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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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Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial.
Molina, JM, Squires, K, Sax, PE, Cahn, P, Lombaard, J, DeJesus, E, Lai, MT, Xu, X, Rodgers, A, Lupinacci, L, et al
The lancet. HIV. 2018;(5):e211-e220
Abstract
BACKGROUND Doravirine is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with a pharmacokinetic profile supporting once-daily dosing, and potent in-vitro activity against the most common NNRTI-resistant HIV-1 variants. We compared doravirine with ritonavir-boosted darunavir, when both were given with two nucleoside reverse transcriptase inhibitors (NRTIs), in adults with previously untreated HIV-1 infection. METHODS In this randomised, controlled, double-blind, multicentre, non-inferiority trial, adults with HIV-1 infection were screened and enrolled at 125 clinical centres in 15 countries. Eligible participants (aged ≥18 years) were naive to antiretroviral therapy with plasma HIV-1 RNA of at least 1000 copies per mL at screening. Participants who had previously been treated for a viral infection other than HIV-1, those taking immunosuppressive drugs, and individuals with active acute hepatitis were excluded. Participants were randomly assigned (1:1) via an interactive voice and web response system to receive oral doravirine 100 mg or darunavir 800 mg plus ritonavir 100 mg once daily, with two investigator-selected NRTIs (tenofovir and emtricitabine or abacavir and lamivudine) for up to 96 weeks. Randomisation was stratified by HIV-1 RNA measurements at screening (≤100 000 vs >100 000 copies per mL) and the NRTI pair. Study participants, funding institution staff, investigators, and study site personnel were masked to treatment group assignment. The primary efficacy endpoint was the proportion of participants achieving HIV-1 RNA of less than 50 copies per mL at week 48 defined by the US Food and Drug Administration snapshot algorithm, with non-inferiority established if the lower bound of the two-sided 95% CI for the treatment difference (doravirine minus darunavir) was greater than -10 percentage points. All participants who received at least one dose of study drug were included in the primary efficacy and safety analyses. This trial is active, but not recruiting, and is registered with ClinicalTrials.gov, number NCT02275780. FINDINGS Between Dec 1, 2014, and Oct 20, 2015, 1027 participants were screened for eligibility, of whom 769 participants were randomly assigned to treatment (385 with doravirine and 384 with ritonavir-boosted darunavir). 56 participants discontinued treatment in the doravirine group compared with 71 in the darunavir group, mostly due to loss to follow-up. 383 participants who received doravirine and 383 who received darunavir were included in the primary efficacy analyses. At week 48, 321 (84%) participants in the doravirine group and 306 (80%) in the darunavir group achieved plasma HIV-1 RNA of less than 50 copies per mL (difference 3·9%, 95% CI -1·6 to 9·4), indicating non-inferiority of the doravirine regimen. The most common study drug-related adverse events were diarrhoea (21 [5%] of 383 participants in the doravirine group and 49 [13%] of 383 participants in the darunavir group), nausea (25 [7%] vs 29 [8%]), and headache (23 [6%] vs ten [3%]). 18 participants (six [2%] of 383 participants in the doravirine group vs 12 [3%] of 383 participants in the darunavir group) discontinued treatment due to adverse events, which were considered drug-related in four (1%) participants in the doravirine group and 8 (2%) participants in the darunavir group. Serious adverse events occurred in 19 (5%) of 383 participants in the doravirine group and 23 (6%) of 383 in the darunavir roup, and were considered study-drug related in one (<1%) participant of each group. INTERPRETATION In treatment-naive adults with HIV-1 infection, doravirine combined with two NRTIs might offer a valuable treatment option for adults with previously untreated HIV-1 infection. FUNDING Merck & Co.
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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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Two-year treatment with rosuvastatin reduces carotid intima-media thickness in HIV type 1-infected patients receiving highly active antiretroviral therapy with asymptomatic atherosclerosis and moderate cardiovascular risk.
Calza, L, Manfredi, R, Colangeli, V, Trapani, FF, Salvadori, C, Magistrelli, E, Danese, I, Verucchi, G, Serra, C, Viale, P
AIDS research and human retroviruses. 2013;(3):547-56
Abstract
Recent studies have shown that rosuvastatin significantly decreases serum levels of inflammatory biomarkers and slows progression of carotid atherosclerosis in the general population. However, there are no data about its effect on progression of atherosclerosis in HIV-infected patients. Adult patients with HIV infection, on stable antiretroviral therapy, with asymptomatic carotid atherosclerosis and hypercholesterolemia, who started a rosuvastatin treatment at 10 mg daily during the period 2007-2009 were enrolled and followed-up for 24 months. Thirty-six patients (30 males) were enrolled, with a mean age of 49 years, a mean duration of current antiretroviral therapy of 38 months, and a mean 10-year risk of myocardial infarction of 18.5%. Rosuvastatin led to a significant decrease in mean values of intima-media thickness in all extracranial carotid arteries, with the greatest magnitude observed in carotid bifurcations (a mean decrease of 18.7% in the right artery and of 21.4% in the left artery) and in internal carotid arteries (a mean decrease of 23.7% in the right artery and of 25.6% in the left artery). Moreover, there was a significant reduction in mean levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides versus respective baseline values associated with a significantly decreased mean cardiovascular risk. The treatment with rosuvastatin was well tolerated, and serious adverse events were not reported. A 24-month treatment with rosuvastatin in HIV-infected patients on highly active antiretroviral therapy (HAART) with subclinical atherosclerosis and a moderate cardiovascular risk seems to promote significantly favorable changes in carotid atherosclerosis, associated with a favorable effect on serum lipid levels and a good tolerability profile.
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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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The success of endosseous implants in human immunodeficiency virus-positive patients receiving antiretroviral therapy: a pilot study.
Oliveira, MA, Gallottini, M, Pallos, D, Maluf, PS, Jablonka, F, Ortega, KL
Journal of the American Dental Association (1939). 2011;(9):1010-6
Abstract
BACKGROUND In a pilot study, the authors aimed to determine the success rate of dental implants placed in patients who were positive for human immunodeficiency virus (HIV) and were receiving different regimens of highly active anti-retroviral therapy (HAART). They considered patients' levels of cluster of differentiation (CD) 4(+) cells and viral load, and they attempted to verify whether patients with baseline biochemical signs of bone mineral density loss could experience osseointegration impairment. MATERIALS AND METHODS One of the authors, a dentist, placed dental implants in the posterior mandibles of 40 volunteers, divided into three groups: one composed of HIV-positive patients receiving protease inhibitor (PI)-based HAART; a second composed of HIV-positive patients receiving nonnucleoside reverse transcriptase inhibitor-based HAART (without PI); and a control group composed of HIV-negative participants. The authors assessed peri-implant health six and 12 months after implant loading. They analyzed the success of the implants in relation to CD4(+) cell counts, viral load and baseline pyridinoline and deoxypyridinoline values. RESULTS The authors followed 59 implants for 12 months after loading. Higher baseline levels of pyridinoline and deoxypyridinoline found in HIV-positive participants did not interfere with osseointegration after 12 months of follow-up. Average peri-implant bone loss after 12 months was 0.49 millimeters in group 1, 0.47 mm in group 2 and 0.55 mm in the control group. CONCLUSIONS The placement of dental implants in HIV-positive patients is a reasonable treatment option, regardless of CD4(+) cell count, viral load levels and type of antiretroviral therapy. Longer follow-up periods are necessary to ascertain the predictability of the long-term success of dental implants in these patients. CLINICAL IMPLICATIONS Limited published scientific evidence is available to guide clinicians in regard to possible increased risks associated with dental implant placement in HIV-positive patients.