bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered Fat Differentiation and Adipocytokine Expression are Inter-Related and Linked to Morphological Changes and Insulin Resistance in HIV-1-Infected Lipodystrophic Patients
Authors: Jan Véronique , Cervera Pascale , Maachi Mustapha , Baudrimont Marielle , Kim Minji , Vidal Hubert , Girard Pierre-Marie , Levan Philippe , Rozenbaum Willy , Lombès Anne , Capeau Jacqueline , Bastard Jean-Philippe 
Published: April 2022

Objective To achieve a better understand of the pathophysiology of HIV-related lipoatrophy, we compared the mRNA expression of adipocytokines in fat samples from patients and healthy HIV-seronegative controls together with fat morphology and we studied the relationship between changes in fat morphology, adipocytokine expression, markers of adipose tissue differentiation and whole body insulin sensitivity. Design Cross-sectional analytical study. Subjects and methods The mRNA expression of adipocytokines and transcriptional factors in fat samples from 26 patients with peripheral lipoatrophy (all under anti-retroviral therapy associating protease inhibitor and nucleoside-analogue reverse transcriptase inhibitors) and from 16 non-HIV-infected controls was measured by real time quantitative RT-PCR. Fat morphology was assessed histologically on a subgroup of 10 patients and six controls: collagen fibres by Sirius Red staining, apoptosis by the TUNEL technique, vessels by smooth muscle α-actin staining and macrophages by CD68 staining. Insulin resistance was assessed by using the homeostasis model assessment. Results The patients’ fat showed higher values of apoptosis ( P=0.005), fibrosis ( P<0.05), vessel density ( P=0.001) and macrophage infiltration ( P<0.05) than the controls’ fat, together with lower adiponectin and leptin mRNA levels and higher interleukin (IL)-6 and tumour necrosis factor (TNF)α mRNA levels. TNFα and IL-6 expression correlated positively with the level of apoptosis ( P=0.05 and P<0.05, respectively) and negatively with CCAAT-enhancer binding protein (C/EBP)α ( P<0.001 and P<0.05, respectively). Apoptosis correlated negatively with the expression level of sterol-regulatory-element-binding-protein-1c (SREBP1c) ( P=0.01) and C/EBPα ( P=0.01) whilst the vessel density correlated negatively with SREBP1c ( P<0.005), C/EBPα ( P=0.001) and β ( P=0.001). Adiponectin and leptin expression correlated positively with each other, and also with adipogenic marker expression and overall insulin sensitivity. These relationships were also present when the patient group was studied separately. Finally, fat morphological abnormalities correlated positively with whole body insulin resistance. Conclusions Adipose tissue from patients with HIV-1-related lipoatrophy shows increased apoptosis, together with decreased adipocyte differentiation. Increased TNFα and IL-6 expression could be a major phenomenon linking these alterations. Decreased adiponectin and leptin expression, which may result from decreased adipocyte differentiation, could be involved in the observed whole body insulin resistance.
Immunomodulation Induced by Tucaresol in HIV Infection: Results of a 16 Week Pilot Phase I/II Trial
Authors: Gori Andrea , Trabattoni Daria , Bandera Alessandra , Saresella Marina , Marchetti Giulia , Gazzola Lidia , Biasin Mara , Rhodes John , McDade Hugh , Panebianco Ruggero , Galli Massimo , Moroni Mauro , Ferrante Pasquale , Thomas Nicola , Franzetti Fabio , Bray Dorothy , Clerici Mario 
Published: April 2022

Objective Immune reconstitution in highly active anti-retroviral therapy (HAART)-treated individuals is incomplete and immunomodulatory compounds are needed to improve the outcome of HIV therapy. In a Phase I/II clinical trial performed on HIV-positive patients we analysed the safety and immunomodulating effects of tucaresol, a novel compound that has previously been described to enhance cell-mediated immune responses. Patients and methods Sixteen weeks pulse dose escalation protocol. Four groups of HIV-positive patients were enrolled: group A ( n=6): HAART, CD4+ 300–500 cells/μl, HIV RNA <80 copies/ml; group B ( n=6): HAART-naive, CD4+ <500 cells/μl, HIV RNA >10 000 copies/ml; group C ( n=3): HAART-naive, CD4+ >500 cells/μl, HIV RNA <10 000 copies/ml; and group D ( n=6): HAART, CD4+ <200 cells/μl, HIV RNA <80 copies/ml. Tucaresol was added to HAART in group A and D patients; group B patients started tucaresol with HAART, group C patients received tucaresol alone. Clinical and immunological analyses were performed at different time points. Results Tucaresol-related serious adverse events were observed in the first week of therapy in 2/21 patients who were viraemic when commencing treatment, but did not occur in patients on stable HAART. Tucaresol did not affect HIV viraemia whereas increases in CD4+ percentages, mainly supported by naive CD4+ cells, were observed. CD8+/28-/45RA+ cells and HIV-specific CD8+ IFNγ- and perforin-producing cells improved whereas IL-10 mRNA diminished in tucaresol-treated patients. The effects were greater with 25 mg given every other day for 1 week. Conclusion In HAART-receiving patients with proper virus suppression, tucaresol was not associated with serious adverse events and resulted in qualitative and quantitative stimulation of HIV-specific cytotoxic T lymphocyte activity and generation of naive T cells. These data may support further exploration of tucaresol use in reconstitution of immune system parameters in HIV patients with proper virus suppression while on HAART.
Alternation of Antiretroviral Drug Regimens for HIV Infection. Efficacy, Safety and Tolerability at Week 96 of the Swatch Study
Authors:   on behalf of the Swatch Study Team, Negredo Eugenia , Paredes Roger , Peraire Joaquim , Pedrol Enric , Côté Helene , Gel Silvia , Fumaz Carmina R , Ruiz Lidia , Abril Vicente , de Castro Eduardo Rodriguez , Ochoa Claudia , Martinez-Picado Javier , Montaner Julio , Rey-Joly Celestino , Clotet Bonaventura , Clotet B , Ruiz L , Martinez-Picado J , Gel S , Fumaz CR , Muñoz-Moreno JA , Bonjoch A , Martínez JC , Miranda J , Puig J , Arisa ER , Tuldrà A , Bonjoch A , Jou A , Tural C , Sirera G , Romeu J , Negredo E , Zala C , Ochoa C , Cahn Pedro , Torres O , Domingo P , Vilaró J , Llibre JM , Peraire J , Vidal F , Richart C , Viladés C , Martín L , Rodríguez R , Mata R , Viciana P , Abril V , Rubio R , Torralba M , Cervantes M , Gatell JM , Lonca M , Ruiz I , Azuaje C , Pedrol E , Rodríguez de Castro E 
Published: April 2022

Introduction Alternation of antiretroviral drug regimens has been proposed as a novel treatment strategy for HIV infection. However, some concerns persist regarding antiviral efficacy, adherence, toxicity and resistance evolution in the long term. Methods A total of 161 antiretroviral-naive HIV-1-infected patients were randomized to receive stavudine/ didanosine/efavirenz (group A) or zidovudine/lamivudine/ nelfinavir (group B) or to alternate between the two regimens every 3 months starting with regimen A (group C). Antiviral efficacy, adherence, safety and tolerability were analysed every 12 weeks. Results After 96 weeks, time to virological failure was significantly delayed in the alternating regimen compared with the standards of care regimens. Virological suppression was seen in 46%, 48% and 58% of patients in groups A, B and C, respectively, in the intention-to-treat analysis and in 75%, 76% and 97% in the on-treatment analysis (A vs C: P=0.014; B vs C: P=0.016; A vs B: P=0.849). At the end of the study, 94% of patients in group A and 92% in groups B and C reported an adherence greater than 95%. Alternating therapy was associated with a similar impact on CD4+ counts in comparison with the standards of care regimens, as well as a lower mitochondrial DNA/nuclear DNA (mtDNA/nDNA) ratio decrease in the mitochondrial substudy performed on 37 patients. The frequency and intensity of adverse events in the alternating group decreased during subsequent cycles. Discussion Our results favour the hypothesis that proactive therapy switching may delay the accumulation of resistance mutations. Moreover, the alternating regimen was well tolerated and adherence remained comparably high in all treatment groups. The lower mtDNA/nDNA ratio decrease observed in this group may imply a lower impact on mitochondrial toxicity than in standard regimens.
Depressive Symptoms after Initiation of Interferon Therapy in Human Immunodeficiency Virus-Infected Patients with Chronic Hepatitis C
Authors: Laguno Montserrat , Blanch Jordi , Murillas Javier , Blanco Jose Luis , León Agathe , Lonca Montserrat , Larrousse Maria , Biglia Alejandra , Martinez Esteban , García Felipe , Miró Jose M , de Pablo Joan , Gatell Josep M , Mallolas Josep 
Published: April 2022

Background Interferon alpha (IFN-α) therapy for chronic hepatitis C (CHC) infection is commonly associated with neuropsychiatric side effects including depressive symptomatology. In this study, we evaluated the incidence and management of depressive symptoms during IFN-α therapy in HIV-infected patients with CHC. Methods HIV-infected patients with CHC who began IFN-α and ribavirin therapy during the recruitment period April 2001 to April 2003 were included in the study. Patients with a history of major depressive disorder were excluded. Results Of 113 co-infected patients who started IFN-α therapy during the recruitment period, 45 (40%) developed symptoms of depression (sadness, tiredness and apathy). Twenty of them (44%) were treated with citalopram, a selective serotonin re-uptake inhibitor, resulting in a significant improvement in their symptoms. Most of the patients (60%) showed depressive side effects in the first 3 months after initiation of IFN-α. In addition, during the study, three patients developed psychotic symptoms and one committed suicide. Conclusions The incidence of depressive symptoms in patients with HIV/HCV co-infection treated with IFN-α is high. Most of the depressive symptoms were not severe and improved with antidepressant therapy, without reduction or cessation of IFN-α therapy. During the first weeks after initiating IFN-α therapy for HIV/HCV co-infection, close assessment of psychiatric symptoms is recommended. Early treatment of these side effects with antidepressants would help avoid early dropouts from interferon therapy.
A Randomized Controlled Trial to Enhance Antiretroviral Therapy Adherence in Patients with a History of Alcohol Problems
Authors: Samet Jeffrey H , Horton Nicholas J , Meli Seville , Dukes Kim , Tripp Tara , Sullivan Lisa , Freedberg Kenneth A 
Published: April 2022

Objective To assess the effectiveness of an individualized multicomponent intervention to promote adherence to antiretroviral therapy (ART) in a cohort of HIV-infected individuals with a history of alcohol problems. Design We conducted a randomized controlled trial to compare the usual medical follow-up with an adherence intervention. Setting The principal enrolment site was Boston Medical Center, a private, not-for-profit, academic medical institution. Subjects HIV-infected patients with a history of alcohol problems on ART. A total of 151 were enrolled and 141 (93%) were assessed at follow-up. Intervention A nurse, trained in motivational interviewing, completed the following over 3 months in four encounters: addressed alcohol problems; provided a watch with a programmable timer to facilitate pill taking; enhanced perception of treatment efficacy; and delivered individually tailored assistance to facilitate medication use. Main outcome measures Prior 30-day adherence ≥95%, prior 3-day adherence of 100%, CD4 cell count, HIV RNA and alcohol consumption, each at both short- and long-term follow-up. Results At follow-up, no significant differences in medication adherence, CD4 cell count, HIV RNA or alcohol consumption were found (all P values >0.25). Conclusions: A multicomponent intervention to enhance adherence among HIV-infected individuals with a history of alcohol problems was not associated with changes in medication adherence, alcohol consumption or markers of HIV disease progression. The failure to change adherence in a group at high risk for poor adherence, despite utilizing an intensive individual-focused patient intervention, supports the idea of addressing medication adherence with supervised medication delivery or markedly simplified dosing regimens.
Similar Reduction of Cytomegalovirus DNA Load by Oral Valganciclovir and Intravenous Ganciclovir on Pre-Emptive Therapy after Renal and Renal–Pancreas Transplantation
Authors: Kalpoe Jayant S , Schippers Emile F , Eling Yoav , Sijpkens Yvo W , de Fijter Johan W , Kroes Aloys CM 
Published: April 2022

Background Pre-emptive treatment of CMV infection in transplant recipients aims at prevention of clinical disease by early detection. However, current treatment requires the intravenous (iv) administration of ganciclovir for 2 weeks, which is a considerable burden for the patient. In this observational study, the efficacy of the new oral prodrug valganciclovir was compared with iv ganciclovir. Methods To facilitate the introduction of valganciclovir, a therapeutic guideline was developed to use this drug under controlled conditions with regard to safety in renal/renal–pancreas transplant recipients requiring CMV therapy. Subsequently, a group of 57 consecutive transplant recipients was evaluated. Onset and treatment of CMV infections were followed by frequent monitoring of CMV DNA in plasma by quantitative real-time PCR. Details of antiviral therapy were documented. Results In 15 out of 57 transplant recipients, a total of 27 anti-CMV treatment episodes were recorded: 18 with valganciclovir (900 mg twice daily) and nine with iv ganciclovir (5 mg/kg twice daily) as initial treatment. Median CMV DNA load reduction during treatment was 0.12 log10/day in the valganciclovir group and 0.09 log10/day in the ganciclovir group. There were no haematological side effects in any group and no patient developed signs of clinical CMV disease. Conclusion Similar reduction of CMV DNA load was observed during pre-emptive treatment with oral valganciclovir and iv ganciclovir in transplant recipients. Oral valganciclovir would provide an attractive and safe alternative for pre-emptive CMV treatment in renal/renal–pancreas transplant patients, however, confirmation in larger randomized studies would be desirable.
Influence of Rosiglitazone on Flow-Mediated Dilation and Other Markers of Cardiovascular Risk in HIV-Infected Patients with Lipoatrophy
Authors: Kovacic Jason C , Martin Allison , Carey Dianne , Wand Handan , Mallon Patrick WG , Feneley Michael P , Emery Sean , Cooper David A , Carr Andrew 
Published: April 2022

Background Antiretroviral therapy for HIV infection is commonly complicated by lipoatrophy, insulin resistance and dyslipidaemia. In HIV-uninfected adults with insulin resistance or type 2 diabetes, thiazolidinediones can lower blood pressure and improve both insulin sensitivity and endothelial function. This study sought to investigate the effects of rosiglitazone on endothelial function and other markers of cardiovascular risk in patients with HIV-related lipoatrophy. Methods HIV-infected, lipoatrophic adults receiving anti-retroviral therapy were randomized to receive either rosiglitazone 4 mg or matched placebo, twice daily. Percentage flow-mediated forearm arterial dilation (FMD%) was measured at weeks 0, 12, 24 and 48, together with other markers of vascular risk (blood pressure, lipids, glycaemic parameters, adiponectin and leptin). Results Out of 64 enrolled adults, 44 (69%) attended all visits (23 rosiglitazone, 21 placebo). Relative to placebo, at week 48, rosiglitazone decreased systolic blood pressure (8 mmHg, P=0.03), insulin (3 μIU/ml, P=0.02), insulin resistance ( P=0.03) and leptin (0.6 ng/ml, P=0.02), whilst adiponectin was increased (3.3 μg/ml, P<0.0001). However, rosiglitazone increased total cholesterol (49.1 mg/dl, P=0.001), low-density lipoprotein cholesterol (23.5 mg/dl, P=0.01) and triglycerides (146 mg/dl, P=0.06). Mean baseline FMD% for the entire cohort was moderately impaired (4.5%). Compared with baseline, mean on-treatment FMD% increased by 0.8% with rosiglitazone and decreased by 0.3% with placebo (mean difference 1.1%, 95% CI -0.2 to 2.5, P=0.09). Conclusions Rosiglitazone has minimal effect on flow-mediated dilation in HIV-infected lipoatrophic adults. However, despite worsening of the lipid profile, the overall effect of rosiglitazone on the cardiovascular risk profile in these subjects was positive.
Mitochondrial Toxicity of Nucleoside Analogues in Primary Human Lymphocytes
Authors: Setzer Bernhard , Schlesier Michael , Thomas Anna K , Walker Ulrich A 
Published: April 2022

Objective To evaluate if nucleoside analogue reverse transcriptase inhibitors (NRTIs) and polymerase-gamma inhibitors deplete mitochondrial DNA (mtDNA) in cultured primary lymphocytes and if such depletion might be associated with functional defects. Methods Primary peripheral blood CD4 and CD8 lymphocytes were purified from six healthy humans (three male and three female), stimulated mitotically (CD3/CD28) and cultured for 10 days in the presence or absence of NRTIs. Lymphocyte proliferation, mtDNA content, the expression of mtDNA-encoded cytochrome c-oxidase II (COXII) and lactate production were assessed. Results In CD4 lymphocytes, 10-day exposure to zalcitabine (1.77 μM), didanosine (118 μM) and stavudine (36 μM) induced a time-dependent decline of mtDNA. Compared with controls, residual mtDNA levels were 25%, 21% and 40%, respectively. COXII was reduced to 55%, 35% and 70% of control values. Lactic acid production was increased (by 214%, 294% and 175%, respectively). At day 10, lymphocyte counts were reduced (to 60%, 51%, and 41%, respectively). Zidovudine (71 μM) also reduced lymphocyte counts to 34% and increased lactic acid production by 170%, but did not induce mtDNA and COXII depletion. All these changes were highly significant. Lower NRTI concentrations (0.177 μM of zalcitabine, 11.8 μM of didanosine, 3.6 μM of stavudine and 7.1 μM of zidovudine) had effects at the border of significance. Similar observations were made in CD8 lymphocytes. Conclusions In human lymphocytes, zalcitabine, didanosine and stavudine induce dose- and time-dependent mtDNA depletion, which is associated with decreased cell proliferation and increased lactate production. Zidovudine impairs lymphocyte division without inducing mtDNA depletion.
Clinical Characteristics of Iris Syndrome in Patients with HIV and Tuberculosis
Authors: Michailidis Christos , Pozniak Anton L , Mandalia Sundhiya , Basnayake Sheena , Nelson Mark R , Gazzard Brian G 
Published: April 2022

Background Some patients with HIV/tuberculosis (TB) coinfection who are on anti-TB treatment and highly active antiretroviral therapy (HAART) will develop an exacerbation of symptoms, signs or radiological manifestations of TB that are not due to relapse or recurrence of their TB. The aetiology of these immune reconstitution inflammatory syndrome (IRIS) reactions is unknown but it is presumed that they occur, at least in part, as a consequence of HAART-related reconstitution of immunity. Methods Patients who were diagnosed with their first episode of definitive or presumed TB between January 2001 and July 2003 were identified from the Chelsea and Westminster TB/HIV database. The patients were classified into those who developed IRIS and those who did not using a set definition of the syndrome. Demographic, clinical and laboratory data relating to both HIV and TB were compared between the two groups. Results A total of 55 cases of TB were identified, of which 45 cases were confirmed on culture or gene probe and 10 were presumed cases. Fourteen cases (25.5%) developed IRIS with a median (range) duration of 2.53 (0.53–14.97) months. The median baseline CD4 [interquartile range (IQR)] for the IRIS group was significantly lower at 80 (33–117) cells/mm3 ( P=0.05) than the non-IRIS group at 139 (77–284) cells/mm3. A significantly greater proportion of patients in the IRIS group [11/14 (78.6%), P=0.011] had baseline CD4 <100 cells/mm3 compared with the non-IRIS group [16/41 (39.0%)]. There was no significant difference between the two groups when comparing the log10 baseline viral load (VL). Eight (57.0%) patients in the IRIS group had disseminated TB at baseline compared with seven (17.0%) in the non-IRIS group ( P=0.006). In those who had a detectable VL at baseline, the median fold change (IQR) in CD4 from baseline to 3 months was significantly higher in the IRIS group patients, 1.5 (0.6–5.6), compared with 0.7 (-0.2 to 1.0) for those in the non-IRIS group ( P=0.046). Conclusions Patients who develop IRIS are more likely to present with disseminated TB, have a CD4 count <100 cells/mm3 and have a prompt rise in CD4 count in the initial 3 months of HAART.
The Clinical Utility of Using Catrimox-14-Treated Whole Blood in Detecting Hepatitis C Virus RNA
Authors: Patel Keyur , Albrecht Jeff , Owens Erin , Dev Anouk , Heaton Shanon , Pianko Stephen , Pockros Paul J , Conrad Andrew , Blatt Lawrence M , McHutchison John G 
Published: April 2022

Background Measuring hepatitis C virus (HCV) RNA in serum or plasma may underestimate the true HCV burden. Extracting viral RNA from whole blood (WB) with a cationic surfactant (Catrimox-14) has resulted in HCV RNA concentrations up to 1000-fold higher than from serum or plasma in some studies, but not others. We compared the Catrimox-14 WB assay with a standard serum assay. Methods Seventy-two chronic HCV patients received 48 weeks of standard or pegylated interferon alpha-2b and ribavirin therapy. Catrimox-14-treated WB and corresponding serum samples were obtained at baseline and weeks 12, 24, 48 and 72. HCV RNA concentrations from WB and serum were quantified by a previously validated RT-PCR assay. Results Overall mean (±SD) baseline serum log10 HCV RNA concentration was 6.5 ((±0.58) copies/ml. Out of 72 patients, 33 had no detectable virus at 72 weeks. Neither assay detected virus in these patients at 12 weeks and neither WB nor serum assays detected virus at end-of-treatment in the 10 patients who subsequently relapsed at 72 weeks. HCV RNA concentrations from WB and serum assays were linearly correlated (R2=0.73; P<0.001), although mean serum HCV RNA concentrations were 0.5 log10 copies/ml higher in serum than in WB [6.0 (±0.82) vs 5.5 ((±0.84), respectively, P=0.12]. Conclusions Catrimox-14-treated WB assays detect changes in HCV RNA, but do not offer clinical advantage over a conventional serum RT-PCR based assay.