bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contribution of Nucleoside-Analogue Reverse Transcriptase Inhibitor Therapy to Lipoatrophy from the Population to the Cellular Level
Authors: Nolan David , Hammond Emma , James Ian , McKinnon Elizabeth , Mallal Simon 
Published: April 2022

Objectives It has been proposed that the contribution of nucleoside-analogue reverse transcriptase inhibitor (NRTI) therapy to subcutaneous fat wasting involves adipose tissue-specific mitochondrial DNA toxicity. We have investigated the relationships between NRTI therapy, adipocyte mitochondrial DNA content, evidence of toxicity in adipose tissue and fat wasting in Caucasian male Western Australian HIV Cohort study participants. Methods: Longitudinal mixed effects analysis of fat wasting was undertaken in individuals receiving initial stavudine- or zidovudine-containing highly active anti-retroviral therapy (HAART) ( n=49, 149 DEXA measurements). Adipocyte mitochondrial DNA (mtDNA) depletion was also assessed according to current NRTI therapy in 92 subcutaneous fat biopsies from 69 HIV-positive individuals and seven healthy controls, and results were correlated with fat wasting among a subset of patients with biopsy data receiving initial stavudine-or zidovudine-containing HAART ( n=22, 103 DEXA measurements). Confocal microscopy was performed in 22 biopsy samples obtained before and after initiating/switching NRTI therapy. Results Stavudine therapy was associated with more severe adipocyte mitochondrial DNA depletion ( P<0.001) and fat wasting over time ( P=0.002) compared with zidovudine therapy in independent analyses. Among patients with concurrent biopsy and longitudinal DEXA data, fat wasting was associated with duration of NRTI therapy ( P=0.001) and adipocyte mtDNA copies/cell ( P=0.01). In this analysis, the significant association between choice of stavudine versus zidovudine and fat wasting ( P=0.03) was lost after adjustment for the effect of mtDNA depletion ( P=0.13). Confocal analysis provided direct evidence of a relationship between severity of adipose tissue toxicity and mitochondrial DNA depletion. No significant effects of HIV protease inhibitor therapy were detected in these analyses. Conclusions Severity of subcutaneous fat wasting is primarily determined by choice of NRTI therapy (stavudine versus zidovudine) and by duration of exposure to the relevant NRTI. At the cellular level, evidence is provided that this effect manifests through NRTI-induced mitochondrial DNA depletion.
Mitochondrial Effects of Antiretroviral Therapies in Asymptomatic Patients
Authors: López Sònia , Miró Òscar , Martínez Esteban , Pedrol Enric , Rodríguez-Santiago Benjamín , Milinkovic Ana , Soler Anna , García-Viejo Miguel A , Nunes Virginia , Casademont Jordi , Gatell Josep M , Cardellach Francesc 
Published: April 2022

Background A decrease in the mitochondrial (mt) DNA to nuclear DNA ratio has gained acceptance as a marker of mitochondrial toxicity in treated HIV-infected patients, but the functional meaning of this alteration is unclear. Methods We assessed mtDNA content, mitochondrial content and function in peripheral blood mononuclear cells (PBMCs) of consecutive asymptomatic HIV-infected patients. Patients selected had been receiving a first-line highly active antiretroviral therapy (HAART) regimen for at least 6 months, consisting of zidovudine plus lamivudine or stavudine plus didanosine plus either nelfinavir or nevirapine, or were antiretroviral-naive. The mtDNA content was assessed by quantitative real-time PCR, mitochondrial content by citrate synthase activity, enzyme activity of complexes III and IV (both partially encoded by mtDNA) of the electron transport chain by spectrophotometry, oxygen consumption by polarography, and oxidative damage in cell membranes by monitoring cis-parinaric acid fluorescence. Results Mitochondrial content was significantly lower in all treated groups. Patients receiving stavudine plus didanosine had mtDNA depletion and a decrease in complex IV activity. However, oxygen consumption capacity and lipid peroxidation were unaffected in all groups. Conclusion Long-term HAART may induce mitochondrial abnormalities in PBMC mitochondria, which do not necessarily translate into functional abnormalities, at least in asymptomatic patients. This study was presented in the 4th International Workshop on Adverse Drug Reactions & Lipodystrophy in HIV (San Diego, Calif., USA, September 2002) and in ‘Late Breakers & Hot Topics’ session in the 6th International Congress on Drug Therapy in HIV Infection (Glasgow, UK, November 2002).
Immune Restoration in HIV-Positive, Antiretroviral-Naive Patients after 1 Year of Zidovudine/Lamivudine plus Nelfinavir or Nevirapine
Authors: Plana Montserrat , Ferrer Elena , Martínez Catalina , Podzamczer Daniel , García Felipe , Maleno María J , Barceló Juan J , García Ana , Barberá María J , Lacarcel Montserrat , Miró José M , Gallart Teresa , Gatell José M 
Published: April 2022

Objectives To evaluate the immunological response in HIV-1-infected, antiretroviral-naive patients receiving highly active antiretroviral therapy regimen of two nucleosides plus a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor. Design and methods Of 142 patients included in a randomized, open, multicentre trial comparing zidovudine/lamivudine plus nelfinavir (NFV) or nevirapine (NVP), 36 patients (16 NFV, 20 NVP) were enrolled in an immunological substudy. Mean baseline CD4 T-cell counts was 360/mm3 (range: 11–679) and mean baseline plasma viral load >50 000 copies/ml (range: 2240–1468210). Viral load (VL), T-cell subsets and T-cell functions were analysed at baseline and after 1 year of treatment. Results After 12 months of follow-up, plasma viral load was reduced similarly in both groups, with 78% (NFV) and 83% (NVP) of patients achieving a VL <200 copies/ml. A significant increase in CD4 T cells was observed in both groups (mean: +182 cells, P=0.001). Both regimens were similarly effective in reducing activated T cells (CD38 and DR). A significant increase of both CD4 and CD8 CD28 T cells occurred in both arms of treatment. Patients of both regimens showed a significant decrease of activated memory (CD45RA–CD45RO+) CD8 T cells and a clear increase of naive (CD45RA+CD45RO-) CD8 T cells. Peripheral blood mononuclear cell proliferative responses to polyclonal stimuli (CD3 and CD3 +CD28) as well as to ubiquitous cytomegalovirus antigen increased significantly in both groups after 12 months of follow-up. Nevertheless, neither at baseline nor after 1 year of treatment, these patients showed any significant T-cell responsiveness to HIV-1 recombinant proteins gp160 or p24. Conclusions Our data indicate that immune restoration achieved after 1 year of therapy with either NFV or NVP was similar. This reinforces the role of NVP-containing regimens as a valid option for initiating antiretroviral therapy. Nevertheless, additional therapeutic approaches should be envisaged to restore HIV-1-specific T-cell responses.
Comparison of Two Reduced-Dose Regimens of Indinavir (600 Mg Vs 400 Mg Twice Daily) and Ritonavir (100 Mg Twice Daily) in Healthy Volunteers (Coredir)
Authors: Wasmuth Jan-Christian , la Porte Charles JL , Schneider Katrin , Burger David M , Rockstroh Juergen K 
Published: April 2022

Objective To assess the pharmacokinetics and tolerability of reduced dosages of twice daily indinavir (IDV) boosted by low-dose ritonavir (RTV) in healthy volunteers. Methods Pharmacokinetics and tolerability of IDV/RTV twice daily (600/100 mg and 400/100 mg) were assessed in a randomized crossover design in 16 healthy volunteers. Each dosage was taken twice daily for 2 weeks before 12 h pharmacokinetics were obtained. Results Sixteen subjects were included, with a mean age ±SD of 30 ±4 years; seven female, nine male. Fifteen subjects completed the study. After dose reduction of IDV AUC, Cmax and Cmin decreased significantly. In the 400 mg group three out of 15 subjects had IDV levels below 0.10 mg/l vs none in the 600 mg group. All subjects reported mild to moderate side effects throughout the study period, which were more severe in the 600 mg group (mostly renal, dry skin/lips, paresthesias/oral discomfort). In the 600 mg group four subjects reported dysuria and one subject discontinued because of flank pain, whereas two subjects reported dysuria and no subject discontinued in the 400 mg group, respectively. Eight subjects developed crystalluria without a significant difference between both groups. No significant change in serum creatinine was observed. Conclusions IDV/RTV 400/100 mg twice daily resulted in significant lower IDV exposure, with three out of 15 subjects revealing Cmin values below the recommended threshold for wild-type virus of 0.10 mg/l. Tolerability, however, was lower in the 600 mg IDV group. Therapeutic drug monitoring in the individual patient appears to be necessary to guarantee appropriate drug levels and simultaneously minimize toxicity. Presented in part at the 6th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland, UK, November 2002. Abstract P182.
Long-Term Virological Response to Multiple Sequential Regimens of Highly Active Antiretroviral Therapy for HIV Infection
Authors:   the Study Swiss HIV Cohort, Kaufmann Gilbert R , Khanna Nina , Weber Rainer , Perrin Luc , Furrer Hansjakob , Cavassini Matthias , Ledergerber Bruno , Vernazza Pietro , Bernasconi Enos , Rickenbach Martin , Hirschel Bernard , Battegay Manuel , Bachmann S , Battegay M , Bernasconi E , Bucher H , Burgisser Ph , Cattacin S , Egger M , Erb P , Fierz W , Fischer M , Flepp M , Fontana A , Francioli P , Furrer HJ , Gorgievski M , Gunthard H , Hirschel B , Kaiser L , Kind C , Klimkait Th , Ledergerber B , Lauper U , Opravil M , Paccaud F , Pantaleo G , Perrin L , Piffaretti C , Rickenbach M , Rudin C , Schupbach J , Speck R , Telenti A , Trkola A , Vernazza P , Weber R , Yerly S 
Published: April 2022

Objective Information about the virological response to sequential highly active antiretroviral therapy (HAART) for HIV infection is limited. The virological response to four consecutive therapies was evaluated in the Swiss HIV Cohort. Design Retrospective analysis in an observational cohort. Methods 1140 individuals receiving uninterrupted HAART for 4.8 ±0.6 years were included. The virological response was classified as success (<400 copies/ml), low-level (LF: 400–5000 copies/ml) or high-level failure (HF: >5000 copies/ml). Potential determinants of the virological response, including patient demographics, treatment history and virological response to previous HAART regimens were analysed using survival and logistic regression analyses. Results 40.1% failed virologically on the first (22.0% LF; 18.1% HF), 35.1% on the second (14.2% LF; 20.9% HF), 34.2% on the third (9.9% LF; 24.3% HF) and 32.7% on the fourth HAART regimen (9% LF; 23.7% HF). Nucleoside pre-treatment (OR: 2.34; 95% CI: 1.67–3.29) and low baseline CD4 T-cell count (OR: 0.79/100 cells rise; 95% CI: 0.72–0.88) increased the risk of HF on the first HAART. Virological failure on HAART with HIV-1 RNA levels exceeding 1000 copies/ml predicted a poor virological response to subsequent HAART regimens. A switch from a protease inhibitor- to a non-nucleoside reverse transcriptase inhibitor-containing regimen significantly reduced the risk of HF. Multiple switches of HAART did not affect the recovery of CD4 T lymphocytes. Conclusion Multiple sequential HAART regimens do not per se reduce the likelihood of long-term virological suppression and immunological recovery. However, early virological failure increases significantly the risk of subsequent unfavourable virological responses. The choice of a potent initial antiretroviral drug regimen is therefore critical. This study has been presented in part at the 10th Conference on Retroviruses & Opportunistic Infections. Boston, Mass., USA, 2003. Abstract #571.
Adherence to Antiretroviral Therapy and Cd4 T-Cell Count Responses among HIV-Infected Injection Drug Users
Authors: Wood Evan , Montaner Julio SG , Yip Benita , Tyndall Mark W , Schechter Martin T , O'Shaughnessy Michael V , Hogg Robert S 
Published: April 2022

Objective To evaluate the time to CD4 cell count response (≥50 cells/mm3) among patients initiating highly active antiretroviral therapy (HAART) with and without a history of injection drug use, and to examine the potential role of non-adherence to HAART on differential CD4 responses. Methods Population-based analysis of treatment-naive patients initiating HAART during the period 1 August 1996 to 31 July 2000 and who were followed until 31 March 2002. Patients were stratified based on 95% adherence and history of injection drug use, and Kaplan-Meier methods and Cox regression were used to evaluate CD4 response rates and factors associated with CD4 responses. Results Overall, the CD4 cell count response rate was slower among injection drug users in Kaplan-Meier analyses (log-rank: P<0.05). However, no differences existed when the analyses were restricted to adherent patients (log-rank: P=0.349). Similarly, the differences in the time to CD4 cell count response observed in univariate Cox regression analyses for patients with a history of injection drug use [relative hazard: 0.85 (95% CI: 0.75–0.97)] diminished after adjustment for adherence [adjusted relative hazard: 1.02 (95% CI: 0.89–1.16)]. Conclusion These data demonstrate the importance of adherence on CD4 cell count responses and highlight the need for interventions to improve antiretroviral adherence among injection drug user.
Il-7/Il-7 Receptor System Regulation following Il-2 Immunotherapy in HIV-Infected Patients
Authors: Marchetti Giulia , Meroni Luca , Molteni Chiara , Taskaris Greta , Gazzola Lidia , Galli Massimo , Clerici Mario , Moroni Mauro , Franzetti Fabio , Gori Andrea 
Published: April 2022

Interleukin-2 (IL-2) and IL-7 are the most intriguing molecules in immune-based HIV infection treatment. An in vitro IL-2/IL-7 cross-talk due to IL-2-driven IL-7 receptor-α-chain (IL-7Rα) down-modulation, potentially blocking IL-7 signalling has been described. We investigated the in vivo IL-2 effect on IL-7/IL-7R system, measuring free IL-7, and IL-7Rα CD4 and CD8 in 12 HIV-positive patients enrolled in a randomized IL-2 trial. Compared to HAART alone, IL-2 induced a parallel expansion in total and naive CD4, TRECs and IL-7 plasma levels, with no IL-7Rα CD4 and IL-7Rα CD8 changes ( P>0.05), suggesting that in vivo IL-2 boosts IL-7 production without down-modulating IL-7Rα, preserving IL-7-mediated T-lymphocyte homeostatic regulation. Our data confirm the pivotal role of IL-2 and IL-7 in the regulation of T-lymphocyte homeostasis in HIV infection.
Pharmacokinetics of Once-Daily Saquinavir/Ritonavir in HIV-Infected Subjects: Comparison with the Standard Twice-Daily Regimen
Authors: Boffito Marta , Dickinson Laura , Hill Andrew , Back David , Moyle Graeme , Nelson Mark , Higgs Chris , Fletcher Carl , Mandalia Sundhiya , Gazzard Brian , Pozniak Anton 
Published: April 2022

Objective To evaluate the steady-state pharmacokinetics and safety of two once-daily saquinavir/ritonavir (SQV/RTV) regimens, 1600/100 and 2000/100 mg, in HIV-positive patients. Methods Eighteen HIV-infected adults treated with the standard twice-daily SQV/RTV 1000/100 mg regimen were enrolled in this open-label, two-phase, crossover pharmacokinetic study. The steady-state pharmacokinetics of SQV administered with 100 mg RTV were investigated following once-daily doses of 1600 mg or 2000 mg or a twice-daily dose of 1000 mg. Plasma drug concentrations were determined by high performance liquid chromatography–tandem mass spectrometry and pharmacokinetic parameters were calculated using a non-compartmental model. Results Compared with SQV 1000 mg twice daily, the Cmax of SQV following a 1600 mg and 2000 mg dose increased in a dose-proportional manner [geometric mean (95% CI) 1915 (1656–2850) ng/ml for 1000 mg, 2782 (2249–4330) ng/ml for 1600 mg and 4179 (3429–6105) ng/ml for 2000 mg doses, respectively]. SQV Ctrough values were 539 (453–1011), 106 (76–223) and 231 (75–822) ng/ml, respectively. A SQV Ctrough value greater than 100 ng/ml was achieved in all subjects on the twice-daily regimen, in 9/18 (50%) subjects on the 1600/100 mg once-daily regimen, and in 14/17 (82%) subjects on the 2000/100 mg once-daily regimen. The once-daily regimens were well tolerated, with mild-to-moderate gastrointestinal symptoms being the only events reported by a small number of patients. Conclusion This is the first study to evaluate the pharmacokinetics of once-daily SQV/RTV 2000/100 mg in HIV-infected subjects. Our findings suggest that this regimen may be an alternative to twice-daily 1000/100 mg doses and should be further evaluated in efficacy studies. The data indicate that most patients (14/17) on once-daily 2000/100 mg achieve trough concentrations above target values (determined for HIV wild-type) for efficacy of SQV with the use of just 100 mg RTV/day and with good tolerability.
Salvage Therapy with Amprenavir, Lopinavir and Ritonavir 200 Mg/D or 400 Mg/D in HIV-Infected Patients in Virological Failure
Authors:   the Puzzle 1 Study Group, Raguin Gilles , Chêne Geneviève , Morand-Joubert Laurence , Taburet Anne-Marie , Droz Cécile , Le Tiec Clotilde , Clavel François , Girard Pierre-Marie , Rozenbaum W , Naït-Ighil L , Nguyen TH , Slama L , Girard PM , Molina JM , Sereni D , Colin de Verdière N , Lascoux-Combes C , Pintado C , Ponscarme D , Prevoteau de Clary F , Tourneur M , Bentata M , Guillevin L , Launay O , Mansouri R , Rouges F , Kazatchkine M , Aouba A , Azizi M , Fiessinger JN , Le Houssine P , Sicard D , Bernasconi C , Salmon D , Silbermann B , Cassuto JP , Ceppi C , Poiree Dr , Raguin G , Merad M , Delfraissy JF , Goujard C , Quertainmont Y , Perronne C , de Truchis P , Dupont B , Bresson JL , Calatroni I , Raffi F , Esnault JL , Leautez S 
Published: April 2022

Objectives To compare the antiviral efficacy of a salvage therapy combining lopinavir and amprenavir with 200 mg/d or 400 mg/d ritonavir, together with nucleoside reverse transcriptase inhibitors, over a 26-week period in HIV-infected patients in whom multiple anti-retroviral regimens had failed. Design Phase IIb, randomized, open-label, multicentre trial. Patients were eligible if they had <500 CD4+ cells/mm3 and >4 log10 copies/ml HIV-RNA after treatment with at least two protease inhibitors (PIs) and one non-nucleoside reverse transcriptase inhibitor. Results At baseline ( n=37), the median CD4+ cell count was 207/mm3 and the median plasma HIV-1 RNA level was 4.7 log10 copies/ml; the median number of PI mutations was seven and the median decrease in phenotypic susceptibility to lopinavir and amprenavir was 9.7 and 2.6, respectively. The mean number of antiretrovirals received prior to randomization was 7.7. The fall in the median HIV-1 RNA level at week 26 was -1.4 log10 copies/ml in the 200 mg/d ritonavir group and -2.5 log10 copies/ml in the 400 mg/d group ( P=0.02). Viral load fell below 50 copies/ml in 32% and 61% of patients, respectively ( P=0.07). After adjustment for the ritonavir dose, a smaller number of PI mutations was the only baseline characteristic associated with a better virological response at week 26. Amprenavir concentrations were significantly lower in presence of lopinavir. The lopinavir inhibitory quotient at week 6 correlated weakly with the change in the HIV-RNA level at week 26. Conclusion Combination of amprenavir, lopinavir and 400 mg/d ritonavir shows significant virological efficacy without increased toxicity in HIV-infected patients in whom multiple antiretroviral regimens have failed.
The NIQ of Lopinavir is Predictive of a 48-Week Virological Response in Highly Treatment-Experienced HIV-1-Infected Subjects Treated with a Lopinavir/Ritonavir-Containing Regimen
Authors: Castagna Antonella , Gianotti Nicola , Galli Laura , Danise Anna , Hasson Hamid , Boeri Enzo , Hoetelmans Richard , Nauwelaers David , Lazzarin Adriano 
Published: April 2022

Objective To investigate the normalized inhibitory quotient (NIQ) of lopinavir (LPV) as a predictor of 48-week virological responses to a lopinavir/ritonavir (LPV/RTV)-containing regimen in highly treatment-experienced patients. Design We calculated the NIQ for 59 patients who completed 48 weeks’ treatment and assessed the factors predicting a week-48 virological response. Methods The NIQ was calculated by dividing each subject's IQ (LPV Ctrough/fold change in LPV susceptibility, as assessed by VirtualPhenotype™) by a reference IQ (mean population LPV Ctrough/fold change in LPV IC50, as assessed by VirtualPhenotype™). HIV-1 RNA was assessed by NASBA (quantification limit: 80 copies/ml). The general linear model and multiple logistic regression, respectively, were used to estimate the independent predictors of a change in viral load and HIV-1 RNA <80 copies/ml. Results The median (interquartile range) baseline levels of CD4+ cells and HIV-1 RNA were 251 (141–385) cells/μl and 4.85 (4.49–5.23) log10 copies/ml, respectively. The median NIQ was 2.2 (0.5–14). At week 48, the median decrease in HIV-1 RNA was 1.4 (0.59–2.79) log10 copies/ml ( P<0.0001), with 24 subjects (41%) reaching <80 copies/ml. Baseline HIV-1 RNA ( P=0.001), CD4+ cells ( P=0.002) and NIQ ( P=0.0006) independently predicted the week-48 change in viral load, whereas baseline CD4+ cells ( P=0.011) and NIQ ( P=0.009) independently predicted a week-48 HIV-1 RNA level of <80 copies/ml. Conclusion The LPV NIQ independently predicts virological responses to an LPV/RTV-containing regimen in highly treatment-experienced HIV-1-infected patients.
The Correlation between Plasma Concentrations of Protease Inhibitors, Medication Adherence and Virological Outcome in HIV-Infected Patients
Authors:   the California Collaborative Treatment Group (CCTG), Yasuda Julie M , Miller Chris , Currier Judith S , Forthal Donald N , Kemper Carol A , Beall Gildon N , Tilles Jeremiah G , Capparelli Edmund V , McCutchan J Allen , Haubrich Richard H 
Published: April 2022

Background Although adherence clearly influences response to antiretroviral therapy (ART), accurate assessment of adherence is problematic. The objective of this analysis was to assess the independent predictive value of protease inhibitor (PI) concentrations as a supplement to self-report as markers of medication adherence. Methods This retrospective analysis was conducted from a prospective clinical trial designed to compare the outcomes of frequent versus infrequent HIV RNA measurement used to manage antiretroviral therapy. For 131 patients, self-reported medication adherence, HIV RNA levels, CD4 counts and PI concentrations (unannounced, random samples) were measured at baseline (when patients changed to a new regimen) and every 2 months thereafter. The change in HIV RNA from baseline to month 6 (area-based measure) was used to evaluate overall response. The proportion of measured PI concentrations below the detection limit was used as an alternative marker of adherence. An undetectable concentration would be expected after missing a single dose. Results The mean baseline CD4 count was 125 cells/mm3 and the mean HIV RNA level was 4.7 log10 copies/ml. The mean change in log10 HIV RNA was -0.73 copies/ml. The mean percentage of self-reported adherence was 91% (range: 15–100%) and the mean proportion of undetectable PI concentrations was 27% (range: 0–100%, mean 2.5 samples/patient). The correlation between the two measures was -0.23 ( P=0.009). In a multivariate model, percentage of visits with undetectable PI concentrations ( P=0.02), percentage of medication adherence ( P=0.02), baseline HIV RNA level ( P=0.005), prior PI use ( P=0.0004), prior lamivudine (3TC) use ( P=0.0009) and randomization to the frequent HIV RNA measurement group ( P<0.0001) were all related to change in HIV RNA. After accounting for adherence, patients who always had detectable PI concentrations had an average of 0.4 log10 additional HIV RNA reduction compared with those who had no detectable concentrations. Conclusions Repeated, random PI concentration values are independently predictive of virological response and may add to self-report of adherence in understanding the response to ART.