bluuebunny/crossref_metadata_2025_split huggingface dataset:
Baseline Factors associated with Haematological Toxicity that Leads to a Dosage Reduction of Pegylated Interferon-α2a and Ribavirin in HIV- and HCV-Coinfected Patients on HCV Antiviral Therapy
Authors: Fuster Daniel , Huertas Jaime A , Gómez Guadalupe , Solà Ricard , García Juan González , Vilaró Josep , Pedrol Enric , Force Lluís , Tor Jordi , Sirera Guillem , Videla Sebastiá , Planas Ramon , Clotet Bonaventura , Tural Cristina ,   for the PEG-TOX Research Group, Fuster Daniel , Tor Jordi , Sirera Guillem , Videla Sebastiá , Planas Ramon , Clotet Bonaventura , Tural Cristina , Huertas Jaime A , Gómez Guadalupe , Solà Ricard , García Juan González , Vilaró Josep , Pedrol Enric , Force Lluís , Cervantes Manel , García Isabel , Roget Mercè 
Published: April 2022

Objective To assess the baseline factors associated with haematological toxicity that lead to ribavirin or pegylated interferon (peginterferon) dosage reductions in hepatitis C and human immunodeficiency virus (HCV/HIV)-coinfected patients. Design Multicentre, prospective, observational study. Setting Eleven hospitals in Spain during the period 2002–2003. Subjects and methods One-hundred and forty-two HIV/HCV-coinfected patients received peginterferon-α2a plus ribavirin. Baseline characteristics and haematological parameters were recorded at baseline, week 4, 8, 12, 24 and 48. Cox's regression model was used to study the factors associated with the appearance of a haemoglobin level below 10g/dl (haemoglobin-endpoint), a neutrophil count below 750/mm3 (neutrophil-endpoint) and a platelet count below 50,000/mm3 (platelet-endpoint). Results Nineteen patients (13.4%) reached the haemoglobin-endpoint, 22.5% the neutrophil-endpoint and 7% the platelet-endpoint. Mean time of follow-up was 8 months (±3.5). A baseline haemoglobin level below 14g/dl [hazard ratio (HR): 3.65; 95% confidence interval (CI): 1.46–9.06] and treatment with zidovudine (HR: 3.25; 95% CI: 1.31–8.11) were the independent factors associated with the appearance of the haemoglobin-endpoint. A baseline neutrophil below 2050/mm3 (HR: 3.59; 95% CI: 1.77–7.28) and baseline weight <60 kg (HR: 2.21; 95% CI: 1.04–4.56) were independently associated with the appearance of the neutrophil-endpoint. Baseline platelet count (x1000/mm3 decrease) (HR: 1.074; 95% CI: 1.04-1.11) was independently associated with the appearance of the platelet-endpoint. Conclusions Baseline factors allow the identification of a subset of HIV/HCV-coinfected patients who are prone to experience haematological toxicity during HCV antiviral therapy.
Improvement in Dyslipidaemia after Switching Stavudine to Tenofovir and Replacing Protease Inhibitors with Efavirenz in HIV-Infected Children
Authors: Viganò Alessandra , Aldrovandi Grace M , Giacomet Vania , Merlo Marzia , Martelli Laura , Beretta Silvia , Luraschi Paola , Rombolà Giuseppe , Mora Stefano 
Published: April 2022

Objective To assess the impact on immunological, virological and metabolic parameters of replacing protease inhibitors (PIs) with efavirenz and replacing stavudine with tenofovir in HIV-infected children. Methods A 48-week prospective evaluation of 28 HIV-infected children, with stable undetectable HIV-1 loads, who were taking highly active antiretroviral therapy (HAART) containing lamivudine, stavudine and a PI. Individuals were randomized to switch PI to efavirenz and stavudine to tenofovir at baseline (Group 1) or at week 24 (Group 2). Patient assessment included: clinical evaluation, viral load, CD4+ T-cell count, fasting blood levels and urine samples. Results All individuals maintained HIV RNA <50 copies/ml and unchanged CD4+ T-cell count through week 48. In Group 1 individuals, a significant decrease in cholesterol ( P<0.05), cholesterol:high-density lipoprotein (HDL) ratio ( P<0.01) and triglycerides ( P<0.05) was observed 24 and 48 weeks after the switch of HAART. The percentage of Group 1 children with increased cholesterol and triglycerides markedly decreased over the study period (from 43% to 0% and from 36% to 7%, respectively). In Group 2 individuals, unchanged lipids in the 24 weeks prior to the switch of HAART and a significant improvement on cholesterol ( P<0.05), cholesterol:HDL ratio ( P<0.01) and triglycerides ( P<0.05) were observed 24 weeks after the switch of HAART. The percentage of Group 2 children with increased cholesterol and triglycerides markedly decreased 24 weeks after the switch of HAART (from 46% to 7% and from 54% to 0%, respectively). Proteinuria and glucosuria were not detected in any individual. The mean values of serum creatinine, serum phosphorus, serum bicarbonate, estimated glomerular filtration rate, urinary microalbumin/creati-nine, α-1-microglobulin/creatinine ratio and maximal tubular phosphate reabsorption remained unchanged in both groups. Conclusions In HIV-infected children, switching PI to efavirenz and stavudine to tenofovir is virologically and immunologically safe, is not associated with renal impairment and provides a significant improvement in lipid profile.
When to Initiate Highly Active Antiretroviral Therapy in Sub-Saharan Africa? A South African Cost-Effectiveness Study
Authors: Badri Motasim , Cleary Susan , Maartens Gary , Pitt Jennifer , Bekker Linda-Gail , Orrell Catherine , Wood Robin 
Published: April 2022

Background Large-scale programmes increasing access to highly active antiretroviral therapy (HAART) are being implemented in sub-Saharan Africa. However, cost-effectiveness of initiating treatment at different CD4 count thresholds has not been explored in resource-poor settings. Methods A cost-effectiveness analysis was conducted from a public health perspective using primary treatment outcomes, healthcare utilisation and cost data (Jan 2004 local prices; US$1=7.6 Rands) derived from the Cape Town AIDS Cohort. A Markov state-transition model was developed to estimate life-expectancy, lifetime costs, quality-adjusted life-years (QALYs), cost per life-year and QALY gained for initiating HAART at three CD4 cell count thresholds (<200/μl, 200–350/μl and >350/μl), including the no antiretroviral therapy (No-ART) alternative. Each treatment option was compared with the next most effective undominated option. Results Mean life-expectancy was 6.2, 18.8, 21.0 and 23.3 years; discounted (8%) QALYs were 3.1, 6.2, 6.7 and 7.4; and discounted lifetime costs were US$5,250, US$5,434, US$5,740, US$6,588 for No-ART, and therapy initiation at <200/μl, 200–350/μl and >350/μl scenarios respectively. Clinical benefits increased significantly with early therapy initiation. Initiating therapy at <200/μl had an incremental cost-effectiveness ratio (ICER) of US$54 per QALY versus No-ART, 200–350/μl had an ICER of US$616 versus therapy initiation at <200/μl, and >350/μl had an ICER of US$1,137 versus therapy initiation at 200–350/μl ICERs were sensitive to HAART cost. Conclusions HAART is reasonably cost-effective for HIV-infected patients in South Africa, and most effective if initiated when CD4 count >200/μl. Deferring treatment to <200/μl would reduce the aggregate cost of treatment, but this should be balanced against the significant clinical benefits associated with early therapy.
An Open-Label, Randomized Comparative Pilot Study of a Single-Class Quadruple Therapy Regimen versus a 2–Class Triple Therapy Regimen for Individuals Initiating Antiretroviral Therapy
Authors: Moyle Graeme , Higgs Christopher , Teague Alastair , Mandalia Sundhiya , Nelson Mark , Johnson Margaret , Fisher Martin , Gazzard Brian 
Published: April 2022

Objective To examine the antiviral potency and tolerability profile of a single-class four drug (quadruple) nucleoside reverse transcriptase inhibitor (NRTI) regimen compared with a 2-class standard-of-care regimen. Methodology A three-centre, randomized, open-label comparative pilot study of zidovudine/lamivudine/efavirenz (triple) versus abacavir/lamivudine/zidovudine/tenofovir (quadruple) therapy in HIV-1-infected, treatment-naive individuals. Both regimens were taken without regard to food and consisted of a twice-daily regimen and 3 pills/day. The study power was based on time-weighted average changes in HIV-1 RNA load. Results A total of 114 individuals (56 triple, 57 quadruple) received at least one dose of medication. Patients were well matched at baseline for viral load (mean 5.26 log10 versus 5.13 log10, respectively) and CD4 cell count (median 193 versus 153 cells/mm3, respectively). The two regimens performed similarly with regards to all endpoints. At week 48, by intention-to-treat, missing=failure analysis, 68% of triple- and 67% of quadruple-drug treated patients had an HIV-1 RNA <50 copies/ml ( P>0.05). On-treatment analysis showed 40/40 (100%) of triple- and 39/40 (97.5%) of quadruple-drug treated patients ( P=0.996) had responded to <50 copies/ml. No unexpected adverse events were reported. Changes in total cholesterol and triglycerides were modest but significantly favoured the quadruple therapy regimen at multiple time points. Conclusion This pilot study suggests a quadruple NRTI-based regimen provides similar antiviral potency, tolerability and administrative characteristics to a 2-class triple therapy regimen. These findings should be confirmed in a more fully powered study. Potent quadruple NRTI-based regimens may have advantages for some individuals with regards to salvageability, tolerability and drug interactions.
Hepatic Interferon Receptor Mrna Expression: Clinical Relevance and Its Relationship with Effectiveness of Interferon plus Ribavirin Therapy in Patients with Genotype 1B Hepatitis C Virus Infection
Authors: Lee Chuan-Mo , Kee Kwong-Ming , Hung Chao-Hung , Eng Hock-Liew , Chang Chien-Hwa , Huang Chao-Min , Wang Jing-Houng , Hu Tsung-Hui , Lu Sheng-Nan , Changchien Chi-Sin , Chen Wei-Jen 
Published: April 2022

Background/aims Hepatic expression of interferon (IFN) receptor mRNA has been shown to correlate with the effectiveness of IFN monotherapy in patients with chronic hepatitis C virus (HCV) infection. We investigated the expression of hepatic IFN receptor alpha/beta (IFNAR2c) mRNA and its association with the effectiveness of IFN plus ribavirin (RBV) therapy and with the clinical features in patients with HCV genotype 1b (HCV-1b) infection. Methods A total of 42 naive patients who had chronic HCV-1b infection were treated with IFN alpha-2b 3 MU or 5 MU three times weekly plus RBV for 24 weeks. Hepatic IFNAR2c mRNA was quantified by real-time RT-PCR. Results There was no significant difference in the mean expression level of IFNAR2c mRNA between patients with sustained virological response (SVR) and non-SVR (0.069 ±0.042 versus 0.053 ±0.033, P=0.182). Multiple linear regression analysis showed that lower fibrosis scores ( P=0.006) and younger age ( P=0.03) were associated with hepatic IFNAR2c mRNA expression with r2=0.34. Conclusions Hepatic IFNAR2c mRNA expression may not be useful for predicting the response to IFN plus RBV therapy in patients with HCV-1b infection, but appeared to correlate inversely with the fibrosis stage and age.
Exploring Mitochondrial Nephrotoxicity as a Potential Mechanism of Kidney Dysfunction among HIV-Infected Patients on Highly Active Antiretroviral Therapy
Authors: Côté Hélène CF , Magil Alex B , Harris Marianne , Scarth Brian J , Gadawski Izabelle , Wang Nancy , Yu Eugenia , Yip Benita , Zalunardo Nadia , Werb Ron , Hogg Robert , Harrigan P Richard , Montaner Julio S 
Published: April 2022

Background Tenofovir (TDF) exposure has been associated with renal dysfunction. Mitochondrial nephrotoxicity was investigated as an underlying mechanism. Given the interaction between TDF and didanosine (ddI), their concurrent use was also investigated. Design Relative kidney biopsy mitochondrial DNA (mtDNA) to nuclear DNA ratios were measured retrospectively. HIV+ individuals on TDF within 6 months preceeding the biopsy (HIV+/TDF+, n=21) were compared to HIV+ individuals who never received TDF (HIV+/TDF-, n=10) and to HIV uninfected controls (HIV–, n=22). Twelve of the HIV+/TDF+ individuals received concurrent ddI, 10 of those once at unadjusted ddI dosage. Tubular mitochondria morphology was also examined by electron microscopy. Statistical analyses were done on log-transformed mtDNA/nDNA, using non-parametric tests. Results Kidney mtDNA levels were different among the three groups ( P=0.046). mtDNA ratios were lower in HIV+/TDF+ subjects (7.5 [2.0–12.1]) than in HIV- ones (14.3 [6.0–16.5], P=0.014), but not lower than HIV+/TDF-controls (6.4 [2.8–11.9], P=0.82). Among HIV+ subjects, there was a difference between TDF-, TDF+/ddI- and TDF+/ddI+ ( P=0.005), with concurrent TDF/ddI use associated with lower mtDNA (2.1 [1.9–5.5], n=12) than TDF+/ddI- (13.8 [7.5–16.4], n=9, P=0.003). No TDF–/ddI+ biopsies were available. In regression analyses, only HIV infection ( P=0.03), and TDF/ddI use ( P=0.003) were associated with lower mtDNA. At the ultrastructural level, abnormal tubular mitochondria was more prevalent in HIV+/TDF+ biopsies than HIV+/TDF- and HIV- ones together ( P<0.001) but not more so in TDF+/ddI+ biopsies than TDF+/ddI- ones ( P=0.67). Conclusions Renal dysfunction in this population may be mediated through mitochondrial nephrotoxicity that involves more than one drug and/or pathogenesis. Kidney mtDNA depletion was associated with HIV infection and concurrent TDF/ddI therapy but not TDF use alone, while kidney ultrastructural mitochondrial abnormalities were seen with TDF use. The interaction between TDF and ddI may be relevant in the kidney where both drugs are cleared. The clinical relevance of our findings needs to be evaluated given the current recommendation for reduced doses of ddI when used in conjunction with TDF.
Risks of Non-Accidental Mortality by Baseline CD4+ T-Cell Strata in Hepatitis-C-Positive and -Negative Individuals Initiating Highly Active Antiretroviral Therapy
Authors: Moore David M , Hogg Robert S , Braitstein Paula , Wood Evan , Yip Benita , Montaner Julio SG 
Published: April 2022

Background Patients coinfected with hepatitis C virus (HCV) and HIV experience higher mortality rates than patients infected with HIV alone. We designed a study to determine whether risks for later mortality are similar for HCV-positive and HCV-negative individuals when subjects are stratified on the basis of baseline CD4+ T-cell counts. Methods Antiretroviral-naive individuals, who initiated highly active antiretroviral therapy (HAART) between 1996 and 2002 were included in the study. HCV-positive and HCV-negative individuals were stratified separately by baseline CD4+ T-cell counts of 50 cell/μl increments. Cox-proportional hazards regression was used to model the effect of these strata with other variables on survival. Results CD4+ T-cell strata below 200 cells/μl, but not above, imparted an increased relative hazard (RH) of mortality for both HCV-positive and HCV-negative individuals. Among HCV-positive individuals, after adjustment for baseline age, HIV RNA levels, history of injection drug use and adherence to therapy, only CD4+ T-cell strata of <50 cells/μl (RH=4.60; 95% confidence interval [CI] 2.72–7.76) and 50–199 cells/μl (RH=2.49; 95% CI 1.63–3.81) were significantly associated with increased mortality when compared with those initiating therapy at cell counts >500 cells/μl. The same baseline CD4+ T-cell strata were found for HCV-negative individuals. Conclusion In a within-groups analysis, the baseline CD4+ T-cell strata that are associated with increased RHs for mortality are the same for HCV-positive and HCV-negative individuals initiating HAART. However, a between-groups analysis reveals a higher absolute mortality risk for HCV-positive individuals.
Antiviral Efficacy and Genotypic Resistance Patterns of Combination Therapy with Stavudine/Tenofovir in Highly Active Antiretroviral Therapy Experienced Patients
Authors: Antinori Andrea , Trotta Maria Paola , Nasta Paola , Bini Teresa , Bonora Stefano , Castagna Antonella , Zaccarelli Mauro , Quirino Tiziana , Landonio Simona , Merli Stefania , Tozzi Valerio , Perri Giovanni Di , Andreoni Massimo , Perno Carlo Federico , Carosi Giampiero 
Published: April 2022

Objectives To evaluate antiviral efficacy of stavudine/tenofovir (d4T/TDF) backbone combination in late-line antiretroviral therapy, and to assess clinical and virological determinants of treatment success. Design Multicentric retrospective analysis on patients starting d4T/TDF after highly active antiretroviral therapy (HAART) failure. Methods The primary endpoint was the change in plasma HIV-1 RNA from the baseline (time of d4T/TDF initiation) to 6 months of therapy; secondary endpoint was the risk of virological failure. Results Among 172 patients included, a mean change in HIV-1 RNA of -1.69 (+1.23) and -1.53 (+1.43) log10 cp/ml was observed respectively at weeks 24 and 48 after starting d4T/TDF combination. Any single type-1 thymidine analogue mutation (TAM; M41L, L210W, T215Y) had a negative effort on the change in HIV RNA at 6 months, whereas among type-2 TAMs (D67N, K70R, K219Q), only D67N showed a trend for a negative effect. Presence of M184V mutation was related with a greater reduction in HIV RNA during d4T/TDF exposure. The risk of virological failure at 6 months after d4T/TDF starting was 22%. Type-1 TAMs were associated with a greater risk of failure (adjusted hazard ratio [HR]=1.65; 95% confidence interval [CI] 1.19–2.29). Conversely, M184V showed a protective effect. In 17 genotypic tests available at failure, no K65R mutation was detected, whereas a trend for an increasing prevalence of d4T-associated mutations was found. Conclusions Combining TDF with a thymidine analogue as d4T may be effective as component of antiretroviral rescue regimens in HIV-infected patients with previous exposure to nucleoside analogue reverse transcriptase inhibitor. Previous selection of type-1 TAMs induces a detrimental effect over virological response.
Impact of Steatosis on Long-Term Histological Outcome in Chronic Hepatitis C after Antiviral Therapy
Authors: Hung Chao-Hung , Kuo Fang-Ying , Wang Jing-Houng , Lu Sheng-Nan , Hu Tsung-Hui , Chen Chien-Hung , Lee Chuan-Mo , Eng Hock-Liew 
Published: April 2022

Background/Aims Steatosis is recognized as a cofactor influencing the presence and progression of fibrosis in chronic hepatitis C. It has been reported that antiviral therapy may reduce the progression of fibrosis and leads to regression in chronic hepatitis C patients achieving a sustained virological response (SVR). Whether steatosis might affect the long-term histological outcome of antiviral therapy remains unclear. Methods One-hundred and sixty-one consecutive patients (genotype 1, n=76; genotype 2, n=73) receiving interferon-α2b and ribavirin were analysed. Ninety patients had paired biopsies with a mean interval of 29.1 ±7.1 months. Results Variables associated with baseline steatosis were higher body mass index (≥25, P=0.002) and higher fibrosis stage (≥2, P=0.019). Neither the presence nor the severity of steatosis was associated with SVR. Evaluation of paired biopsies showed no different distribution of steatosis evolution between patients with and without SVR ( P=0.374). Among patients achieving a SVR, there was a significant difference in fibrosis changes between those with grade 0 or 1 steatosis and with grade 2 or 3 steatosis at post-treatment biopsy (-0.6 ±1.2 vs 0.3 ±1.3, P=0.041), whereas changes in histological activity index did not differ (-3.7 ±2.6 vs -4.0 ±2.9, P=0.740). Stepwise logistic regression analysis showed that SVR (odds ratio [OR]: 16.33, P=0.004) and grade 0 or 1 post-treatment steatosis (OR: 12.82, P=0.018) were independently associated with fibrosis regression. Conclusions In patients with chronic hepatitis C, steatosis not only correlates with advanced fibrosis at baseline but also affects fibrosis regression after antiviral therapy.
Pharmacokinetics of a Once-Daily Regimen of Lopinavir/Ritonavir in HIV-1-Infected Children
Authors: van der Lee Manon , Verweel Gwenda , de Groot Ronald , Burger David 
Published: April 2022

Introduction Lopinavir is an HIV protease inhibitor that is co-formulated with ritonavir. The approved paediatric dose is 230/57.5 mg/m2 twice daily. Once-daily dosing may offer an advantage to adherence. We studied the pharmacokinetics of lopinavir/ritonavir in a once-daily regimen in HIV-1-infected children. Methods HIV-1-infected children on stable antiretroviral therapy with a viral load <50 copies/ml for at least 6 months received lopinavir/ritonavir 460/115 mg/m2 once daily with zidovudine and lamivudine. Blood samples were collected at 0, 2, 4, 6, 8, 12, 18 and 24 h after observed intake during steady state. Target level for lopinavir Cmin was 1.0 mg/l, based on in vitro IC50 data. Results Nineteen HIV-1-infected children with a median (range) age of 4.5 (1.4–12.9) years were enrolled. The median (interquartile range) dose of lopinavir was 456 (444–477) mg/m2. The mean (standard deviation) AUC0–24, Cmax and Cmin of lopinavir were 149.8 ±58.8 h*mg/l, 10.77 ±2.90 mg/l and 2.88 ±3.74 mg/l respectively. These values are comparable to data observed in adults using lopinavir/ritonavir 800/200 mg once daily. In 10/19 (53%) children Cmin was considered to be too low (<1.0 mg/l). Younger children more often experienced subtherapeutic trough levels. Conclusion Our findings indicate that 460/115 mg/m2 lopinavir/ritonavir once daily leads to mean pharmacokinetic parameters comparable to data of 800/200 mg lopinavir/ritonavir once daily in adults, although the variability observed in the trough levels is much higher in children. Further research, especially in young children, is necessary to determine whether a higher dosage of lopinavir/ritonavir once daily must be given to reach the target level for Cmin.