bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of Depressive Symptoms at ART Initiation on HIV Clinical Progression and Mortality: Implications in Clinical Practice
Authors: Villes Virginie , Spire Bruno , Lewden Charlotte , Perronne Christian , Besnier Jean-Marc , Garré Michel , Chêne Geneviève , Leport Catherine , Carrieri Maria Patrizia , Le Moing Vincent ,   ANRS CO-8 APROCO-COPILOTE Study Group
Published: April 2022

Background Depression is common in HIV-infected patients receiving antiretroviral therapy. However, longitudinal studies addressing the role that depression might play in HIV clinical progression and mortality remain rare. This is especially true for those studies that also consider the possible confounding influence of patient's adherence to treatment. Methods The ANRS CO-8 APROCO-COPILOTE cohort study enrolled 1,281 individuals at the initiation of a protease-inhibitor-containing regimen between 1997 and 1999. Adherence, depressive symptoms and other psychosocial factors were measured using self-administered questionnaires. Predictors of progression to AIDS or death were studied using Cox models. Results Out of 1,028 individuals eligible for the present analysis, 92 individuals either died or had an AIDS-defining event during a median follow up of 54 months. At baseline, 377 individuals (41%) reported depressive symptoms and 124 (12%) reported non-adherence at month 4. Depressive symptoms at baseline were associated with progression (hazard ratio [HR] 2.1; P=0.001). Despite the association between depressive symptoms and non-adherence, depressive symptoms remained a predictor of clinical progression (adjusted HR [aHR] [95% confidence interval (CI)] 1.6 [1.0–2.5]) after adjustment for several factors: initial non-adherence (aHR [95% CI] 2.0 [1.1–3.6]), having a steady partner (aHR [95% CI] 0.5 [0.3–0.7]), older age (aHR [95% CI] 1.40 [1.12–1.74] per 10-year increment), HIV clinical stage C (aHR [95% CI] 2.5 [1.6–4.0]), plasma HIV RNA ≥100,000 copies/ml (aHR [95% CI] 1.7 [1.1–2.87]) and more than 8 years since HIV diagnosis (aHR [95% CI] 1.8 [1.1–2.8]). Conclusion Depressive symptoms and non-adherence are independent predictors of HIV clinical progression and mortality. Screening and appropriate treatment of depressive symptoms at antiretroviral treatment initiation should be included in the standard care of HIV-infected patients.
Modelling of Early Viral Kinetics and Pegylated Interferon-α2b Pharmacokinetics in Patients with HBeAg-Positive Chronic Hepatitis B
Authors: Ter Borg Martijn J , Hansen Bettina E , Herrmann Eva , Zeuzem Stefan , Cakaloglu Yilmaz , Karayalcin Selim , Flisiak Robert , Van ‘t Veen Annemarie , De Man Robert A , Schalm Solko W , Janssen Harry LA , Haagmans Bart L ,   for the HBV 99–01 Study Group
Published: April 2022

Background Pegylated interferon α2b (PEG-IFN-α2b) is effective for the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B, although its mechanism of action remains unclear. HBeAg loss is achieved in 36% of patients after one year of PEG-IFN-α2b treatment and combination therapy with lamivudine is not superior to PEG-IFN-α2b monotherapy. Methods Early pharmacokinetics and viral kinetics were analysed in patients treated for 52 weeks with PEG-IFN-α2b with or without lamivudine. Results After 4 weeks of treatment, there was a median viral decline of 2.94 log10 copies/ml in those treated with PEG-IFN-α2b and lamivudine and only 0.45 log10 copies/ml in the PEG-IFN-α2b monotherapy group. Peak PEG-IFN-α2b levels were reached approximately one day after administration and subsequently declined exponentially, consistent with a viral load rebound near to baseline levels at the end of the dosing period in most patients receiving PEG-IFN-α2b monotherapy. Modelling of pharmacokinetics and viral kinetics data in this group revealed that viral load was minimal 3.6 days after PEG-IFN-α2b administration, the mean maximal and mean antiviral effectiveness was 70% and 48% with a mean infected cell loss rate of 0.07 per day, while no significant biphasic decline was observed. Conclusions PEG-IFN-α2b induces a sustained response in a considerable number of patients despite limited direct antiviral activity during the first weeks of antiviral therapy.
Virological response to Salvage Therapy in HIV-Infected Persons Carrying the Reverse Transcriptase K65R Mutation
Authors: Antinori Andrea , Trotta Maria Paola , Lorenzini Patrizia , Torti Carlo , Gianotti Nicola , Maggiolo Franco , Ceccherini-Silberstein Francesca , Nasta Paola , Castagna Antonella , Luca Andrea De , Mussini Cristina , Andreoni Massimo , Perno Carlo Federico ,   for the GNOMO Study Group
Published: April 2022

Background The effect of the HIV reverse transcriptase K65R mutation on virological response to salvage therapy has not been clearly defined. Methods From six Italian clinical centres, all consecutive patients starting salvage antiretroviral therapy after virological failure in the presence of the K65R mutation identified by a genotypic resistance test were selected. Results Among 145 subjects included over a 197 person-year follow-up, the estimated probability of virological response (VR, defined as reaching HIV RNA <50 copies/ml after salvage therapy) at 24 and 48 weeks was 36% and 60%, respectively. The strongest independent predictor of VR was the inclusion of a thymidine analogue (TA) in the salvage regimen. The presence of M184V and the introduction of lopinavir/ritonavir as new drug were both marginally associated with better outcome. After 24 weeks of salvage therapy, the median reduction in HIV-1 RNA was -1.36 log10 copies/ml (interquartile range [IQR] 0.10–2.46): at multivariable regression analysis, salvage regimens containing a TA (β=+0.80; P=0.02) and lamivudine (β=+1.21; P=0.02) as new drug had a positive effect on the reduction of HIV-1 RNA. Conclusions Development of the K65R mutation does not preclude a high rate of virological response to rescue therapy. Inclusion of a TA in the salvage regimen and the presence of a M184V mutation could have a favourable effect on virological outcome.
The 3-O-(3’,3’-dimethylsuccinyl) derivative of betulinic acid (DSB) inhibits the assembly of virus-like particles in HIV-1 Gag precursor-expressing cells
Authors: DaFonseca Sandrina , Blommaert Armand , Coric Pascale , Hong Saw See , Bouaziz Serge , Boulanger Pierre 
Published: April 2022

Background The 3- O-(3’,3’-dimethylsuccinyl) derivative of betulinic acid (DSB) blocks HIV-1 maturation by interfering with viral protease (PR) at the capsid (CA)-SP1 cleavage site, a crucial region in HIV-1 morphogenesis. Methods We analysed the effect of DSB on the assembly of HIV-1 Gag precursor (Pr55GagHIV) into membrane-enveloped virus-like particles (VLP) in baculovirus-infected cells expressing Pr55GagHIV, in a cellular context devoid of viral PR. Results DSB showed a dose-dependent negative effect on VLP assembly, with an IC50∼10 μM. The DSB inhibitory effect was p6-independent and was also observed for intracellular assembly of non-N-myristoylated Gag core-like particles. HIV-1 VLP assembled in the presence of DSB exhibited a lower stability of their inner cores upon membrane delipidation compared with control VLP, suggesting weaker Gag-Gag interactions. DSB also inhibited the assembly of simian immunodeficiency virus SIVmac251 VLP, although with a twofold lower efficacy (IC50∼20 μM). No detectable inhibitory activity was observed for murine leukaemia virus (MLV) VLP; however, fusion of the SP1-NC-p6 domains from HIV-1 to the matrix (MA)-CA domains from MLV conferred DSB sensitivity to the chimaeric Gag precursor Pr72GagMLV–HIV (IC50=30 μM). This observation suggested that the main DSB target on Pr55Gag was the SP1 domain, but the higher degree of DSB resistance for Pr72GagMLV–HIV compared with Pr55GagHIV implied that other upstream Gag region(s) might contribute to DSB reactivity. Conclusions Sequence alignment and three-dimensional modelling by homology of the CA-SP1-NC junction in HIV-1, SIVmac251 and Pr72GagMLV–HIV suggested that a higher hydrophilic character of the CA region immediately upstream to the HIV-1 CA-SP1 junction, as occurred in Pr72GagMLV–HIV, correlated with a lower DSB sensitivity.
A 6-Month Interruption of Antiretroviral Therapy Improves Adipose Tissue Function in HIV-Infected Patients: The ANRS EP29 Lipostop Study
Authors: Kim Min Ji , Leclercq Pascale , Lanoy Emilie , Cervera Pascale , Antuna-Puente Barbara , Maachi Mustapha , Dorofeev Elena , Slama Laurence , Valantin Marc Antoine , Costagliola Dominique , Lombes Anne , Bastard Jean-Philippe , Capeau Jacqueline 
Published: April 2022

Objective To examine the reversibility of adipose tissue alterations in HIV-infected patients after a 6-month interruption of antiretroviral therapy (ART). Methods Forty HIV-infected patients on stable effective ART were enrolled, 33 of them completed the study. Patients underwent a physical examination, laboratory tests and needle biopsy of subcutaneous abdominal adipose tissue both at inclusion and at month 6. Changes in fat morphology, mitochondrial DNA (mtDNA) content and gene expression were examined in 29, 23 and 20 patients, respectively. Results Body fat distribution was not clearly modified at month 6. Adipose tissue inflammation improved markedly, with fewer infiltrating macrophages and fewer tumour necrosis factor a (TNFα)- and interleukin 6 (IL6)-expressing cells. Expression of peroxisome proliferator-activated receptor γ (PPAR-γ) and of markers of mitochondrial function and biogenesis (cytochrome oxidase 2 and PPAR-γ coreceptor 1α) improved after protease inhibitor (PI) withdrawal. In patients who stopped taking stavudine or zidovudine, the number of TNFα- and IL6-expressing cells was lower at month 6 than at month 0, and so was CD68 expression, a macrophage marker. Adipocyte mitochondrial status also improved, with lower mitochondrial density and cytochrome oxidase 4 mRNA levels, and higher mtDNA content. Sterol regulatory element binding protein 1 mRNA levels increased, reflecting better adipocyte differentiation. Conclusions A 6-month ART interruption markedly improved adipose tissue functions, although fat distribution did not visibly change. Stavudine and zidovudine were associated with marked inflammation, which improved when these drugs were withdrawn; they also had a negative effect on differentiation and mitochondrial status. PIs were also associated with altered adipocyte differentiation and mitochondrial status. These data clearly show the detrimental effect of antiretroviral drugs, in particular thymidine analogues, on adipose tissue and argue for switch strategies sparing these drugs.
Tenofovir Use is associated with a Reduction in Calculated Glomerular Filtration Rates in the Swiss HIV Cohort Study
Authors: Fux Christoph A , Simcock Mathew , Wolbers Marcel , Bucher Heiner C , Hirschel Bernard , Opravil Milos , Vernazza Pietro , Cavassini Matthias , Bernasconi Enos , Elzi Luigia , Furrer Hansjakob ,   Swiss HIV Cohort Study, Battegay M , Bernasconi E , Böni J , Bucher H , Bürgisser Ph , Cattacin S , Cavassini M , Dubs R , Egger M , Elzi L , Erb P , Fischer M , Flepp M , Fontana A , Francioli P , Furrer H , Fux C , Gorgievski M , Günthard H , Hirschel B , Hösli I , Kahlert Ch , Kaiser L , Karrer U , Keiser O , Kind C , Klimkait Th , Ledergerber B , Martinez B , Müller N , Nadal D , Opravil M , Paccaud F , Pantaleo G , Perrin L , Piffaretti J-C , Rauch A , Rickenbach M , Rudin C , Schmid P , Schultze D , Schüpbach J , Speck R , Taffé P , Tarr P , Telenti A , Trkola A , Vernazza P , Weber R , Yerly S 
Published: April 2022

Background A growing number of case reports have described tenofovir (TDF)-related proximal renal tubulopathy and impaired calculated glomerular filtration rates (cGFR). We assessed TDF-associated changes in cGFR in a large observational HIV cohort. Methods We compared treatment-naive patients or patients with treatment interruptions ≥12 months starting either a TDF-based combination antiretroviral therapy (cART) ( n=363) or a TDF-sparing regime ( n=715). The predefined primary endpoint was the time to a 10 ml/min reduction in cGFR, based on the Cockcroft-Gault equation, confirmed by a follow-up measurement at least 1 month later. In sensitivity analyses, secondary endpoints including calculations based on the modified diet in renal disease (MDRD) formula were considered. Endpoints were modelled using pre-specified covariates in a multiple Cox proportional hazards model. Results Two-year event-free probabilities were 0.65 (95% confidence interval [CI] 0.58–0.72) and 0.80 (95% CI 0.76–0.83) for patients starting TDF-containing or TDF-sparing cART, respectively. In the multiple Cox model, diabetes mellitus (hazard ratio [HR]=2.34 [95% CI 1.24–4.42]), higher baseline cGFR (HR=1.03 [95% CI 1.02–1.04] by 10 ml/min), TDF use (HR=1.84 [95% CI 1.35–2.51]) and boosted protease inhibitor use (HR=1.71 [95% CI 1.30–2.24]) significantly increased the risk for reaching the primary endpoint. Sensitivity analyses showed high consistency. Conclusion There is consistent evidence for a significant reduction in cGFR associated with TDF use in HIV-infected patients. Our findings call for a strict monitoring of renal function in long-term TDF users with tests that distinguish between glomerular dysfunction and proximal renal tubulopathy, a known adverse effect of TDF.
Contribution of Mitochondrial Dysfunction and Oxidative Stress to Cellular Premature Senescence Induced by Antiretroviral Thymidine Analogues
Authors: Caron Martine , Auclair Martine , Vissian Anais , Vigouroux Corinne , Capeau Jacqueline 
Published: April 2022

Objectives Treatment of HIV-infected patients is associated with early onset of aging-related comorbidities. Some of the adverse effects of antiretroviral therapy have been attributed to the mitochondrial toxicity of nucleoside reverse transcriptase inhibitors (NRTI), and it is of note that mitochondrial dysfunction and oxidative stress are involved in the aging processes. In this regard, we examined whether NRTIs could accelerate the senescence of cultured cells. Methods Human fibroblasts were exposed to NRTIs from culture passage 1 to 14. Cytochrome c-oxidase (COX) subunits 2 and 4, mitochondrial potential and mass, and reactive oxygen species (ROS) were quantified at each passage. Proliferation, cell-cycle arrest, senescence-associated β-galactosidase activity, and morphology were assessed in parallel. Mitochondrial and senescence markers were assessed in cultured murine preadipocytes and in fat samples from lipodystrophic HIV-infected patients. Results Stavudine and zidovudine induced mitochondrial dysfunction and increased ROS levels in fibroblasts at early culture passages, while cell division gradually slowed. At passages 8–12, fibroblasts exposed to stavudine or zidovudine but not abacavir, didanosine, lamivudine and tenofovir were senescent, on the basis of p16INK4 and p21WAF-1 protein expression, cell morphology and senescence-associated-β-galactosidase activity. Senescence markers and COX2 underexpression were also found in 3T3-F442A preadipocytes exposed for 7 weeks to stavudine or zidovudine, but not lamivudine, and in adipose tissue samples from lipodystrophic HIV-infected patients on antiretroviral regimens containing stavudine or zidovudine. Conclusions Mitochondrial changes and oxidative damage could partly explain the premature senescence of fibroblasts and adipose cells induced by stavudine and zidovudine. This suggests that thymidine analogues might be involved in the early aging-related diseases observed in some HIV-infected patients taking antiretroviral drugs.
Does Treatment of Hepatitis B virus (HBV) Infection Reduce Hepatitis Delta virus (HDV) Replication in HIV-HBV-HDV-Coinfected Patients?
Authors: Sheldon Julie , Ramos Belén , Toro Carlos , Ríos Pilar , Martínez-Alarcón José , Bottecchia Marcelle , Romero Miriam , Garcia-Samaniego Javier , Soriano Vincent 
Published: April 2022

Background Hepatitis delta virus (HDV) has a unique replication process that requires coinfection with hepatitis B virus (HBV). Treatment is currently limited to interferon therapy. The role of potent nucleos(t)ide analogues active against HBV has not been well examined in chronic delta hepatitis (CDH). Methods HIV-positive patients with CDH attending our hospital were identified and longitudinally studied. Serum HBV DNA, HDV RNA and HIV RNA, treatment regimens, and biochemical and serological markers were assessed at yearly intervals. Liver fibrosis was measured by transient elastography during the last 2 years. Results Sixteen patients were identified and treated with anti-HBV therapy (median time 6.1 years). The majority were male and previous intravenous drug users. Median baselines were: HDV RNA 7 log10 copies/ml, HIV RNA 1.7 log10 copies/ml, HBV DNA 1.1 log10 IU/ml and alanine aminotransferase (ALT) 98 IU/ml. A significant correlation was found between HDV RNA and HBV DNA (r=0.226, P=0.015), aspartate aminotransferase (r=0.430, P<0.0001), ALT (r=0.441, P<0.0001) and hepatitis B surface antigen (HBsAg) (r=0.557, P<0.0001). Overall, 13 patients showed a reduction in HDV viraemia and ALT levels, and three of them achieved undetectable HDV RNA and normal ALT levels. Conclusion Patients undergoing successful anti-HBV therapy with potent nucleos(t)ide analogues seem to indirectly benefit from suppression of HDV replication, albeit not very efficiently. Hypothetically, a significant and sustained reduction in serum HDV RNA might only be seen when a reduction in HBV covalently closed circular DNA or HBV surface antigen is achieved, which may require long periods of successful anti-HBV therapy. To our knowledge, this is the first evidence of the benefit of potent anti-HBV nucleos(t)ide analogue therapy in CDH.
Antiretroviral-Associated Portal Hypertension: A New Clinical Condition? Prevalence, Predictors and Outcome
Authors: Maida Ivana , Garcia-Gasco Pilar , Sotgiu Giovanni , Rios María José , Vispo María Eugenia , Martin-Carbonero Luz , Barreiro Pablo , Mura María Stella , Babudieri Sergio , Albertos Sonia , Garcia-Samaniego Javier , Soriano Vincent 
Published: April 2022

Background Cases of severe unexplained liver disease in HIV-infected individuals have recently been reported and are often associated with exposure to didanosine (ddI) and nodular regenerative hyperplasia. Herein, we examine the clinical outcome following ddI removal. Methods From 3,300 HIV-infected patients attending three clinics since 2004, all who exhibited persistently elevated aminotransferases and/or significant liver fibrosis in the absence of any known cause of liver damage were identified. Results Thirty-two individuals (prevalence ∼1%) met the inclusion criteria - all were on antiretroviral therapy. Of these, 84% were male and 68% had acquired HIV through homosexual contact. Liver biopsy was performed in 12, of whom three showed nonspecific advanced liver fibrosis, two nodular regenerative hyperplasia and three showed only periportal fibrosis. On follow up, nine patients developed episodes of hepatic decompensation, mainly as a consequence of portal hypertension; in eight cases (25%) portal thrombosis was diagnosed. No association was found with plasma HIV RNA or CD4+ T-cell count. All patients but three had been exposed to ddI for a median of 44 months; removal of ddI in 27 was followed 12 months later by improvement in clinical and laboratory parameters in 13 (48%) patients. Finally, a trend towards liver fibrosis improvement was recognised using FibroScan®. Conclusions Idiopathic persistent liver enzyme elevations in HIV-infected individuals are often associated with cirrhotic and non-cirrhotic portal hypertension. Although this is a relatively rare condition, prolonged exposure to ddI seems to play a pathogenic role and removal of the drug is associated with clinical and laboratory improvements.
Gln151 of HIV-1 Reverse Transcriptase Acts as a Steric Gate Towards Clinically Relevant Acyclic Phosphonate Nucleotide Analogues
Authors: Frangeul Antoine , Bussetta Cécile , Deval Jérôme , Barral Karine , Alvarez Karine , Canard Bruno 
Published: April 2022

Background In the treatment of HIV, the loose active site of the HIV-1 reverse transcriptase (RT) allows numerous nucleotide analogues to act as proviral DNA ‘chain-terminators’. Acyclic nucleotide phosphonate analogues (ANPs) represent a particular class of nucleotide analogue that does not possess a ribose moiety. The structural basis for their substrate efficiency regarding viral DNA polymerases is poorly understood. Methods Pre-steady-state kinetics on HIV-1 RT together with molecular modelling, were used to evaluate the relative characteristics of both the initial binding and incorporation into DNA of three different ANP diphosphates with progressively increasing steric demands on the acyclic linker: adefovir-diphosphate (DP), tenofovir-DP, and cidofovir-DP. Results The increase of steric demand in ANPs induced a proportional loss of the binding affinity to wild-type HIV-1 RT ( K d cidofovir-D P>> K d tenofovir-D P> K d adefovir-DP∼ K d dNTPs), consistent with the lack of HIV-1 inhibitory activity for cidofovir. We show that, starting from adefovir-DP, the steric constraints mainly map to Gln151, as its mutation to alanine provides cidofovir-DP sensitivity. Interactions between the Gln151 residue and the methyl group of tenofovir-DP further increase with the mutation Gln151Met, resulting in a specific discrimination and low-level resistance to tenofovir-DP. This alteration is the result of a dual decrease in the binding affinity ( K d) and the catalytic rate ( k pol) of incorporation of tenofovir-DP. By contrast, the tenofovir resistance mutation K65R induces a broad ‘ k pol-dependent’ nonspecific discrimination towards the three ANPs. Conclusions Overall, our results show that the efficiency of ANPs to compete against natural nucleotides as substrates for RT is determined by their close interaction with specific amino acids such as Gln151 within the RT active site. These results should help us to map and predict ANP sensitivity determinants in cellular and viral DNA polymerase active sites for which the understanding of different ANP sensitivity patterns are of medical importance.
When to Initiate Highly Active Antiretroviral Therapy in Low-Resource Settings: The Moroccan Experience
Authors: Loubiere Sandrine , el Filal Kamal Marhoum , Sodqi Mustapha , Loundou Anderson , Luchini Stéphane , Cleary Susan , Moatti Jean-Paul , Himmich Hakima 
Published: April 2022

Background The aim of this study was to assess the cost-effectiveness of HIV treatment alternatives – with and without highly active antiretroviral therapy (HAART) – within alternative strata based on the CD4+ T-cell count at the initiation of treatment in a low-resource setting. Methods A retrospective observational study was conducted following 286 HIV-positive individuals admitted to the principal teaching hospital in Casablanca, Morocco, between 1995 and 2002. Patients were stratified by CD4+ T-cell count and regression models were fitted to determine risk of opportunistic infection. Data on healthcare resource use were derived from patient records and were evaluated from the hospital perspective. Results HAART led to a significant reduction in the number of HIV-related opportunistic infections ( P<0.0001), extended survival (61.3 versus 55.2 months; P<0.0001) and reduced hospital stays ( P<0.0001) in comparison with care in the absence of HAART. When medical care and drug costs were considered together, HAART was more costly than providing treatment for opportunistic infections. The incremental cost-effectiveness ratio was lower than gross domestic product (GDP) per capita for patients starting HAART with a CD4+ T-cell count <200 cells/mm3, but this increased to nearly three times GDP per capita when HAART was initiated at CD4+ T-cell counts above this threshold. Conclusions HAART is more cost-effective than treating HIV-related opportunistic infections and, contrary to conclusions drawn in developed countries, HAART is more cost-effective when the CD4+ T-cell count drops to <200 cells/mm3.