bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reverse Transcriptase Inhibitors Alter Uncoupling Protein-1 and Mitochondrial Biogenesis in Brown Adipocytes
Authors: Rodríguez de la Concepción M Luisa , Yubero Pilar , Domingo Joan C , Iglesias Roser , Domingo Pere , Villarroya Francesc , Giralt Marta 
Published: April 2022

Objective Human adipose depots contain remnant brown adipocytes interspersed among white adipocytes, and disturbances of brown with respect to white adipocyte biology have been implicated in highly active antiretroviral therapy (HAART)-induced lipo matosis. Brown adipocytes express the uncoupling protein-1 (UCP1) and contain a large number of mitochondria, potential targets of HAART toxicity. The aim of this study was to evaluate the effects of reverse transcriptase inhibitors (RTIs) on primary brown adipocytes differentiated in culture. Design and methods We analysed the effects of RTIs, nucleoside analogues (NRTIs: stavudine, zidovudine, didanosine and lamivudine) and non-nucleoside analogues (NNRTIs: nevirapine and efavirenz), on differentiation, mitochondrial biogenesis and gene expression in brown adipocytes. Results None of the NRTIs altered brown adipocyte differentiation whereas NNTRIs had differing effects. Efavirenz blocked lipid deposition and expression of adipose marker genes but nevirapine induced lipid accumulation and adipose gene expression, promoted mitochondrial biogenesis and increased UCP1. Stavudine, zidovudine and didanosine reduced mitochondrial DNA (mtDNA) content. However, mitochondrial genome expression was only impaired in didanosine-treated adipocytes. Stavudine, but not zidovudine, induced expression of the mitochondrial transcription factors and this may explain compensatory mechanisms for the depletion of mtDNA by up-regulating mtDNA transcription. Stavudine caused a specific induction of UCP1 gene expression through direct interaction with a retinoic acid-dependent pathway. Conclusions Specific disturbances in brown adipocytes in adipose depots may contribute to HAART-induced lipomatosis. Mitochondrial depletion does not appear to be the only mechanism explaining adverse effects in brown adipocytes because there is evidence of compensatory mechanisms that maintain mtDNA expression, and the expression of the UCP1 gene is specifically altered.
Mitochondrial Dna Depletion in HIV-Infected Patients is More Pronounced with Chronic Hepatitis C and Enhanced following Treatment with Pegylated Interferon plus Ribavirin
Authors: de Mendoza Carmen , Sánchez-Conde Matilde , Timmermans Eveline , Buitelaar Marije , de Baar Michel P , Gonzalez-Lahoz Juan , Soriano Vincent 
Published: April 2022

Background Mitochondrial DNA (mtDNA) damage seems to be responsible for many of the toxicities associated with the long-term use of nucleoside analogues in HIV-infected patients. These adverse effects, mainly lipoatrophy, seem to be even more pronounced in subjects with hepatitis C virus (HCV) co-infection. However, there is no information about a possible additive effect of HCV on mtDNA depletion nor about the impact of ribavirin use in HIV/HCV-coinfected individuals. Patients and methods mtDNA was measured in peripheral blood mononuclear cells (PBMC) collected from 192 individuals classified into 4 groups: HIV-neg/HCV-neg (control group, n=11), HIV-pos/HCV-neg (56), HIV-neg/HCV-pos (18) and HIV-pos/HCV-pos (107). A duplex real-time NASBA assay was used to quantify mtDNA on maximal platelet-depleted specimens and all experiments were run in duplicate. The mtDNA copy number per cell was estimated taking as reference the nuclear DNA copy number. Results The mean mtDNA values in the control group was 757 copies/cell, while it was 428, 349 and 296 for HIV-pos, HCV-pos and HIV/HCV-coinfected individuals, respectively ( P<0.001 for all groups relative to the control group). No significant differences were observed when comparing patients with HIV or HCV infections alone, but coinfected individuals showed a lower mtDNA copy number than patients infected with HIV ( P<0.001) or with HCV ( P=0.089). In a subset of 18 patients with HIV/HCV-coinfection, treatment with pegylated interferon plus ribavirin produced a further reduction in mtDNA (mean value, 189 copies/cell; P=0.009). Conclusions HIV and HCV may independently cause mtDNA depletion in PBMC. Coinfection may result in more pronounced mtDNA depletion. The administration of interferon plus ribavirin may further enhance mtDNA depletion. These findings may explain the greater risk of lipoatrophy of antiretroviral therapy in HIV-infected patients with HCV coinfection and why anti-HCV therapy may aggravate this effect.
Facial Fat Volume in HIV-Infected Patients with Lipoatrophy
Authors: Yang Yong , Sitoh Yih-Yian , Tha Naing Oo , Paton Nicholas I 
Published: April 2022

Background The volume and anatomical distribution of facial fat depletion in HIV related lipoatrophy have not been properly quantified. We aimed to determine the extent and distribution of facial fat loss in HIV-infected patients with lipoatrophy and whether this differs from wasting. Design We studied HIV-infected patients with clinically defined moderate to severe lipoatrophy without wasting ( n=15), clinically defined wasting (>10% weight loss and recent opportunistic infection) with no previous reported lipodystrophy ( n=15), and controls without lipodystrophy or wasting ( n=15). Facial MRI scans were performed, and areas of fat were manually traced bilaterally in all individual image slices and summed to calculate volume in anatomically defined regions of interest. Results Patients with lipoatrophy had lower fat volumes in the temporal region (8.9 ±9.4 vs 20.5 ±7.2ml; P<0.001), cheek region (25.6 ±24.9 vs 55.5 ±15.0 ml; P<0.001), periorbital region (1.9 ±1.0 vs 2.7 ±1.0 ml; P=0.09) and buccal fat pad (13.4 ±9.4 vs 21.8 ±9.8 ml; P=0.030) compared with controls. Patients with wasting had temporal, cheek, periorbital and buccal fat pad volumes (10.4 ±6.7 ml, 34.0 ±14.8 ml, 1.4 ±1.1 ml and 13.1 ±4.6 ml respectively) that were lower than controls (all P<0.01) but similar to lipoatrophy patients (all P>0.5). Conclusions Facial fat depletion in lipoatrophy is substantial (approximately 50% volume loss) and involves superficial and deep fat (buccal fat pad). The distribution and volume of fat change is similar to that seen in wasting. Given the extent of the changes, complete surgical correction is unlikely to be possible and hence emphasis should be placed on prevention of
The HIV Protease Inhibitors Saquinavir, Ritonavir, and Nelfinavir Induce Apoptosis and Decrease Barrier Function in Human Intestinal Epithelial Cells
Authors: Bode Hagen , Lenzner Luzie , Kraemer Oliver Holger , Kroesen Anton Josef , Bendfeldt Kerstin , Schulzke Jörg Dieter , Fromm Michael , Stoltenburg-Didinger Gisela , Zeitz Martin , Ullrich Reiner 
Published: April 2022

Background and aims Diarrhoea is a frequent adverse effect of HIV protease inhibitors (PIs) which may be due to intestinal barrier disruption. We investigated whether tight junction dysregulation, apoptosis or necrosis are responsible for this epithelial damage. Methods Saquinavir, nelfinavir, and ritonavir were added to the mucosal or serosal side of HT-29/B6 colon cell monolayers. Transepithelial resistance was monitored for 72 h to assess epithelial barrier function. Apoptosis and necrosis were investigated by light and electron microscopy and quantified by nucleosome ELISA and LDH measurement, respectively. Tight junction components were analysed by Western blots of occludin and zonula occludens. Apoptosis induction in normal human intestinal epithelium was examined by measurement of poly(ADP-ribose) polymerase (PARP) cleavage in Western blots of mucosal tissue explants cultured with PIs for 24 h. Results HIV PIs decreased transepithelial resistance by more than 44% in HT-29/B6 monolayers. Histology revealed massive apoptotic body formation but no evidence for necrosis after PI treatment. Correspondingly, LDH release was lower than 0.2%/h of total LDH, independent of PI treatment, and nucleosomes were increased up to 22-fold after drug treatment versus control. Occludin and zonula occludens-1 expression in the membrane were not diminished. PARP cleavage increased in normal human intestinal tissue treated with PIs. Conclusions PI-induced barrier disruption in intestinal epithelial cells is not due to necrosis or tight junction alterations, but to induction of massive apoptosis which may lead to leak-flux diarrhoea in vivo. Our findings suggest that induction of apoptosis by PIs could have potential for antitumour therapy.
Long-Term Lamivudine Monotherapy in Renal-Transplant Recipients with Hepatitis-B-Related Cirrhosis
Authors: Viganò Mauro , Colombo Massimo , Aroldi Adriana , Lunghi Giovanna , Manenti Elena , Ponticelli Claudio , Lampertico Pietro 
Published: April 2022

Background Chronic hepatitis B virus (HBV) infection is an important cause of morbidity and mortality in renal-transplant recipients. The aim of the study was to assess the efficacy and safety of long-term lamivudine monotherapy in renal-transplant recipients with HBV-related cirrhosis. Methods Seventeen such patients [median age: 45 years; 7 with hepatitis B e antigen (HBeAg)] received daily oral doses of 75–150 mg lamivudine for a median of 48 (range 11–81) months. All patients had baseline serum levels of HBV DNA of over 6 log copies per ml and of 10 alanine transaminase (ALT) of over 1.5 times the upper normal limit (UNL). Clinical lamivudine resistance was defined as a rebound of serum HBV DNA above 5.3 log 10 copies per ml and of serum ALT of over 1.5 times the UNL in patients who initially responded with HBV DNA levels of less than 5.3 log copies per ml and normal ALT 10 values. Controls were 14 renal-transplant patients (median age 44 years; 3 with HBeAg) with HBV-related cirrhosis, naive to any anti-HBV therapy, followed for 58 months (4–135). Results Thirteen (77%) treated patients had a persistent response throughout the study period, including three (18%) who developed genotypic resistance, compared with none of the untreated controls (77% versus 0%, P<0.0001). Four (23%) developed clinical resistance. Two of three patients with initially decompensated cirrhosis had a durable response and clinical improvement compared with the transient responder, whose liver function worsened following lamivudine resistance. Two responders developed chronic rejection requiring chronic haemodialysis. Overall, one treated patient developed liver-related complications, compared with eight untreated controls (6% versus 57%, P<0.01). Conclusions Most renal-transplant patients treated with lamivudine achieved a rapid and durable suppression of HBV, which substantially lowered the risk of liver decompensation and death.
Simplification Therapy with Once-Daily Didanosine, Tenofovir and Efavirenz in HIV-1-Infected Adults with Viral Suppression Receiving a More Complex Antiretroviral Regimen: Final Results of the EFADITE Trial
Authors: Barrios Ana , Negredo Eugenia , Domingo Pere , Estrada Vicente , Labarga Pablo , Asensi Víctor , Morales Dolores , Santos Jesús , Clotet Bonaventura , Soriano Vincent ,   for the EFADITE Study Group
Published: April 2022

Background High pill burden and side effects often impact on the long-term success of highly active anti-retroviral therapy (HAART), which has led clinicians to search for more convenient regimens. Patients and methods A prospective, multicentre, open, comparative study in which HIV-1-infected patients on HAART and with plasma HIV-1 RNA <50 copies/ml for longer than 6 months were switched to tenofovir, didanosine and efavirenz (QD arm) or remained on the same treatment regimen (control arm). Patients with grade 4 toxicities or plasma HIV-1 RNA values repeatedly >1000 copies/ml discontinued the study. Results A total of 390 patients were included in the trial (309 in the QD arm and 81 in the control arm). The main baseline characteristics were well balanced between groups. In the QD arm, 41% of patients received high (standard) didanosine doses and 59% received reduced doses. At 12 months, plasma HIV-1 RNA <400 copies/ml was attained in 66% of QD patients and 73% of controls in the intent-to-treat (ITT) analysis ( P=NS). However, the number of individuals with HIV-1 RNA <400 copies/ml in the QD arm was 56% versus 71% when comparing the use of high versus low didanosine doses ( P=0.007). Treatment discontinuation occurred in 87 QD cases (28%) and 17 controls (21%). Twenty QD individuals (6.5%) and 2 controls (2.5%) discontinued because of virological failure ( P=NS). The median CD4+ cell count change at 12 months was -26 and +27 cells/μl in QD patients and controls, respectively ( P=0.001). In individuals who attained HIV-1 RNA <400 copies/ml, CD4+ cell changes were -25 and +15 cells/μl in QD patients and controls, respectively ( P=0.001). Moreover, CD4+ cell declines in the QD arm were significantly greater in patients taking high versus low didanosine doses (-59 versus -15 cells/μl; P=0.04). The lipid profile improved significantly in the QD arm, particularly in patients who were on protease inhibitors prior to simplification. Conclusions Simplification to didanosine–tenofovir–efavirenz provides a virological suppression rate at 12 months similar to that seen in patients who do not change therapy, as long as low didanosine doses are administered. Decreases in CD4+ cell levels in patients in the QD arm (especially decreases seen with high didanosine doses) and dyslipidaemias along with less convenient pill burden and schedules in controls were the main long-term concerns for each option.
Increased Antiretroviral Potency by the Addition of Enfuvirtide to a Four-Drug Regimen in Antiretroviral-Naive, HIV-Infected Patients
Authors: Moltó José , Ruiz Lidia , Valle Marta , Martinez-Picado Javier , Bonjoch Ana , Bravo Isabel , Negredo Eugenia , Heilek-Sneider Gabrielle M , Clotet Bonaventura 
Published: April 2022

Objective To assess if enfuvirtide (ENF) increases antiviral activity of a highly active four-drug antiretroviral (ARV) regimen containing lopinavir/ritonavir, efavirenz, lamivudine and tenofovir in ARV-naive, HIV-infected patients. Methods Pilot study in ARV-naive, HIV-infected patients with viral load (VL) >10,000 copies/ml and no documented resistance to any of the study drugs. Patients were randomized to receive ENF (ENF Group) or not (Control Group) in combination with lopinavir/ritonavir, efavirenz, lamivudine and tenofovir as a backbone. The primary endpoint was to assess differences in the HIV-1 RNA decay rate during the first phase of viral decay. VL and treatment adherence were measured at baseline, every 6 h during the first 3 days, and once daily from day 3 to 6. Individual HIV-1 RNA decay rates were obtained using a non-linear least squares regression model. Results Eight subjects were included in each study group. Mean (sd) baseline VL was 4.98 (0.38) log10 copies/ml in the ENF Group and 5.10 (0.49) log10 copies/ml in the Control Group ( P=0.607). Baseline CD4+ cell count was 463 (306) and 362 (225) cells/mm3 in the ENF and the Control Group, respectively ( P=0.484). First phase HIV-1 RNA decay rate was 0.802 (0.127) d-1 in the ENF Group and 0.624 (0.182) d-1 in the Control Group ( P=0.045). By day 6, VL was 3.55 (0.40) and 3.92 (0.36) log10 copies/ml in the ENF and the Control Group, respectively ( P=0.079). Conclusion The addition of ENF increased the antiviral potency of a highly active four-drug ARV regimen by 28.5% in ARV-naive, HIV-infected patients. The clinical impact of this finding should be assessed.
Comparison of Two Different Regimens of Combined Interferon-α2A and Lamivudine Therapy in Children with Chronic Hepatitis B Infection
Authors: Kansu Aydan , Doğanci Tümay , Akman Sezin A , Artan Reha , Kuyucu Necdet , Kalayci Ayhan Gazi , Dikici Bünyamin , Dalgiç Buket , Selimoğlu Ayşe , Kasirga Erhun , Özkan Tanju B , Kuloğlu Zarife , Aydoğdu Sema , Boşnak Mehmet , Ertekin Vildan , Tanir Gönül , Haspolat Kenan , Girgin Nurten , Yağci Raşit Vural 
Published: April 2022

Aim To evaluate the efficacy of two regimens of combined interferon-α2a (IFN-α2a) and lamivudine (3TC) therapy in childhood chronic hepatitis B. Methods A total of 177 patients received IFN-α2a, 9 million units (MU)/m2 for 6 months. In group I (112 patients, 8.7±3.5 years), 3TC (4 mg/kg/day, max 100 mg) was started simultaneously with IFN-α2a, in group II (65 patients, 9.6±3.8 years) 3TC was started 2 months prior to IFN-α2a. 3TC was continued for 6 months after antiHBe seroconversion or stopped at 24 months in non-responders. Results Baseline alanine aminotransferase (ALT) was 134.2 ±34.1 and 147.0 ±45.3; histological activity index (HAI) was 7.4 ±2.7 and 7.1 ±2.3; and HBV DNA levels were above 2,000 pg/ml in 76% and 66% of patients in groups I and II, respectively ( P>0.005). Complete response was 55.3% and 27.6% in groups I and II, respectively ( P<0.01). AntiHBe seroconversion was higher and earlier, and HBV DNA clearance was earlier in group I ( P<0.05). HBsAg clearance was 12.5% and 4.6% and antiHBs seroconversion was 9.8% and 6.2% in groups I and II, respectively ( P>0.05). Breakthrough occurred in 17.9% and 24.6%; breakthrough times were 15.9 ±4.6 and 14.1 ±5.1 months; and relapse rates were 6.8% and none in groups I and II, respectively ( P>0.05, P>0.05, P>0.05). Responders had higher HAI (HAI>6) and higher pre-treatment ALT than non-responders. Conclusion Simultaneous 3TC+IFN-α2a yields a higher response and earlier antiHBe seroconversion and viral clearance than consecutive combined therapy. Relapse rate is low. Predictors of response are high basal ALT and high HAI scores. 3TC can be administered for 24 months without any side effect and breakthrough rate is comparable with previous studies.
Drug-Specific T Cells in An HIV-Positive Patient with Nevirapine-Induced Hepatitis
Authors: Drummond Nicola S , Vilar F Javier , Naisbitt Dean J , Hanson Anita , Woods Anthony , Park B Kevin , Pirmohamed Munir 
Published: April 2022

Background Nevirapine is associated with idiosyncratic reactions such as skin rash, hepatitis and hypersensitivity syndrome, which have the hallmarks of being immune mediated. However, there is little laboratory evidence to support an immune pathogenesis. Methods A HIV-positive individual who developed hepatitis within 6 weeks of starting nevirapine, in the absence of any cutaneous manifestations, is described. Other causes of hepatitis were excluded, and the patients liver function normalized on withdrawal of nevirapine. Lymphocytes from the patient, and six individuals with HIV who were on nevirapine without adverse effects, were exposed to nevirapine and its metabolites, and lymphocyte proliferation assessed by 3H-thymidine incorporation on day 5. Results The T cells taken from the nevirapine-hypersensitive patient proliferated in the presence of nevirapine with a stimulation index of greater than 2. There was no proliferation with nevirapine metabolites. T cells taken from HIV-positive control individuals showed no proliferation with either nevirapine or its metabolites. Conclusion The results from our patient suggest that T cells may be involved in the pathogenesis of nevirapine-induced hepatitis. Larger numbers of patients need to be studied to fully evaluate the role of T cells in nevirapine-induced hepatitis and nevirapine hypersensitivity syndrome.
Patients’ Preferences regarding the Timing of Highly Active Antiretroviral Therapy Initiation for Chronic Asymptomatic HIV-1 Infection
Authors: Locadia Mirjam , van Grieken Rosa A , Prins Jan M , de Vries Henry JC , Sprangers Mirjam AG , Nieuwkerk Pythia T 
Published: April 2022

Objective In patients with a chronic asymptomatic HIV-1 infection and >200 CD4+ T-cells/μl, the optimal timing of highly active antiretroviral therapy (HAART) initiation is unclear. It involves a trade-off between a potentially reduced risk of mortality, when started earlier in the course of infection, and an earlier exposure to pill burden and potential toxicities. We investigated patients’ preferences for immediate HAART initiation relative to delaying HAART for 1 year. Methods Consecutive patients were asked for their preference during an interview. A hypothetical difference in 3-year mortality risk between both options was systematically varied between 0% and 10% to determine the threshold at which preference would switch to HAART initiation. Results About 30% of patients preferred HAART initiation even if the mortality risk would be equal for both options. Almost 25% always preferred delaying HAART even if this would result in a 10% greater mortality risk. Most treatment guidelines recommend delaying HAART >350 CD4+ T-cells/μl However, at a risk difference between starting and delaying HAART that corresponds with this CD4+ T-cell count, about 50% would prefer to start HAART immediately. Most guidelines recommend starting HAART below 200 CD4+ T-cells/μl However, at a risk difference between both options corresponding with this CD4+ T-cell count, about 40% preferred delaying HAART. Conclusions We found large variation in patients’ preferences. Some patients were more inclined to initiate HAART earlier than the recommended guidelines, whereas others were more inclined to delay HAART. These findings emphasize the need for shared decision-making when deciding on the most optimal timing of HAART initiation in chronic asymptomatic HIV-1 infection.
Lopinavir/Ritonavir or Efavirenz plus two Nucleoside Analogues as First-Line Antiretroviral Therapy: A Non-Randomized Comparison
Authors:   on behalf of the I.Co.N.A, UCSC, IMIT-MI and INMI cohorts, Luca Andrea De , Cozzi-Lepri Alessandro , Antinori Andrea , Zaccarelli Mauro , Bongiovanni Marco , Giambenedetto Simona Di , Marconi Patrizia , Cicconi Paola , Resta Francesco , Grisorio Benvenuto , Ciardi Maria , Cauda Roberto , Monforte Antonella d'Arminio 
Published: April 2022

Background Although efavirenz (EFV) and lopinavir/ritonavir (LPV/r) are both recommended antiretroviral agents for combination therapy in drug-naive HIV-infected patients, no randomized comparison of their efficacy and tolerability is available yet. A multi-cohort prospective observational comparative study was performed. Methods Efficacy was examined comparing time to virological failure, CD4 recovery and clinical progression. Tolerability was examined comparing time to treatment discontinuation for any reason and for toxicity and time to liver enzymes or lipid alterations. Survival analysis was conducted by an intent-to-treat principle using the Kaplan–Meier method, and standard and weighted Cox regression models. Results A total of 674 antiretroviral-naive patients starting a two nucleoside reverse transcriptase inhibitor regimen plus either EFV ( n=481) or LPV/r ( n=193) were examined. At baseline, patients starting LPV/r had higher HIV RNA and lower CD4+ T-cell counts. There was no difference in the adjusted hazards of virological failure (LPV/r versus EFV relative hazard [RH] 1.16, 95% confidence intervals [CI]: 0.58–2.32, P=0.67), CD4 recovery (RH=0.93, 95% CI: 0.66–1.30, P=0.66), clinical progression (RH=1.64, 95% CI: 0.70–3.84, P=0.25), drug discontinuation for toxicity (RH=0.92, 95% CI: 0.51–1.64, P=0.76) and for any reason, and rates of liver enzyme and total/low density lipoprotein (LDL) cholesterol elevation. In contrast, the rate of triglycerides elevations (>1 NCEP Adult Treatment Panel III category increase) was higher in the LPV/r group (RH=1.69, 95% CI: 1.14–2.50; P=0.01). Models weighted for the inverse of conditional probability of receiving either drug applied to the efficacy endpoints yielded similar results. CD4 recovery with both drugs was also similar in the lowest CD4 strata. Conclusions Our analysis suggests similar efficacy and tolerability for EFV- or LPV/r-based first-line antiretroviral regimens. LPV/r was associated with higher rates of hypertriglyceridaemia.