bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic barriers for integrase inhibitor drug resistance in HIV type-1 B and CRF02_AG subtypes
Authors: Maïga Almoustapha-Issiaka , Malet Isabelle , Soulie Cathia , Derache Anne , Koita Victoria , Amellal Bahia , Tchertanov Luba , Delelis Olivier , Morand-Joubert Laurence , Mouscadet Jean-François , Murphy Robert , Cissé Mamadou , Katlama Christine , Calvez Vincent , Marcelin Anne-Genevieve 
Published: April 2022

Background HIV type-1 (HIV-1) integrase (IN) inhibitor resistance is the consequence of mutations that are selected in the viral IN gene targeted by antiretroviral drugs, such as raltegravir (RAL) and elvitegravir (EVG). The genetic barrier, defined as the number of viral mutations required to overcome the drug-selective pressure, is one of the important factors in the development of drug resistance. The genetic barrier for IN inhibitor resistance was compared between HIV-1 subtype B and HIV-1 subtype CRF02_AG, which is highly prevalent in West Africa and becoming more frequent in developed countries. Methods IN nucleotide sequences from 73 HIV-1 subtype B and 77 HIV-1 subtype CRF02_AG antiretroviral-naive patients were examined at 19 IN amino acid positions implicated in RAL and EVG resistance. Results The majority (14/19) of the studied positions showed a high degree of conservation of the predominant codon sequences leading to a similar genetic barrier between subtypes B and CRF02_AG. Nevertheless, at positions 140 and 151, the variability between subtypes affected the genetic barrier for the mutations G140C, G140S and V151I with a higher genetic barrier being calculated for subtype CRF02_AG. Conclusions The major IN mutations E92Q, Q148K/R/H, N155H and E157Q (implicated in the resistance of IN inhibitors RAL and EVG) are highly conserved between subtypes B and CRF02_AG and display a similar genetic barrier. However, subtype CRF02_AG showed a higher genetic barrier to acquire mutations G140S, G140C and V151I as compared with subtype B, which could play a role in the resistance to RAL and/or EVG.
Differential susceptibility of adenovirus clinical isolates to cidofovir and ribavirin is not related to species alone
Authors: Morfin Florence , Dupuis-Girod Sophie , Frobert Emilie , Mundweiler Stéphanie , Carrington David , Sedlacek Petr , Bierings Marc , Cetkovsky Petr , Kroes Aloys CM , van Tol Maarten JD , Thouvenot Danielle 
Published: April 2022

Background We have previously reported that human adenovirus (HAdV) reference strains clearly show species-dependent resistance to ribavirin, whereas different species of HAdV are equally sensitive to cidofovir. All the serotypes tested were susceptible to cidofovir, whereas only serotypes from species C were sensitive to ribavirin. Here, we aimed to extend these investigations to clinical isolates. Methods In vitro, we tested 126 isolates obtained from 65 patients included in a European survey of HAdV infection. Results Among the 126 isolates tested, all presented cidofovir 50% inhibitory concentration (IC50) in the same range as the HAdV 5 reference strain. Regarding ribavirin, all isolates from species C (79 tested) showed an IC50 comparable with previously reported results for reference strains; however, 24/32, 2/6 and 3/3 tested isolates from species A, B and D, respectively, were shown to have a ribavirin IC50 comparable with the HAdV 5 reference strain (species C), contrary to previous observations for reference strains of the same species. Among patients who were treated with cidofovir for disseminated HAdV infection, ≥4 sequential isolates could be obtained from 9 patients; no variation in cidofovir susceptibility could be detected. Conclusions Cidofovir is active in vitro in all HAdV clinical isolates. Ribavirin was revealed to be active on most HAdV isolates from species A, B and D, and in all isolates from species C. Finally, no resistance to cidofovir became apparent in sequential isolates obtained from treated patients.
Effect of Antiviral Treatment on Serum Markers of Liver Fibrosis in HIV–Hepatitis C virus-Coinfected Patients: The Fibrovic 2 Study – ANRS HC02
Authors: Halfon Philippe , Carrat Fabrice , Bédossa Pierre , Lambert Jérôme , Pénaranda Guillaume , Perronne Christian , Pol Stanislas , Cacoub Patrice 
Published: April 2022

Background Non-invasive liver fibrosis scores have been proposed as alternatives to liver biopsy (LB) in hepatitis C virus (HCV)-infected patients. Here, we aimed to assess the effect of antiviral treatment on non-invasive serological markers of liver fibrosis in HIV–HCV-coinfected patients. Methods We included 114 HIV–HCV-coinfected patients with LBs performed before and 6 months after the end of treatment (week 72; W72). Fibrotest, the Forn's index, age-platelet ratio index, SHASTA, FIB-4, Hepascore and Fibrometer scores were assessed. There were 29 (25%) patients who achieved sustained virological response (SVR). Results At baseline (BL), all non-invasive fibrosis scores except the Forn's index did not show significantly lower values in SVR patients. At W72, all non-invasive scores, except Hepascore, showed a significant decrease in SVR patients ( P<0.01). There was a significant difference in fibrosis stages on LBs between BL and W72 in SVR and non-SVR patients. Conclusions In HIV–HCV-coinfected patients, HCV clearance is associated with a significant reduction in non-invasive fibrosis serological markers, which most likely reflect the histological improvement associated with SVR. If confirmed, such results will reinforce the reliability of these markers in the follow-up after HCV treatment.
Evolution of drug resistance after virological failure of a first-line highly active antiretroviral therapy regimen in Uganda
Authors: Reynolds Steven J , Kityo Cissy , Mbamanya Frank , Dewar Robin , Ssali Francis , Quinn Thomas C , Mugyenyi Peter , Dybul Mark 
Published: April 2022

Background This study aimed to determine the extent of viral resistance over time among non-clade B HIV type-1-infected patients in Uganda who were maintained on first-line highly active antiretroviral therapy (HAART) following virological failure. Methods Genotyping was performed on 16 patients with virological failure who were enrolled in an open-label randomized clinical trial of short-cycle treatment interruption. Results All patients receiving efavirenz-containing HAART had ≥1 efavirenz resistance mutation develop during follow-up. The majority (13/15, 86%) developed lamivudine resistance during follow-up, but no thymidine analogue mutations (TAMs) developed during a median duration of virological failure of 325.5 days. Conclusions Genotype resistance to both efavirenz and lamivudine developed early during the course of treatment after virological failure. TAMs did not emerge early despite moderate exposure time to thymidine analogues during virological failure.
The pharmacokinetics, safety and efficacy of boosted saquinavir tablets in HIV type-1-infected pregnant women
Authors: van der Lugt Jasper , Colbers Angela , Molto Jose , Hawkins David , van der Ende Marchina , Vogel Martin , Wyen Christoph , Schutz Malte , Koopmans Peter , Ruxrungtham Kiat , Richter Clemens , Burger David 
Published: April 2022

Background Pregnancy affects the pharmacokinetics of most protease inhibitors. Saquinavir, when administered in a tablet formulation, has not been studied extensively in this setting. Methods A pharmacokinetic, prospective, multicentre trial of HIV type-1-infected pregnant women treated with saquinavir (500 mg tablets) boosted with ritonavir at a dose of 1,000/100 mg twice daily plus a nucleoside backbone was conducted. Pharmacokinetic curves were recorded for 12 h in the second trimester (week 20 ±2), the third trimester (week 33 ±2) and post-partum (weeks 4–6). Blood was sampled pre-dosing and at 1, 2, 3, 4, 6, 8, 10 and 12 h post-dosing. Pharmacokinetic parameters were calculated using WinNonlin software version 4.1. Results A total of 37 women were included in the analysis. Mean (±sd) values for saquinavir area under the curve (AUC0–12h) were 23.47 h•mg/l (11.92) at week 20 ( n=16), 23.65 h•mg/l (9.07) at week 33 ( n=31) and 25.00 h•mg/l (11.81) post-partum ( n=9). There was no significant difference in the saquinavir AUC0–12h when comparing the data during pregnancy and post-partum. Subtherapeutic plasma concentrations of saquinavir (defined as <0.10 mg/l) were not observed throughout the study. No major safety concerns were noted. Conclusions Saquinavir exposure in the new tablet formulation generates adequate saquinavir concentrations throughout the course of pregnancy and is safe to use; therefore, no dose adjustment during pregnancy is needed.
Pregnancy outcomes in women with HIV type-1 receiving a lopinavir/ritonavir-containing regimen
Authors: Azria Elie , Moutafoff Constance , Schmitz Thomas , Le Meaux Jean Patrick , Krivine Anne , Pannier Emmanuelle , Firtion Ghislaine , Compagnucci Alexandra , Finkielsztejn Laurent , Taulera Olivier , Tsatsaris Vassilis , Cabrol Dominique , Launay Odile 
Published: April 2022

Background The pregnancy-related adverse effects of antiretroviral therapy (ART) have yielded discordant results, which could be explained in part by the heterogeneity of ART protocols. The objective of our study was to explore whether lopinavir/ritonavir (LPV/r) exposure during pregnancy is associated with adverse outcomes. Methods Data on 100 consecutive HIV type-1 (HIV-1)-infected women receiving LPV/r during pregnancy and who delivered after 15 weeks gestational age (GA) between January 2003 and June 2007 in a single centre were analysed. For each HIV-1-infected woman, two uninfected women matched by age, parity and geographical origin were selected among patients delivering during the same period. Preterm delivery (PTD), vasculoplacental complications, gestational glucose intolerance and post-partum complication rates were compared between cases and controls. Factors associated with PTD and post-partum complications were assessed in HIV-1-infected women by a logistic regression model. Results Rates of vasculoplacental complication and gestational glucose intolerance were not higher among HIV-1-infected women than in controls. PTD was higher in HIV-1-infected women (21%) than in controls (10%; P<0.01). In HIV-1-infected women, PTD was associated with HIV-1 RNA level ≥50 copies/ml at delivery (adjusted odds ratio 6.15, 95% confidence interval 1.83–20.63; P=0.003). No association was found between occurrence of PTD and LPV/r exposure before 14 weeks GA. Conclusions In this population of HIV-1-infected pregnant women receiving LPV/r, the risk of PTD was higher than in HIV-1-uninfected controls. As PTD risk was not associated with early exposure to LPV/r, these data support current guidelines to initiate ART earlier in pregnancy.
Predictive value of immune parameters before treatment interruption (TI) for CD4+ T-cell count change during TI in HIV infection
Authors: Huang Kenneth H , Loutfy Mona R , Boulet Salix , Toma Emil , Tsoukas Christos M , Bernard Nicole F 
Published: April 2022

Background Despite the contraindications, stopping treatment for HIV infection continues to be a common practice. Understanding whether T-cell proliferative capacity and phenotypic markers before treatment interruption (TI) can predict CD4+ T-cell count change and nadir during TI would be clinically useful. Methods This retrospective study included 27 HIV- infected patients in the chronic phase of infection while on combination antiretroviral therapy (cART) who underwent a TI. Peripheral blood mononuclear cells from a baseline pre-TI time point were screened for T-cell proliferation to cytomegalovirus (CMV) lysate, an HIV Gag p55 peptide pool as well as positive and negative control stimuli. CD28 and CD57 expression on CD4+ and CD8+ T-cells were measured. Results Baseline viral load, CD4+ T-cell count, pre-cART nadir CD4+ T-cell and percentage CD4+CD28+ T-cells were all predictive of the lowest CD4+ T-cell count during TI (Spearman's correlation P<0.05 for all analyses). In addition, CD4+ and CD8+ T-cells proliferation to CMV lysate, baseline CD4+ T-cell count and percentage CD4+CD57+ T-cells correlated negatively with CD4+ T-cell decrease during TI (Spearman's correlation P<0.05 for all analyses). Conclusions In treated chronic HIV-infected patients, pre-TI immune parameters are potential predictors for both the nadir CD4+ T-cell count and CD4+ T-cell count decrease during TI.
Evaluation of transmitted HIV drug resistance among recently-infected antenatal clinic attendees in four Central African countries
Authors: Aghokeng Avelin F , Vergne Laurence , Mpoudi-Ngole Eitel , Mbangue Madeleine , Deoudje Noe , Mokondji Etienne , Nambei Wilfrid S , Peyou-Ndi Marlyse M , Moka Jean-Jacques L , Delaporte Eric , Peeters Martine 
Published: April 2022

Background The rapid expansion of antiretroviral treatment in resource-limited settings is raising concerns regarding the emergence and transmission of HIV drug resistance (HIVDR). We evaluated the extent of transmission of drug-resistant HIV strains in four Central African countries: the Republic of Congo, Central African Republic, Chad and Cameroon. Methods The World Health Organization (WHO) HIVDR threshold survey was implemented in major treatment areas in each country. Pregnant women who were aged <25 years, who were at first pregnancy and who were HIV type-1-positive were enrolled at each site in 2006–2007 for geno-typing. HIVDR prevalence was categorized using the WHO threshold survey binomial sequential sampling method. Results The prevalence of HIVDR in Brazzaville and Bangui sites could not be classified because the eligible sample number was not reached. HIVDR prevalence was low (<5%) in N'Djamena for all drug classes. In Yaoundé, we found one individual with the D67D/N mutation and two with K103N. HIVDR prevalence was categorized as low (<5%) for protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs), and moderate (≥5-≤15%) for non-NRTIs (NNRTIs). HIVDR prevalence in Douala was low for PIs and NNRTIs, and moderate for NRTIs as we identified one individual with M184V plus K101E plus G190A mutations and a second with D67D/N. Conclusions The moderate HIVDR prevalence found in Yaoundé and Douala indicate that efforts should be made in Cameroon to prevent HIVDR; however, additional surveys are needed to confirm this trend. This study highlighted challenges presented by the WHO methodology, such as additional costs, workload, difficulties in acquiring even small sample numbers and the necessity for better quality assurance of HIV testing and record keeping at antenatal clinics.
Pharmacokinetics and tolerability of once- versus twice-daily lopinavir/ritonavir treatment in HIV-1-infected children
Authors: la Porte Charles , van Heeswijk Rolf , Mitchell Charles D , Zhang Guijun , Parker Jackie , Rongkavilit Chokechai 
Published: April 2022

Background Once-daily lopinavir/ritonavir (LPV/r) is not approved for treatment of HIV paediatric patients. Once daily treatment in children might serve the same goals of patient comfort and adherence as in adults. Methods HIV type-1-infected children aged 6 months to 18 years, who were virologically suppressed on an LPV/r-containing regimen, were eligible. Treatment 1 consisted of once-daily LPV/r 460/115 mg/m2, plus two nucleoside reverse transcriptase inhibitors (NRTIs). Treatment 2 consisted of twice-daily LPV/r 230/57.5 mg/m2 plus two NRTIs. Patients were randomized either to start with treatment 1 followed by treatment 2 or vice versa. Full pharmaco-kinetic profiles were analysed for lopinavir and ritonavir with a validated HPLC tandem mass spectrometry assay. Results Seven patients (five girls and two boys) were included in the study. Median age was 9.8 years (range 5.8–15.5). For the once-daily treatment, the median (range) lopinavir 24 h area under the plasma concentration–time curve (AUC24h), maximum plasma concentration (Cmax) and 24 h plasma concentration (C24h) were 214.6 h•mg/l (114.2–289.2), 13.5 mg/l (8.3–17.5) and 3.4 mg/l (0.6–7.4), respectively. For the twice-daily treatment the median (range) lopinavir 12 h area under the plasma concentration–time curve (AUC12h), Cmax and 12 h plasma concentration (C12h) were 80.9 h•mg/l (23.3–135.9), 9.8 mg/l (3.4–15.2) and 5.7 mg/l (1.7– 9.7), respectively. Conclusions This study suggests that the pharmacokinetics of lopinavir after twice-daily and once-daily dosing are similar, with no observable difference in tolerability, in this group of patients between 5 and 15 years old.
The pattern of pegylated interferon-α2b and ribavirin treatment failure in cirrhotic patients depends on hepatitis C virus genotype
Authors: Aghemo Alessio , Rumi Maria Grazia , Monico Sara , Prati Gian Maria , D'Ambrosio Roberta , Donato Maria Francesca , Colombo Massimo 
Published: April 2022

Background Failure of anti-hepatitis C therapy encompasses both primary non-response and post-treatment relapse. Treatment failure to pegylated interferon (PEG-IFN)-α2b and ribavirin (RBV) largely depends upon virus genotype, but the interaction between genotype, cirrhosis and pattern of treatment failure is unclear. We aimed to assess whether cirrhosis modifies the pattern of PEG-IFN-α2b and RBV treatment failure. Methods A total of 471 treatment-naive patients with histologically proven chronic hepatitis C virus (HCV) infection (106 with cirrhosis; 185 with HCV genotype 1 [HCV-1], 157 with HCV genotype 2 [HCV-2], 92 with HCV genotype 3 [HCV-3] and 37 with HCV genotype 4 [HCV-4]) were consecutively treated with PEG-IFN-α2b 1.5 μg weekly and weight-based RBV. Results The sustained virological response (SVR) rates were 31% in HCV-1 and HCV-4, 80% in HCV-2 and 72% in HCV-3, and were lower in cirrhotic than in non-cirrhotic HCV-1 and HCV-4 (17% versus 36%; P=0.01), and HCV-3 (33% versus 79%; P=0.001), but not HCV-2 (69% versus 83%; P=0.1) patients. Treatment failure was the consequence of lower end-of-treatment response rates (37% versus 53%; P=0.06) plus higher post-treatment relapse rates (55% versus 31%; P=0.07) in cirrhotic HCV-1 and HCV-4 patients and higher rates of post-treatment relapse in HCV-2 (29% versus 10%; P=0.01) and HCV-3 cirrhotic patients (61% versus 12%; P<0.001). By multi-variate analysis, HCV-1 and HCV-4 (odds ratio [OR] 7.44, 95% confidence interval [CI] 4.87–11.36), and cirrhosis (OR 3.00, 95% CI 1.80–5.00) were independent predictors of treatment failure. Conclusions Cirrhosis is an important moderator of SVR, accounting for different patterns of treatment failure in patients infected with different genotypes.
Time course of insulin resistance during antiviral therapy in non-diabetic, non-cirrhotic patients with genotype 1 HCV infection
Authors: Petta Salvatore , Cammà Calogero , Di Marco Vito , Cabibi Daniela , Ciminnisi Stefania , Caldarella Rosalia , Licata Anna , Massenti Maria Fatima , Marchesini Giulio , Craxì Antonio 
Published: April 2022

Background Genotype 1 (G1) hepatitis C virus (HCV) is associated with insulin resistance (IR) and its clearance seems to improve insulin sensitivity. We aimed to evaluate the time course of IR in response to antiviral therapy in non-diabetic, non-cirrhotic G1 HCV patients and to assess the effect of metabolic factors on sustained virological response (SVR). Methods A total of 83 consecutive treatment-naive G1 chronic hepatitis C (CHC) patients were evaluated by anthropometric and metabolic measurements, including IR using the homeostasis model assessment (HOMA). Patients were considered to have IR if HOMA was >2.7. All cases had a liver biopsy scored for staging, grading and steatosis. Anthropometric parameters and HOMA were re-evaluated at the end of antiviral therapy and at follow-up. Results SVR was achieved in 46 (55.4%) patients. By logistic regression, female gender (odds ratio [OR] 0.132, 95% confidence interval [CI] 0.33–0.529), γ-glutamyltransferase >50 IU (OR 0.217, 95% CI 0.066–0.720) and presence of steatosis (OR 0.134, 95% CI 0.028–0.654) were independent negative predictors of SVR, whereas low-density lipoprotein cholesterol >107 IU (OR 6.671, 95% CI 1.164–11.577) was a positive predictor of SVR. The proportion of patients with IR significantly decreased ( P=0.02) during antiviral therapy and at follow-up in patients achieving SVR. A similar trend, even if not significant, was observed in relapsers and non-responders. Conclusions In non-diabetic G1 HCV patients undergoing antiviral therapy, IR improved in all patients, independently of virological outcome. HCV viral clearance was an additional factor in IR improvement. Female gender, hepatic steatosis and other metabolic parameters, but not IR, were identified as negative predictors of SVR in this study.
Naturally occurring substitutions conferring resistance to hepatitis C virus polymerase inhibitors in treatment-naive patients infected with genotypes 1–5
Authors: Legrand-Abravanel Florence , Henquell Cécile , Le Guillou-Guillemette Hélène , Balan Viorica , Mirand Audrey , Dubois Martine , Lunel-Fabiani Francoise , Payan Christopher , Izopet Jacques 
Published: April 2022

Background The hepatitis C virus (HCV) RNA-dependent RNA polymerase, NS5B, is essential for virus RNA replication. It is thus an attractive therapeutic target. Several compound nucleoside analogues, non-nucleoside inhibitors and cyclosporine analogues are being developed to inhibit NS5B activity. However, nucleotide changes in the NS5B gene can confer resistance to them. Methods We investigated the prevalence of known substitutions conferring resistance in HCV polymerase in 124 treatment-naive French patients infected with HCV genotypes 1, 2, 3, 4 or 5 by sequencing the NS5B gene. Results None of the 124 HCV NS5B sequences analysed contained substitutions conferring resistance to nucleoside analogues; however, NS5B polymerases containing substitutions conferring resistance to non-nucleoside inhibitors were frequent within genotype 1 strains (17%) and very common in non-genotype 1 strains. Similarly, substitutions conferring resistance to cyclosporine analogues were more prevalent within the various genotypes. Conclusions Naturally occurring substitutions conferring resistance to NS5B inhibitors are common in treatment-naive patients infected with HCV genotype 1, 2, 3, 4 or 5. Their influence on treatment outcome should be assessed.
Antiretroviral Effect of Two Different Dose Regimens of Ritonavir and Saquinavir on HIV-Infected Adults in a Population-Based Setting
Authors: Jahnke Natalie , Seminari Elena , Hogg Robert S , Yip Benita , O'Shaughnessy Michael V , Montaner Julio SG 
Published: April 2022

Objective To characterize the antiviral effect and tolerability of higher dose (HD, 600 mg two times daily) and lower dose (LD, 400 mg two times daily) combination regimens of ritonavir and saquinavir in British Columbia (BC), Canada. Design Intent-to-treat analysis with suppression of plasma viral load to levels below 500 copies/ml as the main outcome measure. Patients Adult human immunodeficiency virus (HIV)-positive individuals in the province of British Columbia prescribed ritonavir and saquinavir in combination between 1 September 1996 and 30 June 1997, with a minimum of two plasma viral loads, one at baseline and one after the initiation of therapy. Results A total of 84 participants [27 HD (32%) and 57 LD (68%)] were prescribed ritonavir and saquinavir. There was no difference at baseline in the two groups with respect to age ( P=0.466), CD4 cell count ( P=0.373) and baseline plasma viral load ( P=0.656). However, LD were more likely to have had prior protease experience than HD participants (65 versus 40%, P=0.037). The median follow-up time was 9 months. A total of 44 (52%) subjects demonstrated a decrease in plasma viral load to levels <500 copies/ml. After adjusting for length of follow-up, baseline CD4 cell count and prior AIDS diagnosis, HD participants were as likely to be suppressed to <500 copies/ml as LD individuals ( P=0.760). HD participants did report more adverse effects ( P=0.042) than LD subjects. Conclusion Our results provide confirmatory evidence that lower doses of ritonavir and saquinavir in combination are better tolerated and as effective as the standard doses of these drugs. This response, however, is seriously compromised by prior exposure to protease inhibitors.