bluuebunny/crossref_metadata_2025_split huggingface dataset:
Once-Daily Dosing of Saquinavir Soft-Gel Capsules and Ritonavir Combination in HIV-1-Infected Patients (Imea015 Study)
Authors: Lamotte Claire , Landman Roland , Peytavin Gilles , Mentre France , Gerbe Juliette , Brun-Vezinet Françoise , Boue François , Spiridon Gabriella , Valantin Marc-Antoine , Michelet Christian , Farinotti Robert , Yeni Patrick 
Published: April 2022

This was a prospective pilot study evaluating a saquinavir (SQV) soft-gel capsules (SGC)/ritonavir (RTV)-containing once-daily regimen over a follow-up of 3 months. The primary end-point was to determine the number of patients both remaining on treatment at month 3 and with trough SQV plasma concentration 24 h after the last intake (C24h) exceeding the inhibition of 95% of viral replication in vitro (IC95). The secondary end-points were to investigate the immuno-virological efficacy and safety of SQV-SGC/RTV once daily, and to explore SQV concentrations in peripheral blood mononuclear cells (PBMCs). Twenty-three antiretroviral-naive and 17 protease inhibitors (PIs) experienced HIV-1-infected patients with plasma HIV-1 RNA level below 200 copies/ml were enrolled. They were assigned to SQV-SGC/RTV (1600/100 mg once daily) combined with nucleoside and/or non-nucleoside reverse transcriptase inhibitors. In a subgroup of 13 patients, both plasma and intracellular SQV concentrations were determined. By intent to treat analysis the percentage of success at month 3 was 87.5% (confidence interval: 73.2–95.8%) with 78.3% in naive and 100% in PI-experienced patients. SQV C24h and intracellular concentrations [median (range, n)] were 241 ng/ml (40–1209, 35) and 323 ng/ml (168–475, 12), respectively. Intracellular concentrations showed an accumulation of SQV in PBMCs persisting during 24 h. Neither immunological nor virological failure was observed. Clinical and biological tolerance was acceptable in all patients but three with adverse effects leading to discontinuation. These data confirmed the short-term efficacy of SQV-SGC/RTV once-daily regimen based on SQV therapeutic drug monitoring. This work was presented in part at the 2nd International Conference on Clinical Pharmacology of HIV Infection, Noordwijk, the Netherlands, 2-4 April 2001 (Abstract 3.16); and at the 1st International Conference on HIV Pathogenesis & Treatment, Buenos Aires, Argentina, 8–11 July 2001 (Abstract 344).
Antiretroviral Treatment Alters Relationship between Mcp-1 and Neurometabolites in HIV Patients
Authors: Chang Linda , Ernst Thomas , Hillaire Coryse St , Conant Katherine 
Published: April 2022

Objective The relationships between neurometabolites and macrophage chemoattractant protein (MCP-1) in serum and cerebrospinal fluid (CSF) were evaluated in HIV patients before and after antiretroviral treatment. Design: Prior studies found higher CSF MCP-1 levels in patients with HIV-associated dementia compared to those in neuroasymptomatic. We hypothesized that CSF MCP-1 levels would correlate inversely to neuronal metabolites [including N-acetyl compounds, gluta-mate+glutamine, as assessed by principal component analyses (PCA)] and positively to glial metabolites (including myo-inositol and choline compounds). Methods Thirty-nine antiretroviral-naive HIV patients were evaluated prospectively with proton magnetic resonance spectroscopy (1H MRS), and serum and CSF MCP-1 measurements prior to highly active antiretroviral therapy (HAART); 31 of these patients completed follow-up studies after 3 months of HAART but only 24 had follow-up CSF studies. Results After HAART, brain metabolites and clinical signs showed no change despite improvements in systemic (CD4 counts, plasma viral load, MCP-1) and CSF (viral load and MCP-1) variables. CSF, but not serum, MCP-1 levels correlated inversely with the neuronal component (from PCA) prior to treatment ( r=-0.59, P=0.0008). Conversely, after 3 months of HAART, the glial component (from PCA) correlated positively with CSF MCP-1 levels ( r=0.70, P=0.0002; ANCOVA interaction for treatment status, P=0.003). Conclusions These findings suggest that higher CSF MCP-1 levels are associated with neuronal dysfunction in untreated patients. After 3 months of HAART, the decreased systemic factors (viral burden, systemically derived MCP-1) no longer associate with neuronal dysfunction, but subjects with the strongest glial response in the brain continue to produce the highest levels of MCP-1.
Genotypic Determinants of the Virological Response to Tenofovir Disoproxil Fumarate in Nucleoside Reverse Transcriptase Inhibitor-Experienced Patients
Authors:   the ANRS AC11 Resistance study group, Masquelier Bernard , Tamalet Catherine , Montès Brigitte , Descamps Diane , Peytavin Gilles , Bocket Laurence , Wirden Marc , Izopet Jacques , Schneider Véronique , Ferré Virginie , Ruffault Annick , Palmer Pierre , Trylesinski Aldo , Miller Michael , Brun-Vézinet Françoise , Costagliola Dominique 
Published: April 2022

Objective To assess the genotypic determinants of the virological response to tenofovir disoproxil fumarate (TDF) in a multicentre cohort of antiretroviral (ARV)-experienced patients receiving TDF as a part of a salvage therapy. Methods HIV-1 genotype was assessed at baseline in a subgroup of 161 patients of the French expanded access program receiving a stable TDF-including regimen for 3 months or more. Reverse transcriptase mutations associated with the viral load decrease at month 3 with a P-value <0.15 were retained for the construction of a mutation score. The score was then validated using a multivariate analysis and bootstrap resampling method. Results The strongest association with decrease in viral load was observed with a set of seven mutations (TDF mutation score) that consisted of M41L, E44D, D67N, T69D/N/S, L74V, L210W and T215Y/F RT mutations. The RT K65R mutation and the insertions at codon 69 were not included in the analysis due to low prevalences. A TDF mutation score of ≤2 predicted the absence of resistance to TDF and ≥6 mutations predicted resistance to TDF with corresponding reductions in viral load of –1.3 ±1.1, and +0.1 ±0.7 log10 copies/ml, respectively. In patients with a TDF mutation score of 3–5, the decrease in viral load was –0.8 ±1.0 log10 copies/ml and was considered possibly resistant. In the multivariate analysis, a TDF mutation score ≥6, previous use of amprenavir, indinavir and lopinavir, and co-prescription of didanosine were associated with a worse virological response. The bootstrap analysis showed the robustness of the TDF mutation score. Conclusion In ARV-experienced patients receiving TDF-containing regimens, a score derived from seven reverse transcriptase mutations was shown to be independently predictive of the virological response.
Safety and Efficacy of Once-Daily Didanosine, Tenofovir and Nevirapine as a Simplification Antiretroviral Approach
Authors: Negredo Eugènia , Moltó José , Muñoz-Moreno José Antonio , Pedrol Enric , Ribera Esteve , Viciana Pompeyo , Galindo M José , Miralles Celia , Burger David , Fumaz Carmina Rodriguez , Puig Jordi , Gel Sílvia , Rodríguez Eva , Videla Sebastià , Ruiz Lidia , Clotet Bonaventura 
Published: April 2022

Objective To assess the efficacy and safety of a once-daily antiretroviral regimen in HAART-experienced subjects with long-lasting viral suppression. Methods One-hundred-and-sixty-nine patients with chronically suppressed viral load (limit of detection <50 copies/ml) were recruited. Based on patient willingness to simplify treatment, 84 of them continued receiving their usual treatment (BID Group) and 85 switched to once-daily didanosine/tenofovir/nevirapine (QD Group) in a non-randomized fashion. Results At week 48, the proportion of patients with viral suppression in the QD and in the BID Group, respectively, was 97 vs 100% in the per-protocol analysis ( P=0.497), and 76 vs 86% for the intention-to-treat analysis ( P=0.176). Nevertheless, CD4 count decreased in the QD Group, with a mean decline of 95 cells/mm3 (95% CI: 45–145). Twelve subjects in the QD Group (14%) discontinued treatment due to adverse events, mainly nevirapine-related hepatitis (6%). No significant differences regarding the rate of acute pancreatitis or peripheral neuropathy were observed between both groups. A significant improvement in the lipid profile was only seen in the QD Group. High levels of adherence were observed in both groups during follow-up, as well as a good quality of life. At week 48, a reduction in effort to take medication ( P≤0.001) and an increment in the satisfaction with the treatment ( P<0.001) was only seen in the QD group. No differences were observed in median nevirapine trough levels between patients on twice-daily nevirapine at baseline (4820 ng/ml) and subjects in the QD Group (6090 ng/ml, P=0.30). Conclusion Treatment simplification to a once-daily antiretroviral regimen based on didanosine, tenofovir and nevirapine may be a valid approach in HIV-infected subjects with long-lasting viral suppression. Combination of standard doses of didanosine and tenofovir may have contributed to the CD4 cell decline observed with this QD regimen.
Construction, Training and Clinical Validation of An Interpretation System for Genotypic HIV-1 Drug Resistance Based on Fuzzy Rules Revised by Virological Outcomes
Authors: Luca Andrea De , Vendittelli Marilena , Baldini Francesco , Giambenedetto Simona Di , Trotta Maria Paola , Cingolani Antonella , Bacarelli Alessandra , Gori Caterina , Perno Carlo Federico , Antinori Andrea , Ulivi Giovanni 
Published: April 2022

Objectives To evaluate whether fuzzy operators can be usefully applied to the interpretation of genotypic HIV-1 drug resistance by experts, and to improve the prediction of salvage therapy outcome by adapting interpretation rules of genotypic resistance on the basis of their association with virological response data. Methods We used a clinical dataset of 231 patients failing highly active antiretroviral therapy (HAART) and starting salvage therapy with baseline resistance genotyping and virological outcomes after 3 and 6 months. A set of rules predicting genotypic resistance was initially derived from an expert (ADL). Rules were implemented using a fuzzy logic approach and the virological outcomes dataset used for the training phase. The resulting algorithm was validated using a separate set of 184 selected patients by correlating the resulting predicted activity with observed virological response at 3 months. For comparison, the expert systems from the drug resistance group of the Agence Nationale de Recherches sur le SIDA (ANRS-AC11) and the algorithm from the Stanford's HIV drug resistance database (Stanford HIVdb) were evaluated on the same set. Results The starting algorithm had a correlation with virological outcomes of R2=0.06 ( P=0.0001). After the training phase the correlation with virological outcomes increased to R2=0.19 ( P<0.000001). In the validation set of patients, the activity of the salvage regimen predicted by the fuzzy algorithm was the only variable independently predictive of the 3-month viral load change even after adjusting by the activity predicted by the two expert systems and baseline viral load (for each 10% salvage regimen's activity increase, mean HIV RNA change from baseline: -0.27 log10 copies/ml; 95% CI -0.39, -0.15). Conclusion Using fuzzy operators in a virological outcomes training database to implement a rules-based algorithm for genotypic resistance interpretation, significant improvements of outcomes prediction were obtained. The resulting algorithm showed an independent predictive capability of virological outcomes over that of two rules-based interpretation algorithms made by experts. Although the system was trained and validated on a limited number of cases, the approach deserves further evaluation. Presented in part at the XI International Drug Resistance Workshop, Seville, Spain 2002 [Abstract 85]. Antiviral Therapy 2002; 7:S71.
Gynaecomastia in HIV-Infected Men on Highly Active Antiretroviral Therapy: Association with Efavirenz and Didanosine Treatment
Authors:   for the Grupo Andaluz para el Estudio de las Enfermedades Infecciosas (GAEI), Mira José A , Lozano Fernando , Santos Jesús , Ramayo Emilia , Terrón Alberto , Palacios Rosario , León Eva M , Márquez Manuel , Macías Juan , Fernández-Palacín Ana , Gómez-Mateos Jesús , Pineda Juan A 
Published: April 2022

Background Gynaecomastia has been described in HIV-infected men undergoing highly active antiretroviral therapy (HAART). However, there are insufficient data on the relationship between gynaecomastia and any specific antiretroviral drug and hormone abnormality. Objective To assess the frequency of gynaecomastia in HIV-infected men receiving HAART and its association with antiretroviral drugs and hormone abnormalities. Methods We carried out a prospective study of 1304 HIV-infected men undergoing HAART. In addition, we included a case (with gynaecomastia)-control (without gynaecomastia) analysis in the second part of this study. Cases and controls were matched according to age, HIV infection CDC clinical category, HCV infection, the date of study and the physician responsible for the patient. Patients bearing known causes of gynaecomastia were excluded. We analysed epidemiological, clinical, haematological and immunological characteristics and the use and duration of the antiretroviral therapy. In 13 cases and 13 controls a sexual hormone profile was carried out. Results A total of 30 (2.3%) HIV-infected men presented with gynaecomastia of unexplained cause. In 22 (73%) of these individuals, gynaecomastia completely resolved after a median time of 9 months (range: 5–22 months). The percentage of individuals who were receiving efavirenz and didanosine at the time of the study was higher among patients with gynaecomastia [57% vs 17% ( P=0.004) and 50% vs 13% ( P=0.003), respectively]. Plasma total testosterone, free testosterone index and bioavailable testosterone levels were lower in patients with gynaecomastia, whereas plasma free testosterone levels were not significantly different in either population. Conclusions Gynaecomastia is not uncommon in HIV-infected men undergoing HAART and it is usually transient. Efavirenz and didanosine treatment are associated with the emergence of gynaecomastia. An underlying hypoandrogenism seems to contribute to the emergence of this disorder in these patients.
The Plasma and Intracellular Steady-State Pharmacokinetics of Lopinavir/Ritonavir in HIV-1-Infected Patients
Authors: Crommentuyn Kristel ML , Mulder Jan W , Mairuhu Albert TA , van Gorp Eric CM , Meenhorst Pieter L , Huitema Alwin DR , Beijnen Jos H 
Published: April 2022

Therapeutic drug monitoring of protease inhibitors (PIs) is usually performed on plasma samples although their antiretroviral effect takes place inside cells. Little is known, however, about the intracellular accumulation and related plasma pharmacokinetics of PIs such as lopinavir/ritonavir (LPV/RTV). Therefore, we studied the plasma and intracellular (cell-associated) steady-state pharmacokinetics of this PI combination in a dosage of 400/100 mg twice daily in a non-randomized cohort of HIV-1-infected individuals. Plasma (0–12 h) and peripheral blood mononuclear cell (PBMC; 0–8 h) samples were drawn during a 12-h dosing interval in 11 subjects. The plasma concentrations versus time curves of LPV and RTV were characterized by an irregular absorption phase showing double-peaks (Cmax) in most subjects and single-peaks in the remaining patients between 1 and 3 h after drug intake. Pre-dose concentrations of both agents in plasma were significantly higher than the concentrations at the end of the dosing interval indicating the presence of a circadian rhythm in their pharmacokinetics. The course of the intracellular concentrations versus time curves appeared to be similar to the plasma concentration curves, with the highest intracellular concentration measured 3 h after drug intake. The intracellular RTV concentrations were higher than reported in vitro EC50 values and might therefore contribute to the antiretroviral effect of LPV/RTV. The median intracellular-to-plasma concentration ratios (interquartile range) were 1.18 (0.74–2.06) and 4.59 (3.20–7.70) for LPV and RTV, respectively. In conclusion, both LPV and RTV accumulate to potential therapeutic concentrations in PBMCs. Irregular absorption and circadian plasma clearance patterns were observed for the PI combination LPV/RTV.
Lack of Interferon Sensitivity-Determining Region in the Genome of Hepatitis B Virus Genotype Ba
Authors: Liu Chun-Jen , Chen Pei-Jer , Lai Ming-Yang , Chen Ting-Chih , Wang Hurng-Yi , Huang Wen-Ling , Kao Jia-Horng , Chen Ding-Shinn 
Published: April 2022

Background/aims In chronic hepatitis B, both host and viral factors may predict the response to interferon (IFN) treatment. Whether IFN sensitivity-determining regions exist within the hepatitis B virus (HBV) genomic background remains largely unknown. We therefore performed full-length viral genomic comparison between HBVs obtained from IFN responders and non-responders. Methods We enrolled 18 HBV genotype Ba patients who had received 24-week IFN 5 MU three times weekly and were followed monthly for 12 months post-treatment. There were 10 responders and eight non-responders. Pretreatment full-length viral nucleotide consensus sequence was obtained. In six non-responders and four responders, post-treatment viral nucleotide sequence was further compared with their corresponding pre-treatment specimens. In addition, the average number of nucleotide substitutions of the HBV quasispecies was compared between three responders and three non-responders. Results HBV nucleotide consensus sequence was identical between responders and non-responders. We found 0–15 (mean 7.7) nucleotide substitutions in the post-treatment HBV genome in the six non-responders and 0–14 (mean 3.8) nucleotide substitutions in the four responders, respectively. Genetic complexity of HBV quasispecies was comparable between responders and non-responders. Conclusions Our results suggest that an IFN sensitivity-determining region might not exist within the genome of HBV genotype Ba. Host factors and virus–host interactions may be more important in determining the response to IFN treatment.
Antiretroviral Drugs with Adverse Effects on Adipocyte Lipid Metabolism and Survival Alter the Expression and Secretion of Proinflammatory Cytokines and Adiponectin In Vitro
Authors: Lagathu Claire , Bastard Jean-Philippe , Auclair Martine , Maachi Mustapha , Kornprobst Michel , Capeau Jacqueline , Caron Martine 
Published: April 2022

Objective The lipodystrophy syndrome is a major adverse effect of highly active antiretroviral therapy (HAART), associated with altered circulating levels and adipose tissue mRNA expression of proinflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor (TNF)α, and adiponectin. Proinflammatory cytokines and adiponectin, which are secreted by adipose tissue, regulate fat metabolism, insulin sensitivity and adipose cell apoptosis. We examined the direct effects of individual antiretrovirals on lipid metabolism and cytokine and adiponectin production by cultured adipocytes. Methods Differentiating 3T3-F442A cells and differentiated 3T3-L1 adipocytes were treated for 12 or 4 days, respectively, with protease inhibitors (PIs) indinavir, nelfinavir, amprenavir, lopinavir and ritonavir, or nucleoside reverse transcriptase inhibitors (NRTIs) stavudine and zidovudine, at near-Cmax concentrations. Lipid metabolism was estimated by Oil Red O staining of intracellular lipids, mRNA expression of fatty acid synthase and adipocyte lipid binding protein 2, and insulin activation of lipogenesis. Apoptosis was estimated by flow cytometry. The expression and secretion of proinflammatory cytokines (IL-6, TNFα and IL-1β) and adiponectin were evaluated by real-time reverse transcription PCR and ELISA. Results Chronic treatment of 3T3-F442A differentiating adipocytes and differentiated 3T3-L1 adipocytes with PIs and NRTIs reduced lipid accumulation, mRNA expression of lipid markers and insulin-induced lipogenesis. IL-6, TNFα, IL-1β and adiponectin expression and secretion were markedly altered in differentiating 3T3-F442A adipocytes. PIs had either no effect on differentiated 3T3-L1 adipocytes (TNFα expression and secretion) or their effect was less marked than in 3T3-F442A cells. Indinavir and amprenavir did not alter cytokine secretion and expression by mature adipocytes. The effects of stavudine and zidovudine on differentiating and mature adipocytes were similar, despite the difference in treatment procedure. The drugs with the strongest effect on TNFα expression also increased adipocyte apoptosis, in contrast to the drugs that only moderately increased TNFα expression. Conclusions These results suggest that increased cytokine and decreased adiponectin secretion and expression induced by some PIs and NRTIs may contribute to the adipose tissue loss (via apoptosis and lipid leakage) and insulin resistance associated with the lipodystrophy syndrome.
Low-Dose Hepatitis B Immune Globulin and Higher-Dose Lamivudine Combination to Prevent Hepatitis B Virus Recurrence after Liver Transplantation
Authors: Karasu Zeki , Ozacar Tijen , Akyildiz Murat , Demirbas Tolga , Arikan Cigdem , Kobat Arzu , Akarca Ulus , Ersoz Galip , Gunsar Fulya , Batur Yucel , Kilic Murat , Tokat Yaman 
Published: April 2022

Post-transplant prevention of hepatitis B virus (HBV) infection is based on treatment with lamivudine and/or hepatitis B immune globulin (HBIG). However, optimum doses and duration for these drugs are not yet clear. We tested high doses of lamivudine (300 mg/day) in combination with low doses of HBIG (200–400 IU/2–4 weeks). Eighty patients who had post-transplant prophylaxis of lamivudine and HBIG were included in the study. Of those, 20 had hepatitis D virus co-infection and eight were HBV DNA-positive at the time of transplantation. Ten HBV DNA-positive patients were treated with lamivudine (150 mg/day) before transplantation; all were HBV DNA-negative after lamivudine treatment. All patients in the anhepatic phase were given 4000 IU of HBIG. Following this, 400 or 800 IU HBIG was administered intramuscularly daily for 5–10 days post-transplantation and 2–4 times weekly thereafter, according to serum titre of antibodies to hepatitis B surface antigen (anti-HBs). Lamivudine was maintained or initiated at the time of transplantation and was continued indefinitely. Median follow-up was 21 months (range 3–73 months). Recurrence of hepatitis B surface antigen (HBsAg)-positivity occurred in only three out of 78 (4%) patients; two of these three were HBV DNA-positive. Median anti-HBs titre at the final follow-up was 68 IU. Patient and graft survival was 85% at 1 year. In conclusion, a combination of lamivudine 300 mg/day and low-dose HBIG prevents post-transplantation recurrence of hepatitis B, even in the presence of viral replication in the pre-transplant period.