bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drug-Class-Wide Resistance to Antiretrovirals in HIV-Infected Patients Failing Therapy: Prevalence, Risk Factors and Virological Outcome
Authors: Tozzi Valerio , Zaccarelli Mauro , Bonfigli Sandro , Lorenzini Patrizia , Liuzzi Giuseppina , Trotta Maria Paola , Forbici Federica , Gori Caterina , Bertoli Ada , Bellagamba Rita , Narciso Pasquale , Perno Carlo Federico , Antinori Andrea 
Published: April 2022

Background Drug-class-wide resistance (DCWR) to anti-retrovirals substantially reduces treatment options. Methods A database of 602 patients failing highly active antiretroviral therapy (HAART) undergoing genotypic resistance test (GRT) was analysed. DCWR was defined according to the International AIDS Society consensus. A multiple logistic regression model was built to define factors significantly associated with DCWR and to assess virological response to salvage regimens. Results NRTI DCWR was observed in 28.5% of 592 NRTI-exposed patients, NNRTI DCWR in 57.7% of 284 NNRTI exposed patients, PI DCWR in 19.9% of 412 PI exposed patients, and three-class resistance in 21.4% of 112 three-class-exposed patients. The prevalence of NRTI and PI DCWR increased significantly by year of exposure to the same class from 8.9% (<1 year) to 35.3% (>4 years) and from 1.2% (<1 year) to 34.8% (>4 years), respectively ( P<0.001, for trend). The risk of developing NRTI and PI DCWR increased by 25% (95% confidence interval [CI]: 1.6%–51.3%) and by 53% (20.5%–94.3%) for each year of treatment, and by 17% (95% CI: 5.6%–29.3%) and by 32% (17.7%–50.3%) for each previous failing NRTI- and PI-containing regimen, respectively. NRTI DCWR due to at least four nucleoside analogues mutations (NAMs) increased by year of NRTI exposure from 8.9% (<1 year) to 32.6% (>4 years; P<0.001, for trend). After adjustment for confounding factors, the probability of achieving plasma viral load <500 copies/ml was significantly reduced in patients with NRTI (OR: 0.750; 95% CI: 0.574–0.979), NNRTI (OR: 0.746; 95% CI: 0.572–0.975), PI (OR: 0.655; 95% CI: 0.456–0.941), three-class (OR: 0.220; 95% CI: 0.082–0.593) resistance. Conclusions The probability of developing NRTI and PI DCWR increased with length of class exposure and with the number of previously failing regimens. By contrast, high levels of NNRTI DCWR were observed within 1 year in NNRTI-failing patients, with a steady prevalence over time. The increase in prevalence with time of NRTI DCWR was due to the accumulation of NAMs. DCWR to NRTIs, NNRTIs, PIs or all the three together was associated with an increased probability of virological failure to subsequent HAART regimens.
Mitochondrial (Mt)Dna Changes in Tissue May Not be Reflected by Depletion of Mtdna in Peripheral Blood Mononuclear Cells in HIV-Infected Patients
Authors: Maagaard Anne , Holberg-Petersen Mona , Kollberg Gittan , Oldfors Anders , Sandvik Leiv , Bruun Johan N 
Published: April 2022

Objectives Most data on mitochondrial toxicity have been derived from peripheral blood mononuclear cells (PBMCs). However, whether mitochondrial DNA (mtDNA) content in PBMCs reflects the mitochondrial state in tissues remains elusive. We report herein on mitochondrial toxicity in skeletal muscle in HIV-infected patients naive to antiretroviral treatment (ART [HIV+ART-naive]; n=10) patients exposed to nucleoside reverse transcriptase inhibitors (NRTIs [HIV+NRTI+]; n=24) and healthy controls ( n=11), and compare these tissue data with mtDNA in PBMCs. Methods Muscle biopsies were examined for (i) mtDNA and nuclear DNA (nDNA) content using TaqMan realtime PCR system, (ii) mtDNA deletions using long expand PCR with subsequent gel electrophoresis, and (iii) mitochondrial myopathy expressed as cytochrome c oxidase (COX)-deficient muscle fibres. Results The mt/n DNA ratio in muscle from HIV+NRTI+patients was reduced compared with HIV-negative controls ( P=0.028). Moreover, mtDNA deletions were more frequent in HIV+NRTI+ patients than in both HIV-negative controls ( P=0.009) and HIV+ART-naive patients ( P=0.005). HIV+NRTI+ also tended to have more COX-deficient fibres than HIV-negative controls ( P=0.076). COX-deficient fibres were positively correlated with mtDNA deletions in HIV+NRTI+ patients (r=0.83, P<0.001). Patients with current use of didanosine (ddI) had more frequent mtDNA deletions and COX-deficient fibres than HIV+NRTI+ not on current treatment with ddI. It should be noted that mitochondrial alterations were not correlated with mtDNA/cell in PBMCs in any group. Conclusions In skeletal muscle, HIV+NRTI+ had a reduced mt/n DNA ratio, more frequent mtDNA deletions and possibly more COX-deficient muscle fibres than HIV-negative controls. However, the mtDNA/cell in peripheral blood was decreased in both HIV+NRTI+ and HIV+ART-naive patients. Thus, mtDNA in peripheral blood may not be a relevant marker of mitochondrial toxicity in organ-specific tissue.
A Smoking Cessation Programme in HIV-Infected Individuals: A Pilot Study
Authors:   the Swiss HIV Cohort Study, Battegay M , Bernasconi E , Böni J , Bucher H , Bürgisser P , Cattacin S , Cavassini M , Dubs R , Egger M , Elzi L , Erb P , Fischer M , Flepp M , Fontana A , Francioli P , Furrer H , Gorgievski M , Günthard H , Hirschel B , Hösli I , Kahlert Ch , Kaiser L , Karrer U , Keiser O , Kind C , Klimkait T , Ledergerber B , Martinez B , Müller N , Nadal D , Opravil M , Paccaud F , Pantaleo G , Perrin L , Bijker J-C , 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 , Elzi Luigia , Spoerl David , Voggensperger Jacqueline , Nicca Dunja , Simcock Mathew , Bucher Heiner C , Spirig Rebecca , Battegay Manuel 
Published: April 2022

Background Antiretroviral therapy (ART) is a risk factor for cardiovascular disease (CVD) and smoking the most important modifiable cardiovascular risk factor. Methods We prospectively evaluated a smoking cessation programme (SCP) in HIV-infected individuals (intervention: counselling and nicotine replacement therapy). Primary endpoint was the smoking cessation rate at 12 months; secondary endpoints were CVD morbidity and mortality. Controls were a not randomized control group of smokers not participating in the SCP. Results Four-hundred and seventeen of 680 (61%) patients were smokers, and 34 of these participated in the SCP. Of these 34 individuals, 82% were male, the median age was 43 years, prior AIDS was recorded in 29%, and depressive disorder was recorded in 18%. Twenty-five (74%) patients were receiving ART. Additional risk factors were dyslipidaemia (68%), a prior cardiovascular event (24%), hypertension (15%), and a family history of CVD in 2/34 (6%) individuals. According to the Framingham equation, the 10-year risk of CVD was higher in SCP participants than in controls (11.2% versus 8.5%, P=0.06). At termination of the SCP, 17/34 (50%) individuals had stopped smoking compared with 57/383 (15%) controls. Self-reported smoking abstinence for ≥12 months was 13/34 (38%) in the intervention group and 27/383 (7%) in the control group (odds ration 6.2, 95% confidence interval 2.8–14.3). During the follow-up, two SCP participants and 4 controls experienced a myocardial infarction. One patient in the control group died of CVD. Conclusions SCP in HIV-infected individuals is feasible and should be encouraged. The long-term impact of smoking cessation on CVD morbidity and mortality should be evaluated in comparative trials.
A Sustained Virological Response to Interferon or Interferon/Ribavirin Reduces Hepatocellular Carcinoma and Improves Survival in Chronic Hepatitis C: A Nationwide, Multicentre Study in Taiwan
Authors: Yu Ming-Lung , Lin Shi-Ming , Chuang Wan-Long , Dai Chia-Yen , Wang Jing-Houng , Lu Sheng-Nan , Sheen I-Shyan , Chang Wen-Yu , Lee Chuan-Mo , Liaw Yun-Fan 
Published: April 2022

Background The long-term benefit for chronic hepatitis C (CHC) patients treated with interferon (IFN)/ribavirin (RBV) combination therapy remains unclear. We aimed to evaluate the long-term effects of IFN monotherapy and IFN/RBV combination therapy on reducing hepatocellular carcinoma (HCC) and mortality in patients with chronic hepatitis C virus (HCV) infection, adjusting for risk factors. Methods A total of 1,619 patients with biopsy-proven CHC, including 1,057 receiving IFN-based therapy (760 on IFN/RBV combination therapy) and 562 untreated controls from three medical centres and one regional core hospital in Taiwan were enrolled in this retrospective-prospective cohort study. Results The incidence of HCC and survival during a follow-up period of 1.0–15.3 (mean 5.18) and 1–16 (mean 5.15) years in treated and untreated patients, respectively, was analysed using Cox proportional hazards regression. The cumulative incidence of HCC was 35.2% and 12.2% for untreated and treated groups, respectively ( P=0.0013). The cumulative survival rate was 93.1% and 96.2% for untreated and treated groups, respectively ( P=0.3928). Significantly lower incidences of HCC and mortality were observed in sustained virological responders (both for IFN monotherapy and IFN/RBV combination) but not in non-responders when compared with untreated patients. HCV genotype 1 patients had significantly higher incidences of HCC than genotype non-1 patients. In multivariate analysis, pre-existing cirrhosis, non-response, HCV geno-type-1 and age were associated with HCC; pre-existing cirrhosis and non-response correlated to mortality. Conclusion A sustained virological response secondary to IFN monotherapy or IFN/RBV combination therapy could reduce the risk for HCC and improve survival of CHC patients.
Pegylated Interferon-α for the Treatment of Sexually Transmitted Acute Hepatitis C in HIV-Infected Individuals
Authors: Vogel Martin , Nattermann Jacob , Baumgarten Axel , Klausen Gerd , Bieniek Bernhard , Schewe Knud , Jessen Heiko , Boesecke Christoph , Rausch Michael , Lutz Thomas , Fenske Stefan , Schranz Dietmar , Kümmerle Tim , Schuler Christoph , Theisen Albert , Mayr Christoph , Seidel Thomas , Rockstroh Jürgen K 
Published: April 2022

Background Sexually transmitted acute hepatitis C among HIV-positive homosexual men has been noted as an emerging epidemic. Methods Forty-seven patients with mainly sexually acquired, acute hepatitis C were enrolled in this prospective, multicentre trial, and 36 of these patients were treated within the acute phase of hepatitis C infection with pegylated interferon (peg-IFN) therapy. Results Early treatment resulted in sustained virological response in 61% of patients. Peg-IFN alone showed similar treatment response rates and lower incidence of anaemia compared with peg-IFN+ribavirin combination therapy. Higher treatment response rates were observed in patients treated over 48 weeks compared with 24 weeks. Conclusions Treatment of hepatitis C in HIV-positive individuals in the acute phase of infection leads to high rates of sustained virological response. Optimal time and mode of therapy have yet to be defined.
A Virological Benefit from an Induction/Maintenance Strategy: The Forte Trial
Authors: Asboe David , Williams Ian G , Goodall Ruth L , Darbyshire Janet H , Hooker Malcolm H , Babiker Abdel G 
Published: April 2022

Objective To evaluate whether the addition of a fourth drug for up to 32 weeks to a standard three-drug anti-retroviral combination decreases the risk of virological failure without increasing toxicity in treatment-naive patients. Design Induction/maintenance (IM) therapy [two nucleoside reverse transcriptase inhibitors (NRTIs) + one non-NRTI (NNRTI) + one protease inhibitor for 24–32 weeks until plasma HIV RNA viral load (VL) ≤50 copies/ml then two NRTIs + NNRTI] was compared with standard therapy (ST) (two NRTIs + NNRTI). The primary endpoint was virological failure: VL >50 copies/ml at 32 (and 24) weeks or subsequent rebound to >400 copies/ml. Results 122 (62 IM, 60 ST) participants were randomized and followed for a median of 81 weeks (IQR 64–145). 52% were asymptomatic; median CD4+ T-cell count was 160x106/l (IQR 92-260) and median VL 98,830 copies/ml (IQR 37,500–241,290). In an intent-to-treat analysis, the proportion of participants with virological failure at or after 32 weeks was higher in the ST arm [26 (43%) versus 11 (18%), P=0.002]. The mean decrease in VL at 48 weeks was 0.84 95% confidence interval (CI) (0.15, 1.53) log10 copies/ml greater in the IM arm ( P=0.02). There were no significant differences between the two arms in the change in CD4+ T-cell count from baseline to 48 weeks, the number of participants with adverse events or the frequency of progression to AIDS/death. Drug resistance at failure was detected less frequently in the IM arm. Conclusions Starting antiretroviral therapy with an IM strategy improved virological outcomes compared with a three-drug regimen, without significantly increasing toxicity.
A Computer-Based System to aid in the Interpretation of Plasma Concentrations of Antiretrovirals for Therapeutic Drug Monitoring
Authors: Goicoechea Miguel , Vidal Andrea , Capparelli Edmund , Rigby Andrew , Kemper Carol , Diamond Catherine , Witt Mallory D , Haubrich Richard 
Published: April 2022

Objectives To develop a computer-based system for modelling and interpreting plasma antiretroviral concentrations for therapeutic drug monitoring (TDM). Methods Data were extracted from a prospective TDM study of 199 HIV-infected patients (CCTG 578). Lopinavir (LPV) and efavirenz (EFV) pharmacokinetic (PK) parameters were modelled using a Bayesian method and interpreted by an expert committee of HIV specialists and pharmacologists who made TDM recommendations. These PK models and recommendations formed the knowledge base to develop an artificial intelligence (AI) system that could estimate drug exposure, interpret PK data and generate TDM recommendations. The modelled PK exposures and expert committee TDM recommendations were considered optimum and used to validate results obtained by the AI system. Results A group of patients, 67 on LPV, 46 on EFV and three on both drugs, were included in this analysis. Correlations were high for LPV and EFV estimated trough and 4 h post-dose concentrations between the AI estimates and modelled values (r>0.79 for all comparisons; P<0.0001). Although trough concentrations were similar, significant differences were seen for mean predicted 4 h concentrations for EFV (4.16 μg/ml versus 3.89 μg/ml; P=0.02) and LPV (7.99 μg/ml versus 8.79 μg/ml; P<0.001). The AI and expert committee TDM recommendations agreed in 53 out of 69 LPV cases [kappa (κ)=0.53; P<0.001] and 47 out of 49 EFV cases (κ=0.91; P<0.001). Conclusions The AI system successfully estimated LPV and EFV trough concentrations and achieved good agreement with expert committee TDM recommendations for EFV- and LPV-treated patients.
Frequency, determinants and consequences of delayed access to care for HIV infection in France
Authors: Lanoy Emilie , Mary-Krause Murielle , Tattevin Pierre , Perbost Isabelle , Poizot-Martin Isabelle , Dupont Caroline , Costagliola Dominique ,   on behalf of the ANRS CO04 French Hospital Database on HIV Clinical Epidemiological Group
Published: April 2022

Background and objectives We analysed the frequency and predictors of delayed access to care (DAC) for HIV infection, and its influence on survival. Methods We studied predictors of DAC among 18,721 patients enrolled between 1997 and 2002 in the French Hospital Database on HIV (FHDH), DAC being defined by a CD4+ T-cell count below 200 copies/mm3 and/or AIDS at FHDH enrolment. The association of DAC with the initiation of combined antiretroviral therapy (cART) and of DAC with survival were analysed with Cox multivariable models. Results The overall prevalence of DAC was 35.7%. Compared with patients under 30 years of age, patients over 60 were 3.5 times more likely to have DAC (P<10-4). Compared with non-migrant women, odds ratios (OR) of DAC were higher among migrant women (1.5), non-migrant men (1.6) and migrant men (1.9; all P<10-4). Compared with men who have sex with men, other transmission groups had an estimated OR for DAC of 1.6 (P<10-4). DAC was more frequent among patients with a recent diagnosis of HIV infection [OR=1.3, 95% confidence intervals (CI)=(1.2;1.4)]. Patients with DAC received cART earlier than other patients [hazard ratio (HR)=2.2, 95% CI=(2.1;2.3)]. The DAC/mortality HR was 13.9 in the first 6 months after enrolment in the FHDH, and remained significantly higher than 1 during the subsequent 4 years. Conclusion DAC is common in France and was associated with a higher mortality, despite early initiation of cART. Earlier access to care and specific clinical management of patients with DAC should be considered.
Uridine Supplementation for the treatment of Antiretroviral Therapy-Associated Lipoatrophy: A Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Sutinen Jussi , Walker Ulrich A , Sevastianova Ksenia , Klinker Hartwig , Häkkinen Anna-Maija , Ristola Matti , Yki-Järvinen Hannele 
Published: April 2022

Background Highly active antiretroviral therapy (HAART) is associated with loss of subcutaneous fat (lipoatrophy) presumably due to mitochondrial toxicity of nucleoside reverse transcriptase inhibitors. In vitro, uridine abrogates thymidine analogue-induced toxicity in adipocytes. Methods A total of 20 patients with HAART-associated lipoatrophy were randomized to receive either a dietary uridine supplement (36 g three times a day for 10 consecutive days/month) or placebo, for 3 months. Body composition was measured using dual energy X-ray absorptiometry, magnetic resonance imaging and proton spectroscopy. Data are mean ± standard error of mean. Results The mean increases in limb fat (880 ±140 versus 230 ±270 g; P<0.05), intra-abdominal fat (210 ±80 versus -80 ±70 cm3; P<0.05) and total body fat (1,920 ±240 versus 240 ±520 g; P<0.01) were significantly greater in the uridine than in the placebo group. Within the uridine group, the changes from baseline to 3 months were statistically significant in total limb fat ( P<0.001), intra-abdominal fat ( P<0.05) and total body fat ( P<0.001). The proportion of limb fat to total fat increased from 18% to 25% ( P<0.05) in the uridine group. Liver fat content and lean body mass remained unchanged in both groups. High-density lipoprotein-cholesterol concentrations decreased in the uridine and increased in the placebo group, whereas fasting serum insulin concentrations did not change. Uridine supplementation was well tolerated and the virological effect of HAART was not affected. Conclusion Uridine supplementation significantly and predominantly increased subcutaneous fat mass in lipoatrophic HIV-infected patients during unchanged HAART.
Does Tenofovir Influence Efavirenz Pharmacokinetics?
Authors: Rotger Margalida , Colombo Sara , Furrer Hansjakob , Décosterd Laurent , Buclin Thierry , Telenti Amalio ,   the Swiss HIV Cohort Study
Published: April 2022

Introduction A recent report described a possible interaction between tenofovir (TFV) and efavirenz (EFV). Patients developed neuropsychiatric manifestations upon introduction of TFV on a stable EFV-containing regimen. We evaluated the possibility of a pharmacokinetic interaction between TFV and EFV by assessing cross-sectional and longitudinal data in 169 individuals receiving EFV. Results EFV plasma area-under-the-curve (AUC) levels were comparable among individuals receiving ( n=18) or not receiving TFV ( n=151); 57,962 versus 52,293 ng*h/ml. However, under conditions of limited EFV metabolism, that is, the group of 23 individuals carrying two copies of CYP2B6 loss/diminished-function alleles, plasma AUC values were highest among individuals receiving TFV ( n=5, 353,031 ng*h/ml), compared with those not receiving TFV ( n=18, 180,689 ng*h/ml). Statistical analysis identified both a global, sixfold effect of CYP2B6 loss/diminished function ( P<0.0001) and a significant interaction between the number of loss/diminished-function alleles and the co-medication with TFV ( P=0.009). Conclusion Although there is no clear evidence for a pharmacokinetic interaction between TFV and EFV, we cannot rule out an interaction between these drugs restricted to individuals who are slow EFV metabolizers.
Normalization of Fat Accrual in Lipoatrophic, HIV-Infected Children Switched from Stavudine to Tenofovir and from Protease Inhibitor to Efavirenz
Authors: Viganò Alessandra , Brambilla Paolo , Cafarelli Laura , Giacomet Vania , Borgonovo Simona , Zamproni Ilaria , Zuccotti Gianvincenzo , Mora Stefano 
Published: April 2022

Objective An antiretroviral regimen based on lamivudine +stavudine+protease inhibitor impairs peripheral fat accrual in HIV-infected children and adolescents. We assess the effect on body composition parameters of replacing stavudine with tenofovir and protease inhibitor with efavirenz in paediatric patients. Methods A 96-week prospective study on 24 patients, (age range: 5.0–17.9 years) with stable undetectable HIV-1 loads, who were switched from stavudine to tenofovir and from protease inhibitor to efavirenz. Patient assessment included: body composition parameters measured by dual-energy X-ray absorptiometry (DXA), viral load and CD4+ T-count and percentage. As a control group for DXA data, we studied 143 healthy controls (HCs; age range: 4.9–20.0 years). Results Virological suppression and unchanged CD4+T-cell count and percentage were maintained in all patients. At baseline, patients showed decreased total, arm and leg fat masses ( P<0.01) but a similar trunk fat mass to HCs. From baseline to week 96, patient fat mass increases were comparable to those for HCs (total fat: 1.3 vs 1.2 kg; fat in arms: 0.09 vs 0.08 kg; fat in legs: 0.5 vs 0.5 kg; trunk fat: 0.6 vs 0.6 kg). However, at week 96, total and leg fat mass in patients were still significantly lower than those in HCs ( P<0.02). At baseline and at week 96, lean mass in patients was similar to that expected in HCs. Conclusions Replacing stavudine with tenofovir and protease inhibitor with efavirenz for 96 weeks in lipoatrophic paediatrics patients led to a restoration of physiological fat accrual. Lipoatrophy did not progress but was still present, indicating the need for additional strategies.
Low-level HCV Viraemia after Initial Response during Antiviral Therapy: Transcription-Mediated Amplification Predicts Treatment Failure
Authors: Gelderblom Huub C , Reesink Henk W , Beld Marcel GHM , Weegink Christine J , Jansen Peter LM , Dijkgraaf Marcel GW , Zaaijer Hans L 
Published: April 2022

Background In chronic hepatitis C patients with an initial virological response (IVR) during antiviral therapy (that is, HCV RNA becomes negative before week 16 of treatment) the significance of reappearing viraemia below the detection limit of PCR is not known. We studied this phenomenon in subsets of patients. Methods We assessed HCV RNA at weeks 16 and 20 of therapy by PCR and by more sensitive transcription-mediated amplification (TMA) in 23 patients with breakthrough or relapse and in 34 patients with sustained virological response (SVR). All patients participated in a high-dose-interferon induction study for difficult-to-treat patients. Therapy consisted of amantadine hydrochloride and ribavirin, combined with interferon-α2b induction during the first 6 weeks and thereafter combined with weekly pegylated interferon-α2b. Results Among the 57 IVR patients, we detected transient or persistent reappearance of low levels of HCV RNA in 10 of the 23 (43%) patients with eventual breakthrough or relapse; but in none of the 34 SVR patients. In 5 of 10 patients reappearing HCV RNA was only detectable by TMA. Conclusion Reappearance of low levels of HCV RNA in patients with IVR predicts treatment failure.