bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Zidovudine, Stavudine and β-Aminoisobutyric Acid on Lipid Homeostasis in Mice: Possible Role in Human Fat Wasting
Authors: Maisonneuve Caroline , Igoudjil Anissa , Begriche Karima , Lettéron Philippe , Guimont Marie-Christine , Bastin Jean , Laigneau Jean-Pierre , Pessayre Dominique , Fromenty Bernard 
Published: April 2022

Objective Although mitochondrial DNA (mtDNA) depletion could play a role in nucleoside reverse transcriptase inhibitor-induced lipoatrophy, poor correlations between fat mtDNA levels and lipoatrophy suggest additional mechanism(s). Stavudine (d4T), zidovudine (AZT) and the thymine catabolite, β-aminoisobutyric acid (BAIBA), but not zalcitabine (ddC) or didanosine (ddI), can increase fatty acid oxidation in liver mitochondria and plasma ketone bodies in mice. Since fat oxidation in non-adipose tissue can influence body adiposity, we sought to determine whether d4T, AZT and BAIBA can cause lipoatrophy in mice by this catabolic mechanism. Methods Lean or obese ob/ob mice were treated for 6 weeks with d4T, AZT or BAIBA, and lean mice with ddC or ddI. Body fat mass was assessed by dual energy X-ray absorptiometry, and mtDNA by Slot blot hybridization in epididymal fat. Results Whereas ddC or ddI did not change plasma β-hydroxybutyrate and body fat mass, d4T, AZT and BAIBA increased plasma β-hydroxybutyrate in lean mice suggesting increased hepatic fatty acid oxidation and ketogenesis. Despite unchanged food consumption, a supra-pharmacological dose of d4T tended to decrease, whilst AZT and BAIBA decreased body fat mass. Fat mtDNA and plasma triglycerides, cholesterol, glucose, insulin, leptin and adiponectin levels were unchanged. In obese mice, d4T, AZT and BAIBA did not increase plasma β-hydroxybutyrate, and only AZT decreased body fat mass without reducing fat mtDNA. Conclusions d4T and AZT can enhance hepatic fat oxidation and cause fat wasting, without decreasing adipose tissue mtDNA and without causing insulin resistance in mice. BAIBA, a thymine catabolite, reproduces these effects. These catabolic effects could play a role in the lipoatrophy, which can occur in AZT- or d4T-treated patients.
Long-Term Follow-Up of HIV-Infected Patients with Chronic Hepatitis C Virus Infection Treated with Interferon-Based Therapies
Authors: Soriano Vincent , Maida Ivana , Núñez Marina , García-Samaniego Javier , Barreiro Pablo , Martín-Carbonero Luz , González-Lahoz Juan 
Published: April 2022

Background Chronic hepatitis C virus (HCV) infection is frequent among HIV-infected patients. Clearance of serum HCV RNA 6 months after discontinuing HCV therapy is generally interpreted as a cure of HCV infection in HIV-negative subjects. However, the occurrence of liver complications (including hepatocellular carcinoma) and/or HCV relapses in coinfected patients when followed for long periods of time after HCV therapy is not well known. Methods All HIV-infected patients who had been treated for chronic hepatitis C at our institution and had a minimum follow-up of 6 months after discontinuing therapy were retrospectively analysed. They had received one of three HCV treatment modalities: IFN monotherapy, IFN plus ribavirin (RBV) or pegylated interferon (PEG-IFN) plus RBV. Results A total of 351 patients were retrospectively analysed. Sustained virological response (SVR) to HCV therapy had been reached by 77 (22%) of them: 22/119 (18.5%) with IFN monotherapy, 17/106 (16%) with IFN plus RBV and 38/126 (30.2%) with PEG-IFN plus RBV. Considering the HCV genotypes, SVR had been reached by 19/184 (10.3%) of patients with genotype 1, 54/138 (39.1%) with genotypes 2 or 3, and 4/29 (13.8%) of those with genotype 4. Within a total of 4466 patient-months follow-up (mean of 58 months), none of the 77 patients with SVR showed HCV-RNA rebounds, elevations in liver enzymes potentially linked to HCV, development of hepatocellular carcinoma or episodes of decompensated cirrhosis. In contrast, all 274 patients who did not reach SVR with HCV therapy showed evidence of persistent serum HCV RNA and 90% of them showed liver enzyme elevations during a total of 15 344 patient-months follow-up (mean of 56 months). Moreover, 11 (4%) developed clinical complications of liver cirrhosis and two of them died of end-stage liver disease. Conclusions HCV replication and HCV-related liver disease seem to be permanently halted in HIV/HCV-coinfected patients showing HCV-RNA clearance 6 months after completing any kind of IFN-based therapy. In contrast, complications of liver disease due to persistent HCV infection continue to occur in non-responders. The role of maintenance HCV therapy should be explored in HIV/HCV-coinfected patients.
The HIV Protease Inhibitors Nelfinavir and Saquinavir, but Not a Variety of HIV Reverse Transcriptase Inhibitors, Adversely Affect Human Proteasome Function
Authors: Piccinini Marco , Rinaudo Maria T , Anselmino Annalisa , Buccinnà Barbara , Ramondetti Cristina , Dematteis Antonio , Ricotti Emanuela , Palmisano Lucia , Mostert Michael , Tovo Pier-Angelo 
Published: April 2022

Background In HIV-infected patients some clinical and immunological benefits of antiretroviral therapy, which frequently include a combination of HIV protease inhibitors (PIs) and reverse transcriptase inhibitors (RTIs), cannot be solely explained by the drugs’ action on viral enzymes. Proteasomes constitute the central protease of the ubiquitin ATP-dependent pathway involved in many cellular processes, as well as in HIV maturation and aggressiveness. Objective: To explore whether the PIs nelfinavir and saquinavir and the RTIs abacavir, nevirapine, delavirdine, stavudine and didanosine affect proteasome function in vitro and in vivo. Methods Peptidase activity of purified human 26S and 20S proteasomes was assayed with and without the drugs at different concentrations. Intracellular proteasome proteolytic activity was evaluated by searching for ubiquitin-tagged proteins in HL60 cells incubated with and without the drugs. Results At therapeutic dosages, nelfinavir and saquinavir inhibited proteasome peptidase activity and caused intracellular accumulation of polyubiquitinated proteins, a hallmark of proteasome proteolytic inhibition in vivo; the RTIs failed to evoke either effect. Conclusion Proteasomes are targeted by the two PIs but not the RTIs. Therefore, in HIV-infected patients the beneficial effect of a therapy including one of the two PIs should partly rely on inhibition of host proteasome function.
Pre-Incubation of Cell-Free HIV-1 Group M Isolates with Non-Nucleoside Reverse Transcriptase Inhibitors Blocks Subsequent Viral Replication in Co-Cultures of Dendritic Cells and T Cells
Authors: Njai Harr F , Lewi Paul J , Janssen Cornelus GM , Garcia Sergio , Fransen Katrien , Kestens Luc , Vanham Guido , Janssen Paul AJ 
Published: April 2022

In order to study the inhibitory effect of various reverse transcriptase inhibitors (RTIs) on cell-free HIV, we adapted a recently described in vitro system, based on co-cultures of dendritic cells and resting CD4 T cells, modelling early target cells during sexual transmission. The compounds tested included the second-generation non-nucleoside RTI (NNRTI) TMC-120 (R147681, dapivirine) and TMC-125 (R165335, travertine), as well as the reference nucleoside RTI AZT (zidovudine), the nucleotide RTI PMPA (tenofovir) and the NNRTI UC-781. The virus strains included the reference strain HIV-1Ba-L and six primary isolates, representative of the HIV-1 group M pandemic. They all display the non-syncytium-inducing and CCR5 receptor-using (NSI/R5) phenotype, important in transmission. Cell-free virus was immobilized on a poly-L-lysine (PLL)-treated microwell plate and incubated with compound for 1h. Afterwards, the compound was thoroughly washed away; target cells were added and cultured for 2 weeks, followed by an extended culture with highly susceptible mitogen-activated T cells. Viral production in the cultures was measured on supernatant with HIV antigen ELISA. Negative results were confirmed by showing absence of proviral DNA in the cells. TMC-120 and TMC-125 inhibited replication of HIV-1Ba-L with average EC50 values of 38 nM and 117 nM, respectively, whereas the EC50 of UC-781 was 517 nM. Complete suppression of virus and provirus was observed at compound concentrations of 100, 300 and 1000 nM, respectively. Inhibition of all primary isolates followed the same pattern as HIV-1Ba-L. In contrast, pre-treating the virus with the nucleotide RTI PMPA and AZT failed to inhibit infection even at a concentration of 100000 nM. These data clearly suggest that NNRTIs inactivate RT enzymatic activity of different viral clades (predominant in the epidemic) and might be proposed for further testing as a sterilizing microbicide worldwide.
Incidence and Risk Factors for Mitochondrial Toxicity in Treated HIV/HCV-Coinfected Patients
Authors: Laguno Montse , Milinkovic Ana , de Lazzari Elisa , Murillas Javier , Martínez Esteban , Blanco Jose Luis , Loncá Montse , Biglia Alejandra , Leon Agathe , García Mercedes , Larrousse Maria , García Felipe , Miró Jose Maria , Gatell Jose Maria , Mallolas Josep 
Published: April 2022

Background Coinfection with hepatitis C virus (HCV) and HIV is not uncommon and therapies for both infections are currently available. A major drawback, however, could be a potentially higher risk for mitochondrial toxicity (MT), defined as the elevation of pancreatic enzymes or lactate levels due to the nucleoside analogue reverse transcriptase inhibitors contained in both therapies. Methods Prospective analyses of clinical and laboratory data, including plasma lactate levels and pancreatic enzymes, of 113 consecutive HIV/HCV-coinfected patients were assigned to receive ribavirin (RBV) plus interferon (IFN)-α. Results Fourteen patients (12%) showed increased levels of amylase/lipase and/or hyperlactataemia. No patient developed clinical pancreatitis. Four patients with hyperlactataemia had clinical symptoms of lactic acidosis and recovered uneventfully by 2 weeks after treatment withdrawal. The variables significantly associated with MT in the univariate analysis were: therapy with didanosine (ddI), ddI plus stavudine (d4T), previous history of diabetes and the baseline lactate level. However, ddI use was the only independent risk factor for MT identified in the multivariate analysis. MT was not associated with gender, age, alcohol consumption, type of IFN, degree of steatosis and fibrosis in liver biopsy, presence of lipodystrophy, CD4+ cell count, HCV or HIV viral load, mitochondrial DNA and COXII-expression in liver tissue, or antiretroviral therapy containing d4T or protease inhibitors. Conclusions 12% of HIV/HCV-coinfected patients receiving IFN plus RBV concomitantly with highly active antiretroviral therapy developed laboratory markers of MT. Although most of cases were asymptomatic, our study suggests that concomitant use of RBV plus ddI should be avoided, and that routine monitoring of lactate and pancreatic enzymes may be recommended.
Comparison of Tests and Procedures to Build Clinically Relevant Genotypic Scores: Application to the Jaguar Study
Authors: Flandre Philippe , Marcelin Anne-Geneviève , Pavie Juliette , Shmidely Nathalie , Wirden Marc , Lada Olivier , Bernard Marie-Charlotte , Molina Jean-Michel , Calvez Vincent 
Published: April 2022

Objective To compare non-parametric tests and procedures of selection in building clinically validated genotypic scores. Design and patients In the Jaguar study, 111 patients on a stable antiretroviral regimen experiencing virological failure were randomized in the didanosine (ddI) arm to receive ddI for 4 weeks in addition to their current combination therapy. Methods The virological response was HIV-1 RNA reduction from baseline to week 4. The univariate impact of each mutation associated with resistance to ddI on virological response was quantified by comparing reduction in plasma HIV-1 RNA in patients with or without the specific mutation, using a Wilcoxon–Mann–Whitney test. The next step was to select the combination of mutations most strongly associated with the virological response. Two procedures and two tests were compared using either the set of resistance mutations or the set of resistance mutations and mutations providing a better virological response. The Kruskal–Wallis and the Jonckheere test for ordered alternatives were compared in order to build a genotypic score using the two distinct procedures. Results Eight mutations were associated with a reduced virological response to ddI: M41L, D67N, T69D, L74V, V118I, L210W, T215Y/F and K219Q/E and two mutations with a better virological response: K70R and M184V/I. The Jonckheere–Terpstra test for trend provided the combination of mutations (M41L+T69D-K70R+L74V-M184V /I+T215Y/F+ K219A/E) that were the most predictive for the week 4 virological response, that is, leading to the lowest P value. The ‘removing’ procedure, starting from a set of mutations retained and removing mutations one by one to find the best combination, provides lower P values than the ‘adding’ procedure starting with a single mutation and adding mutations one by one. Whatever the set of mutations and the procedure used, the Jonckheere–Terpstra test selects combinations of mutations leading to lower P values than the Kruskal–Wallis test. Conclusion The Jonckheere–Terpstra test for trend is recommended for building a genotypic score when compared with the Kruskal–Wallis. The choice of the selection procedure is discussed here and may be dependent on the objective of the score.
Haematological Changes in Adults Receiving a Zidovudine-Containing Haart Regimen in Combination with Cotrimoxazole in Côte D'ivoire
Authors: Moh Raoul , Danel Christine , Sorho Souleymane , Sauvageot Delphine , Anzian Amani , Minga Albert , Gomis Olivier Ba , Kanga Constance , Inwoley André , Gabillard Delphine , Bissagnene Emmanuel , Salamon Roger , Anglaret Xavier 
Published: April 2022

Objective Neutropenia is the most frequent side effect of cotrimoxazole in sub-Saharan Africa. We estimated the incidence of haematological disorders during the first 6 months of a zidovudine-containing highly active anti-retroviral therapy (HAART) regimen in sub-Saharan African adults receiving cotrimoxazole. Methods Prospective cohort study in Abidjan, with blood cell count measurement at baseline (HAART initiation), month 1, month 3 and month 6. Results A total of 498 adults [baseline: 80% currently on cotrimoxazole prophylaxis; median CD4 count 237/mm3 [interquartile range (IQR) 181;316]; median neutrophil count 1647/mm3 (IQR 1221;2256); median haemoglobin 113 g/l (IQR 102;122)] started zidovudine (AZT)/lamivudine/efavirenz. During follow-up, 118 patients had a grade 3–4 neutropenia [(56.3/100 person-years (PY)], 23 had a grade 3–4 anaemia (9.6/100 PY) and no cases of grade 3–4 thrombocytopenia. Of the 118 patients with grade 3–4 neutropenia, 86 (73%) had to stop cotrimoxazole because neutropenia persisted, and one (<1%) had to stop AZT because of persistent neutropenia after cotrimoxazole was stopped (neutropenia-related HAART modification: 0.4/100 PY). Of the 23 patients with grade 3–4 anaemia, 11 had to stop AZT (anaemia-related HAART modification: 4.4/100 PY). In patients who stopped cotrimoxazole but not AZT, the median gain in neutrophils at 1 month was +540/mm3 (IQR +150;+896). Conclusions At baseline, most patients had a normal neutrophil count and 80% of them were already receiving cotrimoxazole. An unexpectedly high rate of grade 3–4 neutropenia occurred shortly after introduction of AZT. Almost all of the persistent severe neutropenia disappeared after cotrimoxazole was stopped. This suggests an accentuated drug interaction between the two drugs in these sub-Saharan African individuals. Grade 3–4 anaemia was much less frequent, but remained the first cause of AZT discontinuation.
Comparison of Three Different Interventions for the Correction of HIV-Associated Facial Lipoatrophy: A Prospective Study
Authors: Guaraldi Giovanni , Orlando Gabriella , De Fazio Domenico , Lorenzi Ilario De , Rottino Antonio , Santis Giorgio De , Pedone Antonio , Spaggiari Antonio , Baccarani Alessio , Borghi Vanni , Esposito Roberto 
Published: April 2022

Objective To compare autologous fat transfer (AFT), injections of reabsorbable [polylactic acid (PLA)] and non-reabsorbable [polyacrylamide hydrogel (PAAG)] filler materials for the treatment of HIV-related facial lipoatrophy. Design and methods Eligible individuals with enough residual subcutaneous fat in the abdomen or in the dorso-cervical region were offered AFT surgery. Other individuals were blindly assigned to two different surgical teams, who administered a set of PLA or PAAG injections every 4 weeks. The primary endpoint was the measurement of Bichat's fat pad region, determined by the result of dermal plus subcutaneous thickness. Secondary endpoints included body image evaluation (determined by ABCD questionnaire), facial aesthetic satisfaction (determined by Visual Analogue Scale), and aesthetic pre- and post-picture comparisons by independent reviewers. All variables were measured at baseline and at 24 weeks after the last treatment session. Results Twenty-four individuals received AFT and 35 were selectively randomized to PLA (20) or PAAG (15) infiltrations. PLA and PAAG groups received a mean of 5 and 6 injections respectively ( P=NS). The mean change in dermal and subcutaneous thickness was 3.3 ±4.1 mm, 3.5 ±4.0 mm; 2.1 ±3.0 mm ( P=0.687), respectively. The mean change in ABCD score result was poorer in the AFT arm, but there were no other differences in other measured factors. Four serious adverse events were documented in the AFT arm only. Conclusions All three interventional techniques were highly effective in improving the aesthetic satisfaction of the patients. Longer follow-up is necessary to determine the most durable and suitable treatment.
Altered Mitochondrial Rna Production in Adipocytes from HIV-Infected Individuals with Lipodystrophy
Authors: Galluzzi Lorenzo , Pinti Marcello , Guaraldi Giovanni , Mussini Cristina , Troiano Leonarda , Roat Erika , Giovenzana Chiara , Nemes Elisa , Nasi Milena , Orlando Gabriella , Salomoni Paolo , Cossarizza Andrea 
Published: April 2022

Background Damage to mitochondria (mt) is a major side effect of highly active antiretroviral therapy (HAART) that includes a nucleoside reverse transcriptase inhibitor (NRTI). Such damage is associated with the onset of lipodystrophy in HAART-treated HIV+ patients. To further investigate mt changes during this syndrome, we analysed the expression of mtRNA in adipocytes from lipodystrophic HIV+ patients taking NRTI-containing HAART and compared it with similar cells from healthy individuals. Materials and methods Total RNA was extracted from adipocytes collected from different anatomical locations of 11 HIV+ lipodystrophic patients and seven healthy control individuals. RNA was reverse transcribed and Taqman-based real-time PCR was used to quantify three different mt transcripts (ND1, CYTB and ND6 gene products). mtRNA content was normalized versus the housekeeping transcript L13. Results ND1, CYTB and ND6 expression was significantly reduced in HIV+ lipodystrophic patients. HIV+ men and women did not differ in a statistically significant way regarding the levels of ND1 and ND6, whereas the opposite occurred for CYTB. Conclusions Lipodystrophy following treatment with NRTI-containing HAART is associated with a decrease in adipose tissue mtRNAs.
Boosted versus Unboosted Indinavir with Zidovudine and Lamivudine in Nucleoside Pre-Treated Patients: A Randomized, Open-Label Trial with 112 Weeks of Follow-Up (HIV-Nat 005)
Authors: Boyd Mark A , Srasuebkul Preeyaporn , Khongphattanayothin Mana , Ruxrungtham Kiat , Hassink Elly AM , Duncombe Christopher J , Ubolyam Sasiwimol , Burger David M , Reiss Peter , Stek Michael , Lange Joep MA , Cooper David A , Phanuphak Praphan 
Published: April 2022

Introduction The use of HIV protease inhibitors (PIs) in a ritonavir (RTV)-boosted form is now common. However, randomized data comparing boosted with unboosted PI strategies are scarce. Methods This randomized, open-label trial compared indinavir (IDV) 800 mg three times daily with IDV/RTV 800/100 mg twice daily, both given with zidovudine (AZT)/lamivudine (3TC) twice daily in individuals with at least 3 months previous AZT experience. The primary endpoint was the time-weighted average change in HIV RNA from baseline. Designed as a 48-week study, follow-up continued until week 112. Primary analysis is by intention to treat. Results One hundred and three patients commenced therapy and are included in the analysis. Patients had a median of 29 months past nucleoside reverse transcriptase inhibitor (NRTI) exposure. Baseline median (interquartile range) log10 HIV RNA was 4.0 (3.3–4.5) and CD4+T-cell count 166 (40–323) cells/μl. After 112-weeks of study there was no significant difference observed between arms in the mean (sd) change in time-weighted average HIV RNA from baseline (-1.6 [1.1] HIV RNA copies/week/ml three times daily arm; -1.4 [1.1] HIV RNA copies/week/ml twice daily arm; P=0.3). Both arms were associated with substantial toxicity expressed as serious adverse events and study drug interruptions. The twice daily arm experienced greater dyslipidaemia. Mean (sd) changes in time-weighted CD4+ T-cell count from baseline were similar [88 (84) cells/week/μl three times daily arm; 70 [109] cells/week/μl twice daily arm; P=0.3). Conclusions RTV-boosted IDV 800/100 mg twice daily demonstrated comparable efficacy to unboosted IDV 800mg three times daily dosing. Both regimens were associated with substantial toxicity. Use of lower doses of RTV-boosted IDV may result in better tolerability without loss of efficacy and warrant further research.
In Vitro Evaluation of the Anti-HIV Activity and Metabolic Interactions of Tenofovir and Emtricitabine
Authors: Borroto-Esoda Katyna , Vela Jennifer E , Myrick Florence , Ray Adrian S , Miller Michael D 
Published: April 2022

Background Tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are nucleoside reverse transcriptase inhibitors (NRTIs) with once-daily dosing approved for use in HIV-1 infection. We evaluated this combination for anti-HIV activity and intracellular metabolic interactions in vitro. Methods Intracellular anabolism of combinations of FTC and tenofovir (TFV) were studied in the human T leukaemic cell line CEM and human peripheral blood mononuclear cells (PBMCs). The anti-HIV activity of the combination was studied in the human T leukaemic MT-2 cell line against wild-type or mutant virus (K65R and M184V) and in PBMCs against wild-type virus. Antiviral synergy was quantitated by isobologram and MacSynergy methods. Results Both TFV and FTC were efficiently converted to their active metabolites in PBMCs and CEM cells. In CEM cells, there was a statistically significant increase in the levels of TFV diphosphate ( P=0.047) and FTC triphosphate ( P=0.0069) following a 24 h incubation with the combination compared with the levels seen with the individual drugs. In PBMCs, similar levels of active metabolites were observed for each drug when they were incubated individually or in combination. The combination of TFV and FTC displayed additive to synergistic activity against HIV replication in PBMCs and resulted in strongly synergistic anti-HIV activity in MT-2 cells against both wild-type and mutant virus. Conclusions The combination of TFV and FTC showed additive to synergistic anti-HIV activity in vitro, which correlated with the levels of intracellular phosphorylation observed. These results support the use of these drugs as a dual NRTI backbone in combination therapy for the treatment of HIV-1.