bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cenicriviroc blocks HIV entry but does not lead to redistribution of HIV into extracellular space like maraviroc
Authors: Kramer Victor , Hassounah Said , Colby‐Germinario Susan , Mesplède Thibault , Lefebvre Eric , Wainberg Mark 
Published: November 2014

IntroductionCenicriviroc (CVC), a once‐daily, dual CCR5/CCR2 co‐receptor antagonist, has completed Phase 2b development. CVC demonstrated favourable safety and similar efficacy compared with efavirenz (EFV) in Study 202 (NCT01338883); an ex vivo sub‐analysis evaluated treatment effects on HIV entry, measured by intracellular HIV DNA declines, in subjects with virologic success at Week 24. In addition, in vitro assays determined and compared the extent of any cell‐free virion redistribution that CVC or maraviroc (MVC) may cause.MethodsEx vivo: intracellular DNA (frozen PBMCs) from 30 subjects with virologic success at Week 24 (10, 13 and 7 subjects on CVC 100 mg, CVC 200 mg and EFV, respectively). Early (strong‐stop) and late (full‐length) reverse transcript levels were measured by qPCR. In vitro: PM‐1 cells were infected with CCR5‐tropic HIV‐1 BaL in the presence or absence of inhibitory concentrations of CVC (20 nM), MVC (50 nM) or controls. P24 and viral load levels were measured by ELISA and qRT‐PCR after 4 hours.ResultsEx vivo analysis showed full‐length HIV DNA declines were similar across all groups (CVC 100 mg, CVC 200 mg and EFV) at Week 24. Strong‐stop HIV DNA declines (a marker of HIV entry) at Week 24 were pronounced for both CVC arms (CVC 100 mg, 51% decline; CVC 200 mg, 37% decline) compared to no decline for the EFV arm. In vitro experiments revealed that CVC‐treated cells had lower levels of supernatant P24 at 4 hours versus baseline (0 hrs: 506 ng/mL; 4 hrs: 192 ng/mL), but P24 levels remained constant for MVC‐treated cells after 4 hours (0 hrs: 506 ng/mL; 4 hrs: 520 ng/mL). Viral load levels for CVC‐treated cells remained stable after 4 hours (0 hrs: 1.19×1010 copies/mL; 4 hrs: 1.26×1010 copies/mL). MVC‐treated cells exhibited a slight increase in viral load after 4 hours (0 hrs: 1.19×1010 copies/mL; 4 hrs: 1.67×1010 copies/mL).ConclusionsEx vivo analysis confirmed that CVC treatment blocks HIV entry (strong‐stop HIV DNA declines), while in vitro analysis showed that CVC‐treated cells do not repel virus back into the extracellular space, as seen with MVC. Experiments are underway to determine whether or not interactions between CVC and HIV at the binding site may explain these unanticipated findings.
Factors associated with the continuum of care of HIV‐infected patients in Belgium
Authors: Van Beckhoven Dominique , Lacor Patrick , Moutschen Michel , Piérard Denis , Sasse André , Vaira Dolorès , Van den Wijngaert Sigi , Vandercam Bernard , Van Ranst Marc , Van Wijngaerden Eric , Vandekerckhove Linos , Verhofstede Chris , Verbrugge Ruth , Demeester Rémy , De Wit Stéphane , Florence Eric , Fransen Katrien , Delforge Marie‐Luce , Goffard Jean‐Christophe , Goubau Patrick ,   BREACH
Published: November 2014

IntroductionWe studied factors associated with the continuum of HIV care in Belgium.MethodsData of the national registration of new HIV diagnosis and of the national cohort of HIV‐infected patients in care were combined to obtain estimates of and factors related with proportions of HIV‐infected patients in each step of the continuum of care from diagnosis to suppressed viral load (VL). Factors associated with ignorance of HIV seropositivity were analyzed among patients co‐infected with HIV and STI in the Belgian STI sentinel surveillance network. Associated factors were identified by multivariate logistic regression.ResultsAmong 4038 individuals diagnosed with HIV between 2007 and 2010, 90.3% were linked to care. Of 11684 patients in care in 2010, 90.8% were retained in care up to the following year, 88.3% of those were on ART, of whom 95.3% had suppressed VL (<500 cp/ml) (Figure 1). In multivariate analyses, factors associated with ignoring HIV+ status were being younger (p<0.001), being heterosexual compared to MSM, and of a region of origin other than Belgium, Sub‐Saharan Africa and Europe. Non‐Belgian regions of origin were associated with lower entry and retention in care (p<0.001 for both). Preoperative HIV testing was associated with lower entry in care (p=0.003). MSM had a higher retention in care (p<0.001), whilst IDU had lower retention (p=0.004). Low CD4 at first clinical contact and clinical reasons for HIV testing were independently associated with being on ART (p<0.001 for both); whilst prenatal HIV diagnosis was associated with lower proportion on ART (p=0.016) and lower proportion with suppressed VL among those on ART (p=0.005). Older age was associated with both being on ART and having suppressed VL among those on ART (p=0.007 and p<0.001 respectively), independently of time since HIV diagnosis (Table 1).ConclusionsRegions of origin and risk groups (MSM/heterosexual/IDU) are the main factors associated with ignorance of HIV seropositivity, entry and retention in care, but once the HIV patient is retained in care, no effect of these factors on the proportions on ART and with suppressed VL are observed. The association of prenatal HIV diagnosis and proportions on ART and with suppressed VL could be biased by transitory CD4 disturbances during pregnancy and ART discontinuation after pregnancy. The higher probabilities of older patients to be on ART and have suppressed VL once retained in care could be influenced by factors not studied here like comorbidities, adherence or duration on ART.
No difference in persistence to treatment with atazanavir or darunavir in HIV patients in a real‐world setting
Authors: Farr Amanda M , Johnston Stephen S , Ritchings Corey , Brouillette Matthew , Rosenblatt Lisa 
Published: November 2014

IntroductionThere is a lack of data comparing the protease inhibitors (PIs) atazanavir (ATV) and darunavir (DRV) in a real‐world setting. This study compared persistence (time to switch/discontinuation) to therapy between ATV‐treated and DRV‐treated patients with human immunodeficiency virus (HIV).Materials and MethodsRetrospective, observational cohort study using US insurance claims for commercially and Medicaid‐insured patients. Patients were aged ≥18 years and initiated an ATV‐ or DRV‐based regimen boosted with ritonavir between 7/1/2006 and 3/31/2013, with ≥6 months of continuous enrolment prior to and ≥3 months of continuous enrolment following initiation; patients were required to have ≥1 inpatient or outpatient medical claim with an ICD‐9‐CM diagnosis code for HIV during that time period of enrolment. Patients with no claims for antiretroviral therapy (ART) any time prior to initiation were considered to be ART‐naïve. Time to switch/discontinuation was defined as the number of days from initiation of the regimen until earliest of: (1) a ≥30‐day continuous gap in therapy in ATV or DRV; (2) a prescription claim for an ART agent that was not part of the initial regimen (with the exception of changes in concomitant nucleoside reverse transcriptase inhibitors or the addition of integrase inhibitors); (3) censoring at a ≥30‐day continuous gap in therapy in ritonavir; (4) censoring at disenrolment from insurance benefits or (5) censoring at the study end date (9/30/2013 in the commercial data and 12/31/2013 in the Medicaid data). Time to switch/discontinuation was compared using incidence rates and multivariable Cox proportional hazards models adjusted for calendar time, patient demographics and clinical characteristics.ResultsTable 1 displays the study results and cohort sample sizes. Mean ages across the cohorts were 41–42 years. The proportions of patients who were ART‐naïve were 58–59% among the ATV/r cohorts and 53–55% among the DRV/r cohorts. There were no significant differences in the adjusted hazards of switch/discontinuation between the cohorts.ConclusionsThe incidence of switch/discontinuation was higher among Medicaid patients (who may be socioeconomically disadvantaged) than Commercial patients. There were no significant differences in persistence (time to switch/discontinuation) with the initiated PI among HIV patients who initiated an ATV‐based regimen versus a DRV‐based regimen.
Cerebrospinal‐fluid exposure of efavirenz and its major metabolites when dosed at 400 and 600 mg once daily; a randomized controlled trial
Authors: Winston Alan , Puls Rebekah , CSF Sub‐study group Encore 
Published: November 2014

IntroductionThe optimal penetration of antiretroviral agents into central nervous system (CNS) may be a balance between providing adequate drug exposure to inhibit HIV‐replication whilst avoiding concentrations associated with toxicities.MethodsCerebrospinal‐fluid (CSF) exposure of efavirenz and metabolites 7‐hydroxy (7OH‐) and 8OH‐efavirenz were assessed after at least 12 weeks of antiretroviral therapy in HIV‐infected subjects randomized to commence antiretroviral regimens containing efavirenz at either 400 mg or 600 mg once daily. Clinical, pharmacokinetic and pharmacogenomic factors associated with CSF efavirenz and its metabolite concentrations were assessed.ResultsOf 28 subjects who completed all study procedures (14/14 on efavirenz 400 mg/600 mg), CSF HIV RNA was below 20 copies/mL in all at the time of examination. Concentrations of efavirenz and 7OH‐efavirenz in the CSF were slightly lower when dosed at 400 mg versus 600 mg, although this was not statistically significant. A different trend was observed regarding 8OH‐efavirenz concentrations where CSF exposure was slightly increased in the 400 mg efavirenz arm (see Table 1). Efavirenz concentration in the CSF was above 0.51 ng/mL (proposed CSF IC50 for WT virus) in all subjects and 8OH‐efavirenz concentration in the CSF was above 3.3 ng/mL (a proposed toxicity threshold, reference) in 11/14 and 7/14 subjects randomized to the 400 mg and 600 mg doses of efavirenz, respectively. Whilst CSF efavirenz concentration was significantly associated with plasma concentration (P<0.001) and CYP2B6 genotype (CSF efavirenz GG to GT/TT GM ratio 0.56, 90% CI 0.42–0.74), CSF 8OH‐efavirenz concentration was not (P=0.242 for association with plasma concentration and CSF 8OH‐efavirenz GG to GT/TT GM ratio 1.52, 90% CI 0.97–2.36). Lastly, CSF 8OH‐efavirenz concentration was associated with efavirenz symptom questionnaire results at one year (Spearman's correlation 0.13, P=0.05).ConclusionsWith both doses of efavirenz studied, CSF concentrations were considered adequate to inhibit HIV‐replication, although concentrations of 8OH‐efavirenz were greater than that reportedly associated with neuronal toxicity. CSF exposure of 8OH‐efavirenz was not dependent on plasma exposure and we postulate may be subject to saturable pharmacokinetic effects.
Epi‐aortic lesions, pathologic FMD, endothelial activation and inflammatory markers in advanced naïve HIV‐infected patients starting ART therapy
Authors: Bellacosa Chiara , Maggi Paolo , Volpe Anna , Altizio Sergio , Ladisa Nicoletta , Cicalini Silvia , Viglietti Rosaria , Chirianni Antonio , Bellazzi Lara , Zanaboni Domenico , Maserati Renato , Martinelli Canio , Corsi Paola , Sofia Silvia , Celesia Maurizio , Sozio Ferdinando , Abbrescia Nicola , Angarano Gioacchino 
Published: November 2014

IntroductionPREVALEAT II (PREmature VAscular LEsions and Antiretroviral Therapy II) is an ongoing multicenter, longitudinal cohort study aimed to the evaluation of cardiovascular (CV) risk in advanced HIV‐infected antiretroviral (ARV) naïve patients starting their first antiretroviral therapy (ART).Patients and methodsAll consecutive naïve patients with CD4 cell count<200/mL starting any PI/r‐based or NNRTI‐based + 2 NRTIs regimen from January 2010 to January 2013 in the participant centres were enrolled. At baseline and after 3 (T1), 6 (T2) and 12 (T3) months patients were subjected to epi‐aortic vessels ultrasonography and brachial artery flow mediated dilation (FMD). Viral load, CD4+ cell count, serum lipid values, serum glucose, endothelial activation (ICAM‐1 and VCAM‐1) and inflammatory markers (IL‐6 and hsCRP) values were recorded at the same time. Data about independent risk factors for HIV infection and CV disease are taken at time 0. We enrolled 94 patients: 81% males, 87% caucasians, 40% smokers, 8.2% HCV co‐infected and 3.5% with lipodystrophy; 33% of them were homosexuals, 12% drug addicts; 23% were AIDS at presentation. Statistical data analysis has been conducted by the χ2 nonparametric method.ResultsIn Table 1 it is reported the percentage of patients with pathologic values, moreover, at T3, 60.46% showed undetectable viraemia and 69.77% had CD4 + > 200.ConclusionsOur data evidence at baseline has a relevant deterioration of CV conditions in terms of ultrasonographic data, FMD, inflammation and cytokine markers among advanced naïves. During follow‐up epi‐aortic lesions tend to worsen but not significantly, percentage of pathologic FMD remains stable. Regarding markers of endothelial activation ICAM‐1 significantly worsens during the period of observation; also VCAM‐1 has a trend towards the worsening while not significantly. Conversely, a significant improvement was observed for the markers of inflammation D‐dimers and high sensitivity C‐reactive protein (hsCRP). IL‐6 improved but not significantly. Serum lipid profile shows an increase of HDLc and total cholesterol, but not of LDLc. In conclusion, after a twelve‐month follow‐up period, CV risk of the patients remains high. ARV therapy seems in fact to improve only non‐specific and poor sensitive inflammation biomarkers and HDLc; markers of endothelial activations tend to worsen, intima‐media ultrasonography and FMD do not show relevant modifications. Further data are warranted to better understand the role of the different ARV regimens.
Randomized, crossover, double‐blind, placebo‐controlled trial to assess the lipid lowering effect of co‐formulated TDF/FTC
Authors: Ramón Santos José , Saumoy María , Curran Adrian , Bravo Isabel , Navarro Jordi , Estany Carla , Podzamczer Daniel , Ribera Esteban , Negredo Eugenia , Clotet Bonaventura , Paredes Roger 
Published: November 2014

IntroductionPrevious studies have described improvements on lipid parameters when switching from other antiretroviral drugs to tenofovir (TDF) and impairments in lipid profile when discontinuing TDF. [1–3] It is unknown, however, if TDF has an intrinsic lipid‐lowering effect or such findings are due to the addition or removal of other offending agents or other reasons.Materials and MethodsThis was a randomized, crossover, double‐blind, placebo‐controlled clinical trial (NCT 01458977). Subjects with HIV‐1 RNA <50 copies/mL during at least 6 months on stable DRV/r (800/100 mg QD) or LPV/r (400/100 mg BID) monotherapy, with confirmed fasting total cholesterol ≥200 or LDL‐cholesterol ≥130 mg/dL and not taking lipid‐lowering drugs were randomized to (A) adding TDF/FTCduring 12 weeks followed by 24 weeks without TDF/FTC, or (B) continuing without TDF/FTC for 12 weeks, adding TDF/FTC for 12 weeks and then withdrawing TDF/FTC for 12 additional weeks. Randomization was stratified by DRV/r or LPV/r use at study entry. All subjects received a specific dietary counselling. Primary endpoints were changes in median fasting total, LDL and HDL‐cholesterol 12 weeks after TDF/FTC addition. Analyses were performed by ITT.Results46 subjects with a median age of 43 (40–48) years were enrolled in the study: 70% were male, 56% received DRV/r and 44% LPV/r. One subject withdrew the study voluntarily at week 4 and another one interrupted due to diarrhoea at week 24. Treatment with TDF/FTC decreased total, LDL and HDL‐cholesterol from 235.9 to 204.9 (p<0.001), 154.7 to 127.6 (p<0.001) and 50.3 to 44.5 mg/dL (p<0.001), respectively. In comparison, total, LDL and HDL‐cholesterol levels remained stable during placebo exposure. Week 12 total cholesterol (p<0.001), LDL‐cholesterol (p<0.001) and HDL‐cholesterol (p=0.011) levels were significantly lower in TDF/FTC versus placebo. Treatment with TDF/FTC reduced the fraction of subjects with abnormal fasting total‐cholesterol (≥200 mg/dL) from 86.7% to 56.8% (p=0.001) and LDL‐cholesterol (≥130 mg/dL) from 87.8% to 43.9% (p<0.001), which was not observed with placebo. There were no virological failures, and CD4 and triglyceride levels remained stable regardless of exposure.ConclusionCoformulated TDF/FTC has an intrinsic lipid‐lowering effect, likely attributable to TDF.
Higher rates of metabolic syndrome among women taking zidovudine as compared to tenofovir in rural Africa: preliminary data from the CART‐1 study
Authors: Labhardt Niklaus Daniel , Cheleboi Molisana , Faturyiele Olatunbosun , Motlatsi Mokete M , Pfeiffer Karolin , Ismael Lejone Thabo , Cerutti Bernard , Muser Jürgen , Shankar Gupta Ravi , Lynen Lutgarde , Hatz Christoph 
Published: November 2014

IntroductionDue to its side effects stavudine (D4T) has been replaced by zidovudine (AZT) and tenofovir (TDF) in most low‐ and middle‐income countries (LMICs). In 2014 about 38% of adult first‐line regimens contain AZT and 62% TDF [1]. Whereas the unfavourable metabolic outcomes of D4T in comparison to TDF have been described extensively, studies from LMICs comparing metabolic profiles between patients on AZT and TDF are scarce. Given the high number of patients in LMICs still taking AZT, data on their metabolic profile are needed. We present rates of metabolic syndrome (MS) in adult patients taking either AZT‐ or TDF‐containing first‐line, non‐nucleoside reverse transcriptase (NNRTI)‐based regimens.Materials and MethodsData derived from a cross‐sectional multi‐disease screening conducted in ten facilities in two rural districts of Lesotho, Southern Africa [2]. Patients were eligible if aged ≥25 years and on NNRTI‐containing first‐line ART ≥6 months. The MS definition for Africa of the International Diabetes Federation was applied [3]. Assessed potential predictors for MS were age, time on ART, virologic suppression, body‐mass index (BMI), alcohol consumption, wealth quintile, NNRTI (nevirapine (NVP) or Efavirenz (EFV)), history of previous D4T exposure and ART‐backbone (AZT or TDF). Statistical analyses – stratified for sex – comprised univariate logistic regression for each predictor variable with subsequent construction of a multivariate model including all predictors with an association to MS at a significance level<0.1 in univariate analysis.ResultsOut of 1026 patients, 660 (64.3%) were female. MS prevalence was 9.8% (95% CI 6.9–13.4) in men and 22.9% (19.7–26.3) in women. In women, aged ≥35 years, AZT‐backbone, NVP‐base, BMI ≥25kg/m2 and taking ART for ≥4.5 years were associated with MS in univariate analysis. In the multivariate model only AZT (adjusted odds‐ratio: 2.2, 95% CI 1.4–3.6; p=0.001) and BMI ≥25kg/m2 (9.8; 2.8–34.1, p<0.001) were associated with MS. For men, age, higher wealth quintile, history of D4T exposure and BMI were associated with MS in univariate analysis. In the multivariate model only a BMI ≥25kg/m2 was associated with MS (8.9; 3.8–20.9, p<0.001).ConclusionsIn rural Lesotho, Southern Africa, the use of AZT instead of TDF among women who are on ART for ≥6 months predisposes to the development of metabolic syndrome. Given that, still 38% of first‐line regimens in LMIC contain AZT, this finding needs to be verified in other settings in Sub‐Saharan Africa.
Investigating presentations and outcomes of a joint HIV–renal clinic
Authors: Scott Jake , Williams Deborah 
Published: November 2014

IntroductionHIV patients are at risk of renal dysfunction directly from HIV, indirectly from chronic inflammation as well as from antiretroviral drug toxicity. In particular, tenofovir (TDF) has been associated with proximal renal tubular dysfunction. A joint HIV–renal clinic was set up in 2009 to facilitate a timely review and minimize additional follow‐up appointments. Brighton has a cohort of 2,150 HIV patients, 90% are on ARVs with 910/1,935 (47.0%) on regimens including TDF. This study aims to investigate the utility of this clinic and describe renal disease in this cohort.Materials and MethodsNotes of patients scheduled for assessment at the clinic between 2012 and 2014 were reviewed. Demographics, HIV history, number of visits, reason for referral and outcome information were collected.ResultsSixty‐five patients, median age 51 years (28–88) and median duration of HIV 163 months (20–335), were reviewed. Forty‐two were taking TDF for a mean of 55.8 months (9–122). Forty‐two patients were reviewed once with a median number of visits of 1 (1–4).Of those on TDF with proteinuria, 5 (13.2%) had TDF toxicity diagnosed and were discontinued at once, 27 continued with close monitoring with a further 7 subsequently discontinuing; total discontinued were 12 (32%). Overall, blood pressure control was the commonest intervention, 23/65 (35.4%), with 8/12 (66.7%) in the non‐TDF proteinuria group. Four (6%) patients underwent renal biopsy (2 focal segmental glomerulosclerosis, 1 IgA nephropathy and 1 glomerulonephritis and granuloma). In 4 (6%) creatinine rise was attributed to NSAIDs, creatine or protein supplements usage.ConclusionsTDF toxicity was the commonest reason for referral but only a minority (13.2%) needed to discontinue immediately. Optimizing BP control was the most frequent outcome suggesting this is an underappreciated cause for renal dysfunction amongst HIV physicians, as were other causes such as creatine and protein supplement usage. Running a “one‐stop‐shop” clinic supports continuation of tenofovir in patients with proteinuria, and supports the diagnosis and management of poorly controlled hypertension and streamlines the management of these patients.
No association between vitamin D deficiency and parathyroid hormone, bone density and bone turnover in a large cohort of HIV‐infected men on tenofovir
Authors: Samarawickrama Amanda , Jose Sophie , Sabin Caroline , Walker‐Bone Karen , Fisher Martin , Gilleece Yvonne 
Published: November 2014

IntroductionCombination antiretroviral therapy (cART) may affect vitamin D [25(OH)D], parathyroid hormone (PTH), bone mineral density (BMD) and bone turnover (BT). Reduced BMD and secondary hyperparathyroidism have been reported with tenofovir (TDF). We investigated the associations between TDF and bone markers, especially in 25(OH)D‐deficient patients.Materials and MethodsIn a single‐centre longitudinal study investigating BMD in HIV‐positive men, serum 25(OH)D, calcium, phosphate, PTH and alkaline phosphatase (ALP) were measured. Lumbar spine, non‐dominant total hip and non‐dominant femoral neck BMD (g/cm2) were measured using dual‐energy X‐ray absorptiometry. BT was assessed by serum type 1 procollagen (P1NP) and carboxy‐terminal collagen cross‐links (CTX). Mann–Whitney U tests compared serum markers and BT, and t‐tests compared BMD according to TDF in all and 25(OH)D‐deficient patients.ResultsA total of 422 men were recruited: mean age 47 (SD 9.8) years, 94% white ethnicity, 93% MSM, diagnosed HIV positive for median 9.6 (IQR 5.0,15.5) years, median CD4 547 (IQR 411,696) cells/µL, HIV RNA <40 copies/mL in 87% (96% of those on cART). 25(OH)D (nmol/L) was normal (>75), insufficient (50–75), deficient (25–50) and severely deficient (<25) in 14%, 29%, 50% and 7%, respectively. Of 381 men on cART, 77% were currently on TDF. TDF was not associated with median calcium (p=0.69) or phosphate (p=0.52), but patients had higher (but normal) median ALP [81 (IQR 69,103) vs. 73 (IQR 60,89) IU/L, p=0.005) compared to non‐TDF cART. There was no difference in the association between vitamin D and PTH according to whether someone currently was (r=0.11, p=0.06, Figure 1) or was not using TDF (r=0.12, p=0.29, Figure 1). TDF was also not associated with PTH, BMD or BT in either all patients on cART (Table 1a) or in patients with 25(OH)D deficiency (Table 1b).ConclusionsIn this largely TDF‐experienced cohort of HIV‐positive men, there was no association between TDF and 25(OH)D deficiency, hyperparathyroidism, reduced BMD or increased BT, although patients on TDF had higher but normal ALP. We found no evidence to support additional monitoring of bone markers in patients on TDF regardless of 25(OH)D status.