bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tubular Cell Apoptosis and Cidofovir-Induced Acute Renal Failure
Authors: Ortiz Alberto , Justo Pilar , Sanz Ana , Melero Rosa , Caramelo Carlos , Guerrero Manuel Fernández , Strutz Frank , Müller Gerhard , Barat Antonio , Egido Jesús 
Published: April 2022

Cidofovir is an antiviral drug with activity against a wide array of DNA viruses including poxvirus. The therapeutic use of cidofovir is marred by a dose-limiting side effect, nephrotoxicity, leading to proximal tubular cell injury and acute renal failure. Treatment with cidofovir requires the routine use of prophylactic measures. A correct knowledge of the cellular and molecular mechanisms of cidofovir toxicity may lead to the development of alternative prophylactic strategies. We recently cared for a patient with irreversible acute renal failure due to cidofovir. Renal biopsy showed tubular cell apoptosis. Cidofovir induced apoptosis in primary cultures of human proximal tubular cells in a temporal (peak apoptosis at 7 days) and concentration (10–40 μg/ml) pattern consistent with that of clinical toxicity. Apoptosis was identified by the presence of hypodiploid cells, by the exposure of annexin V binding sites and by morphological features and was associated with the appearance of active caspase-3 fragments. Cell death was specific as it was also present in a human proximal tubular epithelial cell line (HK-2), but not in a human kidney fibroblast cell line, and was prevented by probenecid. An inhibitor of caspase-3 (DEVD) prevented cidofovir apoptosis. The survival factors present in serum, insulin-like growth factor-1 and hepatocyte growth factor, were also protective. The present data suggest that apoptosis induction is a mechanism contributing to cidofovir nephrotoxicity. The prophylactic administration of factors with survival activity for tubular epithelium should be further explored in cidofovir renal injury.
Nevirapine and Efavirenz Pharmacokinetics and Covariate Analysis in the 2Nn Study
Authors:   for the 2NN study group, Kappelhoff Bregt S , van Leth Frank , MacGregor Thomas R , Lange Joep MA , Beijnen Jos H , Huitema Alwin DR 
Published: April 2022

Objective The aim of this 2NN pharmacokinetic substudy was to investigate the population pharmacokinetics of nevirapine and efavirenz. Methods Treatment-naive, HIV-1-infected patients received nevirapine (once or twice daily), efavirenz or a combination with lamivudine and stavudine. Blood samples were collected on day 3 and weeks 1, 2, 4, 24 and 48. Using non-linear mixed effects modelling, pharmacokinetics of nevirapine and efavirenz and factors involved in the inter-individual variability were investigated. Results Clearance of nevirapine in the induction phase (<14 days) and at steady state (>28 days) were 2.02 l/h and 2.81 l/h, respectively. Volume of distribution and absorption rate constant were 77.0 l and 1.66 h-1, respectively. Clearance of nevirapine was lower in females (13.8%) and in patients with hepatitis B (19.5%). Patients from South America and Western countries had higher clearance of nevirapine compared with Thai and South African patients. The clearances of efavirenz in the induction phase and at steady state were 7.95 l/h and 8.82 l/h, respectively. The volume of distribution and absorption rate constant were 418 l and 0.287 h-1, respectively. Concomitant use of nevirapine increased clearance of efavirenz (43%). Patients from Thailand had lower clearance than the rest of the population. Conclusions The population pharmacokinetics of nevirapine and efavirenz were assessed in the 2NN trial. For both drugs, an induction phase was distinguished from the steady-state phase. Gender, hepatitis B and geographical region were involved in the variability of the pharmacokinetics of nevirapine. Region and concomitantly used nevirapine were determinants of the pharmacokinetics of efavirenz.
Response to Interferon-Based Therapies in HIV-Infected Patients with Chronic Hepatitis C Due to Genotype 4
Authors: Soriano Vincent , Núñez Marina , Sánchez-Conde Matilde , Barreiro Pablo , García-Samaniego Javier , Martín-Carbonero Luz , Romero Miriam , González-Lahoz Juan 
Published: April 2022

Background The hepatitis C virus (HCV) genotype is the main predictor of response to interferon (IFN)-based therapies. HCV genotype 4 is spreading among European intravenous drug users, who are frequently coinfected with HIV. Information about treatment response in this subset of patients is scarce and conflicting results have been reported. Methods All HIV-infected patients treated for chronic hepatitis C at our institution with a minimum follow-up of 6 months after discontinuing therapy were retrospectively analysed. They had received one of three HCV treatment modalities: IFN monotherapy, IFN plus ribavirin (RBV) or pegylated interferon (PEG-IFN) plus RBV. Treatment responses were stratified according to HCV genotype. Results A total of 390 patients were analysed. Sustained virological response (SVR) to HCV therapy had been reached by 90 (23.1%): 22/119 (18.5%) with IFN monotherapy; 17/106 (16%) with IFN plus RBV; and 51/165 (30.9%) with PEG-IFN plus RBV. SVR was significantly higher among those with HCV genotypes 2 or 3 (40.4%; 61/151) than in patients with either HCV genotype 1 (11.2%; 22/197) or HCV genotype 4 (16.7%; 7/42) ( P<0.0001). In contrast, there were no significant differences in the response rate comparing HCV genotypes 1 and 4 ( P=0.53). Conclusions Response to IFN-based therapies in HIV-positive patients with hepatitis C due to HCV genotype 4 is poor, similar to that obtained for HCV genotype 1 and much lower than for HCV genotypes 2 and 3. Therefore, HIV-infected patients with hepatitis C due to genotype 4 should be considered as a particular subset of difficult-to-treat patients. New treatment strategies and drugs for these patients are eagerly awaited.
Pharmacokinetics of Reduced-Dose Indinavir/Ritonavir 400/100 Mg Twice Daily in HIV-1-Infected Thai Patients
Authors: Boyd Mark , Mootsikapun Piroon , Burger David , Chuenyam Theshinee , Ubolyam Sasiwimol , Mahanontharit Apicha , Sangkote Jongkol , Bunyaprawit Parichart , Horsakulchai Manasinee , Lange Joep , Cooper David , Phanuphak Praphan , Ruxrungtham Kiat 
Published: April 2022

Objective To study the pharmacokinetics of indinavir/ ritonavir 400/100 mg twice daily in antiretroviral-naive patients at Srinagarind Hospital in Khon Kaen, Thailand. Methods This was a steady-state, open-label pharmacokinetic study of 19 patients. A 12 h pharmacokinetic curve was recorded after an overnight fast. Plasma levels of indinavir and ritonavir were determined by a validated HPLC method. Virological failure was defined according to the most recent US Department of Health and Human Services guidelines as a viral load above 400 copies/ml at week 24. Results Median baseline values for CD4 and viral load were 13 cells/mm3 and 167000 copies/ml, respectively. The median (interquartile ranges) for indinavir AUC, Cmax and Cmin were 18.1 (15.3–23.8) mg/l•h, 4.1 (3.6–4.8) mg/l and 0.17 (0.12–0.30) mg/l, respectively. These values represent 37%, 39% and 24% of the AUC, Cmax and Cmin values found, respectively, for the indinavir/ritonavir 800/100 mg dose in HIV-1-infected Thai patients. Short-term virological response was satisfactory. There were three subjects with an indinavir Cmin below the target value of 0.10 mg/l, of whom one had virological failure (33%). Among the other 16 subjects with an indinavir Cmin above 0.10 mg/l, there was also one virological failure (6%) ( P=0.30). Conclusions Indinavir exposure in this reduced-dose regimen of 400 mg with 100 mg ritonavir twice daily was more than dose-proportionally lower than previously observed with the indinavir/ritonavir 800/100 mg twice daily regimen. Therapeutic Cmin levels of indinavir were achieved in >80% of the subjects and short-term virological response was satisfactory in this cohort of patients starting highly active antiretroviral therapy at an advanced disease stage with high baseline viral loads.
Muscle and Liver Lactate Metabolism in Haart-Treated and Naive HIV-Infected Patients: The Mitovir Study
Authors: Ghosn Jade , Guiguet Marguerite , Jardel Claude , Benyaou Rabah , Zeller Valérie , Simon Anne , Valantin Marc-Antoine , Amellal Bahia , Assoumo Lambert , Hogrel Jean-Yves , Costagliola Dominique , Katlama Christine , Lombès Anne 
Published: April 2022

Objective To assess the impact of nucleoside analogue reverse transcriptase inhibitor (NRTI) combination therapy on muscle and liver lactate metabolism in HIV-infected patients. Methods This cross-sectional study involved HIV-infected patients who were either antiretroviral-naive (Group 1) or were receiving either a stable triple-drug combination including at least one d-drug (zidovudine, zalcitabine, stavudine, didanosine; Group 2) or a backbone of abacavir and lamivudine (Group 3). Lactataemia was measured at rest. Muscle lactate metabolism was assessed during a standardized exercise test and liver lactate metabolism during intravenous lactate infusion. Mitochondrial DNA was quantified in peripheral blood mononuclear cells. Results A total of 65 patients were enrolled (16, 31 and 18 patients in Group 1, Group 2 and Group 3, respectively). None of the patients had symptoms of hyperlactataemia. Patients in Group 3 had received d-drugs for a median of seven years before switching to abacavir and lamivudine. Median baseline lactataemia, although within the normal range, was significantly higher in both treatment groups than in the naive patients (Group 2: 1.4, Group 3: 1.5, and Group 1: 1.0 mmol/l, P=0.005). Muscle lactate clearance was significantly lower in both treatment groups than in naive patients (Group 2: 1.6, Group 3: 1.8, and Group 1: 2.1, P=0.01). Lactate liver metabolism and mitochondrial DNA levels did not differ among the three groups. Conclusions In HIV-infected patients without symptomatic hyperlactataemia, all NRTI-containing HAART regimens appear to cause muscle mitochondrial damage but to spare the liver. Absence of difference between Group 2 and Group 3 raises questions about the potential reversibility of muscle mitochondrial dysfunction, and/or the ability of abacavir and lamivudine to induce such mitochondrial damage.
Efficacy and Safety of Once-Daily Combination Therapy with Didanosine, Lamivudine and Nevirapine in Antiretroviral-Naive HIV-Infected Patients
Authors: Ribera Esteban , Rodríguez-Pardo Dolors , Rubio Manuel , Soler Anna , Pedrol Enric , Blanco José L , González Alicia , Crespo Manel , Falcó Vicenç , Ocaña Imma , Deig Elisabeth , Miró Jose M , Pahissa Albert 
Published: April 2022

Background Simplified antiretroviral regimens are needed to improve patient adherence and quality of life. The purpose of this study was to evaluate the efficacy and safety of a once-daily regimen consisting of didanosine (ddI), lamivudine (3TC) and nevirapine (NVP) for adult antiretroviral-naive patients with HIV-1 infection. Methods This was a prospective, one-arm, multicentre pilot study. Daily drug dosage was 250 or 400 mg didanosine, 300 mg lamivudine and 400 mg nevirapine. The primary outcome measure was the percentage of patients with a plasma HIV-RNA level <50 copies/ml at 12 months on an intention-to-treat (ITT) basis. Results Seventy patients were enrolled in the study. At baseline, mean plasma HIV-1 RNA was 5.10 log10 copies/ml, and mean CD4 cell count was 262 cells/μl. At month 12, 67% (95% CI: 56–78) of patients maintained a viral load of <50 copies/ml in the ITT analysis and CD4 counts increased a median of 201 cells/μl. The treatment was more effective in patients with baseline CD4 counts >100 cells/μl than in those with a poorer immunological status at baseline, although the number of patients with CD4 counts <100 was low. Four patients died during the study period. Therapy was discontinued in 18 patients due to virological failure in 11, adverse events in seven, loss to follow-up or withdrawal of consent in four and death in one. Eight out of nine patients with available genotype after virological failure showed resistance mutations to NVP (Y181C and others) and 3TC (M184V/I), and four of them also had ddI resistance (L74V). The lipid profile was favourable, with a decrease in the ratio of total-to-high density lipoprotein cholesterol. Conclusion A once-daily combination of ddI, 3TC and NVP seems to be an effective, safe and easy-to-take regimen in antiretroviral-naive patients, at least in those who do not have severe immunodepression at baseline.
Lipid Profiles for Antiretroviral-Naive Patients Starting Pi- and Nnrti-Based Therapy in the Swiss HIV Cohort Study
Authors:   the Swiss HIV Cohort Study, Young Jim , Weber Rainer , Rickenbach Martin , Furrer Hansjakob , Bernasconi Enos , Hirschel Bernard , Tarr Philip E , Vernazza Pietro , Battegay Manuel , Bucher Heiner C , Battegay M , Bernasconi E , Böni J , Bucher H , Bürgisser Ph , Cattacin S , Cavassini M , Dubs R , Egger M , Elzi L , Erb P , Fantelli K , Fischer M , Flepp M , Fontana A , Francioli P , Furrer H , Gorgievski M , Günthard H , Hirschel B , Kaiser L , Kind C , Klimkait Th , Lauper U , Ledergerber B , Opravil M , Paccaud F , Pantaleo G , Perrin L , Piffaretti J-C , Rudin C , Schmid P , Schüpbach J , Speck R , Telenti A , Trkola A , Vernazza P , Weber R , Yerly S 
Published: April 2022

Background Blood lipid abnormalities in patients on highly active antiretroviral therapy (HAART) have been associated with exposure to protease inhibitors (PIs), particularly ritonavir. First therapy with a non-nucleoside reverse transcriptase inhibitor (NNRTI) leads to relatively favourable lipid profiles. We report on medium-term lipid profiles (up to 5 years) for antiretroviral-naive patients starting NNRTI- and PI-based HAART in the Swiss HIV Cohort Study. Methods Since April 2000, blood samples taken at visits scheduled every 6 months have been analysed for cholesterol and triglyceride concentrations. For 1065 antiretroviral-naive patients starting HAART after April 2000, we estimated changes in concentration over time using multivariate linear regression with adjustment for baseline covariates, use of lipid-lowering drugs and whether the sample was taken in a fasting state. Results Non-high density lipoprotein (HDL) cholesterol levels increase with increasing exposure to either PI- or NNRTI-based therapy, HDL cholesterol levels increase and triglyceride levels decrease with increasing exposure to NNRTI-based therapy, whereas triglyceride levels increase with increasing exposure to PI-based therapy. Between NNRTI-based therapies, there is a slight difference in triglyceride levels, which tend to increase with increasing exposure to efavirenz and to decrease with increasing exposure to nevirapine. Of the three common PI-based therapies, nelfinavir appears to have a relatively favourable lipid profile, with little change with increasing exposure. Of the other two PI therapies, lopinavir with ritonavir has a more favourable profile than indinavir with ritonavir, with smaller increases in both non-HDL cholesterol and triglycerides and an increase in HDL cholesterol. Increasing exposure to abacavir is associated with a decrease in the level of triglycerides. Conclusion In general, NNRTI-based therapy is associated with a more favourable lipid profile than PI-based therapy, but different PI-based therapies are associated with very different lipid profiles. Nelfinavir appears to have a relatively favourable lipid profile. Of the two boosted PI therapies, lopinavir appears to have a more favourable lipid profile than indinavir.
The Prevalence, Clinical Features and Response to Antiviral Therapy of Patients with Chronic Hepatitis C who are Seropositive for Liver–Kidney Microsome Type 1 Antibodies
Authors: Monti Valentina , Aghemo Alessio , Rumi Maria Grazia , Donato Maria Francesca , Ninno Ersilio Del , Colombo Massimo 
Published: April 2022

Background Antibodies to liver–kidney microsome type 1 (anti-LKM-1), which are a marker of autoimmune hepatitis, are found in a minority of patients with chronic hepatitis C virus (HCV) infection. Whether interferon/ribavirin therapy is safe and effective in these patients is unclear. Aim To describe the prevalence, clinical features and response to interferon/ribavirin therapy of anti-LKM-1 seropositive patients with chronic hepatitis C. Patients and methods All anti-LKM-1 seropositive patients with chronic hepatitis C who between 1997 and 2002 underwent a diagnostic liver biopsy at the Liver Center Maggiore Hospital, Milan, were studied. Serum HCV RNA was tested by in-house PCR with a limit sensitivity of 50 IU/ml. Tissue antibodies were assessed by indirect immunofluorescence on cryostat sections from rat liver, kidney and stomach. Liver biopsies were graded and staged by the Ishak score. Autoimmune hepatitis was defined according to the International Autoimmune Hepatitis Grading (IAHG) score. Results Forty-eight (1.8%) of 2675 HCV patients circulated anti-LKM-1 (30 females, 55 years of age). Twenty-eight had genotype 2, 18 genotype 1, and two genotype 3. Aminotransferase levels had been high for 23 ± 12 years, on average. Using IAHG, autoimmune hepatitis was excluded in 44 patients (92%) and found to be probable in 4 patients (8%). Chronic hepatitis was histologically mild in 34 patients (70%), moderate to severe in 7 patients (15%) and with cirrhosis in 7 patients (15%). A sustained virological response (SVR) was achieved in 20 of the 27 patients who received interferon/ribavirin (13 genotype 2c with 87% SVR, and 7 genotype 1b with 58% SVR). None of the patients had serum aminotransferases, immunoglobulins or anti-LKM-1 levels flaring following therapy. Conclusions LKM-1 antibodies rarely occur in patients with chronic hepatitis C and do not predict autoimmune hepatitis, interferon/ribavirin hyporesponsiveness or immune-related reactions to therapy.
Saquinavir 500 mg Film-Coated Tablets Demonstrate Bioequivalence to Saquinavir 200 mg Hard Capsules When Boosted with Twice-Daily Ritonavir in Healthy Volunteers
Authors: Bittner Beate , Riek Myriam , Holmes Beverly , Grange Susan 
Published: April 2022

Objective To establish the bioequivalence of a 500 mg film-coated tablet of saquinavir mesylate (FCT SQV) to the 200 mg hard-capsule saquinavir mesylate (HC SQV), both boosted with ritonavir and administered under fed conditions. Methods We carried out a multi-centre, open-label, randomized, two-sequence, four-period, two-treatment, replicated crossover study in 93 healthy men and 7 healthy women. Individuals were randomly assigned to receive sequential single doses of saquinavir in one of two treatment sequences: ABAB or BABA. Individuals received 100mg ritonavir twice daily for 24 days. On days 14, 17, 20 and 23, study participants took 1000mg of HC SQV (five 200 mg capsules, treatment A) or FCT SQV (two 500 mg tablets, treatment B) with a high-fat, high-calorie breakfast, and pharmacokinetic analyses were carried out over the next 24 hours. Area under the saquinavir concentration–time curve (AUC0–∞), maximum saquinavir plasma concentration (Cmax), time to Cmax and terminal half-life were calculated. The relative bioavailability of FCT SQV versus HC SQV was calculated as the ratio of the respective estimated mean saquinavir AUC0-∞ and Cmax. The calculation was based on an ANOVA including the factors site, sex, sequence, period, treatment and study participant to the log-transformed parameters log(AUC0-∞) and log(Cmax); the relative bioavailability and the 90% confidence intervals (CIs) were estimated using the treatment contrasts of the ANOVA. Bioequivalence was concluded as for both parameters, AUC0-∞ and Cmax, the 90% CIs for the relative bioavailability were entirely included in the reference region [0.80–1.25]. Results Saquinavir plasma concentration–time profiles for the two formulations were similar. Geometric mean AUC0-∞ and Cmax values were clearly increased for FCT SQV (26 826 versus 24 430 h*ng/ml; and 3644 versus 3064 ng/ml, respectively); ratios of mean exposures were estimated to be 1.10 for AUC0-∞ and 1.19 for Cmax of saquinavir. However, the corresponding two-sided 90% CIs (1.04–1.16 and 1.14–1.25, respectively) all fell within the limits set for equivalence (0.80, 1.25). The adverse event profile for FCT SQV was similar to that for HC SQV. Conclusion The new 500 mg FCT SQV formulation is bioequivalent to the 200 mg HC SQV formulation, at the dose of 1000 mg, in combination with 100 mg ritonavir under fed conditions. The 500 mg FCT SQV formulation reduces pill count for boosted saquinavir (SQV/r) from six capsules to three tablets twice daily. This may increase patient acceptability of SQV/r, particularly in less treatment-experienced patients.
Predictors of Hypertension and Changes of Blood Pressure in HIV-Infected Patients
Authors: Thiébaut Rodolphe , El-Sadr Wafaa M , Friis-Møller Nina , Rickenbach Martin , Reiss Peter , Monforte Antonella D'Arminio , Morfeldt Linda , Fontas Eric , Kirk Ole , Wit Stephane De , Calvo Gonzalo , Law Matthew G , Dabis François , Sabin Caroline A , Lundgren Jens D ,   for the “Data Collection of Adverse events of anti-HIV Drugs” (D:A:D) Study Group, El-Sadr W , Calvo G , Dabis F , Kirk O , Law M , Monforte A d'Arminio , Morfeldt L , Pradier C , Reiss P , Weber R , Wit S De , Zaheri S , Gras L , Thiébaut R , Balestre E , Petoumenos K , Mateu S , Torres F , Sommereijns B , Poll B , Bartsch G , Thompsen G , Kjær J , Pezzotti P , Fontas E , Caissotti C , Sundström A , Thulin G , Rickenbach M , Keiser O , Sabin CA , Phillips AN , Collins S , Friis-Møller N , Worm S W , Sawitz A , Lundgren JD , Mertenskoetter T , Loeliger E , Tressler R , Weller I 
Published: April 2022

Objective We assessed predictors of changes in systolic (SBP) and diastolic (DBP) blood pressure during follow-up and of the development of hypertension in HIV-infected individuals. Methods International cohort collaborative study (D:A:D) of established prospective cohorts of HIV-1-infected patients. Longitudinal analysis of changes in blood pressure (BP) was performed using mixed effects models in 17170 patients. Predictors of development of hypertension during follow-up (systolic BP ≥140 and/or diastolic BP ≥90 mmHg or initiation of antihypertensive treatment) were assessed using Cox models in 8 984 patients with a normal BP level at baseline. Results 73548 BP measurements with a median of 4 per patient (interquartile range [IQR]: 2–6) were recorded over a median follow-up of 2.3 years (IQR: 1.5–2.6). Risk factors significantly associated with a development of higher systolic BP and diastolic BP (differences ≥5 mmHg and P-values <0.001) during follow-up were: older age, male sex, higher body mass index (BMI) and use of BP-lowering drugs. In patients with normal BP at baseline, 1186 developed hypertension for an incidence of 72.1 per 1000 person-years (95% confidence interval: 68.2–76.0). Factors associated with development of hypertension were: male sex, higher BMI, older age, higher BP at baseline, high total cholesterol and clinical lipodystrophy. Cumulative duration of exposure to nucleoside reverse transcriptase inhibitors ( P=0.75), protease inhibitors ( P=0.92) as well as type of antiretroviral treatment at baseline ( P=0.18) were not associated with a higher risk of hypertension. Cumulative duration of exposure to non-nucleoside reverse transcriptase inhibitors (NNRTIs) was significantly associated with lower risk of hypertension (hazard ratio=0.78 and 0.67 for those treated ≤10 months and >10 months compared with no exposure; P=0.005). Conclusions Increased blood pressure in HIV-infected individuals is associated with established risk factors for hypertension. There was no evidence for an independent deleterious effect of any class of antiretroviral drugs on BP, although the use of NNRTIs was associated with a lower risk of development of hypertension.