bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nevirapine Plasma Concentrations and Concomitant Use of Rifampin in Patients Coinfected with HIV-1 and Tuberculosis
Authors: Autar Reshma S , Wit Ferdinand WNM , Sankote Jongkol , Mahanontharit Apicha , Anekthananon Thanomsak , Mootsikapun Piroon , Sujaikaew Khanjtta , Cooper David A , Lange Joep MA , Phanuphak Praphan , Ruxrungtham Kiat , Burger David M 
Published: April 2022

Objectives In countries with high numbers of HIV/tuberculosis coinfection nevirapine and rifampin are used extensively. However, limited data are available about whether or not nevirapine and rifampin can be safely coadministered without the plasma concentration of nevirapine falling below therapeutic levels. Methods Blood samples for determination of nevirapine plasma concentrations were collected from patients using nevirapine 200 mg twice daily with or without concomitant rifampin. Bivariate and multivariate linear regression models were used to investigate factors possibly related to nevirapine concentrations. Results We received 74 blood samples from patients using nevirapine plus rifampin, and collected blood samples from an equal number of controls using nevirapine only. Groups were similar for age, gender, weight, height and body mass index (BMI). In the rifampin group the mean nevirapine concentration was 5.47 ±2.66mg/l, whereas in the control group the mean nevirapine concentration was 8.72 ±3.98 mg/l. In the rifampin group seven nevirapine trough concentrations were low (<3.1 mg/l), while in the control group two patients had low nevirapine trough concentrations ( P=0.164). In the multivariate linear regression analysis, corrected for time after drug intake, the use of rifampin was significantly ( P<0.001) associated with lower nevirapine plasma concentrations, whereas higher BMI reached borderline significance ( P=0.065). Conclusion Although nevirapine plasma concentrations were 3.3 mg/l lower when co-administered with rifampin, still more than 86% of these patients had nevirapine plasma concentrations >3.1 mg/l. Our results suggest that from a pharmacological point of view the majority of Thai coinfected patients, who have low BMIs, reach nevirapine plasma concentrations that are adequate for treatment of HIV. However this can only be undertaken if nevirapine plasma concentration monitoring is available and can be closely followed.
Ritonavir-Boosted Atazanavir-Lopinavir Combination: A Pharmacokinetic Interaction Study of Total, Unbound Plasma and Cellular Exposures
Authors: Colombo Sara , Buclin Thierry , Franc Claudia , Guignard Nicole , Khonkarly Mona , Tarr Philip E , Rochat Bertrand , Biollaz Jérôme , Telenti Amalio , Decosterd Laurent A , Cavassini Matthias 
Published: April 2022

Objectives To assess potential pharmacokinetic (PK) interactions between atazanavir (ATV, 300 mg, once daily) and lopinavir (LPV, 400 mg, twice daily), both boosted by ritonavir (RTV, 100 mg). Design Two-parallel groups, addition of LPV in patients receiving ATV ( n=6), and addition of ATV in patients receiving LPV ( n=7), with before/after comparisons. Methods Each group had two complete PK profiles before and 2 weeks after the addition of the second protease inhibitor (PI). Total plasma concentrations (Ctot) were analysed by HPLC-UV and unbound plasma concentrations (Cu) and cellular concentrations (Ccell) were analysed by LC-MS/MS. Plasma and cellular PK parameters were also calculated. Unbound and cellular fractions were expressed as Cu/Ctot and Ccell/Ctot ratio. Data were analysed by paired Student t-test on log values; correlations between Ccell, Cu and Ctot were explored by log-log linear regression. Results Adding LPV to ATV did not influence the plasma and cellular PK parameters of ATV. Adding ATV to LPV was associated with a decrease in LPV concentrations (by 16% for area under the time-concentration curve, maximum concentration and trough concentration, NS; and by 35% for Cmin, P=0.04). The RTV PK parameters remained unmodified. The Ccell/Ctot and Cu/Ctot ratio was unaffected by the addition of the second PI and remained stable throughout dosing interval. Good correlations were observed between Ccell, Cu and Ctot for each drug. No relevant toxicity was observed. Conclusions Adding LPV to ATV did not influence the plasma and cellular PK parameters of ATV. Adding ATV to LPV caused a limited decrease in LPV concentrations. The clinical significance of this decrease is unknown and warrants further investigation to determine the need for tailoring LPV dosage in selected cases.
Evaluation of the HIV Lipodystrophy Case Definition in a Placebo-Controlled, 144-Week Study in Antiretroviral-Naive Adults
Authors: Law Matthew , Puls Rebekah , Cheng Andrew K , Cooper David A , Carr Andrew 
Published: April 2022

Objective To compare three versions of the objective HIV-associated lipodystrophy (HIVLD) case definition (LDCD) and derived severity scale to spontaneous clinical LD assessment in adults initiating antiretroviral therapy. Design and main outcome measures: The LDCD versions were the ‘primary’ LDCD [which includes dual-energy X-ray absorptiometry (DXA) and computerized tomography (CT)], a simpler ‘central’ LDCD that omits CT data, and a simpler but probably less accurate ‘non-imaging’ LDCD. Physician LD assessments were passively reported. Two of the 10 parameters in the primary LDCD were not collected and were imputed. Setting, participants and interventions Retrospective analysis of a randomized, placebo-controlled, 144-week study of tenofovir DF or stavudine (d4T) in 600 anti-retroviral-naive adults. Results Central LDCD and clinical assessment diagnosed LD in 27% and 19% of d4T recipients at week 144, respectively ( P<0.001), and 3% and 3% of tenofovir DF recipients, respectively ( P=0.248). The central LDCD performed at least as well as the primary LDCD; both were more sensitive than the non-imaging model. There was poor concordance between clinical and LDCD-based diagnosis (kappa 0.02–0.20); most clinical cases did not fulfill any LDCD. Using the central LDCD, most LD was grade 1; 6% of d4T recipients and no tenofovir DF recipient had grade 3–4 LD at week 144 ( P=0.007). Independent risk factors for LD using the central LDCD were d4T, increasing age, female sex and higher baseline triglycerides, whereas clinical assessment consistently identified only d4T. The LDCD score was more sensitive than DXA for assessing LD severity. Conclusions In this prospective study of a first antiretroviral regimen, the LDCD was more sensitive for LD diagnosis and identified more lipodystrophy risk factors than spontaneous clinical assessment or DXA, and also objectively quantified LD severity. The central LDCD should make objective LD assessment cheaper and simpler. Spontaneous clinical LD assessment of is of limited value, even in placebo-controlled trials.
Eligibility for and Outcome of Hepatitis C Treatment of HIV-Coinfected Individuals in Clinical Practice: The Swiss HIV Cohort Study
Authors:   the Swiss HIV Cohort Study, Zinkernagel Annelies S , von Wyl Viktor , Ledergerber Bruno , Rickenbach Martin , Furrer Hansjakob , Battegay Manuel , Hirschel Bernard , Tarr Philip E , Opravil Milos , Bernasconi Enos , Schmid Patrick , Weber Rainer 
Published: April 2022

Background Morbidity and mortality of individuals co-infected with HIV and hepatitis C virus (HCV) is often determined by the course of their HCV infection. Only a selected proportion of those in need of HCV treatment are studied in randomized controlled trials (RCTs). We analysed the prevalence of HCV infection in a large cohort, the number of individuals requiring treatment, the eligibility for HCV treatment, and the outcome of the combination therapy with pegylated interferon-α and ribavirin in routine practice. Methods We analysed prescription patterns of HCV treatment and treatment outcomes among participants from the Swiss HIV Cohort Study with detectable hepatitis C viraemia (between January 2001 and October 2004). Efficacy was measured by the number of patients with undetectable HCV RNA at the end of therapy (EOTR) and at 6 months after treatment termination (SVR). Intention-to-continue-treatment principles were used. Results A total of 2,150 of 7,048 (30.5%) participants were coinfected with HCV; HCV RNA was detected in 60%, and not assessed in 26% of HCV-antibody-positive individuals. One hundred and sixty (12.5%) of HCV-RNA-positive patients started treatment. In patients infected with HCV genotypes 1/4 or 2/3, EOTR was achieved in 43.3% and 81.2% of patients, respectively, and SVR rates were 28.4% and 51.8%, respectively. More than 50% of the HCV-treated patients would have been excluded from two large published RCTs due to demographic, clinical and laboratory criteria. Conclusions Despite clinical and psychosocial obstacles encountered in clinical practice, HCV treatment in HIV-coinfected individuals is feasible with results similar to those obtained in RCTs.
Evidence of Differential Selection of HIV-1 Variants Carrying Drug-Resistant Mutations in Seroconverters
Authors: Corvasce Stefano , Violin Michela , Romano Laura , Razzolini Francesca , Vicenti Ilaria , Galli Andrea , Duca Piergiorgio , Caramma Ilaria , Balotta Claudia , Zazzi Maurizio 
Published: April 2022

Objectives To estimate the relative efficiency of transmission of different HIV-1 drug-resistance mutations from patients failing treatment, considered as potential transmitters (PTs), to seroconverters (SCs). Design Ecological cross-sectional study. Methods HIV-1 protease and reverse transcriptase (RT) sequence data, obtained from 155 SCs and 2,690 PTs at the Department of Molecular Biology of the University of Siena, Italy, in the period 1997–2004 were used. The efficiency of transmission was studied by odds ratio (OR) analysis and evaluation of 95% confidence intervals (95% CIs). For mutations not detected in viruses from SCs, a binomial probability model was used, assuming P-values <0.05 as indicative of a negative selection at transmission. Results The overall prevalence of drug mutations associated with nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs) and protease inhibitors (PIs) was 13.2%, 4.6% and 2.0% in SCs, and 69.9%, 27.6% and 33.7% in PTs, respectively. Among RT mutations present both in PTs and SCs, M184I/V and T215F/Y had the lowest relative efficiency of transmission, whereas V118I, Y181C/I and K219E/Q showed the highest relative efficiency. Of the three major protease mutations that could be evaluated by this approach, M46I/L had a lower rate of transmission than I84V and L90M. Among the mutations not detected in viruses from SCs, the RT E44D, V108I, Q151M and Y188C/H/L, and the protease D30N, G48V and V82A/F/S/T substitutions appeared to be negatively selected. Conclusions The transmission rate of drug-resistant HIV-1 variants may be differentially affected by the mutational pattern. The binomial model enabled to evaluate the negative selection against specific substitutions. Given the low prevalence of some resistance mutations in SCs, very large data sets are required to evaluate the potential selection of such mutations.
Association of Apolipoproteins C3 and E with Metabolic Changes in HIV-Infected Adults Treated with a Protease-Inhibitor-Containing Antiretroviral Therapy
Authors: Bard Jean-Marie , Lassalle Régis , Capeau Jacqueline , Bach-Ngohou Kalyane , Nazih-Sanderson Françoise , Rémy Gérard , Reynes Jacques , Ecobichon Jean-Luc , Savès Marianne , Raffi François 
Published: April 2022

Objective To examine the relationship between plasma levels of apolipoproteins C3 (APOC3) and E (APOE) and the presence of lipid and carbohydrate metabolism abnormalities or clinical signs of lipodystrophy in HIV-1-infected patients started with a protease-inhibitor-containing antiretroviral therapy. Methods The Aproco (Antiproteases Cohort) Study enrolled 1,181 HIV-1-infected adults in 47 French healthcare centres from May 1997 to June 1998. From December 1998 through July 1999, the APROCO-Metabolic Complications (APROCO-MC) cross-sectional study was performed at the month 20 visit for those patients enrolled in 1997 and at the month 12 visit for those enrolled in 1998. The current analysis presents results from a subset of patients who had undergone additional tests to measure APOC3 and APOE in order to study their relationship with metabolic syndrome ( n=157) and abnormal results in an oral glucose tolerance test ( n=135). Results Increases in triglycerides and non-high-density lipoprotein (HDL) cholesterol were associated with significantly higher levels of APOC3, in both Lp B (lipoproteins containing apolipoprotein B) and Lp non-B (lipoproteins free of apolipoprotein B), and a significant higher level of APOE Lp B. APOC3 and APOC3 Lp non-B were increased when glucose metabolism abnormalities were more severe. The presence of a metabolic syndrome was associated with increased plasma APOC3, APOC3 Lp B and APOC3 Lp non-B levels. In a multiple regression analysis, high levels of APOC3 in Lp B and APOC3 Lp non-B were associated with the presence of clinical signs of lipodystrophy, even after adjustment for triglycerides and HDL-cholesterol levels. Conclusions Lipid and/or glucose metabolism abnormalities in treated HIV-1-infected patients are associated with increased levels of APOC3 and, to a lesser extent, APOE plasma concentrations. Increased values are also related to clinical signs of insulin resistance and lipodystrophy.
Change in T-Lymphocyte Count after Initiation of Highly Active Antiretroviral Therapy in HIV-Infected Patients with History of Mycobacterium Avium Complex Infection
Authors: Lazaro Estibaliz , Coureau Gaelle , Guedj Jérémie , Blanco Patrick , Pellegrin Isabelle , Commenges Daniel , Dabis François , Moreau Jean-François , Pellegrin Jean-Luc , Thiébaut Rodolphe 
Published: April 2022

Objective To compare changes in CD4+, CD8+ and total lymphocyte counts after initiation of highly active anti-retroviral therapy (HAART) between HIV-infected patients with and without a recent history of Mycobacterium avium complex (MAC) infection. Method Matched exposed-non-exposed retrospective cohort study. Results Fifty-one patients with a recent history of MAC infection (MAC+) started a combination of at least three antiretroviral drugs. They were individually matched to 145 patients without any history of MAC infection (MAC-) according to CD4+ T-cell count (±30 cells/mm3), previous experience of antiretroviral treatment, AIDS clinical stage at the time of HAART initiation (baseline), age (±10 years) and gender. MAC+ and MAC- patients presented comparable median levels of total lymphocytes (488 vs 688/mm3, P=0.09), CD4+ (11 vs 16/mm3, P=0.15), CD8+ count (359 vs 386/mm3, P=0.39) and plasma HIV RNA (5.3 vs 5.1 log10 copies/ml, P=0.22) at baseline. After 6 months on HAART, the median increase of CD4+ T-cell count was 28 cells/mm3 (interquartile range [IQR]: 1–63) in MAC+ and 72 cells/mm3 (IQR: 34–120) in MAC- patients ( P<0.0001), whereas the percentage of CD4+ T cells was not significantly different between the two groups ( P=0.13). Comparable differences were observed for total lymphocytes and CD8+ T cells ( P<0.001). The 6 months decline of plasma HIV RNA was not significantly different according to MAC exposure (-1.6 in MAC+ vs -1.8 log10 copies/ml in MAC- patients, P=0.65). Results were confirmed after adjustment for other characteristics than the matching variables and after taking into account potential informative bias due to unbalanced number of deaths between the two groups. Conclusion MAC infection at the time of HAART initiation is an important deleterious factor for immune reconstitution. A better understanding of the underlying mechanism and an evaluation of additional treatment strategies are necessary to help immune restoration in such circumstances.
Influence of Hepatitis C Genotypes on Lipid Levels in HIV-Positive Patients during Highly Active Antiretroviral Therapy
Authors: Lapadula Giuseppe , Torti Carlo , Paraninfo Giuseppe , Castelnuovo Filippo , Uccelli Maria Cristina , Costarelli Silvia , Ladisa Nicoletta , Maserati Renato , Pietro Massimo Di , Silvestri Annalisa De , Tinelli Carmine , Puoti Massimo , Carosi Giampiero 
Published: April 2022

Background The independent role of HCV genotype a3 (HCV-3) in dyslipidaemia following highly active anti-retroviral therapy (HAART) is still unexplored. Methods Analysis of data from a cohort of 307 HIV/HCV-coinfected patients and 415 HIV-monoin-fected controls was conducted. Patients with available lipid levels at baseline and minimum 3-month follow-up were ranked into three groups by HCV status (HCV-3, other HCV genotypes or HCV negative). Univariate and multivariate GEE models were performed to assess factors correlated with lipid serum levels as coefficient (Coef., defined as mean difference [mg/dl] across the follow-up). Univariate and multivariate logistic regression analyses were performed for prediction of relevant hypertriglyceridaemia (≥500 mg/dl) and relevant hyper-cholesterolaemia (≥240 mg/dl) at 3 months of follow-up. Results HCV-3 correlated with lower triglyceridaemia (Coef.=-38.22; P=0.001), independently from the other considered variables, including age, gender and use of stavudine or lopinavir. Even though HCV infection per se appeared to be protective, HCV-3 in particular was also independently associated with lower choles-terolaemia (Coef.=-46.35; P<0.001). At logistic regression analyses, HCV-3, but not HCV-non-3, was associated with lower risk of relevant hypercholestero-laemia (odds ratio [OR] 0.06; P=0.01) and relevant hypertriglyceridaemia (OR 0.11; P=0.05), independently from other considered variables. Conclusions Our data confirm that HCV coinfection per se is associated with lower risk of hypercholestero-laemia after HAART. This effect was particularly attributed to HCV-3, which was the only genotype associated with lower triglyceridaemia during HAART.
Virological Responses to Atazanavir–Ritonavir-Based Regimens: Resistance-Substitutions Score and Pharmacokinetic Parameters (Reyaphar Study)
Authors: Pellegrin Isabelle , Breilh Dominique , Ragnaud Jean-Marie , Boucher Sébastien , Neau Didier , Fleury Hervé , Schrive Marie-Hélène , Saux Marie-Claude , Pellegrin Jean-Luc , Lazaro Estibaliz , Vray Muriel 
Published: April 2022

Objective To assess the impact of baseline HIV-1 substitutions, individual pharmacokinetic (PK) parameters (Cmin, Cmax, area under the curve [AUC0→24 h]) and genotype-inhibitory quotient (GIQ) on virological responses (VR) to atazanavir-ritonavir (300 mg/100 mg)-based highly active antiretroviral therapy (HAART) in 71 antiretroviral-experienced, atazanavir-naive patients in virological failure (VF) on HAART. Methodology VR was defined as HIV RNA <1.7 log10 copies/ml at week 12 (W12). A clinically relevant genotype-substitutions score for atazanavir-ritonavir was developed and validated (Reyaphar substitutions score). Previously published substitutions scores were also tested. Results Patients had a median (Q1; Q3) of 6 (3; 8) previous treatment lines during 9 (7; 11) years. Baseline (W0) values were as follows: 262 (187; 435) CD4+/μl, 3.9 (2.6; 4.9) log10 HIV-1 RNA copies/ml, 4 (2; 6) protease substitutions and 3 (1; 4) NRTI-related substitutions. Respective steady-state Cmin, Cmax and AUC0→24h were 300 (200; 700) ng/ml, 620 (430; 750) ng/ml and 78,000 (61,000; 94,000) ng.h/ml. At W12, 49% of the patients had VR with a median decrease of -1.2 (-0.5; -2.3) log10 HIV-1 RNA copies/ml. The Reyaphar score included 12 baseline protease substitutions from the International AIDS Society USA list that were associated with poorer VR: L10I/F/R/V, K20I/M/R, L24I, M46I/L, I54L/M/T/V, L63P, A71I/L/V/T, G73A/C/F/T, V77I, V82A/F/S/T, I84V, L90M and the polymorphism substitution Q58E. Comparing <5 versus ≥5 Reyaphar substitutions, the W12-W0 HIV-1 RNA decrease was -1.4 (-0.7; -2.3) versus -0.5 (-1.2; +0.5) log10 copies/ml ( P=0.009) with VR in 63% versus 11% ( P<10–4), respectively. This score predicted VF at W12 with 46% sensitivity, compared to 33% and 28% for the ANRS 2004 and 2005 scores. PK parameters alone were not associated with VR, but GIQ was associated with virological outcome ( P=0.04). I50L, known to be correlated with atazanavir-specific resistance, emerged in 2 (8%) of the 24 failing patients with paired genotypes at W0 and VF. Conclusions These findings highlight the need to cross-validate genotype-based algorithms to interpret substitution impact on virological outcome using different patient databases before their implementation in routine clinical practice.
Amino Acid Variations in Hepatitis C Virus P7 and Sensitivity to Antiviral Combination Therapy with Amantadine in Chronic Hepatitis C
Authors: Mihm Ulrike , Grigorian Natalia , Welsch Christoph , Herrmann Eva , Kronenberger Bernd , Teuber Gerlinde , von Wagner Michael , Hofmann Wolf-Peter , Albrecht Mario , Lengauer Thomas , Zeuzem Stefan , Sarrazin Christoph 
Published: April 2022

Background Formation of transmembrane ion channels by hepatitis C virus (HCV) p7 and abrogation of channel function by amantadine was demonstrated in vitro. The relevance of HCV p7 amino acid (aa) variations for response to antiviral therapy with amantadine is unknown. Methods HCV p7 was sequenced in 86 individuals who were infected with HCV genotype 1. Thirty-six of 86 patients received amantadine within an interferon-α (IFN-α)-based antiviral therapy. Helical wheel modelling for HCV p7 was performed. Results No significant correlation of overall aa variations within HCV p7 was observed with response to IFN-α-based therapy with amantadine in HCV genotype 1a/b infected patients. When analysis was restricted to non-conservative aa variations, a higher number of aa substitutions within complete HCV p7 and transmem-brane helix 2 was associated with non-response in HCV-1b-infected patients receiving therapy with amantadine ( P=0.015 and P=0.037, respectively), without amantadine ( P=0.106 and P=0.118, respectively), and in the total cohort of HCV-1b-infected patients ( P=0.00007 and P=0.011, respectively). Furthermore, substitution L20F was observed more often in non-responders than responders with HCV-1b infection and therapy with amantadine ( P=0.099). By in silico modelling, aa 20 was located toward the p7 channel lumen. Substitution L20F may impair amantadine action by altering the shape of the ion channel pore. Conclusion Substitution L20F within HCV p7 may be associated with non-response to combination therapy specifically with amantadine in HCV-1b-infected patients. Non-responders with HCV-1b infection showed higher numbers of non-conservative aa variations within HCV p7 than responders, irrespective of the application of amantadine.