bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Randomized Placebo-Controlled, Dose-Finding Study of Oral Lb80380 in Hbeag-Positive Patients with Chronic Hepatitis B
Authors: Yuen Man-Fung , Kim John , Kim Chung Ryeol , Ngai Vincent , Yuen John Chi-Hang , Min Changhee , Kang Hyang Mi , Shin Beom Soo , Yoo Sun Dong , Lai Ching-Lung 
Published: April 2022

Background LB80380 is potent antiviral agent against hepatitis B virus (HBV) in vitro and in the woodchuck model. It has an excellent preclinical safety profile including lower potential for renal toxicity than adefovir. It is effective against both wild-type and YMDD mutant HBV. LB80380 is converted to its parent drug, LB80331, after oral absorption, and further metabolized to its active form, LB80317. Aims/Methods This randomized placebo-controlled Phase I/II clinical study of LB80380 was conducted to assess the safety, antiviral activity and pharmacokinetics of its parent drug LB80331 and its active form LB80317 in 29 Asian adults with chronic hepatitis B positive for hepatitis B e antigen in four escalating dose groups (30, 60, 120 and 240 mg once per day) for 4 weeks with a 12-week follow-up period. Results The mean maximum HBV DNA reduction was 3.05, 4.20, 3.67 and 3.68 log10 copies/ml for 30, 60, 120 and 240 mg per day, respectively. Viral dynamic analysis suggested a high degree of inhibition of HBV replication at doses of 60 mg or higher per day. LB80380 was well tolerated at all dose groups, and no dose-related clinical or laboratory adverse event was reported. Conclusion LB80380 is shown to be a potent and safe antiviral agent for HBV. Marked HBV DNA suppression was observed in all dose groups. The HBV DNA suppression was approximately constant at doses of 60 mg and higher over the 28-day dosing period. The dose response of LB80380 will be evaluated further in large clinical studies.
Early Antiviral Treatment of Hepatitis C Virus Recurrence after Liver Transplantation in HIV-Infected Patients
Authors: Castells LLuís , Esteban Juan I , Bilbao Itxarone , Vargas Víctor , Allende Helena , Ribera Esteban , Piron Maria , Sauleda Silvia , Len Oscar , Pahissa Albert , Esteban Rafael , Guardia Jaime , Margarit Carlos 
Published: April 2022

Objective To investigate the efficacy of early antiviral treatment for hepatitis C virus (HCV) recurrence in HIV/HCV-coinfected patients undergoing liver transplantation for end-stage liver disease. Methods Open prospective trial of early treatment of HCV recurrence in consecutive HIV/HCV-coinfected patients transplanted at a tertiary hospital in Barcelona between 2002 and 2004. All patients had indication for liver transplantation, no previous CDC class C HIV-associated opportunistic events, a CD4+ T-cell count >100 cells/fxl, and undetectable plasma HIV RNA on highly active antiretroviral therapy. Treatment with pegylated interferon-a2b (1.5 μg/kg/week) and ribavirin (800–1000 mg/day) was given for 24 to 48 weeks, as soon as HCV recurrence was histologically documented. Results Of six patients who underwent transplant, five patients surviving the early post-transplantation period developed HCV recurrence, presenting as severe cholestatic hepatitis in three, and were started on antiviral treatment a median of 12 weeks (range: 5–31) after transplantation. After a median follow-up of 24 months all treated patients were alive. Biochemical response was achieved in all patients, although only one achieved a sustained virological response. Mild rejection before HCV recurrence occurred in two cases. Treatment was well tolerated with no episodes of rejection or mitochondrial toxicity. No patient required modification of the antiretroviral regimen. Liver biopsies performed in patients without virological response, 12–34 months after transplantation, showed cirrhosis in two and moderate chronic active hepatitis in the remainder. Conclusions Despite early antiviral treatment, severe HCV recurrence after liver transplantation may compromise long-term survival in HIV-infected patients. Improved treatment strategies for these patients are urgently required.
Quantitative Subtyping of Hepatitis B Virus Reveals Complex Dynamics of Ymdd Motif Mutants Development during Long-Term Lamivudine Therapy
Authors: Ding Chunming , Wong Vincent WS , Chow Katherine CK , Chan Hoi-Yun , Hui Alex Y , Wong Grace LH , Lo YM Dennis , Sung Joseph JY , Chan Henry LY 
Published: April 2022

Background/aims Treatment of chronic hepatitis B (CHB) with lamivudine (3TC) is limited by development of drug-resistant mutants at the YMDD motif. We aimed to validate the use of mass spectrometry to detect YMDD mutants and quantify viral subpopulations. Methods A total of 21 Chinese patients with severe acute exacerbation of CHB treated with 3TC were studied. Serial serum samples were tested for wild-type and YMDD mutants using matrix assisted laser desorption/ionization time-of-flight mass spectrometry. INNO-LiPA assay was performed for comparison. Results At a median follow-up of 192 weeks, 11 patients developed YMDD mutants (six had YIDD, four had YVDD and one had YV/IDD). Mass spectrometry was concordant with INNO-LiPA in all but one patient, in which INNO-LiPA detected coexistence of YIDD and YVDD but mass spectrometry and direct sequencing detected YVDD only. Mass spectrometry was able to reliably detect a minor hepatitis B virus (HBV) subtype at 5% or above. By serial quantitative measurement, several patterns of viral dynamics were observed. In some cases, YMDD mutants dominated the whole viral population. In other cases, the proportion of YMDD mutants fluctuated with time. When more than one mutant was present (that is, YIDD and YVDD), the different mutants might dominate during different time periods. Conclusions Mass spectrometry is an accurate and cheap method for the detection of YMDD mutants, even in the presence of overwhelming wild-type HBV. We observed some intriguing mutant viral dynamics during 3TC treatment. Further studies are needed to clarify whether they have any clinical significance.
Nelfinavir Induces Adipocyte Insulin Resistance through the Induction of Oxidative Stress: Differential Protective Effect of Antioxidant Agents
Authors: Ben-Romano Ronit , Rudich Assaf , Etzion Sharon , Potashnik Ruth , Kagan Ella , Greenbaum Uri , Bashan Nava 
Published: April 2022

Background Antiretroviral therapy is frequently associated with adverse metabolic effects and lipodystrophy, but the role of HIV protease inhibitors and the mechanisms involved are poorly understood. The HIV protease inhibitor nelfinavir (NFV) impairs insulin signal propagation by inducing similar signalling defects to those induced by exposure to oxidative stress. Aim We set out to determine if oxidative stress is involved in NFV-induced insulin resistance in 3T3-L1 adipocytes, and whether antioxidant agents with unique modes of action can prevent this effect. Results Cells exposed to NFV exhibited the following markers of increased oxidative stress: a decrease in both total and low molecular weight reduced thiols, a 20-fold increase in haem oxygenase 1 (HO-1) mRNA, an increase in intracellular reactive oxygen species production (determined by 2′,7′-dichlorofluorescein fluorescence), and increased markers of apoptosis. Enhancing cellular thiols with N-acetylcystein prevented the NFV-induced drop in reduced thiols and partially protected against the induction in HO-1, but failed to prevent insulin resistance or cleavage of poly ADP ribose polymerase (PARP), a process indicative of activation of pro-apoptotic caspases. Conversely, the superoxide dismutase-mimetic antioxidant MnTBAP had no effect on cellular thiols in response to NFV, but protected against HO-1 induction and against the impairment in insulin-stimulated Akt/protein kinase B activation and PARP cleavage. Conclusions Induction of oxidative stress plays a role in adipocyte insulin resistance and apoptosis induced by NFV through a radical-dependent but thiol-independent mechanism(s). The results may suggest a new mechanism for the adverse effects of NFV on fat cells, and offer potential new intervention approaches.
Macroenzyme Creatine Kinase (Ck) Type 2 in HIV-Infected Patients is Significantly Associated with Tdf and Consists of Ubiquitous Mitochondrial Ck
Authors: Schmid Holger , Mühlbayer Dieter , Röling Jörg , Sternfeld Thomas , Jülg Boris , Schlattner Uwe , Nelson Peter J , Bogner Johannes R , Wallimann Theo , Goebel Frank D 
Published: April 2022

Objective To evaluate the prevalence and origin of macroenzyme creatine kinase type 2 (Macro CK2) in HIV-1-infected patients on antiretroviral treatment. Design CK, CK-MB activity and protein weight, electrophoretic behaviour, glomerular filtration rate (GFR), aspartate aminotransferase (AST), alanine aminotransferase (ALT), bone alkaline phosphatase (AP), (2-microglobulin serum levels and proteinuria were analysed in 468 HIV-infected outpatients. Sera with detectable Macro CK2 were further analysed using immunoblotting. Results CK-MB isoenzyme activity and mass concentration revealed the presence of Macro CK2 in 32/408 (7.8%) outpatients. Tenofovir DF (TDF) treatment was a prominent common feature in these patients. Prospective examination of sera from 41 patients collected prior to and during TDF exposure showed Macro CK2 in 20/41 (48%) TDF-treated patients and in 0/19 control sera from patients with TDF-free regimens. Macro CK2 was not present prior to TDF exposure. Patients with Macro CK2 showed a significant elevation of serum (2-microglobulin levels. GFR, AST/ALT ratio, bone AP and proteinuria remained unchanged. Electrophoresis and immunoblotting demonstrated that the Macro CK2 in TDF-treated patients consisted of the ubiquitous (uMtCK) and not the sarcomeric type (sMtCK) of mitochondrial CK (MtCK). Conclusions Macro CK2 consisting of uMtCK is associated with the use of TDF-containing regimens. Whether the appearance of uMtCK in these patients reflects mitochondrial damage remains to be clarified.
Outcome of Chronic Hepatitis C Patients who Required Early Termination of Pegylated Interferon-α plus Ribavirin Combination Therapy
Authors: Yu Ming-Lung , Dai Chia-Yen , Lee Li-Po , Hsieh Ming-Yen , Hou Nai-Jen , Huang Jee-Fu , Lin Zu-Yau , Chen Shinn-Cherng , Hsieh Ming-Yuh , Wang Liang-Yen , Chang Wen-Yu , Chuang Wan-Long 
Published: April 2022

Background Pegylated interferon/ribavirin (peg-IFN/RBV) combination therapy is effective for chronic hepatitis C (CHC) but frequently causes adverse events, leading to early termination. Little is known about the outcome of CHC patients who required early termination. Methods Of 617 treatment-naive CHC patients prescribed a 24-week protocol of peg-IFN/RBV, 29 (4.7%) patients who terminated treatment early at <20 weeks were recruited to evaluate the rate of and the factors associated with sustained virological response (SVR), defined as seronegativity of hepatitis C virus (HCV) RNA throughout the 24-week off-treatment follow-up period. Results The reasons for early termination were flu-like symptoms/signs ( n=9, 31.0%), irritability ( n=1, 3.4%), severe urticaria ( n=1, 3.4%), insomnia ( n=2, 6.9%), pulmonary tuberculosis ( n=1, 3.4%), suicide idea ( n=2, 6.9%), poor response ( n=2, 6.9%), depression ( n=2, 6.9%), unwilling to continue ( n=1, 3.4%), mortality ( n=1, 3.4%), gastrointestinal upset ( n=1, 3.4%), pancytopenia complicated with cellulitis ( n=1, 3.4%), anaemia ( n=3, 10.3%), overseas work ( n=1, 3.4%) and an unknown cause ( n=1, 3.4%). Five (17.2%) patients achieved an SVR, comprising none of 16 HCV genotype-1 and five of the 13 (38.5%) genotype-2 patients ( P=0.001). All sustained responders were HCV RNA seronegative at week 4 of treatment. The SVR rate among HCV-2 patients was 0% (0/1), 0% (0/2), 25% (1/4), 33% (1/3) and 100% (3/3) in those who received peg-IFN/RBV for 1–3, 4–7, 8–11, 12–15 and 16–19 weeks, respectively ( P=0.019, χ2 with linear trend). Conclusions Based on this limited study, we observed that an SVR might be achieved in patients who required early termination of a 24-week regimen of peg-IFN/RBV, especially for HCV-2 patients with HCV RNA seronegativity at week 4.
Prediction of Treatment-Related HBsAg Loss in HBeAg-Negative Chronic Hepatitis B: A Clue from Serum HBsAg Levels
Authors: Manesis Emanuel K , Hadziyannis Emilia S , Angelopoulou Olga P , Hadziyannis Stephanos J 
Published: April 2022

Background Quantification of HBsAg in serum may be of clinical importance in predicting HBsAg seroconversion and complete response to treatment. Methods Serum HBsAg was quantified by ADVIA Centaur® in 63 patients with HBeAg-negative chronic hepatitis B (CHBe-). A total of 42 had received interferon-α2b (IFN-α2b) (median 12.1 months; 19 sustained responders including 12 HBsAg-seroconvertors; 23 non-sustained responders) and 21 were on lamivudine (LAM) (median 33.0 months). Measurements were done at baseline, during and at the end of treatment, and during and at the end of follow-up. Results Baseline median [interquartile range (IQR)] HBsAg levels in all patients were 3,286 (1,602–7,458) IU/ml, not different between IFN- and LAM-treated ( P=0.139). IFN significantly depressed HBsAg in all patients except IFN non-responders, but HBsAg decline persisted only in sustained responders. Low pretreatment HBsAg level was the only significant prognostic variable of HBsAg seroconversion by multivariate analysis. LAM treatment also suppressed HBsAg levels but at a significantly slower rate compared with IFN ( P=0.022). The median (IQR) estimated time to HBsAg undetectability (ETU-HBsAg), derived from best curve fitting, was 127 (87.6–263.5) months for LAM virological responders and 65.3 (36.3–95.0) months for IFN sustained responders ( P=0.002). In 12 HBsAg seroconvertors, ETU-HBsAg was similar to the real time of HBsAg loss ( P=0.525) and seroconversion (0.056). Conclusions In CHBe-, IFN induces a sharper decrease in serum HBsAg compared with LAM and low pretreatment levels are significantly associated with HBsAg seroconversion. Serial HBsAg measurements may be useful for prediction of HBsAg loss and our data suggest that to achieve this, 5.4 years of sustained response to IFN or 10.6 years of effective LAM therapy are probably needed.
Evaluation of Cytomegalovirus DNAaemia versus pp65-Antigenaemia Cutoff for Guiding Preemptive therapy in Transplant Recipients: A Randomized Study
Authors: Gerna Giuseppe , Baldanti Fausto , Torsellini Maria , Minoli Lorenzo , Viganò Mario , Oggionni Tiberio , Rampino Teresa , Castiglioni Barbara , Goglio Antonio , Colledan Michele , Mammana Carmelo , Nozza Francesca , Lilleri Daniele 
Published: April 2022

Methods A bicentre, randomized, prospective open-label study aimed at defining a DNAaemia versus antigenaemia cutoff for guiding preemptive therapy of human cytomegalovirus (HCMV) infections in solid organ transplant recipients (SOTR) was completed. Overall, 99 patients were enrolled in the DNAaemia arm and 101 patients in the antigenaemia arm. Patients were randomized to be monitored for HCMV infection in the blood by either assay. Antiviral treatment was started in both seropositive and seronegative patients when levels greater than 300,000 DNA copies/ml blood or 100 pp65-positive leukocytes in the relevant arm were reached. Results HCMV infection was detected in 81/99 (81.8%) patients in the DNAaemia arm and in 87/101 (86.1%) patients in the antigenaemia arm ( P=ns). Antiviral treatment was given to 23/99 (23.0%) patients in the DNAaemia arm and 42/101 (41.0%) patients in the antigenaemia arm ( P=0.01). In the DNAaemia arm, antiviral therapy was significantly delayed and duration of the first course of treatment was significantly greater than in the antigenaemia arm. However, total duration of treatment was comparable in the two arms. No case of HCMV disease occurred in patients treated after reaching the relevant cutoff. However, four patients (three in the antigenaemia arm, and one in the DNAaemia arm) suffered from HCMV disease prior to reaching the relevant cutoff. Conclusions Compared with antigenaemia, a single DNAaemia cutoff: (i) significantly reduces the number of patients requiring treatment; (ii) may be safely adopted to guide preemptive therapy of both primary and reactivated HCMV infections in SOTR; and (iii) does not significantly modify the overall duration of treatment.
Renal Function in Antiretroviral-Experienced Patients treated with Tenofovir Disoproxil Fumarate associated with Atazanavir/ritonavir
Authors: Gérard Laurence , Chazallon Corine , Taburet Anne-Marie , Girard Pierre-Marie , Aboulker Jean-Pierre , Piketty Christophe 
Published: April 2022

Objective To determine the evolution of renal function in highly treatment-experienced patients with normal renal function at baseline receiving tenofovir disoproxil fumarate (TDF) as part of a fixed combined antiretroviral regimen and to identify prognostic factors of change in renal function, including tenofovir concentrations. Methods A prospective 48-week open-label trial was carried out, evaluating the safety of TDF, associated with atazanavir/ritonavir, and optimized nucleoside reverse transcriptase inhibitors, in patients with documented failure in previous treatments. Statistical analysis was performed on an intent-to-treat basis. Results Fifty-three patients were included, with a median CD4+ T-cell count of 206x106/l and a median HIV RNA level of 5 log10 copies/ml. All patients had normal serum creatinine levels and creatinine clearances (CLCr) at baseline, which were stable within the 2 months preceding inclusion. Two patients discontinued TDF as a result of severe renal impairment. Two patients never started TDF. A total of 49 patients without clinical nephrotoxicity were analysed. The median creatinine level increased significantly from baseline to week 48 (+0.04 mg/dl [+5.8%]; P=0.008), and the median CLCr decreased significantly (-7.8 ml/min [-7.6%]; P=0.005). Trough tenofovir concentration was not associated with change in CLCr ( P=0.79). No risk factors, including tenofovir plasma trough levels, were significantly associated with change in CLCr at week 24. Conclusions This study confirms that TDF-related severe nephrotoxicity is an uncommon event. In patients without clinical nephrotoxicity, the use of TDF during a 1-year period was associated with a slight but significant alteration of renal function, which was not associated with increased trough concentration.
Genetic Diversity and Drug Resistance Mutations in HIV type 1 from Untreated Patients in Bamako, Mali
Authors: Derache Anne , Traore Ousmane , Koita Victoria , Sylla Aliou , Tubiana Roland , Simon Anne , Canestri Ana , Carcelain Guislaine , Katlama Christine , Calvez Vincent , Cisse Mamadou , Marcelin Anne-Geneviève 
Published: April 2022

Objective To determine the genetic diversity of HIV-1 reverse transcriptase (RT) and protease sequences and the presence of mutations linked to antiretroviral (ARV) resistance in treatment-naive, HIV-1-infected individuals living in Mali. Methods Ninety-eight samples from ARV drug-naive, HIV-1-infected patients were collected in one clinical centre in Bamako, Mali in 2005. RT and protease genes were sequenced in order to perform phylogenetic and resistance analyses. Results The most prevalent subtype was CRF02-AG (75% of cases), followed by the CRF06-cpx subtype (20%). Intersubtype recombinants between CRF02-AG, CRF01-AE and CRF06-cpx were also described in 5% of cases. After 4 years of ARV use in Mali, two previously untreated individuals (2%; 95% CI: 0.00–4.77%) were found to have resistant viruses, one with a single nucleoside mutation and one with K103N non-nucleoside reverse transcriptase inhibitor resistance mutation. No evidence of transmitted protease inhibitor resistance mutations was found. Conclusion These data provide direct evidence for the circulation of HIV-1 isolates containing resistance mutations in treatment-naive patients in Mali. Since ARV use in Mali began, more than 5,000 patients have started treatment, mostly with Triomune (stavudine/lamivu-dine/nevirapine). The resistance-associated mutations detected in the present study are consistent with this treatment regimen. Continued surveillance will be required to monitor the emergence of ARV resistance in this country.
Improved Prediction of Response to Antiretroviral Combination Therapy using the Genetic Barrier to Drug Resistance
Authors: Altmann André , Beerenwinkel Niko , Sing Tobias , Savenkov Igor , Däumer Martin , Kaiser Rolf , Rhee Soo-Yon , Fessel W Jeffrey , Shafer Robert W , Lengauer Thomas 
Published: April 2022

Background The outcome of antiretroviral combination therapy depends on many factors involving host, virus, and drugs. We investigate prediction of treatment response from the applied drug combination and the genetic constellation of the virus population at baseline. The virus's evolutionary potential for escaping from drug pressure is explored as an additional predictor. Methods We compare different encodings of the viral genotype and antiretroviral regimen including phenotypic and evolutionary information, namely predicted phenotypic drug resistance, activity of the regimen estimated from sequence space search, the genetic barrier to drug resistance, and the genetic progression score. These features were evaluated in the context of different statistical learning procedures applied to the binary classification task of predicting virological response. Classifier performance was evaluated using cross-validation and receiver operating characteristic curves on 6,337 observed treatment change episodes from the Stanford HIV Drug Resistance Database and a large US clinic-based patient population. Results We find that the choice of appropriate features affects predictive performance more profoundly than the choice of the statistical learning method. Application of the genetic barrier to drug resistance, which combines phenotypic and evolutionary information, outperformed the genetic progression score, which uses exclusively evolutionary knowledge. The benefit of phenotypic information in predicting virological response was confirmed by using predicted fold changes in drug susceptibility. Moreover, genetic barrier and predicted phenotypic drug resistance were found to be the best encodings across all datasets and statistical learning methods examined. Availability THEO (THErapy Optimizer), a prototypical implementation of the best performing approach, is freely available for research purposes at http://www.geno2pheno.org .
New Functional Domains of Human Cytomegalovirus pUL89 predicted by Sequence Analysis and Three-Dimensional Modelling of the Catalytic Site DEXDc
Authors: Champier Gaël , Hantz Sébastien , Couvreux Anthony , Stuppfler Stéphanie , Mazeron Marie-Christine , Bouaziz Serge , Denis François , Alain Sophie 
Published: April 2022

Introduction Benzimidazole d-ribonucleosides inhibit DNA packaging during human cytomegalovirus (HCMV) replication. Although they have been shown to target pUL56 and pUL89, the large and small subunits of the HCMV terminase respectively, their mechanism of action is not yet fully understood. Methods and results To better understand HCMV DNA maturation and the mechanism of action of benzimidazole derivatives, we studied the HCMV pUL89 protein by a genetic approach combined with primary structure analysis. The pUL89 sequence analysis of 25 HCMV strains and counterparts among herpesviruses allowed identification of 12 conserved regions. We also built a three-dimensional model of the pUL89 ATPasic catalytic site, including ATPase motor motifs I, II and III, that may facilitate the development of future antiviral drugs active against HCMV. Finally, we identified several putative functional domains in pUL89, such as pUL89 zinc finger (pUL89-ZF), DNA cutting sites and portal binding sites, that are probably involved in CMV DNA cleavage and packaging.