bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolution of Antiretroviral Phenotypic and Genotypic Drug Resistance in Antiretroviral-Naive HIV-1-Infected Children Treated with Abacavir/Lamivudine, Zidovudine/Lamivudine or Abacavir/Zidovudine, with or without Nelfinavir (The Penta 5 Trial)
Authors: Gibb Diana M , Walker A Sarah , Kaye Steve , De Rossi Anita , Ait-Khaled Mounir , Pillay Deenan , Muñoz-Fernandez Maria Angeles , Loveday Clive , Compagnucci Alexandra , Dunn David T , Babiker Abdel G 
Published: April 2022

Purpose and methods To describe the evolution of resistance to zidovudine (ZDV), lamivudine (3TC), abacavir (ABC) and nelfinavir (NFV), 113 previously untreated children in the PENTA 5 trial had resistance assayed at baseline, rebound and/or 24, 48, 72 weeks (VIRCO: phenotyping and genotyping with ‘Virtual Phenotype’ interpretation). Results At baseline, few reverse transcriptase mutations and no primary protease inhibitor mutations were observed. Time to detectable HIV-1 RNA with reduced phenotypic susceptibility to any drug was shortest in the ZDV+3TC arm (overall logrank P=0.02). Through a median follow-up of 55 weeks, at their last assessment 11 (28%), 16 (40%) and 13 (32%) children with detectable HIV-1 RNA and a resistance test available had mutations conferring resistance to none, one, or two or more trial drugs, respectively, according to the virtual phenotype. Reduced phenotypic susceptibility to ABC only occurred in the 3TC+ABC arm and required K65R and/or L74V in addition to M184V. NFV-resistant virus was selected slowly through D30N or L90M pathways, and selection of ZDV-resistant virus was rare. Conclusions Selection of 3TC-resistant virus was most frequent, followed by NFV and/or ABC; selection of ZDV-resistant virus was rare. Importantly, although in vitro, ABC selects for M184V as the first mutation, ABC did not select for M184V when combined with ZDV without 3TC. The most sustained HIV-1 RNA response was in the 3TC+ABC arm, but mutations conferring reduced susceptibility to 3TC and/or ABC evolved more frequently if virological failure occurred with 3TC+ABC than with ZDV+ABC.
Adipocyte-Derived Hormone Levels in HIV Lipodystrophy
Authors: Kosmiski Lisa , Kuritzkes Daniel , Lichtenstein Kenneth , Eckel Robert 
Published: April 2022

Objective Despite evidence for the role of adipocyte-derived hormones in insulin resistance, little is known about their levels in human lipodystrophic states. We examined the relationships of plasma leptin and adiponectin levels to fat distribution and insulin sensitivity in the HIV lipodystrophy syndrome. Design Cross-sectional study Setting HIV primary care practices Patients HIV-infected men with (n=13) and without (12) lipodystrophy and healthy uninfected controls (12). Main outcome measures: Plasma adiponectin and leptin levels were measured in the fasting state. Body composition was assessed by physical examination, dual-energy x-ray absorptiometry and computed tomography. Insulin sensitivity (SI) was measured using the insulin-modified frequently sampled intravenous glucose tolerance test. Results Leptin levels were significantly higher in HIV-infected men with lipodystrophy as compared to HIV-infected controls (5.2 vs 3.0 ng/ml, P=0.01). Across the entire study population, leptin levels were positively correlated with measures of general adiposity. In the HIV-infected patients, leptin levels were negatively correlated with SI after adjustment for fat mass (r=-0.38, P=0.07). Adiponectin levels were significantly lower in HIV-infected men with lipodystrophy as compared to both HIV-infected and healthy controls (1.6 vs 3.4 μg/ml, P<0.05 and 1.6 vs 6.7 μg/ml, P<0.001, respectively). Adiponectin levels, after adjustment for fat mass, were correlated with measures of fat distribution. Finally, in the HIV-infected patients, adiponectin levels were significantly and positively correlated with SI after adjustment for fat mass (r=0.75, P≤0.001), and adiponectin level was also an independent determinant of SI. Conclusions Plasma leptin and adiponectin levels are altered in the HIV lipodystrophy syndrome. Adiponectin deficiency may play a role in the insulin resistance associated with HIV lipodystrophy.
Normal Erythropoietin Response in Chronic Hepatitis C Patients with Ribavirin-Induced Anaemia
Authors: Mangoni Emanuele Durante , Marrone Aldo , Saviano Donatella , Vecchio Carmen Del , Utili Riccardo , Ruggiero Giuseppe 
Published: April 2022

Background Ribavirin administration for chronic hepatitis C is associated with the development of haemolytic anaemia, which affects treatment efficacy and tolerability. In a pilot study, the exogenous administration of erythropoietin has been shown to be beneficial, reducing the rate of ribavirin dose reduction. How ribavirin administration affects normal erythropoietin production has not been determined. Aim To investigate the endogenous erythropoietin response in hepatitis C patients with ribavirin-induced anaemia. Methods Serum erythropoietin was measured before and during interferon–ribavirin treatment in 18 HCV-positive subjects. Mathematical analysis and modelling were applied to compare the degree of erythropoietin increase in HCV-positive and in otherwise healthy anaemic patients, and estimate the endogenous excess erythropoietin production in response to ribavirin-induced anaemia. Results Erythropoietin concentration increased significantly in response to anaemia caused by ribavirin. The physiological erythropoietin response to the ribavirin-induced anaemia was as adequate in HCV-positive subjects as it is in anaemic subjects without liver disease. The recommended exogenous erythropoietin dose appears three-times greater than the endogenous erythropoietin boost. Conclusion Chronic liver damage by HCV does not affect the physiological erythropoietin response to ribavirin-induced anaemia. While the rationale for erythropoietin treatment of ribavirin-induced anaemia is not straightforward, the currently recommended dosing regimen should be reassessed.
Changes in Viral Load in People with Virological Failure who Remain on the Same Haart Regimen
Authors: Cozzi-Lepri Alessandro , Phillips Andrew N , Miller Veronica , Katlama Christine , Ledergerber Bruno , Vella Stefano , Weber Jonathan , Bruun Johan N , Kirk Ole , Clotet Bonaventura , Lundgren Jens D 
Published: April 2022

Objectives To assess the rate of change in viral load and CD4 count over time in HIV-infected patients experiencing virological failure on a HAART regimen. Design Study population included patients from EuroSIDA, a large, multicentre, observational study enrolling HIV-infected patients across Europe. Methods Median change in viral load and CD4 count per month were estimated using the viral load and CD4 measurements obtained over a 12-month period after confirmed virological failure between 3 and 4 log10 copies/ml in a population of 488 HIV-infected patients who were left on a failing HAART regimen. Results The estimated median viral load change in our study population was 0.024 log10 copies/ml per month, statistically different from 0 (P=0.0001). In 20.9% of the patients studied viral load showed a tendency to decrease, in 47.8% showed a tendency to increase by a positive rate no higher than 0.04 log10 copies/ml per month and in the remaining 31.3% showed a tendency to increase by a rate greater than 0.04 log10 copies/ml per month. On average, CD4 counts were estimated to remain stable (decrease at a slow rate of about –0.53 cells/μl per month). Conclusions In patients that remained on a stable, but virologically failing HAART regimen (with viral load ranging 1000–10000 copies/ml), the viral load over the ensuing 12-month period increased at a relatively slow rate. In contrast, the CD4 count remained stable, possibly because of partial but sustained viral suppression below the viral load natural set-point. The time-course of selecting more replication-competent virus in patients with virological failure remains to be fully clarified.
K65R with and without S68: A New Resistance Profile in Vivo Detected in Most Patients Failing Abacavir, Didanosine and Stavudine
Authors: Røge Birgit T , Katzenstein Terese L , Obel Niels , Nielsen Henrik , Kirk Ole , Pedersen Court , Mathiesen Lars , Lundgren Jens , Gerstoft Jan 
Published: April 2022

Antiretroviral treatment with three nucleoside reverse transcriptase inhibitors (NRTIs) is widely used, but the combination of abacavir, didanosine and stavudine has never been investigated. We describe the surprising and consistent genotypic and phenotypic outcome in patients failing this combination. As part of a Danish multicentre study, 60 antiretroviral-naive patients were randomized to treatment with abacavir, didanosine and stavudine. Failure was defined as one HIV-1 RNA >400 copies/ml. Genotyping was performed using TrueGene™ HIV-1 assay (Visible Genetics, London, UK). Phenotypic susceptibilities were determined with the Virco Antivirogram assay. Eight patients failed treatment with a median viral load of 2.980 copies/ml (range 478-5.950). At baseline, five patients were wild-type. Three patients harboured nucleoside excision mutations (NEMs), but phenotypic susceptibilities were within normal range. All five patients with wild-type virus developed K65R and four of these patients also acquired the S68G mutation. Phenotypic susceptibility decreased towards abacavir (median 8.9-fold) and didanosine (median 3.2-fold), while susceptibility towards stavudine was unchanged (median 0.8-fold). Susceptibility towards lamivudine and tenofovir decreased median 14.2- and 4.0-fold, respectively. In two patients with baseline resistance mutations, further accumulation of NEMs and V75T or L74V was observed. One patient developed Q151M. Failure of a triple NRTI regimen is possible and frequent with only the K65R mutation. Under adequate selection pressure K65R can easily emerge in vivo and may compromise several future treatment options including newer NRTIs. The unexpected high incidence of S68G suggests a functional role of this mutation in viruses harbouring K65R.
Intracellular Indinavir Pharmacokinetics in HIV-Infected Patients: Comparison with Plasma Pharmacokinetics
Authors: Hennessy Martina , Clarke Susan , Spiers J Paul , Mulcahy Fiona , Kelleher Dermot , Meadon Emma , Maher Bridget , Bergin Colm , Khoo Saye , Tjia John , Hoggard Patrick , Back David , Barry Michael 
Published: April 2022

Objective To determine intracellular concentrations of indinavir (IDV) and investigate the relationship between plasma and intracellular IDV pharmacokinetics in HIV-infected patients. Methods A pharmacokinetic study of 10 patients receiving IDV plus dual nucleoside analogue therapy. Peripheral blood mononuclear cells were isolated by density gradient centrifugation and cell counts estimated. IDV was extracted from cells in the presence of 60% methanol and evaporated to dryness. Both plasma and intracellular IDV samples were assayed by high performance liquid chromatography linked to mass spectrometry. Data were subjected to non-compartmental pharmacokinetic analysis. Results The mean intracellular IDV area under the curve over 8 h (AUC0-8) was lower than the plasma AUC0-8 (7574 ±1003 vs 25060 ±4171 ng/ml/h; P<0.004). However, both the elimination half-life (t1/2) and the mean residence time (MRT) of IDV intracellularly were prolonged compared with plasma (t1/2: 2.0 ±0.3 vs 1.2 ±0.09 h; MRT: 3.6 ±0.6 vs 2.1 ±0.1 h; P<0.05). All patients were responsive to therapy at the time of the study, as assessed by HIV plasma RNA levels. Individual plasma versus intracellular time course results suggest that, due to the prolonged intracellular half-life, some patients may achieve acceptable intracellular IDV concentrations despite sub-therapeutic plasma levels. Similarly, potentially inadequate intracellular concentrations may occur despite therapeutic plasma concentrations. Conclusions There is no significant intracellular accumulation of IDV within the lymphocytes of HIV-1-infected patients relative to plasma. However, intracellular concentrations are compatible with reported IDV-free drug concentrations in plasma. The intracellular elimination half-life and mean residence time of IDV are significantly prolonged compared with plasma. This may in part explain why certain patients maintain adequate viral suppression despite sub-therapeutic plasma IDV levels.
Pharmacokinetics of Nelfinavir in Children: Influencing Factors and dose Implications
Authors: Bergshoeff Alina S , Fraaij Pieter LA , van Rossum Annemarie MC , Wolfs Tom FW , Geelen Sibyl PM , de Groot Ronald , Burger David M 
Published: April 2022

Objectives The study describes the pharmacokinetics (PK) of the protease inhibitor nelfinavir and its active metabolite M8 in children and evaluates the influence of patient-related factors on nelfinavir plasma levels. Methods HIV-1-infected children treated with nelfinavir every 8 h (q8h) were eligible for inclusion in this retrospective study. 0–8 h intensive plasma pharmacokinetics (PK) sampling was performed at steady state. Nelfinavir maximum concentration (Cmax), area under the plasma concentration-time curve in 0–8 h (AUC0-8), trough level at the 8 h time point (C8) and relative apparent oral clearance (Cl*F/kg) were calculated. Results Twenty-four children (median age: 4.5 years, median nelfinavir dose: 28 mg/kg q8h) were included. Nelfinavir PK were highly variable: 10/24 children had an AUC0-8 below the value of 12.5 mg/l*h, which has previously been associated with an increased virological failure rate in children. With children aged <2 years and a dose of 20 mg/kg q8h, a non-significant trend was observed to more AUC0-8<12.5 mg/l*h [odds ratio (OR) (95% CI): 2.44 (0.41–14.7) and 8.7 (0.79–95), respectively]. Nelfinavir C8 correlated strongly with AUC0-8 (r=0.89, P<0.001). C8 >0.69 mg/l predicted an AUC0-8 >12.5 mg/l*h with 71% sensitivity and 80% specificity. Dose of nelfinavir per body surface area was a better predictor of AUC0-8 than dose per body weight. Conclusion Nelfinavir PK show high interindividual variability in children. Children <2 years old tend to be at increased risk for low nelfinavir levels. These data show that the nelfinavir dose of 20 mg/kg q8h is inadequate in most children. Also, these data suggest that paediatric dosing of nelfinavir based on body surface area should be considered. Therapeutic drug monitoring (TDM) can detect abnormal plasma levels and is therefore useful in optimizing nelfinavir therapy in HIV-infected children. However, further research is needed to more firmly establish a therapeutic range for nelfinavir in children.
Increase of HIV-1 Pro-Viral Dna per Million Peripheral Blood Mononuclear Cells in Patients with Advanced HIV Disease (Cd4<200 Cells/Mm3) Receiving Interleukin 2 Combined with Haart Versus Haart Alone (Anrs-082 Trial)
Authors: Delaugerre Constance , Gourlain Karine , Tubiana Roland , Carcelain Guislaine , Marcelin Anne-Geneviève , Chouquet Cécile , Mouroux Mireille , Duvivier Claudine , Autran Brigitte , Costagliola Dominique , Katlama Christine , Calvez Vincent 
Published: April 2022

Objective To assess the effect of interleukin (IL)-2 combined with highly active antiretroviral therapy (HAART) on HIV-1 pro-viral DNA quantification in HIV-1-infected patients with CD4<200/mm3. Patients and methods Seventy patients with CD4<200 cells/mm3 and CV<1000 copies/ml were enrolled in a 6-month randomized controlled study to evaluate the subcutaneous injection of IL-2 in addition to HAART versus HAART alone. Then, in a non-comparative phase from week 28 to week 80, IL-2 was proposed to patients from both groups. The HIV-1 pro-viral DNA was quantified at baseline, week 24 and week 50 by a real-time polymerase chain reaction (PCR) assay in peripheral blood mononuclear cells (PBMC). Analysis of resistance mutations was performed at baseline and after 6-months of IL-2. Results HIV-1 DNA level in PBMC increased significantly in patients treated with 6 months of HAART combined to IL-2 (+0.24 log10, P=0.009) compared to a slight decrease in patients treated with HAART alone (–0.05 log10). Moreover, a DNA increase was observed in control group patients when receiving 6 months of IL-2 (+0.34 log10). No increase of HIV-1 DNA was seen when this measure was expressed per million CD4 cells; it was probably hidden by the intense increase of CD4 lymphocytes after 6 months of IL-2 administration. No evolution of resistance mutations in pro-viral DNA was observed during 6 months of IL-2, despite the increase of pro-viral DNA and the occurrence of transient increase of viraemia. Conclusion Administration of IL-2 combined with HAART in HIV-1 infected-patients with advanced disease led to an increase of HIV-1 pro-viral DNA per million PBMC without virological failure or emergence of resistance.
A Controlled Phase Ii Trial Assessing Three Doses of Enfuvirtide (T-20) in Combination with Abacavir, Amprenavir, Ritonavir and Efavirenz in Non-Nucleoside Reverse Transcriptase Inhibitor-Naive HIV-Infected Adults
Authors: Lalezari Jacob P , DeJesus Edwin , Northfelt Donald W , Richmond Gary , Wolfe Peter , Haubrich Richard , Henry David , Powderly William , Becker Stephen , Thompson Melanie , Valentine Fred , Wright David , Carlson Margrit , Riddler Sharon , Haas Frances F , DeMasi Ralph , Sista Prakash R , Salgo Miklos , Delehanty John 
Published: April 2022

Enfuvirtide is a novel antiretroviral that blocks HIV-1 cell fusion and viral entry. This Phase II, controlled, open-label, randomized, multicentre dose-ranging trial explored the safety, antiviral activity and pharmacoki-netics of enfuvirtide, administered by subcutaneous (SC) injection, in 71 HIV-1-infected, protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive adults for 48 weeks. Study participants were randomized to receive enfuvirtide at a deliverable dose of 45, 67.5 or 90 mg twice daily; the 45 mg twice daily dose required 2 injections/day, while the higher doses required 4 injections/day. A background oral antiretroviral (ARV) regimen of abacavir (300 mg twice daily), amprenavir (1200 mg twice daily), ritonavir (200 mg twice daily) and efavirenz (600 mg once daily) was provided with enfuvirtide. A control group received the background ARV regimen alone. All potential participants underwent an HIV genotype at screen to ensure a homogenous population and to exclude patients with evidence of genotypic resistance to NNRTIs. Overall, the tolerability of the combination of abacavir, amprenavir, ritonavir, efavirenz and enfuvirtide was generally comparable to control through 48 weeks. No enfuvirtide dose-dependent adverse events (AEs) were observed across treatment groups. Injection site reactions (ISRs) occurred at least once in 68.5% of the enfuvirtide-treated population, and most ISRs were mild to moderate in severity, with no apparent dose relationship. Excluding ISRs, the most common treatment-emergent AEs were nausea, diarrhoea, dizziness and fatigue; with no clinically significant differences in the incidence of AEs observed between the control and enfuvirtide groups. Each treatment group benefited from ARV therapy, with a trend of increasing antiviral and immunological activity associated with increasing enfuvirtide dose. At 48 weeks, the median HIV-1 RNA change from baseline for the ITT population was –2.24 log10 copies/ml for the combined enfuvirtide groups compared with –1.87 log10 copies/ml for the control group. In addition, 54.9% of patients in the enfuvirtide group achieved HIV-1 RNA ≤400 copies/ml versus 36.8% of patients in the control group. These results indicate that enfuvirtide has a favourable safety profile and is a promising new antiviral agent for HIV-infected patients who have been on previously failing ARV regimens.
Mitochondrial Proliferation, Dna Depletion and Adipocyte Differentiation in Subcutaneous Adipose Tissue of HIV-Positive Haart Recipients
Authors: Pace Craig S , Martin Annalise M , Hammond Emma L , Mamotte Cyril D , Nolan David A , Mallal Simon A 
Published: April 2022

Objectives To examine the in vivo effects of highly active antiretroviral therapy (HAART) regimens on adipose tissue mitochondrial DNA (mtDNA) depletion, mitochondrial organellar proliferation, and markers of adipocyte differentiation and phenotype. Design and methods DNA and mRNA quantification using real-time PCR methods was performed on adipose tissue samples from 31 HIV-infected individuals, of whom 11 were treatment-naive and 20 were receiving HAART. mtDNA depletion was measured as mtDNA copies/cell, and mitochondrial proliferation by quantification of mitochondrial protein mass. Regulation of mitochondrial biogenesis was assessed by NRF-1 and mtTFA mRNA. PPAR γ, UCP2 and UCP1 mRNA expression was used to assess adipocyte differentiation and phenotype. Results Stavudine-based HAART recipients ( n=10) displayed significant mtDNA depletion (12.8% of control, P<0.001), mildly increased mitochondrial protein mass (2.6-fold of control, P=0.032) and decreased expression of PPARγ (53.9% of control, P=0.021), UCP2 (62.2% of control, P=0.024) and UCP3 (51.8% of control, P=0.047) mRNA compared with controls. Zidovudine-based HAART recipients ( n=7) also displayed significant mtDNA depletion (34.45% of control, P=0.031), increased mitochondrial protein mass (5.7-fold of control, P=0.009), and markedly increased UCP1 (18-fold of control, P=0.009) mRNA. Elevated UCP1 mRNA expression was found to be associated with non-stavudine (zidovudine or abacavir), protease inhibitor (PI)-containing HAART (95-fold of non-stavudine, non-PI-containing HAART, P=0.006). Conclusion Differential effects of stavudine and zidovudine therapy on mtDNA depletion and expression of adipocyte differentiation markers PPARγ and UCP2 were observed, consistent with increased adipose tissue toxicity associated with stavudine therapy. Increased UCP1 mRNA, a marker of brown adipose tissue phenotype, was associated with non-stavudine, PI-containing HAART, and may represent an adaptive response to the increased fatty acid flux associated with PI therapy, and may contribute to the increased resting energy expenditure reported in such patients.
Once-A-Day Therapy for HIV Infection: A Controlled, Randomized Study in Antiretroviral-Naive HIV-1-Infected Patients
Authors: Maggiolo Franco , Ripamonti Diego , Gregis Gianpietro , Quinzan Gianpaolo , Callegaro Annapaola , Arici Claudio , Ravasio Laura , Suter Fredy 
Published: April 2022

Background Complex antiretroviral regimens require optimal adherence to maintain long-lasting effectiveness. Simpler regimens, possibly with easy schedule and low pill burden, are needed for the long-term treatment of HIV infection. Objective To assess the efficacy and tolerability of a once-a-day highly active antiretroviral therapy (HAART) compared with two other conventional twice-a-day regimens. Methods In a prospective and randomized study, anti-retroviral-naive patients received either EFV+ddI+3TC (once-a-day regimen; OD), or EFV+Combivir® (twice-a-day and low-pill burden regimen; BID-low) or NFV+Combivir (twice-a-day and high-pill burden regimen; BID-high). Primary outcome was the proportion of patients with viral load <50 copies/ml at week 52 of follow-up. Results were evaluated according to intention-to-treat and on-treatment analysis. Results Thirty-four patients in each arm were enrolled. Baseline characteristics were similar in the three groups. The proportion of patients with viral load <50 copies/ml at week 52 were 74.4, 74.4 and 50.0% for OD group, BID-low group and BID-high group, respectively ( P=0.02, ITT analysis). According to on-treatment analysis, the same figures were 88.9, 85.7 and 60% ( P<0.02). Overall, 26 (25.5%) patients discontinued treatment for different reasons and immune recovery was similar in all study arms. Conclusions Once-a-day HAART with ddI+3TC+EFV is a safe and effective alternative to twice-a-day regimens. Once-a-day therapy, with its simple daily schedule, may be proposed as one of the first choice treatments in HIV infection.