bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ritonavir/Saquinavir plus One Nucleoside Reverse Transcriptase Inhibitor (NRTI) versus Indinavir plus Two Nrtis in Protease Inhibitor-Naive HIV-1-Infected Adults (Iris Study)
Authors: Florence Eric , Dreezen Christa , Desmet Patrick , Smets Eric , Fransen Katrien , Vandercam Bernard , Pelgrom Jolanda , Clumeck Nathan , Colebunders Robert 
Published: April 2022

Objectives To compare the efficacy, tolerability and safety of a ritonavir 400 mg/saquinavir hard gel fomulation 400 mg twice daily versus an indinavir 800 mg once every 8 h containing first-line protease inhibitor (PI) treatment regimen. Methods Open, randomized, multicentre clinical trial. PI-naive patients received either ritonavir/saquinavir and one nucleoside reverse transcriptase inhibitor (NRTI) or indinavir and two NRTIs. Intention-to-treat (ITT) and on-treatment (OT) analyses were performed. Results The baseline characteristics of the study participants were similar in both arms, 67 patients (37%) were naive to antiretroviral treatment. The proportion of patients who achieved a plasma viral load below the level of detection of 400 copies/ml at week 48 was 43% (39/90) in the ritonavir/saquinavir arm and 63% (57/90) in the indinavir arm ( P=0.005, ITT analysis). Using an OT analysis, these percentages were 84% and 88%, respectively ( P=0.6). There were more drop-outs in the ritonavir/saquinavir arm than in the indinavir arm (35.6% (32/90) versus 15.6% (14/90), P=0.002), mainly due to gastro-intestinal side-effects. Abnormal liver tests and increased lipids levels were more frequently reported in the ritonavir/saquinavir arm than in the indinavir arm. Conclusion In PI-naive patients, indinavir in combination with two NRTIs was more effective and better tolerated than ritonavir/saquinavir plus one NRTI. Both treatments were very effective for patients who were able to tolerate them.
A Genotypic Drug Resistance Interpretation Algorithm that Significantly Predicts Therapy Response in HIV-1-Infected Patients
Authors: Van Laethem Kristel , De Luca Andrea , Antinori Andrea , Cingolani Antonella , Perno Carlo Federico , Vandamme Anne-Mieke 
Published: April 2022

Objectives The development of a genotypic drug resistance interpretation algorithm, and the evaluation of its power to predict therapy outcome. Design A rule-based algorithm was established by an individual expert and was based on published and inhouse results, independently from the data of the patients used in this evaluation. The predictive value of the algorithm for virological outcomes was retrospectively evaluated using the baseline genotype observed in patients on highly active antiretroviral therapy, failing virologically and subsequently starting a salvage regimen. Methods The independent association between the susceptibility score (calculated according to the algorithm) and the virological response at 3 months, was analysed using multivariable logistic regression and multiple linear regression models. Results In two clinical centres 240 patients were studied. At 3 months 35% had a viral load of <500 RNA copies/ml. Using multivariable logistic regression, the odds ratio of achieving a viral load <500 RNA copies/ml at month 3 per unit increase of susceptibility score was 2.0 (95% CI 1.3–3.1; P=0.002) after adjusting for baseline viral load, genotype-driven salvage therapy, number of new drugs in the regimen, use of a new drug class in the regimen, nelfinavir-containing salvage therapy and history of prior viral load <500 RNA copies/ml. Using multiple linear regression, the susceptibility score showed a significant linear correlation with the log viral load change (slope=–0.27 log10 RNA copies/ml; 95% CI –0.11 to –0.43; P=0.001) after adjusting for history of prior viral load <500 RNA copies/ml, number of new drugs in the salvage therapy, use of a new drug class in the salvage therapy and baseline viral load. Conclusions This algorithm proved to be a significant independent predictor of therapy response at 3 months in this cohort of HIV-1-infected patients on salvage therapy. However, it should be subject to regular updates as is needed in this fast developing field.
Impact of Stavudine Phenotype and Thymidine Analogues Mutations on Viral Response to Stavudine plus Lamivudine in Altis 2 Anrs Trial
Authors: Calvez Vincent , Costagliola Dominique , Descamps Diane , Yvon Anne , Collin Gilles , Cécile Agnès , Delaugerre Constance , Damond Florence , Marcelin Anne-Geneviève , Matheron Sophie , Simon Anne , Valantin Marc-Antoine , Katlama Christine , Brun-Vézinet Françoise 
Published: April 2022

Objective Stavudine-based antiretroviral combinations are less effective in zidovudine-experienced patients than in naive subjects and recently, mutations have been described to be associated to the use of both stavudine and zidovudine. In the ALTIS 2 trial, it was shown that a combination of stavudine and lamivudine is less effective in zidovudine-experienced patients than in naive patients. We conducted a retrospective genotypic and phenotypic resistance study (expressed as stavudine phenotypic index, calculated by dividing the inhibitory concentrations 50% [IC50] by the mean value of the sensitive viruses) to evaluate the factors associated with decrease in plasma HIV-1 RNA. Design Associations with continuous variables were studied using non-parametric Spearman correlation coefficients. Associations with categorical variables were studied using non-parametric Mann–Whitney tests. Multivariate stepwise regression analyses were used to determine independent prognostic factors of the virological response. Results At baseline, most of the subjects harboured zidovudine-associated mutations in plasma and peripheral blood mononuclear cells. Zidovudine and stavudine IC50 and IC90 were strongly associated with response. It appears that a cut-off of stavudine phenotypic index of 1.8-fold of IC50, much lower than the usually used value, could be clinically significant for response to stavudine. In the multivariate analysis, the stepwise model with the higher multiple correlation coefficient ( R2=0.742) included the presence of a 215 Y/F mutation, the number of previously used nucleoside analogues and a resistant stavudine phenotype. Conclusion These results argue for a phenotypic and genotypic cross resistance between stavudine and zidovudine. Modest increases of IC50 and IC90 for stavudine had an important impact on the virological response during the trial and plead for a new definition of the threshold value for stavudine phenotypic index.
Transient Rebounds of Low-Level Viraemia among HIV-Infected Patients under Haart are Not Associated with Virological or Immunological Failure
Authors: Mira José A , Macías Juan , Nogales Carmen , Fernández-Rivera Javier , García-García José A , Ramos Antonio , Pineda Juan A 
Published: April 2022

Objective To analyse whether blips are associated with a higher risk of virological or immunological failure than persistent undetectable viraemia (UND) among HIV-infected patients receiving HAART. Design Retrospective cohort study. Subjects Patients with blips or UND were selected from a prospective cohort of 330 patients under HAART for over 48 weeks. Blips were defined as detectable viraemia up to a maximum of 1000 copies/ml preceded by two consecutive visits and followed by one visit showing undetectable viraemia. Patients were included according to the following criteria: i) Blip group: patients that showed transient relapses of viraemia; ii) UND group: patients who had achieved UND on HAART before 24 weeks of therapy and that sustained viral suppression for four consecutive visits. Main outcome measures: Virological and immunological failure. Results Thirty seven (11%) and 65 (20%) patients showed blips and persistent UND, respectively. Virological failure was observed in three (8.1%) patients in the blip group and 11 (16.9%) patients in the UND group ( P=0.25). The time to virological failure was shorter in the UND group ( P=0.12). The rates of virological failure and the time to virological failure were similar between both groups after excluding patients with compliance <95%. The time to immunological failure was also similar in both groups ( P=0.5). In a Cox model, only the use of saquinavir hard gel-based regimens was independently associated with the time to virological and immunological failure. Conclusion Patients under HAART with transient low-level viraemia are not at an increased risk of developing virological or immunological failure.
Lifetime Cost of HIV Care in France during the Era of Highly Active Antiretroviral Therapy
Authors: Yazdanpanah Yazdan , Goldie Sue J , Losina Elena , Weinstein Milton C , Lebrun Thérèse , Paltiel A David , Seage George R , Leblanc Garmenick , Ajana Faisa , Kimmel April D , Zhang Hong , Salamon Roger , Mouton Yves , Freedberg Kenneth A 
Published: April 2022

Objective To estimate the treatment and health care costs of HIV infection or AIDS in France during the era of highly active antiretroviral therapy (HAART). Design We used a clinical database of HIV-infected patients to calculate the resource use and cost of care for different stages of HIV infection. Costs were incorporated into a computer-based, probabilistic simulation model of the natural history and treatment of HIV infection to estimate the lifetime cost of treating patients with HIV disease. Setting A northern France HIV clinical cohort. Participants 1232 HIV-infected patients followed from January 1994 through July 1998. Results In the absence of an AIDS-defining event, the average total cost of care ranged from 670 euros (1 euro=US $1.19) per person-month in the highest CD4 stratum (>500/μl) to 1060 euros per person-month in the lowest CD4 stratum (≤50/μl). The mean cost of care was estimated at 3370 euros per person-month during the initial months around the occurrence of an AIDS-defining event; at 1750 euros per person-month during the period spanning from 2 months after the diagnosis of specific AIDS-defining event to 1 month prior to death; and at 13 010 euros per person-month in the final month prior to death. If clinical management of HIV infection began at a CD4 cell count of 378/μl, as in this cohort, the discounted lifetime cost of treating an HIV-infected French patient was estimated at 214 000 euros. The undiscounted costs were 309 000 euros over a projected life expectancy of 16.4 years. Conclusion The cost of HIV disease varies widely depending upon the stage of illness. These estimates of stage-specific and lifetime costs of HIV care will assist health policy planners in assessing the burden of disease in the era of HAART and projecting future resource requirements.
Dynamics of the Pool of Infected Resting Cd4 Hla-Dr- T Lymphocytes in Patients Who Started a Triple Class Five-Drug Antiretroviral Regimen During Primary HIV-1 Infection
Authors: Sankatsing Sanjay UC , van Praag Rieneke ME , van Rij Ronald P , Rientsma Ronald , Jurriaans Suzanne , Lange Joep MA , Prins Jan M , Schuitemaker Hanneke 
Published: April 2022

Starting standard antiretroviral therapy within 10 days after the onset of a primary HIV-1 infection cannot prevent the establishment of a reservoir of HIV-1-infected memory CD4 T cells. Here we studied the reservoir of HIV-1-infected memory CD4 T cells in four patients who started a triple class, five-drug regimen during primary HIV-1 infection. There was a strong correlation between the proportion of productively infected CD4 HLA-DR- T lymphocytes and plasma HIV-1 RNA levels (r=0.852; P<0.001) during the first 24 weeks of therapy. Within 45 weeks of treatment, in three of the four patients the proportion of productively infected CD4 HLA-DR- T lymphocytes was reduced below the level of quantification. In the fourth patient the cellular reservoir remained quantifiable. In two patients who stopped therapy 44 weeks after initiation an immediate rebound of the plasma HIV-1 RNA level and the proportion of productively infected CD4 HLA-DR– T lymphocytes occurred. In conclusion, initiation of a potent five-drug, triple class regimen during primary HIV-1 infection does not result in virus-specific immune control upon discontinuation of therapy after 44 weeks. Therefore, longer or even stronger suppression of viral replication might be necessary to achieve this goal in primary HIV-1 infection.
Administration of Indinavir and Low-Dose Ritonavir (800/100 Mg Twice Daily) with Food Reduces Nephrotoxic Peak Plasma Levels of Indinavir
Authors: Aarnoutse Rob E , Wasmuth Jan-Christian , Fätkenheuer Gerd , Schneider Katrin , Schmitz Karina , de Boo Theo M , Reiss Peter , Hekster Yechiel A , Burger David M , Rockstroh Jürgen K 
Published: April 2022

Background The objective of this study was to compare indinavir peak plasma (Cmax) values after administration of indinavir/ritonavir 800/100 mg on an empty stomach or with food. High indinavir Cmax values have been associated with indinavir-related nephrotoxicity. Methods This was an open-label, randomized, two-treatment, two-period, cross-over pharmacokinetic study performed at steady state. HIV-infected patients who had been using indinavir/ritonavir 800/100 mg twice daily for at least 4 weeks were randomized to take this combination with a light breakfast (two filled rolls and 130 ml of fluid) on a first study day, and without food on a second day, or in the reverse order. The pharmacokinetics of indinavir and ritonavir were assessed after plasma and urine sampling during 12 h. Results Data for nine patients were evaluated. Administration of indinavir/ritonavir 800/100 mg on an empty stomach resulted in a higher indinavir Cmax [geometric mean (GM) ratio – fasting/fed and 95% confidence interval (CI): 1.28 (1.08–1.52), P=0.01] and a trend to a shorter indinavir tmax ( P=0.07) compared to administration with food. The mode of administration of indinavir/ritonavir did not affect plasma indinavir Cmin and AUC values, parameters that have been associated with the antiviral efficacy of indinavir, nor the urinary excretion of indinavir. Conclusions Administration of indinavir/ritonavir 800/100 mg on an empty stomach results in a higher indinavir Cmax compared to ingestion with a light meal. Stated the other way round, intake with a light meal reduces indinavir Cmax, which probably reflects a food-induced delay in the absorption of indinavir. It is recommended to administer indinavir/ritonavir 800/100 mg with food, as a possible means to prevent indinavir-related nephrotoxicity in patients who start or continue with this regimen.
Modest Decreases in Nnrti Susceptibility Do Not Influence Virological Outcome in Patients Receiving Initial Nnrti-Containing Triple Therapy
Authors: Harrigan P Richard , Hertogs Kurt , Verbiest Werner , Larder Brendan , Yip Benita , Brumme Zabrina L , Alexander Christopher , Tilley Jessica , O'Shaughnessy Michael V , Montaner Julio SG 
Published: April 2022

Objective To assess the prevalence of modest (<10-fold) decreases in baseline non-nucleoside reverse transcriptase inhibitor (NNRTI) susceptibility and their impact on virological response to NNRTI-containing triple therapy in drug-naive individuals. Methods Baseline HIV resistance phenotype, genotype and response to therapy were examined retrospectively for all antiretroviral-naive individuals initiating therapy with two nucleoside analogues and an NNRTI in British Columbia, Canada, between 05/1997 and 08/1999 ( n=279), followed until July 31 2001. Time to viral suppression (first of at least two consecutive plasma viral loads <400 copies HIV RNA copies/ml) and viral rebound (to ≥400 copies/ml after first pVL <400 copies HIV RNA copies/ml), were estimated by Kaplan-Meier methods. Multivariate analyses were performed using Cox proportional hazards regression. Results Nevirapine was the most commonly prescribed NNRTI (96%). Four- to 10-fold decreased susceptibility to NNRTIs was observed in >30% of untreated individuals at baseline, an observation strongly driven by decreased susceptibility to delavirdine (22.4%). A >10-fold decrease in susceptibility to any NNRTI was observed only rarely (<2%). There was no association between four- and 10-fold decreased baseline susceptibility to NNRTIs and virological outcome ( P>0.05). In multivariate analyses, the strongest predictors of poor virological response to NNRTI-based therapy were baseline plasma viral load and the proportion of time on therapy in the first year of follow-up. There was no relationship between the presence of previously reported mutations associated with decreased NNRTI susceptibility (at codons 135 and 283 in HIV reverse transcriptase) and virological response. Conclusions These data suggest that the clinically significant level of resistance to NNRTIs, particularly nevirapine, in drug-naive individuals is likely greater than four- to 10-fold.
Intracellular Disposition and Metabolic Effects of Zidovudine, Stavudine and Four Protease Inhibitors in Cultured Adipocytes
Authors: Janneh Omar , Hoggard Patrick G , Tjia John F , Jones Simon P , Khoo Saye H , Maher Bridget , Back David J , Pirmohamed Munir 
Published: April 2022

Objective The pathogenesis of lipodystrophy caused by the HIV protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) is unclear. We have investigated the disposition of these drugs in adipocytes and the consequent effect on adipocyte metabolism and viability. Design Laboratory study utilizing two murine cell lines, 3T3-L1 and 3T3-F442A. Methods Intracellular NRTI phosphate and PI concentrations were determined by HPLC and HPLC-MS/MS, respectively. The cytotoxicity of the drugs was examined on the different adipogenic stages together with their effects on glucose uptake plus or minus insulin, and on glycerol and triglyceride levels. Results There was rapid intracellular accumulation and phosphorylation of [3H]-zidovudine and -stavudine to their phosphate metabolites in adipocytes. The NRTIs were not cytotoxic, did not affect preadipocyte protein synthesis and did not inhibit adipogenesis or induce lipolysis. PIs accumulated in adipocytes (nelfinavir>saquinavir>ritonavir>indinavir). All PIs, except indinavir, were cytotoxic and inhibited adipogenesis, increased lipolysis and impaired preadipocyte protein synthesis. PIs inhibited glucose uptake in the rank order: indinavir>saquinavir>ritonavir>nelfinavir. Conclusion These data demonstrate that PIs may play a role in the insulin resistance observed in lipodystrophy by affecting glucose uptake, adipogenesis and lipolysis. NRTIs alone do not seem to have any effect on adipocyte metabolism despite undergoing phosphorylation to their triphosphorylated anabolites, although their effects in combination with PIs in perturbing adipocyte metabolism warrants further investigation.
Uridine Abrogates Mitochondrial Toxicity Related to Nucleoside Analogue Reverse Transcriptase Inhibitors in Hepg2 Cells
Authors: Walker Ulrich A , Venhoff Nils , Koch Eva C , Olschewski Manfred , Schneider Josef , Setzer Bernhard 
Published: April 2022

Objective To assess in vitro if uridine may be suitable to prevent or treat mitochondrial toxicity related to nucleoside analogue reverse transcriptase inhibitors (NRTIs). Methods Human HepG2-hepatocytes were exposed to NRTIs with or without uridine for 25 days. Cell growth, lactate production, intracellular lipids, mitochondrial DNA (mtDNA) and the ratio between the respiratory chain components COX II (mtDNA-encoded) and COX IV (nuclear-encoded) were measured. Results HepG2 cells exposed to zalcitabine (177 nM) without uridine developed a severe depletion of mtDNA (to 8% of wild-type mtDNA levels), resulting in a decline of cell proliferation and COX II levels, with increased lactate and lipid accumulation. Uridine fully abrogated the adverse effects of zalcitabine on hepatocyte proliferation and normalized lactate synthesis, intracellular lipids and COX II levels by adjusting mtDNA levels to about 65% of NRTI-unexposed control cells. This effect was dose-dependent, with a maximum at 200 μM of uridine. Uridine also rapidly and fully restored cell function when added to cells with established mitochondrial dysfunction (zalcitabine for 15 days) despite continued zalcitabine exposure. Uridine also normalized cell proliferation in HepG2 cells exposed to 36 μM of stavudine and protected HepG2-cells exposed to 7 μM of zidovudine + 8 μM of lamivudine (pyrimidine analogues), but failed to improve cell function or mtDNA in cells exposed to 11.8 or 118 μM of didanosine (a purine analogue). Conclusions The pyrimidine precursor uridine may attenuate the mitochondrial toxicity of antiretroviral pyrimidine NRTIs in vitro, and its supplementation may represent a promising strategy in the prevention or treatment of mitochondrial toxicities in HIV-infected patients.
Monitoring the Emergence of Hepatitis B Virus Polymerase Gene Variants during Lamivudine Therapy in Human Immunodeficiency Virus Coinfected Patients: Performance of Clip™ Sequencing and Line Probe Assay
Authors: Roque-Afonso Anne-Marie , Férey Marie-Pierre , Mackiewicz Vincent , Fki Lamia , Dussaix Elisabeth 
Published: April 2022

Sera from 12 patients infected with human immunodeficiency virus and hepatitis B virus (HBV), on lamivudine as part of an antiretroviral therapy, were retrospectively analysed for the presence of HBV polymerase mutations by the line probe assay, INNO-LiPA HBV DR, and by the direct sequencing assay, TRUGENE™ HBV genotyping kit. Results at codons 180, 204 and 207 were compared for 44 samples. Full concordance was observed for 81.4% of the 129 analysed codons. Discordance involved only mixed populations: LiPA detected additional species in 19 codons and TRUGENE in five. Viral breakthrough occurred in seven patients, 12-33 months after lamivudine initiation. In five cases with close sampling available, both assays detected mutations before the rise in viral load, although earlier by LiPA for three patients. The time interval between the first mutant detection and viral escape ranged from 2 to 22 months. Mutations were detected in four of the five remaining patients: 1) at therapy initiation in a primary non-responder; 2) after 37 months, but replication became undetectable after tenofovir introduction; 3) transiently at 6 months by LiPA but treatment was ceased thereafter; 4) after 23 months but replication levels remained low during a 5-year follow-up. Interestingly, TRUGENE sequencing identified on late samples from three patients a variant carrying rtV173L plus rtL180M plus M204V mutations, having the in vitro characteristics of ‘vaccine escape’ mutants. Both assays appear to be valuable tools for the early detection of mutated HBV strains. The detection of genotypic resistance could improve therapeutic decision-making, although clinical or other virological factors may determine the rapidity of the viral breakthrough.