bluuebunny/crossref_metadata_2025_split huggingface dataset:
Absence of Resistance Mutations in Antiretroviral-Naive Patients Treated with Ritonavir-Boosted Saquinavir
Authors: Ananworanich Jintanat , Hirschel Bernard , Sirivichayakul Sunee , Ubolyam Sasiwimol , Jupimai Thidarat , Prasithsirikul Wisit , Chetchotisakd Ploenchan , Kiertiburanakul Sasisopin , Munsakul Warangkana , Raksakulkarn Phitsanu , Tansuphasawadikul Somboon , Schutz Malte , Snowden Wendy , Ruxrungtham Kiat 
Published: April 2022

Background There are few data on the selection of resistance by ritonavir-boosted saquinavir (SQV/r), particularly in antiretroviral (ARV)-naive patients. Objective To assess the incidence of virological failure and evolution of resistance in ARV-naive individuals receiving SQV/r in the induction phase of the Staccato trial. Methods ARV-naive subjects ( n=272) received SQV/r 1,600/100 mg once daily with two nucleoside reverse transcriptase inhibitors (NRTIs) for at least 24 weeks. Patients were defined as having virological failure (VF) when there were two consecutive HIV-1 RNA measurements >500 copies/ml after week 12. Viral genotypes (reverse transcriptase [RT] and protease [PRO]) were determined at baseline in all patients and as close as possible to the time of initial failure in patients experiencing VF. Results VF was observed in 9/272 patients receiving SQV/r 1,600/100 mg once daily with two NRTIs (3.3%) and occurred 19–48 weeks after treatment initiation. Eight of these patients were evaluable at failure. No major PRO mutations were detected, but 2/8 displayed single new minor PRO substitutions (M36I, L10I) at VF that were known or suspected not to have been present at baseline; both these substitutions exist as natural polymorphisms. A third patient displayed a single new RT mutation (M184I). Conclusions SQV/r plus two NRTIs (1,600/100 mg once daily) is an effective initial treatment option for ARV-naive patients, resulting in a low rate of viral rebound (3.3%). Furthermore, no major protease mutations were detected following VF, suggesting that future treatment options are preserved.
Significance of Viral Load, Core Promoter/Precore Mutations and Specific Sequences of Polymerase Gene in Hbv-Infected Patients on 3-Year Lamivudine Treatment
Authors: Yuen Man-Fung , Sablon Erwin , Libbrecht Evelien , Velde Hilde Van De , Wong Danny Ka-Ho , Fung James , Wong Benjamin Chun-Yu , Lai Ching-Lung 
Published: April 2022

Background Comprehensive study on viral factors predicting treatment responsiveness to lamivudine is lacking. Aims To define the significance of various viral factors and changes of viral population with lamivudine treatment. Patients and methods Hepatitis B virus (HBV) DNA levels at baseline, week 24, 52 and year 3 were measured in 80 patients on continuous lamivudine therapy for 3 years. Genotypes, core promoter/precore mutations, YMDD mutations, polymorphic sequence of polymerase gene (rt91I/L, rt256S/C) were determined at baseline, week 12, 24 and 52. YMDD mutations were also determined at year 3. Results High alanine aminotransferase levels and presence of core promoter/ precore mutations at baseline were associated with higher chance of achieving HBV DNA <1,000 copies/ml (good response) and higher rate of hepatitis Be antigen (HBeAg) seroconversion at week 52. Achieving HBV DNA levels <1,000 copies/ml at week 24 as well as baseline core promoter/precore mutations were associated with higher chance of achieving good response, higher rate of HBeAg seroconversion and lower rate of YMDD mutations at year 3. Lamivudine reversed core promoter mutations to wild type in 25% of patients. All 5 patients with rt256C had poor HBV DNA response, persistent HBeAg and YMDD mutations by year 3. There was no difference in treatment response between patients with genotype B and C. Conclusions Achieving HBV DNA levels <1,000 copies/ml at 24 week is the best target for short- and long-term treatment efficacy. Core promoter and precore mutations were associated with better treatment outcome, and rt256C polymorphism in the polymerase gene with poor response.
Impact of HIV-1 Reverse Transcriptase Polymorphism at Codons 211 and 228 on Virological Response to Didanosine
Authors: Marcelin Anne-Genevieve , Flandre Philippe , Furco Andre , Wirden Marc , Molina Jean-Michel , Calvez Vincent 
Published: April 2022

Objective To determine the potential impact of reverse transcriptase (RT) mutations, other than those currently known to confer nucleoside reverse transcriptase inhibitors (NRTIs) resistance, on the virological response to didanosine (ddI). Design and patients In the placebo-controlled Jaguar trial, 168 patients were randomly assigned to receive ddI ( n=111) or placebo ( n=57) in addition to their currently failing regimen for 4 weeks. Methods The virological response was a reduction of HIV-1 RNA from baseline to week 4. In an univariate analysis, we investigated the impact on the virological response to ddI of all the mutations in the RT gene (codons 21–236), except those known to confer NRTI resistance. Using the removing procedure, with a test for trend (Jonckheere's test), a new potential score was calculated incorporating all potential mutations associated to the week 4 virological response. Results Two RT polymorphisms were associated with a reduced virological response to ddI, R211A/D/G/K/S and L228H/M/R, and one with a better virological response: F214L. A mutation score (M41L+D67N+T69D-K70R +L74V-M184V/I+T215Y/F+K219Q/E+R211A/D/G/K/S+ L228H/M/R), including two RT polymorphisms not previously described to be associated with ddI resistance (211 and 228) and RT mutations previously described, was associated with a continuum of virological response and increased the predictability of virological response to ddI. Conclusion RT polymorphisms should be taken into account to define algorithms able to correctly define resistance to NRTIs and more specifically ddI.
Rare Selection of the K65R Mutation in Antiretroviral-Naive Patients Failing a First-Line Abacavir/Lamivudine-Containing Haart Regimen
Authors: Descamps Diane , Ait-Khaled Mounir , Craig Charles , Delarue Séverine , Damond Florence , Collin Gilles , Brun-Vézinet Françoise 
Published: April 2022

Objective Previous studies have described the presence of the L74V reverse transcriptase (RT) mutation in highly experienced individuals as a risk factor for reduced response to tenofovir and selection of the K65R mutation. This study examined whether, in the context of a first-line abacavir/lamivudine highly active anti-retroviral therapy (HAART) regimen, K65R might occur as a minority population where L74V was detected at virological failure. Methods Four previously ART-naive individuals undergoing virological failure were selected, all receiving abacavir and lamivudine with either protease inhibitors or efavirenz and with virus displaying L74V and M184V or M184V alone following transient L74V emergence. Clonal analyses from plasma viral RNA were performed on samples taken at baseline and after virological failure. Clones were screened for the presence of K65R by real time K65R-selective PCR (K65R-sPCR). RT genes from clones displaying K65R were sequenced. Results At baseline, all clones were wild type at codon 65 by K65R-sPCR, except in one patient in which one of 720 clones exhibited K65R. At failure with M184V and L74V present by bulk sequencing, this K65R was retained in one of 855 clones assessed. One additional patient (M184V alone by bulk sequencing) displayed K65R in one of 466 failure clones. Virological failure samples from the remaining two patients were wild type at codon 65 in all of 524 and 270 clones, respectively. Conclusions Minority species harbouring K65R are uncommon and occur at very low population densities in patients experiencing virological failure on first-line abacavir/lamivudine-containing HAART.
HIV-1 Subtypes and Response to Combination Antiretroviral Therapy in Europe
Authors:   for the EuroSIDA study group, Bannister Wendy P , Ruiz Lidia , Loveday Clive , Vella Stefano , Zilmer Kai , Kjær Jesper , Knysz Brygida , Phillips Andrew N , Mocroft Amanda , Lundgren Jens D 
Published: April 2022

Background Combination antiretroviral therapy (cART) may vary in ability to suppress viral load and increase CD4+ T-cell count in people infected with different HIV-1 subtypes, possibly due to differences in resistance development. Antiretroviral drugs have predominantly been developed in Western Europe/North America on the basis of the most prevalent subtype, B. However, non-B subtypes are increasingly spreading worldwide. Objective To compare virological and immunological response to cART between patients infected with B and non-B subtypes across Europe. Design EuroSIDA prospective, observational cohort with 11,928 HIV-1-infected patients. Methods Response to cART was analysed in patients with subtypes determined pre-cART, via multivariable logistic regression on the first measurements 6–12 months after starting cART. A virological response was defined as a viral load <500 copies/ml and immunological response as a CD4+ T-cell count increase of ≥100 cells/mm3. Results Forty-five percent of patients were antiretroviral naive at initiation of cART. Virological suppression was achieved by 58% of 689 subtype-B-infected patients and 66% of 102 non-B-infected patients ( P=0.159). After adjustment for potential confounders, there was no significant difference in odds of achieving virological suppression (non-B compared with B; odds ratio [OR]: 1.05, 95% confidence interval [CI]: 0.58–1.93, P=0.866). An immunological response was achieved by 43% of 753 B-infected patients and 48% of 114 non-B-infected patients ( P=0.334). After adjustment, there was no significant difference in odds of an immunological response (OR: 1.17, 95% CI: 0.73–1.87, P=0.524). Conclusions There was no evidence of significant differences in virological or immunological response to cART between patients infected with HIV-1 B and non-B subtypes.
Sustained Virological Response following HCV Therapy is Associated with Non-Progression of Liver Fibrosis in HCV/HIV-Coinfected Patients
Authors: Barreiro Pablo , Labarga Pablo , Martín-Carbonero Luz , Amor Aranzazu , Ruiz-Sancho Andrés , Castellares Carol , González-Lahoz Juan , Soriano Vincent 
Published: April 2022

Background Chronic hepatitis C leads to progressive liver fibrosis, which is accelerated in HIV-coinfected patients. Unfortunately, hepatitis C virus (HCV) therapy provides sustained virological response (SVR) to only 40% of coinfected patients. Little is known about the regression of hepatic fibrosis in treated patients. Methods All coinfected patients who had completed a full course of HCV therapy at our institution were identified. Liver fibrosis staging was estimated using non-invasive procedures at the time of initiating HCV therapy and reassessed at the last patient's follow-up using elastometry (FibroScan®). Results A total of 103 coinfected patients were identified. HCV genotype distribution was 1 (63%), 3 (29%) and 4 (8%). SVR had been attained by 34 individuals, while the remaining 69 were non-responders and/or relapsers. The mean lag time between the end of HCV therapy and the current assessment of liver fibrosis was 40 months, without differences between groups. Metavir score estimates were comparable before initiating HCV therapy in SVR and non-SVR patients. By contrast, current Metavir scores were lower in SVR than in non-SVR patients; for instance, F3-F4 estimates were 12% versus 54%, respectively ( P<0.001). Moreover, the longer the time elapsed after HCV therapy, the lower the liver fibrosis in SVR patients (ρ=-0.39; P=0.02). Conversely, liver fibrosis staging directly correlated with the lag following HCV therapy in non-SVR patients (ρ=0.25; P=0.03). Conclusions SVR after HCV therapy is associated with non-progression of liver fibrosis in HCV/HIV-coinfected patients, although this benefit may not be universal and improvement only been recognizable after several years of follow-up.
A Randomized Controlled Trial of Genotypic HIV Drug Resistance Testing in HIV-1-Infected Children: The Pera (Penta 8) Trial
Authors:   on behalf of the Paediatric European Network for the Treatment of AIDS (PENTA), Green Hannah , Gibb Diana M , Compagnucci Alexandra , Giacomet Vania , de Rossi Anita , Harper Lynda , Saïdi Yacine , Castelli-Gattinara Guido , Pillay Deenan , Babiker Abdel G , Aboulker Jean-Pierre , Lyall Hermione , Bacheler Lee T , Walker A Sarah , Debré Marianne , Rosso Raffaella , Burger David M , Negra Marinella Della , Dunn David T , Giaquinto Carlo 
Published: April 2022

Objective To evaluate the longer-term utility of genotypic resistance testing in HIV-1-infected children with virological failure. Methods Children aged 3 months-18 years switching antiretroviral therapy (ART) with HIV-1 RNA >2,000 copies/ml were randomized between genotypic testing (Virtual PhenotypeTM) and no testing at baseline and subsequent virological failures. Children were followed to at least 96 weeks. Results One hundred and seventy eligible children, from 24 clinical centres in six countries, were randomized to resistance testing ( n=87) or no testing ( n=83) between June 2000-July 2003. At baseline, mean HIV-1 RNA and CD4+ T-cell percentage were 4.7 log10 copies/ml and 20%, respectively. Children had taken ART for a mean of 5 years; 24% had received all three classes, 53% nucleoside reverse transcriptase inhibitors (NRTIs)+protease inhibitors (PIs), 9% NRTIs+non-nucleoside reverse transcriptase inhibitors (NNRTIs) and 14% NRTIs only. There was no difference between the arms in the drug classes or the individual PIs/NNRTIs prescribed. However, 49% in the resistance test arm (RT) versus 19% in the no-test arm (NT) continued at least one NRTI from their failing regimen; 56% versus 19% were prescribed didanosine+stavudine as their NRTI backbone. Adjusting for baseline HIV-1 RNA, mean reductions in HIV-1 RNA at 48 weeks were 1.51 log10 copies/ml in the RT arm and 1.23 in the NT arm ( P=0.3); the difference between the arms was smaller at week 96 (RT: 1.50, NT: 1.47; P=0.9). Conclusion In this first paediatric trial of resistance testing, we observed a substantial difference in NRTI-prescribing behaviour across arms. However statistically significant evidence of a long-term virological or immunological benefit was not observed. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN14367816.
Safety and Efficacy of Extended-Release Niacin for the Treatment of Dyslipidaemia in Patients with HIV Infection: Aids Clinical Trials Group Study A5148
Authors:   for the AIDS Clinical Trials Group A5148 Study Team, Meixner Linda , Hoffman Julie , Zwickl Beth , Goldman Mitch , Whitely Kim , Conrad Ann , Fichtenbaum Carl J , Hyc Fran , Spitz Teresa , Shaw Debra Demarco , Norris Jane , Stoudt Sylvia , Castro Jose , Colon Lillian , Cavert Winston P. , Fox Kathy A. , Dubé Michael P , Wu Julia W , Aberg Judith A , Deeg Mark A , Alston-Smith Beverly L , McGovern Mark E , Lee Daniel , Shriver Sharon L , Martinez Ana I , Greenwald Martha , Stein James H 
Published: April 2022

Background Dyslipidaemia is very common in patients with HIV infection, but current therapies are often suboptimal. Since niacin may cause insulin resistance and hepatotoxicity, it has generally been avoided in this setting. Methods Non-diabetic male subjects ( n=33) who had well-controlled HIV infection on antiretroviral therapy, fasting triglycerides ≥2.26 mmol/l and non-high density lipoprotein cholesterol (non-HDL-C) ≥4.66 mmol/l received escalating doses of extended-release niacin (ERN) up to 2,000 mg nightly for up to 44 weeks. Results Fourteen subjects (42%) had pre-diabetes at entry. Twenty-three subjects (70%) received the maximum dose, eight (24%) received 1,500 mg. Niacin was well-tolerated. Only four subjects (12%) discontinued study treatment. There were small increases in fasting glycaemia and insulin resistance estimated by the homeostasis model assessment, but insulin resistance measures from the 2-h oral glucose tolerance test only transiently worsened. No subject developed persistent fasting hyperglycaemia; one had persistently elevated 2-h glucose >11.1 mmol/l. There were no significant changes in serum transaminases or uric acid. At week 48, the median change in fasting lipid levels in mmol/l (interquartile range) were: total cholesterol -0.21 (-1.35, -0.05), HDL-C +0.013 (-0.03,+0.28), non-HDL-C -0.49 (-1.37, +0.08) and triglycerides -1.73 (-3.68, -0.72). Favourable changes in large HDL and large very low density lipoprotein particle concentration were observed by nuclear magnetic resonance spectroscopy. Conclusions ERN in doses up to 2,000 mg daily was safe, well-tolerated and efficacious in HIV-infected subjects with atherogenic dyslipidaemia. Increases in glycaemia and insulin resistance tended to be transient.
Evolution of Resistance Mutations during Low-Level Viral Replication in HIV-1–Infected Patients Treated with Zidovudine/Lamivudine/Abacavir as a First-Line Regimen
Authors: Stürmer Martin , Dauer Brenda , Moesch Manfred , Haberl Annette , Mueller Axel , Locher Leo , Knecht Gaby , Hanke Nora , Doerr Hans W , Staszewski Schlomo 
Published: April 2022

Objective Long-term evaluation of viral evolution in patients who continued first-line therapy with zidovudine/lamivudine/abacavir (Trizivir [TZV]) in the presence of low-level viral replication and assessment of the impact of mutational patterns selected under TZV on viral load (VL), CD4+ T-cell count (CD4) and subsequent therapeutic options. Design Analysis of viral evolution based on genotypic resistance tests (GRT) from samples collected during non-suppressive first-line therapy with TZV. Methods Patients from the Frankfurt HIV cohort with at least 3 months uninterrupted first-line therapy with TZV in whom VL and CD4 measurements were performed at baseline and at follow up were identified. Criteria for virological failure (VF) were two consecutive VL >400 copies/ml. GRTs were required at baseline, VF and last visit (LV). Results Initially, 23/119 patients were classified as VF; 4/23 were lost to follow up. Median time to VF was 48 weeks. Because of the observed virological and immunological benefit, patients continued TZV for a median of 87 weeks despite detectable viraemia. Median CD4 increase and VL reduction at LV were 120 cells/mm3 and 317,100 copies/ml, respectively, compared to baseline. After 54 weeks of treatment with detectable VL, three mutational patterns were observed: Group A ( n=4) characterized by M184V without further regimen-associated mutations, group B ( n=9) by M184V accompanied by one to three thymidine analogue mutations (TAMs), and group C ( n=6) by M184V and four to six TAMs. No virological or CD4 parameters correlated with these patterns. Group A remained unchanged, thus preserving activity of most nucleoside analogues (NA). However, in the majority of patients (groups B and C) accumulation of mutations at different rates was observed, leading to a sequential loss of NA options. Conclusions Continuous treatment with TZV in the presence of viral replication is associated with a stepwise accumulation of resistance mutations. M184V was present in all cases, not followed by further selection of TAMs in a small, unpredictable subgroup of patients. However, in the majority of patients selection of M184V was associated with accumulation of TAMs at different rates leading to a substantial loss of active NAs, despite continuous virological and immunological benefit when compared with baseline.
Conservation of First-Line Antiretroviral Treatment Regimen where Therapeutic Options are Limited
Authors: Orrell Catherine , Harling Guy , Lawn Stephen D , Kaplan Richard , McNally Matthew , Bekker Linda-Gail , Wood Robin 
Published: April 2022

Objectives To determine rates and causes of switching from first- to second-line antiretroviral treatment (ART) regimens in a large treatment-naive cohort (a South African community-based ART service) where a targeted adherence intervention was used to manage initial virological breakthrough. Methods ART-naive adults ( n=929) commencing first-line non-nucleoside-based ART [according to WHO (2002) guidelines] between September 2002 and August 2005 were studied prospectively. Viral load (VL) and CD4+ T-cell counts were monitored every 4 months. All drug switches were recorded. Counsellor-driven adherence interventions were targeted to patients with a VL >1,000 copies/ml at any visit (virological breakthrough) and the VL measurement was repeated within 8 weeks. Two consecutive VL measurements >1,000 copies/ml was considered virological failure, triggering change to a second-line regimen. Results During 760 person-years of observation [median IQR) 189 (85–441) days], 823 (89%) patients were retained on ART, 2% transferred elsewhere, 7% died and 3% were lost to follow-up. A total of 893 (96%) patients remained on first-line therapy and 16 (1.7%) switched to second-line due to hypersensitivity reactions ( n=9) or lactic acidosis ( n=7). A Kaplan-Meier estimate for switching to second-line due to toxicity was 3.0% at 32 months. Virological breakthrough occurred in 67 (7.2%) patients, but, following use of a targeted adherence intervention, virological failure was confirmed in just 20 (2.2%). Kaplan-Meier estimates at 32 months were 20% for virological breakthrough but only 5.6% for confirmed virological failure. Conclusion Regimen switches were due to virological failure or toxicity. Although follow-up time was limited, over 95% of individuals remained on first-line ART using a combination of viral monitoring and a targeted adherence intervention.
Adefovir Dipivoxil Monotherapy and Combination Therapy with Lamivudine for the Treatment of Chronic Hepatitis B in an Asian Population
Authors: Fung James , Lai Ching-Lung , Yuen John Chi-Hang , Wong Danny Ka-Ho , Tanaka Yasuhito , Mizokami Masashi , Yuen Man-Fung 
Published: April 2022

Aim To determine differences in Chinese patients treated with adefovir (ADV) monotherapy or ADV in combination with lamivudine (3TC) after development of resistance to 3TC, with respect to biochemical improvement, HBV DNA suppression and development of subsequent ADV resistance. Methods All hepatitis B patients with 3TC resistance treated with ADV for 3 months or more at our centre were included, and monitored 3–6 monthly for biochemical and virological response, and development of ADV resistance. Results A total of 56 patients were included, 50% switched to ADV monotherapy and 50% received combination 3TC/ADV therapy. Median follow-up was 15.5 months. Normalization of alanine aminotransferase (ALT) occurred in 25 (89%) patients in the ADV group compared with 24 (86%) in the 3TC/ADV group (P=0.686). Virological response (VR) was achieved in seven (35%) patients in the ADV group at 12 months compared with five (28%) in the 3TC/ADV group (P=0.637). By 24 months, seven (64%) patients in the ADV group achieved VR compared with two (40%) in the 3TC/ADV group (P=0.377). Cumulative probability of developing genotypic ADV resistance in the ADV group at 24 months was 18% compared with 7% in the 3TC/ADV group (P=0.94). Conclusions There was no obvious improvement in ALT normalization and virological suppression or reduction in the development of ADV-resistant mutations with 3TC/ADV therapy compared with ADV monotherapy. Further studies with longer follow-ups are required to determine whether combination 3TC/ADV therapy will reduce the emergence of ADV resistance compared with ADV monotherapy.