bluuebunny/crossref_metadata_2025_split huggingface dataset:
HIV Genotypic Resistance Testing to Optimize Antiretroviral Prescribing: Is There Room for Improvement?
Authors: Uy Jonathan , Brooks John T , Baker Rose , Hoffman Mark , Moorman Anne , Novak Richard ,   the HOPS investigators
Published: April 2022

Background Clinical utilization of genotype resistance testing is evolving. We examined the extent to which HIV care providers requesting genotype resistance tests used the information appropriately and the impact of inappropriate utilization. Methods Data from a prospective cohort of HIV-infected patients (the HIV Outpatient Study) were used in the analysis. We analysed the frequency with which patients were prescribed any non-nucleoside reverse transcriptase inhibitor after identification of the K103N mutation in reverse transcriptase and the frequency of prescription of nelfinavir after identification of the D30N mutation in HIV protease; the short-term impact of this action on HIV viral load and CD4+ T-cell count was assessed. Results Among 441 patients demonstrating either mutation, 18% who were taking the resistant antiretroviral at the time of the test were continued on the medication for >6 months after this finding. In 33% of these instances, prescribers reported these actions were erroneous oversights. For persons taking the resistant antiretroviral at the time of the genotype test, stopping this medication within 6 months of the test produced greater decreases in viral load (-1.35 versus -0.43 log copies/ml, P=0.025) and a greater likelihood of achieving an undetectable viral load (25.3% versus 7.3%, P=0.012) at 9 months. Changes in CD4+ T-cell count differed (+22.8 versus -23.0 cells/mm3), but not significantly ( P=0.167). Conclusions Following evidence of definitive resistance by genotype testing, a substantial fraction of antiretroviral prescriptions were continued in error leading to an attenuated therapeutic response. These data highlight the need to consider better systems to manage genotype resistance testing data in the clinical setting.
Natural History of Compensated and Decompensated HCV-Related Cirrhosis in HIV-Infected Patients: A Prospective Multicentre Study
Authors: Girón-González José A , Brun Francisco , Terrón Alberto , Vergara Antonio , Arizcorreta Ana 
Published: April 2022

Objective To define the course of HIV-HCV-coinfected patients with compensated and decompensated liver cirrhosis and to investigate the survival and the risk factors for death. Patients and methods Ninety-two HIV-infected patients with HCV-related cirrhosis (50 of them without and 42 with previous decompensations) were prospectively followed up during a median period of 20 months. Clinical, biochemical, virological and immunological factors were analysed. Multivariate analyses were performed of those factors associated with decompensations and mortality. Results There were 168 readmissions due to liver-disease-related causes. A Child-Pugh index ≥6 in those without previous decompensations (hazard ratio [HR] 7.94, 95% confidence interval [CI] 1.59–39.58; P=0.014), and Child-Pugh index ≥9 (HR 2.68, 95% CI 1.13–6.33; P=0.003) and absence of HAART (HR 0.44, 95% CI 0.19–0.98; P=0.048) in those with previous decompensations were independently associated with decompensation during the follow up. There were 27 deaths, 22 of them attributable to liver disease. Independent factors associated with liver-related mortality were a Child-Pugh index ≥9 (HR 6.24, 95% CI 2.31–16.85; P<0.001), progression of Child-Pugh index during the follow up (HR 4.27, 95% CI 1.54–11.80; P=0.008), more than one decompensation (HR 24.25, 95% CI 7.27–40.45; P<0.001) and absence of HAART (HR 0.35, 95% CI 0.12–0.98; P=0.002). Conclusions Evolution from compensated to decompensated cirrhosis and death is influenced by markers of liver function and the absence of HAART. The importance of this last element must be adequately stressed.
Different Mutations in the HHV-6 DNA Polymerase Gene Accounting for Resistance to Foscarnet
Authors: Bonnafous Pascale , Naesens Lieve , Petrella Stéphanie , Gautheret-Dejean Agnès , Boutolleau David , Sougakoff Wladimir , Agut Henri 
Published: April 2022

Background Human herpesvirus 6 (HHV-6), which is closely related to human cytomegalovirus, is sensitive to foscarnet (PFA). Up to now, the resistance of HHV-6 to PFA has not been investigated. Objectives The goal of the study was to isolate and characterize PFA-resistant HHV-6 mutants in order to determine the mechanisms of resistance to the drug. Methods PFA-resistant viruses, isolated in MT4 cell culture under increasing concentrations of PFA, were characterized phenotypically and genotypically. The mutations identified in the HHV-6 DNA polymerase gene were evaluated in a functional assay using recombinant mutated forms of the enzyme, and their effect on protein structure was analysed in a three-dimensional model derived from available structures of DNA polymerases. Results Two mutants were selected and were 8- and 15-fold more resistant to PFA than the wild-type strain. Four amino acid changes were detected in the HHV-6 DNA polymerase in association with PFA resistance: T435R, H507Y, C525S, located in the δC conserved domain, and F292S. Either alone or in combination, these substitutions significantly decreased the inhibitory effect of PFA at the level of the polymerase, as measured by the incorporation of radiolabeled nucleotides in a DNA elongation assay. In the three-dimensional model of HHV-6 DNA polymerase structure the four changes were not located within the putative catalytic site, but they might induce either a disturbance of local conformation or a restricted access of PFA to its target site. Conclusion This first characterization of HHV-6 resistance to PFA highlights the role of distinct DNA polymerase gene mutations.
Predictors of Clinical Progression among HIV-1–Positive Patients starting HAART with CD4+ T-cell Counts ≥200 cells/mm3
Authors: Lapadula Giuseppe , Torti Carlo , Maggiolo Franco , Casari Salvatore , Suter Fredy , Minoli Lorenzo , Pezzoli Chiara , Pietro Massimo Di , Migliorino Guglielmo , Quiros-Roldan Eugenia , Ladisa Nicoletta , Sighinolfi Laura , Costarelli Silvia , Carosi Giampiero ,   for the Italian MASTER Cohort, Carosi G , Puoti M , Torti C , Roldan E Quiros , Paraninfo G , Casari S , Antinori A , Antonucci G , Ammassari A , Angarano A , Saracino A , Cauda R , De Luca A , Monforte A D'Arminio , Cicconi P , Mazzotta F , Caputo S Lo , Marino N , Minoli L , Maserati R , Novati S , Tinelli C , Ghinelli F , Sighinolfi L , Pastore G , Ladisa N , Quirino T , Migliorino M , Suter F , Maggiolo F , Suligoi Barbara , Zeni Cristina , Brognoli Francesca , Bando Ruth 
Published: April 2022

Background Baseline and follow-up predictors of new AIDS-defining events (ADE) or death among patients who started HAART with CD4+ T-cell counts ≥200 cells/mm3 have rarely been assessed simultaneously. Methods A prospective observational cohort study (1996–2002) is reported. HIV-infected patients initiating HAART with a CD4+ T-cell count ≥200 cells/mm3 were studied. Baseline and time-varying factors were tested for the prediction of new ADE/death using Cox regression models. Results A total of 896 subjects were studied over a median of 5.1 years. The incidence of a new ADE was 1.6 (95% confidence interval 1.3–2.1) per 100 person-years. Among baseline factors, higher CD4+ T-cell counts before HAART were associated with lower risk of ADE/death, but not after adjustment for time-varying factors. On a multivariable analysis including both baseline and time-varying covariates, longer delay from HIV diagnosis to HAART was an independent predictor of ADE/death (per year, hazard ratio [HR] 1.06; P=0.025) and was independent of CD4+ T-cell count before treatment. Longer time spent with HIV RNA <400 copies/ml (per month, HR 0.96; P=0.003) and higher latest CD4+ T-cell count (per log2 cells/mm3, HR 0.65; P<0.001) were found to be protective. Conclusions Patients with higher CD4+ T-cell counts before HAART initiation had a better prognosis. However, except for the delay in starting HAART, viro-immunological evolution outweighed the effect of baseline factors. Moreover, suppressing HIV replication for as long as possible could improve the clinical outcome. Prospective randomized clinical trials to assess the optimal timing of HAART initiation are both feasible and urgently needed.
Sexual Dysfunction in HIV-Infected Men: Role of Antiretroviral Therapy, Hypogonadism and Lipodystrophy
Authors: Guaraldi Giovanni , Luzi Kety , Murri Rita , Granata Antonio , Paola Maria De , Orlando Gabriella , Squillace Nicola , Malmusi Davide , Carani Cesare , Comelli Dante , Esposito Roberto , Martinez Esteban 
Published: April 2022

Background Both psychological and organic factors have been recognized to be associated with sexual dysfunction in HIV-infected individuals. Methods In this cross-sectional study we evaluated the prevalence and factors associated with sexual dysfunction in a cohort of HIV-infected adult men. Evaluation tools included: the International Index of Erectile Function (erectile dysfunction [ED], desire, orgasm, intercourse satisfaction, overall satisfaction), the Assessment of Body Change and Distress (body image satisfaction), the Medical Outcomes Study HIV Health Survey (mental and physical health-related quality of life), and plasma free and total testosterone level (hypogonadism). Results Three-hundred and fifty-seven men were enrolled. Among 336 patients reporting sexual activities in the 4 weeks before, 94 (29.6%) had mild, 30 (9.4%) moderate and 34 (10.1%) severe dysfunction. The Mental Health Summary score was 2.28 units (95% confidence interval [CI] 1.51, 3.06) lower for each unit higher of body image dissatisfaction and 0.31 units (95% CI 0.27, 0.36) higher for each unit higher of the score for body change interference with habits. At regression analysis, ED was independently related to the body mass index (B=0.31, 95% CI 0.08, 0.62). Desire, orgasm and overall satisfaction domains were associated with mental health score (B=0.87, 95% CI 0.47, 1.27; B=0.75, 95% CI 0.23, 1.26; B=0.86, 95% CI 0.45, 1.28, respectively). An improved intercourse satisfaction domain was associated with a lower interference of body changes with habits and social life (B=0.39, 95% CI 0.05, 0.73). Testosterone, metabolic alterations and HAART were not associated with sexual function domains. Conclusions Body image and mental health but not HAART or hypogonadism were associated with sexual function domains.
Predictors of Severe Haematological Toxicity Secondary to Pegylated Interferon plus Ribavirin Treatment in HIV-HCV-Coinfected Patients
Authors: Mira José A , López-Cortés Luis F , Merino Dolores , Arizcorreta-Yarza Ana , Rivero Antonio , Collado Antonio , Ríos-Villegas María J , González-Serrano Mercedes , Torres-Tortosa Manuel , Macías Juan , Valera-Bestard Bárbara , Fernández-Fuertes Elisa , Girón-González José A , Lozano Fernando , Pineda Juan A ,   for the Grupo para el Estudio de las Hepatitis Víricas de la Sociedad Andaluza de Enfermedades Infecciosas (SAEI)
Published: April 2022

Background Haematological adverse events related to pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy could affect the patients’ quality of life; however, the risk factors for severe haematological toxicity associated with this therapy in patients coinfected with hepatitis C virus (HCV) and HIV are unclear. The objective of this study was to identify predictors of severe haematological toxicity among HIV-HCV-coinfected patients treated with PEG-IFN plus RBV. Methods This retrospective multicentric study included 237 HIV-HCV-coinfected patients on PEG-IFN plus RBV. Predictors of severe anaemia, neutropenia, thrombocytopenia and overall haematological toxicity were analyzed. Results Eighty (34%) individuals showed an episode of severe haematological toxicity. Severe anaemia, neutropenia and thrombocytopenia occurred in 32 (13%), 42 (18%) and 26 (11%) patients, respectively. In the multivariate analysis, zidovudine use (adjusted odds ratio [AOR] 3.3; 95% confidence interval [CI] 1.6–10; P=0.001), baseline body weight <65 kg (AOR 2.5; 95% CI 1.1–5; P=0.024), cirrhosis (AOR 5; 95% CI 1.6–16.6; P=0.006), PEG-IFN-α2a (AOR 2.7; 95% CI 1.1–6.6; P=0.029) and pretreatment haemoglobin level <14 g/dl (AOR 2.7; 95% CI 1.3–5.5; P=0.005) were associated with any kind of severe haematological toxicity. Likewise, haemoglobin level <13 g/dl, neutrophil counts <2,500 cells/mm3 and platelet counts <175,000 cells/mm3 were independent predictors of severe anaemia, neutropenia and thrombocytopenia, respectively. Conclusions Zidovudine treatment, cirrhosis, baseline low body weight, use of PEG-IFN-α2a, and baseline haemoglobin level <14 g/dl are predictors of overall severe haematological toxicity secondary to PEG-IFN plus RBV in HIV-infected individuals. Low pretreatment levels of each haematological series predict a significant decrease of their values during therapy.
Early Monitoring of Ribavirin Serum Concentration is not Useful to Optimize Hepatitis C Virus treatment in HIV-Coinfected Patients
Authors: Crespo Manuel , Pou Leonor , Esteban Juan I , Falcó Vicenç , Ribera Esteban , Lopez Rosa , Sauleda Silvia , Curran Adriá , Del Saz Sara Villar , Feijoo María , Ocaña Inma , Pahissa Albert 
Published: April 2022

Background Emerging data suggest that higher ribavirin (RBV) exposure could improve early hepatitis C virus (HCV) response. Furthermore, interindividual RBV bioavailability shows high variation, and dose-limiting haemolytic anaemia is a common adverse event. Therefore, it has been suggested that monitoring RBV serum levels could be used to drive dose modification and to optimize management of HCV-infected patients receiving combination treatment. Methods To assess the effect of RBV serum levels on HCV RNA clearance at week 4 and 12 of treatment, and to determine the correlation between RBV serum concentration and haemoglobin decrease, RBV trough levels were measured by HPLC in stored serum samples obtained from 94 HCV-HIV-coinfected patients at week 4 and 12 of treatment with peginterferon-α2b (1.5 μg/kg/weekly) plus ribavirin (800–1,200 mg/day). Results The median RBV levels increased from 1.70 μg/ml at week 4 to 1.97 μg/ml at week 12 of treatment ( P=0.001) and were independently predicted by weight-adjusted dose of RBV and co-administration of tenofovir. Haemoglobin drop was higher among patients who received zidovudine and weakly correlated with RBV level. Although RBV concentration was lower in genotype 1 or 4 HCV-infected patients who cleared the virus at treatment week 4, the ability of this parameter to discriminate between responders and non-responders at treatment week 4 and 12 was poor. Conclusion Intracellular RBV accumulation early in treatment might improve the kinetics of HCV response in difficult to treat patients. Although this hypothesis and the potential interaction between RBV and tenofovir warrant further research, our data do not support RBV serum monitoring as a tool to optimize treatment in HCV-HIV-coinfected patients.
Long-Term Lamivudine Therapy Reduces the Risk of Long-Term Complications of Chronic Hepatitis B Infection even in Patients without Advanced Disease
Authors: Yuen Man-Fung , Seto Wai-Kay , Chow Danny Hoi-Fan , Tsui Kit , Wong Danny Ka-Ho , Ngai Vincent Wing-Shun , Wong Benjamin Chun-Yu , Fung James , Yuen John Chi-Hang , Lai Ching-Lung 
Published: April 2022

Background Long-term effects of lamivudine treatment on chronic hepatitis B patients without advanced disease remain unknown. Our aim was to investigate the effects of long-term lamivudine treatment and lamivudine-resistant virus (YMDD) on the development of cirrhosis and hepatocellular carcinoma (HCC) in asymptomatic patients without advanced disease. Methods One hundred and forty-two hepatitis B e antigen (HBeAg)-positive patients (median age: 33.9 years) on long-term lamivudine (median treatment duration: 89.9 months) and 124 HBeAg-positive controls (median age: 33.4 years) were prospectively followed up. Patients were monitored for the development of cirrhosis and HCC, liver biochemistry, hepatitis B virus (HBV) DNA levels, HBeAg seroconversion and hepatitis flares. YMDD mutations (YMDD-MT) were determined annually. Results Lamivudine-treated patients had a significantly lower cumulative rate of development of cirrhosis and/or HCC compared with controls ( P=0.005). YMDD-MT occurred in 76.3% of patients after 8 years of lamivudine treatment. When compared with controls and patients with YMDD-MT, patients without YMDD-MT had the greatest reduction of HBV DNA and bilirubin levels, slowest decline of albumin level, highest rate of HBeAg seroconversion and lowest risk of hepatitis flare. Patients with YMDD-MT still had a lower risk for developing cirrhosis and/or HCC ( P=0.024) and a greater HBV DNA reduction ( P=0.001) in comparison with controls. Patients with YMDD-MT and controls had a similar chance of hepatitis flares and hepatic decompensation. Conclusions Long-term lamivudine treatment was associated with a reduced chance of developing cirrhosis and HCC in patients without advanced disease. Although YMDD-MT reduced the benefits from lamivudine therapy, the outcome of these patients was still better than untreated patients.
In vitro and in vivo Protection against the Highly Pathogenic H5N1 Influenza virus by an Antisense Phosphorothioate Oligonucleotide
Authors: Duan Ming , Zhou Zhe , Lin Ru-Xian , Yang Jing , Xia Xian-Zhu , Wang Sheng-Qi 
Published: April 2022

Background Current vaccination strategies and antiviral drugs only provide limited protection against influenza virus infection. In this study, we investigated the use of a novel antisense oligonucleotide (named IV-AS), which is specific for the 5’-terminal conserved sequence found in all eight viral RNA segments of influenza A virus. Methods The activity of IV-AS was monitored both in vitro, in Madin-Darby canine kidney (MDCK) cells, and in vivo using a mouse model. IV-AS was given intranasally to H5N1-infected mice once daily for 6 days starting 6 h after infection. A three-base mismatch of IV-AS was used as a control. Results IV-AS inhibited influenza virus A induced cytopathic effects in MDCK cells with the 50% effective concentration (EC50) ranging from 2.2 to 4.4 μM. IV-AS was effective against H5N1 virus in preventing death, lessening weight reduction, inhibiting lung consolidation and reducing lung virus titres. Dosages of 40 and 60 mg/kg/day provided 40% and 60% survival rates and prolonged mean survival days in comparison with the infected control group ( P<0.05). The lung index in mice treated with IV-AS, at a dose of 20, 40 or 60 mg/kg/day, had been inhibited on day 4 or 6 ( P<0.05 or P<0.01); virus titres in lung had declined to 2.42, 1.51 and 1.54 log10 TCID50/g of lung, respectively, whereas the yields in the infected control mice were 6.00 log10 TCID50/g of lung. Conclusions Our results suggest that the 5’-terminal conserved region of influenza A virus RNA segments can be targeted using antisense technology; therefore, IV-AS is a potential drug for prophylaxis and control of influenza virus infections.
Antiviral Activity and Safety of Aplaviroc with Lamivudine/Zidovudine in HIV-Infected, Therapy-Naive Patients: The ASCENT (CCR102881) Study
Authors:   the ASCENT study team, Currier Judith , Lazzarin Adriano , Sloan Louis , Clumeck Nathan , Slim Jihad , McCarty Deb , Steel Helen , Kleim Jörg-Peter , Bonny Tab , Millard Judith 
Published: April 2022

Background This Phase IIb study explored the antiviral activity and safety of the investigational CCR5 antagonist aplaviroc (APL) in antiretroviral-naive patients harbouring R5-tropic virus. Methods One hundred and forty-seven patients were randomized 2:2:1 to one of two APL dosing regimens or efavirenz (EFV). All dosage arms were administered twice daily and in combination with lamivudine/zidovudine (3TC/ZDV; Combivir, COM). Efficacy, safety, and pharmacokinetic parameters were assessed. Results This study was prematurely terminated due to APL-associated idiosyncratic hepatotoxicity. The primary endpoint of the study was the proportion of patients with plasma HIV-1 RNA <400 copies/ml who remained on randomized treatment through week 12. Of the 147 patients enrolled, 145 patients received one dose of treatment and were included in the intention-to-treat population. The proportion of patients with HIV-1 RNA <400 copies/ml at week 12 was 53%, 50% and 66% in the APL 600 mg twice daily, APL 800 mg twice daily, and EFV arms, respectively. Common clinical adverse events (AEs) were diarrhoea, nausea, fatigue and headache. APL demonstrated non-linear pharmacokinetics with high interpatient variability. In addition to the hepatic findings, there was an apparent dose–response relationship in the incidence of diarrhoea. Conclusions Whereas target plasma concentrations of APL were achieved, the antiviral activity of APL as the third agent in a triple drug regimen did not appear to be comparable to EFV in this treatment-naive patient population.
Should Treatment of Hepatitis B Depend on Hepatitis B virus Genotypes? A Hypothesis Generated from an Explorative Analysis of Published Evidence
Authors: Wiegand Johannes , Hasenclever Dirk , Tillmann Hans L 
Published: April 2022

Objective Standard treatment for hepatitis B is either based on interferon or on nucleos(t)ide analogues. Available evidence on treatment outcome by hepatitis B virus genotype was summarized and analysed to determine whether the genotype has a substantial role in selecting treatment. Methods Abstracts from PubMed, the European Association for the Study of the Liver and the American Association for the Study of the Liver Diseases were screened for publications with at least 30 patients and reporting hepatitis B treatment results (hepatitis B e antigen [HBeAg] seroconversion, loss of HBeAg or loss of HBV DNA) broken down by hepatitis B genotypes. Twenty reports were identified and included. Forest-plot techniques were applied to visualize the association of HBV genotypes (A versus D and B versus C) with treatment outcome given by type of treatment and HBeAg status. The potential size of a treatment by genotype interaction was estimated. Results Treatment response to nucleos(t)ide analogues is not significantly influenced by HBV genotype in HBeAg-positive or HBeAg-negative individuals. In contrast, HBV genotypes are informative concerning responses to interferon treatment in all patients with genotype A versus D and in HBeAg-positive patients with genotype B versus C. Conclusion If no contraindications are present, interferon may be considered as first-line therapy in all genotype A patients and in individuals with genotype B who are HBeAg positive. However, confirmation of this observation in a prospective clinical trial is warranted, because this analysis is explorative and hypothesis generating only.