bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship between Changes in Thymic Emigrants and Cell-Associated HIV-1 Dna in HIV-1-Infected Children Initiating Antiretroviral Therapy
Authors:   for the Paediatric European Network for Treatment of AIDS (PENTA), De Rossi Anita , Walker A Sarah , Forni Davide De , Klein Nigel , Gibb Diana M , Aboulker J-P , Babiker A , Compagnucci A , Darbyshire J , Debré M , Gersten M , Giaquinto C , Gibb DM , Jones A , Aboulker J-P , Babiker A , Blanche S , Bohlin A-B , Butler K , Castelli-Gattinara G , Clayden P , Darbyshire J , Debré M , de Groot R , Faye A , Giaquinto C , Gibb DM , Griscelli C , Grosch-Wörner I , Levy J , Lyall H , Mellado Pena M , Nadal D , Peckham C , Ramos Amador JT , Rosado L , Rudin C , Scherpbier H , Sharland M , Tovo PA , Valerius N , Wintergerst U , Boucher C , Clerici M , de Rossi A , Klein N , Loveday C , Muñoz-Fernandez M , Pillay D , Rouzioux C , Babiker A , Darbyshire J , Gibb DM , Harper L , Johnson D , Kelleher P , McGee L , Poland A , Walker AS , Aboulker J-P , Carrière I , Compagnucci A , Debré M , Eliette V , Leonardo S , Moulinier C , Saidi Y , Galli L , Foot A , Kershaw H , Caul O , Tarnow-Mordi W , Petrie J , McIntyre P , Appleyard K , Gibb DM , Novelli V , Klein N , McGee L , Ewen S , Johnson M , Gibb DM , Cooper E , Fisher T , Barrie R , Norman J , King D , Larsson-Sciard E-L 
Published: April 2022

Objectives and methods To investigate the relationship between cell-associated HIV-1 dynamics and recent thymic T-cell emigrants, HIV-1 DNA and T-cell receptor rearrangement excision circles (TREC, a marker of recent thymic emigrants) were measured in peripheral blood mononuclear cells in 181 samples from 33 HIV-1-infected children followed for 96 weeks after antiretroviral therapy (ART) initiation. Results At baseline, HIV-1 DNA was higher in children with higher TREC ( P=0.02) and was not related to age, CD4 or HIV-1 RNA in multivariate analyses ( P>0.3). Overall, TREC increased and HIV-1 DNA decreased significantly after ART initiation, with faster HIV-1 DNA declines in children with higher baseline TREC ( P=0.009). The greatest decreases in HIV-1 DNA occurred in children with the smallest increases in TREC levels during ART ( P=0.002). However, this inverse relationship between changes in HIV-1 DNA and TREC tended to vary according to the phase of HIV-1 RNA decline ( P=0.13); for the same increase in TREC, HIV-1 DNA decline was much smaller during persistent or transient viraemia compared with stable HIV-1 RNA suppression. Conclusions Overall, these findings indicate that TREC levels predict HIV-1 DNA response to ART and suggest that immune repopulation by thymic emigrants adversely affects HIV-1 DNA decline in the absence of persistent viral suppression, possibly by providing a cellular source for viral infection and replication.
HIV-1 Infection Leads to Increased HLA-E Expression Resulting in Impaired Function of Natural Killer Cells
Authors: Nattermann Jacob , Nischalke Hans Dieter , Hofmeister Valeska , Kupfer Bernd , Ahlenstiel Golo , Feldmann Georg , Rockstroh Jürgen , Weiss Elisabeth H , Sauerbruch Tilman , Spengler Ulrich 
Published: April 2022

HIV has evolved several strategies to evade recognition by the host immune system including down-regulation of major histocompatibility complex (MHC) class I molecules. However, reduced expression of MHC class I molecules may stimulate natural killer (NK) cell lysis in cells of haematopoietic lineage. Here, we describe how HIV counteracts stimulation of NK cells by stabilizing surface expression of the non-classical MHC class I molecule, HLA-E. We demonstrate enhanced expression of HLA-E on lymphocytes from HIV-infected patients and show that in vitro infection of lymphocytes with HIV results in up-regulation of HLA-E expression and reduced susceptibility to NK cell cytotoxicity. Using HLA-E transfected K-562 cells, we identified the well-known HIV T-cell epitope p24 aa14-22a as a ligand for HLA-E that stabilizes surface expression of HLA-E, favouring inhibition of NK cell cytotoxicity. These results propose HIV-mediated up-regulation of HLA-E expression as an additional evasion strategy targeting the antiviral activities of NK cells, which may contribute to the capability of the virus in establishing chronic infection.
Impact of Human Immunodeficiency Virus Type 1 Subtype on First-Line Antiretroviral Therapy Effectiveness
Authors: Bocket Laurence , Cheret Antoine , Deuffic-Burban Sylvie , Choisy Philippe , Gerard Yann , de la Tribonnière Xavier , Viget Nathalie , Ajana Faïzo , Goffard Anne , Barin Francis , Mouton Yves , Yazdanpanah Yazdan 
Published: April 2022

Objective The effectiveness of antiretroviral treatment (ART) was compared in 416 naive patients from a French clinical cohort infected with B and non-B HIV-1 subtypes. Methods Time to HIV viral load (VL) undetectability was calculated for each subtype group. Three other parameters were estimated 3, 6 and 12 months after enrolment: clinical progression (that is, AIDS-defining events or death), changes in CD4 cell counts from baseline and proportion of patients achieving an undetectable VL (<400 HIV-RNA copies/ml). Results In this cohort, 317 patients (76%) were infected with a B subtype and 99 (24%) with a non-B subtype. Median time to VL undetectability was similar in the B subtype group [147 days, 95% confidence interval (CI) 119–165] and non-B subtype group (168 days, 95% CI: 105–234; P=0.16). After adjusting for AIDS-defining events at enrolment, baseline CD4 cell counts and VL, and for the treatment on which patients were initiated, no association was found between HIV subtypes and time to VL undetectability (B subtype vs non-B subtype: hazard ratio=0.80, 95% CI: 0.62–1.02, P=0.07). In the 3, 6 and 12 months after enrolment, subtype had no impact on clinical progression, CD4 cell count or VL responses to ART. This suggests that B and non-B subtypes do not affect first-line therapy efficacy, which is encouraging in view of the worldwide spread of non-B HIV-1 subtypes and the increasing availability of ART in developing countries. However, in this study we did not take into account individual non-B subtype species, therefore further studies should be designed to evaluate the efficacy of these regimens in patients with particular non-B subtypes.
Plasma Pharmacokinetics of Once- versus Twice-Daily Lamivudine and Abacavir: Simplification of Combination Treatment in HIV-1-Infected Children (Penta-13)
Authors: Bergshoeff Alina , Burger David , Verweij Corrien , Farrelly Laura , Flynn Jacquie , Le Prevost Marthe , Walker Sarah , Novelli Vas , Lyall Hermione , Khoo Saye , Gibb Di 
Published: April 2022

Background There are few data on plasma and intracellular pharmacokinetics (PK) of once-daily (q24h) nucleoside analogues in HIV-infected children. Methods Children aged 2–13 years receiving combination treatment containing lamivudine (3TC) (4 mg/kg) and/or abacavir (ABC) (8 mg/kg) twice daily (q12h) were included in this single-arm, open-label, crossover study. Intensive plasma PK sampling was performed at steady state, after which children switched to q24h dosing and PK sampling was repeated 4 weeks later. Daily area under the curve (AUC0–24) and peak level (Cmax) of q24h and q12h regimens were compared by geometric mean ratios (GMRs) with 90% confidence intervals (CIs). Children were followed for 24 weeks to evaluate safety and virological response. Results 24 children were enrolled, of whom 20 [median age (range) 5.6 (2.1–12.8) years] had evaluable PK data for 3TC ( n=19) and/or ABC ( n=14). GMRs of 3TC and ABC AUC0–24 and Cmax q24h versus q12h significantly exceeded 1.0. GMRs were not significantly different between children aged 2–6 versus 6–13 years old ( P>0.08). Of note, 3TC Cmax values for both q12h and q24h were significantly lower in children aged 2–6 versus 6–13 years old. No child discontinued due to adverse events. At baseline, 16 out of 20 children had a viral load <100 copies/ml compared with 17 out of 19 at week 24. Conclusion AUC0–24 and Cmax of both 3TC and ABC q24h were not inferior to q12h dosing in children. Insufficient results were obtained concerning intracellular levels of the active triphosphate moieties of both agents. Virological data did not indicate a marked difference in antiviral activity between q12h and q24h regimens.
The Steady-State Pharmacokinetics of Nelfinavir in Combination with Tenofovir in HIV-Infected Patients
Authors: Kruse Guido , Esser Stefan , Stocker Hartmut , Breske Antje , Koerber Andreas , Kopperman Maija , Wiehler Heidi , Ross Birgit , Möcklinghoff Christiane , Hill Andrew , Becker Mark , Kurowski Michael 
Published: April 2022

Background The nucleotide analogue, tenofovir, has been shown to lower plasma atazanavir levels in pharmacokinetic trials, an interaction that may be partly reversed by the addition of ritonavir, whereas plasma tenofovir levels are themselves raised when the drug is combined with lopinavir/ritonavir. Objective To investigate the effect of tenofovir coadministration on the steady-state pharmacokinetics of nelfinavir in HIV-infected patients. Methods Eighteen patients received nelfinavir 1250 mg twice daily plus prescribed nucleoside reverse transcriptase inhibitors for at least 14 days, with pharmacokinetic measurements performed on day 15. Treatment with nelfinavir was continued for another 7 days with the addition of 300 mg tenofovir once daily. Pharmacokinetic measurements were repeated on day 22. Plasma samples were analysed by liquid chromatography–tandem mass spectrometry for nelfinavir, its primary metabolite, M8, and tenofovir. The parameters AUC0–12, C0, Cmax and Tmax were compared for nelfinavir with and without tenofovir by calculating geometric mean ratios (GMRs) of the pharmacokinetic parameters with associated 95% confidence intervals (95% CIs). Safety was assessed throughout the study. Results The addition of tenofovir to the nelfinavir-based regimen had no effect on the pharmacokinetics of nelfinavir. The GMR of the nelfinavir AUC0–12 values was 0.97 (95% CI: 0.80–1.17). There was a slight decrease in M8 metabolite (AUC0–12 ratio, 0.87; 95% CI: 0.68–1.11) but this was not significant. No serious adverse events occurred through the study period. Conclusion Nelfinavir does not require dose adjustment when coadministered with tenofovir and appears to be well-tolerated by HIV-infected patients.
The Influence of the M184V Mutation in HIV-1 Reverse Transcriptase on the Virological Outcome of Highly Active Antiretroviral Therapy Regimens with Or without Didanosine
Authors: Sproat Michael , Pozniak Anton L , Peeters Monika , Winters Bart , Hoetelmans Richard , Graham Neil M , Gazzard Brian G 
Published: April 2022

Background In vitro phenotypic resistance studies suggest that the presence of the M184V mutation leads to a reduction in HIV-1 susceptibility to didanosine (ddI). The relevance of this to clinical outcomes remains unclear. In this study, we compared the virological response of ddI- and non-ddI-containing regimens in the presence or absence of the M184V mutation. Methods Data from an observational cohort study of all HIV-1 patients who had phenotypic resistance testing following the emergence of virological failure to an existing highly active antiretroviral therapy (HAART) regimen were analysed. A total of 586 patients entered the study and were followed-up over 48 weeks; 281 (48%) were switched to ddI-containing HAART, of whom 105 had the M184V mutation at baseline. Virological efficacy of combination therapy was studied by reference to average area under the curve of viral load (VL) response and the proportion of patients attaining an undetectable VL (<400 copies/ml). Baseline characteristics and univariate analysis of changes in VL were compared using the Wilcoxon rank sum test. Multivariate analyses were performed using the Van Elteren test. Additional variables included the number of baseline nucleoside reverse transcriptase inhibitor mutations and the number of active antiretroviral drugs given to each group as compared by ‘real phenotype’ resistance test results. Results Amongst patients on ddI-containing HAART, median fold changes in phenotypic susceptibility to ddI were greater in patients with the M184V mutation (fold changes of 2.2 vs 1.2, P<0.001). Nonetheless, the median change in VL and percentage of patients attaining an undetectable VL were similar in those taking ddI, irrespective of whether the M184V mutation was present at baseline. In the group of patients with the M184V mutation at baseline, the virological outcome was significantly better in those treated with ddI-containing HAART than in those on HAART without ddI ( P<0.05). Conclusions While the M184V did increase the fold resistance of HIV to ddI, these changes appeared to be lower than the clinically relevant threshold for phenotypic resistance for this drug.
Influence of Metabolic Syndrome, Viral Genotype and Antiviral Therapy on Superimposed Fatty Liver Disease in Chronic Hepatitis C
Authors: Liu Chun-Jen , Jeng Yung-Ming , Chen Pei-Jer , Lai Ming-Yang , Yang Hung-Chih , Huang Wen-Ling , Kao Jia-Horng , Chen Ding-Shinn 
Published: April 2022

Background/aims The prevalence and clinical implications of non-alcoholic fatty liver disease in patients with chronic hepatitis C remain unknown in Taiwan. Methods We addressed the relevant issues by analysing 95 naive Taiwanese patients infected with either hepatitis C virus (HCV) genotype 1 ( n=57) or 2 ( n=38), receiving interferon alone ( n=41) or in combination with ribavirin ( n=54) therapy. A single pathologist scored steatosis and steatohepatitis at baseline and 24 weeks after antiviral treatment. Results At baseline, steatosis and steatohepatitis were present in 44 (46%) and four (4%) patients, respectively. Variables associated with steatosis in logistical regression were hyperglycaemia ( P=0.01), hypertriglyceridaemia ( P=004) and body mass index ≥27 ( P=0.009), but not HCV genotype or viral load. The grade of steatosis correlated well with the number of metabolic syndrome parameters ( P=0.018). Interferon monotherapy, advanced age and HCV genotype 1, but not steatosis, correlated with lower sustained response rate. After treatment, steatosis improved in 19 and worsened in nine, which also did not correlate with HCV genotype ( P=0.850) or sustained response to antiviral therapy ( P=0.246). Conclusions Hepatic steatosis in Taiwanese patients with chronic hepatitis C was associated with features of the metabolic syndrome, but did not correlate with HCV genotype, advanced fibrosis or the response to antiviral therapy.
The Relationship between Cd4 Cell Count Nadirs and the Toxicity Profiles of Antiretroviral Regimens
Authors: Smith Colette J , Sabin Caroline A , Lampe Fiona C , Shah Sapna , Tyrer Mervyn , Youle Mike S , Cropley Ian , Johnson Margaret A , Phillips Andrew N 
Published: April 2022

Background It has been suggested that a lower pre-highly active antiretroviral therapy (HAART) CD4 count nadir may lead to a greater risk of experiencing HAART-related toxicity. We investigated the relationship between the pre-HAART CD4 count nadir, HAART and the occurrence of laboratory-defined toxicities. Methods Previously antiretroviral-naive individuals starting HAART at the Royal Free Hospital, London, UK, were included. Drug discontinuation, increases in total cholesterol (by >1mmol/l), alanine aspartate transferase/ alanine aminotransferase (AST/ALT) (by >2.5 times the upper limit of normal), bilirubin (by >2.5 times the upper limit of normal), triglycerides (by >1 mmol/l) and decreases in haemoglobin (by >2 g/dl) were assessed. Results 377/847 (45%) individuals starting HAART stopped at least one antiretroviral within the first 48 weeks. Lower CD4 nadirs were not associated with a greater rate of discontinuing antiretrovirals (adjusted hazard ratio (HR)=1.04 per 100 cells/mm3 higher; 95% confidence intervals (CI) 0.99–1.10; P=0.15). 70/297 (24%), 39/192 (20%) and 73/358 (20%) with a CD4 cell nadir of 0–100, 100–200 and 200+ cells/mm3, respectively, stopped for toxicity reasons; 11/297 (4%), 5/192 (3%) and 3/358 (1%) stopped for reasons of insufficient efficacy; 63/297 (21%), 33/192 (17%) and 80/358 (22%) stopped for other reasons ( P=0.1). Reasons for stopping were similar between CD4 nadir groups. Lower CD4 nadirs were not associated with an increased risk of hypercholesterolaemia, anaemia, hypertriglyceridaemia or increases in AST/ALT but were associated with increased incidence of hyperbilirubinaemia (HR=0.67 per 100 cells/mm3 higher; 95% CI 0.49–0.92; P=0.01). Discussion Lower CD4 nadirs were not found to be associated either with discontinuing an antiretroviral or with a higher risk of toxicity, except for an increased risk of experiencing an increase in bilirubin levels.
Therapeutic Drug Monitoring and Drug–Drug Interactions Involving Antiretroviral Drugs
Authors: Boffito Marta , Acosta Edward , Burger David , Fletcher Courtney V , Flexner Charles , Garaffo Rodolphe , Gatti Giorgio , Kurowski Michael , Perno Carlo Federico , Peytavin Gilles , Regazzi Mario , Back David 
Published: April 2022

The consensus of current international guidelines for the treatment of HIV infection is that data on therapeutic drug monitoring (TDM) of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) provide a framework for the implementation of TDM in certain defined scenarios in clinical practice. However, the utility of TDM is considered to be on an individual basis until more data are obtained from large clinical trials showing the benefit of TDM. In April 2004, a panel of experts met for the second time in Rome, Italy. This was following the inaugural meeting in Perugia, Italy, in October 2000, which resulted in the manuscript published in AIDS 2002, 16(Suppl 1):S5–S37. The objectives of this second meeting were to review and update the numerous questions surrounding TDM of antiretroviral drugs and discuss the clinical utility, current concerns and future prospects of drug concentration monitoring in the care of HIV-1-infected individuals. A major focus of the meeting was to discuss and critically analyse recent and precedent clinical drug–drug interaction data to provide a clear framework of the pharmacological basis of how one drug may impact the disposition of another. This report, which has been updated to include material published or presented at international conferences up to the end of December 2004, reviews recent pivotal pharmacokinetic interaction data and provides advice to clinical care providers on how some drug–drug interactions may be prevented, avoided or managed, and, when data are available, on what dose adjustments and interventions should be performed.
A Prospective Study of Efficacy and Safety of Once-Daily Saquinavir/Ritonavir plus Two Nucleoside Reverse Transcriptase Inhibitors in Treatment-Naive Thai Patients
Authors:   for the Staccato Study Group, Phanuphak Praphan , Ubolyam Sasiwimol , Sankote Jongkol , Pongprayoon Patcharee , Saenawat Sukontha , Wicharuk Saijai , Nonenoy Siriporn , Wannachai Natnipa , Chautrakarn Sineenart , Chuenyam Theshinee , Jeanpan Nittaya , Nuchapong Thantip , Jupimai Thidarat , le Braz Michelle , Bunyaprawit Parichat , Putthawong Suchittra , Penglimoon Yaowaluk , Seekaow Napawan , Karakate Wipawan , Khongsawad Sopha , Kiatatchasai Wiphawee , Ananworanich Jintanat , Hill Andrew , Siangphoe Umaporn , Ruxrungtham Kiat , Prasithsirikul Wisit , Chetchotisakd Ploenchan , Kiertiburanakul Sasisopin , Munsakul Warangkana , Raksakulkarn Phitsanu , Tansuphasawadikul Somboon , Nuesch Reto , Cooper David A. , Hirschel Bernard 
Published: April 2022

Objective To assess the efficacy and safety of first-line treatment with once-daily saquinavir/ritonavir with two nucleoside reverse transcriptase inhibitors (NRTIs), as induction therapy before enrollment in a randomized trial of structured treatment interruption strategies. Design Two-hundred antiretroviral-naive patients with CD4+ cell counts between 200–350 at screening were enrolled in this open-label 24week study. Methods Patients were followed up every 8 weeks for CD4+ cells, HIV RNA, and clinical and laboratory toxicities. Results: Two-hundred patients were enrolled with median baseline CD4+ cell count of 267 cells/μl and HIV RNA 50 118 (4.7 log10) copies/ml. After 24 weeks of treatment, 191 of 200 (96%) patients had below 400 copies/ml HIV RNA, with 177/200 (89%) below 50 copies/ml (intent to treat, missing equals failure method), with a median rise in CD4+ cell count of 122 cells/μl. There was no significant correlation between the minimum concentration of saquinavir and HIV RNA reductions at week 8 ( P=0.957) or absolute HIV RNA at week 24 ( P=0.77). Conclusion First-line highly active antiretroviral therapy (HAART) with once-daily saquinavir/ritonavir plus two NRTIs showed strong antiviral efficacy over 24 weeks, and should be evaluated in larger prospective randomized clinical trials.
The Impact of Haematopoietic Growth Factors on the Management and Efficacy of Antiviral Treatment in Patients with Hepatitis C Virus
Authors: Lebray Pascal , Nalpas Bertrand , Vallet-Pichard Anaïs , Broissand Christine , Sobesky Rodolphe , Serpaggi Jeanne , Fontaine Hélèn , Pol Stanislas 
Published: April 2022

Aim To evaluate the benefits of haematopoietic growth factors (HGFs) during the treatment of chronic hepatitis C virus (HCV) infection with severe haematotoxicity. Methods This was a 1-year retrospective study of HCV-positive patients receiving pegylated interferon and ribavirin. Patients received different HGFs, depending on certain criteria: they received erythropoietin (EPO) when their haemoglobin (Hb) levels were less than 10 g/dl and granulocyte colony-stimulating factor (G-CSF) when their neutrophil count was less than 750 cells/mm3. Haematological data, adherence and virological response were analysed and compared according to HGF use. Results In total, 132 patients were studied and 31 (23.5%) required HGF. Under multivariate analysis, baseline Hb levels of less than 13g/dl or a drop in Hb levels of over 2% per week predicted severe anaemia, and a base-line neutrophil count under 2900/mm3 predicted severe neutropaenia. HGF administration restored Hb values and the neutrophil count to above 10 g/dl and 1500 cells/mm3, respectively, in all 31 patients. Adherence to antiviral treatment was achieved in 25% of patients versus 58% of controls without severe haematotoxicity. The primary and sustained virological response did not differ statistically between HGF support and the control group (61% versus 57% and 32% versus 39%, respectively). Conclusion HGF administration counteracts the severe haematological adverse effects which occur during antiviral therapy and maintains the rate of sustained response.