bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative Analysis of Hepatitis D Virus RNA and Hepatitis B Surface Antigen Serum Levels in Chronic Delta Hepatitis Improves Treatment Monitoring
Authors: Manesis Emanuel K , Schina Maria , Le Gal Frédéric , Agelopoulou Olga , Papaioannou Christos , Kalligeros Constantine , Arseniou Vaios , Manolakopoulos Spilios , Hadziyannis Emilia S , Gault Elyanne , Koskinas John , Papatheodoridis George , Archimandritis Athanasios J 
Published: April 2022

Background/aims Treatment of chronic delta hepatitis is long and difficult and better monitoring is needed. Methods In this study, hepatitis delta virus (HDV) RNA, hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA were retrospectively quantified in 53 patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis delta. Twenty-one had received 28 courses of 3–5 MU interferon-α2b (IFN-α2b) thrice weekly for a median of 12.6 months (interquartile range [IQR]: 7.3–31.6), five had received eight courses of 100 mg lamivudine (LAM) daily for 23.6 months (IQR: 8.4–61.5) and 27 were untreated. The controls were 54 untreated, randomly selected, HBeAg-negative chronic hepatitis B patients without delta infection. Quantification of serum HDV RNA, HBsAg and HBV DNA were performed at baseline, during and at the end of treatment and end of follow up. Results Untreated patients had significantly higher median HBsAg levels than controls (5,872 vs 3,501 IU/ml; P=0.046), but lower median HBV DNA levels (2.933 vs 6.459 log10 copies/ml; P<0.001). Median baseline HDV RNA (6.374 log10 copies/ml) was similar in IFN-α2b-treated, LAM-treated and untreated patients. At the end of treatment, IFN-α2b significantly suppressed in paired measurements HDV RNA ( P=0.012) and HBsAg ( P=0.043), but LAM was inefficient. In IFN-α2b-treated patients, HDV RNA became undetectable in five patients within a median of 30 months (IQR: 8–90), followed by a slower decrease in HBsAg. Conclusions In untreated chronic delta hepatitis, suppressed HBV replication is associated with significantly increased HBsAg serum levels. IFN-α2b significantly suppresses both HDV RNA and HBsAg, but LAM has no effect. Long-term IFN-α2b treatment (IQR: 1.5–5.0 years) appears necessary for undetectable serum HDV RNA and further treatment is required for HBsAg loss. Monitoring of HDV RNA and HBsAg serum levels in patients with chronic delta hepatitis provides insight during treatment.
Synergistic Inhibition of Protease-Inhibitor-Resistant HIV type 1 by Saquinavir in Combination with Atazanavir or Lopinavir
Authors: Dam Elisabeth , Lebel-Binay Sophie , Rochas Séverine , Thibaut Laurent , Faudon Jean-Louis , Thomas Claire-Marie , Essioux Laurent , Hill Andrew , Schutz Malte , Clavel François 
Published: April 2022

Background Double-boosted protease inhibitors (PIs) are under investigation for the treatment of patients who are unable to take nucleoside reverse transcriptase inhibitors because of cross-resistance and/or intolerance. Evidence of synergistic inhibition of wild-type HIV has been reported for saquinavir with atazanavir or lopinavir. Methods We investigated the activity of these two combinations against a panel of six site-directed mutant HIV-1 strains and 14 clinically derived recombinant HIV-1 strains presenting a range of PI-resistance profiles. Results No evidence of synergy was observed against wild-type virus for either combination. The combination of saquinavir and lopinavir showed evidence of synergy against four viruses displaying high-level resistance to lopinavir and low-level resistance to saquinavir. Similarly, evidence of synergy between saquinavir and atazanavir was only observed in two viruses which were more susceptible to saquinavir than to atazanavir. Conclusions We hypothesize that differences between the PIs in intracellular protein-binding behaviour or inhibition of drug transporters (P glycoprotein, MDR1 and MDR2) could result in intracellular levels of saquinavir being increased by co-administration with lopinavir or atazanavir. The effect of this increase would be masked in cases involving viruses that were susceptible to atazanavir or lopinavir. In virus resistant to lopinavir or atazanavir but susceptible to saquinavir, the majority of the antiviral effect is due to saquinavir; thus even small increases in intracellular concentration could significantly increase virus inhibition. These results confirm that in vitro synergy can be observed between PIs and suggest that the degree of synergy observed might depend on the resistance profile of the virus.
Evolution of T-cell Responses to Hepatitis C Virus (HCV) during Pegylated Interferon plus Ribavirin treatment in HCV-Monoinfected and in HCV/HIV-Coinfected Patients
Authors: Capa Laura , Soriano Vincent , García-Samaniego Javier , Nuñez Marina , Romero Miriam , De Mendoza Carmen , Cascajero Almudena , Muñoz Fernando , González-Lahoz Juan , Benito José M 
Published: April 2022

Background The role of T-cell immunity in chronic hepatitis C virus (HCV) infection remains controversial. As in HIV infection, virus replication could drive or be contained by T-cell immunity. We have examined the effect of HIV coinfection and of suppression of HCV replication with therapy on HCV-specific T-cell responses. Patients and Methods Thirty-five patients with chronic hepatitis C (17 coinfected with HIV) initiating anti-HCV therapy were analysed. HCV-specific responses were assessed at different time points using intracellular interferon-γ staining in response to a panel of overlapping peptides comprising E2, NS3, NS5a and NS5b HCV proteins. Results At baseline, HCV-specific responses were significantly lower in HIV-coinfected patients. At week 12 of therapy, CD8+ T-cell responses against all HCV proteins significantly decreased in HCV-monoinfected patients and this was maintained throughout the follow-up period. Although the same trend occurred in the HIV-coinfected group, differences were not significant. CD4+ T-cell responses against NS3 significantly diminished in the HCV-monoinfected group, whereas in coinfected patients CD4+ T-cell responses were low at baseline and did not experience any significant variation. Conclusions HCV-specific T-cell responses are lower in HIV-coinfected patients and vanish following complete suppression of HCV replication under successful HCV therapy, suggesting that they are dependent on continuous antigenic stimulation.
Immunizations with Chimeric Hepatitis B Virus-Like Particles to Induce Potential Anti-Hepatitis C Virus Neutralizing Antibodies
Authors: Vietheer Patricia TK , Boo Irene , Drummer Heidi E , Netter Hans-Jürgen 
Published: April 2022

Background Virus-like particles (VLPs) are highly immunogenic and proven to induce protective immunity. The small surface antigen (HBsAg-S) of hepatitis B virus (HBV) self-assembles into VLPs and its use as a vaccine results in protective antiviral immunity against HBV infections. Chimeric HBsAg-S proteins carrying foreign epitopes allow particle formation and have the ability to induce anti-foreign humoral and cellular immune responses. Methods/results The insertion of the hypervariable region 1 (HVR1) sequence derived from the envelope protein 2 (E2) of hepatitis C virus (HCV) into the major antigenic site of HBsAg-S (‘a’-determinant) resulted in the formation of highly immunogenic VLPs that retained the antigenicity of the inserted HVR1 sequence. BALB/c mice were immunized with chimeric VLPs, which resulted in antisera with anti-HCV activity. The antisera were able to immunoprecipitate native HCV envelope complexes (E1E2) containing homologous or heterologous HVR1 sequences. HCV E1E2 pseudotyped HIV-1 particles (HCVpp) were used to measure entry into HuH-7 target cells in the presence or absence of antisera that were raised against chimeric VLPs. Anti-HVR1 VLP sera interfered with entry of entry-competent HCVpps containing either homologous or heterologous HVR1 sequences. Also, immunizations with chimeric VLPs induced anti-surface antigen (HBsAg) antibodies, indicating that HBV-specific antigenicity and immunogenicity of the ‘a’-determinant region is retained. Conclusions A multivalent vaccine against different pathogens based on the HBsAg delivery platform should be possible. We hypothesize that custom design of VLPs with an appropriate set of HCV-neutralizing epitopes will induce antibodies that would serve to decrease the viral load at the initial infecting inoculum.
Resistance Profiling of Hepatitis C Virus Protease Inhibitors using Full-Length NS3
Authors: Dahl Göran , Sandström Anja , Åkerblom Eva , Danielson U Helena 
Published: April 2022

Background The NS3 protease of hepatitis C virus (HCV) is a prime target for anti-HCV drugs but resistance towards inhibitors of the enzyme is likely to emerge because of mutations in the viral genome that modify the structure of the protein. Enzyme inhibition data supporting this is limited to studies with few compounds and analysis performed with truncated NS3. Experimental The potential of HCV acquiring resistance towards NS3 protease inhibitors and the structural features associated with resistance has been explored with a series of inhibitors and by using full-length NS3 protease/helicase variants with amino acid substitutions (A156T, D168V and R155Q) in the protease domain. Results The A156T and D168V substitutions did not influence the kinetic properties of the protease, whereas the R155Q substitution reduced the catalytic efficiency 20 times, as compared with the wild type. Inhibition studies revealed that these substitutions primarily affected the potency of compounds which effectively inhibit the wild-type enzyme, and had little effect on weak or moderate inhibitors. As a consequence, all compounds had similar inhibitory potencies to the substituted enzyme variants. An exception was VX-950, which inhibited the D168V enzyme more efficiently than the wild type. For this inhibitor, the present data correlated better with replicon data than data from assays with truncated enzyme. Conclusions These results have provided a structural basis for designing inhibitors that may be less susceptible to resistance by three known mutations, and suggest that the present variants of full-length NS3 constitute effective models for resistance profiling of NS3 protease inhibitors.
Serum α-Foetoprotein Level Predicts Treatment Outcome in Chronic Hepatitis C
Authors: Males Sylvia , Gad Rita Raafat , Esmat Gamal , Abobakr Hasan , Anwar Mohamed , Rekacewicz Claire , Hoseiny Mostafa El , Zalata Khaled , Abdel-Hamid Mohamed , Bedossa Pierre , Pol Stanislas , Mohamed Mostafa K , Fontanet Arnaud 
Published: April 2022

Objectives To analyse the association between serum α-foetoprotein (AFP) levels and sustained virological response (SVR) in treated patients. Methods One-hundred patients with chronic hepatitis C were treated with pegylated interferon α-2a plus ribavirin for 48 weeks. The primary endpoint was SVR. Linear regression analysis was performed to identify clinical, biological, and histological factors affecting baseline AFP levels. The association between pretreatment serum AFP and SVR was assessed by multivariate logistic regression analysis. Results Of 100 patients, 95 were infected with genotype 4, one with genotype 1, and four with undetermined genotype. The median serum AFP level was 4.5 ng/ml and AFP values ranged from 1.2 to 49.8 ng/ml. In multivariate analysis, higher fibrosis stage and higher steatosis score were independently associated with higher serum AFP levels. SVR rate was 61.0% (61/100), and was lower for patients with AFP levels above rather than below the median value (40.8% versus 80.4%, respectively, P<0.001). In multivariate analysis, including adjustment for age, gender, body mass index, steatosis score, fibrosis stage, ALT level, haemoglobin level, clotting time, HCV RNA viral load, and treatment dose received, a baseline serum AFP level above the median value was associated with a lower SVR rate (OR [95% CI]=0.10 [0.03–0.42], P<0.001). None of the seven patients with increased (above 15 ng/ml) pretreatment AFP achieved SVR. Conclusions In this study, higher baseline serum AFP levels independently predicted a lower SVR rate among patients with chronic hepatitis C. If confirmed with genotypes other than 4, these findings would suggest adding serum AFP to the list of factors predictive of treatment response.
Substitutions Due to Antiretroviral Toxicity or Contraindication in the First 3 years of Antiretroviral Therapy in a Large South African Cohort
Authors: Boulle Andrew , Orrell Catherine , Kaplan Richard , Van Cutsem Gilles , McNally Matthew , Hilderbrand Katherine , Myer Landon , Egger Matthias , Coetzee David , Maartens Gary , Wood Robin ,   Collaboration for the International Epidemiological Databases to Evaluate Aids in Southern Africa (IeDEASA)
Published: April 2022

Introduction The patterns and reasons for antiretroviral therapy (ART) drug substitutions are poorly described in resource-limited settings. Methods Time to and reason for drug substitution were recorded in treatment-naive adults receiving ART in two primary care treatment programmes in Cape Town. The cumulative proportion of patients having therapy changed because of toxicity was described for each drug, and associations with these changes were explored in multivariate models. Results Analysis included 2,679 individuals followed for a median of 11 months. Median CD4+ T-cell count at baseline was 85 cells/μl. Mean weight was 59 kg, mean age was 32 years and 71% were women. All started non-nucleoside reverse transcriptase inhibitor-based ART (60% on efavrienz) and 75% started on stavudine (d4T). After 3 years, 75% remained in care on-site, of whom 72% remained on their initial regimen. Substitutions due to toxicity of nevirapine (8% by 3 years), efavirenz (2%) and zidovudine (8%) occurred early. Substitutions on d4T occurred in 21% of patients by 3 years, due to symptomatic hyper-lactataemia (5%), lipodystrophy (9%) or peripheral neuropathy (6%), and continued to accumulate over time. Those at greatest risk of hyperlactataemia or lipodystrophy were women on ART ≥6 months, weighing ≥75 kg at baseline. Discussion A high proportion of adult patients are able to tolerate their initial ART regimen for up to 3 years. In most instances treatment-limiting toxicities occur early, but continue to accumulate over time in patients on d4T. Whilst awaiting other treatment options, the risks of known toxicities could be minimized through early identification of patients at the highest risk.
Abacavir Plasma Pharmacokinetics in the Absence and Presence of Atazanavir/Ritonavir or Lopinavir/Ritonavir and Vice Versa in HIV-Infected Patients
Authors: Waters Laura J , Moyle Graeme , Bonora Stefano , D'Avolio Antonio , Else Laura , Mandalia Sundhiya , Pozniak Anton , Nelson Mark , Gazzard Brian , Back David , Boffito Marta 
Published: April 2022

Background Significant interactions between abacavir and other antiretrovirals have not been reported. This study investigated the steady-state plasma pharmacokinetics of abacavir when co-administered with atazanavir/ritonavir or lopinavir/ritonavir in HIV-infected individuals. Methods HIV-infected subjects on abacavir (600 mg once daily) plus two nucleoside reverse transcriptase inhibitors (NRTIs) (excluding tenofovir) underwent a 24 h pharmacokinetic assessment for plasma abacavir concentrations. Atazanavir/ritonavir (300/100 mg once daily; arm 1) or lopinavir/ritonavir (400/100 mg twice daily; arm 2) were then added and the 24 h pharmacokinetic assessment repeated. Arm 3 included subjects stable on atazanavir/ritonavir or lopinavir/ritonavir and two NRTIs (excluding tenofovir or abacavir). These patients underwent a pharmacokinetic assessment for atazanavir/ritonavir or lopinavir/ritonavir concentrations on day 1, abacavir (600 mg once daily) was then added to the regimen and the pharmacokinetic assessment repeated. Within-subject changes in drug exposure were evaluated by geometric mean (GM) ratios and 95% confidence intervals (CI). Results Twenty-four patients completed the study. GM (95% CI) abacavir area under the curve (AUC) was 18,621 (15,900–21,807) and 15,136 (13,339–17,174) ng.h/ml without and with atazanavir/ritonavir and 15,136 (12,298–18,628) and 10,471 (9,270–11,828) ng.h/ml without and with lopinavir/ritonavir. GM (95% CI) atazanavir AUC without and with abacavir was 26,915 (13,252–54,666) and 28,840 (19,213–43,291) ng.h/ml; lopinavir AUC without and with abacavir was 60,253 (48,084–75,509) and 63,096 (48,128–82,718) ng.h/ml. Conclusions No changes in atazanavir or lopinavir exposures were observed following the addition of abacavir; however, decreases in abacavir plasma exposure of 17% and 32% were observed following the addition of atazanavir/ritonavir or lopinavir/ritonavir, respectively.
Pharmacokinetics of Darunavir/Ritonavir and TMC125 alone and Coadministered in HIV-Negative Volunteers
Authors: Schöller-Gyüre Monika , Kakuda Thomas N , Sekar Vanitha , Woodfall Brian , De Smedt Goedele , Lefebvre Eric , Peeters Monika , Hoetelmans Richard M 
Published: April 2022

Objective To evaluate the pharmacokinetics of TMC125 (etravirine) and darunavir (DRV) with low-dose ritonavir (DRV/r). Design Open-label, randomized, two-way crossover Phase I trial. Methods Thirty-two HIV-negative volunteers were randomized 1:1 to two panels. All received TMC125 100 mg twice daily for 8 days and, after 14 days washout, DRV/r 600/100 mg twice daily for 16 days. During days 9–16, TMC125 100 or 200 mg twice daily was coadministered (Panel I or II, respectively). Results Twenty-three volunteers completed the trial. With DRV/r coadministration, mean exposure (area under the plasma concentration-time curve from 0 to 12 h [AUC12h]) to TMC125 given as 100 mg twice daily was decreased by 37%; maximum and minimum plasma concentrations (Cmax and Cmin) were decreased by 32% and 49%, respectively. For TMC125 200 mg twice daily coadministered with DRV/r, AUC12h, Cmax and Cmin of TMC125 were 80%, 81% and 67% greater, respectively, versus TMC125 100mg twice daily alone. DRV pharmacokinetics were unchanged except a 15% increase in AUC12h when given with TMC125 200 mg twice daily. Conclusions No clinically relevant changes in DRV pharmacokinetics were observed when combined with TMC125; therefore DRV dose adjustment is not required. Coadministration of TMC125 100 mg twice daily with DRV/r decreased TMC125 exposure by 37%. The increase of TMC125 exposure by 80% when given as 200 mg twice daily reflects the higher dose and the interaction with DRV/r. The magnitude of this interaction is comparable to TMC125 interactions with other boosted PIs observed in Phase IIb trials in HIV-1-infected patients. As these trials demonstrated TMC125 efficacy, no dose adjustment of TMC125 is needed when combined with DRV/r.
Treatment and Prognosis of AIDS-Related Lymphoma in the Era of Highly Active Antiretroviral Therapy: Findings from the Swiss HIV Cohort Study
Authors: Simcock Mathew , Blasko Monika , Karrer Urs , Bertisch Barbara , Pless Miklos , Blumer Liisa , Vora Samir , Robinson James Owen , Bernasconi Enos , Terziroli Benedetta , Moirandat-Rytz Sophie , Furrer Hansjakob , Hirschel Bernard , Vernazza Pietro , Sendi Pedram , Rickenbach Martin , Bucher Heiner C , Battegay Manuel , Koller Michael T ,   the Swiss HIV Cohort Study, Battegay M , Bernasconi E , Böni J , Bucher H , Bürgisser Ph , Cattacin S , Cavassini M , Dubs R , Egger M , Elzi L , Erb P , Fischer M , Flepp M , Fontana A , Francioli P , Furrer H , Gorgievski M , Günthard H , Hirsch H , Hirschel B , Hösli I H , Kahlert Ch , Kaiser L , Karrer U , Kind C , Klimkait Th , Ledergerber B , Martinetti G , Martinez B , uUller N M , Nadal D , Opravil M , Paccaud F , Pantaleo G , Rickenbach M , Rudin C , Schmid P , Schultze D , Schüpbach J , Speck R , Taffé P , Tarr P , Telenti A , Trkola A , Vernazza P , Weber R , Yerly S 
Published: April 2022

Objective To assess the characteristics of combination antiretroviral therapy (cART) administered concomitantly with chemotherapy and to establish prognostic determinants of patients with AIDS-related non-Hodgkin's lymphoma. Methods The study included 91 patients with AIDS-related non-Hodgkin's lymphoma from the Swiss HIV Cohort Study enrolled between January 1997 and October 2003, excluding lymphomas of the brain. We extracted AIDS-related non-Hodgkin's lymphoma- and HIV-specific variables at the time of lymphoma diagnosis as well as treatment changes over time from charts and from the Swiss HIV Cohort Study database. Cox regression analyses were performed to study predictors of overall and progression-free survival. Results During a median follow up of 1.6 years, 57 patients died or progressed. Thirty-five patients stopped chemotherapy prematurely (before the sixth cycle) usually due to disease progression; these patients had a shorter median survival than those who completed six or more cycles (14 versus 28 months). Interruptions of cART decreased from 35% before chemotherapy to 5% during chemotherapy. Factors associated with overall survival were CD4+ T-cell count (<100 cells/μl) (hazard ratio [HR] 2.95 [95% confidence interval (CI) 1.53–5.67], hepatitis C seropositivity (HR 2.39 [95% CI 1.01–5.67]), the international prognostic index score (HR 1.98–3.62 across categories) and Burkitt histological subtypes (HR 2.56 [95% CI 1.13–5.78]). Conclusions Interruptions of cART were usually not induced by chemotherapy. The effect of cART interruptions on AIDS-related non-Hodgkin's lymphoma prognosis remains unclear, however, hepatitis C seropositivity emerged as a predictor of death beyond the well-known international prognostic index score and CD4+ T-cell count.
HIV-1 Viral Replication below 50 Copies/ml in Patients on Antiretroviral Therapy is not associated with CD8+ T-cell Activation
Authors: Steel Alan , Cox Alison E , Shamji Mohamed H , John Laurence , Nelson Mark , Henderson Don C , Gotch Frances M , Gazzard Brian G , Kelleher Peter 
Published: April 2022

Objectives To determine if the expression of CD38 on CD8+ T-cells could be used as a marker of viral replication <50 copies/ml in peripheral blood. Methods In a cross-sectional study of patients attending a single HIV clinic in London, an ultra-sensitive HIV RNA viral load assay, with a limit of detection of 3 copies/ml, was used to determine HIV-1 replication in plasma in 70 patients who had sustained viral suppression <50 copies/ml by bDNA assays. Immune activation using the expression of CD38 on CD8+ T-cells was also assessed in patients on antiretroviral therapy (ART) with sustained viral suppression, individuals with persistent low-level viraemia <400 copies/ml and subjects failing ART (viral load >400 copies/ml). Results There was no significant difference in the percentage of CD8+CD38++ T-cells between patients with <50 copies or <3 copies/ml. Immune activation was significantly increased in patients with persistent low-level viraemia and in subjects failing ART. CD4+ T-cell counts in patients on long-term successful ART are inversely associated with CD8+ T-cell activation. Conclusions T-cell activation in patients on long-term successful ART is not due to residual low-level viral replication in the blood compartment of HIV-1. CD8+ T-cell activation in this patient group appears to be associated with poor CD4+ T-cell recovery.
Potent Inhibition of Genital Herpesvirus Infection in Goats by Cidofovir
Authors: Tempesta Maria , Camero Michele , Bellacicco Anna Lucia , Tarsitano Elvira , Crescenzo Giuseppe , Thiry Julien , Martella Vito , Decaro Nicola , Elia Gabriella , Neyts Johan , Thiry Etienne , Buonavoglia Canio 
Published: April 2022

Background Like human herpesvirus 2 (HHV-2) in humans, infection by caprine herpesvirus 1 in goats is associated with genital lesions, and this provides a unique model to study the efficacy and effects of anti-herpetic drugs. Methods The antiviral activity of cidofovir was assessed in goats infected experimentally, using various therapeutic protocols. Results Topic administration of cidofovir 1% cream prevented the onset of virus-induced genital lesions and drastically reduced virus shedding. Conclusion Cidofovir appears to be a very efficient drug for the prevention of genital lesions caused by an alphaherpesvirus.