bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Transient Antiretroviral Treatment during acute HIV Infection: Comparison of the Quest Trial Results with CASCADE Natural History Study
Authors: Lampe Fiona C , Porter Kholoud , Kaldor John , Law Matthew , Loes Sabine Kinloch-de , Phillips Andrew N 
Published: April 2022

Objective The benefit of transient combination antiretroviral treatment (CART) during acute HIV infection is uncertain. We used the seroconverter database CASCADE to provide a historical comparison for the Quest trial, in which 79 subjects with acute HIV infection received CART for an average of 2.6 years, and 17.7% (95% confidence interval [CI]: 10.9–27.6) fulfilled the primary endpoint of VL≤1,000 copies/ml 24 weeks after CART discontinuation. Methods We estimated the prevalence of VL ≤1,000 copies/ml three years after seroconversion and prior to any ART among 385 sexually infected subjects in CASCADE who seroconverted between 1988 and 1996. We conducted a pre-specified comparison with the recently published Quest results, and considered potential biases. Results and discussion The prevalence of VL ≤1,000 copies/ml at year three in CASCADE was 10.1% (95% CI: 7.5–13.5) (absolute difference compared to 17.7% in Quest: 7.6%; 95% CI: -0.1–17.8; P=0.053). In CASCADE, VL≤1,000 copies/ml was less common among homosexual and heterosexual men compared with women (8.5%, 7.3% and 17.6% respectively) and in subjects with symptomatic infection compared with those without (6.2% and 12.6%, respectively). As Quest had a much greater proportion of symptomatic subjects than CASCADE, any true difference in VL might be underestimated. Therefore this comparison suggests that transient CART in acute infection might result in a modest increase in the probability of low VL subsequently. However, several factors mitigate this conclusion. First, this historical comparison might be subject to other unmeasured confounders. Second, a comparison of median VL at the same time point was not significant (4.02 copies/ml and 4.20 copies/ml in Quest and CASCADE, respectively; P=0.55). Finally, additional analysis suggested that the observed difference in low VL at year three would be consistent with an immediate effect of CART only - a delay of usual VL decline without additional benefit. Conclusions A small but significant proportion of seroconverters have low VL without ART. Transient CART in acute infection might increase the probability of low VL after treatment discontinuation, but such an effect is likely to be modest, and might represent a delay of natural history rather than a long-term therapeutic benefit.
A Phase I/IIa Study with Succinylated Human Serum Albumin (Suc-HSA), a candidate HIV-1 Fusion Inhibitor
Authors: Vermeulen Joost N , Meijer Dirk KF , Over Jan , Lange Joep MA , Proost Johannes H , Bakker Hester I , Beljaars Leonie , Wit Ferdinand WNM , Prins Jan M 
Published: April 2022

Background Succinylated human serum albumin (Suc-HAS) is a negatively charged neo-glycoprotein that binds to the positively charged V3–loop of HIV-1 gp120, acting as HIV-1-fusion inhibitor in vitro (IC50: 0.5–5.0 μg/ml). Suc-HSA was safe in rats and monkeys, and showed antiretroviral effect in a human-to-mouse model. We evaluated safety and pharmacokinetics of single and multiple doses of Suc-HSA in HIV-1-infected individuals. Methods First, six untreated, chronically HIV-1-infected patients were randomized to a single dose of 1 or 10 mg/kg Suc-HSA intravenously. Second, five consecutive daily doses (10 mg/kg, based on the results of the single dose study) were given to four patients. Safety laboratory assessments, Suc-HSA plasma levels, plasma HIV-1 RNA (pVL), and CD4+ T-cell counts were determined. Results Increase of liver transaminases (grade 1/2) occurred in one of six patients in the single-dose phase and in three of four patients in the multiple-dosing phase. Suc-HSA plasma levels were undetectable 4 h after a single dose of 1 mg/kg. After a dose of 10 mg/kg, plasma levels were more sustained, but declined under the target plasma concentration (10 μg/ml) 12–24 h post-dosing. After multiple dosing, plasma levels reached peak values 2h post-dosing as predicted by our kinetic model. However, trough levels were below the target concentrations. There was no change in pVL or CD4+ T-cell count in either the single- or multiple-dosing phase. Conclusions At the chosen dosing regimens, adequate antiviral plasma levels were not maintained, probably because the hepatic clearance was more rapid than expected. This may partially explain the lack of effect on pVL and CD4+ T-cell count. The observed liver transaminase increases prohibit further dose escalation.
Two-year Lamivudine treatment for Hepatitis B e Antigen-Negative Chronic Hepatitis B: A Double-Blind, Placebo-Controlled Trial
Authors: Chan Henry Lik-Yuen , Wang Hao , Niu Junqi , Chim Angel Mei-Ling , Sung Joseph Jao-Yiu 
Published: April 2022

Objective We conducted a multicentre, double-blind, placebo-controlled, randomized study to investigate the efficacy of 2-year lamivudine treatment in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. Methods One-hundred-and-thirty-nine treatment-naive patients with HBeAg-negative chronic hepatitis B were randomized to receive either lamivudine (100 mg daily) or placebo in a 2:1 ratio for 24 months and were followed for an additional 6 months. The primary endpoint was complete response, defined as hepatitis B virus (HBV) DNA <10,000 copies/ml and normalization of alanine aminotransferase (ALT) levels at month 24. Results On intent-to-treat analysis at month 24, significantly more patients in the lamivudine group than in the placebo group had complete response (56% and 11%, respectively; P<0.001) or negative HBV DNA (26% and 6%, respectively; P=0.006). After adjustment of baseline HBV DNA and ALT, the odds ratio for complete response of the lamivudine group versus the placebo group was 10.8 (95% confidence interval: 3.8–30.2; P<0.001). The median log HBV DNA reduction was 3.21 copies/ml for the lamivudine group compared with 0.47 copies/ml for the placebo group ( P<0.001). Genotypic resistance was detected in 23% and 31% of patients in the lamivudine group at months 12 and 24, respectively. Negative HBV DNA at month 6 was associated with high complete response (84%) and low drug resistance (1%) at month 24. At month 30, there was no difference between lamivudine and placebo groups in the rates of complete response (26% vs 19%, respectively; P=0.38) or negative HBV DNA (10% vs 2%, respectively; P=0.09). Conclusions Two-year lamivudine treatment is effective in HBeAg-negative chronic hepatitis B. However, the response is not sustained after treatment cessation.
Five-Year Follow up of Once-Daily Therapy with Emtricitabine, Didanosine and Efavirenz (Montana ANRS 091 Trial)
Authors: Molina Jean-Michel , Journot Valérie , Furco André , Palmer Pierre , Castro Nathalie De , Raffi François , Morlat Philippe , May Thierry , Rancinan Corinne , Chêne Geneviève ,   for the Montana (ANRS 091) Study Group, Modaï J , Decazes J-M , Molina JM , Madeleine I , Sombardier MN , Martinie M , Séréni D , Lascoux-Combes C , Michon C , Vinceneux Ph , Delfraissy JF , Goujard C , Peretti D , Rannou MT , Galanaud P , Boue F , Colson C , Rozenbaum W , Girard PM , Adda N , Saimot AG , Coulaud JP , Landman R , Matheron S , Hoen B , Derancourt C , Drobacheff C , Salard D , Laurent R , Estavoyer JM , Beylot J , Morlat P , Lacoste D , Bonarek M , Bonnet F , Bernard N , Nouts C , Trepo C , Cotte L , Schlienger I , Rougier P , Carre C , Raffi F , Bonnet B , Allavena C , Esnault JL , Charonnat MF , Sicot M , Canton P , Burty C , Brel F , May T , Lecompte T Doco 
Published: April 2022

Background Once-daily combination therapy with emtricitabine, didanosine and efavirenz has been highly effective in clinical trials but its long-term efficacy and safety has not been previously reported. Methods This multicentre, single-arm, open-label trial enrolled 40 antiretroviral-naive HIV-1-infected patients who received a once-daily regimen of emtricitabine, didanosine and efavirenz. The objective was to assess the long-term effects of this combination on plasma HIV RNA levels, CD4+ T-cell counts, safety and tolerability. Results After 5 years, 73% and 68% of patients had plasma HIV RNA levels <400 and <50 copies/ml, respectively, in an intent-to-treat, missing-equals-failure analysis. Genotypic resistance on treatment emerged in six patients. There was a significant increase in CD4+ T-cell count of 294x106 cells/l. Only six patients discontinued study treatment, because of non-severe adverse events. Lipodystrophy was infrequent, and lipid and glucose profiles were favourable with a significant increase in high-density lipoprotein cholesterol. Conclusions A convenient once-daily regimen of emtricitabine, didanosine and efavirenz provided durable antiretroviral response and was well tolerated through 5 years of therapy.
Natural Polymorphism of the HIV-1 Integrase Gene and Mutations associated with Integrase Inhibitor Resistance
Authors: Lataillade Max , Chiarella Jennifer , Kozal Michael J 
Published: April 2022

Background Two inhibitors of the HIV-1 integrase enzyme (INIs) are in late stage clinical development. To date, approximately 42 mutations within the HIV-1 integrase (IN) gene have been associated with INI drug resistance. Naturally occurring IN gene polymorphisms may have important implications for INI development. In this study, we evaluated clinical HIV-1 strains from INI-naive patients to determine the prevalence of IN gene polymorphisms, and the frequency of naturally occurring amino acid (aa) substitutions at positions associated with INI resistance and at sites crucial for LEDGF/p75 binding and HIV-1 integration. Methods The IN gene from 67 INI-naive, HIV-1 clade B-infected patients were sequenced using standard population-based DNA sequencing methods. In addition, 176 unique full-length HIV-1 clade B IN gene sequences from INI-naive patients obtained from the HIV Los Alamos database were analysed. Results Analysis of 243 IN genes from HIV-1 clade B, INI-naive clinical strains revealed that 64% of the aa positions were polymorphic. Of the 42 aa substitutions currently associated with INI resistance, 21 occurred as natural polymorphisms: V72I, L74I, T97A, T112I, A128T, E138K, Q148H, V151I, S153Y/A, M154I, N155H, K156N, E157Q, G163R, V165I, V201I, I203M, T206S, S230N and R263K. IN aa positions crucial to LEDGF/P75 binding and HIV-1 integration were well conserved. Conclusion Major INI mutations within the catalytic domain and extended active sites associated with high level resistance to the compounds in late stage development, especially strand transfer inhibitors (STIs), were infrequent in our study, which may help explain the excellent virological responses demonstrated in clinical trials.
A Novel Mutation Pattern Emerging during Lamivudine Treatment Shows Cross-Resistance to Adefovir Dipivoxil Treatment
Authors: Karatayli Ersin , Karayalçin Selim , Karaaslan Hayri , Kayhan Handan , Türkyilmaz A Resat , Sahin Fikret , Yurdaydin Cihan , Bozdayi A Mithat 
Published: April 2022

Aims This study was conducted to clarify the resistance profile of a novel mutation pattern emerging during lamivudine (3TC) therapy and showing cross-resistance to adefovir dipivoxil (ADV) in a patient with chronic hepatitis B. Methods and results Successful suppression of hepatitis B virus (HBV) replication by sequential therapy of 9 MU thrice weekly interferon (IFN) and 3TC was followed by genotypical resistance detected at month 28 of therapy (month 19 of lamivudine treatment). ADV was added to 3TC therapy on month 44 of antiviral treatment. Neither alanine aminotransferase normalization nor a stable decrease in HBV viral load was observed, although ADV was used for more than 40 months. The HBV pol region was amplified from serum samples obtained before and after ADV treatment. The complete genome was cloned into a TA vector. PCR products and 7–10 clones from each cloned vector were sequenced. A novel mutation, A181S, in the reverse transcriptase gene leading to a conversion of W172C in the overlapping surface antigen gene was detected along with a M204I mutation. The complete genome comprising the A181S+M204I pattern was cloned into an expression vector and its in vitro susceptibility to 3TC, ADV, tenofovir (PMPA), clevudine (l-FMAU) and emtricitabine (FTC) were determined in transiently transfected Huh7 cells. This mutation pattern displayed more than 1,000-fold resistance to the nucleoside analogues 3TC and FTC and approximately sixfold resistance to l-FMAU, while it confers 28.23- and 5.57-fold resistance for the nucleotide analogues ADV and PMPA, respectively. Conclusion A new mutation pattern, A181S+M204I, arising under lamivudine treatment confers cross-resistance to ADV both in vivo and in vitro.
Impact of Early Viral Kinetics on T-Cell Reactivity during Antiviral Therapy in Chronic Hepatitis B
Authors: Lau George KK , Cooksley Helen , Ribeiro Ruy M , Powers Kimberly A , Shudo Emi , Bowden Scott , Hui Chee-Kin , Anderson Jane , Sorbel Jeff , Mondou Elsa , Rousseau Franck , Lewin Sharon , Perelson Alan S , Locarnini Stephen , Naoumov Nikolai V 
Published: April 2022

Background The patterns of hepatitis B viral dynamics during different antiviral therapies and the associated changes in HBV-specific T-cell reactivity are not well defined. Methods We investigated the impact of early viral load decline on virus-specific T-cell reactivity in 30 hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B randomized to monotherapy with adefovir dipivoxil (ADV) or in combination with emtricitabine (ADV/FTC). Viral kinetics were analysed by mathematical modelling. T-cell reactivity to HBV core and/or surface antigens and natural killer T cell frequency were tested longitudinally, baseline to week 48, using EliSPOT assays and/or flow cytometry. Results Mathematical modelling of early HBV kinetics identified two subsets of patients: 11 fast responders (undetectable viraemia by week 12; eight on ADV/FTC three on ADV) and 19 slow responders who remained viremic (six on ADV/FTC 13 on ADV). The rate of infected hepatocyte loss was higher in fast than in slow responders ( P=0.0007), and correlated inversely with pre-treatment levels of intrahepatic covalently closed circular HBV DNA. The frequency of HBV core-specific CD4+ T-cells increased significantly only in fast responders, peaking between week 16 and 24, while the HBV surface-specific CD4+ T-cells increased in both subsets. These changes in CD4+ T-cell reactivity were transient however, and no increase in HBV-specific CD8+ T-cells was observed. By week 48, HBeAg seroconversion occurred only in 3/30 (10%) patients. Conclusions Early viraemia clearance facilitates recovery of virus-specific CD4+ T-cell reactivity, but appears insufficient to establish clinically relevant antiviral immunity.
Effect of Transporter Modulation on the Emergence of Nelfinavir Resistance In Vitro
Authors: Chandler Becky , Detsika Maria , Owen Andrew , Evans Sorcha , Hartkoorn Ruben C , Cane Patricia A , Back David J , Khoo Saye H 
Published: April 2022

Background HIV drug resistance is of increasing concern and could result from inadequate drug potency, poor therapy adherence and the existence of pharmacological sanctuary sites for viral replication. One contributing factor to the generation of such sites could be drug efflux transporters, which have been shown capable of effluxing HIV protease inhibitors from cells. Methods In this ‘proof-of-concept’ study, the ability of the efflux transport inhibitor verapamil to modulate the intracellular accumulation of radiolabeled nelfinavir (NFV) and the antiviral effect of NFV was assessed in MT4 cells. Wild-type virus was then serially passaged with increasing concentrations of NFV with and without verapamil and resistance mutations monitored by sequencing of the viral protease gene. Results The cellular accumulation ratio of 3H-NFV was 116.8 ±9.7 in controls and was significantly increased to 149.8 ±24.5 following incubation with verapamil (P<0.05, n=4). The EC50 of NFV was decreased in MT4 cells in the presence of verapamil from 8.5 ±1.3 nM to 4.4 ±0.8 nM ( P<0.001, n=6). Of the 24 isolates passaged without verapamil, 21 carried the D30N mutation at detectable levels. Of the 23 passaged with verapamil, 14 carried the mutation (odds ratio=4.5; P<0.05). Conclusions These results suggest that ‘intracellular boosting’ of PIs is achievable through inhibition of drug efflux proteins in vitro and that such boosting has the ability to enhance suppression of viral replication, slowing the emergence of resistance mutations.
Declining Prevalence of HIV-1 Drug Resistance in Treatment-Failing Patients: A Clinical Cohort Study
Authors: Giambenedetto Simona Di , Bracciale Laura , Colatigli Manuela , Pannetti Carmen , Bacarelli Alessandra , Prosperi Mattia , Fadda Giovanni , Cauda Roberto , De Luca Andrea 
Published: April 2022

Objectives A major barrier to successful viral suppression in HIV type 1 (HIV-1)-infected individuals is the emergence of virus resistant to antiretroviral drugs. We explored the evolution of genotypic drug resistance prevalence in treatment-failing patients from 1999 to 2005 in a clinical cohort. Patients and Methods Prevalence of major International AIDS Society-USA HIV-1 drug resistance mutations was measured over calendar years in a population with treatment failure and undergoing resistance testing. Predictors of the presence of resistance mutations were analysed by logistic regression. Results Significant reductions of the prevalence of resistance to all three drug classes examined were observed. This was accompanied by a reduction in the proportion of treatment-failing patients. Independent predictors of drug resistance were the earlier calendar year, prior use of suboptimal nucleoside analogue therapy, male sex and higher CD4 levels at testing. Conclusions In a single clinical cohort, we observed a decrease in the prevalence of resistance to all three examined antiretroviral drug classes over time. If this finding is confirmed in multicentre cohorts it may translate into reduced transmission of drug-resistant virus from treated patients.
CD4+ T-Cell Count Increase in HIV-1-Infected Patients with Suppressed Viral Load Within 1 year after start of antiretroviral therapy
Authors: Wolbers Marcel , Battegay Manuel , Hirschel Bernard , Furrer Hansjakob , Cavassini Matthias , Hasse Barbara , Vernazza Pietro L , Bernasconi Enos , Kaufmann Gilbert , Bucher Heiner C ,   Swiss HIV Cohort Study, Battegay M , Bernasconi E , Böni J , Bucher H , Bürgisser Ph , Cattacin S , Cavassini M , Dubs R , Egger M , Elzi L , Erb P , Fischer M , Flepp M , Fontana A , Francioli P , Furrer H , Gorgievski M , Günthard H , Hirsch H , Hirschel B , Hösli I H , Kahlert Ch , Kaiser L , Karrer U , Kind C , Klimkait Th , Ledergerber B , Martinetti G , Martinez B , Müller N , Nadal D , Opravil M , Paccaud F , Pantaleo G , Rickenbach M , Rudin C , Schmid P , Schultze D , Schüpbach J , Speck R , Taffé P , Tarr P , Telenti A , Trkola A , Vernazza P , Weber R , Yerly S 
Published: April 2022

Background CD4+ T-cell recovery in patients with continuous suppression of plasma HIV-1 viral load (VL) is highly variable. This study aimed to identify predictive factors for long-term CD4+ T-cell increase in treatment-naive patients starting combination antiretroviral therapy (cART). Methods Treatment-naive patients in the Swiss HIV Cohort Study reaching two VL measurements <50 copies/ml >3 months apart during the 1st year of cART were included ( n=1,816 patients). We studied CD4+ T-cell dynamics until the end of suppression or up to 5 years, subdivided into three periods: 1st year, years 2–3 and years 4–5 of suppression. Multiple median regression adjusted for repeated CD4+T-cell measurements was used to study the dependence of CD4+ T-cell slopes on clinical covariates and drug classes. Results Median CD4+ T-cell increases following VL suppression were 87, 52 and 19 cells/μl per year in the three periods. In the multiple regression model, median CD4+ T-cell increases over all three periods were significantly higher for female gender, lower age, higher VL at cART start, CD4+ T-cell <650 cells/μ l at start of the period and low CD4+ T-cell increase in the previous period. Patients on tenofovir showed significantly lower CD4+T-cell increases compared with stavudine. Conclusions In our observational study, long-term CD4+ T-cell increase in drug-naive patients with suppressed VL was higher in regimens without tenofovir. The clinical relevance of these findings must be confirmed in, ideally, clinical trials or large, collaborative cohort projects but could influence treatment of older patients and those starting cART at low CD4+ T-cell levels.
Genotypic Drug Resistance and Long-Term Mortality in Patients with Triple-Class Antiretroviral Drug Failure
Authors: Lohse Nicolai , Jørgensen Louise B , Kronborg Gitte , Møller Axel , Kvinesdal Birgit , Sørensen Henrik T , Obel Niels , Gerstoft Jan ,   Danish HIV Cohort Study, Gerstat J , Obel N , Kronborg G , Pedersen C , Larsen CS , Pedersen G , Laursen AL , Kvinesdal B , Møller A 
Published: April 2022

Objective To examine the prevalence of drug-resistance-associated mutations in HIV patients with triple-drug class virological failure (TCF) and their association with long-term mortality. Design Population-based study from the Danish HIV Cohort Study (DHCS). Methods We included all patients in the DHCS who experienced TCF between January 1995 and November 2004, and we performed genotypic resistance tests for International AIDS Society (IAS)-USA primary mutations on virus from plasma samples taken around the date of TCF. We computed time to all-cause death from date of TCF. The relative risk of death according to the number of mutations and individual mutations was estimated by Cox regression analysis and adjusted for potential confounders. Results Resistance tests were done for 133 of the 179 patients who experienced TCF. The median number of resistance mutations was eight (interquartile range 2–10), and 81 (61%) patients had mutations conferring resistance towards all three major drug classes. In a regression model adjusted for CD4+ T-cell count, HIV RNA, year of TCF, age, gender and previous inferior antiretroviral therapy, harbouring ≥9 versus ≤8 mutations was associated with increased mortality (mortality rate ratio [MRR] 2.3 [95% confidence interval (CI) 1.1–4.8]), as were the individual mutations T215Y (MRR 3.4 [95% CI 1.6–7.0]), G190A/S (MRR 3.2 [95% CI 1.6–6.6]) and V82F/A/T/S (MRR 2.5 [95% CI 1.2–5.3]). Conclusions In HIV patients with TCF, the total number of genotypic resistance mutations and specific single mutations predicted mortality.