bluuebunny/crossref_metadata_2025_split huggingface dataset:
Self-Reported Non-Adherence to Antiretroviral Therapy Repeatedly assessed by Two Questions Predicts Treatment Failure in Virologically Suppressed Patients
Authors:   the Swiss HIV Cohort Study, Glass Tracy R , De Geest Sabina , Hirschel Bernard , Battegay Manuel , Furrer Hansjakob , Cavassini Matthias , Vernazza Pietro L , Bernasconi Enos , Rickenbach Martin , Weber Rainer , Bucher Heiner C 
Published: April 2022

Background The aim of this study was to explore the predictive value of longitudinal self-reported adherence data on viral rebound. Methods Individuals in the Swiss HIV Cohort Study on combined antiretroviral therapy (cART) with RNA <50 copies/ml over the previous 3 months and who were interviewed about adherence at least once prior to 1 March 2007 were eligible. Adherence was defined in terms of missed doses of cART (0, 1, 2 or >2) in the previous 28 days. Viral rebound was defined as RNA >500 copies/ml. Cox regression models with time-independent and -dependent covariates were used to evaluate time to viral rebound. Results A total of 2,664 individuals and 15,530 visits were included. Across all visits, missing doses were reported as follows: 1 dose 14.7%, 2 doses 5.1%, >2 doses 3.8%, taking <95% of doses 4.5% and missing ≥2 consecutive doses 3.2%. In total, 308 (11.6%) patients experienced viral rebound. After controlling for confounding variables, self-reported non-adherence remained significantly associated with the rate of occurrence of viral rebound (compared with zero missed doses: 1 dose, hazard ratio [HR] 1.03, 95% confidence interval [CI] 0.72–1.48; 2 doses, HR 2.17, 95% CI 1.46–3.25; >2 doses, HR 3.66, 95% CI 2.50–5.34). Several variables significantly associated with an increased risk of viral rebound irrespective of adherence were identified: being on a protease inhibitor or triple nucleoside regimen (compared with a non-nucleoside reverse transcriptase inhibitor), >5 previous cART regimens, seeing a less-experienced physician, taking co-medication, and a shorter time virally suppressed. Conclusions A simple self-report adherence questionnaire repeatedly administered provides a sensitive measure of non-adherence that predicts viral rebound.
Low Rate of Emergence of Nevirapine and Lamivudine Resistance after Post-Partum Interruption of a Triple-Drug Regimen
Authors: Pérez Héctor , Vignoles Moira , Laufer Natalia , Gómez Alejandro , Coll Patricia , Lattner Jorge , Rolón María , Salomón Horacio , Cahn Pedro 
Published: April 2022

Introduction Emergence of nevirapine (NVP) resistance may be a consequence of its use in monotherapy to prevent HIV mother-to-child transmission (MTCT). The aim of this study was to evaluate the emergence of strains resistant to NVP and lamivudine (3TC) after discontinuation of anti-retroviral therapy (ART) with 3TC/zidovudine (ZDV)/NVP. Methods Twenty pregnant women (ART-naive or pre-exposed only to ZDV), to whom 3TC/ZDV/NVP was prescribed as MTCT prophylaxis, were studied. They received ART for a median of 4 months with median viral load (VL) at labour <50 copies/ml. Samples were collected between 1 and 15 months (median: 3 months) after ART interruption. Sequence-selective real-time PCR (SPCR), which quantifies minority viral populations containing K103N, Y181C and M184V mutations, and standard genotypic sequencing were assayed. Results No mutations associated with resistance to 3TC or NVP were found by standard population sequencing. Analysis of K103N by SPCR showed that 35% of the patients contained ≤0.1% of viruses carrying either the AAC or AAT mutations. For Y181C mutation, 10% of the patients contained <0.5% of viruses with TGT codon change. For M184V mutation, one patient contained 6.2% of virus with GTG mutation and 13 patients (65%) contained <0.9% of mutated viruses. Four women were re-exposed to 3TC/ZDV/NVP and achieved HIV VL <50 copies/ml. No perinatal transmission occurred in any of the 22 births. Conclusions NVP associated with ZDV/3TC as a regimen to prevent MTCT may involve a low risk for the selection of antiretroviral-resistant strains and may not jeopardize the use of these same drugs for future treatment.
Cytokine Profiling in Abacavir Hypersensitivity Patients
Authors: Almeida Coral-Ann M , Martin Annalise M , Nolan David , Lucas Andrew , Cameron Paul U , James Ian , Phillips Elizabeth , Mallal Simon 
Published: April 2022

Background Abacavir hypersensitivity in genetically susceptible individuals implicates an abacavir-specific T-cell response to either the parent drug or a metabolite generated in vivo. We have analysed the cytokine profile in antigen-presenting cells and the T-lymphocytes that are involved in the pathological immune response to abacavir. Methods In this study, we compared abacavir-specific cytokine responses in cultured peripheral blood mononuclear cells (PBMCs) from HIV-infected abacavir hypersensitive, tolerant and naive individuals. Cells were cultured in the presence or absence of abacavir. Cytokine expression was determined by microarray analysis, enzyme-linked immunosorbent assays and flow cytometry. Results We demonstrated using in vitro models of immune activation that the production of interferon-γwas specifically induced by abacavir treatment in PBMCs obtained from hypersensitive patients carrying the HLA-B*5701 allele (median 123.86 compared with -30.83 for tolerant controls, P=0.001). Conclusion These results provide further insight into the immunological and metabolic basis of abacavir hypersensitivity syndrome. In vitro assays could assist in the identification of susceptible loci by providing a surrogate marker for the hypersensitivity reaction. Such a marker could be studied in unexposed individuals to shed further light on the immunopathogenesis of the abacavir hypersensitivity syndrome.
Use of Diet, Nutritional Supplements and Exercise in HIV-Infected Patients Receiving Combination Antiretroviral Therapies: A Systematic Review
Authors: Leyes Pere , Martínez Esteban , de Talló Forga Maria 
Published: April 2022

Background The use of combination antiretroviral therapy (cART) has improved the prognosis of HIV infection, but it has also been linked to a spectrum of body composition changes and metabolic alterations known as the lipodystrophy syndrome. Nutritional status could influence body composition changes. Methods We performed a systematic search of published peer-reviewed data on the effects of diet, nutrition support and exercise on body composition and metabolic complications in patients receiving cART. Results Few controlled studies, most of them with small sample size, were found. Oral nutritional support increases protein and energy intake, and results in body weight and fat mass gains. Resistance exercise, with or without an aerobic component, increases lean mass and can improve insulin resistance. Low-fat diets or exercise can result in loss of fat mass, and they should be used with caution in subjects with lipoatrophy. Conclusions Nutritional support and exercise result in small but significant body composition changes and can be used as complementary interventions. There is a need for further research on nutritional interventions in HIV-infected patients receiving cART.
Silver Nanoparticles Inhibit Hepatitis B virus Replication
Authors: Lu Lei , Sun Raymond Wai-Yin , Chen Rong , Hui Chee-Kin , Ho Chi-Ming , Luk John M , Lau George KK , Che Chi-Ming 
Published: April 2022

Background Silver nanoparticles have been shown to exhibit promising cytoprotective activities towards HIV-infected T-cells; however, the effects of these nanoparticles towards other kinds of viruses remain largely unexplored. The aim of the present study was to investigate the effects of silver nanoparticles on hepatitis B virus (HBV). Methods Monodisperse silver nanoparticles with mean particle diameters of ∼10 nm (Ag10Ns) and ∼50 nm (Ag50Ns) were prepared from AgNO3 in HEPES buffer. The in vitro anti-HBV activities of these particles were determined using the HepAD38 cell line as infection model. Results Ag10Ns and Ag50Ns were able to reduce the extracellular HBV DNA formation of HepAD38 cells by >50% compared with the vehicle control (that is, HepAD38 cells in the absence of silver nanoparticles). Silver nanoparticles had little effect on the amount of HBV covalently closed circular DNA (cccDNA), but could inhibit the formation of intracellular HBV RNA. Gel mobility shift assays indicated that Ag10Ns bound HBV double-stranded DNA at a DNA:silver molar ratio of 1:50; an absorption titration assay showed that the nanoparticles have good binding affinity for HBV DNA with a binding constant ( Kb) of (8.8 ±1.0)x105 dm3mol-1. As both the viral and Ag10Ns systems are in the nanometer size range, we found that Ag10Ns could directly interact with the HBV viral particles as revealed by transmission electronic microscopy. Conclusions Silver nanoparticles could inhibit the in vitro production of HBV RNA and extracellular virions. We hypothesize that the direct interaction between these nanoparticles and HBV double-stranded DNA or viral particles is responsible for their antiviral mechanism.
Virological Response to Darunavir/Ritonavir-Based Regimens in Antiretroviral-Experienced Patients (PREDIZISTA Study)
Authors:   the ANRS Co3 Aquitaine Cohort, Pellegrin Isabelle , Wittkop Linda , Joubert Laurence Morand , Neau Didier , Bollens Diane , Bonarek Mojgan , Girard Pierre-Marie , Fleury Hervé , Winters Bart , Saux Marie-Claude , Pellegrin Jean-Luc , Thiébaut Rodolphe , Breilh Dominique 
Published: April 2022

Background We assessed the association of baseline HIV-1 mutations, phenotypic sensitivity and pharmacokinetics with virological failure (VF) at week 12 (W12) after onset of a darunavir/ritonavir (DRV/r)-based regimen in a cohort of 67 antiretroviral-experienced HIV-patients failing on highly active antiretroviral therapy (HAART). Methods VF was defined as HIV RNA >2.3 log10copies/ml at W12. HIV reverse transcriptase and protease sequencing was performed at W0; mutations with a P-value <0.25 in univariable analyses were used for a backward selection to find the best mutation set for VF prediction. Genotypic and phenotypic sensitivity scores were calculated and virtual phenotype predicted fold change (FC) assessed. DRV Cmin, Cmax, AUC0→12 h and genotypic inhibitory quotient (GIQ) were determined. Results Patients had a median of 15 previous treatments for 10 years. Median W0 values included a T-cell count of 129 cells/μl, 4.7 log10 HIV RNA copies/ml, four major protease and six nucleoside reverse transcriptase inhibitor resistance mutations. At W12, median HIV RNA decrease was -2.1 log10 copies/ml with a gain of +67 CD4+ T-cells/μl; 40% of patients failed. We determined the genotypic score I13V+V32I+L33F/I/V+E35D+ M36I/L/V+I47V+F53L+I62V According to <4, 4–5 and >5 mutations, failure occurred in 11%, 48% and 100% of patients. Failure was associated with CDC stage, baseline CD4+ T-cell count, number of major protease inhibitor resistance mutations, FC and DRV/r score. Pharmacokinetics were not associated with failure, but GIQ was. Conclusion At W12, 60% of heavily pretreated patients responded on DRV/r-based HAART. Genotypic and phenotypic information constituted the main virological response determinant in patients with optimal drug concentrations.
Virological Pattern in Plasma, Peripheral Blood Mononuclear Cells and Liver Tissue and Clinical Outcome in Chronic Hepatitis B and C virus Coinfection
Authors: Coppola Nicola , Pisapia Raffaella , Tonziello Gilda , Martini Salvatore , Imparato Michele , Piai Guido , Stanzione Maria , Sagnelli Caterina , Filippini Pietro , Piccinino Felice , Sagnelli Evangelista 
Published: April 2022

Background We aim to evaluate in chronic hepatitis B virus–hepatitis C virus (HBV–HCV) coinfection the interplay of these viruses in liver tissue, peripheral blood mononuclear cells (PBMC), and plasma and to analyze the effect on disease course and response to treatment. Methods We enrolled 19 patients with chronic HBV–HCV coinfection, 20 with chronic HCV and 20 with chronic HBV infection at their first liver biopsy, all were naive for antiviral therapy. The patients’ plasma, PBMC and liver biopsy samples were tested for HBV DNA and/or HCV RNA by real-time PCR, according to the presence/absence of hepatitis B surface antigen and antibodies against HCV in the serum. Results Contemporary presence of HBV DNA and HCV RNA was rare in plasma (5.3% of cases) and PBMC (10.6%), but frequent in liver tissue (52.6%). Of 10 cases circulating only HCV RNA and treated with pegylated interferon (PEG-IFN) plus ribavirin for 12 months, two showed a sustained response, and eight cleared HCV RNA but became HBV-DNA-positive in plasma; these eight had detectable HBV DNA in liver at baseline. One patient, who was plasma HBV-DNA-positive/HCV-RNA-negative at baseline, showed a sustained response after 18 months of PEG-IFN treatment; another, who was plasma HBV-DNA/HCV-RNA-positive at baseline, cleared only HCV RNA during 12 months of PEG-IFN plus ribavirin treatment. Seven cases remained untreated. Conclusion Despite a reciprocal inhibition in plasma, HBV and HCV frequently coexist in liver tissue, a condition to be taken into consideration when deciding therapy.
A Systematic Review of T-cell Epitopes in Hepatitis B Virus: Identification, Genotypic Variation and Relevance to Antiviral Therapeutics
Authors: Desmond Christopher P , Bartholomeusz Angeline , Gaudieri Silvana , Revill Peter A , Lewin Sharon R 
Published: April 2022

Background The immune response to hepatitis B virus (HBV) is important for both viral control and disease pathogenesis. A detailed understanding of the HBV-specific T-cell responses may potentially lead to novel therapeutic strategies for HBV. Methods All English language journal articles (including articles in press) up to October 2007 were retrieved using searches of MEDLINE, EMBASE and the Cochrane Controlled Trial Registry. An extensive database of HBV sequences (SeqHepB) and GenBank were used to assess the degree of sequence variation in each epitope. The new standardized nomenclature for HBV amino acid position number was applied to all previously defined epitopes. Results Forty-four HBV-specific human leukocyte antigen (HLA) class I restricted and 32 HBV-specific HLA class II restricted epitopes have been defined and have been identified in all HBV genes. The majority of HLA class I restricted epitopes have been defined in HLA-A2-positive individuals in the setting of acute HBV infection. There is significant sequence variation of these epitopes within and between HBV genotypes. Newer HBV immunotherapeutics appear promising but are still in early phases of development. Conclusions Identification of HBV-specific epitopes in non-HLA-A2-positive individuals and recognition of genotypic variation across epitopes are important for the future development of novel immunotherapeutic strategies for the management of chronic HBV infection.
Long-Term Efficacy and Safety of First-Line Therapy with Once-Daily Saquinavir/Ritonavir
Authors:   Staccato Thailand Study Group, Ananworanich Jintanat , Gayet-Ageron Angele , Ruxrungtham Kiat , Chetchotisakd Ploenchan , Prasithsirikul Wisit , Kiertiburanakul Sasisopin , Munsakul Warangkana , Raksakulkarn Phitsanu , Tansuphasawadikul Somboon , LeBraz Michelle , Jupimai Thidarat , Ubolyam Sasiwimol , Schutz Malte , Hirschel Bernard 
Published: April 2022

Background The aim of this study was to assess the long-term efficacy and safety of first-line treatment with once-daily saquinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors (NRTIs). Methods A total of 272 antiretroviral-naive patients with a CD4+ T-cell count of 200–350 cells/mm3 were treated with two NRTIs and saquinavir/ritonavir 1,600/100 mg per day for ≥24 weeks. Patients were followed up every 12 weeks for CD4+ T-cell counts, HIV RNA levels, clinical and laboratory toxicities. Intention-to-treat analyses were used for the first 24 weeks of treatment and as-treated analysis after week 24. Results The median baseline CD4+ T-cell count was 269 cells/mm3 and HIV RNA was 4.7 log10 copies/ml. At a median follow-up time of 56 (interquartile range [IQR] 25–113) weeks, 262/272 (96.3%) had HIV RNA <400 copies/ml, with a median HIV RNA decline of -2.89 (IQR 3.31–2.37) log10 copies/ml ( P<0.001) and a median rise in CD4+ T-cell count of 192 (IQR 117–317) cells ( P<0.001). At weeks 24, 48, 72 and 96, 249/272 (91.5%), 157/164 (95.7%), 113/126 (89.7%) and 84/90 (93.3%) had HIV RNA <400 copies/ml, respectively; at the same time points, 83.8%, 92.7%, 85.7% and 85.6% had HIV RNA <50 copies/ml. Drug-related adverse events were reported in 6.3%. Significant rises in total cholesterol, triglyceride, low-density lipoprotein and high-density lipoprotein were seen. Conclusion First-line highly active antiretroviral therapy with once-daily saquinavir/ritonavir plus two NRTIs showed strong antiviral efficacy.
A Randomized Study to Evaluate Injection Site Reactions using Three Different Enfuvirtide Delivery Mechanisms (the OPTIONS Study)
Authors: Boyd Mark A , Truman Matt , Hales Gillian , Anderson Jonathan , Dwyer Dominic E , Carr Andrew 
Published: April 2022

Background The antiretroviral enfuvirtide (ENF) is injected subcutaneously using a 27-gauge needle. Injection site reactions (ISRs) can affect long-term ENF tolerability. Alternative ENF delivery methods may ameliorate ISRs. Methods We conducted a multicentre, open-label, randomized controlled trial in which patients receiving ENF were randomized to continue receiving ENF by a 27-gauge needle, a shorter 31-gauge needle or a gas-powered, needle-free injection device (NFID). The primary study endpoint was the proportion of participants with <grade 2 ISR induration at week 12. Results Sixty patients received treatment and were included in the intention-to-treat population. The cohort was predominantly male (95%) with a mean age of 49.1 (SD ±7.7) years who had injected ENF for a mean of 821 (SD ±561) days. Response rates for ISR induration at week 12 were 38%, 25% and 42% for the 27-gauge, 31-gauge and NFID groups, respectively (all pairwise treatment comparison P-values >0.2). There was no significant between-group difference for any ISR endpoint, except for changes in the composite ISR score (that is, no ongoing pain of ≥grade 1 or ISR for ongoing pain ≥grade 1 with induration ISR <grade 3 and for nodules <grade 2), which favoured the 27-gauge needle and NFID groups over the 31-gauge group ( P=0.012 and 0.047, respectively). Plasma HIV RNA load was unaffected. There were seven adverse events related to the delivery system: five attributed to the NFID. At week 12, 85% of participants elected to use the NFID. Conclusion Needle-free ENF injection offers a reasonable, reliable alternative to needle-based injecting in this population, at least in the short term.
Rapid Semiquantitative Real-Time PCR for the Detection of Human Cytomegalovirus UL97 Mutations Conferring Ganciclovir Resistance
Authors: Göhring Katharina , Mikeler Elfriede , Jahn Gerhard , Rohde Frank , Hamprecht Klaus 
Published: April 2022

Background The development of infections with ganci-clovir (GCV)-resistant human cytomegalovirus (HCMV) remains a serious problem in recipients of stem cell or organ transplants. Nearly all GCV-resistant clinical isolates have mutations in the viral UL97 gene. The rapid detection of GCV-resistant HCMV infections is necessary and the relative proportions of wild-type and mutant strains are predictive for the efficiency of antiviral therapy. To date, genotypical resistance screening has been limited to restriction fragment length polymorphism (RFLP) and sequencing analyses. Here, we present a comprehensive real-time PCR approach for the detection of most frequent mutations in the UL97 gene associated with GCV resistance. Methods The laboratory strains AD169 and Towne, different wild-type isolates and plasmids constructed by site-directed mutagenesis and overlap extension with specific point-mutations in the UL97 gene were analysed by LightCycler PCR and compared with UL97 RFLP and sequencing analyses. Results A new and comprehensive set of LightCycler PCRs was created using specific hybridization probes with melting-point analysis for the relevant codons 594, 595, 603 and 607. Different wild-type isolates and plasmids containing specific UL97 mutations conferring GCV resistance were investigated in the real-time PCR assay. Total processing time was 80 min per assay, whereas combinations of RFLP and sequencing needed at least 3–4 days. Proportions of co-existing wild-type and mutant strains in mixed viral populations can be obtained. Conclusions We established a rapid real-time PCR approach for the detection of most frequent HCMV UL97 mutations associated with GCV resistance. Moreover, the method allows semiquantitative differentiation of the proportions of co-existing wild-type and mutant strains. This approach represents a new alternative for laborious RFLP analysis.
Modelled in vivo HIV Fitness under drug Selective Pressure and Estimated Genetic Barrier Towards Resistance are Predictive for Virological Response
Authors:   the EuroSIDA Study Group, Deforche Koen , Cozzi-Lepri Alessandro , Theys Kristof , Clotet Bonaventura , Camacho Ricardo J , Kjaer Jesper , Van Laethem Kristel , Phillips Andrew , Moreau Yves , Lundgren Jens D , Vandamme Anne-Mieke 
Published: April 2022

Background A method has been developed to estimate a fitness landscape experienced by HIV-1 under treatment selective pressure as a function of the genotypic sequence thereby also estimating the genetic barrier to resistance. Methods We evaluated the performance of two estimated fitness landscapes (nelfinavir [NFV] and zidovudine [AZT] plus lamivudine [3TC]) to predict week 12 viral load (VL) change for 176 treatment change episodes (TCEs) and probability of week 48 virological failure for 90 TCEs, in treatment experienced patients starting these drugs in combination. Results A higher genetic barrier for AZT plus 3TC, (quantified per additional mutation required to develop resistance against these drugs) was associated with a 0.54 (95% confidence interval [CI] 0.30–0.77) larger log10 VL reduction at 12 weeks ( P<0.0001) and a 0.39 (95% CI 0.23–0.66) lower odds of virological failure at 48 weeks ( P=0.0005), in analyses adjusting for the pre-TCE VL and the exact time-lag between the TCE and the date of determining response VL. The strength of these associations was comparable with those seen with expert interpretation systems (Rega, ANRS and HIVDB). A higher genetic barrier to NFV resistance was the only genotypic predictor that tended to be associated with a 0.19 (95% CI 0–0.39) higher log10 VL reduction at 12 weeks ( P=0.05) and a 0.63 (95% CI 0.36–1.09) lower odds of virological failure at 48 weeks ( P=0.10) per additional mutation. Conclusions These results suggest that an estimated genetic barrier derived from fitness landscapes may contribute to an improvement of predicted treatment outcome for NFV and this approach should be explored for other drugs.