bluuebunny/crossref_metadata_2025_split huggingface dataset:
Triple Nucleoside Combination Zidovudine/Lamivudine/Abacavir versus Zidovudine/Lamivudine/Nelfinavir as First-Line Therapy in HIV-1-Infected Adults: A Randomized Trial
Authors: Matheron Sophie , Descamps Diane , Boué François , Livrozet Jean-Michel , Lafeuillade Alain , Aquilina Christian , Troisvallets Didier , Goetschel Agnès , Brun-Vezinet Françoise , Mamet Jean-Philippe , Thiaux Cécile ,   CNAF3007 study group, Allegre T , Bataille P , Bazin C , Bentata M , Bergmann JF , Beytout J , Bicart-See A , Bodard L , Brottier-Mancini E , Caron F , Cassuto JP , Chousterman M , Counillon E , Delfraissy JF , Dellamonica P , Doll J , Faller JP , Gallais H , Garre M , Gastaut JA , Gilquin J , Herson S , Hoen B , Jarousse B. , Katlama C , Lacoste D , Lange JM , Lecomte I , Lepeu G , Lucht F , Malkin JE , Massip P , Mechali D , Molina JM , Mouton Y , Pathe JP , Peyramond D , Philibert P , Plaisance N , Polomenie P , Remy G , Rispal P , Roue R , de Saint Martin L , Sereni D , Sicard D , Sobel A , Stahl JP , Trepo C , De Truchis P , Vermersch A , Welker Y , Izopet J , Vabret A , Peytavin. G 
Published: April 2022

Objective To compare the efficacy and safety of a triple nucleoside combination to a protease inhibitor-containing triple regimen as first-line antiretroviral therapy (ART) in HIV-1-infected patients. Design Open-label study in HIV-1-infected ART-naive adults, randomized to receive either Combivir® (lamivudine 150 mg/zidovudine 300 mg twice daily) + abacavir (300 mg twice daily), or Combivir® + nelfinavir (750 mg every 8 h) for 48 weeks. Plasma HIV-1 RNA, CD4 cell count and adverse events were assessed at baseline and weeks 4, 8, 16, 24, 32, 40 and 48. Results 195 subjects (131 men, 64 women), median age 34 years, were randomized: 98 received combivir/abacavir and 97 combivir/nelfinavir. Baseline median plasma HIV-1 RNA was 4.2 log10 copies/ml [Interquartile range (IQR): 3.7-4.5.2] and 4.1 log10 copies/ml (IQR: 3.8–4.6), respectively. Baseline median CD4 cell count was 387 cells/mm3 (IQR: 194–501) and 449 cells/mm3 (IQR: 334–605), respectively. Nine patients (3 vs 6, respectively) did not start treatment or did not have any available efficacy data. At week 48, using the intent to treat analysis (switch/missing equals failure), plasma HIV-1 RNA was <50 copies/ml in 54/95 (57%) and 53/91 (58%) of subjects, respectively. Median CD4 increase was +110 and +120 cells/mm3, respectively. Possible hypersensitivity reactions to abacavir were reported in four subjects (4%). Conclusion The triple nucleoside combination combivir/abacavir is well tolerated as a first-line ART regimen in HIV-1-infected adults, with comparable antiviral activity to a nelfinavir-containing regimen at week 48.
Pharmacokinetics of Lower Doses of Saquinavir Soft-Gel Caps (800 and 1200 Mg Twice Daily) Boosted with Itraconazole in HIV-1-Positive Patients
Authors: Cardiello Peter G , Samor Tarika , Burger David , Hoetelmans Richard , Mahanontharit Apicha , Ruxrungtham Kiat , Lange Joep M , Cooper David A , Phanuphak Praphan 
Published: April 2022

Objective The pharmacokinetics of 800 mg and 1200 mg of saquinavir soft-gel caps (SQV-SGC) twice daily plus 100 mg itraconazole once daily were compared to 1400 mg SQV-SGC twice daily without itraconazole. Methods The pharmacokinetics of SQV were determined in 17 randomly selected patients on 1400 mg twice daily SQV-SGC without itraconazole and after 2 weeks with lower SQV-SGC doses plus itraconazole. SQV plasma concentrations were determined by HPLC. Pharmacokinetic parameters were calculated by a non-compartmental model. Results Median (+IQR) area under plasma concentration-versus-time curve (AUC0–12h) were 3.33 (1.96–7.34), 4.29 (3.14–7.67) and 4.07 (2.76–4.49) mg/l.h for SQV 1400 mg without itraconazole, SQV 1200 mg with itraconazole and SQV 800 mg with itraconazole, respectively. These differences were not statistically significant. The median Cmin was above the proposed minimum effective concentration of 0.05 mg/l for all three regimens. Conclusion SQV-SGC 800 mg or 1200 mg twice daily boosted with 100 mg of itraconazole once daily resulted in adequate SQV pharmacokinetics not significantly different from SQV-SGC 1400 mg twice daily.
Predictors of the Virological Response to a Change in the Antiretroviral Treatment Regimen in HIV-1-Infected Patients Enrolled in a Randomized Trial Comparing Genotyping, Phenotyping and Standard of Care (Narval Trial, Anrs 088)
Authors: Vray Muriel , Meynard Jean-Luc , Dalban Cécile , Morand-Joubert Laurence , Clavel François , Brun-Vézinet Françoise , Peytavin Gilles , Costagliola Dominique , Girard Pierre-Marie ,   the Narval Trial Group
Published: April 2022

Objective To identify predictors of the virological response to antiretroviral therapy in patients in whom initial therapy has failed. Methods The Narval trial was designed to compare phenotyping, genotyping and standard of care for the choice of antiretroviral therapy in patients in whom a protease inhibitor (PI)-containing regimen had failed. Virological success was defined as viral load below 200 copies/ml at week 12. Baseline variables including demographic, clinical and biological characteristics, HIV reverse transcriptase and protease mutations, the randomization arm, the drugs prescribed, as well as adherence to treatment and plasma concentrations of PIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) at week 12 were tested in the model. Variables that were significantly associated with virological success in univariate analysis were included in a logistic regression model. Results Five-hundred-and-forty-one patients were randomized. Virological success at week 12 was obtained in 200 patients. In multivariate analysis, the following factors were significantly associated with virological success: prescription of efavirenz to NNRTI-naive patients (OR=4.37; 95% CI: 2.76–6.90), randomization to the genotyping arm (OR=2.13, 1.20–3.79), prescription of lamivudine (OR=1.69, 1.01–2.83) and prescription of abacavir to abacavir-naive patients (OR=1.66, 1.02–2.72). Factors significantly associated with virological failure were prescription of nelfinavir (OR=0.30, 0.13–0.68), a high baseline viral load (OR=0.37, 0.28–0.50), the presence of at least five PI mutations (OR=0.42, 0.26–0.66), the presence of at least three thymidine analogue mutations (OR=0.61, 0.39–0.97) and at least 30 months of prior PI exposure (OR=0.64, 0.41–0.99). Conclusions These results confirm that among heavily pretreated patients, prescription of efavirenz to NNRTI-naive patients is associated with a good virological response, while a high baseline viral load, a large number of PI mutations and nelfinavir prescription at baseline are associated with a poor virological response. Genotyping was found to be beneficial, while this was not the case for phenotyping. This work was presented at the XI International HIV Drug Resistance Workshop, Sevilla, Spain, July 3–6 2002 (Abstract N°133); and at the XIV International Conference on AIDS, Barcelona, Spain, July 7–11 2002 (Abstract N°ThOrB138).
Age, Adherence and Injection Drug use Predict Virological Suppression among Men and Women Enrolled in a Population-Based Antiretroviral Drug Treatment Programme
Authors: O'Connell Jacqueline M , Braitstein Paula , Hogg Robert S , Yip Benita , Craib Kevin JP , O'Shaughnessy Michael V , Montaner Julio SG , Burdge David R 
Published: April 2022

Objectives To characterize 1-year virological response to antiretroviral therapy and its determinants by sex. Methods This is a population-based analysis of anti-retroviral therapy naive HIV-positive adult men and women. Factors associated with sex and with plasma HIV RNA viral load suppression to below 500 copies/ml were examined using non-parametric tests and logistic regression analyses. Results A total of 739 subjects (92 women and 647 men) were eligible. Female participants were younger (34 vs 37 years; P<0.001), less likely to have AIDS (6.5 vs 14.4%; P=0.039), more frequently injection drug users (44.6 vs 25.2%; P=0.001) and were less likely to be adherent to therapy (34.8 vs 62.9%; P<0.001) than male participants. There was no difference in baseline median CD4 count ( P=0.424) or HIV RNA levels ( P=0.140), physician experience ( P=0.057), or with respect to antiretroviral regimens containing protease inhibitors or non-nucleoside reverse transcriptase inhibitors ( P=0.911). With treatment, 46.7% (43/92) of women and 64.8% (419/647) of men ( P=0.001) suppressed HIV RNA viral load to below 500 copies/ml at 1 year. In a multivariate analysis, the association of sex with HIV RNA response to antiretroviral therapy fell from statistical significance (odds ratio 1.18; 95% CI: 0.72–1.95) after adjusting for adherence, injection drug use and age. Conclusion Our data indicate that in this population-based setting, sex differences in 1-year virological response to antiretroviral therapy are explained by age, adherence and injection drug use.
Changes in Body Fat Composition after 1 Year of Salvage Therapy with Lopinavir/Ritonavir-Containing Regimens and Its Relationship with Lopinavir Plasma Concentrations
Authors: Gutiérrez Félix , Padilla Sergio , Masiá Mar , Navarro Andrés , Gallego Juan , Hernández Ildefonso , Ramos José Manuel , Martin-Hidalgo Alberto 
Published: April 2022

Objective To determine whether an association existed between lopinavir (LPV) plasma concentrations and changes in body fat composition. Design A prospective, non-randomized study. Setting HIV clinic of a University Hospital. Subjects, participants: HIV-infected subjects who had virological failure on protease inhibitor-containing regimens. Twenty-two consecutive patients were enrolled, 19 completed 24 weeks of treatment and 16 completed the full 48-week study period. Intervention: Patients were treated with LPV/ritonavir (LPV/r) in combination with other antiretroviral agents. LPV trough plasma concentrations were measured at baseline and weeks 4, 8, 12, 24, 36 and 48. Body fat composition was quantified by computerized tomographic scanning at baseline, and weeks 24 and 48. Results LPV trough concentrations correlated with absolute and proportional changes in limb fat from baseline to week 48. Significant differences were found in mean LPV trough concentrations between patients losing less than 5% of limb fat, those experiencing a limb fat loss between 5 and 20%, and those losing more than 20% at week 24 [mean (SD), 4.67 (1.67); 8.57 (1.77); 9.49 (2.67) μg/ml, respectively; P=0.013] and week 48 [mean (SD), 4.5 (2.24); 7.04 (1.77); 9.7 (2.8) μg/ml, respectively; P=0.027]. Most patients losing more than 5% of limb fat during LPV/r therapy had mean LPV trough concentrations ≥8 μg/ml. Conclusions In patients receiving salvage therapy with LPV/r there was an association between LPV plasma trough concentrations and limb fat loss. The risk of peripheral limb fat loss may be greater among patients achieving higher LPV trough concentrations.
Meta-Analysis of Mutations in the Ns5A Gene and Hepatitis C Virus Resistance to Interferon Therapy: Uniting Discordant Conclusions
Authors: Schinkel Janke , Spaan Willy JM , Kroes Aloys CM 
Published: April 2022

Background Hepatitis C virus genotype 1B responds poorly to treatment with interferon, in contrast to the more interferon-sensitive genotypes 2 and 3. Studies on combination therapy regimens with PEG-interferon and ribavirin report sustained response rates that generally do not exceed 50%, in contrast to sustained response rates of 80% for genotype 2 and 3. In Japan, a correlation was found between the number of mutations in an ‘interferon sensitivity determining region’ (ISDR) and outcome of interferon treatment in genotype 1B-infected patients. However, an ongoing controversy on the existence of an ISDR in non-Japanese isolates resulted, as non-Japanese studies failed to confirm this association. The present study approached this issue by carrying out a meta-analysis of ISDR sequences and response to interferon treatment. Methods Twenty-seven studies were included, reporting 1351 ISDR sequence data of genotype 1B-infected patients and their virological response to interferon treatment. Both summary statistics and individual patient data were used systematically to explore the association between ISDR mutations and response to interferon. Results The ISDR effect on response was universally present but appeared to be stronger in Japan, with a relative risk of 5.73 for mutant viruses as compared to 4.66 for non-Japanese isolates. High interferon dose, in Japan administered more frequently, was associated with an increase in response rate only among patients infected with mutant isolates. Interaction between dose and ISDR type was confirmed in a logistic regression model. After stratifying for dose, differences in response rate between Japanese and non-Japanese patients were no longer present. Conclusion This study puts an end to a longstanding controversy by confirming the universal existence of an ISDR in genotype 1B-infected patients. Apparent discrepant findings from Japanese and non-Japanese studies can be explained by differences in dosing regimens and a dose-dependent differential effect of ISDR mutations on response to treatment.
Persistence of Multidrug-Resistant HIV-1 without Antiretroviral Treatment 2 Years after Sexual Transmission
Authors: Delaugerre Constance , Morand-Joubert Laurence , Chaix Marie-Laure , Picard Odile , Marcelin Anne-Genevieve , Schneider Veronique , Krivine Anne , Compagnucci Alexandra , Katlama Christine , Girard Pierre-Marie , Calvez Vincent 
Published: April 2022

Objectives To understand the virological mechanisms of 2-year persistence of multidrug-resistant virus without selective antiretroviral pressure in HIV-1-infected patients. Patients and Methods Two patients were contaminated recently by their HIV-1-infected partners, who had received, before the transmission, all available antiretroviral drugs and who exhibited a severe therapeutic failure. The resistance mutations analysis was performed by clonal sequencing of 1.2 kb of pol gene in plasma of index and sources patients. Sequencing of HIV-1 DNA was performed in PBMCs of index patients. Results Genotypic testing performed in index patients at time of seroconversion showed resistance mutations to three classes of drugs. All mutations were linked on the same viral genome and all quasispecies carried all mutations. No wild-type virus was detected. The same results were found in source patients and showed that all mutations were transmitted. In the index patients, all mutations persisted over 2 years without antiretroviral treatment. Moreover, the resistance mutations were all archived in the cellular reservoir. Viral load and CD4 count of index patients remained unchanged during 2 years of follow-up. Discussion Only multidrug-resistant viruses were detected in the source patients and could be transmitted in index patients. In the latter, an expansion of predominant multidrug-resistant quasispecies and the ‘archival’ of all mutations were observed. These results explain the persistence of mutations and suggest that it is highly difficult to return to a wild-type viral population, sensitive to an antiretroviral treatment. The treatment of index patients is limited and the major risk is the transmission of these multidrug-resistant viruses. This work was presented in part in the XII International HIV Drug Resistance Workshop, Los Cabos, Mexico, June 2003; and in the 2nd IAS Conference on HIV Pathogenesis & Treatment, Paris, France, July 2003.
Infrequent Transmission of HIV-1 Drug-Resistant Variants
Authors:   the Swiss HIV Cohort Study (SHCS), Yerly Sabine , Jost Stéphanie , Telenti Amalio , Flepp Markus , Kaiser Laurent , Chave Jean-Philippe , Vernazza Pietro , Battegay Manuel , Furrer Hansjakob , Chanzy Bruno , Burgisser Philippe , Rickenbach Martin , Gebhardt Martin , Bernard Marie-Charlotte , Perneger Thomas , Hirschel Bernard , Perrin Luc 
Published: April 2022

Transmission of drug-resistant variants is influenced by several factors, including the prevalence of drug resistance in the population of HIV-1-infected patients, HIV-1 RNA levels and transmission by recently infected patients. In order to evaluate the impact of these factors on the transmission of drug-resistant variants, we have defined the population of potential transmitters and compared their resistance profiles to those of newly infected patients. Sequencing of pol gene was performed in 220 recently infected patients and in 373 chronically infected patients with HIV-1 RNA >1000 copies/ml. Minimal and maximal drug-resistance profiles of potential transmitters were estimated by weighting resistance profiles of chronically infected patients with estimates of the Swiss HIV-1-infected population, the prevalence of exposure to antiviral drugs and the proportion of infections attributed to primary HIV infections. The drug-resistance prevalence in recently infected patients was 10.5% (one class drug resistance: 9.1%; two classes: 1.4%; three classes: 0%). Phylogenetic analysis revealed significant clustering for 30% of recent infections. The drug-resistance prevalence in chronically infected patients was 72.4% (one class: 29%; two classes: 27.6%; three classes: 15.8%). After adjustment, the risk of transmission relative to wild-type was reduced both for one class drug resistance (minimal and maximal estimates: odds ratio: 0.39, P<0.001; and odds ratio: 0.55, P=0.011, respectively), and for two to three class drug resistance (odds ratios: 0.05 and 0.07, respectively, P<0.001). Neither sexual behaviour nor HIV-1 RNA levels explained the low transmission of drug-resistant variants. These data suggest that drug-resistant variants and in particular multidrug-resistant variants have a substantially reduced transmission capacity.
Prevalence of Lipoatrophy and Mitochondrial DNA Content of Blood and Subcutaneous Fat in HIV-1-Infected Patients Randomly Allocated to Zidovudine- or Stavudine-Based Therapy
Authors: van der Valk Marc , Casula Miriam , Weverling Gerrit-Jan , van Kuijk Kees , van Eck-Smit Berthe , Hulsebosch Hendrick-Jan , Nieuwkerk Pythia , van Eeden Arne , Brinkman Kees , Lange Joep , de Ronde Anthony , Reiss Peter 
Published: April 2022

Introduction Mitochondrial toxicity resulting from mitochondrial DNA (mtDNA) depletion is suggested to be involved in the pathogenesis of lipodystrophy. Methods We cross-sectionally assessed lipodystrophy both clinically and radiographically in patients who, 4 years before, had been enrolled in a randomized comparative trial of stavudine- or zidovudine-based therapy. mtDNA content was measured in peripheral blood mononuclear cells (PBMCs) and subcutaneous adipose tissue from the thigh and back. Results Twenty-eight of the 45 patients enrolled in the original trial were included. Despite comparable exposure to stavudine or zidovudine (51 and 50 months, respectively), lipoatrophy prevalence by intent-to-treat analysis was significantly greater in stavudine recipients (82 vs 9%, P=0.0001). Likewise, those allocated to stavudine had significantly less peripheral fat. In an analysis restricted to patients who had remained on randomly allocated nucleoside reverse transcriptase inhibitors (NRTIs), mtDNA in PBMCs decreased after the start of treatment in both groups ( P<0.0001) (-73% for stavudine and -67% for zidovudine, P=0.11), resulting in significantly lower levels in patients with lipoatrophy ( P=0.007). The mtDNA content in subcutaneous adipose tissue from the thigh, but not from the back, was significantly lower in patients allocated to stavudine compared to zidovudine ( P=0.01). mtDNA in adipose tissue from either location did not differ significantly between those with or without lipoatrophy. Discussion This study objectively confirms that regimens containing stavudine are associated with a greater risk of lipoatrophy than those containing zidovudine. mtDNA in PBMCs markedly declined with both treatments and was lowest in patients with lipoatrophy. The lack of difference in mtDNA in adipose tissue from patients with as opposed to without lipoatrophy may have been masked by a relative preponderance of stromal and vascular tissue in the subcutaneous tissue samples from these patients, combined with compensatory mitochondrial proliferation in remaining adipocytes. However, our findings may also suggest that the different risk of lipoatrophy observed between NRTIs cannot solely be explained by differences in mtDNA depletion directly at the level of peripheral adipose tissue.
Atp Binding Cassette Multidrug Transporters Limit the Anti-HIV Activity of Zidovudine and Indinavir in Infected Human Macrophages
Authors: Jorajuria Sylvie , Dereuddre-Bosquet Nathalie , Becher François , Martin Solenne , Porcheray Fabrice , Garrigues Alexia , Mabondzo Aloise , Benech Henri , Grassi Jacques , Orlowski Stéphane , Dormont Dominique , Clayette Pascal 
Published: April 2022

Objectives To investigate whether P-glycoprotein (P-gp) and multidrug resistance proteins (MRPs), which limit the bioavailability of HIV protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs), modulate the anti-HIV activity of NRTIs, non-NRTIs and PIs in vitro. Design: We used primary cultures of major HIV target cells: human monocyte-derived macrophages (MDMs) and lymphocytes. Methods P-gp and MRP expression in response to long-term zidovudine (3′-azido-3′-deoxythymidine; AZT) or indinavir treatment was quantified by RT-PCR. MDM and lymphocytes were infected in vitro with HIV-1/Ba-L and HIV-1-LAI, respectively, and treated with antiretroviral drugs. We evaluated the activity of these drugs in combination with PSC833, a P-gp inhibitor, and/or probenecid, an MRP1 inhibitor. Intracellular AZT triphosphate derivative (AZT-TP) was quantified by HPLC-MSMS. P-gp ATPase activity was measured with inside-out native membrane vesicles enriched in P-gp. Results Levels of MDR1, mrp4 and mrp5 mRNA were high following AZT treatment. In infected MDM, PSC833 and probenecid increased the anti-HIV activity of AZT and indinavir. AZT (5 nM) decreased HIV replication by 34% alone and by 72% in combination with P-gp/MRP inhibitors. Indinavir (10 nM) gave 14% inhibition alone and 81% in combination. The increase in anti-HIV activity of AZT was correlated with an increase in intracellular AZT-TP concentration. However, unlike PIs, neither AZT nor its metabolites interacted with P-gp. Conclusion AZT increases the expression of multidrug transporters, thereby decreasing its pharmacological activity. The cellular efflux of AZT probably involves MRP4 or MRP5. In contrast, increases in indinavir anti-HIV activity require the inhibition of both P-gp and MRP1.