bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of Mass Spectrometric Analysis and TRUGENE™ HBV Genotyping for Monitoring Lamivudine Resistance in Chronic Hepatitis B Patients
Authors: Woo Hee-Yeon , Park Hyosoon , Kim Byung-Ik , Jeon Woo-Kyu , Cho Yong Kyun , Kim Young Jae 
Published: April 2022

Background There is an increasing need for the early detection of emerging mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of hepatitis B virus (HBV) DNA polymerase with using sensitive molecular methods. Methods We evaluated the usefulness of monitoring lamivudine resistance using a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry-based assay (the restriction fragment mass polymorphism; RFMP) in comparison with the direct sequencing assay, the TRUGENE™ HBV genotyping kit. We also investigated the treatment responses in relation to the presence of YMDD mutants. The sera from 50 chronic HBVs patients were analysed for the presence of YMDD mutants by performing RFMP and TRUGENE. The results at codons 180 and 204 were compared for 46 patients. Results The concordance rate between the two assays was 65.2% (30/46). All the discordance corresponded to the detection of additional virus populations by RFMP. Early detection of mutants before viral breakthrough was accomplished by RFMP in two patients. Persistence of very low viraemia was observed in five patients who harboured mutant virus populations. Additional information was provided by TRUGENE in eight patients. Conclusions RFMP showed a superior ability for detecting minor mutant virus populations compared with TRUGENE. However, the results of highly sensitive RFMP should be interpreted carefully because lamivudine could be effective despite the presence of mutants. RFMP could be a practical tool in conjuction with regular measurements of the HBV viral load for the early detection of lamivudine resistance and the timely introduction of new antiviral drugs.
Improvements in Parameters of End-Stage Liver Disease in Patients with HIV/HBV-related Cirrhosis Treated with Tenofovir
Authors: Matthews Gail V , Cooper David A , Dore Gregory J 
Published: April 2022

Background Mortality related to end-stage liver disease is increasing in HIV/hepatitis B virus (HBV)-coinfected patients and effective treatment options are limited. Tenofovir is now widely used in HIV/HBV coinfection and results in significant HBV suppression, in both patients with and patients without lamivudine resistance. The safety and efficacy of tenofovir in HIV/HBV cirrhosis has not been previously described. Methods Seven cirrhotic HIV/HBV patients treated with tenofovir were identified within the HIV clinic. Parameters of hepatic function, CD4+ T-cell counts, HBV DNA levels and Child-Pugh Class (C-P-C) were determined before and after addition of tenofovir. All patients had prior lamivudine experience with a median baseline HBV DNA of 6.23x107 copies/ml. Results Four of seven patients were C-P-C -A and hepatitis ‘e’ antigen (HBeAG) was positive in 4/7 patients. After a median duration of tenofovir of 28 months, all laboratory parameters improved, with significant changes in albumin and prothrombin (PT) (median pre-/post-tenofovir: alanine aminotransferase 63/39; bilirubin 26/18; albumin 39/44, P=0.028; PT 17.5/15, P=0.018). All three patients with C-P-C -B or -C improved to C-P-C -A, which for one patient enabled removal from the liver transplant waiting list. Three patients lost HBeAG with two anti-HBe seroconversions. Median HBV DNA was suppressed to <35 copies/ml. Conclusions This study demonstrates that tenofovir can produce HBV viral suppression, HBeAg seroconversion and improvement in markers of hepatic function in HIV/HBV-coinfected patients with cirrhosis. The potential reversal of end-stage liver disease may provide an important survival benefit in this population.
Relationship of Mitochondrial DNA Depletion and Respiratory Chain Activity in Preadipocytes treated with Nucleoside Reverse Transcriptase Inhibitors
Authors: Stankov Metodi V , Lücke Thomas , Das Anibh M , Schmidt Reinhold E , Behrens Georg MN 
Published: April 2022

Objective To study the impact of adipocyte differentiation on nucleoside reverse transcriptase inhibitor (NRTI)-mediated mitochondrial DNA (mtDNA) depletion and to correlate mtDNA depletion with the activity of the respiratory chain complexes. Methods We studied adipocyte phenotype, viability, differentiation (CCAAT/enhancer-binding protein [C/EBP]-α and peroxisome proliferator-activated receptor [PPAR]-γ expression), adiponectin production, mtDNA content, activity of respiratory chain complexes and citrate synthase activity in 3T3–L1 adipocytes. Cells were exposed to zidovudine (6 μM or 180 μM), stavudine (3 μM or 90 μM), and zalcitabine (0.1 μM or 3 μM) at different developmental stages for up to 2 months. Results Zidovudine and stavudine impaired adiponectin production in vitro at therapeutic Cmax concentrations, but none of the tested NRTIs had a negative impact on adipocyte differentiation or led to mtDNA depletion at these concentrations. Susceptibility of preadipocytes to mtDNA depletion was dependent on cell proliferation and differentiation, and mtDNA depletion occurred only after exposure to high drug concentrations. Under these conditions, stavudine led to up to 80% mtDNA depletion in both dividing and differentiating preadipocytes, whereas zidovudine affected mtDNA only in the differentiating cells. Despite mtDNA depletion by NRTIs, activity of the respiratory chain complexes was found to be unimpaired. Conclusions We found mtDNA depletion in adipocytes but proliferation and/or differentiation of the cells seems to be a prerequisite for this phenomenon. Depletion of mtDNA up to 80%, however, was not associated with impaired respiratory chain activity in 3T3-L1 preadipocytes.
Hypogonadism in HIV-1-Infected Men is common and does not resolve during antiretroviral therapy
Authors: Wunder Dorothea M , Bersinger Nick A , Fux Christoph A , Mueller Nicolas J , Hirschel Bernard , Cavassini Matthias , Elzi Luigia , Schmid Patrick , Bernasconi Enos , Mueller Bruno , Furrer Hansjakob ,   the Swiss HIV Cohort Study
Published: April 2022

Objectives To assess the prevalence of abnormal testosterone and gonadotropin values in HIV-infected men before and after 2 years of combination antiretroviral therapy (cART). Design Multicentre cohort of HIV-infected adults. Methods We identified 139 Caucasian antiretroviral-naive male patients who started zidovudine/ lamivudine-based cART that was virologically successful over a 2 year period. Ninety-seven were randomly chosen and plasma hormone determinations of free testosterone (fT) and luteinizing hormone (LH) at baseline and after 2 years of cART were evaluated. Results At baseline 68 patients (70%) had subnormal fT levels. In these, LH levels were low in 44%, normal in 47% and high in 9%. There was a trend for an association between lower CD4+ T-cell counts and hypogonadism. Most participants had normal FSH levels. No significant changes of fT, LH and FSH levels were observed after 2 years of cART. Conclusions Low fT levels, mainly with normal or low LH levels and thus indicating secondary hypogonadism, are found in the majority of HIV-infected men and do not resolve during 2 years of successful cART.
The Impact of Reducing Stavudine dose versus switching to tenofovir on plasma lipids, body composition and mitochondrial function in HIV-infected patients
Authors: Milinkovic Ana , Martinez Esteban , López Sonia , De Lazzari Elisa , Miró Oscar , Vidal Sergi , Blanco José L , Garrabou Gloria , Laguno Montserrat , Arnaiz Joan A , Leon Agathe , Larrousse Maria , Lonca Montserrat , Mallolas Josep , Gatell José M 
Published: April 2022

Background Stavudine (d4T)-containing regimens are associated with a potential for lipoatrophy and dyslipidaemia. We assessed the safety and efficacy of reducing the dose of stavudine compared with switching to tenofovir or maintaining the standard dose of d4T. Methods Clinically stable HIV-infected patients receiving antiretroviral therapy containing stavudine 40 mg twice daily with a plasma HIV RNA <200 copies/ml for at least 6 months were randomized to maintain stavudine 40 mg twice daily (d4T40 arm), to reduce to 30 mg twice daily (d4T30 arm), or to switch from d4T to tenofovir (TDF arm). Results Fifty-eight (93% male) patients were included: 22 in the d4T40 arm, 19 in the d4T30 arm and 17 in TDF arm. At baseline, median time on d4T was 6 years (interquartile range [IQR] 2.6–7.1), median age 43 years (IQR 36–51) and median CD4+ T-cell count was 587/mm3 (IQR 329–892). At week 24, median limb fat changes (g) were as follows: d4T40=-182 (95% CI: -469—5); d4T30=527 (95% CI: -343–694); and TDF=402 (95% CI: 130–835; d4T40 versus TDF, P=0.0003). Significant differences between median values of laboratory parameters were detected: triglycerides (mg/dl): d4T40=19; d4T30=-23 and TDF=-79 (d4T40 versus TDF, P=0.03); and total cholesterol (mg/dl): d4t40=22, d4T30=-4, and TDF=-28 (d4T40 versus TDF, P=0.04). No significant difference was observed in mitochondrial function assessed in peripheral blood mononuclear cells. Conclusions Although both strategies were associated with a trend toward a decrease in plasma lipids and an increase in body fat, the only significant changes were observed among those who switched to tenofovir.
Fate and Function of Hepatitis-C-Virus-Specific T-Cells during Peginterferon-α2b therapy for Acute Hepatitis C
Authors: Wiegand Johannes , Cornberg Markus , Aslan Nuray , Schlaphoff Verena , Sarrazin Christoph , Kubitschke Anne , Buggisch Peter , Ciner Ayse , Jaeckel Elmar , Manns Michael P , Wedemeyer Heiner 
Published: April 2022

Background Strong hepatitis C virus (HCV)-specific T-cell responses are associated with spontaneous clearance of acute hepatitis C. However, recent studies described a decline in HCV-specific CD8+ T-cells during interferon treatment, suggesting that the success of acute HCV therapy might be independent of adaptive immunity. Methods T-cell responses of eight human leukocyte antigen (HLA)-A2-positive, acutely infected patients treated with peginterferon-α2b were studied by ELISPOT and proliferation assays and flow cytometry analysis using HCV-specific tetramers. Results HCV-specific T-cells predominately declined during therapy. However, diverse patterns of CD4+ and CD8+ T-cell kinetics were observed. In patients with sustained virological response chemokine receptor 3 (CXCR-3) expression of HCV-specific CD8+ T-cells was upregulated, indicating homing to the liver. Low levels of T-cells remained detectable throughout treatment and follow up. In contrast, T-cells of a relapse patient did not upregulate CXCR-3 but displayed a higher staining for annexin-V, followed by a complete loss of peripheral virus-specific CD8+ T-cells by week 12. Conclusions Kinetics of HCV-specific T-cell responses are heterogeneous in interferon-treated patients with acute hepatitis C. The decline of T-cells might be a consequence of both apoptosis and homing. The balance between cell death and regulation of chemokine receptors might lead to different long-term outcomes.
Premature Treatment Discontinuation in HIV/HCV-Coinfected Patients Receiving Pegylated Interferon plus Weight-Based Ribavirin
Authors: Soriano Vincent , Miralles Celia , Berdún Miguel Angel , Losada Elena , Aguirrebengoa Koldo , Ocampo Antonio , Arazo Piedad , Cervantes Manuel , De Los Santos Ignacio , Joaquín Isabel San , Echeverria Santiago , Galindo María J , Asensi Victor , Barreiro Pablo , Sola Julio , Hernandez-Burruezo Juan J , Guardiola Josep , Blanco Francisco , Martin-Carbonero Luz , García-Samaniego Javier , Nuñez Marina 
Published: April 2022

Background Chronic hepatitis C therapy in HIV patients is often penalized by more frequent premature treatment discontinuations. It is unclear what the relative contribution of more adverse events and/or early virological failures are. Methods PRESCO was a prospective, multicentre, comparative trial, in which 389 HIV/HCV-coinfected patients with CD4+ T-cell counts >300 cells/ml and elevated aminotransferases received pegylated interferon-α2a (peg IFN-α2a) 180 mg per week plus ribavirin (RBV) 1,000–1,200 mg daily. Patients with HCV genotypes 1 or 4 were treated for 48 or 72 weeks while HCV genotypes 2 or 3 carriers were treated for 24 or 48 weeks. Use of didanosine was not allowed. Results Sustained virological response (SVR) was achieved by 193 (49.6%), and was significantly greater in HCV-2/3 than in HCV-1/4 patients (72.4% versus 35%; P<0.0001). Premature treatment discontinuations occurred in 174 patients (44.7%). This was due to early virological failure in 66 (17%), serious adverse events in 32 (8.2%), loss-to-follow-up in 12 (3.1%) and voluntary withdrawal in 64 (16.4%). Only 10 patients (2.6%) stopped HCV therapy due to severe anaemia. Two patients stopped HCV medication due to symptomatic mitochondrial toxicity. There were no episodes of hepatic decompensation. Conclusions Treatment with RBV 1,000–1,200 mg/day plus peg IFN-α2a is relatively safe and provided SVR in nearly half of the HIV/HCV-coinfected patients, twice as many amongst the HCV-2/3 than HCV-1/4 carriers. Avoidance of didanosine, limited use of zidovudine and therapy restricted to patients with CD4+ T-cell counts >300 cells/ml most probably explains the lower and different spectrum of serious adverse events in PRESCO compared with prior trials conducted in coinfected patients.
Altered Expression of Nucleoside Transporter Genes (SLC28 and SLC29) in Adipose Tissue from HIV-1–Infected Patients
Authors: Guallar Jordi P , Cano-Soldado Pedro , Aymerich Ivette , Domingo Joan C , Alegre Marta , Domingo Pere , Villarroya Francesc , Casado F Javier , Giralt Marta , Pastor-Anglada Marçal 
Published: April 2022

Background Nucleoside transporter proteins (NTs) encoded by members of the SLC28 and SLC29 gene families contribute to nucleoside and nucleobase recycling but also modulate extracellular adenosine levels and thus adenosine-regulated metabolic targets. Methods We have examined the expression pattern of NT-encoding genes in human adipose tissue and we have further analysed whether the mRNA related to these genes show changes in their amounts associated with either HIV-1 infection, highly active antiretroviral therapy (HAART) or development of HIV-1-associated lipodystrophy syndrome (HALS). Results Human adipocytes express SLC28A1, SLC28A2 and SLC28A3 (encoding hCNT1, hCNT2 and hCNT3, respectively) and SLC29A1 and SLC29A2 (encoding hENT1 and hENT2, respectively). HIV-1 infection, prior to HAART and HALS development, is associated with the upregulation of the mRNA levels of the genes encoding hCNT1, hCNT3 and hENT2. The increase in the mRNA amounts for the former two genes may be due to the action of tumour necrosis factor-α (TNF-α), a cytokine with enhanced expression in adipose tissue following HIV-1 infection, as the effect is also observed in human adipocytes in culture after treatment with TNF-α. HAART and HALS development are associated with the upregulation of the mRNA levels encoding hCNT2 and hENT1, and further enhancement of hCNT1, hCNT3 and hENT2 gene expression. Conclusions These data suggest that selected genes of the SLC28 and SLC29 families are not only targets of HIV-1 infection, but might also contribute to the development of adipose tissue alterations leading to lipodystrophy.
Relationships between Drug Exposure, Changes in Metabolic Parameters and Body Fat in HIV-Infected Patients Switched to a Nucleoside Sparing Regimen
Authors: Autar Reshma S , Boyd Mark A , Wit Ferdinand WMN , Ruxrungtham Kiat , Sankote Jongkol , Lange Joep MA , Cooper David A , Phanuphak Praphan , Burger David M , Reiss Peter 
Published: April 2022

Background The pathogenesis of metabolic disturbances in treated HIV infection is incompletely understood. Methods Relationships between fasted metabolic parameters, body composition, and drug plasma concentrations were investigated in 59 patients who switched from failed nucleoside analogue treatment to ritonavir-boosted indinavir and efavirenz therapy. Metabolic parameters, peripheral fat, visceral adipose tissue (VAT) and drug plasma concentrations were measured prospectively. Results Ritonavir exposure was found to be negatively correlated with high-density lipoprotein cholesterol (HDL-c) changes, with a 2.4% decrease in HDL-c for each unit increase in ritonavir concentration ratio. Significant associations between indinavir or efavirenz concentrations and metabolic disturbances were not observed. Total cholesterol (TC) correlated positively with high body mass index (BMI) and negatively with baseline limb fat mass: each unit increase in BMI and each kilogram reduction in baseline limb fat corresponded with a TC increase of 2.4% and 4.1%, respectively. Baseline triglyceride levels were lower in those patients with relatively greater limb fat mass: each kilogram reduction of total limb fat mass was associated with a 15.7% increase in triglyceride concentration. Changes in VAT were positively correlated with TC: for every unit TC increase a 0.3% VAT increase was observed (over 48 weeks). Conclusions Reduced limb fat mass at the start of the study treatment, increases in VAT mass, and higher plasma concentrations of ritonavir on study treatment were each - to varying degrees - associated with various metabolic disturbances.
Response to HAART in French patients with resistant HIV-1 treated at primary infection: ANRS Resistance Network
Authors: Chaix Marie-Laure , Desquilbet Loic , Descamps Diane , Costagliola Dominique , Deveau Christiane , Galimand Julie , Goujard Cécile , Signori-Schmuck Anne , Schneider Veronique , Tamalet Catherine , Pellegrin Isabelle , Wirden Marc , Masquelier Bernard , Brun-Vezinet Francoise , Rouzioux Christine , Meyer Laurence ,   for the French PRIMO Cohort Study Group (ANRS CO 06) and the French ANRS AC11 Resistance Study Group
Published: April 2022

Objective The aim of the study was to analyse the response to highly active antiretroviral therapy (HAART) initiated at the time of primary HIV infection (PHI) in patients infected with a virus resistant to ≥1 drug of their treatment compared with patients infected with a wild-type virus. Methods We analysed data from 350 patients who were enrolled from 1996–2004 in the French ANRS PRIMO Cohort or in the ANRS Resistance Group and treated with HAART during PHI. During the study period, HAART was initiated before the result of the genotypic resistance test was available. We compared patients infected with a virus resistant to ≥1 drug of their regimen (GR group, n=46) with patients harbouring a wild-type virus (WT group, n=304). Virological and immunological response to treatment according to drug-resistance profile was analysed 3 months and 6 months after HAART initiation. Results In GR and WT groups, HIV RNA level was <400 copies/ml in 68% and 83% ( P=0.02) and <50 copies/ml in 23% and 40% ( P=0.08) 3 months after HAART initiation. In multivariable logistic regression taking into account gender, age, boosted PI regimen, plasma HIV RNA and CD4+ T-cell count at HAART initiation, patients with virus resistant to ≥1 drug of their regimen were significantly less likely to achieve undetectable viral load at month 3 (odds ratio 0.32, 95% confidence interval 0.15–0.72) than the others. This difference was sustained up to month 6. Conclusion In this large cohort of HAART-treated PHI-patients, the presence of drug resistance mutations led to suboptimal response to early therapy.
Health-Related Quality of Life and Tolerability in Treatment-Experienced HIV-1–Infected Patients on Tipranavir versus Comparator Regimens
Authors: Huang I-Chan , Wu Albert W , Finnern Henrik W , Thijs Herbert , Gathe Joseph C , Fairclough Diane L 
Published: April 2022

Background Antiretroviral therapy including tipranavir boosted with ritonavir (TPV/r) has shown superior viral suppression and immunological response compared with comparator ritonavir-boosted protease inhibitor (CPI/r) regimens in treatment-experienced HIV-1-infected patients. This study assesses the influence of adverse events (AEs) on health-related quality of life (HRQOL) and change in HRQOL in patients treated with TPV/r versus CPI/r regimens. Methods Changes in HRQOL over 48 weeks were assessed using Medical Outcomes Study HIV Health Survey (MOS-HIV) data combined from two randomized, open-label, Phase III studies (RESIST-1 and RESIST-2). Generalized estimating equations (GEE) were used to compare physical health and mental health summary scores and 10 subscale scores, and to compare scores of patients with and without AEs. To compare AE incidences in the two treatment groups, AEs were exposure-adjusted. Results There were 984 patients in the HRQOL analysis. AE occurrence and severity resulted in significantly lower MOS-HIV scores across both treatment arms ( P<0.05). Overall incidence of AEs was higher in the CPI/r versus TPV/r group (562.8 versus 514.4 per 100 patient-exposure years); treatment-related AEs were more frequent in the TPV/r group (75.0 versus 56.6 per 100 patient-exposure years). HRQOL was maintained in patients on TPV/r over 48 weeks of treatment across all summary and subscale scores. Compared with CPI/r, TPV/r was associated with a significant but small (sd<0.2) improvement in pain scores (+4.8 points; P<0.05). Conclusions HRQOL was maintained across both summary and all subscale scores from baseline to 48 weeks in the TPV/r and CPI/r treatment arms, despite the incidence of treatment-related AEs.
Suboptimal Response to Adefovir Dipivoxil Therapy for Chronic Hepatitis B in Nucleoside-Naive Patients is not due to Pre-Existing Drug-Resistant Mutants
Authors: Carrouée-Durantel Sandra , Durantel David , Werle-Lapostolle Bettina , Pichoud Christian , Naesens Lieve , Neyts Johan , Trépo Christian , Zoulim Fabien 
Published: April 2022

Background Adefovir dipivoxil (ADV) has demonstrated activity against wild-type and lamivudine-resistant hepatitis B virus (HBV). After 1 year of therapy, a median 3.5–4.0 log10 decrease in viral load is observed. Our aim was to characterize the different profiles of response to ADV in relation to the in vitro susceptibility of viral strains to ADV. Methods In an international Phase III randomized, placebo-controlled study of ADV in patients positive for hepatitis B virus e antigen (HBeAg), different profiles of virological response to ADV 10 mg/day were identified at week 48. The top 25% patients (quartile 1, Q1) showed >4.91 log10 reduction in serum HBV DNA at week 48, in Q2 patients demonstrated a 3.52 to 4.90 log10 reduction of viral load, whereas in Q3 a 2.22 to 3.51 log10 reduction in viral load was observed. The bottom 25% of patients (Q4) showed <2.22 log10 reduction in HBV DNA levels. The influence of baseline characteristics and drug compliance on response was investigated. The replication capacity and drug susceptibility of HBV genomes of selected clinical isolates that were considered representative of the treatment response quartiles were analysed using a phenotypic assay. Results The lowest quartile of response (Q4) appears to have worse compliance. Higher alanine aminotransferase levels at baseline are associated with improved response. Phenotypic analysis of viral strains in vitro in Huh7 and HepG2 cells showed that HBV genomes remained susceptible to ADV, regardless of treatment response observed in patients. Conclusion Suboptimal response to ADV might result from a host pharmacological effect or from patient compliance issues rather than from a reduced susceptibility of HBV to ADV.