bluuebunny/crossref_metadata_2025_split huggingface dataset:
Virological Profiles in Hepatitis B Virus/Hepatitis C Virus Coinfected Patients under Interferon plus Ribavirin Therapy
Authors: Saitta Carlo , Pontisso Patrizia , Brunetto Maurizia R , Fargion Silvia , Gaeta Giovanni B , Niro Grazia A , Picciotto Antonio , Smedile Antonina , Squadrito Giovanni , Raimondo Giovanni 
Published: April 2022

Background Hepatitis C virus (HCV) is believed to exert a suppressive effect on hepatitis B virus (HBV) in most HBV/HCV-coinfected patients; once HCV is cured by interferon-based therapy, these patients may show HBV reactivation. However, recent evidence revealed that the virological status in HBV/HCV-untreated individuals may vary over time and may show fluctuating profiles. Methods To evaluate the behaviour of apparently inactive HBV infection in patients under treatment for a concurrent HCV infection, we performed a prospective study that evaluated nine consecutive patients (eight males with a median age of 45.9 years, and one female aged 62 years) longitudinally followed-up with bi-monthly evaluation of HBV/HCV viraemia levels and liver biochemistry during a 1-year treatment with interferon plus ribavirin. Results In seven cases the HBV infection maintained its inactive status independently of the HCV response to therapy. By contrast, two non-responder cases with persistently high HCV RNA levels showed HBV DNA flairs during the follow-up, indicating a status of active HBV infection with fluctuating virological profiles. Conclusions This study suggests that the HBV behaviour may be independent of the HCV activity during anti-HCV therapy in HBV/HCV-coinfected patients, and that the HBV virological profile should be monitored to recognize possible reactivations that might lead to more proper therapeutic choices or adjustments.
Exploiting Information Inherent in Binding Sites of Virus-Specific Antibodies: Design of An HCV Vaccine Candidate Cross-Reactive with Multiple Genotypes
Authors: Grollo Lara , Torresi Joseph , Drummer Heidi , Zeng Weiguang , Williamson Nicholas , Jackson David C 
Published: April 2022

Background/Aims The role of antibody in hepatitis C virus (HCV) infection remains unclear although many reports attest to its role in viral clearance. Here we describe epitopes that are recognized by antibody present in the serum of infected patients and show that such epitopes can induce neutralizing antibodies. Methods Human serum containing hyperimmune anti-HCV IgG was used to extract epitopes from a library of synthetic peptides that encompassed the sequences of the E1 and E2 proteins of HCV genotype 1a H77. Peptides that were bound by IgG were identified by mass spectrometry. Assembly of these epitopes with a helper T cell determinant was then carried out in order to construct candidate epitope-based vaccines. Results Three distinct antigenic sites were defined in the E1E2 glycoproteins by epitopes identified by antibody present in infected individuals. Four of the peptide epitopes identified are conserved in at least three HCV genotypes and are bound by antibody present in the sera of chronically infected and convalescent individuals. Synthetic vaccines based on these epitopes elicited antibodies that are capable of (i) capturing HCV virions from the serum of viraemic patients and (ii) inhibiting HCV pseudovirus particle entry into Huh7 cells. Conclusions This approach exploits the information inherent in the binding sites of virus-specific antibodies and represents a novel method for the design of synthetic epitope-based vaccines.
The Development of Artificial Neural Networks to Predict Virological response to Combination HIV Therapy
Authors: Larder Brendan , Wang Dechao , Revell Andrew , Montaner Julio , Harrigan Richard , De Wolf Frank , Lange Joep , Wegner Scott , Ruiz Lidia , Pérez-Elías María Jésus , Emery Sean , Gatell Jose , Monforte Antonella D‘Arminio , Torti Carlo , Zazzi Maurizio , Lane Clifford 
Published: April 2022

Introduction When used in combination, antiretroviral drugs are highly effective for suppressing HIV replication. Nevertheless, treatment failure commonly occurs and is generally associated with viral drug resistance. The choice of an alternative regimen may be guided by a drug-resistance test. However, interpretation of resistance from genotypic data poses a major challenge. Methods As an alternative to current interpretation systems, we have developed artificial neural network (ANN) models to predict virological response to combination therapy from HIV genotype and other clinical information. Results ANN models trained with genotype, baseline viral load and time to follow-up viral load (1,154 treatment change episodes from multiple clinics), produced predictions of virological response that were highly significantly correlated with actual responses (r2=0.53; P<0.00001) using independent test data from clinics that contributed training data. Augmented models, trained with the additional variables of baseline CD4+ T-cell count and four treatment history variables, were more accurate, explaining 69% of the variance in virological response. Models trained with the full input dataset, but only those data involving highly active antiretroviral therapy (three or more full-dose antiretroviral drugs in combination), performed at an intermediate level, explaining 61% of the variance. The augmented models performed less well when tested with data from unfamiliar clinics that had not contributed data to the training dataset, explaining 46% of the variance in response. Conclusion These data indicate that ANN models can be quite accurate predictors of virological response to HIV therapy even for patients from unfamiliar clinics. ANN models therefore warrant further development as a potential tool to aid treatment selection.
HIV-1 drug resistance surveillance using dried whole blood spots
Authors: Bertagnolio Silvia , Soto-Ramirez Luis , Pilon Richard , Rodriguez Roberto , Viveros Monica , Fuentes Luis , Harrigan P Richard , Mo Theresa , Sutherland Don , Sandstrom Paul 
Published: April 2022

Background Field-friendly methods for HIV drug resistance (HIVDR) surveillance in resource-limited regions are urgently needed. Despite evidence that dried blood spots (DBS) are suitable for HIV serology, viral load and CD4+ T-cell enumeration, no study has evaluated DBS for HIVDR genotyping. We assessed the feasibility of genotyping HIV-1 from field-collected DBS stored under challenging environmental conditions. Methods We prospectively collected specimens from newly diagnosed, treatment-naive HIV-positive subjects in Mexico. Whole blood was spotted onto filter cards, air dried at ambient temperature and stored with desiccant at 37°C and 85% humidity for 3 months. Genotypes obtained from DBS-extracted nucleic acids using an in-house nested reverse transcription-PCR method were compared to genotypes derived from matched plasma. Results Genotypes from 103 phylogenetically matched plasma and DBS were compared. In total, 90.1% of all DBS specimens could be amplified in either the region of HIV protease or the region of reverse transcriptase. Failure to amplify from DBS did not correlate with low plasma viral loads. Between paired specimens, the median nucleotide similarity was 99.95%. In the nine specimens with drug resistance mutations, all differences between pairs were partial discordances. Mutations identified in plasma were found in the majority of replicate DBS amplifications. Conclusion The results suggest that genotypes obtained from DBS are equivalent to those from plasma. DBS are a promising public health tool for HIVDR surveillance of treatment-naive subjects, especially in regions where specimens might be exposed to severe environmental conditions and where logistical difficulties could prevent timely specimen processing. More studies are needed to validate DBS for patient monitoring.
Molecular Assessment of the Potential for Renal Drug Interactions between Tenofovir and HIV Protease Inhibitors
Authors: Cihlar Tomas , Ray Adrian S , Laflamme Genevieve , Vela Jennifer E , Tong Leah , Fuller Michael D , Roy Anupma , Rhodes Gerald R 
Published: April 2022

Background Active renal secretion of tenofovir (TFV) across proximal tubules occurs via uptake by human organic anion transporters 1 and 3 (hOAT1 and hOAT3) coupled with efflux by multidrug resistance protein 4 (MRP4). Co-administration of some HIV protease inhibitors (PIs) with tenofovir disoproxil fumarate (TDF), an oral prodrug of TFV, has been shown to increase systemic levels of TFV, leading to a hypothesis that PIs may affect tubular secretion of TFV and potentially alter the renal safety of TDF. Methods The effect of PIs on the transport of TFV by hOAT1, hOAT3 and MRP4 was assessed using in vitro cell-based transport models. Results At concentrations equal to their therapeutic peak plasma levels (Cmax) all PIs showed <20% inhibition of TFV transport by hOAT1. hOAT3 was more sensitive to PIs with ritonavir (RTV) and lopinavir being the most potent inhibitors of TFV transport (62% and 37% inhibition, respectively, at their Cmax). In the absence of human serum, RTV at concentrations exceeding its therapeutic Cmax also exhibited a minor effect on the cellular efflux of TFV by MRP4 (<30% inhibition at 20 μM). However, no effects of PIs on hOAT1, hOAT3 or MRP4 were detected in the presence of human serum with the exception of RTV that inhibited hOAT3 by approximately 35% at its Cmax. In addition, PIs did not affect the cytotoxicity of TFV or TDF in MRP4- or MRP2-overexpressing cells. Conclusion These data indicate a low potential of PIs to interfere with the active tubular secretion of TFV and to alter the clinical renal safety profile of TDF.
Risk of Discontinuation of Nevirapine due to Toxicities in Antiretroviral-Naive and -Experienced HIV-Infected patients with High and Low CD4+ T-cell Counts
Authors: Mocroft Amanda , Staszewski Schlomo , Weber Rainer , Gatell José , Rockstroh Jurgen , Gasiorowski Jacek , Panos George , Monforte Antonella d'Arminio , Rakhmanova Aza , Phillips Andrew N , Lundgren Jens D 
Published: April 2022

Introduction It is unknown whether the increased risk of toxicities in antiretroviral-naive HIV-infected patients initiating nevirapine-based (NVPc) combination antiretroviral therapy (cART) with high CD4+ T-cell counts is also observed when NVPc is initiated in cART-experienced patients. Patients and methods 1,571 EuroSIDA patients started NVPc after 1/1/1999, with CD4+ T-cell counts and viral load measured in the 6 months before starting treatment, and were stratified into four groups based on CD4+ T-cell counts at initiation of NVPc (high [H], >400/mm3 or >250/mm3 for male or female, respectively, or low [L], ≤400/mm3 or ≤250/mm3 for male or female) and prior antiretroviral experience (antiretroviral-naive [N] or -experienced [E]). Cox proportional hazards models compared the risks of discontinuation of nevirapine due to toxicities or patient/physician choice (TOXPC). Results After adjustment, there was a significantly lower risk of discontinuation of nevirapine due to TOXPC in the HE group ( n=588; proportion discontinued by 3/12 months: 10/17%, respectively) than in HN (n=62; 21/32% respectively; overall relative hazard [RH]: 0.56; 95% confidence interval [CI]: 0.34–0.94; P=0.027). This difference was most pronounced during the first 3 months of NVPc (RH: 0.44; 95% CI: 0.23–0.87; P=0.017). There were no deaths in the 6 months after starting NVPc resulting from exposure to <3 months of NVPc exposure within the HE group (incidence: 0; per 1,000 person-years follow up; 95% CI: 0–6.9). After adjustment, there were no differences between the HE and HN groups in discontinuation due to TOXPC in patients starting efavirenz-based cART (RH: 0.91; 95% CI: 0.60–1.38; P=0.66) or protease-inhibitor-based cART (RH: 1.13; 95% CI: 0.77–1.66; P=0.52). Conclusions Results from this non-randomized study suggest that NVPc might be safer to initiate in antiretro-viral-experienced than in antiretroviral-naive patients with high CD4+T-cell counts.
In Vitro Susceptibility of Adefovir-Associated Hepatitis B Virus Polymerase Mutations to other Antiviral Agents
Authors: Qi Xiaoping , Xiong Shelly , Yang Huiling , Miller Michael , Delaney William E 
Published: April 2022

Background Adefovir dipivoxil is a nucleotide prodrug approved for the treatment of chronic hepatitis B. During clinical trials, ADV-associated mutations were observed in 0, 3, 11, 18 and 29% of patients after 48, 96, 144, 192 and 240 weeks of therapy, respectively. Hepatitis B virus (HBV) polymerase mutations associated with virological breakthrough to ADV include rtA181V and rtN236T, which occur alone or in combination. The rtA181T mutation has also been observed at low frequency, alone or in combination with rtN236T. Methods To investigate the in vitro activity of adefovir and other anti-HBV agents against these mutants, we generated five stable cell lines that each expressed one of the following HBV mutants: rtN236T, rtA181V, rtA181V+rtN236T, rtA181T+rtN236T and rtA181T. Using these cell lines, we quantified in vitro changes in drug susceptibility for eight nucleotide/nucleoside analogues. Results The rtN236T mutant had 7-fold resistance to adefovir but remained sensitive to entecavir, telbivudine and torcitabine (≤3.2-fold reduced susceptibility). The A181V mutant had 4.3-fold resistance to adefovir and had reduced susceptibility to multiple other agents ranging from 3.2-fold (tenofovir) to >191-fold (clevudine). The A181V+rtN236T double mutant was the most highly resistant showing 18-fold resistance to adefovir and higher levels of resistance to other tested drugs with the exception of tenofovir (10-fold reduced susceptibility). Our results and preliminary clinical data suggest that patients with rtN236T or rtA181V remain susceptible to tenofovir, entecavir and lamivudine. Further clinical data are necessary to precisely define in vitro cutoffs indicative of clinically-relevant resistance, particularly for drugs in development such as emtricitabine, telbivudine, torcitabine and clevudine.
Pharmacokinetic interaction between TMC114/r and efavirenz in healthy volunteers
Authors: Sekar Vanitha J , Pauw Martine De , Mariën Kris , Peeters Monika , Lefebvre Eric , Hoetelmans Richard MW 
Published: April 2022

Background This open-label, crossover study investigated the pharmacokinetic interaction between TMC114 (darunavir [Prezista™]), administered with low-dose ritonavir (TMC114/r) and efavirenz (EFV) in HIV-negative, healthy volunteers. Methods Volunteers received TMC114/r 300/100 mg twice daily for 6 days, and once daily on day 7 (session 1). After a 7-day washout period volunteers received EFV 600 mg once daily for 18 days (session 2), with coadministration of TMC114/r 300/100 mg twice daily from day 11–day 16 and TMC114/r once daily on day 17. Results When coadministered with TMC114/r, plasma concentrations of EFV were slightly increased. In the presence of TMC114/r, EFV minimum (Cmin) and maximum (Cmax) plasma concentrations increased by 15–17%, and by 21% for EFV area under the curve (AUC24h). TMC114/r and EFV coadministration resulted in TMC114 Cmin, Cmax and AUC12h decreases of 31%, 15% and 13%, respectively. No serious adverse events (AEs) or AEs leading to withdrawal were reported in this trial. Overall, TMC114/r and EFV coadministration was well tolerated. Conclusions The clinical significance of the changes in AUC and Cmin seen with TMC114/r and EFV coadministration has not been established; this combination should be used with caution. Similar findings are expected with the approved TMC114/r 600/100 mg twice daily dose.
Primary Resistance to Enfuvirtide (T20) in recently HIV-1 Infected, Antiretroviral-Naive Patients from the ANRS Aquitaine Cohort
Authors: Peuchant Olivia , Capdepont Sophie , Ragnaud Jean-Marie , Aurillac-Lavignolle Valérie , Thiébaut Rodolphe , Fleury Hervé , Masquelier Bernard ,   on behalf of the ANRS CO3 Aquitaine Cohort
Published: April 2022

Background Transmission of HIV-1 variants with resistance to reverse transcriptase (RT) and protease inhibitors has been widely characterized in developed countries. However, no clear evidence of primary resistance to HIV-1 fusion inhibitors has been shown so far. We wished to investigate the possibility of genotypic resistance to enfuvirtide (T20) in a cohort of antiretroviral-naive, recently infected patients. Methods We included patients from the Aquitaine Cohort with an estimated date of seroconversion in 2004 and 2005, a plasma sample obtained less than 18 months after seroconversion and no prior history of antiretroviral therapy. RT, protease and gp41 sequences were determined by direct population sequencing from plasma samples and drug resistance mutations were reported. Results A total of 55 patients were included in the study. The overall prevalence of transmitted HIV-1 resistance was 20%. Two patients had viruses with resistance mutations to T20. The first case had an N42D mutation in the HR1 region of the gp41, along with transmitted resistance mutations in the protease (D30N, M36I, N88D) and in the RT (M41L, L210W, T215D). The second case had a G36D HR1 mutation, with no evidence of other drug resistance mutations. Conclusion We have shown the first cases of primary resistance to T20 in recently infected patients in southwestern France. Epidemiological surveillance of the transmission of drug-resistant HIV-1 should include the resistance to T20.
A Randomized Study of Antiviral Medication Switch at Lower-Versus Higher-Switch Thresholds: AIDS Clinical Trials Group Study A5115
Authors: Riddler Sharon A , Jiang Hongyu , Tenorio Allan , Huang Hairong , Kuritzkes Daniel R , PAcosta Edward , Landay Alan , Bastow Barbara , Haas David W , Tashima Karen T , Jain Mamta K , Deeks Steven G , Bartlett John A 
Published: April 2022

Background Clinical stability has been observed with continued antiretroviral therapy (ART) in the setting of partial virological suppression. The optimal time to switch treatment in patients with low but detectable HIV-1 RNA is not known. Methods Subjects on stable ART with HIV-1 RNA 200–10,000 copies/ml were randomized to an immediate treatment switch, or to a delayed switch when HIV-1 RNA increased to ≥10,000 copies/ml or CD4+ T-cell count decreased by 20%. The primary outcome measures were immune activation (proportion of CD8+ T-cells expressing CD38 at week 48) and evolution of genotypic drug resistance. Results The study failed to fully accrue the originally planned 108 subjects. Only 47 subjects were randomized to immediate- or delayed-switch arms. Of the subjects in the delayed-switch arm, 10/23 (43%) met the criteria for ART switch during the study (median follow-up 82 weeks). After 48 weeks of observation, the level of immune activation was comparable in the two arms. New resistance mutations were observed in 3/17 and 8/19 subjects in the immediate- and delayed-switch groups, respectively. The loss of future treatment options, however, was comparable in the delayed- and immediate-switch groups. Conclusions Individuals with partial viral suppression tend to remain immunologically stable, however, the accumulation of drug resistance mutations is an ongoing risk. Delayed switch in ART may be a reasonable short-term strategy for individuals with very limited treatment options.
Virological Response to Different Combination Regimes of Peginterferon α-2b and Lamivudine in Hepatitis B e Antigen Positive Chronic Hepatitis B
Authors: Chan Henry Lik-Yuen , Wong Vincent Wai-Sun , Chim Angel Mei-Ling , Choi Paul Cheung-Lung , Chan Hoi-Yun , Hui Alex Yui , Wong Grace Lai-Hung , Sung Joseph Jao-Yiu 
Published: April 2022

Objective To investigate whether simultaneous commencement of peginterferon α-2b and lamivudine treatment has more potent hepatitis B virus (HBV) DNA suppression than staggered regimes. Methods Thirty HBeAg-positive chronic hepatitis B patients were randomized in 1:1:1 ratio to 32-week peginterferon started simultaneously with lamivudine (group 1), eight weeks before lamivudine (group 2) or eight weeks after commencement of lamivudine (group 3). All patients received lamivudine until week 104. Results At week 52, the log HBV DNA reduction in group 1 (6.38) was more profound than that in group 2 (3.43, P=0.022) and tended to be superior to that in group 3 (4.44, P=0.060). HBeAg seroconversion developed in six (67%) patients in group 1, three (33%) patients in group 2 ( P=0.35 versus group 1) and one (10%) patient in group 3 ( P=0.037 versus group 1). At week 104, the log HBV DNA reduction in group 1 (6.13) versus that in group 2 (5.24) and group 3 (5.15) was insignificantly different. Lamivudine resistance was found in four (14%) patients at week 104. There was 1.22 and 2.52 median log reduction in covalently closed circular DNA and total intrahepatic HBV DNA, respectively, at week 104, but there was no difference among the three groups. At 24 weeks post-treatment, sustained HBeAg seroconversion was observed in five (56%), three (33%) and four (40%) of the patients in groups 1, 2 and 3, respectively ( P>0.05). Conclusions Simultaneous commencement of peginterferon and lamivudine tend to provide more profound viral suppression than staggered regimes in the early phase of treatment.
The Influence of HIV Infection and Antiretroviral Therapy on the Mitochondrial Membrane Potential of Peripheral Mononuclear Cells
Authors: Sternfeld Thomas , Schmid Mathias , Tischleder Annette , Mudra Susanne , Schlamp Angelika , Kost Bernd P , Gruber Rudolf , Youle Mike , Bogner Johannes R , Goebel Frank-Detlef 
Published: April 2022

Objectives Clinical disorders occurring in HIV-infected patients on antiretroviral therapy (ART) have been linked to mitochondrial dysfunction, for example, lactic acidosis and lipodystrophy. Mitochondrial membrane potential (ΔΨm) is the most direct measure of the state of energization of the mitochondria. We analysed ΔΨm of peripheral blood mononuclear cells (PBMCs) in HIV-negative, healthy subjects ( n=8), HIV-infected, treatment-naive patients ( n=30), and HIV-infected patients on ART ( n=58). The influence of ART was analysed in six patients who started their first regimen. Methods The ΔΨm of PBMC was measured by flow cytometry using the dye JC-1. Results The ΔΨm was significantly lower in HIV-infected patients than in HIV-negative controls. This difference was detected in both treated ( P=0.0001) and untreated patients ( P=0.001). The ΔΨm of PBMCs was highly correlated with CD4+ T-cell count in therapy-naive patients ( P=0.002, r=0.546) and in treated patients ( P=0.028, r=0.288). The ΔΨm increased significantly in therapy-naive patients after starting ART ( P=0.001). Patients with lipoatrophy had significantly lower ΔΨm than patients without lipodystrophy or with lipohypertrophy ( P=0.023). Conclusions In HIV-infected persons ΔΨm is significantly reduced. Patients with lipoatrophy have significantly reduced ΔΨm. This is the first study showing that the ΔΨm of PBMCs is highly correlated with CD4+ T-cell count in HIV infection.