bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiviral Potency Analysis and Functional Comparison of Consensus Interferon, Interferon-α2a and Pegylated Interferon-α2b against Hepatitis C virus Infection
Authors: Erickson Andrea K , Seiwert Scott , Gale Michael 
Published: April 2022

Background Current treatments for chronic hepatitis C virus (HCV) employing pegylated interferon (PEG-IFN) plus ribavirin are successful in approximately 50% of patients. Consensus IFN (CIFN) is a recombinant type I IFN that has demonstrated efficacy where conventional therapy has failed. We evaluated the host cell antiviral response and anti-HCV actions induced by IFN-α2a, PEG-IFN-α2b or CIFN on cultured immortalized human hepatocytes, Huh7 human hepatoma cells and Huh7 cells that harboured genetically distinct HCV RNA replicons or were infected with HCV 2a. Methods Cultured cells were treated with each IFN at relevant dosing based upon the pharmacological attainable in vivo serum maximum IFN concentrations. Gene expression and antiviral properties were measured using protein, RNA and virus quantification assays. Results CIFN treatment maximally triggered Janus kinase signal transducer and activator of transcription signalling in association with enhanced IFN-stimulated gene (ISG) expression. Increased antiviral potency of CIFN was associated with enhancement of IFN-induced blockade upon viral protein synthesis, protection of the cellular IFN promoter stimulator-1 (IPS-1) protein from HCV proteolysis and reduced replication of an IFN-resistant HCV replicon variant. Microarray analyses revealed that CIFN treatment induced a distinct pattern of ISG expression in cultured hepatocytes compared with other IFNs. Conclusions CIFN exhibits increased anti-HCV potency over IFN-α2a and PEG-IFN through maximal and distinct induction of ISG expression and enhanced intracellular innate antiviral response, while protecting IPS-1 from HCV proteolysis. CIFN might offer a treatment regimen imparting translational control programmes and restoration of the retinoic acid-inducible gene-1/IPS-1 pathway and could be considered for previous treatment failures.
Abacavir does not Influence the Rate of Virological Response in HIV–HCV-Coinfected Patients Treated with Pegylated Interferon and Weight-Adjusted Ribavirin
Authors: Laufer Natalia , Laguno Montserrat , Perez Iñaki , Cifuentes Carmen , Murillas Javier , Vidal Francesc , Bonet Lucia , Veloso Sergio , Gatell José María , Mallolas Josep 
Published: April 2022

Background The combination of pegylated interferon (PEG-IFN) plus ribavirin (RBV) is the standard of care for hepatitis C virus (HCV) treatment in HIV-coinfected individuals. In 2007, abacavir (ABC)-based antiretroviral therapy was, for the first time, reported to be associated with early virological failure during HCV treatment. The aim of our study was to evaluate the effect of ABC on the response rate to HCV therapy. Methods A retrospective analysis of HIV–HCV- coinfected patients treated with PEG-IFN and weight-adjusted RBV in four hospitals in Spain was performed. An analysis of baseline descriptive variables was conducted. Logistic regression models were used to test possible associations between non-response and pretreatment characteristics, including antiretroviral drugs. Results A total of 244 HIV–HCV-coinfected patients treated with PEG-IFN and RBV were included. Overall, 85% of patients were on highly active antiretroviral therapy; of these patients, 24% received ABC-based regimens. The most frequent genotypes were 1 and 3. RBV dosing was ≥13.2 mg/kg/day in 97% of the patients. In the global intent-to-treat analyses, 46.3% of patients reached a sustained virological response (SVR; 46.2% in ABC group versus 46.7% in non-ABC group, P=1). The only two factors in the multivariate analysis that were statistically associated with an increased risk of failure to achieve SVR were HCV genotypes 1 or 4 and older age. The use of ABC was not associated with failure to achieve SVR at any of the other time points evaluated. Conclusions Our data suggest that the use of ABC-based regimens in the context of HCV therapy does not negatively affect the outcome of this treatment.
Raltegravir Susceptibility and Fitness Progression of HIV Type-1 Integrase in Patients on Long-Term Antiretroviral Therapy
Authors: Buzón Maria José , Marfil Silvia , Puertas Maria C , Garcia Elisabet , Clotet Bonaventura , Ruiz Lidia , Blanco Julià , Martinez-Picado Javier , Cabrera Cecilia 
Published: April 2022

Background HIV type-1 (HIV-1) protease (PR), reverse transcriptase (RT) and integrase (IN) share the same precursor polyprotein and there is much evidence to suggest functional interactions between IN and RT. We aimed to elucidate whether long-term highly active antiretroviral therapy (HAART) targeting PR and RT could influence raltegravir susceptibility and the fitness of IN. Methods HIV-1 IN sequences from 45 heavily antiretroviral-experienced patients with longitudinal samples separated by a median of 10 years were obtained to estimate the rate of nucleotide substitution. IN recombinant viruses were generated from five selected patients. Phenotypic susceptibility to raltegravir was tested in vitro. Changes in viral replication capacity were assayed by growth kinetics and competition of intrapatient IN recombinant viruses. Results The amino acid substitution rate within IN was 0.06% per year during long-term antiretroviral treatment. Some substitutions had previously been associated with resistance to different IN inhibitors. Despite this, neither the early- nor late-derived IN recombinant viruses showed an increase in phenotypic susceptibility to raltegravir. Moreover, IN recombinant viruses corresponding to IN samples after 10 years of HAART had a replication capacity that was similar to or better than IN recombinant viruses from baseline samples. Conclusions HIV-1 IN from longitudinal samples taken from patients treated with IN inhibitor-sparing regimens showed no evidence of genotypic or phenotypic resistance to raltegravir. Additionally, long-term pressure with PR and RT inhibitors did not impair the fitness of HIV-1 IN. These data suggest that current antiretroviral regimens do not diminish the fitness of IN or influence raltegravir efficacy.
A Hepatitis C Viral Kinetic Model that Allows for Time-Varying Drug Effectiveness
Authors: Shudo Emi , Ribeiro Ruy M , Talal Andrew H , Perelson Alan S 
Published: April 2022

Background The standard model of hepatitis C virus (HCV) dynamics under high-dose daily interferon (IFN) therapy assumed that the drug effectiveness remains constant. However, for treatment with pegylated (PEG)-IFN-α2b dosed weekly, drug levels fall substantially and viral load rebounds have been observed toward the end of the weekly dosing interval, implying non-constant drug efficacy. Methods In this paper, we developed the decreasing effectiveness (DE) model, a new mathematical model that allows the drug effectiveness to change with time. Results The DE model can describe viral load rebounds as well as other viral kinetic patterns observed in clinical practice, such as biphasic viral declines. We applied the DE model to the HCV RNA kinetic data under PEG-IFN-α2b therapy. The average drug effectiveness during the first week of therapy estimated in the DE model agreed with the one estimated from HCV RNA kinetic data plus pharmacokinetic data. Conclusions We illustrated the usefulness of the DE model by analysing HCV RNA data from patients who received PEG-IFN-α2b once weekly plus daily ribavirin.
Severe Hyperlactataemia Complicating Stavudine First-Line Antiretroviral Therapy in South Africa
Authors: Stead David , Osler Meg , Boulle Andrew , Rebe Kevin , Meintjes Graeme 
Published: April 2022

Background In the public sector antiretroviral therapy (ART) programme in South Africa the standardized first-line regimen includes stavudine (d4T). Severe symptomatic hyperlactataemia (SHL) is a potentially life- threatening complication of d4T. Methods GF Jooste Hospital is a referral centre for six ART clinics. We retrospectively reviewed cases referred with lactate levels ≥5 mmol/l that were attributed to nucleoside reverse transcriptase inhibitors from August 2003 to November 2005. We calculated cumulative ART exposure in patients attending these clinics to derive a referral rate. Results In total, 75 patients were referred with severe SHL (71 female). All had been on d4T and on ART for a median of 10 months. The referral rate for severe SHL was 17.5 cases per 1,000 patient-years. In 53 patients (71%), lactic acidosis (standard bicarbonate [SHCO3]<20 mmol/l) was confirmed, resulting in a referral rate of 12.3 cases per 1,000 patient-years. Twelve patients (16%) died during acute admission (≤30 days). SHCO3<15 mmol/l and pH<7.2 were the only factors associated with acute mortality (odds ratio [OR] 22.5, 95% confidence interval [CI] 2.8–1,045.7 and OR 13.9, 95% CI 2.7–86.9, respectively). A total of 30 less severe cases were rechallenged with zidovudine without recurrence of SHL. Conclusions This study confirms a high incidence of severe SHL in Africa, which has been shown in previous studies. Rechallenge with zidovudine in less severe cases was found to be safe.
Tenofovir use is Associated with an Increase in Serum Alkaline Phosphatase in the Swiss HIV Cohort Study
Authors: Fux Christoph A , Rauch Andri , Simcock Mathew , Bucher Heiner C , Hirschel Bernard , Opravil Milos , Vernazza Pietro , Cavassini Matthias , Bernasconi Enos , Elzi Luigia , Furrer Hansjakob ,   the Swiss HIV Cohort Study
Published: April 2022

Background Tenofovir (TDF) use has been associated with proximal renal tubulopathy, reduced calculated glomerular filtration rates (cGFR) and losses in bone mineral density. Bone resorption could result in a compensatory osteoblast activation indicated by an increase in serum alkaline phosphatase (sAP). A few small studies have reported a positive correlation between renal phosphate losses, increased bone turnover and sAP. Methods We analysed sAP dynamics in patients initiating ( n=657), reinitiating ( n=361) and discontinuing ( n=73) combined antiretroviral therapy with and without TDF and assessed correlations with clinical and epidemiological parameters. Results TDF use was associated with a significant increase of sAP from a median of 74 U/l (interquartile range 60–98) to a plateau of 99 U/l (82–123) after 6 months ( P<0.0001), with a prompt return to baseline upon TDF discontinuation. No change occurred in TDF-sparing regimes. Univariable and multivariable linear regression analyses revealed a positive correlation between sAP and TDF use ( P≤0.003), but no correlation with baseline cGFR, TDF-related cGFR reduction, changes in serum alanine aminotransferase (sALT) or active hepatitis C. Conclusions We document a highly significant association between TDF use and increased sAP in a large observational cohort. The lack of correlation between TDF use and sALT suggests that the increase in sAP is because of the bone isoenzyme and indicates stimulated bone turnover. This finding, together with published data on TDF-related renal phosphate losses, this finding raises concerns that TDF use could result in osteomalacia with a loss in bone mineral density at least in a subset of patients. This potentially severe long-term toxicity should be addressed in future studies.
Cystatin C as a Marker of Renal Function is Affected by HIV Replication Leading to an Underestimation of Kidney Function in HIV Patients
Authors: Mauss Stefan , Berger Florian , Kuschak Dieter , Henke Julia , Hegener Petra , Wolf Eva , Schauseil Stephan , Schmutz Guenther 
Published: April 2022

Background Broad use of tenofovir and an ageing HIV-infected population have created an interest in renal function in HIV patients. Serum cystatin C is a newer marker of renal function and might be more sensitive than creatinine. Methods Patients were enrolled consecutively in an observational study. HIV-seropositive patients naive to antiretroviral therapy ( n=261) were compared with healthy volunteers undergoing check-up procedures ( n=193). Estimated glomerular filtration rate (eGFR) was derived using creatinine-based Modification of Diet in Renal Disease (MDRD) and Cockcroft–Gault formulas or cystatin C-based calculations. HIV-seropositive patients starting antiretroviral therapy ( n=92) were followed prospectively after enrolment. Results MDRD showed a higher median eGFR in antiretroviral- naive HIV-seropositive patients compared with controls (104 versus 93 ml/min; P<0.001). Cockcroft–Gault gave similar results (118 versus 106 ml/min; P<0.001). By contrast, cystatin C levels in HIV-seropositive individuals were higher, resulting in a lower median eGFR compared with controls (99 versus 120 ml/min; P<0.001). Cystatin C was positively correlated with HIV RNA ( r=0.33, P<0.01) and inversely correlated with CD4+ T-cell count ( r=-0.29, P<0.01). Initiating antiretroviral therapy ( n=92) decreased cystatin C levels and led to an increased cystatin C-based eGFR from median 84 to 103 ml/min at week 24 ( P<0.001). Serum creatinine was not substantially altered. Conclusions Correlation of cystatin C with HIV RNA and CD4+ T–cell count, plus decrease of cystatin C after suppression of HIV replication, suggest an increase of cystatin C levels by active HIV infection. This might result in overestimation of renal impairment, particularly in treatment-naive patients. Therefore, use of cystatin C to calculate GFR in HIV-seropositive individuals should not be recommended without further validation.
Adefovir for Chronic Hepatitis B Treatment: Identification of Virological Markers Linked to Therapy Response
Authors: Rodriguez-Frias Francisco , Jardi Rosendo , Schaper Melanie , Buti Maria , Ferrer-Costa Carles , Tabernero David , Homs Maria , Esteban Rafael 
Published: April 2022

Background HBV variants rtA181V/T, rtN236T and rtI233V, which confer resistance to adefovir dipivoxil (ADV), are not detected in many non-responding patients. Virological characteristics useful for predicting response have not been clearly elucidated. We determined pre-treatment virological markers to predict non-response and possible emergence of new variants during therapy. Methods This longitudinal study included 41 patients with chronic hepatitis B virus (HBV) infection receiving ADV monotherapy or ADV plus lamivudine (3TC). A fragment of HBV polymerase including catalytic domains was analysed for ADV-resistant variants. Results Complete virological response (CVR; HBV DNA<2.5 log10 copies/ml) was observed in 15 (36.6%) patients and partial virological response (PVR; HBV DNA<4 log10 copies/ml) in 23 (56.1%) patients. On multivariate analyses, hepatitis B e antigen (HBeAg) status was independently associated with CVR (hazard ratio [HR]=0.27, P=0.002) and PVR (HR=0.21, P<0.001) and viral genotype with CVR (HR=0.13, P=0.01). Predictive values for HBeAg were 88% for PVR in HBeAg-negative and 79% for non-CVR in HBeAg-positive patients. Predictive values for viral genotype were 93% for non-CVR and 72% for non-PVR for genotype A. On sequencing, variant rt217R (associated with subgenotype A2) was predictive of non-CVR (100%) and non-PVR (72.7%); the rtS219A variant emerged during therapy in three non-PVR patients. Both positions are located in a region likely to be related to the substrate union site, as predicted by our structural model of the HBV polymerase. Conclusions Virological pretreatment characteristics (HBeAg, viral genotype and rtL217R polymorphism) are potentially associated with ADV response. HBV polymerase structural modelling has provided a hypothesis to explain the molecular mechanism for ADV resistance associated with rtR217.
Recommendations for surveillance of transmitted HIV drug resistance in countries scaling up antiretroviral treatment
Authors: Bennett Diane E , Myatt Mark , Bertagnolio Silvia , Sutherland Donald , Gilks Charles F 
Published: April 2022

Background The World Health Organization (WHO) HIV drug resistance (HIVDR) threshold survey method was developed for surveillance of transmitted HIVDR in resource-limited countries. The method is being implemented with minimal resources as a routine public health activity to produce comparable results in multiple countries and areas within countries. Transmitted drug resistant HIV strains will be seen first in cities or health districts where antiretroviral treatment (ART) has been widely available for years. WHO recommends countries begin surveillance in these areas. Methods Each survey requires ≤47 specimens from individuals consecutively diagnosed with HIV to categorize resistance to each relevant drug class as <5%, 5–15% or >15%. Use of routinely collected information and remnant specimens is recommended to minimize costs. Site and individual eligibility criteria are designed to minimize inclusion of ARV-experienced individuals and individuals infected before ART was available. Results Surveys have been implemented in 21 countries. In this supplement, seven countries report results of <5% transmitted HIVDR in areas where ART has been available for the longest time period. The main challenges in implementation are acquiring sufficient numbers of eligible specimens and optimizing specimen handling. Conclusion The WHO HIVDR threshold survey method is feasible in resource-limited countries and produces information relevant to ART and drug resistance prevention planning.
HIV drug resistance threshold survey using specimens from voluntary counselling and testing sites in Hanoi, Vietnam
Authors: Nguyen Hien Tran , Duc Nguyen Bui , Shrivastava Ritu , Tran Tram Hong , Nguyen Tuan Anh , Thang Pham Hong , McNicholl Janet M , Leelawiwat Wanna , Chonwattana Wannee , Sidibe Kassim , Fujita Masami , Luu Chau Minh T , Kakkar Reshma , Bennett Diane E , Kaplan Jonathan , Cosimi Lisa , Wolfe Mitchell I 
Published: April 2022

Background In countries where antiretroviral therapy has been available or is being rapidly expanded, the World Health Organization (WHO) recommends surveillance for transmitted HIV drug resistance (HIVDR) by threshold surveillance methods using specimens from antenatal clinics or voluntary counselling and testing (VCT) sites. The aim of this study was to implement the HIVDR threshold survey in VCT sites in Vietnam, where HIV prevalence is high. Estimating transmitted resistance in the infected population will enable the appropriateness of current antiretroviral drug regimens to be assessed and will inform plans for future HIVDR surveillance. Methods Consecutive blood specimens were collected from 70 newly diagnosed HIV-positive clients 18–24 years of age at two sites in Hanoi, Vietnam. Informed consent and serum specimens were obtained from each eligible client, with serum frozen at -70°C until shipping to Thailand for resistance testing using the TruGene system. Results From February until August 2006, 559 clients were eligible to participate in this survey. Of the 535 clients (95.7%) who agreed to participate, 70 (13%) were HIV-positive and were included in the survey. Of the 70 specimens sent for genotyping, 52 consecutive samples were amplified, 49 of which could be genotyped. Only 1 of 49 genotyped specimens had mutations associated with drug resistance (L74V and Y181C) in the reverse transcriptase gene, indicating that the prevalence of transmitted HIVDR to all drugs and drug classes evaluated was <5%. Conclusion The prevalence of transmitted HIVDR was low in Hanoi as determined using threshold surveillance methods. The Ministry of Health plans to repeat this survey methodology in one more province and to confirm these findings by expanded HIVDR surveillance.
Are mutations in HIV type-1 reverse transcriptase 245 codon predictive of abacavir hypersensitivity reaction?
Authors: Bracciale Laura , Santangelo Rosaria , Fanti Iuri , Prosperi Mattia , Colafigli Mauela , Di Giambenedetto Simona , Marchetti Simona , Di Franco Aldo , Cauda Roberto , De Luca Andrea 
Published: April 2022

Background HLA-B*5701 is strongly related to abacavir hypersensitivity reactions (HSRs). Polymorphisms at position 245 of HIV type-1 (HIV-1) reverse transcriptase (RT) show an association with HLA-B*5701 suggesting that viral genotyping performed for antiretroviral drug resistance testing could reduce human leukocyte antigen (HLA) screening necessity to prevent abacavir HSR. Methods To further test the validity of 245 codon analysis results for predicting HSR, we analysed 1,179 sequences from 752 HIV-1-infected patients. Results Mutant amino acid residues in RT 245 were found in 30.6% of sequences. Among 239 patients with multiple longitudinal genotypes, 245 residues varied in 37 (15.5%) from wild type to mutant and/or vice versa. All these changes appeared during antiretroviral treatment. A total of 15 out of 229 (6.5%) abacavir-treated patients developed a clinically confirmed HSR: all carried B subtypes. There was no significant difference in the prevalence of 245 mutants between abacavir-treated patients with HSR (27%) and those without (29%), even after limiting the analysis to subtype B carriers. Conclusions The significant intraindividual variability of 245 residues and the lack of their association with clinically confirmed HSR argue against their use as viral genetic markers to exclude patients at risk for HSR.
Absence of a relation between efavirenz plasma concentrations and toxicity-driven efavirenz discontinuations in the EuroSIDA study
Authors:   on behalf of the EuroSIDA study group, van Luin Matthijs , Bannister Wendy P , Mocroft Amanda , Reiss Peter , Perri Di Giovanni , Peytavin Gilles , Molto José , Karlson Anders , Castagna Antonella , Beniowski Marek , Lundgren Jens D , Burger David M 
Published: April 2022

Background Conflicting data exist regarding the effect of efavirenz (EFV) plasma concentrations on central nervous system (CNS) toxicity. We aimed to determine whether patients with high EFV plasma concentrations have an increased likelihood of toxicity-driven EFV discontinuations. Methods EFV plasma concentrations were measured from patients in the EuroSIDA study starting EFV after 1 January 1999. Patients with a plasma concentration available were divided into those that discontinued EFV because of any toxicity or by the choice of the patient or physician within 2 years (TOXPC group) and those that continued EFV for ≥2 years (no toxicity group). Multivariable logistic regression modelling was used to investigate the effects of the EFV plasma concentration and those of other potentially relevant factors on the risk of toxicity-induced EFV discontinuations. Results A total of 843 patients were included. Of these patients, 138 patients (16.4%) discontinued EFV because of TOXPC and 705 (83.6%) patients continued EFV for ≥2 years. A total of 20 (14.5%) patients in the TOXPC group had high EFV plasma concentrations (>4.0 mg/l) compared with 99 (14.0%) patients in the no toxicity group ( P=0.890). A positive hepatitis C status ( P=0.026), but not the EFV plasma concentration, was an independent predictor of toxicity-driven EFV discontinuations. Conclusions No association was found between EFV plasma concentrations and the risk of EFV discontinuations because of (CNS) toxicity. This result questions the designation of EFV plasma concentrations >4.0 mg/l as being ‘toxic’, at least when defined by treatment discontinuation.