bluuebunny/crossref_metadata_2025_split huggingface dataset:
Specific Targeting of the F13L Protein by St-246 Affects Orthopoxvirus Production Differently
Authors: Duraffour Sophie , Vigne Solenne , Vermeire Kurt , Garcel Aude , Vanstreels Els , Daelemans Dirk , Yang Guang , Jordan Robert , Hruby Dennis E , Crance Jean-Marc , Garin Daniel , Andrei Graciela , Snoeck Robert 
Published: April 2022

Background ST-246 is a potent anti-orthopoxviral molecule targeting the F13L protein of vaccinia virus, which is involved in the wrapping of viruses. The discrepancy in sensitivities of several orthopoxviruses to ST-246 has raised questions about potential differences in their replicative cycles and/or the presence of another drug target. Methods Density gradients were used to evaluate the differences between the viral cycles of vaccinia, cow-pox and camelpox viruses. Also, to investigate if ST-246 inhibits a single target, we compared its activity to that of small interfering RNAs designed to silence the F13L gene (siF13Ls). Results We showed that the spread of vaccinia virus involved both intracellular and extracellular enveloped viruses, whereas both cowpox and camelpox viruses seemed to propagate via non-enveloped intracellular forms and cell-associated viral particles. Although ST-246 exerted a clear antiviral activity by interfering with the egress of the virus from infected cells, we observed that cowpox and camelpox viruses, in contrast to vaccinia virus, could be directed towards a lytic cycle under ST-246 treatment. We specifically knocked down the F13L transcripts of vaccinia and camelpox viruses by >85%, reduced virus progeny by 90% and showed that siF13Ls affect camelpox and vaccinia virus propagation differently. Flow cytometry data validated that ST-246 interfered with the activity of the F13L protein, whereas siF13Ls silenced the F13L gene. Conclusions Our observations support that vaccinia, cow-pox and camelpox viruses exhibit different levels of sensitivity to ST-246 because of dissimilarities between their ways of propagation, and provide a better understanding of the mode of action of ST-246.
Threshold survey evaluating transmitted HIV drug resistance among public antenatal clinic clients in Addis Ababa, Ethiopia
Authors: Abegaz Woldaregay Erku , Grossman Zehava , Wolday Dawit , Ram Daniela , Kaplan Jonathan , Sibide Kassim , Wuhib Tadesse , Ismael Shabbir , Nkengasong John , Mekonen Teferi , Berhanu Hiwot , Messele Tsehaynesh , Lulseged Sileshi , Maayan Shlomo , Mengistu Yohannes 
Published: April 2022

Background Expanded access to HIV therapy in the developing world raises serious concerns regarding the potential emergence and transmission of drug-resistant HIV strains. Although HIV drug resistance surveillance is recommended to track transmitted HIV drug resistance among newly infected individuals, the financial constraints in resource-limited countries prohibit such surveillance on a regular basis. The World Health Organization (WHO) recently introduced guidelines to address this issue. Methods A survey was conducted in Ethiopia following the WHO guidelines to assess transmitted HIV drug resistance among recently HIV-infected individuals in Addis Ababa. Antiretroviral drug usage started 3 years earlier than commencement of the current expanded access to antiretroviral therapy in Ethiopia. Results Of 75 eligible samples, 39 (52%) were successfully sequenced and genotyped in the protease and reverse transcriptase region, using both the ViroSeq® and TrueGene® genotyping systems, and analysed for drug resistance mutations using an algorithm from the Stanford HIV Reverse Transcriptase and Protease Database. The analysis revealed that transmitted HIV drug resistance in Addis Ababa is below the 5% threshold level for all three classes of antiretrovirals. Conclusions The current first-line antiretroviral therapy strategy can be used with confidence in Ethiopia at this time; however, Ethiopia should conduct similar periodic surveys that include the capitals of Ethiopia's larger regional states to ensure early detection of any changes in the country's HIV drug resistance trend.
Surveillance of transmitted HIV drug resistance with the World Health Organization threshold survey method in Lilongwe, Malawi
Authors:   the Malawi HIV Drug Resistance Task Force, Kamoto Kelita , Aberle-Grasse John 
Published: April 2022

Background Malawi started rapid scale-up of antiretroviral therapy (ART) in 2004 and by December 2006 had initiated 81,821 patients on treatment in the public sector. Owing to capacity constraints, standard patient care, treatment initiation and follow up are based on World Health Organization (WHO) clinical staging and do not provide laboratory monitoring to assess treatment failure. Methods To monitor possible transmission of HIV drug resistance (HIVDR) an HIVDR threshold surveillance based on the WHO guidelines was implemented in Malawi. Anonymous dried blood specimens were collected from routine blood samples of HIV-positive women attending primagravida antenatal care and aged <25 years. Results Of 59 samples tested, 54 were successfully amplified indicating good specimen quality and processing. The WHO protocol algorithm to classify the prevalence of transmitted drug resistance in the site sample only required the genotyping of 34 of the samples. None of the major drug resistance mutations on the WHO surveillance list were found in these 34 specimens. Conclusions Malawi HIVDR transmission can be classified as <5% for all relevant drugs and drug classes in this population. On the basis of the very positive experience of this survey, an expanded HIVDR surveillance system will be implemented to inform the ART program as it continues to scale-up.
Surveillance of transmitted HIV drug resistance among women attending antenatal clinics in Dar es Salaam, Tanzania
Authors: Somi Geofrey R , Kibuka Tabitha , Diallo Karidja , Tuhuma Tulli , Bennett Diane E , Yang Chunfu , Kagoma Charles , Lyamuya Eligius F , Swai Roland O , Kassim Sidibe 
Published: April 2022

Background In resource-limited settings where antiretroviral treatment (ART) access is being scaled-up, the World Health Organization (WHO) recommends surveillance of transmitted HIV drug resistance (HIVDR). We used the WHO HIVDR threshold survey method to assess transmitted HIVDR in Dar es Salaam where ART was introduced in 1995 and where ∼11,000 people are currently on ART. Methods From November 2005 to February 2006, dried blood spot (DBS) specimens were made from remnant specimens collected during the national HIV serosurvey from 60 primagravidas <25 years old attending six antenatal clinics for routine syphilis testing. Genotyping was performed at the Centers for Disease Control and Prevention, Atlanta, Georgia, USA. Protease and reverse transcriptase drug resistance mutations were identified using the Stanford University HIV drug resistance database. We used the National Institutes of Health genotyping tool for HIV-1 subtyping. HIVDR prevalence categorization was based on the WHO threshold survey binomial sequential sampling method. Results Among the 60 eligible specimens collected, 50 DBS were successfully amplified using RT-PCR. Sequencing was performed on the first 39 specimens: 13 (33.3%) were subtype A1, 13 (33.3%) subtype C, and 4 (10.3%) subtype D, the remainder differed in the closest subtype based on protease versus reverse transcriptase. No resistance mutations were seen; HIVDR to all drug classes was categorized as <5%. Conclusions Our survey indicates that prevalence of transmitted HIVDR among recently infected pregnant women in Dar es Salaam is low (<5%). The survey should be repeated during the next HIV sentinel survey in Dar es Salaam and extended to other regions where ART is being scaled up.
Factors affecting early viral load decline of Asian chronic hepatitis C patients receiving pegylated interferon plus ribavirin therapy
Authors: Hsu Ching-Sheng , Liu Chen-Hua , Liu Chun-Jen , Chen Chi-Ling , Lai Ming-Yang , Chen Pei-Jer , Chen Ding-Shinn , Kao Jia-Horng 
Published: April 2022

Background Early viral load decline following pegylated interferon-α2a and ribavirin therapy is an important predictor of the treatment responses in chronic hepatitis C (CHC) patients, thus, it is essential to evaluate the influence of host and viral factors on early viral load decline. Methods Clinical and serial virological data were collected from 145 consecutive Asian CHC patients with pegylated interferon-α2a plus ribavirin therapy. A dose of pegylated interferon-α2a was administered at week 1 and then weekly with daily oral ribavirin for 24 or 48 weeks. Genotyping and quantification of hepatitis C virus (HCV) RNA were done using molecular methods. Results A total of 81 patients were infected with HCV genotype 1, 61 with genotype 2 and 3 with both genotypes 1 and 2. At the end of follow-up, 110 patients attained sustained virological response (SVR). In multivariate analyses, body mass index (BMI) and genotype were related to viral load decline at day 2, baseline viral load and high-density lipoprotein (HDL) cholesterol levels were correlated with viral load decline between days 2 and 28. Genotype, baseline viral load, alanine aminotransferase (ALT) levels and BMI independently predicted rapid virological response, whereas only genotype 2, lower baseline viral load and more substantial viral load decline at day 28 predicted a higher SVR. Conclusions HCV genotype, baseline viral load, pretreatment BMI, HDL and ALT levels have a significant effect on early viral load decline of Asian CHC patients with interferon-based therapy. Only HCV genotype, baseline viral load and viral load decline at day 28 can independently predict SVR.
Effects of dietary supplementation with conjugated linoleic acid on experimental human rhinovirus infection and illness
Authors: Peterson Kristine M , O'Shea Marianne , Stam Wiro , Mohede Inge CM , Patrie James T , Hayden Frederick G 
Published: April 2022

Background Because studies suggest that the dietary supplement conjugated linoleic acid (CLA) has immunomodulatory activities that might benefit common colds, we performed two studies of CLA effects in experimental human rhinovirus (HRV) infection. Methods The first study explored whether CLA supplementation (Safforin™; Loders Croklaan, BV, Wormerveer, the Netherlands) altered the virological or clinical course of experimental HRV infection, and the second explored whether CLA affected the frequency and severity of HRV cold-associated sore throat and cough. The trials were randomized, double-blinded and placebo-controlled. In total, 50 healthy volunteers aged 18–45 years and susceptible to HRV type-39 (serum neutralizing antibody titre ≤1:2) participated in study 1 and 80 similar volunteers susceptible to Hank's HRV participated in study 2. Participants ingested CLA 2 g/day or placebo for 4 weeks before and 4 days following intranasal HRV inoculation. The primary endpoint for study 1 was the frequency of colds and for study 2 was the symptom severity scores for sore throat and cough. Results In study 1, 10/24 (42%) placebo compared with 7/21 (33%) CLA participants developed colds ( P=0.53). CLA was associated with significant reductions in mean scores for cough (0 CLA versus 0.9 placebo) and sore throat (0.8 CLA versus 2.9 placebo). In study 2, clinical colds developed in 19/33 (58%) placebo and 27/43 (63%) CLA participants. Symptom scores for cough (0.9 CLA versus 1.0 placebo) and sore throat (2.6 CLA versus 3.2 placebo) were not significantly different. Similarly no differences in nasal viral titres or serological responses were found. Conclusions CLA dietary supplementation had no consistent effects on the virological or clinical course of experimental HRV colds. A larger study would be required to detect more subtle effects of CLA on HRV cold-associated symptoms.
Inhibitory effect of the combination of CpG-induced cytokines with lamivudine against hepatitis B virus replication in vitro
Authors: Vincent Isabelle E , Lucifora Julie , Durantel David , Hantz Olivier , Chemin Isabelle , Zoulim Fabien , Trepo Christian 
Published: April 2022

Background Currently approved antiviral monotherapies against chronic hepatitis B fail to eradicate hepatitis B virus (HBV), to overcome the defects in HBV-specific immune responses and to prevent HBV relapse after cessation of therapy. CpG oligodesoxynucleotides (CpG ODN) are synthetic agonists of Toll-like receptor 9 and potent inducers of innate and acquired immunity. Our aim was to establish the proof of concept of the antiviral benefit of combining a nucleoside analogue with CpG-induced cytokines on HBV replication in vitro. Methods Peripheral blood mononuclear cells from HBV-negative individuals were stimulated with CpG ODN to generate CpG-induced cytokine supernatants. Proliferating HepaRG and HepG2 cells were transduced with recombinant HBV baculovirus and differentiated HepaRG cells were inoculated with HBV virions. Antiviral effects of CpG-induced cytokine with or without lamivudine were evaluated by analysing HBV DNA, HBV RNA and antigen secretion (hepatitis B surface antigen [HBsAg] and hepatitis B e antigen [HBeAg]). Results Following transduction or HBV inoculation, CpG-induced cytokines strongly inhibited HBV viral intermediates of replication, as well as HBsAg and HBeAg secretion from infected cells. Strikingly, in transduced HepaRG cells, the combination of CpG-induced cytokines with lamivudine reduced the 50% effective concentration of lamivudine by 100-fold. Importantly, the treatment of CpG-induced cytokines prior to HBV inoculation conferred a partial protection against infection to hepatocytes. Conclusions CpG-induced cytokines associated with polymerase inhibitors represent a promising combination to suppress HBV replication. Such an immunotherapeutic strategy should be evaluated in vivo to assess restoration and duration of anti-HBV-specific immune responses.
Association of baseline viral factors with response to lamivudine therapy in chronic hepatitis B patients with high serum alanine aminotransferase levels
Authors: Tseng Tai-Chung , Liu Chun-Jen , Wang Chia-Chi , Chen Pei-Jer , Lai Ming-Yang , Chen Ding-Shinn , Kao Jia-Horng 
Published: April 2022

Background With the exception of alanine aminotransferase (ALT) level, baseline factors predictive of therapeutic response to lamivudine in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) remain unknown. We thus studied the influence of pre-therapy viral factors on end-of-treatment responses to lamivudine. Methods A total of 116 treatment-naive HBeAg-positive CHB patients who had pre-therapy ALT level >5x the upper limit of normal (ULN) and received lamivudine for 12–18 months were enrolled. HBeAg seroclearance and combined HBeAg seroclearance, ALT normalization and undetectable hepatitis B virus DNA at the end of therapy were defined as primary and secondary endpoints, respectively. Pre-therapy viral factors including viral load, genotype, precore (PC) stop codon status, basal core promoter status and pre-S deletion were determined to correlate with therapeutic endpoints. Results The frequency of patients with detectable PC stop codon mutation (G1896A), basal core promoter mutation (A1762T/G1764A) and pre-S deletion at baseline was 22.4%, 21.6% and 12.1%, respectively. After the end of 12–18 months of lamivudine therapy, the overall HBeAg seroclearance rate was 56.0%. Patients with HBeAg seroclearance had a higher prevalence of baseline PC stop codon mutation than those without (30.8% versus 11.8%; P=0.015). By using multivariate analyses, the odds ratio of patients with the PC stop codon mutation to develop HBeAg seroclearance was 3.33 ( P=0.024). The presence of the PC stop codon mutation also correlated with the combined response. Conclusions For lamivudine-treated HBeAg-positive CHB patients with pre-therapy ALT levels >5xULN, the PC stop codon mutation could predict a higher HBeAg seroclearance rate at the end of 12–18 months of therapy.
Risk factors for loss of virological suppression in patients receiving lopinavir/ritonavir monotherapy for maintenance of HIV suppression
Authors: Pulido Federico , Pérez-Valero Ignacio , Delgado Rafael , Arranz Alberto , Pasquau Juan , Portilla Joaquín , Rubio Rafael , González-García Juan , Miralles Pilar , Pérez-Elías Maria J , Ocampo Antonio , Hernando Asunción , Estrada Vicente , Clotet Bonaventura , Podzamczer Daniel , Arribas José R 
Published: April 2022

Background Risk factors for loss of virological response in patients receiving lopinavir/ritonavir (LPV/r) monotherapy as maintenance treatment have not been determined. Methods In 121 patients enrolled in the OK and OK04 clinical trials assigned to receive monotherapy with LPV/r, we attempted to identify factors associated with loss of virological suppression at 48 weeks, defined as confirmed serum HIV type-1 RNA>50 copies/ml, with missing data or changes caused by toxicity censored. Univariate and multivariate Cox proportional hazard models were used to calculate hazard ratios for the risk of loss of virological suppression. Results At week 48, 15 patients experienced loss of virological suppression. Probability of loss of virological suppression was 12.7%. Less than 9 months of maintenance of virological suppression prior to monotherapy, a lower baseline haemoglobin and low adherence measured by self-reported total missed doses in the week prior to study visit were associated with loss of virological suppression in the univariate analyses. Independent factors associated with loss of virological suppression by multivariate analyses were ≥2 visits with self-reported missed doses in the week prior to the study visit, a lower baseline haemoglobin and a nadir CD4+ T-cell count <100 cells/μl Conclusions Suboptimal adherence, lower baseline haemoglobin and a nadir CD4+ T-cell count <100 cells/μl were the main risk factors for losing virological suppression in patients randomized to monotherapy with LPV/r.
Constraints on the dominant mechanism for HIV viral dynamics in patients on raltegravir
Authors: Sedaghat Ahmad R , Siliciano Robert F , Wilke Claus O 
Published: April 2022

Background Raltegravir is the first publicly released HIV integrase inhibitor. In clinical trials, patients on a raltegravir-based highly active antiretroviral therapy (HAART) regimen were observed to have 70% less viraemia in the second-phase decay of viraemia than patients on an efavirenz- based HAART regimen. Because of this accelerated decay of viraemia, raltegravir has been speculated to have greater antiretroviral activity than efavirenz. Alternative explanations for this phenomenon are also possible. For example, the stage in the viral life cycle at which raltegravir acts might explain the distinct viral dynamics produced by this drug. Methods In this report, we use a mathematical model of HIV viral dynamics to explore several hypotheses for why raltegravir causes different viral dynamics than efavirenz. Using the experimentally observed viral dynamics of raltegravir, we calculated constraints on the mechanisms possibly responsible for the unique viral dynamics produced by raltegravir. Results We predicted that the dominant mechanism for the 70% reduction in the second-phase viraemia is not antiviral efficacy but the stage of the HIV viral life cycle at which raltegravir acts. Furthermore, we found that the kinetic constraints placed on the identity of the virus-producing cells of the second phase were most consistent with monocytes/macrophages. Conclusions Our model predictions have important implications for the motivation behind the use of raltegravir and our understanding of the virus-producing cells of the second-phase viraemia. Our results also highlight that the viral dynamics produced by different antiretroviral drugs should not be directly compared with each other.
Historical resistance profile helps to predict salvage failure
Authors:   for the Collaborative Group for Clinical Use of HIV Genotype Resistance Test, Zaccarelli Mauro , Lorenzini Patrizia , Ceccherini-Silberstein Francesca , Tozzi Valerio , Forbici Federica , Gori Caterina , Trotta Maria P , Boumis Evangelo , Narciso Pasquale , Perno Carlo F , Antinori Andrea 
Published: April 2022

Background This study compared the predictive value for treatment failure of extended resistance detected in the current genotype resistance test (GRT) versus those from GRT history in patients with multiple combination anti-retroviral therapy (cART) failures. Methods Patients who underwent three GRT between 1999 and 2007 were included. Extended resistance at genotypic sensitivity score (GSS) using the Rega 7.1 interpretation system compared with a non-standard definition (defined as class-wide resistance [CWR] on the basis of International AIDS Society–USA mutations) was assessed both for current and historical GRTs (a combination of mutations was detected in all three tests). The predictive role of extended resistance for treatment failure was evaluated with an adjusted Cox proportional hazard model. Results Overall, 177 patients were included. The historical GRT increased the number of patients with extended resistance to all three major drug classes by 25% in comparison with the current GRT. Using the GSS method, the absence of detection of any active drug in any drug class was predictive of failure with both the current and historical GRTs. Similarly, the number of active drugs in the cART regimen after the third resistance test, used as continuous variable, was also predictive of failure. Using both GSS approaches, current genotype had a higher effect than historical genotype on risk of treatment failure. Using the non-standard definition (CWR), historical resistance predicted failure better than current resistance. Conclusions Our results provide an epidemiological demonstration that analysis of a combined latest and historical GRT, which also considers archived mutations, might better identify of the more virologically impaired patients in order to assess the best salvage treatment.
Evolution and predictors of HIV type-1 drug resistance in patients failing combination antiretroviral therapy in Italy
Authors: Di Giambenedetto Simona , Zazzi Maurizio , Corsi Paola , Gonnelli Angela , Di Pietro Massimo , Giacometti Andrea , Almi Paolo , Trezzi Michele , Boeri Enzo , Gianotti Nicola , Menzo Stefano , Gobbo Romana Del , Francisci Daniela , Nerli Alessandro , Galli Luisa , Luca Andrea De 
Published: April 2022

Background This study aimed to examine the evolution of genotypic drug resistance prevalence in treatment-failing patients in the multicentre, Italian, Antiretroviral Resistance Cohort Analysis (ARCA). Methods Patients with a drug resistance genotype test performed between 1999 and 2006 at failure of a combination antiretroviral therapy and with complete treatment history were selected. The prevalence of resistance was measured overall, per calendar year, per drug class and per treatment line at failure. Results The overall resistance prevalence was 81%. Resistance to nucleoside reverse transcriptase inhibitors (NRTIs) declined after 2002 (68% in 2006; χ2 for trend P=0.004); resistance to non-NRTIs (NNRTIs) stabilized after 2004; and resistance to protease inhibitors (PIs) declined after 2001 (43% in 2006; P=0.004). In first-line failures, NRTI resistance decreased after 2002 ( P=0.006), NNRTI resistance decreased after 2003 ( P=0.001) and PI resistance decreased after 2001 ( P<0.001). Independent predictors of resistance to any class were HIV type-1 transmission by heterosexual contacts as compared with injecting drug use, a higher number of experienced regimens, prior history of suboptimal therapy, higher viral load and CD4+ T-cell counts, more recent calendar year and viral subtype B carriage, whereas the use of PI-based versus NNRTI-based regimens at failure was associated with a reduced risk of resistance. There was an increase of type-1 thymidine analogue and of protease mutations L33F, I47A/V, I50V and I54L/M, whereas L90M decreased over calendar years. Conclusions During more recent years, emerging drug resistance has decreased, particularly in first-line failures. The prevalence continues to be high in multiregimen-failing patients.