bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid virological response at week 4 predicts response to pegylated interferon plus ribavirin among HIV/HCV-coinfected patients
Authors: Mira José A , Valera-Bestard Bárbara , Arizcorreta-Yarza Ana , González-Serrano Mercedes , Torre-Cisneros Julián , Santos Ignacio , Vergara Salvador , Gutiérrez-Valencia Alicia , Girón-González José A , Macías Juan , López-Cortés Luis F , Pineda Juan A 
Published: April 2022

Introduction The clinical applicability of early viral kinetics at week 4 in predicting sustained virological response (SVR) of pegylated interferon (peg-IFN) plus ribavirin (RBV) in HIV/HCV-coinfected patients is unclear. Our objective was to determine if rapid virological response (RVR) at week 4 of therapy with peg-IFN and RBV could predict SVR among HIV/HCV-coinfected patients. Methods HIV/HCV-coinfected patients in whom an HCV viral load determination had been carried out at week 4 of therapy were included in the study. The positive predictive value (PPV) and the negative predictive value (NPV) of RVR (undetectable serum HCV RNA at 4 week) for SVR were calculated in the study population. Receiver operating characteristic curves were calculated to determine the best cutoff of HCV RNA decrease to predict treatment failure. Results A total of 101 HIV/HCV-coinfected patients were included. RVR and SVR were observed in 39 (39%) and in 49 (48%) individuals, respectively. Of patients with RVR, 37/39 patients achieved SVR (PPV: 95%), whereas 50/62 individuals without RVR did not show SVR (NPV: 81%). The highest NPV (96%) was reached by using a cutoff level of HCV RNA decrease of 0.6 log10. By applying this cutoff level, treatment could have been discontinued in 25 (25%) patients. Conclusions An undetectable serum HCV RNA determination at week 4 of treatment with peg-IFN plus RBV is a reliable predictor of SVR in HIV/HCV-coinfected patients. In addition, a decrease of HCV RNA less than 0.6 log10 at this point of treatment could identify an appreciable proportion of individuals who will fail to achieve SVR.
High frequency of primary mutations associated with antiretroviral drug resistance in recently diagnosed HIV-infected children
Authors: Vignoles Moira , Barboni Graciela , Agosti María Rosa , Quarleri Jorge , García Mariel Karina , Giraudi Vera , Ayala Silvia González , Salomón Horacio 
Published: April 2022

Introduction The aim of our study was to analyse the frequency of primary mutations associated with HIV drug resistance in a population of children born to HIV-infected mothers. Design A prospective study included newly HIV-diagnosed children treated at two public paediatric hospitals. Patients and methods Clinical and antiretroviral therapy (ART) data were collected in mother-child pairs. HIV-1 subtyping and ART resistance mutations were assayed in children by sequencing a region of HIV pol gene. Results: A total of 67 children were enrolled 22 less than 12 months of age, 20 between 1 and 5 years and 25 between 6 and 14 years. Six (9.0%) children had viral strains with at least one primary mutation associated with resistance to reverse transcriptase and protease inhibitors. A significantly ( P=0.019) higher frequency of resistance (22.7%, n=5/22) was found among children aged <12 months. Fourteen children (20.9%) had a subtype B HIV-1 strain and 53 (79.1%) had an inter-subtype B/F recombinant variant. Discussion A high percentage of recently diagnosed infants were found to carry primary ART resistance mutations. Limited options for ART of HIV-infected children might lead to increased HIV-associated morbidity and mortality. Thus, consideration should be given to mandatory screening for primary ART resistance before initiating therapy for infants aged <12 months in countries where HIV mother-to-child transmission is still present, such as in Argentina. This will allow for the rationalized and individualized use of drugs and will contribute to the increased cost-effectiveness of local health systems.
Amphipathic DNA Polymers are Candidate Vaginal Microbicides and Block Herpes Simplex Virus Binding, Entry and Viral Gene Expression
Authors: Guzman Esmeralda M , Cheshenko Natalia , Shende Vikas , Keller Marla J , Goyette Nathalie , Juteau Jean-Marc , Boivin Guy , Vaillant Andrew , Herold Betsy C 
Published: April 2022

Background Amphipathic DNA polymers are promising therapies for the prevention of HIV and genital herpes infections. Recent studies on a panel of such compounds indicated potent activity against HIV binding and entry. This current study was conducted to explore the anti-herpes simplex virus (HSV) activity of the same panel of compounds and to determine their mechanism of activity. Methods The anti-HSV activity of a 40-nucleotide degenerate polymer (REP 9), a 40-nucleotide polycytidine amphipathic DNA polymer (REP 9C) and an analogue lacking amphipathic activity (Randomer 3) were compared in plaque reduction assays in the absence or presence of human genital tract secretions; the mechanisms of anti-HSV activity were explored. Results REP 9 inhibited HSV infection 10,000-fold, whereas Randomer 3 displayed no anti-HSV activity. The antiviral activity was independent of sequence but was dependent on size: the most potent activity was observed for analogues of 40 nucleotides in length. Mechanistic studies indicated that REP 9 and REP 9C blocked HSV-2 binding and entry, were active when added post-entry, inhibited viral gene expression and blocked HSV-induced apoptosis. Confocal microscopy studies showed rapid delivery of fluorescently tagged REP 9 and REP 9C into human epithelial cells, and delivery was significantly greater in infected cells as compared with uninfected cells. REP 9 exhibited no cytotoxicity and retained anti-HSV activity in the presence of cervicovaginal secretions and when virus was introduced in seminal plasma. Conclusions REP 9 and REP 9C represent a novel class of antiviral agents that act by multiple mechanisms. These compounds warrant further development for systemic or topical delivery for the prevention and treatment of HIV and HSV.
Lipodystrophy and metabolic changes in HIV-infected children on non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy
Authors: Aurpibul Linda , Puthanakit Thanyawee , Lee Benjamin , Mangklabruks Ampica , Sirisanthana Thira , Sirisanthana Virat 
Published: April 2022

Background Highly active antiretroviral therapy (HAART) has recently been implemented in Thailand. Its long-term effects have not been clearly evaluated. The objective of this study was to estimate the prevalence of lipodystrophy (LD) and other metabolic changes in HIV-infected children receiving HAART. Methods Ninety children who began HAART (either nevirapine or efavirenz, together with lamivudine and stavudine) were prospectively followed. LD was assessed by waist-to-hip ratio and LD checklist. Hypercholesterolemia was defined as total cholesterol >200 mg/dl and low-density lipoprotein cholesterol >130 mg/dl. Low levels of high-density lipoprotein cholesterol (HDL-c), hypertriglyc-eridaemia and hyperglycaemia were defined as HDL-c <40 mg/dl, triglyceride >200 mg/dl and plasma glucose >110 mg/dl, respectively. Results The mean age at entry was 7.6 (sd 2.9) years. Fifty-three children received nevirapine- and 37 received efavirenz-based HAART. The prevalence of LD was 9%, 47% and 65% at 48, 96 and 144 weeks after HAART initiation, respectively. Patterns of LD at week 144 were central lipohypertrophy (46%), peripheral lipoatrophy (20%), and combined type (34%). A higher prevalence of LD was found among females (61% versus 39%; P=0.04) and those with more advanced disease (CDC category B or C) at baseline (73% versus 51%; P=0.04). There was no difference in prevalence of LD between the two regimens. At 144 weeks, fasting hypertriglyceridaemia was detected in 12%, hypercholesterolaemia in 11%, and increased plasma glucose in 4% of children. Low HDL-cholesterolaemia decreased from 94% at baseline to 12% at week 144 ( P<0.01). Conclusions More than half of the children developed LD at 144 weeks after HAART. Dyslipidaemia occurred in 11–12% of children.
The Prophylactic Administration of a Monoclonal Antibody against Human Metapneumovirus Attenuates viral Disease and Airways Hyperresponsiveness in Mice
Authors: Hamelin Marie-Eve , Couture Christian , Sackett Melanie , Kiener Peter , Suzich JoAnn , Ulbrandt Nancy , Boivin Guy 
Published: April 2022

Background Human metapneumovirus (hMPV) is one of the most frequent causes of respiratory tract infections in children. Our objective was to assess the prophylactic benefit of a monoclonal antibody (mAb) against the hMPV fusion protein in a murine model. Methods BALB/c mice received one intramuscular injection of either 5 or 10 mg/kg of mAb 338 (MedImmune, Inc.) and were infected intranasally 24 h later with 1x108 TCID50 (50% tissue culture infectious dose) of hMPV. On days 5 and 42 post-infection, lung samples were collected for determination of viral titres and for histopathological studies. Pulmonary function was characterized by plethysmography. Results Mean lung viral titres were significantly lower in mice treated with 5 or 10 mg/kg of mAb 338 compared with infected controls on day 5 (283, 45.6 and 1.49x105 TCID50/g, respectively; P<0.05). Similarly, lung viral RNA copies were significantly reduced in treated mice on day 42 (292, 101 and 607 copies per 0.01 g of lungs for mice that received 5 mg/kg, 10 mg/kg or no mAb, respectively; P<0.05). Histopathological changes characterized by important alveolar and interstitial inflammation were less severe in treated mice on days 5 and 42 compared with control. Airways obstruction was also significantly reduced in both treated groups on days 5 and 42, but development of hyperresponsiveness following the acute phase of infection was only significantly reduced in 10 mg/kg treated mice. Conclusions Prophylactic administration of mAb 338 attenuates acute and late consequences of hMPV disease in this mouse model.
Early Therapy in HIV-1-Infected Children: Effect on HIV-1 Dynamics and HIV-1-Specific Immune Response
Authors: Zanchetta Marisa , Anselmi Alessia , Vendrame Daniela , Rampon Osvalda , Giaquinto Carlo , Mazza Antonio , Accapezzato Daniele , Barnaba Vincenzo , Rossi Anita De 
Published: April 2022

Background Perinatal HIV-1 infection is acquired in the milieu of a developing immune system, leading to high levels of uncontrolled viral replication. Few data have been reported that address the viral dynamics and immunological response in infants who initiated aggressive antiretroviral therapy (ART) shortly after birth. Methods Six HIV-1-infected infants who started ART within 3 months of age were studied. The median follow-up was 61 months. Plasma HIV-1 RNA, cell-associated HIV-1 DNA, unspliced and multiply spliced HIV-1 mRNAs, HIV-1 antibodies, and CD4+ and CD8+ T-cell subsets were assessed in sequential peripheral blood samples. HIV-1 cellular immune response was measured by EliSpot assay. Results All children showed a decline in plasma viraemia to undetectable levels. HIV-1 DNA persisted in four children, but only two of these had detectable HIV-1 mRNA. All viral parameters remained persistently negative in two children. Only two children produced HIV-1 antibodies, while the others, after having lost maternal antibodies, remained seronegative. No HIV-1 cellular immune response was observed in any child. Therapy interruption was performed in two children: one HIV-1-seropositive and one HIV-1-seronegative with persistently undetectable levels of all viral parameters. Rebound of HIV-1 plasma viraemia in the seronegative child was more rapid and higher than that observed in the seropositive child. Conclusions Early ART treatment in infants modifies the natural course of infection by controlling HIV-1 replication and reducing viral load to below the threshold levels required for onset of HIV-1 immune response, but does not prevent the establishment of a reservoir of latently infected cells that precludes virus eradication.
Sequential Combination Therapy Leads to Biochemical and Histological Improvement Despite Low Ongoing Intrahepatic Hepatitis B virus Replication
Authors: Lutgehetmann Marc , Volz Tassilo , Quaas Alexander , Zankel Myrga , Fischer Conrad , Dandri Maura , Petersen Joerg 
Published: April 2022

Background We previously reported that 48 weeks of combination therapy with pegylated interferon-α2b (PEG-IFN-α2b) and adefovir dipivoxil (ADV) in patients with chronic hepatitis B led to marked decreases of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) (-2.4 log10 copies/ml). Combination therapy was followed by 96 weeks of ADV monotherapy. Methods Here, we report on the final outcome after 144 weeks of sequential antiviral treatment. Twenty-four patients were analysed, triplet liver biopsies (taken at baseline, week 48 and week 144) were available from 16 patients. Results At week 144, 12/15 patients positive for hepatitis B virus e antigen (HBeAg) had lost HBeAg, alanine transaminase (ALT) levels were normal in 23 patients (96%), median serum HBV DNA had decreased by -4.9 log10 copies/ml and was undetectable (<100 copies/ml) in 11/24 individuals (46%). Median total intrahepatic HBV DNA had decreased by -2.2 log. Although no further significant cccDNA changes occurred between week 48 and week 144, two years of ADV monotherapy proved capable of controlling cccDNA levels in most patients. Analysis of intrahepatic HBV DNA species demonstrated that combination therapy with PEG-IFN-α2b and ADV inhibited viral productivity by 99% and subsequent ADV monotherapy by 76%, respectively. Virus suppression to undetectability within the first 12 weeks of treatment was strongly associated with long-term virological response and HBeAg and hepatitis B virus surface antigen HBsAg seroconversion. Histological improvement was determined in 11/16 patients at week 144. Two patients developed ADV resistance during the third year of treatment. Conclusions Reduction of intrahepatic viral load achieved after 48 weeks of combination therapy with PEG-IFN-α2b and ADV was maintained in the following 96 weeks of ADV monotherapy and translated into long-term clinical benefit for most of the treated patients.
Effect of Pioglitazone on HIV-1-Related Lipodystrophy: A Randomized Double-Blind Placebo-Controlled Trial (ANRS 113)
Authors: Slama Laurence , Lanoy Emilie , Valantin Marc-Antoine , Bastard Jean-Philippe , Chermak Aziza , Boutekatjirt Amal , William-Faltaos Demiana , Billaud Eric , Molina Jean-Michel , Capeau Jacqueline , Costagliola Dominique , Rozenbaum Willy 
Published: April 2022

Background Although thiazolidinediones have been shown to increase subcutaneous fat in congenital lipodystrophy, rosiglitazone did not show convincing results in HIV lipoatrophy. We assess a potential specific effect of pioglitazone in this setting. Methods One-hundred and thirty HIV-1-infected adults with self-reported lipoatrophy confirmed by physical examination were randomized to receive pioglitazone 30 mg once daily ( n=64) or placebo ( n=66) for 48 weeks. Changes in limb fat between weeks 0 and 48 were measured using dual-energy X-ray absorptiometry. Subcutaneous and visceral fat was measured by single-slice computed tomography; fasting plasma measurements of glucose, insulin and lipids levels were recorded. Results Limb fat increased by 0.38 kg in the pioglitazone group and 0.05 kg in the placebo group at week 48 (mean difference 0.33 kg, 95% confidence interval [CI] 0.10–0.56; P=0.051) by intention-to-treat analysis. In patients not receiving stavudine, an increase of 0.45 kg versus 0.04 kg was observed (mean difference, 0.40 kg, 95% CI 0.12–0.69; P=0.013), but this was not seen in patients on stavudine ( n=36; P=0.404). Overall, there was no significant difference in subcutaneous abdominal fat or in visceral fat areas on computed tomography at L4 vertebra. The lipid profile was not significantly different at week 48 except for levels of high-density lipoprotein cholesterol, which was improved in the pioglitazone group (+0.08 mmol/l versus -0.08; P=0.005). Conclusions Pioglitazone 30 mg once daily for 48 weeks improved limb fat atrophy in antiretroviral-treated HIV-1-infected patients, although clinical benefits were not perceived by the patients. Treatment did lead to a favourable lipid profile, however, suggesting that this thiazolidinedione should be considered in the context of HIV-related lipoatrophy.
Failure of Lamivudine to Reverse Hepatitis B Virus-Associated Changes in ERK, Akt and Cell Cycle Regulatory Proteins
Authors: Chin Ruth , Earnest-Silveira Linda , Koeberlein Bernd , Franz Susanne , Zentgraf Hanswalter , Bowden Scott , Bock C-Thomas , Torresi Joseph 
Published: April 2022

Background Chronic infection with hepatitis B virus (HBV) is a major factor associated with the development of hepatocellular carcinoma, but the mechanism by which this occurs is unknown. Treatment of chronic hepatitis B with lamivudine results in virological suppression and histological improvement; however, the role of lamivudine in preventing the development of hepatocellular carcinoma is less well defined. We recently reported that replication of HBV in a cell-culture system was associated with the upregulation of pERK, pAkt, pc-Myc, nuclear cyclin B1, p21cip1 and p53 together with G2 cell cycle arrest. Methods In order to determine whether lamivudine is able to reverse the HBV-induced changes on signal transduction and cell cycle, we infected Huh7 cells with a recombinant adeno-HBV virus in the presence of 0–50 μM of lamivudine. Signal transduction and cell cycle regulatory proteins were analysed by western immunoblot. Results Although lamivudine was able to inhibit HBV replication, it failed to reverse the changes on ERK and Akt phosphorylation. Correspondingly, levels of phospho-GSK3β and p21cip1/waf1 were increased, as were cyclin D1, cyclin B1, p53 and pc-Myc. Conclusions Lamivudine was ineffective in reversing the HBV-induced changes in signal transduction pathways and cell cycle regulatory proteins, indicating that the HBV-infected cells remained primed for oncogenic transformation despite viral suppression.
Retinoic Acid Analogues Inhibit Human Herpesvirus 8 Replication
Authors: Caselli Elisabetta , Galvan Monica , Santoni Fabio , Alvarez Susana , de Lera Angel R , Ivanova Diana , Gronemeyer Hinrich , Caruso Arnaldo , Guidoboni Massimo , Cassai Enzo , Dolcetti Riccardo , Di Luca Dario 
Published: April 2022

Background Retinoids have a pronounced antiviral effect against several viruses. In this study we aimed to investigate the effect of retinoids on human herpesvirus 8 (HHV-8). Methods A panel of retinoic acid compounds were tested for their antiviral activity against HHV-8 in human umbilical vascular endothelial cells (HUVECs) and in a human epithelial cell line. The presence, transcription and antigen expression of HHV-8 in infected cells – in the presence or absence of retinoic acid compounds – were evaluated by PCR, reverse transcriptase PCR and immunofluorescence assays; HHV-8 viral load was determined by real-time quantitative PCR. Angiogenesis induced by HHV-8 was also assessed using Cultrex® basement membrane extract. Results The compounds tested specifically inhibited viral promoters, during the early and late phases of infection in both cell systems tested, and resulted in up to 100fold reduction of viral titre and release of progeny virus. The inhibition of viral replication induced by retinoids in endothelial cells, the primary target of HHV-8-driven transformation in Kaposi's Sarcoma, prevented endothelial cells from developing spindle morphology and in vitro tube formation, characteristic changes associated with HHV-8 infection and transformation. Conclusions We show that retinoids inhibit HHV-8 replication and identify new retinoid compounds with a strong antiviral effect. Selective retinoids, particularly those with retinoic acid receptor agonist activity, may be good candidates for the development of antiviral drugs.
Prevalence, Genotypic Associations and Phenotypic Characterization of K65R, L74V and other HIV-1 RT Resistance Mutations in a Commercial Database
Authors: McColl Damian J , Chappey Colombe , Parkin Neil T , Miller Michael D 
Published: April 2022

Background Nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations (NAMs) can affect response to treatment with NRTIs and might also result in HIV-1 with reduced replication capacity. Methods A large commercial HIV-1 database ( n=60,487) was analysed for the prevalence of NAMs, antiviral drug susceptibilities and viral replication capacity. Results Thymidine analogue mutations (TAMs) and M184V were the most commonly observed NAMs (>25%). L74V/I was detected in 11% of isolates. K65R was detected in 3.3% of isolates and its frequency remained stable from 2003 to 2006, similar to trends observed for other NAMs. TAMs were rarely observed in combination with K65R, but frequently associated with L74V/I. HIV-1 with K65R or L74V/I alone were fully susceptible to zidovudine and stavudine. K65R was associated with reduced susceptibility to tenofovir, didanosine, abacavir and lamivudine; L74V/I was associated with reduced susceptibility to abacavir and didanosine. The addition of M184V to either K65R or L74V/I improved susceptibility to tenofovir, zidovudine and stavudine, but reduced susceptibility to abacavir, didanosine and lamivudine. Other NAMs commonly associated with K65R were A62V, S68G and Y115F; their NRTI susceptibilities were similar to those of viruses containing K65R alone. The replication capacity for HIV-1 with M184V/I or K65R was significantly reduced compared with wild-type (median 68% and 72%, respectively; P<0.0001), whereas replication capacity for HIV-1 with L74V or TAMs was not significantly reduced (88% and 97%, respectively). Conclusions These results demonstrate a relative stability in the prevalence of HIV-1 clinical isolates with NAMs from 2003 to 2006. Differences between the genotypic patterns, phenotype and replication capacity associated with common NAMs are described.