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Vitamin D3 Supplementation Increases Spine Bone Mineral Density in Adolescents and Young Adults With Human Immunodeficiency Virus Infection Being Treated With Tenofovir Disoproxil Fumarate: A Randomized, Placebo-Controlled Trial.
Havens, PL, Stephensen, CB, Van Loan, MD, Schuster, GU, Woodhouse, LR, Flynn, PM, Gordon, CM, Pan, CG, Rutledge, B, Harris, DR, et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2018;(2):220-228
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Abstract
BACKGROUND Tenofovir disoproxil fumarate (TDF) decreases bone mineral density (BMD). We hypothesized that vitamin D3 (VITD3) would increase BMD in youth receiving TDF. METHODS This was a randomized, double-blind, placebo-controlled trial of directly observed VITD3 vs placebo every 4 weeks for 48 weeks in youth aged 16-24 years with HIV, RNA load <200 copies/mL, taking TDF-containing combination antiretroviral therapy (TDF-cART) for ≥180 days. Participants (N = 214) received a daily multivitamin containing VITD3 400 IU and calcium 162 mg, plus monthly randomized VITD3 50000 IU (n = 109) or placebo (n = 105). Outcome was change from baseline to week 48 in lumbar spine BMD (LSBMD). Data presented are median (Q1, Q3). RESULTS Participants were aged 22.0 (21.0, 23.0) years, 84% were male, and 74% were black/African American. At baseline, 62% had 25-hydroxy vitamin D (25-OHD) <20 ng/mL. Multivitamin adherence was 49% (29%, 69%), and VITD3/placebo adherence 100% (100%, 100%). Vitamin D intake was 2020 (1914, 2168) and 284 (179, 394) IU/day, and serum 25-OHD concentration was 36.9 (30.5, 42.4) and 20.6 (14.4, 25.8) ng/mL at 48 weeks in VITD3 and placebo groups, respectively (P < .001). From baseline to week 48, LSBMD increased by 1.15% (-0.75% to 2.74%) in the VITD3 group (n = 99; P < .001) and 0.09% (-1.49% to 2.61%) in the placebo group (n = 89; P = .25), without between-group difference (P = .12). VITD3 group changes occurred with baseline 25-OHD <20 ng/mL (1.17% [-.82% to 2.90%]; P = .004) and ≥20 ng/mL (0.93% [-.26% to 2.15%]; P = .033). CONCLUSIONS For youth taking TDF-cART, LSBMD increased through 48 weeks with VITD3 plus multivitamin, but not with placebo plus multivitamin, independent of baseline vitamin D status. CLINICAL TRIALS REGISTRATION NCT01751646.
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Virological and immunological responses to raltegravir and dolutegravir in the gut-associated lymphoid tissue of HIV-infected men and women.
Weber, MD, Andrews, E, Prince, HA, Sykes, C, Rosen, EP, Bay, C, Shaheen, NJ, Madanick, RD, Dellon, ES, De Paris, K, et al
Antiviral therapy. 2018;(6):495-504
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Abstract
BACKGROUND Raltegravir (RTG) and dolutegravir (DTG) have different pharmacokinetic patterns in the gastrointestinal tract. To determine if this results in pharmacodynamic differences, we compared HIV RNA, HIV DNA and immunological markers in gut-associated lymphoid tissue (GALT) of HIV-infected participants receiving RTG or DTG with tenofovir+emtricitabine (TDF/FTC). METHODS GALT specimens from the terminal ileum, splenic flexure and rectum were obtained by colonoscopy at a single time point in 20 adults treated with RTG (n=10) or DTG (n=10) with HIV RNA <50 copies/ml. Flow cytometry, drug concentrations, and HIV RNA and DNA were analysed in tissue. CD4/8+ T-cells were tested for γδ TCR, and markers of T-cell activation and exhaustion. Data are reported as median (Q1-Q3). RESULTS A total of 15 men and 5 women were enrolled. There was no difference in time since HIV diagnosis for those on RTG (9.5 [4-22] years) and DTG (17 [1-24] years; P=0.6), although time on RTG (5.4 [2.3-6.7] years) was greater than DTG (1.0 [0.1-1.5] years; P<0.001). Concentrations of RTG and DTG in rectal tissue were similar to previous reports: median tissue:plasma ratio was 11.25 for RTG and 0.44 for DTG. RNA:DNA ratios were 1.14 (0.18-5.10) for the RTG group and 0.90 (0.30-18.87) for the DTG group (P=0.95). No differences (P≥0.1) between CD4+ and CD8+ T-cell markers were found. CONCLUSIONS RTG produced higher tissue exposures than DTG, but no significant differences in GALT HIV RNA, DNA or most immunological markers were observed. ClinicalTrials.gov NCT02218320.
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NCp7: targeting a multitask protein for next-generation anti-HIV drug development part 2. Noncovalent inhibitors and nucleic acid binders.
Iraci, N, Tabarrini, O, Santi, C, Sancineto, L
Drug discovery today. 2018;(3):687-695
Abstract
Nucleocapsid protein 7 (NCp7) represents a viable target not yet reached by the currently available antiretrovirals. It is a small and highly basic protein, which is essential for multiple stages of the viral replicative cycle, with its structure preserved in all viral strains, including clinical isolates. NCp7 can be inhibited covalently, noncovalently and by shielding the nucleic acid (NA) substrates of its chaperone activity. Although covalent NCp7 inhibitors have already been detailed in the first part of this review series, the focus here is based on noncovalent and NA-binder inhibitors and on the analysis of the NCp7 3D structure to deliver fruitful insights for future drug design strategies.
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Dolutegravir Plus Rilpivirine as a Switch Option in cART-Experienced Patients: 96-Week Data.
Capetti, AF, Cossu, MV, Sterrantino, G, Barbarini, G, Di Giambenedetto, S, De Socio, GV, Orofino, G, Di Biagio, A, Celesia, BM, Rusconi, S, et al
The Annals of pharmacotherapy. 2018;(8):740-746
Abstract
BACKGROUND Data from clinical studies confirm the efficacy of switching to dolutegravir (DTG) plus rilpivirine (RPV) in selected patients. OBJECTIVE The primary objective is to report the 96-week virological suppression in our cohort, assessing the durability of this strategy in complicated situations. The secondary objective is to describe the safety and metabolic profile. METHODS All patients who had switched to DTG plus RPV between October 1, 2014, and September 30, 2015, were analyzed using a retrospective-prospective design, approved by ethics committees. Routine metabolic, immunological, and virological data were regularly sent to the coordinating center. Viral control was classified as HIV-1 RNA ≥50 copies/mL, 1 to 49 copies/mL, or undetectable (no virus detected [NVD]). RESULTS We followed 145 patients for a median of 101 weeks. The median age was 52 years; 31.7% were women, and 9.6% non-Caucasian; 50.3% had failed at least 1 antiretroviral regimen; and 15% had ≥50 copies/mL at baseline. The reasons for switching were as follows: simplification (51.7%), toxicity (36.5%), drug-drug interactions (6.9%), persistent low-level viremia (3.0%), nonadherence (2.1%), and viral failure (1.4%). By week 96, seven patients dropped out. At week 96, none had ≥50 HIV-1 RNA copies/mL, 138 (95.2%) had <50 copies/mL, and 123 (84.8%) had NVD. The low- to high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio decreased significantly ( P = 0.04). Of the 287 baseline altered laboratory parameters, 32.7% normalized by week 96. Serum glucose and total- and LDL-cholesterol normalization were statistically significant. CONCLUSIONS Switching to DTG plus RPV improved viral suppression and LDL-C/HDL-C ratio.
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Maternal health outcomes among HIV-infected breastfeeding women with high CD4 counts: results of a treatment strategy trial.
Hoffman, RM, Angelidou, KN, Brummel, SS, Saidi, F, Violari, A, Dula, D, Mave, V, Fairlie, L, Theron, G, Kamateeka, M, et al
HIV clinical trials. 2018;(6):209-224
Abstract
BACKGROUND IMPAACT PROMISE 1077BF/FF was a randomized study of antiretroviral therapy (ART) strategies for pregnant and postpartum women with high CD4+ T-cell counts. We describe postpartum outcomes for women in the study who were randomized to continue or discontinue ART after delivery. METHODS Women with pre-ART CD4+ cell counts ≥350 cells/mm3 who started ART during pregnancy were randomized postpartum to continue or discontinue treatment. Women were enrolled from India, Malawi, South Africa, Tanzania, Uganda, Zambia, and Zimbabwe. The primary outcome was a composite of progression to AIDS-defining illness or death. Log-rank tests and Cox regression models assessed treatment effects. Incidence rates were calculated per 100 person-years. A post hoc analysis evaluated WHO Stage 2/3 events. All analyses were intent-to-treat. FINDINGS 1611 women were enrolled (June 2011-October 2014) and 95% were breastfeeding. Median age at entry was 27 years, CD4+ count 728 cells/mm3 and the majority of women were Black African (97%). After a median follow-up of 1.6 years, progression to AIDS-defining illness or death was rare and there was no significant difference between arms (HR: 0·55; 95%CI 0·14, 2·08, p = 0.37). WHO Stage 2/3 events were reduced with continued ART (HR: 0·60; 95%CI 0·39, 0·90, p = 0.01). The arms did not differ with respect to the rate of grade 2, 3, or 4 safety events (p = 0.61). INTERPRETATION Serious clinical events were rare among predominately breastfeeding women with high CD4+ cell counts over 18 months after delivery. ART had significant benefit in reducing WHO 2/3 events in this population.
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Prevention of HIV-1 Transmission Through Breastfeeding: Efficacy and Safety of Maternal Antiretroviral Therapy Versus Infant Nevirapine Prophylaxis for Duration of Breastfeeding in HIV-1-Infected Women With High CD4 Cell Count (IMPAACT PROMISE): A Randomized, Open-Label, Clinical Trial.
Flynn, PM, Taha, TE, Cababasay, M, Fowler, MG, Mofenson, LM, Owor, M, Fiscus, S, Stranix-Chibanda, L, Coutsoudis, A, Gnanashanmugam, D, et al
Journal of acquired immune deficiency syndromes (1999). 2018;(4):383-392
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Abstract
BACKGROUND No randomized trial has directly compared the efficacy of prolonged infant antiretroviral prophylaxis versus maternal antiretroviral therapy (mART) for prevention of mother-to-child transmission throughout the breastfeeding period. SETTING Fourteen sites in Sub-Saharan Africa and India. METHODS A randomized, open-label strategy trial was conducted in HIV-1-infected women with CD4 counts ≥350 cells/mm (or ≥country-specific ART threshold if higher) and their breastfeeding HIV-1-uninfected newborns. Randomization at 6-14 days postpartum was to mART or infant nevirapine (iNVP) prophylaxis continued until 18 months after delivery or breastfeeding cessation, infant HIV-1 infection, or toxicity, whichever occurred first. The primary efficacy outcome was confirmed infant HIV-1 infection. Efficacy analyses included all randomized mother-infant pairs except those with infant HIV-1 infection at entry. RESULTS Between June 2011 and October 2014, 2431 mother-infant pairs were enrolled; 97% of women were World Health Organization Clinical Stage I, median screening CD4 count 686 cells/mm. Median infant gestational age/birth weight was 39 weeks/2.9 kilograms. Seven of 1219 (0.57%) and 7 of 1211 (0.58%) analyzed infants in the mART and iNVP arms, respectively, were HIV-infected (hazard ratio 1.0, 96% repeated confidence interval 0.3-3.1); infant HIV-free survival was high (97.1%, mART and 97.7%, iNVP, at 24 months). There were no significant differences between arms in median time to breastfeeding cessation (16 months) or incidence of severe, life-threatening, or fatal adverse events for mothers or infants (14 and 42 per 100 person-years, respectively). CONCLUSIONS Both mART and iNVP prophylaxis strategies were safe and associated with very low breastfeeding HIV-1 transmission and high infant HIV-1-free survival at 24 months.
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Effects of a Nutritional Protein-Rich Drink on the Pharmacokinetics of Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Alafenamide, and Tenofovir Compared With a Standard Meal in Healthy Japanese Male Subjects.
Yamada, H, Ikushima, I, Nemoto, T, Ishikawa, T, Ninomiya, N, Irie, S
Clinical pharmacology in drug development. 2018;(2):132-142
Abstract
This study investigated the effects of ingested meal types on the pharmacokinetics of elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), tenofovir alafenamide (TAF), and tenofovir (TFV) following a single administration of the single-tablet regimen (STR) of EVG/COBI/FTC/TAF (150/150/200/10 mg) in Japanese HIV-negative healthy subjects (n = 12). In this open-label, randomized, 3-way crossover study, the bioequivalence of the EVG/COBI/FTC/TAF STR following ingestion of a nutritional protein-rich drink with a reference treatment of taking a standard breakfast was evaluated. Administration under fasted conditions, no food intake, resulted in decreases in the mean AUCinf and Cmax of EVG by 50% and 57%, respectively, relative to the administration with a standard breakfast, whereas the systemic exposure of EVG with a nutritional protein-rich drink was comparable to that with a standard breakfast. The mean AUCinf and Cmax of COBI, FTC, TAF, and TFV were comparable regardless of meal intake or meal types. Although the package insert of the EVG/COBI/FTC/TAF STR states that the medication is recommended to be taken with food, this study provides an additional insight into HIV-1-infected patients that a light meal like a nutritional protein-rich drink can be an alternative to a standard meal.
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A switch to a raltegravir containing regimen does not lower platelet reactivity in HIV-infected individuals.
van der Heijden, WA, van Crevel, R, de Groot, PG, Urbanus, RT, Koenen, HJPM, Bosch, M, Keuter, M, van der Ven, AJ, de Mast, Q
AIDS (London, England). 2018;(17):2469-2475
Abstract
OBJECTIVE Platelet hyperreactivity and increased platelet-monocyte aggregation (PMA) are associated with increased cardiovascular risk and inflammation. In a previous cross-sectional study, individuals using a raltegravir (RAL)-based regimen were found to have reduced platelet reactivity and PMA compared with other antiretroviral regimens. Our aim was to investigate whether switching from a nonintegrase inhibitor regimen to a RAL-based regimen reduces platelet reactivity or PMA. DESIGN An investigator initiated, single-centre, prospective randomized, open-label, blinded endpoint trial. METHODS Forty HIV-infected adults using a nonintegrase inhibitor containing regimen with undetectable viral load were randomized to either continue their regimen or switch to a RAL-based regimen for 10 weeks, continuing the same backbone. The primary outcome was the change in platelet reactivity at week 10, which was determined as the expression of the platelet activation marker P-selectin and binding of fibrinogen before and after ex-vivo stimulation with different platelet agonists. Secondary outcomes included PMA, plasma markers of platelet activation and markers of inflammation and immune cell activation. RESULTS Twenty-one participants were enrolled in the continuation group and 19 in the RAL group. Baseline characteristics were comparable between groups. There were no differences in the change in platelet reactivity to either platelet agonist at week 10, nor in plasma markers of platelet activation. PMA, C-reactive protein, T-cell activation (CD38HLA-DR) and monocyte (CD14CD16) subsets. CONCLUSION Switching a nonintegrase inhibitor containing regimen to a RAL-based regimen does not reduce platelet reactivity, platelet-leukocyte aggregation, inflammation and immune activation in virologically suppressed HIV-infected individuals. CLINICAL TRIAL NUMBER NCT02383355.
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First-line Raltegravir/Emtricitabine/Tenofovir Combination in Human Immunodeficiency Virus Type 2 (HIV-2) Infection: A Phase 2, Noncomparative Trial (ANRS 159 HIV-2).
Matheron, S, Descamps, D, Gallien, S, Besseghir, A, Sellier, P, Blum, L, Mortier, E, Charpentier, C, Tubiana, R, Damond, F, et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2018;(8):1161-1167
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BACKGROUND New options for first-line treatment of human immunodeficiency virus type 2 (HIV-2) infection are needed. We evaluated an integrase inhibitor (raltegravir)-containing regimen. METHODS Antiretroviral therapy (ART)-naive adults with symptomatic infection by HIV-2 only, CD4 count <500 cells/μL or CD4 decrease >50 cells/μL/year over the past 3 years, or a confirmed plasma HIV-2 RNA (pVL) load ≥100 copies/mL were eligible for this noncomparative trial. The composite primary endpoint was survival at 48 weeks without any of the following: CD4 gain from baseline <100 cells/μL, confirmed pVL ≥40 copies/mL from week 24, raltegravir permanent discontinuation, or incident B or C event. HIV-2 ultrasensitive pVL (uspVL) and total DNA were assessed using in-house polymerase chain reaction (PCR) assays. RESULTS Baseline median CD4 count of 30 enrolled individuals (67% women) was 436 cells/µL (interquartile range [IQR], 314-507 cells/µL); pVL was ≥40 copies/mL in 67% of them, uspVL was ≥5 copies/mL in 92%, and total DNA was >6 copies by PCR in 32%. At week 48, the composite endpoint of success was reached in 40% [95% confidence interval, 22.7%-59.4%]. Failure was mainly (50%) due to CD4 gain <100 cells/µL; uspVL was <5 copies/mL in 87% and total DNA >6 copies by PCR in 12% of participants. Median CD4 gain was 87 cells/µL (IQR, 38-213 cells/µL; n = 28). No serious adverse reactions were reported. CONCLUSIONS Raltegravir-containing ART is a safe option for first-line treatment of HIV-2 infection, yielding a comparable success rate to protease inhibitors. CLINICAL TRIALS REGISTRATION NCT 01605890.
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Changes in cerebral function parameters with maraviroc-intensified antiretroviral therapy in treatment naive HIV-positive individuals.
Mora-Peris, B, Bouliotis, G, Ranjababu, K, Clarke, A, Post, FA, Nelson, M, Burgess, L, Tiraboschi, J, Khoo, S, Taylor, S, et al
AIDS (London, England). 2018;(8):1007-1015
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Abstract
BACKGROUND Maraviroc-intensified antiretroviral therapy (ART) may be associated with cognitive benefits. METHODS Therapy-naive, cognitively asymptomatic, HIV-positive individuals were randomly allocated on a 1 : 1 basis to standard ART (Arm1: tenofovir-emtricitabine and atazanavir/ritonavir) or maraviroc intensified ART (Arm2: abacavir-lamivudine and darunavir/ritonavir/maraviroc). Over 48 weeks, detailed assessments of cognitive function tests were undertaken and cerebral metabolites measured using proton magnetic resonance spectroscopy. Our primary endpoint was mean change in cognitive function across treatment arms with factors associated with cognitive function changes also assessed. RESULTS Of 60 individuals randomized (30 Arm1 and 30 Arm2), 58 were men and 44 of white ethnicity. Treatment groups had similar disease characteristics including overall mean (SD) baseline CD4 cell count 428 (209) and 414 (229) cells/μl, Arms1 and 2, respectively. At week 48, plasma HIV RNA was less than 50 copies/ml in 55 of 56 of those completing study procedures. Cognitive function improved over 48 weeks [mean change z-score (SD) 0.16 (0.09) Arm1 and 0.25 (0.08) Arm2, P = 0.96 for differences between study arms]. A greater increase in frontal grey matter N-acetyl aspartate/creatine ratio was observed in Arm1 [ratio change of 0.071 (SD 0.16)] versus Arm2 [change -0.097 (SD 0.18), P = 0.009], although this was not associated with changes in cognitive function (P = 0.17). CONCLUSION Maraviroc-intensified ART had no demonstrable benefit on cognitive function in individuals initiating ART. Greater improvement in neuronal metabolites (N-acetyl aspartate/creatine) was observed with standard ART. Future work should focus on maraviroc-intensified ART in individuals with cognitive impairment.