C, Hayes, RJ, Marshak, JO, et al
Journal of clinical microbiology. 2010;(10):3496-503
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Herpes simplex virus type 2 (HSV-2) is the most common cause of genital ulcer disease and is a cofactor for HIV-1 acquisition and transmission. We analyzed specimens from three separate phase III trials of acyclovir (ACV) for prevention of HIV-1 acquisition and transmission to determine if failure of ACV to interrupt HIV acquisition and transmission was associated with genotypic ACV resistance. Acyclovir (400 mg twice daily) or placebo was provided to HSV-2-infected persons at risk of HIV-1 infection in the Mwanza and HPTN 039 trials and to persons dually infected with HSV-2 and HIV-1 who had an HIV-negative partner in the Partners in Prevention study. We extracted HSV DNA from genital ulcer swabs or cervicovaginal lavage fluids from 68 samples obtained from 64 participants randomized to ACV and sequenced the HSV-2 UL23 gene encoding thymidine kinase. The UL23 sequences were compared with published and unpublished data. Variants were observed in 38/1,128 (3.4%) nucleotide positions in the UL23 open reading frame, with 58% of these encoding amino acid changes. No deletions, insertions, or mutations known to be associated with resistance were detected. Thirty-one of the variants (81.5%) are newly reported, 15 of which code for amino acid changes. Overall, UL23 is highly polymorphic compared to other loci in HSV-2, but no drug resistance mutations were detected that could explain the failure to reduce HIV incidence or to prevent HIV-1 transmission in these studies.
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Adherence to Mediterranean diet is favorably associated with metabolic parameters in HIV-positive patients with the highly active antiretroviral therapy-induced metabolic syndrome and lipodystrophy.
Tsiodras, S, Poulia, KA, Yannakoulia, M, Chimienti, SN, Wadhwa, S, Karchmer, AW, Mantzoros, CS
Metabolism: clinical and experimental. 2009;(6):854-9
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The objective of the study was to investigate whether closer adherence to a Mediterranean dietary pattern is associated with metabolic aspects of the highly active antiretroviral therapy (HAART)-induced metabolic syndrome (fat redistribution [FR], insulin resistance, dyslipidemia) in HIV-positive patients. This was a cross-sectional study. Two hundred twenty-seven HIV-infected patients were evaluated during a single outpatient visit to the General Clinical Research Center of Beth Israel Deaconess Medical Center. Usual dietary intake and physical activity habits were evaluated; the Mediterranean Diet Score (MedDietScore) was calculated. Dual-energy x-ray absorptiometry, computed tomographic findings, anthropometrics, and data from the study interviews and questionnaires were used for the assessment of body composition using specific criteria. A complete metabolic profile was available for all subjects. In the entire study sample, a weak inverse association was found between insulin resistance, estimated using the homeostasis model assessment, and MedDietScore (standardized beta = -0.15, P = .03). Interaction models revealed that this was largely driven by an inverse association in patients with FR (standardized beta = -0.13, P = .02). Moreover, MedDietScore was positively correlated with high-density lipoprotein cholesterol (standardized beta = 0.15, P = .01) and marginally negatively associated with circulating triglyceride levels (standardized beta = -0.16, P = .13) in this group of patients. Adherence to a Mediterranean dietary pattern was favorably related to cardiovascular risk factors in HIV-positive patients with FR. Further clinical studies are needed to confirm our data in different populations and to explore the underlying mechanisms.
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Increased lipoprotein remnant cholesterol levels in HIV-positive patients during antiretroviral therapy.
Anuurad, E, Thomas-Geevarghese, A, Devaraj, S, Albu, J, Minolfo, R, El-Sadr, WM, Lu, G, Karmally, W, Berglund, L
Atherosclerosis. 2008;(1):192-7
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Increased levels of postprandial triglycerides (TG) and remnant like particles (RLP) are associated with cardiovascular disease. We evaluated whether postprandial lipemia differed in HIV-positive patients with or without different antiretroviral regimens. A standardized high fat load was administered to 28 subjects: 11 HIV-positive subjects receiving protease inhibitors (PI), 10 HIV-positive subjects receiving non-nucleoside reverse transcriptase inhibitors (NNRTI) and 7 HIV-positive subjects not receiving highly active antiretroviral therapy, HAART (Naïve). Baseline TG levels and TG area under the curve (AUC) did not differ among the three groups. The postprandial TG concentration curves were similar in the NNRTI and Naïve groups, peaking at 3-5-h. Baseline RLP cholesterol was higher in the NNRTI group compared to other two groups (P=0.035). Both HAART groups (NNRTI and PI) had higher postprandial RLP cholesterol AUC than the Naïve group (P=0.024, ANOVA). In conclusion, during HIV conditions, HAART resulted in a pro-atherogenic pattern with accumulation of remnant lipoproteins.