bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and Safety of Adefovir Dipivoxil plus Pegylated Interferon-α2a for the Treatment of Lamivudine-Resistant Hepatitis B virus Infection in HIV-Infected Patients
Authors: Ingiliz Patrick , Valantin Marc-Antoine , Thibault Vincent , Duvivier Claudine , Dominguez Stephanie , Katlama Christine , Poynard Thierry , Benhamou Yves 
Published: April 2022

Background Up to 10% of the HIV-positive population is coinfected with hepatitis B virus (HBV). Generally, combined treatment includes agents against both viruses, such as lamivudine (3TC). However, HBV resistance to 3TC is high. Adefovir dipivoxil (ADV) has shown its efficacy for treating 3TC-resistant (3TC-R) HBV in HIV-coinfected patients. ADV combined with pegylated interferon (PEG-IFN) has never been evaluated in this population. Methods HIV-HBV-coinfected patients with positive HBV e antigen (HBeAg), documented 3TC-R HBV mutation and antiretroviral treatment including 3TC were selected and received ADV (10 mg daily) and PEG-IFN-α2a (180 μg weekly) for 48 weeks. Results Of 18 eligible patients ( n=16 [89%] male, mean ±sd age 40.45 ±4.82 years), 17 were treated for 48 weeks. One stopped IFN treatment because of adverse events and continued ADV only. The median (interquartile range) HBV DNA at baseline was 8.0 (5.30–8.97) log10 copies/ml and the median (95% confidence interval [CI]) decrease after 48 and 72 weeks was 3.6 (4.9–2.4) and 1.4 (-5.0–2.2) log10 copies/ ml, respectively. None of the patients became HBeAg-negative. Median (95% CI) decrease of serum alanine aminotransferase was 27.8 (-66.2–10.5) IU/ml after 48 weeks and 93.0 (-80.0–26.1) IU/ml after 72 weeks. Conclusions ADV and PEG-IFN is safe and effective for treating 3TC-R HBV in HIV patients. However, on-treatment response was not maintained off therapy and did not lead to HBV seroconversion. The combination had no effect on HIV disease progression.
Differences in Virological Response to Pegylated Interferon and Ribavirin between Hepatitis C Virus (Hcv)-Monoinfected and HCV–Hiv-Coinfected Patients
Authors: Tural Cristina , Galeras Josep Antón , Planas Ramon , Coll Susanna , Sirera Guillem , Giménez Dolors , Salas Anna , Rey-Joly Celestino , Cirera Isabel , Márquez Carmen , Tor Jordi , Videla Sebastià , García-Retortillo Montserrat , Clotet Bonaventura , Solà Ricard 
Published: April 2022

Background Suboptimal doses of ribavirin have been suggested to explain the diminished efficacy of pegylated interferon (PEG-IFN) plus ribavirin in hepatitis C virus (HCV)–HIV-coinfected patients. Methods A cohort of 104 coinfected patients and an age-, sex- and genotype-matched cohort of HCV-monoinfected patients ( n=104) were compared. All patients received PEG-IFN-α2a 180 μg/week plus ribavirin 800–1,200 mg daily (HCV genotype 2/3 patients received 800 mg daily and those with genotype 1/4 received 1,000–1,200 mg daily) for 48 weeks (24 weeks for monoinfected patients with genotypes 2/3). HCV RNA levels were determined qualitatively at weeks 4, 12, 24, 48 and 72 and quantified monthly until week 12. Results The coinfected cohort had more advanced liver disease and lower body weight. HCV genotype 1 patients coinfected with HIV showed higher levels of HCV RNA than monoinfected patients. A significantly higher proportion of coinfected patients interrupted the prescribed treatment period prematurely (84% versus 98%). During the first 12 weeks, smaller decreases in HCV RNA levels were observed in coinfected patients. Among patients with HCV genotype 1, coinfected patients achieved lower rates of early virological response (64% versus 87%), end-of-treatment response (47.3% versus 80%) and sustained virological response (SVR; 27.3% versus 56.4%), but not rapid virological response (RVR). HCV–HIV-coinfected patients with HCV genotype 2/3 achieved significantly lower rates of RVR (52% versus 88%). Multivariate analysis identified RVR, gender and liver fibrosis as independent predictors of SVR. Conclusions Differences in efficacy of PEG-IFN-α2a plus ribavirin treatment between HCV–HIV-coinfected and HCV-monoinfected patients were maintained despite optimized ribavirin dose.
Pharmacokinetics of Lopinavir in HIV Type-1-Infected Children Taking the New Tablet Formulation Once Daily
Authors: van der Flier Michiel , Verweel Gwenda , van der Knaap Linda C , van Jaarsveld Petronette , Driessen Gert-Jan , van der Lee Manon , Hartwig Nico G , Burger David M 
Published: April 2022

Background Recently, a new tablet formulation of the widely used HIV protease inhibitor lopinavir/ritonavir was licensed. Here, we present a pilot study of the pharmaco-kinetics of the new adult tablet formulation taken once daily in children. Methods Lopinavir pharmacokinetics of the new adult tablet formulation were evaluated in 15 HIV type-1-infected children between 4 and 15 years of age. A target dose of 460/115 mg/m2 was administered once daily. Plasma concentrations of lopinavir over the course of 24 h were determined with a validated HPLC method. Results The median lopinavir dose was 498 mg/m2 (range 424–548). The mean ±sd for lopinavir area under the 24 h curve was 217.9 ±44.9 mg/l•h, the maximum concentration was 14.8 ±2.4 mg/l and the concentration 24 h after intake was 3.1 ±2.6 mg/l. The half-life of lopinavir was 5.8 ±4.5 h and the median time to maximum concentration was 5.8 h (range 1.8-12.2). Overall, the tablet formulation resulted in greater exposure to lopinavir with less variability compared with the soft-gel capsule formulation. All children treated with the new adult tablet formulation had undetectable viral loads (<50 copies/ml) during 24 weeks follow-up. Conclusions The tablet formulation could probably result in improved lopinavir dosing and increases the feasibility of once-daily lopinavir/ritonavir-based regimens in children.
HIV drug resistance transmission threshold survey in Bangkok, Thailand
Authors: Sirivichayakul Sunee , Phanuphak Praphan , Pankam Tippawan , O-Charoen Rachanee , Sutherland Donald , Ruxrungtham Kiat 
Published: April 2022

Background Antiretroviral therapy (ART) began in Thailand in the Bangkok Metropolitan Area (BMA) in 1988 and scale-up began in 2001. The national first-line regimen is stavudine, lamivudine and nevirapine in fixed-dose combination, which is a regimen with a low genetic barrier for resistance. Because viral load and resistance testing are not widely available, unidentified HIV drug resistance (HIVDR) may occur during treatment and could be transmitted. Methods We undertook a threshold survey to assess HIVDR transmission in two subsets of recently infected individuals in the BMA. The first group consisted of returning blood donors tested at the Thai Red Cross National Blood Centre who seroconverted within the past 12 months. The second group comprised recently infected (as defined by BED assay) clients of the Thai Red Cross voluntary counselling and testing centre (VCT). Results Genotyping of 50 consecutive specimens each from blood donors and VCT clients during 2005–2006 showed no mutations associated with HIVDR in the reverse transcriptase or protease regions of the HIV pol gene. These results are categorized by the WHO HIV drug resistance threshold survey method as representing a low prevalence (<5%) of transmitted HIV drug resistance. Conclusions Every effort should be made to minimize the emergence of resistance in treated individuals and to prevent primary and secondary HIV transmission. To continue to monitor HIVDR transmission, Thailand has planned additional surveys – including longitudinal surveys – in these and additional groups of individuals.
A Phase I study to explore the activity and safety of SCH532706, a small molecule chemokine receptor-5 antagonist in HIV type-1-infected patients
Authors: Pett Sarah L , McCarthy Michael C , Cooper David A , MacRae Karen , Tendolkar Amol , Norris Richard , Strizki Julie M , Williams Kenneth M , Emery Sean 
Published: April 2022

Background SCH532706 is a novel small molecule chemokine receptor-5 (CCR5) antagonist with high in vitro potency (mean 90% inhibitory concentration [IC90] 0.15– 7.0 nM) against diverse HIV type-1 (HIV-1) isolates. Methods A single arm study was undertaken to examine the safety, antiviral activity and pharmacokinetics (PK) of 10 days of SCH532706 coadministered with ritonavir (RTV). The trial enrolled formerly treated (off therapy >3 months) or untreated HIV-1-infected patients. Results The study enrolled 12 males with CD4+ T-cell count >100 cells/μl. Median (range) CD4+ T-cell count was 327 cells/μl (117–1,008), HIV-1–RNA was 4.6 log10 copies/ml (3.8–5.5) and patients had phenotypically con-firmed R5-tropic HIV-1 only. Mean (95% confidence interval) changes from baseline plasma HIV-1–RNA at days 10 and 15 (4 days off SCH532706) were -1.31 log10 copies/ ml (-1.6– -1.0) and -1.62 log10 copies/ml (-2.0– -1.3), respectively. Day 10 median (range) time to maximum plasma concentration, mean (±sd) effective half-life and mean (±sd) trough concentration were 1.4 h (1.0-4.0), 39.4 h (±14.5) and 178 ng/ml (±34), respectively. All virus isolates remained R5-tropic pre-study, on study and at study end. There were no laboratory or QTc interval changes reportable as adverse events. In total, 11 patients reported ≥1 treatment emergent adverse event, most commonly gastrointestinal upset. One serious adverse event, pericarditis (grade 2), occurred 13 days after drug administration. It was considered to be possibly related to study drug. Conclusions Overall, SCH532706 with RTV was safe, generally well tolerated and active against HIV-1 over 10 days of dosing. In this setting, SCH532706 trough concentrations exceed the mean in vitro IC (1.1 ng/ml) by >30-fold (after correction for 80% plasma protein binding) and provide a PK rationale for the observed efficacy.
Compilation and prevalence of mutations associated with resistance to non-nucleoside reverse transcriptase inhibitors
Authors: Tambuyzer Lotke , Azijn Hilde , Rimsky Laurence T , Vingerhoets Johan , Lecocq Pierre , Kraus Guenter , Picchio Gaston , de Béthune Marie-Pierre 
Published: April 2022

Background Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are an important component of antiretroviral therapy for HIV type-1 (HIV-1)-infected patients. Development of NNRTI resistance can lead to treatment failure and is conferred by the presence of specific resistance-associated mutations (RAMs) in the reverse transcriptase. In addition to the widely used list of NNRTI RAMs provided by the International AIDS Society-USA HIV-1 Drug Resistance Mutation Group, which were identified on the basis of clinical experience with the approved NNRTIs, a more comprehensive list of NNRTI RAMs is needed to guide the study of baseline and emerging resistance to new NNRTIs. Methods We conducted an extensive review of the existing literature on NNRTI resistance, together with several in vitro and in vivo studies on the mechanism of HIV-1 resistance to approved NNRTIs and to NNRTIs formerly or currently in clinical development. Results In total, 44 NNRTI RAMs were identified. These included V90I, A98G, L100I, K101E/P/Q, K103H/N/S/T, V106A/I/M, V108I, E138G/K/Q, V179D/E/F/G/I, Y181C/ I/V, Y188C/H/L, V189I, G190A/C/E/Q/S, H221Y, P225H, F227C/L, M230I/L, P236L, K238N/T and Y318F. These NNRTI RAMs were observed, either alone or in combination with others, ranging in frequency from 0.02% to 56.96% in a panel of 101,679 NNRTI-resistant isolates submitted to Virco BVBA (Mechelen, Belgium) for routine clinical resistance testing. Phenotypical data from site-directed mutants helped to establish the contribution of each mutation to NNRTI resistance. Conclusions The list of 44 NNRTI RAMs compiled in this study provides a comprehensive overview of mutations that play a role in HIV-1 NNRTI resistance and can be used to guide further in vitro and in vivo research on the mechanisms of HIV-1 NNRTI resistance.
Advantages of predicted phenotypes and statistical learning models in inferring virological response to antiretroviral therapy from HIV genotype
Authors: Altmann André , Sing Tobias , Vermeiren Hans , Winters Bart , Craenenbroeck Elke Van , Van der Borght Koen , Rhee Soo-Yon , Shafer Robert W , Schülter Eugen , Kaiser Rolf , Peres Yardena , Sönnerborg Anders , Fessel W Jeffrey , Incardona Francesca , Zazzi Maurizio , Bacheler Lee , Vlijmen Herman Van , Lengauer Thomas 
Published: April 2022

Background Inferring response to antiretroviral therapy from the viral genotype alone is challenging. The utility of an intermediate step of predicting in vitro drug susceptibility is currently controversial. Here, we provide a retrospective comparison of approaches using either genotype or predicted phenotypes alone, or in combination. Methods Treatment change episodes were extracted from two large databases from the USA (Stanford-California) and Europe (EuResistDB) comprising data from 6,706 and 13,811 patients, respectively. Response to antiretroviral treatment was dichotomized according to two definitions. Using the viral sequence and the treatment regimen as input, three expert algorithms (ANRS, Rega and HIVdb) were used to generate genotype-based encodings and VircoTYPE™ 4.0 (Virco BVBA, Mechelen, Belgium) was used to generate a predicted phenotype-based encoding. Single drug classifications were combined into a treatment score via simple summation and statistical learning using random forests. Classification performance was studied on Stanford- California data using cross-validation and, in addition, on the independent EuResistDB data. Results In all experiments, predicted phenotype was among the most sensitive approaches. Combining single drug classifications by statistical learning was significantly superior to unweighted summation ( P<2.2x10-16). Classification performance could be increased further by combining predicted phenotypes and expert encodings but not by combinations of expert encodings alone. These results were confirmed on an independent test set comprising data solely from EuResistDB. Conclusions This study demonstrates consistent performance advantages in utilizing predicted phenotype in most scenarios over methods based on genotype alone in inferring virological response. Moreover, all approaches under study benefit significantly from statistical learning for merging single drug classifications into treatment scores.
Clinical usefulness of sequential hepatitis B virus DNA measurement (the roadmap concept) during adefovir treatment in lamivudine-resistant patients
Authors: Shin Jung Woo , Park Neung Hwa , Jung Seok Won , Park Bo Ryung , Kim Chang Jae , Jeong In Du , Bang Sung-Jo , Kim Do Ha 
Published: April 2022

Background Sequential on-treatment monitoring of hepatitis B virus (HBV) DNA levels, known as the roadmap concept, might predict the efficacy of oral therapy with nucleoside/nucleotide analogues among patients naive to this treatment. The goal of this study was to verify the usefulness of the roadmap concept to predict clinical outcomes of adefovir dipivoxil monotherapy in hepatitis B e antigen (HBeAg)-positive patients with lamivudine resistance. Methods In 231 patients, serum HBeAg, antibody against HBeAg and HBV DNA levels were measured at weeks 12, 24 and 48 of treatment and every 3 months thereafter. Results Complete (HBV DNA<60 IU/ml by PCR), partial (HBV DNA 60–<2,000 IU/ml) and inadequate (HBV DNA≥2,000 IU/ml) virological responses at week 24 were observed in 49 (21.2%), 66 (28.6%) and 116 (50.2%) lamivudine- resistant patients, respectively, who were treated with adefovir dipivoxil monotherapy. At final assessment, rates of complete virological response in these groups were 100%, 71.2%, and 22.4%. Of the total 42 virological breakthroughs, 33 (78.6%) and 8 (19.1%) developed in the inadequate and partial response groups, respectively. Among the 91 patients who had HBV DNA<200 IU/ml at week 48, complete virological response and HBeAg seroconversion were finally achieved in 87 (95.6%) and 39 (42.9%) patients, respectively. Of these 91 patients, virological breakthrough and genotype mutations developed in only 4 (4.4%) and 3 (3.3%) patients. The roadmap concept predicted virological response, HBeAg seroconversion and breakthrough (odds ratios 3.68, 9.67 and 0.15, respectively). Conclusions The roadmap concept is useful for choosing between continuation of adefovir dipivoxil monotherapy or early switching to another therapy, or to suggest additional therapy in patients showing lamivudine resistance.
Overestimation of liver fibrosis staging using transient elastography in patients with chronic hepatitis C and significant liver inflammation
Authors: Vispo Eugenia , Barreiro Pablo , del Valle José , Maida Ivana , de Ledinghen Victor , Quereda Carmen , Moreno Alberto , Macías Juan , Castera Laurent , Pineda Juan Antonio , Soriano Vincent 
Published: April 2022

Background Transient elastography (TE) is a non-invasive method that allows liver fibrosis staging on the basis of hepatic stiffness measurements. Little is known about the influence of chronic liver inflammation on the stiffness of hepatic tissue. Methods A total of 112 patients with chronic hepatitis C underwent a liver biopsy and TE. Results Mean values of liver stiffness (in kPa) by inflammation strata were 4.8, 6.4, 9.4 and 12.6 for A0, A1, A2 and A3, respectively, in hepatitis C virus (HCV)-monoinfected individuals ( P=0.018). These figures were 8.0, 10.4, 12.9 and 12.6 for A0, A1, A2 and A3, respectively, in HIV– HCV-coinfected patients ( P=0.35). In HCV-monoinfected patients with fibrosis staging F3-F4, mean liver stiffness was greater if inflammation was ≥A2 versus A0-A1 (14.6 versus 6.2 kPa; P=0.04). By contrast, no differences in liver stiffness according to inflammation were seen in HCV-monoinfected patients with <F3 or in HIV-HCV-coinfected patients regardless of liver fibrosis staging. Among HCV-monoinfected patients, mean liver stiffness was greater for alanine aminotransferase >100 versus <100 IU/l (10.5 versus 8.5 kPa; P=0.04). Conclusions The extent of liver inflammation might affect the accuracy of TE for staging liver fibrosis, particularly in HCV-monoinfected patients with advanced fibrosis on liver biopsy and/or increased alanine aminotransferase levels.
Mitochondrial toxicity in HIV type-1-exposed pregnancies in the era of highly active antiretroviral therapy
Authors: Gingelmaier Andrea , Grubert Thomas A , Kost Bernd P , Setzer Bernhard , Lebrecht Dirk , Mylonas Ioannis , Mueller-Hoecker Josef , Jeschke Udo , Hiedl Stephan , Friese Klaus , Walker Ulrich A 
Published: April 2022

Background The aim of this study was to determine the effects of HIV type-1 (HIV-1) infection and antiretroviral therapy (ART) on placental mitochondria. Methods HIV-1-infected pregnant women and HIV-1 -uninfected controls were enrolled prospectively. Placental mitochondrial DNA (mtDNA) copy numbers were determined by quantitative PCR, subunits II and IV of cytochrome c oxidase (COX) were quantified by western blot and mitochondrial ultrastructure was evaluated by electron microscopy. Venous blood lactate was measured in newborns. Results In total, 45 HIV-1-infected pregnant women on ART and 32 controls were included. Mean ±sd mtDNA copy numbers were significantly reduced in ART and HIV-1-exposed placentas (240 ±118 copies/ cell) in comparison with controls (686 ±842 copies/cell; P<0.001). The mean COX II/IV ratio was 48% lower in the investigational group compared with controls ( P<0.001). There was no evidence of severe ultrastructural damage within mitochondria of HIV-1-infected ART-exposed placentas. Although lactate levels between newborns did not differ, they were negatively correlated with placental mtDNA levels. There was no clear association between mitochondrial parameters and a particular nucleoside reverse transcriptase inhibitor (NRTI), the number of NRTIs or time of NRTI exposure. Conclusions Placental tissue of HIV-1-infected ART-exposed pregnancies shows evidence of mtDNA depletion with secondary respiratory chain compromise. The clinical effects of this finding warrant further investigation.
Early initiation of highly active antiretroviral therapy fails to reverse immunovirological abnormalities in gut-associated lymphoid tissue induced by acute HIV infection
Authors: Tincati Camilla , Biasin Mara , Bandera Alessandra , Violin Michela , Marchetti Giulia , Piacentini Luca , Vago Gian Luca , Balotta Claudia , Moroni Mauro , Franzetti Fabio , Clerici Mario , Gori Andrea 
Published: April 2022

Background During the acute phase of HIV infection, large CD4+ T-cell depletion occurs in the gastrointestinal tract. The kinetics of CD4+ T-cell decrease and highly active antiretroviral therapy (HAART)-mediated immune reconstitution were evaluated. Methods Rectosigmoid colonic (RSC) biopsies and blood samples of nine patients with acute HIV infection were collected. CD4+ T-cell count, HIV RNA, intracellular HIV DNA and messenger RNA cytokine expression were evaluated before and after 6 months of HAART. Results All nine patients presented symptomatic retroviral infection. Early HAART was associated with a sustained and comparable reduction of HIV RNA in plasma, peripheral blood mononuclear cells (PBMCs) and RSC biopsies. HIV DNA decreased in PBMCs, but was only marginally reduced in RSC biopsies. Comparisons between reduction rates of HIV DNA in these two compartments confirmed that HIV DNA clearance was less efficient in RSC biopsies compared with PBMCs. Assessment of immunological profiles in PBMCs and RSC biopsies showed that the T-helper (Th)1-like/Th2-like ratio was sharply decreased in RSC biopsies and increased in PBMCs throughout the study period. A persistent Th2-like profile was detected in RSC biopsies. Efficient clearing of HIV DNA observed in PBMCs correlated with the establishment of a more favourable Th1-like profile. Conclusions A less efficient clearance of intracellular HIV DNA following early introduction of HAART is associated with persistent immunological impairment in gut-associated lymphoid tissue (GALT), which is refected by the skewed expression of cytokines in this reservoir. The present study shows that early initiation of HAART, in the short-term, is not effective in containing the establishment of HIV infection and in reversing associated immunological GALT abnormalities.