bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interruption of Antiretroviral Therapy and Risk of Cardiovascular Disease in Persons with HIV-1 Infection: Exploratory Analyses from the SMART Trial
Authors: Phillips Andrew N , Carr Andrew , Neuhaus Jacquie , Visnegarwala Fehmida , Prineas Ronald , Burman William J , Williams Ian , Drummond Fraser , Duprez Daniel , Belloso Waldo H , Goebel Frank-Detlef , Grund Birgit , Hatzakis Angelos , Vera Jose , Lundgren Jens D 
Published: April 2022

Background The SMART trial found a raised risk of cardiovascular disease (CVD) events in patients undergoing CD4+ T cell-count guided intermittent antiretroviral therapy (ART) compared with patients on continuous ART. Exploratory analyses were performed to better understand the reasons for this observation. Methods A total of 5,472 patients with CD4+ T-cell counts >350 cells/mm3 were recruited and randomized to either continuous ART (the viral suppression arm; VS) or CD4+ T-cell count-guided use of ART (the drug conservation arm; DC). Results Major CVD events developed in 79 patients. The hazard ratio (HR) for risk of CVD events for DC versus VS was 1.57 (95% confidence interval 1.00–2.46; P=0.05). There was no evidence that being off ART or a higher current HIV viral load were associated with increased CVD risk. Total cholesterol and low-density lipoprotein cholesterol were reduced as a result of ART interruption in DC patients but so was high-density lipoprotein (HDL) cholesterol, leading to a net unfavourable change in the total/HDL cholesterol ratio. Conclusions Reasons for the higher risk of CVD for DC compared with VS patients remain unclear. There was no clear evidence to suggest that ART interruption per se or a higher HIV viral load were associated with an increased CVD risk in the DC group. Lipid changes were less favourable among DC compared with VS patients, which could offer a partial explanation.
Low Current and Nadir CD4+ T-Cell Counts are Associated with Higher Hepatitis C virus RNA Levels in the Swiss HIV Cohort Study
Authors:   the Swiss HIV Cohort Study,   For The Cost-Effectiveness of Preventing AIDS Complications (CEPAC) Investigators, Rauch Andri , Gaudieri Silvana , Evison John , Nolan David , Cavassini Matthias , Weber Rainer , James Ian , Furrer Hansjakob 
Published: April 2022

Background The aim of this study was to evaluate the effect of CD4+ T-cell counts and other characteristics of HIV-infected individuals on hepatitis C virus (HCV) RNA levels. Methods All HIV–HCV-coinfected Swiss HIV Cohort Study participants with available HCV RNA levels and concurrent CD4+ T-cell counts before starting HCV therapy were included. Potential predictors of HCV RNA levels were assessed by multivariate censored linear regression models that adjust for censored values. Results The study included 1,031 individuals. Low current and nadir CD4+ T-cell counts were significantly associated with higher HCV RNA levels ( P=0.004 and 0.001, respectively). In individuals with current CD4+ T-cell counts <200/μl, median HCV RNA levels (6.22 log10 IU/ml) were +0.14 and +0.24 log10 IU/ml higher than those with CD4+ T-cell counts of 200-500/μ l and >500/μl. Based on nadir CD4+ T-cell counts, median HCV RNA levels (6.12 log10 IU/ml) in individuals with <200/μl CD4+ T-cells were +0.06 and +0.44 log10 IU/ml higher than those with nadir T-cell counts of 200-500/μ l and >500/μ l. Median HCV RNA levels were also significantly associated with HCV genotype: lower values were associated with genotype 4 and higher values with genotype 2, as compared with genotype 1. Additional significant predictors of lower HCV RNA levels were female gender and HIV transmission through male homosexual contacts. In multivariate analyses, only CD4+ T-cell counts and HCV genotype remained significant predictors of HCV RNA levels. Conclusions Higher HCV RNA levels were associated with CD4+ T-cell depletion. This finding is in line with the crucial role of CD4+ T-cells in the control of HCV infection.
Low Response to Pegylated Interferon plus Ribavirin in HIV-Infected Patients with Chronic Hepatitis C Treated with Abacavir
Authors: Vispo Eugenia , Barreiro Pablo , Pineda Juan A , Mira José A , Maida Ivana , Martín-Carbonero Luz , Rodríguez-Nóvoa Sonia , Santos Ignacio , López-Cortes Luis F , Merino Dolores , Rivero Antonio , Soriano Vincent 
Published: April 2022

Background There is little information about the influence of antiretroviral drugs on the antiviral activity of pegylated interferon (PEG-IFN) plus ribavirin (RBV) against hepatitis C virus (HCV). Methods All HIV-infected patients with chronic hepatitis C who received first-line PEG-IFN plus RBV were retrospectively analyzed. Only patients in whom virological stopping rules were applied and who did not change their antiretrovirals were chosen. Plasma RBV concentrations were measured at week 4. Results A total of 493 patients (78% males, mean age 41 years, 78% on antiretroviral therapy, mean CD4+ T-cell count 561 cells/μl) fit the study inclusion criteria. Mean baseline serum HCV RNA was 5.89 log10 IU/ml, 65% were infected by genotypes 1 or 4 and 40% had advanced liver fibrosis (Metavir F3F4). The overall rate of sustained virological response (SVR) was 38%. Factors associated with lack of SVR in the multivariate analyses (odds ratio [95% confidence interval], P-value) were higher baseline serum HCV RNA (2.42 per log10 IU/ml [1.31–4.46], 0.005), HCV genotypes 1 or 4 (5.95 [2.50–14.29], <0.001) and lower RBV plasma trough concentrations (1.74 per μg/ml [1.15–2.63], 0.009). Interestingly, a trend was noticed for abacavir use (2.22 [0.91–5.40], 0.08), which become significant when only considering the subset of patients with RBV plasma levels <2.3 μg/ml (7.63 [1.39–41.67], 0.02). Conclusions The use of abacavir might interfere with the anti-HCV activity of PEG-IFN plus RBV. As both antivirals are guanosine analogues, an inhibitory competition between abacavir and RBV might explain this observation, which is more prominent in patients with lower RBV exposure.
Distinct Signature Type I Interferon Responses are Determined by the Infecting virus and the Target Cell
Authors: Baig Ehtesham , Fish Eleanor N 
Published: April 2022

Background Type I interferons (IFN) include multiple IFN-α subtypes which exhibit considerable amino acid identity and activate the same cell-surface receptor. The promoter regions of the IFN-α genes, however, have different transcription factor binding sites, implying differential transcriptional activation. Evolutionary conservation of multiple subtypes may have resulted from external pressures associated with the crucial nature of an IFN response, namely that different viruses that are tropic for different target tissues determine the nature and extent of an IFN response, specifically the IFN-α subtype profile. Methods Studies were undertaken to examine inducible IFN gene expression profiles in response to infection with single-stranded RNA viruses: Sendai virus (SeV), murine hepatitis virus (MHV-1) and coxsackie virus B3 (CVB3). Results In vitro, distinct signature profiles of SeV and MHV-1-inducible gene expression for IFN-α2, IFN-α4 and IFN-α5 subtypes in L2 and L929 mouse fibroblast cells, in relation to the extent and kinetics of their induction, were identified. In vivo, whereas A/J mice are highly permissive for both MHV-1 and CVB3 infections and mount a poor IFN response, C57Bl/6 mice are relatively resistant to both virus infections and mount a vigorous IFN response. Conclusions These data suggest that the infecting virus and the target cell type dictate the extent and signature of inducible type I IFN gene expression. The extent of IFN response to viral infection influences the subsequent biological outcome: a robust IFN response prescribes a level of resistance, whereas a poor IFN response contributes towards a permissive phenotype for infection.
Specific Inhibition of Orthopoxvirus Replication by a Small Interfering RNA Targeting the D5R Gene
Authors: Vigne Solenne , Germi Raphaële , Duraffour Sophie , Larrat Sylvie , Andrei Graciela , Snoeck Robert , Garin Daniel , Crance Jean-Marc 
Published: April 2022

Background Concerns about the potential use of smallpox in bioterrorism have stimulated interest in the development of novel antiviral treatments. Currently, there are no effective therapies against smallpox and new treatment strategies are greatly needed. Methods In this study, specifically designed small interfering RNAs (siRNAs), targeting five proteins essential for orthopoxvirus replication, were investigated for their ability to inhibit vaccinia virus strain Western Reserve (VACVWR) replication. Results Among these siRNAs, 100 nM siD5R-2, an siRNA targeting the D5 protein, decreased VACVWR replication up to 90% when used either prophylactically or therapeutically in human lung carcinoma A549 cells. This siRNA induced a striking concentration-dependent inhibition of VACVWR replication and a prolonged prophylactic antiviral effect that lasted for 72 h, at a concentration of 100 nM. Confocal microscopy of Alexa–siD5R-2-treated VACVWR-infected cells confirmed a decrease in viral replication. Furthermore, siD5R-2 was shown to specifically reduce the D5R mRNA and protein expression using real-time reverse tran-scriptase-PCR and western blotting analysis, without inducing interferon-β in A549 cells. We also demonstrated the antiviral potency of siD5R-2 against different pathogenic orthopoxviruses, such as cowpox and monkeypox viruses, which were inhibited up to 70% at the lowest concentration (1 nM) tested. Finally, siD5R-2 showed antiviral effects in VACVWR-infected human keratinocyte and fibroblast cell cultures. Conclusions These results suggest that siD5R-2 could be a potential candidate to treat poxvirus infections.
A Decline in Hepatitis B virus Surface Antigen (HBsAg) Predicts Clearance, but does not Correlate with Quantitative HBeAg or HBV DNA Levels
Authors: Wiegand Johannes , Wedemeyer Heiner , Finger Andrea , Heidrich Benjamin , Rosenau Jens , Michel Gerd , Bock C Thomas , Manns Michael P , Tillmann Hans L 
Published: April 2022

Background The elimination of hepatitis B virus surface antigen (HBsAg) is the final goal of hepatitis B treatment, but is rarely achieved. As quantitative assays for HBsAg recently became available, we have investigated whether quantitative HBsAg measurements can substitute for hepatitis B virus (HBV) DNA quantification in treatment monitoring. Methods Within this study, 23 liver transplant patients and 18 heart transplant recipients were retrospectively analysed. Patients had been treated with famciclovir and/or lamivudine, in addition some had also received adefovir in cases of lamivudine resistance. Quantitative HBsAg and hepatitis B virus e antigen (HBeAg) levels were determined with the ArchitectTM assay. HBV DNA levels were determined with different assays available at given time points. Results We did not find a significant correlation between either HBsAg or HBeAg and HBV DNA levels – both in treated and untreated patients. More importantly, there was no significant concordance between an increase or decrease of HBsAg or HBeAg with HBV DNA. However, the curve and decline of quantitative HBsAg enabled prediction of eventual viral clearance. Eight patients showed a 2 log10 drop of HBsAg levels and eight patients demonstrated a reduction of HBsAg levels below 100 IU/ml; five patients fulfilled both criteria. Three of those five cleared HBsAg and became positive for antibodies against HBsAg. Conclusions Quantitative HBsAg and HBeAg cannot substitute for HBV DNA quantification during the assessment of antiviral therapy; however, the decline of HBsAg does predict eventual HBsAg clearance. A 2 log10 drop to below 100 IU/ml is associated with a high likelihood of HBsAg clearance.
Effect of Lopinavir/Ritonavir Monotherapy on Quality of Life and Self-Reported Symptoms among Antiretroviral-Naive Patients: Results of the MONARK Trial
Authors: Spire Bruno , Marcellin Fabienne , Cohen-Codar Isabelle , Flandre Philippe , Boue Francois , Dellamonica Pierre , Raffi François , Norton Michael , Ngo Van Philippe , Delfraissy Jean-François 
Published: April 2022

Background Standard-of-care for HIV-infected patients consists of combining three antiretroviral drugs. However, other therapeutic strategies could be beneficial given long-term toxicity and quality of life (QOL) issues associated with taking multiple antiretroviral drugs for many years. In the prospective, open label, randomized, pilot monotherapy antiretroviral Kaletra® (MONARK) trial among antiretroviral-naive patients, lopinavir/ritonavir (LPV/r) monotherapy was found to be less suppressive for HIV RNA than a standard triple-drug therapy of LPV/r plus zidovudine/lamivudine (on-treatment analysis after 48 weeks). We present data from the MONARK trial concerning QOL and patient-reported symptoms. Methods Patient-reported symptoms were collected at baseline and at weeks 4, 12, 24 and 48 using a list of 22 symptoms. QOL was assessed at baseline, week 24 and week 48 using the six-domain World Health Organization QOL short form questionnaire for HIV-infected individuals including an evaluation of global health perception. Results Patients treated with the standard triple-drug therapy reported significantly more symptoms over 48 weeks of treatment than patients treated with LPV/r monotherapy (incidence rate ratio [95% confidence interval] 1.3 [1.1, 1.6] P=0.001 and 1.4 [1.2, 1.7] P=0.0004 for the total number of symptoms and the number of symptoms causing discomfort, respectively). No baseline differences and no significant changes were observed in the six QOL scores. The percentage of patients with a positive perception of their global health status increased significantly in the monotherapy arm from 32% at baseline to 67% at week 48 ( P<0.0001). Conclusions These results suggest that the number of self-reported symptoms could be used as a treatment-sensitive measure of patients’ well-being in clinical trials.
Long-Term follow-up of Lamivudine Treatment in Patients with Severe Acute Exacerbation of Hepatitis B e Antigen (HBeAg)-Positive Chronic Hepatitis B
Authors: Wong Vincent Wai-Sun , Wong Grace Lai-Hung , Tsang Steven Woon-Choy , Hui Alex Yui , Chim Angel Mei-Ling , Yiu Karen Kar-Lum , Chan Hoi-Yun , Chan Francis Ka-Leung , Sung Joseph Jao-Yiu , Chan Henry Lik-Yuen 
Published: April 2022

Background The long-term efficacy of lamivudine treatment for patients suffering from severe acute exacerbation of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B is unknown. Methods Consecutive patients with severe acute exacerbation of HBeAg-positive chronic hepatitis B were prospectively recruited from 1999 to 2004 and treated with lamivudine. All patients had alanine amino-transferase (ALT) and serum bilirubin levels 10x and 3x above the upper limit of normal, respectively. HBeAg-positive patients without severe acute exacerbation served as controls. Results Forty-five patients with severe acute exacerbation and 31 controls were treated with lamivudine for a median of 2.8 (range 1.0–7.1) years and 3.8 (range 3.5–8.4) years, respectively. Compared with controls, patients with severe acute exacerbation had higher HBeAg seroconversion rates (78% versus 52%; P=0.02) and lower risk of virological breakthrough. However, 33% of patients with severe acute exacerbation still developed lamivudine resistance and virological breakthrough by year 5. HBV DNA levels at week 4 and prolonged baseline prothrombin time were independent factors associated with virological breakthrough. All patients with week 4 HBV DNA <3 log10 copies/ml had maintained virological response. Among 15 patients who stopped lamivudine after sustained HBeAg seroconversion for ≥6 months, 11 (73%) had virological relapse at a median of 1.4 (0.2-3.9) years. ALT increased beyond 10x the upper limit of normal in six (38%) patients who stopped lamivudine and two (7%) patients on maintained lamivudine treatment ( P=0.02). Conclusion Among patients with severe acute exacerbation of HBeAg-positive chronic hepatitis B treated with lamivudine, virological breakthrough and post-treatment relapse are common despite a high rate of HBeAg seroconversion. Severe hepatitis flare is also common particularly among patients developing virological relapse after discontinuation of lamivudine.
Rapid Quantitation of Neuraminidase Inhibitor Drug Resistance in Influenza virus Quasispecies
Authors: Lackenby Angie , Democratis Jane , Siqueira Marilda M , Zambon Maria C 
Published: April 2022

Background Emerging resistance of influenza viruses to neuraminidase inhibitors is a concern, both in surveillance of global circulating strains and in treatment of individual patients. Current methodologies to detect resistance rely on the use of cultured virus, thus taking time to complete or lacking the sensitivity to detect mutations in viral quasispecies. Methodology for rapid detection of clinically meaningful resistance is needed to assist individual patient management and to track the transmission of resistant viruses in the community. Methods We have developed a pyrosequencing methodology to detect and quantitate influenza neuraminidase inhibitor resistance mutations in cultured virus and directly in clinical material. Our assays target polymorphisms associated with drug resistance in the neuraminidase genes of human influenza A H1N1 as well as human and avian H5N1 viruses. Quantitation can be achieved using viral RNA extracted directly from respiratory or tissue samples, thus eliminating the need for virus culture and allowing the assay of highly pathogenic viruses such as H5N1 without high containment laboratory facilities. Results Antiviral-resistant quasispecies are detected and quantitated accurately when present in the total virus population at levels as low as 10%. Pyrosequencing is a real-time assay; therefore, results can be obtained within a clinically relevant timeframe and provide information capable of informing individual patient or outbreak management. Conclusions Pyrosequencing is ideally suited for early identification of emerging antiviral resistance in human and avian influenza infection and is a useful tool for laboratory surveillance and pandemic preparedness.
Population Trends in the Prevalence and Patterns of Protease Resistance Related to Exposure to Unboosted and Boosted Protease Inhibitors
Authors:   The UK Collaborative Group on HIV Drug Resistance and the UK Collaborative HIV Cohort Study, Dunn David , Geretti Anna Maria , Green Hannah , Fearnhill Esther , Pozniak Anton , Churchill Duncan , Pillay Deenan , Sabin Caroline , Phillips Andrew 
Published: April 2022

Background In recent years, several new drugs from the protease inhibitor (PI) class designed to treat HIV infection have become available and the use of ritonavir-boosting has increased in popularity. These changes might be expected to affect the prevalence and patterns of protease resistance in the population of patients who experience treatment failure. Methods The UK HIV Drug Resistance Database aims to capture the results of all genotypic resistance tests conducted nationally. Tests on antiretroviral therapy-experienced patients were identified through linkage with the UK Collaborative HIV Cohort Study, from which detailed clinical information on these patients, including a full antiretroviral therapy history, was obtained. Results Analyses were on the basis of 8,553 genotypic resistance tests carried out between 1998 and 2005, during which time the overall prevalence of protease resistance halved from 35% to 16%. Substantial declines were observed regardless of whether the patient had been exposed to unboosted PIs and/or boosted PIs. The frequency of protease resistance among patients who had received boosted PIs fell sharply until 2002 with a weaker trend thereafter, falling to 12% in 2005. Individual mutations L33F, M46I/L, V82A/F/T/S/L and I84V became relatively more frequent over the period of study. Conclusions The decline in protease resistance was partly due to increasing use of ritonavir-boosting. Nonetheless, the prevalence of resistance was higher than suggested by clinical trials, indicating that prolonged exposure to a boosted PI could ultimately select for major protease mutations.
Mitochondrial DNA Depletion in Oocytes of HIV-Infected Antiretroviral-Treated Infertile Women
Authors: López Sònia , Coll Oriol , Durban Mercè , Hernàndez Sandra , Vidal Ricard , Suy Anna , Morén Constanza , Casademont Jordi , Cardellach Francesc , Mataró Daniel , Miró Òscar , Garrabou Glòria 
Published: April 2022

Background HIV-infected women under highly active antiretroviral therapy (HAART) undergoing in vitro fertilization (IVF) have a lower pregnancy rate than non-infected controls, which depends on oocyte-related factors. We hypothesized that mitochondrial toxicity caused by antiretrovirals could be the underlying mechanism of such disturbance. Methods We have studied 16 and 19 frozen-thawed oocytes obtained after oocyte retrieval IVF cycles from 8 and 14 infertile HIV-infected and uninfected women, respectively, matched by age. At inclusion, HIV-positive women had been infected for >13 years and had received HAART for >9 years, including at least one nucleoside reverse transcriptase inhibitor. All of them had undetectable HIV viral load and a good immunological status. Mitochondrial DNA (mtDNA) content was determined by quantitative real-time PCR in each individual oocyte. Results HIV-infected infertile women on HAART showed significant oocyte mtDNA depletion when compared with uninfected controls (32% mtDNA decrease, P<0.05). This oocyte mtDNA depletion was even greater on those HIV-infected women who failed to become pregnant when compared with controls (39% mtDNA decrease, P=0.03). No significant correlation was found between mtDNA oocyte content and cumulative doses of antiretrovirals or the immunological status of HIV patients. Conclusions Oocytes from infertile HIV-infected HAART-treated women show decreased mtDNA content, and this could explain their poor reproductive outcome.
Effect of Nucleoside and Nucleotide Reverse Transcriptase Inhibitors of HIV on Endogenous Nucleotide Pools
Authors: Vela Jennifer E , Miller Michael D , Rhodes Gerald R , Ray Adrian S 
Published: April 2022

Background Alterations in endogenous nucleotide pools as a result of HIV therapy with nucleoside and nucleotide reverse transcriptase inhibitors (N[t]RTIs) is a proposed mechanism for therapy-related adverse events and drug interactions resulting in treatment failure. In vitro studies were performed in order to understand the effect of N(t)RTIs on endogenous nucleotide pools. Methods The T-cell line CEM-CCRF was treated with control antimetabolites or the N(t)RTIs abacavir, didanosine, lamivudine, tenofovir (TFV) and zidovudine (AZT), either alone or in combination. The levels of natural 2′-deoxynucleoside triphosphates (dNTP) and ribonucleoside triphophosphates were determined by liquid chromatography coupled with triple quadrupole mass spectrometry. Results Antimetabolites altered nucleotide pools in a manner consistent with their known mechanisms of action. AZT was the only N(t)RTI that significantly altered dNTP pools. Incubation of 10 μM AZT, either alone or in combination with other N(t)RTIs, increased 2′-deoxyadenosine triphosphate, 2′-deoxyguanosine triphosphate and thymidine triphosphate levels by up to 1.44-fold the concentrations observed in untreated cells. At higher than pharmacological concentrations of AZT, evidence for inhibition of 2′-deoxycytidylate deaminase and enzymes involved in the salvage of thymidine was also observed. Phosphorylated metabolites of TFV are known to inhibit purine nucleoside phosphorylase (PNP). However, in contrast to a potent PNP inhibitor, TFV was unable to alter intracellular dNTP pools upon addition of exogenous 2′-deoxyguanosine. Conclusions N(t)RTIs have the potential to alter nucleotide pools; however, at the pharmacologically relevant concentrations, tested N(t)RTI or their combinations did not have an effect on nucleotide pools with the notable exception of AZT.