bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clevudine is Efficiently Phosphorylated to the Active Triphosphate form in Primary Human Hepatocytes
Authors: Niu Congrong , Murakami Eisuke , Furman Phillip A 
Published: April 2022

Background Clevudine (CLV) is a nucleoside analogue of the unnatural l-configuration that has demonstrated potent activity against hepatitis B virus (HBV) in vitro and in Phase III clinical studies. Human hepatoma cell lines are the only liver-derived cells in which CLV metabolism has been investigated. Here, we examine CLV metabolism in primary human hepatocytes, which better represent CLV metabolism in the liver. Methods HPLC analysis of primary human hepatocyte extracts incubated with radiolabelled CLV was used to determine the time course of CLV phosphorylation. Effects of the exogenous cell concentration of CLV on phosphorylation were assessed and the half-life of the CLV phosphorylated forms was determined. Results The major CLV metabolite formed in human primary hepatocytes was 5‘-monophosphate, whereas in the hepatoma cell lines the major metabolite was 5’-triphosphate. The level of CLV 5’-triphosphate was similar in both cell types. In primary hepatocytes the conversion of CLV 5’-monophosphate to the corresponding 5’-diphosphate was the rate-limiting step in CLV phosphorylation; the level of CLV phosphorylation was dependent upon exogenous drug concentration and exposure time. CLV 5’-triphosphate accumulated rapidly with peak levels observed after ∼8 h. When cells were incubated with 1 μM CLV, the approximate maximal plasma concentration achieved in individuals receiving the 30 mg dose, the average intracellular concentration of CLV 5’-triphosphate was 41.3 ±8.4 pmols/106 cells (∼10 μM). The initial half-life of CLV triphosphate was ∼11 h. Conclusions These results are consistent with once daily CLV dosing currently being used in Phase III clinical studies.
Living with HIV, Antiretroviral Treatment Experience and Tobacco Smoking: Results from a Multisite Cross-Sectional Study
Authors:   the EVIT Study Group, Duval Xavier , Baron Gabriel , Garelik Daniel , Villes Virginie , Dupré Thierry , Leport Catherine , Lert France , Peretti-Watel Patrick , Ravaud Philippe , Spire Bruno 
Published: April 2022

Background To assess the prevalence of and factors associated with tobacco smoking and dependence in HIV patients. Methods In a one-day cross-sectional national survey of a representative sample of 82 French units specialized in HIV-infected patient care, 727 consecutive outpatients were asked to complete a self-administered questionnaire, assessing smoking habits, dependence, cessation motivation, other substance abuse, sociocultural characteristics, life with HIV and its treatment. Smoking prevalence and dependence were assessed and compared with a representative sample of the general French population. Results The questionnaire was completed by 593 (82%) patients: 12% were active or ex-intravenous drug users, 37% were homosexual men, and 43% were active smokers (compared with 31% in the French population) of whom 56% were classified as moderately or highly dependent. Fourteen percent of smokers were highly motivated and free of other substance abuse and of depressive symptoms. Smoking was independently associated with male sex (odds ratio [OR]=2.38; 95% confidence interval [CI] 0.99–1.11), lower body mass index (OR 1.08; 95% CI 1.14–1.03), smoking environment (OR 4.75; 95% CI 3.02–7.49), excessive alcohol consumption (OR 2.50; 95% CI 1.20–5.23), illicit drug use (OR 2.43; 95% CI 1.41–4.19), HIV status disclosure to family (OR 1.81; 95% CI 1.16–2.85) and experience of rejection due to disclosure (OR 1.90; 95% CI 1.14–3.17). Disclosure and drug substitute usage were associated with high tobacco dependence. Conclusions Very few HIV smokers seem to be good candidates for a standard tobacco cessation program. Tobacco reduction or cessation strategies should be adapted to this population.
Insulin Resistance, Hepatic Lipid and Adipose Tissue Distribution in HIV-Infected Men
Authors: He Qing , Engelson Ellen S , Ionescu Gabriel , Glesby Marshall J , Albu Jeanine B , Kotler Donald P 
Published: April 2022

Background A large proportion of HIV-infected patients on antiretroviral medication develop insulin resistance, especially in the context of fat redistribution. This study investigates the interrelationships among fat distribution, hepatic lipid content, and insulin resistance in HIV-infected men. Methods We performed a cross-sectional analysis of baseline data from 23 HIV-infected participants in three prospective clinical studies. Magnetic resonance spectroscopy was used to quantify hepatic lipid concentrations. Magnetic resonance imaging was used to quantify whole-body adipose tissue compartments: that is, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes, as well as the intermuscular adipose tissue (IMAT) subcompartment and the omental-mesenteric adipose tissue (OMAT) and retroperitoneal adipose tissue (RPAT) subcompartments of VAT. The homeostasis model for assessment of insulin resistance (HOMA-IR) was calculated from fasting glucose and insulin concentrations. Results Hepatic lipid content correlated significantly with total VAT (r=0.62, P=0.0014), but not with SAT (r=0.053, P=0.81). In univariate analysis, hepatic lipid content was associated with the OMAT (r=0.67, P=0.0004) and RPAT (r=0.53, P=0.009) subcompartments; HOMA-IR correlated with both VAT and hepatic lipid contents (r=0.61, P=0.057 and r=0.68, P=0.0012, respectively). In stepwise linear regression models, hepatic lipid had the strongest associations with OMAT and with HOMA-IR. Conclusion Hepatic lipid content is associated with VAT volume, especially the OMAT subcompartment, in HIV-infected men. Hepatic lipid content is associated with insulin resistance in HIV-infected men. Hepatic lipid content might mediate the relationship between VAT and insulin resistance among treated, HIV-infected men.
Cord Blood Lipids in Infants Born to HIV-1-Infected Women Treated with Combination Antiretroviral Therapy
Authors: Melvin Ann J , Kang Minhee , Hitti Jane , Livingston Elizabeth , Cohn Susan E , Stocker Vicki , Ross Allison C , Watts Heather , McComsey Grace A 
Published: April 2022

Background To investigate the effect of exposure to protease inhibitor (PI) therapy in utero on cord blood lipids in infants born to mothers enrolled in AIDS Clinical Trials Group protocol 5084, a prospective, multi-centre, observational study of antiretroviral therapy (ART) during pregnancy. Methods Clinical outcome was determined in 80 infants born to women treated with PIs and 73 infants born to women treated with other antiretrovirals during pregnancy. Cord blood serum from 117 of these infants was assayed for total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglyceride, apolipoprotein A1 (apoA1), apolipoprotein B100 (apoB) and lipoprotein (a). Covariates considered in the analysis included race/ethnicity, gestational age, infant gender, infant birth weight, mode of delivery, maternal tobacco and alcohol use, post-partum body mass index, and ART duration. Results Cord blood total and HDL cholesterol, triglyceride, apoA1, apoB, lipoprotein (a) and apoB/apoA1 ratio were not different between the two groups. Cord blood lipid levels in these HIV-exposed infants were similar to those reported in other neonatal cohorts. Controlling for race/ethnicity, infants born to women treated with PIs had higher LDL cholesterol than those born to women not treated with PIs (29 mg/dl versus 27 mg/dl, P=0.006). Conclusion Only LDL cholesterol was significantly higher in the cord blood of PI-exposed infants versus those not exposed to PIs in utero. As the difference between the two groups was small, the clinical relevance of the effect of maternal PI treatment on infant LDL cholesterol levels at birth is not clear.
Enfuvirtide Cerebrospinal Fluid (CSF) Pharmacokinetics and Potential use in Defining CSF HIV-1 Origin
Authors: Price Richard W , Parham Robin , Kroll Jing Lu , Wring Stephen A , Baker Brian , Sailstad Jeff , Hoh Rebecca , Liegler Teri , Spudich Serena , Kuritzkes Daniel R , Deeks Steven G 
Published: April 2022

Background Enfuvirtide is a potent inhibitor of systemic HIV-1 replication, but its penetration into the human central nervous system (CNS) has not been analysed. Here, we define cerebrospinal fluid (CSF) enfuvirtide pharmacokinetics and present a case illustrating the use of enfuvirtide as a probe to trace the origins of CSF HIV-1 quasispecies. Methods Enfuvirtide CSF pharmacokinetics were assessed in 18 CSF and plasma sample pairs from four HIV-1-infected individuals. Enfuvirtide levels were measured by liquid chromatography tandem mass spectrometry using known standards and controls that included spiked CSF samples from untreated, HIV-negative individuals. A segment of the gp41 coding region encompassing the heptad repeat HR-1 and HR-2 domains was amplified from selected CSF and plasma samples and independent clones sequenced to assess resistance-associated mutations. Results CSF and plasma samples obtained between 2 and 20 h after enfuvirtide injection showed plasma concentrations similar to previous reports (mean 3.687 SD ±1.828 mg/ml) with prolonged decay. By contrast, enfuvirtide in all CSF samples was below the assay detection limit of 0.025 mg/ml. In one individual, who developed a transient increase in CSF HIV-1 RNA, seven of seven CSF and plasma clones had identical enfuvirtide resistance-associated V38A mutations, suggesting that the CSF quasispecies derived from that of blood. Conclusions Enfuvirtide penetration into CSF is negligible; thus, in clinical settings, where direct CNS drug exposure is crucial, this drug Is not likely to directly contribute to the local therapeutic effect. Enfuvirtide can be used as a tool to dissect the origin of the CNS virus.
Antiviral Resistance Mutations Potentiate hepatitis B virus Immune Evasion through Disruption of its Surface Antigen a Determinant
Authors: Sloan Richard D , Ijaz Samreen , Moore Penny L , Harrison Tim J , Teo Chong-Gee , Tedder Richard S 
Published: April 2022

Background The hepatitis B virus (HBV) pol gene overlaps the S gene encoding surface antigen (HBsAg). It has been reported previously that drug-induced changes in HBsAg alter its binding to sera from humans immunized against HBV. We investigate here the changes to specific epitopes in the a determinant (the major target of neutralizing antibody) caused by a number of drug-resistant mutations. Methods Recombinant HBsAgs, produced by transfection of Chinese hamster ovary cells with S gene plasmids into which lamivudine, adefovir and entecavir resistance and common antibody-escape mutations had been introduced, were probed with monoclonal antibodies to epitopes in the first and second loops of the a determinant. Results The mutations rtF166L/sF158Y (lamivudine-associated, compensatory) and rtI169T/sF161L (entecavir-associated, primary) acting alone, and the mutations rtV173L/sE164D (lamivudine-associated, compensatory) and rtSilent/sD144E (antibody escape-associated) each when combined with rtM204V/sI195M (lamivudine-associated, primary) led to decreases in antibody reactivity to epitopes in the first or second loop, or in both loops. The rtM204V/ sI195M+rtV173L/sE164D mutations yielded an epitope–antibody profile similar to the rtR153Q/sG145R vaccine escape mutant. The rtM204V/sI195M mutation combined with the rtF166L/sF158Y or rtR153Q/sG145R mutation restored reactivity to second-loop epitopes previously abrogated by single mutations. Conclusions Mutations associated with resistance to nucleos(t)ide analogue therapy, singly or in combination with each other or antibody escape-associated mutations, alter HBsAg immunoreactivity through concomitant amino acid substitutions at codons within and downstream of the a determinant. The findings have implications for understanding the native structure of HBsAg, optimizing treatment of chronic hepatitis B and evaluating the success of immunization programmes.
Evidence of Long-Term Suppression of Hepatitis B virus DNA by Tenofovir as Rescue Treatment in Patients Coinfected by HIV
Authors: Quiros-Roldan Eugenia , Calabresi Alessandra , Lapadula Giuseppe , Tirelli Valeria , Costarelli Silvia , Cologni Giuliana , Zaltron Serena , Puoti Massimo , Carosi Giampiero , Torti Carlo 
Published: April 2022

Background The efficacy of long-term hepatitis B virus (HBV) treatment with tenofovir (TDF) in relation to lamivudine (LMV) resistance in HIV patients failing on LMV deserves further investigations. Methods HIV–HBV coinfected patients were selected, provided that LMV was included in the first highly active antiretroviral therapy regimen and TDF was subsequently introduced. Results Forty HIV–HBV patients were included, 25 had undetectable HBV DNA on LMV and 15 were failing on LMV treatment. Three cases of triple 173V+180M+ 204V HBV reverse transcriptase (rt) mutants were identified, as well as several mutations or polymorphisms in the surface antigen gene at positions possibly correlating with vaccine escape. A new mutation (rtI233V) was found in one adefovir-naive patient. In 10 patients, uninterrupted TDF treatment led to a sustained treatment response for a median of 160 (interquartile range 111–189) weeks. Two patients underwent intermittent treatment with TDF and LMV, responding any time TDF was reintroduced. In one patient, TDF without LMV provided treatment response. One patient did not respond to TDF because of low treatment adherence. One patient infected with the triple rt mutant did not respond to entecavir, but TDF was successful as rescue. Conclusions Combination therapy with TDF was effective against HBV mutant viruses resistant to LMV and provided sustained control of HBV replication over long-term follow-up, even after entecavir failure. Moreover, suppression of HBV vaccine escape variants could provide important benefits from a public health perspective.
Factors Influencing Efavirenz and Nevirapine Plasma Concentration: Effect of Ethnicity, Weight and Co-Medication
Authors: Stöhr Wolfgang , Back David , Dunn David , Sabin Caroline , Winston Alan , Gilson Richard , Pillay Deenan , Hill Teresa , Ainsworth Jonathan , Pozniak Anton , Leen Clifford , Bansi Loveleen , Fisher Martin , Orkin Chloe , Anderson Jane , Johnson Margaret , Easterbrook Phillippa , Gibbons Sara , Khoo Saye 
Published: April 2022

Background The aim of this study was to examine factors influencing plasma concentration of efavirenz and nevirapine. Methods Data from the Liverpool Therapeutic Drug Monitoring (TDM) registry were linked with the UK Collaborative HIV Cohort (CHIC) Study. For each patient, the first measurement of efavirenz (600 or 800 mg/day) or nevirapine (400 mg/day) plasma concentration was included. Linear regression was used to evaluate the association of dose, gender, age, weight, ethnicity and concomitant antiretroviral drugs or rifampicin with log-transformed drug concentration, adjusted for time since last intake. Results Data from 339 patients on efavirenz (34% black, 17% rifampicin) and 179 on nevirapine (27% black, 6% rifampicin) were included. Multivariable models revealed the following predictors for efavirenz concentration: black ethnicity (59% higher; P<0.001), weight (10% lower per additional 10 kg; P=0.002), 800 mg/day (52% higher; P=0.027), rifampicin (35% lower; P=0.039), and zidovudine (25% lower; P=0.010). Notably, without adjustment for other factors, patients on rifampicin had 48% higher efavirenz concentration, as these patients were mostly black and on 800 mg/day. For nevirapine the predictors were black ethnicity (39% higher; P=0.002), rifampicin (40% lower; P=0.002), protease inhibitor (28% higher; P=0.008) and tenofovir (22% higher; P=0.024). Conclusions We observed clear associations between ethnicity and concentrations of nevirapine and efavirenz. Our analyses confirm that concomitant rifampicin substantially decreases concentration of both efavirenz and nevirapine; however, for efavirenz this effect was more than counterbalanced by the effect of ethnicity and increased efavirenz dose. There was also an additional impact of weight, which should be considered when determining optimal dosage. Other associations from our analysis (between tenofovir or protease inhibitor and nevirapine, and zidovudine and efavirenz), require confirmation in formal pharmacokinetic studies.
Mitochondrial RNA and DNA alterations in HIV lipoatrophy are linked to antiretroviral therapy and not to HIV infection
Authors: McComsey Grace A , Libutti Daniel E , O'Riordan MaryAnn , Shelton Jessica M , Storer Norma , Ganz Jason , Jasper John , Harrill Danielle , Gerschenson Mariana 
Published: April 2022

Background The aim of this study was to assess the effect of antiretroviral therapy (ART) versus HIV on mitochondria in fat. Methods Subcutaneous fat was collected from 45 HIV-infected patients on ART with lipoatrophy, 11 HIV-infected ART-naive patients and nine healthy controls. Three mitochondrial transcripts: NADH dehydrogenase subunit 1 (ND1), cytochrome B (CYTB) and NADH dehydrogenase subunit 6 (ND6) genes were quantitated using TaqMan® probes and normalized to nuclear-encoded ribosomal L13. Results ND1/L13 and CYTB/L13 were lower in HIV-positive patients on ART with lipoatrophy versus ART-naive patients (3.4 versus 7.2 [ P=0.017] and 2.5 versus 4.6 [ P=0.006], respectively). No difference was found between ART-naive patients and controls ( P>0.70). ND6/ L13 was similar between all groups. Dual-energy X-ray absorptiometry-measured limb fat and mitochondrial DNA in fat were also lower in HIV-positive patients on ART with lipoatrophy versus HIV-infected, ART-naive patients (4,382 versus 7,662 g [ P=0.02] and 726 versus 1,372 copies/cell [ P=0.03], respectively), but no difference was found between ART-naive and controls. In a multiple regression analysis, limb fat correlated with all three mitochrondrial RNA, whereas mitochondrial DNA did not correlate with mitochondrial RNA or limb fat. Conclusions In contrast to ART-naive patients, HIV-positive patients on ART with lipoatrophy had significant depletion in mitochondrial DNA in fat and mitochondrial RNAs. This suggests that mitochondrial toxicity in lipoatrophy could be driven by ART and not by HIV itself. In addition, mitochondrial RNA abnormalities, and not mitochondrial DNA depletion, could be a key driving force behind lipoatrophy.
Estimating Glomerular Filtration Rate in HIV-Infected Adults in Africa: Comparison of Cockcroft–Gault and Modification of Diet in Renal Disease Formulae
Authors: Stöhr Wolfgang , Walker A Sarah , Munderi Paula , Tugume Stefano , Gilks Charles F , Darbyshire Janet H , Hakim James 
Published: April 2022

Background Cockcroft–Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulae are recommended for glomerular filtration rate (GFR) estimation, but neither has been validated or directly compared longitudinally in HIV-infected patients or in Africa. Methods We investigated differences between formulae in baseline GFR, GFR changes and incidence of impaired GFR after initiation of antiretroviral therapy (ART) in 3,316 HIV-infected adults in Africa, considering sex, age, body mass index and baseline laboratory parameters as predictors. Results Participants were 65% women, median age 36.8 years, median weight 56.7 kg. Baseline GFR was lower using CG (median 89 ml/min/1.73 m2, 7.4% <60 ml/ min/1.73 m2) versus MDRD (103 ml/min/1.73 m2, 3.1% <60 ml/min/1.73 m2). At 36 weeks, median CG-GFR increased (92 ml/min/1.73 m2), whereas MDRD-GFR decreased (96 ml/min/1.73 m2). Weight (explicitly a factor in CG only) concurrently increased to 62.0 kg. GFR changes from weeks 36–96 (after weight stabilization) were similar across formulae. By 96 weeks, 56 patients developed severe GFR impairment (<30 ml/min/1.73 m2) using one or both formulae (both n=45, CG n=7, MDRD n=4) compared with only 24 by serum creatinine alone. Multivariate models identified different sets of predictors for each formula. Conclusions Although severe GFR impairments are similarly classified by different formulae, moderate impairments were more frequently identified using CG-GFR versus MDRD-GFR (with Black ethnicity correction factor 1.21), and creatinine alone had low sensitivity. Given overestimation in underweight patients and sensitivity to weight changes, this MDRD formula might not necessarily be superior for monitoring ART in African HIV-infected adults.
Determinants of Virological Failure after Successful Viral Load Suppression in First-Line Highly Active Antiretroviral Therapy
Authors: Geretti Anna M , Smith Colette , Haberl Annette , Garcia-Diaz Ana , Nebbia Gaia , Johnson Margaret , Phillips Andrew , Staszewski Schlomo 
Published: April 2022

Background We aimed to investigate the long-term virological outcomes of a cohort initially showing good responses to first-line highly active antiretroviral therapy (HAART) with no evidence of virological failure during the first year after achieving viral load (VL) undetectability (<50 copies/ml). Methods Virological failure was defined as a confirmed VL>400 copies/ml or a single VL>400 copies/ml followed by a treatment change or end of follow-up. Risk factors for low-level VL rebound (50–400 copies/ml) in the first year after achieving undetectability and for virological failure during subsequent follow-up were investigated by logistic and Poisson regression. Results In the first year after achieving VL undetectability, 354/1,386 (25.5%) patients experienced low-level VL rebound, the remaining patients maintained consistent undetectability. Low-level rebound occurred less commonly with non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART than with other regimens ( P=0.01). Over median 2.2 (range 0.0–7.4) years of subsequent follow-up, 86 (6.2%) patients experienced virological failure, corresponding to 2.30 failures per 100 person-years (95% confidence interval [CI] 1.82–2.79). Independent predictors of virological failure included low-level rebound during the first year after achieving undetectability relative to consistent undetectability (rate ratio [RR] 2.18, 95% CI 1.15–4.10), female gender (RR 1.79, 95% CI 1.12–2.85) and receiving a ritonavir-boosted protease inhibitor (PI/r) relative to NNRTI-based HAART (RR 1.88, 95% CI 1.02–3.46). Conclusions Patients on first-line HAART who maintain consistent VL undetectability for 1 year have a low risk of subsequent virological failure. A subset might benefit from targeted interventions, including women and patients on PI/r-based HAART.