bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selection of Hepatitis B Virus Polymerase Mutations in HIV-Coinfected Patients Treated with Tenofovir
Authors: Sheldon Julie , Camino Nuria , Rodés Berta , Bartholomeusz Angeline , Kuiper Michael , Tacke Frank , Núñez Marina , Mauss Stefan , Lutz Thomas , Klausen Gerd , Locarnini Stephen , Soriano Vincent 
Published: April 2022

Background Tenofovir (TDF) is an adenosine nucleotide analogue that has been approved for the treatment of HIV-1 infection. It also shows activity against hepatitis B virus (HBV) in patients with or without lamivudine (LAM)-associated mutations. Development of clinical or virological HBV breakthrough during TDF therapy has not been reported so far. The aim of this study was to analyse the HBV polymerase (pol) from HIV/HBV-coinfected patients with detectable serum levels of HBV DNA during treatment with TDF for longer than 6 months. Methods The HBV pol was sequenced from 43 patient's serum before and during TDF therapy. Phenotypic analyses were performed using HBV replication-competent plasmids carrying unique mutations selected under TDF therapy. Results Mean exposure to LAM was 35.3 ±27.5 months and to TDF 11.2 ±6.7 months. Genotypic analyses from 21 of the patients revealed LAM-associated mutations, and a further two patients developed a novel mutation, rtA194T, along with LAM-resistance-associated mutations. Phenotypic analyses revealed that constructs harbouring rtA194T combined with rtL180M and rtM204V displayed an over 10-fold increase in the IC50 for TDF compared with the wild type. Conclusion The selection of HBV mutations in HBV/HIV-coinfected patients failing TDF therapy is an unlikely event within the first 12 months of treatment. However, HBV from two of the 43 patients treated with TDF for more than 12 months was found to contain one novel mutation located distal to the catalytic site of the HBV pol. In vitro, rtA194T conferred a reduced susceptibility to TDF in the presence of LAM-associated mutations.
Efficacy and Tolerability of the Oral Neuraminidase Inhibitor Peramivir in Experimental Human Influenza: Randomized, Controlled Trials for Prophylaxis and Treatment
Authors: Barroso Luis , Treanor John , Gubareva Larisa , Hayden Frederick G 
Published: April 2022

Objective Oseltamivir is the only oral neuraminidase inhibitor currently available; we determined the tolerability and antiviral efficacy of oral peramivir for treatment and prophylaxis of experimental human influenza A and B. Participants 288 susceptible, healthy volunteers (ages 18–45) were inoculated intranasally with A/Texas/36/ 91/H1N1 or B/Yamagata/16/88 virus in four randomized, double-blind, placebo-controlled trials. Interventions: For treatment dosing was initiated at 24 h after inoculation with peramivir doses ranging from 100–800 mg/day for 5 days. For prophylaxis dosing was initiated 24 h before inoculation and continued for 4 days with peramivir doses ranging from 50–800 mg/day. Outcomes The primary outcome measure for treatment was quantitative viral detection defined by the area under the curve (AUC) for nasal wash viral titres. For prophylaxis the primary outcome measure was the incidence of virus recovery. Results In influenza A treatment, peramivir 400 mg q24h and 200mg q12h, but not lower doses, resulted in significant reductions in viral titre AUC. In influenza B treatment, both 400 and 800/400 mg once daily dose groups reduced AUC values. In influenza A prophylaxis, the percentage of individuals with nasal viral shedding did not differ significantly in the placebo (58%), 50 mg (61%), 200 mg (37%) and 400 mg (31%) dose groups. In influenza B prophylaxis, shedding frequencies were similar in placebo (55%), 200 mg (41%), 400 mg (35%) and 800 mg (47%) dose groups. The drug was well tolerated in all four studies, with nausea and headache being the most common side effects. No drug-resistant variants were detected. Conclusion Early treatment with peramivir was associated with significant antiviral effects in experimentally induced influenza in humans. Prophylaxis did not significantly reduce viral shedding. The relatively low blood peramivir concentrations observed may explain the lack of more robust antiviral effects, and parenteral dosing should be studied.
Uridine Abrogates the Adverse Effects of Antiretroviral Pyrimidine Analogues on Adipose Cell Functions
Authors: Walker Ulrich A , Auclair Martine , Lebrecht Dirk , Kornprobst Michel , Capeau Jacqueline , Caron Martine 
Published: April 2022

Objectives Side effects of antiretroviral treatment such as lipoatrophy have been mainly attributed to mitochondrial toxicity of nucleoside reverse transcriptase inhibitors (NRTIs). We assessed whether uridine can abrogate the adverse effects of NRTIs on adipocyte functions. Methods 3T3-F442A preadipocytes were exposed to stavudine (d4T; 10 μM), zidovudine (ZDV; 1 μM), zalcitabine (ddC; 0.2 μM) or didanosine (ddI; 10 μM) in the absence or presence of uridine 21 days prior to and 7 days after induction of differentiation. Then, lipid accumulation (oil red staining), apoptosis (flow cytometry, PARP-cleavage), mitochondrial mass (Mitotracker) and DNA (mtDNA), cytochrome c oxidase (COX) subunits and mitochondrial membrane potential (JC-1) were quantified. Results Whereas ddI had no effects, d4T, ZDV and ddC significantly decreased cellular lipid accumulation (by 32%, 46% and 24%, respectively), increased apoptosis and induced mitochondrial depolarization. d4T, ZDV and ddC decreased adipocyte mtDNA (by 64%, 53% and 46%, respectively) and reduced the mtDNA encoded COX II subunit. Uridine (200 μM) had no intrinsic effect, but prevented all adverse effects of d4T, ZDV and ddC on adipocyte morphology, lipid staining, apoptosis, mtDNA depletion (partial prevention with ZDV), mitochondrial mass and membrane potential. The effects of uridine were concentration-dependent. Uridine also fully reverted established d4T toxicities despite continued d4T exposure. Conclusions Uridine supplementation protects adipocytes from the adverse effects of d4T, ZDV and ddC on lipid accumulation, cell survival and mitochondrial functions, suggesting that the toxic effects could be linked to intracellular depletion of uridine or its metabolites. Uridine is an interesting candidate in the prevention of NRTI-induced lipoatrophy in vivo.
Salvage Therapy with Atazanavir/Ritonavir Combined to Tenofovir in HIV-Infected Patients with Multiple Treatment Failures: Randomized Anrs 107 Trial
Authors: Piketty Christophe , Gérard Laurence , Chazallon Corine , Marcelin Anne-Geneviève , Clavel François , Taburet Anne-Marie , Calvez Vincent , Madelaine-Chambrin Isabelle , Molina Jean-Michel , Aboulker Jean-Pierre , Girard Pierre-Marie 
Published: April 2022

Background Ritonavir (RTV)-boosted atazanavir (ATV) and tenofovir disoproxil fumarate (TDF-DF) are promising in highly experienced patients because of their pharmacokinetic profile, activity, safety and resistance properties. Methods A 26-week study of the safety and efficacy of RTV-boosted ATV plus TDF-DF was conducted in 53 HIV-infected patients who were failing their current highly active antiretroviral therapy (HAART) regimen. Patients with history of failure to at least two protease inhibitors (PIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) were randomized to either continue their current regimen (group 1) or replace the PI by ATV (300 mg once daily) boosted by RTV (100 mg; group 2) for 2 weeks. Then, all patients received the same combination of ATV, RTV and TDF-DF (300 mg) plus optimized NRTIs regimen. Results At baseline, median CD4+ T-cell count was 206/mm3, median viral load (VL) 5.0 log10/ml and median numbers of NRTI, NNRTI and PI resistance mutations were 7, 1 and 8, respectively. At week 2, median VL remained unchanged from baseline in group 2 as compared with group 1 (-0.1 vs -0.1 log10/ml). At week 26, a mild decrease in median VL from baseline of 0.2 log10/ml was observed, with 16 (31%) and 9 (17%) patients exhibiting a decrease in viral load of at least 0.5 and 1.0 log10/ml, respectively. Baseline phenotypic and genotypic resistance to ATV were the most predictive independent factors of virological response. The regimen was well tolerated. Conclusion In these very advanced patients failing highly HAART, the combination of boosted ATV plus TDF-DF yielded low antiretroviral activity.
The Role of Viruses in the Aetiology of Community-Acquired Pneumonia in Adults
Authors: Marcos Maria Angeles , Camps Marta , Pumarola Tomás , Martinez José Antonio , Martinez Esteban , Mensa Josep , Garcia Elisa , Peñarroja Georgina , Dambrava Póvilas , Casas Inmaculada , de Anta Maria Teresa Jiménez , Torres Antoni 
Published: April 2022

Background The role of viruses in community-acquired pneumonia may have been previously underestimated. We aimed to study the incidence and clinical characteristics of community-acquired pneumonia (CAP) due to respiratory viruses in adults adding PCR to routine conventional laboratory tests. Methods Consecutive adult patients diagnosed of CAP from January 2003 to March 2004 were included. Conventional tests including cultures of blood, sputum, urine antigen detection of Streptococcus pneumoniae and Legionella pneumophila, and paired serologies were routinely performed. Nasopharyngeal swabs were processed for study of respiratory viruses through antigen detection by indirect immunofluorescence assay, isolation of viruses in cell culture and detection of nucleic acids by two independent multiplex RT-PCR assays. According to the aetiology, patients were categorized in 4 groups: group 1, only virus detected; group 2, only bacteria detected; group 3, viral and bacterial; and group 4, unkown aetiology. Results Of 340 patients diagnosed with CAP, 198 had nasopharyngeal swabs available and were included in this study. Aetiology was established in 112 (57%) patients: group 1, n=26 (13%); group 2, n=66 (33%); group 3, n=20 (10%). The most common aetiological agent was S. neumoniae (58 patients, 29%), followed by respiratory viruses (46 patients, 23%). Forty-eight respiratory viruses were identified: influenza virus A ( n=16), respiratory syncytial virus A ( n=5), adenovirus ( n=8), parainfluenza viruses ( n=5), enteroviruses ( n=1), rhinoviruses ( n=8) and coronavirus ( n=5). There were two patients coinfected by two respiratory viruses. Serology detected 6 viruses, immunofluorescence 8, viral culture 12, and PCR 45. For the viruses that could be diagnosed with conventional methods, the sensitivity and specificity of RT-PCR was 85% and 92%, respectively. The only clinical characteristic that significantly distinguished viral from bacterial aetiology was a lower number of leukocytes ( P=0.004). Conclusion PCR revealed that viruses represent a common aetiology of CAP. There is an urgent need to reconsider routine laboratory tests for an adequate diagnosis of respiratory viruses, as clinical characteristics are unable to reliably distinguish viral from bacterial aetiology.
Access to HIV Prophylaxis for Survivors of Sexual Assault: The Tip of the Iceberg
Authors: Patrizia Carrieri Maria , Karim Bendiane Marc , Paul Moatti Jean , Dominique Rey 
Published: April 2022

Background In France non-occupational post-exposure prophylaxis (nPEP) is recommended in case of sexual assault and can be prescribed, after risk evaluation, in emergency or AIDS care units. Methods A survey was carried out on retrospective data of individuals being consulted for nPEP in southeastern France. Results Of the 915 consultations for sexual exposures, 94 were sexual assaults concerning adults. Most were prescribed nPEP (91.5%), but half were lost to follow-up. Conclusions During the study period throughout the same region, 623 survivors reported sexual assault to the police. The comparison of these figures shows that the number of victims who have no access to medical consultation for nPEP may be alarmingly high and strongly suggests the urgency to develop strategies for guaranteeing prompt HIV medical assessment for victims of sexual assault and assure adherence to medical follow-up.
Results of a Study of Prolonging Treatment with Pegylated Interferon-α2A plus Ribavirin in HIV/HCV-Coinfected Patients with No Early Virological Response
Authors: Fuster Daniel , Planas Ramon , Gonzalez Juan , Force Lluís , Cervantes Manel , Vilaró Josep , Roget Mercè , García Isabel , Pedrol Enric , Tor Jordi , Ballesteros Angel L , Salas Anna , Sirera Guillem , Videla Sebastià , Clotet Bonaventura , Tural Cristina 
Published: April 2022

Objective To assess the efficacy and safety of an extended treatment period in HIV/hepatitis C virus (HCV)-coinfected patients without early virological response (EVR). Methods Patients received pegylated interferon (peg-INF)-α2a 180 μg/week plus ribavirin 800 mg/d for 12 weeks. Patients achieving EVR at week 12 continued under therapy for an additional 12 or 36 weeks depending on genotype. Patients without EVR were randomized to complete the standard treatment or treatment lasting 72 weeks (extension arm). Results One hundred and ten patients were included (mean age 38.7 years, mean weight 68 kg, 74% males, 74% on highly active antiretroviral therapy, mean CD4+ T-cell count 564 cells/mm3). Fifty-one patients harboured genotype 1, 44 genotype 2/3, and 15 genotype 4. Fifty-three had an HCV load >800,000 IU/ml. Premature interruptions occurred in 32.7%. EVR was achieved in 63.6% (51% in genotype 1, 88.6% in genotype 2/3, 33.3% in genotype 4). End-of-treatment response was 52.7% (47.2% in genotype 1, 68.2% in genotype 2/3, 26.7% in genotype 4). Sustained virological response (SVR) was achieved in 41.8% (37.3% in genotype 1, 54.6% in genotype 2/3, 20% in genotype 4). Only one patient allocated to the extended arm achieved SVR. The rate of drop-outs in the extension arm was 68%. The negative predictive value of EVR was 97.5%. Conclusions This study shows no benefit of extending therapy in patients without EVR at week 12. Measures to improve adherence to HCV antiviral therapy should be considered when new approaches based on extended periods of treatment are investigated.
Investigation of Baseline Susceptibility to Protease Inhibitors in HIV-1 Subtypes C, F, G and Crf02_Ag
Authors: Abecasis Ana B , Deforche Koen , Bacheler Lee T , McKenna Paula , Carvalho Ana Patrícia , Gomes Perpétua , Vandamme Anne-Mieke , Camacho Ricardo Jorge 
Published: April 2022

Objective To compare baseline susceptibility to protease inhibitors among HIV-1 isolates of subtypes C, F, G and CRF02_AG, and to identify polymorphisms that determine the differences in susceptibility. Methods A total of 42 samples of drug-naive patients infected with subtypes G ( n=19), CRF02_AG ( n=10), F ( n=6) and C ( n=7) were phenotyped and genotyped with the Antivirogram and the ViroSeq 2.0 genotyping system, respectively. A Bayesian network approach was used for a preliminary analysis of the collected data and the dependencies indicated by the network were statistically confirmed. Results CRF02_AG samples were found to be more susceptible to nelfinavir and ritonavir than other subtypes. Hypersusceptibility to these drugs was associated with the 70R polymorphism. 37D/S/T was associated with reduced susceptibility to indinavir and 89M with reduced susceptibility to lopinavir. Susceptibility to tipranavir was the lowest among the subtype F samples and the highest for subtype G samples, with samples carrying 57R being more susceptible than samples carrying 57K. Conclusions Our study suggests that there are baseline susceptibility differences between subtypes and these differences are due to naturally occurring polymorphisms in these subtypes. The predictive value for phenotype of these polymorphisms was even valid in subtypes where these polymorphisms are less prevalent. Taking into account such polymorphisms should improve current algorithms for interpretation of genotyping results in a subtype-independent way.
Protease Inhibitor Effects on Triglyceride Synthesis and Adipokine Secretion in Human Omental and Subcutaneous Adipose Tissue
Authors: Cianflone Katherine , Zakarian Robert , Stanculescu Cristina , Germinario Ralph 
Published: April 2022

Objective Significant advances in the treatment of the morbidity and mortality associated with AIDS are also associated with undesirable side-effects in fat redistribution (lipodystrophy), insulin resistance and cardiovascular risk, which is directly linked to protease inhibitor (PI) treatment. Methods The effects of four different PIs on triglyceride (TG) storage and adipokine production (leptin, adiponectin, and acylation stimulating protein [ASP]) in omental (OM) and subcutaneous (SC) adipose tissues were examined. Results Initial results demonstrated that saquinivir (SQV) and ritonivir (RTV) had little observed effect on de novo TG synthesis ([3H]glucose incorporation into TG) or fatty acid re-esterification ([14C]oleate incorporation into TG), whereas amprenivir (APV) and indinivir (IDV) reduced TG synthesis, especially in SC tissue up to 30 ±5.8% P<0.05 and 46 ±7.8% P<0.001, at 20 μM, respectively. There was no observed effect on phospholipid synthesis, tissue protein or toxicity. Only APV and IDV decreased leptin and adiponectin secretion in SC tissue, in a time- and concentration-dependent manner: at 18 h, leptin was inhibited by 54 ±3.1% ( P<0.001) and 44 ±6.4% ( P<0.001) by APV and IDV (40 μM), respectively, and adiponectin was inhibited by 35 ±5.6%( P<0.001) and 25 ±12.3% ( P<0.05) by APV and IDV (40 μM), respectively. By contrast, both IDV and APV decreased ASP secretion in OM tissues by a maximum of 53 ±7.8% ( P<0.001) and 59 ±5.9% ( P<0.001), respectively, and by a maximum of 86 ±1.6% ( P<0.001) and 72 ±4% ( P<0.001), respectively, in SC tissues. Conclusion PI have a direct effect on human adipose tissue which are site, PI and adipokine specific; these effects may contribute to the overall adipose imbalance and development of lipodystrophy, and metabolic syndrome in HIV-positive individuals.
Prevalence, Incidence and Predictors of Severe Anaemia with Zidovudine-Containing Regimens in African Adults with HIV Infection within the Dart Trial
Authors: Ssali Francis , Stöhr Wolfgang , Munderi Paula , Reid Andrew , Walker A Sarah , Gibb Diana M , Mugyenyi Peter , Kityo Cissy , Grosskurth Heiner , Hakim James , Byakwaga Helen , Katabira Elly , Darbyshire Janet H , Gilks Charles F 
Published: April 2022

Objective To describe the prevalence, incidence and predictors of severe anaemia in previously untreated symptomatic HIV-infected adults with CD4+ T-cells <200 cells/mm3 initiating zidovudine-containing regimens in Africa. Design DART is a randomized trial comparing two strategies for HIV/AIDS management in Uganda and Zimbabwe. Methods We analysed the occurrence of anaemia at weeks 4 and 12, and then every 12 weeks. We also evaluated sex, age, WHO stage, body mass index (BMI), baseline laboratory measurements and first regimen as predictors of developing grade 4 anaemia (<6.5 mg/dl) by week 48 using logistic regression. Results To May 2005, 3,314 participants (65% women, 23% at WHO stage 4, median age=37 years, baseline CD4+ T-cell=86 cells/mm3 and median baseline haemo-globin=11.4 g/dl) had a median 72 weeks follow-up. Prevalence of grade 4 anaemia was 0.7%, 2.0%, 0.5% and <0.5% at weeks 4, 12, 24 and ≥36, respectively. Overall, 219 (6.6%) participants developed grade 4 anaemia by week 48; women and those with lower haemoglobin, CD4+ T-cell count and BMI at baseline were at significantly higher risk ( P<0.05), but not those with lower neutrophils or receiving cotrimoxazole at baseline. Conclusions We observed a higher incidence of grade 4 anaemia than in studies from industrialized countries, which is likely to be due in part to population characteristics and in part to a higher rate of concurrent HIV-related clinical events. Clinical vigilance and haemoglobin measurements 4, 8 and 12 weeks after starting zidovudine could help to manage serious anaemia.
Antiretroviral Efficacy and Virological Profile of a Zidovudine/Lamivudine/Tenofovir Disoproxil Fumarate Combination Therapy in Antiretroviral-Naive Patients
Authors: Masquelier Bernard , Neau Didier , Boucher Sébastien , Lavignolle-Aurillac Valérie , Schrive Marie-Hélène , Recordon-Pinson Patricia , Ragnaud Jean-Marie , Fleury Hervé 
Published: April 2022

Objective To study the antiviral efficacy and the mutations selected by a triple therapy with zidovudine (AZT), lamivudine (3TC) and tenofovir disoproxil fumarate (TDF). Methods Antiretroviral-naive patients received 300 mg AZT/150 mg 3TC twice a day plus 300 mg TDF once a day in an open pilot study. Follow-up was assessed at baseline therapy (M0) and at months 1, 3, 6, 9 and 12. Reverse transcriptase (RT) genotypic resistance analysis and in selected cases, a recombinant drug susceptibility and replication capacity assay were performed from plasma RNA at baseline and in case of virological failure (VF); that is, rebound of viral load >50 copies/ml on therapy. Results Twenty-four patients were included. At baseline, the median CD4+ T-cell count was 443 cells/μl and the median plasma viral load (VL) was 4.38 log10 copies/ml. RT resistance mutations were observed at M0 in 4 patients. At M12, the proportion of patients with a VL <50 copies/ml reached 88% using an on-treatment analysis and 67% with an intent-to-treat analysis. The median increase in CD4+ T cells at M12 was 94 cells/μl. Four patients had a VF on therapy: two with wild-type viruses, one with selection of M184V and thymidine analogue mutations (TAMs) on a background of TAMs, and one with selection of K65R and M184V, with a replication capacity at 2.4%. Conclusion The virological response in our study demonstrates the antiviral efficacy of the AZT/3TC/TDF combination therapy, which needs further evaluation. The moderate frequency of selection of K65R could be due to the presence of AZT in the regimen.
Antiretroviral Therapy at Conception in Pregnant Women with HIV in Italy: Wide Range of Variability and Frequent Exposure to Contraindicated Drugs
Authors:   on behalf of The Italian Group on Surveillance on Antiretroviral Treatment in Pregnancy, Floridia Marco , Tamburrini Enrica , Ravizza Marina , Anzidei Gianfranco , Tibaldi Cecilia , Bucceri Anna , Maccabruni Anna , Guaraldi Giovanni , Meloni Alessandra , Probizer Maria Fernanda Ravagni , Guerra Brunella , Martinelli Pasquale 
Published: April 2022

Methods Data from a large national surveillance study was used to describe antiretroviral regimens in pregnant women with HIV, with particular reference to the presence at conception of antiretroviral treatments contraindicated in pregnancy. Therapeutic changes during pregnancy were also analysed. Results Among 334 women on antiretroviral treatment at conception, less than half (42.4%) reported current pregnancy as planned. A large number of different regimens (80) was observed. All the regimens included at least one nucleoside or nucleotide reverse transcriptase inhibitor. Non-nucleoside reverse transcriptase inhibitors and protease inhibitors were present in similar proportions (39.2% and 40.7%, respectively). The most commonly used drugs were lamivudine (83.2% of regimens), zidovudine (50.0%), stavudine (d4T; 38.0%), nevirapine (25.7%), didanosine (ddI; 17.7%) and nelfinavir (17.7%). Treament with efavirenz (13.5% of regimens) and ddI+d4T (9.6%) was markedly frequent. Use of efavirenz at conception was associated with a subsequent treatment change during pregnancy (odds ratio [OR]: 13.2.; 95% confidence interval [CI]: 3.2–53.8, P<0.001). A similar but less strong association was found for ddI (OR: 1.8; 95% CI: 1.03–3.25, P=0.033), whereas being on nevirapine was associated with a lower risk (OR: 0.58; 95% CI: 0.38–0.81, P=0.013). Conclusions Our data show that treatment at conception frequently represents the regimen previously selected for the treatment of the non-pregnant woman. The observed rates of exposure to contraindicated treatment should lead prescribing physicians to consider in HIV-positive women therapeutic choices that take into account the likelihood of an unplanned pregnancy. Such an approach is likely to reduce not only unintended exposures to contraindicated drugs, but also therapeutic changes during pregnancy.