bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nevirapine Concentrations in HIV-Infected Children treated with Divided Fixed-Dose Combination Antiretroviral Tablets in Malawi and Zambia
Authors: Ellis Jane C , L'homme Rafaëlla FA , Ewings Fiona M , Mulenga Veronica , Bell Frank , Chileshe Regina , Molyneux Elizabeth , Abernethy Julia , Van Oosterhout Joep JG , Chintu Chifumbe , Walker A Sarah , Gibb Diana M , Burger David M 
Published: April 2022

Objective To investigate nevirapine concentrations in African HIV-infected children receiving divided Triomune tablets (stavudine+lamivudine+nevirapine). Design Cross-sectional study. Methods Steady-state plasma nevirapine concentrations were determined in Malawian and Zambian children aged 8 months to 18 years receiving Triomune in routine outpatient settings. Predictors from height-for-age, body mass index (BMI)-for-age, age, sex, post-dose sampling time and dose/m2/day were investigated using centre-stratified regression with backwards elimination ( P<0.1). Results Of the 71 Malawian and 56 Zambian children (median age 8.4 vs 8.5 years, height-for-age -3.15 vs -1.84, respectively), only 1 (3%) of those prescribed ≥300 mg/m2/day nevirapine had subtherapeutic concentrations (<3mg/l) compared with 22 (23%) of those prescribed <300 mg/m2/day; most children with subtherapeutic nevirapine concentrations were taking half or quarter Triomune tablets. Lower nevirapine concentrations were independently associated with lower height-for-age (indicating stunting) (0.37 mg/l per unit higher [95% confidence interval (CI): -0.003, +0.74]; P=0.05), lower prescribed dose/m2 (+0.89 mg/l per 50mg/m2 higher [95% CI: 0.32, 1.46]; P=0.002) and higher BMI-for-age (indicating lack of wasting) (-0.42mg/l per unit higher [95% CI: -0.80, -0.04]; P=0.03). Conclusions Currently available adult fixed-dose combination tablets are not well suited to children, particularly at younger ages: Triomune 30 is preferable to Triomune 40 because of the higher dose of nevirapine relative to stavudine. Further research is required to confirm that concentrations are reduced in stunted children but increased in wasted children. Development of appropriate paediatric fixed-dose combination tablets is essential if antiretroviral therapy is to be made widely available to children in resource-limited settings.
Clinical Validation of Saquinavir/Ritonavir Genotypic Resistance Score in Protease-Inhibitor-Experienced Patients
Authors: Marcelin Anne-Genevieve , Flandre Philippe , De Mendoza Carmen , Roquebert Benedicte , Peytavin Gilles , Valer Luisa , Wirden Marc , Abbas Sarah , Katlama Christine , Soriano Vincent , Calvez Vincent 
Published: April 2022

Objective To identify a genotypic score for resistance to saquinavir boosted with ritonavir (SQV/r; 1,000/100 mg twice daily)-based regimens in protease inhibitor (PI)-experienced patients. Methods One-hundred and fifty-one PI-experienced patients receiving a SQV/r-containing regimen were enrolled retrospectively. The virological response (VR) was defined as the decrease in HIV RNA at months 3–5. The effect of each mutation in the protease gene on the VR to SQV/r regimen was assessed using non-parametric univariate analyses and then a step-by-step analysis was carried out using a Jonckheere-Tepstra (JT) non-parametric test to retain the group of mutations most strongly associated with VR. Results Among the 138 patients with detectable plasma SQV, the median VR was -1.48 [range: -4 to +1.2] log10 copies/ml. Changes at 12 codons were associated with a reduced VR to SQV/r: codons 10, 15, 20, 24, 46, 54, 62, 71, 73, 82, 84 and 90. The JT procedure led to selection of the following genotypic score, 10+15+20+ 24+62+73+82+84+90, as providing the strongest association with VR. In the 35 patients with none of the mutations in this score, the median decrease in HIV RNA was -2.24 log10 copies/ml and it was -1.88 ( n=29), -1.43 ( n=24), -0.52 ( n=30), -0.18 ( n=9), -0.11 ( n=6) and -0.30 ( n=5) log10 copies/ml in those with 1, 2, 3, 4, 5 and 6 mutations, respectively. Conclusion With this resistance score to SQV/r, the isolates were classified as having no evidence of resistance (0–2), possible resistance (3) or resistance (≥4) by grouping the number of mutations in samples for which the viral load reduction was similar.
Amantadine-Oseltamivir Combination therapy for H5N1 Influenza Virus Infection in Mice
Authors: Ilyushina Natalia A , Hoffmann Erich , Salomon Rachelle , Webster Robert G , Govorkova Elena A 
Published: April 2022

Background The clinical management of H5N1 influenza virus infection in humans remains unclear. Combination chemotherapy with drugs that target different viral proteins might be more effective than monotherapy. Methods BALB/c mice were treated by oral gavage for 5 days with amantadine (1.5, 15 or 30 mg/kg/day) and oseltamivir (1 or 10 mg/kg/day) separately or in combination. Mice were challenged 24 h after initiation of treatment with 10 mouse 50% lethal doses of either amantadine-sensitive (having S31 in the M2 protein) or amantadine-resistant (having N31 in the M2 protein) recombinant A/Vietnam/1203/04 (H5N1) virus. Results Combination treatment with amantadine (15 or 30 mg/kg/day) and oseltamivir (10 mg/kg/day) provided greater protection (60% and 90%, respectively) against lethal infection with amantadine-sensitive H5N1 virus than did monotherapy. Moreover, spread of the virus to the brain was prevented by both combination regimens. The efficacy of the drug combinations against amantadine-resistant H5N1 virus was comparable to that of oseltamivir alone. Oseltamivir produced a dose-dependent effect against both recombinant H5N1 viruses ( P<0.05) but did not provide complete protection against lethal infection. Importantly, no mutations in the HA, NA and M2 proteins were detected when the two drugs were used in combination. Conclusions Combination chemotherapy provided a survival advantage over single-agent treatment of mice inoculated with neurotropic H5N1 influenza virus. This strategy might be an option for the control of pandemic influenza viruses that are sensitive to amantadine. Combinations that include other drugs should be explored.
High Doses of Stavudine Induce Fat Wasting and Mild Liver Damage without Impairing Mitochondrial Respiration in Mice
Authors: Igoudjil Anissa , Abbey-Toby Adjé , Begriche Karima , Grodet Alain , Chataigner Karine , Peytavin Gilles , Maachi Mustapha , Colin Marion , Robin Marie-Anne , Lettéron Philippe , Feldmann Gérard , Pessayre Dominique , Fromenty Bernard 
Published: April 2022

Objective Stavudine (d4T), a nucleoside reverse-transcriptase inhibitor (NRTI), can induce lipoatrophy, fatty liver, hyperlactataemia and abnormal liver tests. NRTI toxicity is usually ascribed to mitochondrial DNA (mtDNA) depletion and impaired mitochondrial respiration. However, NRTIs could have effects unrelated to mtDNA. Recently, we reported that 100 mg/kg/day of d4T stimulated fatty acid oxidation (FAO) in mouse liver, and reduced body fatness without depleting white adipose tissue (WAT) mtDNA. We hypothesized that higher d4T doses could further reduce adiposity, while inhibiting hepatic FAO. Methods Mice were treated for 2 weeks with d4T (500 mg/kg/day), L-carnitine (200 mg/kg/day) or both drugs concomitantly. Body fatness was assessed by dual energy X-ray absorptiometry, and investigations were performed in plasma, liver, muscle and WAT. Results D4T reduced the gain of body adiposity, WAT leptin, whole body FAO and plasma ketone bodies, and increased liver triglycerides and plasma aminotransferases with mild ultrastructural abnormalities in hepatocytes. Plasma lactate and respiratory chain activities in tissues were unchanged. Stearoyl-CoA desaturase (SCD-1), an enzyme negatively regulated by leptin, was overexpressed in liver. High doses of β-aminoisobutyric acid (BAIBA), a d4T catabolite, increased plasma ketone bodies. Although L-carnitine did not correct body adiposity, it prevented d4T-induced impairment of FAO and liver abnormalities. Conclusions D4T overdosage triggers fat wasting, leptin insufficiency and mild liver damage, without causing respiratory chain dysfunction. Overexpression of SCD-1 reduces fatty acid oxidation and overcomes the stimulating effect of BAIBA on hepatic FAO. L-carnitine does not correct leptin insufficiency but prevents d4T-induced impairment of FAO and liver damage.
Nevirapine-Based Antiretroviral Therapy Started Early in the Course of Tuberculosis Treatment in Adult Malawians
Authors: Van Oosterhout Joep JG , Kumwenda Johnstone J , Beadsworth Michael , Mateyu Gabriel , Longwe Temba , Burger David M , Zijlstra Eduard E 
Published: April 2022

Background The tuberculosis (TB) mortality rate of registered TB patients in Malawi is 23%, and 59% of the deaths occur in the first 2 months of treatment. HIV-related complications appear to be an important cause. Starting antiretroviral therapy early during tuberculosis treatment may improve outcome but problems often arise with drug interactions, adherence, toxicity and immune reconstitution disease (IRD). Methods We prospectively followed 27 HIV-infected adult Malawians after starting Triomune® (a generic fixed drug combination of stavudine, lamivudine and nevirapine) in the second week of tuberculosis treatment. Results At baseline, 88% had CD4+ T-cell counts <100 cells/ml, all were anaemic and 78% were malnourished. Five patients (19%) died, two withdrew consent and one stopped all drugs due to hepatitis. At 6 months, all but one of the 19 remaining patients had good virological results (16 patients: <400 copies/ml, two patients: <1,000 copies/ml) and the median CD4+ T cell increase was 170 cells/ml. Adverse events were numerous, particularly in the first 2 months. Suspected IRD episodes could be managed without treatment interruptions. During the lead-in phase, 59% of nevirapine plasma levels were sub-therapeutic despite good adherence, compared with only 14% during weeks 4 and 8. Conclusion It is feasible to start Triomune® early during TB treatment with good treatment outcome. The nevirapine lead-in phase should be avoided when rifampicin-based tuberculosis treatment is started >1 week beforehand.
Factors Associated with Early Hospital Discharge of Adult Influenza Patients
Authors: Lee Nelson , Chan Paul KS , Choi Kin Wing , Lui Grace , Wong Bonnie , Cockram Clive S , Hui David SC , Lai Raymond , Tang Julian W , Sung Joseph JY 
Published: April 2022

Background Understanding factors affecting length of hospital stay (LOS) in patients with severe influenza may improve their management. Methods A retrospective cohort study on laboratory-confirmed, adult influenza patients hospitalized in 2004 and 2005 was conducted. For all influenza cases during that period, immunofluorescence assay on nasopharyngeal aspirate was used for rapid diagnosis, and oseltamivir (75 mg twice daily for 5 days) prescribed if the patient presented within 2 days of symptom onset. Independent factors associated with time to discharge were identified using Cox proportional hazards models. An adjusted hazard ratio (aHR) >1 signifies a higher chance of early discharge. Viral shedding and influenza vaccination history were studied during one ‘flu’ season. Results A total of 356 patients (influenza A 93.5%) were studied. The majority of patients were old (70.2 ±8.4years), had ≥1 comorbid illness (69.1%) and developed respiratory or cardiovascular complications (69.4%). Oseltamivir initiated within 2 days of illness was associated with shorter total LOS (Kaplan-Meier estimated median 4 versus 6 days [-33%]; aHR for discharge 1.54, 95% confidence intervals [95% CI] 1.23–1.92, P<0.0001). Older age (≥70 years), comorbidities and complications were associated with prolonged LOS. Prolonged viral RNA detection >day 4 of illness (23 out of 99 consecutive patients) was also independently associated with longer LOS (aHR 0.36 [95% CI 0.19–0.71], P=0.003), whereas influenza vaccination within 6 months was associated with shorter LOS (aHR 2.14 [95% CI 1.18–3.85], P=0.012). Conclusion Our analyses suggest that timely oseltamivir treatment is independently associated with shorter LOS in patients hospitalized for severe influenza. Efforts to ensure early diagnosis and therapeutic intervention are warranted.
Three-Year Immune Reconstitution in PI-Sparing and PI-Containing Antiretroviral Regimens in Advanced HIV-1 Disease
Authors: Samri Assia , Goodall Ruth , Burton Catherine , Imami Nesrina , Pantaleo Giuseppe , Kelleher Anthony , Poli Guido , Gotch Frances , Autran Brigitte 
Published: April 2022

Background The long-term immunological benefit of protease inhibitor (PI)-sparing antiretroviral therapy (ART) using non-nucleoside reverse transcriptase inhibitors (NNRTIs) remains poorly investigated. Methods A total of 120 ART-naive, HIV-1-infected participants were included in the immunology substudy of INITIO, an international randomized trial comparing two NRTIs (didanosine + stavudine) combined with either: one NNRTI (efavirenz; EFV), one non-boosted PI (nelfinavir; NFV), or one NNRTI + one PI (EFV/NFV). CD4+ T-cell counts, HIV-1 plasma RNA load (VL), T-cell pheno-type, T-cell proliferation and IFN-γ production against opportunistic/recall and HIV-1 antigens/peptides were compared at baseline and at week (W) 96 and W156. Results Participants (37 EFV, 44 NFV, 39 EFV/NFV) had similar baseline VL; median CD4+ T-cell counts/mm3 were: 144 (64–303) EFV, 212 (42–313) NFV and 257 (86–331) EFV/NFV. At W156, the proportion of patients with VL ≤50 copies/ml was not different between the arms ( P=0.3). From baseline to W156 there was a significant increase in CD4+ T-cell counts ( P<0.001) and in naive CD4+ T cells ( P<0.001), with no difference between arms and percentages of total and activated CD8+ T cells decreased significantly ( P<0.001) in all arms. The decrease in activated memory CD4+T-cells was significantly greater in the EFV arm at W96 ( P=0.03) and W156 ( P=0.01), but did not persist after adjusting for baseline CD4+ T-cell counts. During follow-up, responses to opportunistic pathogens increased in all patients while specific T-cell responses to HIV-1-p24 and gp160 recombinant proteins or to Gag and Nef peptides were not restored. Conclusion Regimens using/sparing PIs provide similar levels of long-term immune reconstitution even in patients with low CD4+ T-cell counts.
The Independent Effect of Highly Active Antiretroviral Therapy on Severe Opportunistic Disease Incidence and Mortality in HIV-Infected Adults in Côte D'Ivoire
Authors: Losina Elena , Yazdanpanah Yazdan , Deuffic-Burban Sylvie , Wang Bingxia , Wolf Lindsey L , Messou Eugène , Gabillard Delphine , Seyler Catherine , Freedberg Kenneth A , Anglaret Xavier 
Published: April 2022

Background Studies in developed countries have shown highly active antiretroviral therapy (HAART) decreases incidence of severe opportunistic diseases (ODs) in HIV-infected patients beyond that which is expected from changes in CD4+T-cell count. Objective To estimate the independent impact of HAART on reducing ODs and mortality in Côte d'Ivoire. Methods Within two longitudinal studies of HIV-infected adults (1996–2003), we identified time on ‘cotrimoxazole alone’ and ‘HAART plus cotrimoxazole’. WHO stage 3–4 defining events and severe malaria were divided into those preventable and not preventable with cotrimoxazole. Incidence of ODs by CD4 count stratum was estimated using incidence density analysis. CD4+ T-cell count at time of OD was estimated using linear interpolation. Using Poisson regression, we estimated the effect of HAART on OD incidence and mortality by CD4 count stratum. Results Totals of 446 and 135 adults were followed during 6,216 and 3,412 person-months in the cotrimoxazole alone and HAART plus cotrimoxazole periods, respectively. There was a CD4+ T-cell-independent risk reduction for ODs and mortality during the HAART plus cotrimoxazole period compared with cotrimoxazole alone, which varied by time on HAART, CD4 count stratum and OD type. It was mainly seen after 6 months on HAART and for ODs not preventable by cotrimoxazole. The HAART effect differed significantly by CD4 count stratum ( P=0.02), but was significant in all strata after 6 months on HAART. Conclusions In these sub-Saharan African adults, HAART initiation reduced ODs and mortality beyond that which was expected through the HAART-induced CD4+ T-cell increase. Further studies should examine practical implications of this independent ‘HAART effect’ on clinical outcomes in patients on HAART.
Safety, Pharmacokinetics and Immune Effects in Normal Volunteers of CPG 10101 (ACTILON™), an Investigational Synthetic Toll-like Receptor 9 Agonist
Authors: Vicari Alain P , Schmalbach Tess , Lekstrom-Himes Julie , Morris Mary Louise , Al-Adhami Mohammed J , Laframboise Chantal , Leese Philip , Krieg Arthur M , Efler Susan M , Davis Heather L 
Published: April 2022

CPG 10101 (ACTILON™) is a novel potent and selective unmethylated cytidine-phosphate-guanosine (CpG)-containing oligodeoxynucleotide agonist of Toll-like receptor 9 (TLR9) being developed for the treatment of chronic infections such as HCV. Objectives and Methods In this randomized, double-blind, placebo-controlled Phase I study in 48 normal volunteers, we investigated the safety, pharmacokinetic parameters and immune effects of subcutaneous administration of CPG 10101. Five sequential escalating doses from 0.25 to 20 mg were administered twice, 14 days apart. In addition, a 4 mg dose was administered twice weekly for four weeks. Results A maximum tolerated dose was not reached and the adverse event profile was consistent with the known immunostimulatory effects of TLR9 agonists, mostly consisting of injection site reactions or flu-like symptoms that were generally mild in intensity. CPG 10101 induced interferons, cytokines and chemokines in a pattern consistent with the biology of TLR9. The most sensitive marker was IP-10/CXCL10, whose induction was detected in some subjects even at the 0.25 mg dose. Some cytokines showed transient circulating levels, while the levels of others such as the antiviral cytokine 2’,5’-oligoadenylate synthetase were sustained for several days. Conclusion This study warrants further investigation of CPG 10101 for the treatment of chronic infections such as HCV.
Dynamics of Apoptotic Activity during Antiviral Treatment of Patients with Chronic Hepatitis C
Authors: Kronenberger Bernd , Zeuzem Stefan , Sarrazin Christoph , Mihm Ulrike , Von Wagner Michael , Hofmann W Peter , Piiper Albrecht , Herrmann Eva 
Published: April 2022

Introduction Cell death during antiviral therapy of patients with chronic hepatitis C is not well understood. Methods In the present study, apoptotic activity was monitored by quantification of apoptotic cytokeratin-18 neoepitopes in serum from patients with chronic hepatitis C before and 4, 12, 24 and 48 weeks after initiation of antiviral therapy with pegylated interferon-α2a and ribavirin and was compared with viral kinetic parameters. Results After 4 weeks of treatment apoptotic activity decreased significantly compared with baseline. Later during treatment, however, apoptotic activity increased again to levels similar to baseline. Alanine aminotransferase (ALT) activity also showed a significant decrease at week 4 compared with baseline but, in contrast to apoptotic activity, ALT remained at a reduced level during the treatment period. Baseline apoptotic activity was inversely correlated with the infected cell loss while an increase of apoptotic activity within the first 4 treatment weeks compared with baseline was positively correlated with the infected cell loss. Conclusions Apoptosis appears to be an important form of cell death during interferon-α-based treatment and is associated with infected cell loss and underestimated by ALT activity.
Effect of Ribavirin on the Hepatitis C Virus (JFH-1) and its Correlation with Interferon Sensitivity
Authors: Brochot Etienne , Duverlie Gilles , Castelain Sandrine , Morel Virginie , Wychowski Czeslaw , Dubuisson Jean , François Catherine 
Published: April 2022

Background The consensus therapy for chronic hepatitis C infection is based on a synergistic combination of pegylated interferon and ribavirin. The therapy leads to a sustained virological response in around 60% of infected patients. The mechanism by which this synergy occurs has not yet been elucidated. Several mechanisms of action have been proposed; one suggests that ribavirin, which is a nucleoside analogue, is incorporated into the RNA strand and generates an increase in the error rate. Such an accumulation of mutations would threaten the integrity of the virus's genetic information. Methods The effects of ribavirin on the new infectious hepatitis C virus cell culture (HCVcc) system were investigated using Huh-7 cells. Cells were cultured for 1 month in either 0 μM, 20 μM or 50 μM ribavirin. The HCV interferon sensitivity and the NS5A quasispecies were analysed. Results An increase in the mutation rate in the HCV NS5A gene was observed when the infected cells were treated with 50 μM ribavirin for 1 month. Amino acid sequence analysis revealed that ribavirin exerts an increase in G to A transition events as predicted by its mutagenic effect and a selective pressure on the HCV NS5A sequence. Furthermore, ribavirin treatment modified the efficacy of interferon (IFN) treatment. The IFN half-inhibition concentration (IC50) was significantly lower for viruses obtained after 1 month's exposure to 50 μM ribavirin than for viruses cultured in the absence of ribavirin. Conclusions ribavirin's mutagenic effect could explain in part its synergistic action with interferon.
Transient Viral Load Increases in HIV-Infected Children in the UK and Ireland: What do They Mean?
Authors: Lee Katherine J , Shingadia Delane , Pillay Deenan , Walker A Sarah , Riordan Andrew , Menson Esse , Duong Trinh , Tudor-Williams Gareth , Gibb Diana M 
Published: April 2022

Objectives To investigate transient increases in viral load during sustained suppression in children in the UK and Ireland Collaborative HIV Paediatric Study (CHIPS). Design Cohort of HIV-infected children from 39 centres. Methods Transient viraemia was defined as ≥1 detectable viral loads (≥50 copies/ml) between two undetectable values (<50 copies/ml) <280 days apart, during a period of sustained viral suppression (from a confirmed level of <50 copies/ml until the last undetectectable measurement before antiretroviral therapy change or until a confirmed level of >50 copies/ml). Results Of 595 children initiating HAART without previous treatment, 347 (58%) achieved sustained suppression. Of these, 78 (23%) experienced 109 episodes of transient viraemia (median 134 copies/ml); 92 (84%) had levels of <1,000 copies/ml (maximum 39,839). Transient viraemia was more common during second-line therapy (25/100 child-years [CY]) and following a previous episode (19/100 CY) compared with first-line therapy without a previous episode (11/100 CY). Rates decreased with age at HAART initiation (incidence rate ratio [IRR] 0.95 per year older; P=0.05), but were higher in those suppressed for longer (IRR 1.63 in those suppressed for ≥1 year versus <1 year; P=0.03). CD4+ and CD8+ T-cell counts were similar before and after transient viraemia. Of detectable viral loads during periods of suppression 44% were transient increases rather than virological failure: experiencing transient viraemia did not increase subsequent virological failure ( P=0.20). Conclusions Transient viraemia is relatively common among children on HAART, occurring more frequently in those starting HAART at younger ages, on second-line therapy and after longer suppression. It does not appear to affect CD4+ or CD8+ T-cell counts or the risk of subsequent virological failure. Natural variation, assay effects and adherence might all have a role.