bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Longitudinal Analysis of Healthcare Costs after Treatment Optimization following Genotypic Antiretroviral Resistance Testing: Does Resistance Testing pay off?
Authors: Simcock Mathew , Sendi Pedram , Ledergerber Bruno , Keller Tamara , Schüpbach Jörg , Battegay Manuel , Günthard Huldrych F ,   Swiss HIV Cohort Study, Backmann S , Battegay M , Bernasconi E , Bucher H , Bürgisser Ph , Egger M , Erb P , Fierz W , Fischer M , Flepp M , Francioli P , Furrer HJ , Gorgievski M , Günthard H , Grob P , Hirschel B , Kaiser L , Kind C , Klimkait Th , Ledergerber B , Lauper U , Nadal D , Opravil M , Paccaud F , Pantaleo G , Perrin L , Piffaretti J-C , Rickenbach M , Rudin C , Schüpbach J , Speck R , Telenti A , Trkola A , Vernazza P , Weber R , Yerly S 
Published: April 2022

Objective To assess the impact of antiretroviral therapy optimized by genotypic antiretroviral resistance testing (GRT) on healthcare costs over a 2-year period in patients after antiretroviral treatment failure. Study design Non-randomized, prospective, tertiary care, clinic-based study. Patients One-hundred and forty-two HIV patients enrolled in the ‘ZIEL’ study and the Swiss HIV Cohort Study who experienced virological treatment failure. Methods For all patients GRT was used to optimize the antiretroviral treatment regimen. All healthcare costs during 2 years following GRT were assessed using micro-costing. Costs were separated into ART medication costs and healthcare costs other than ART medication (that is, non-ART medication costs, in-patient costs and ambulatory [out-patient] costs). These cost estimates were then split into four consecutive 6-month periods (period 1–4) and the accumulated cost for each period was calculated. Univariate and multivariate regression modelling techniques for repeated measurements were applied to assess the changes of healthcare costs over time and factors associated with healthcare costs following GRT. Results Overall healthcare costs after GRT decreased over time and were significantly higher in period 1 (32%; 95% confidence interval [CI]: 18–47) compared with period 4. ART medication costs significantly increased by 1,017 (95% CI: 22–2,014) Swiss francs (CHF) from period 1–4, whereas healthcare costs other than ART medication costs decreased substantially by a factor of 3.1 (95% CI: 2.6–3.7) from period 1 to period 4. Factors mostly influencing healthcare costs following GRT were AIDS status, costs being 15% (95% CI: 6–24) higher in patients with AIDS compared with patients without AIDS, and baseline viral load, costs being 12% (95% CI: 6–17) higher in patients with each log increase in plasma RNA. Conclusions Optimized antiretroviral treatment regimens following GRT lead to a reduction of healthcare costs in patients with treatment failure over 2 years. Patients in a worse health state (that is, a positive AIDS status and high baseline viral load) will experience higher overall costs.
Three-Year Clinical Outcomes of Resistance Genotyping and Expert Advice: Extended follow-up of the Argenta Trial
Authors: Luca Andrea De , Giambenedetto Simona Di , Cingolani Antonella , Bacarelli Alessandra , Ammassari Adriana , Cauda Roberto 
Published: April 2022

Objective To investigate the influence of genotypic resistance-guided HIV-treatment decisions on long-term clinical and virological outcomes in patients failing anti-retroviral therapy by a prospective 30-month observation following a 6-month randomized study (Argenta trial). Methods Patients ( n=174) with virological failure on highly active antiretroviral therapy (HAART) were initially randomized (1:1) to receive empirical therapy or guidance by genotypic resistance results. After month 6, all patients with HIV RNA >1,000 copies/ml received genotypic resistance tests and expert advice. Predictors of virological and clinical outcomes were analysed by logistic regression and Cox's regression models. Results There was a gradual increase in the proportion of patients with HIV RNA <400 copies/ml with 29.3% at 36 months (intent-to-treat) without differences between initial randomization arms. Independent predictors of 36-month virological response were the use of a salvage therapy with less daily doses and a more pronounced 3-month viral load drop. At 36 months, 84% survived without new AIDS events/death. Independent predictors of new AIDS events/death were previous AIDS events, higher baseline viral load, less pronounced 3-month viral load drop and, in a separate model, baseline protease substitutions K20M/R and I84V Conclusions The virological benefit of genotype-guided treatment decisions was continuously appreciable over time. Short-term virological response and viral cross-resistance were independent predictors of long-term outcomes.
Prevalence and Impact of HIV-1 Protease Codon 33 Mutations and Polymorphisms in Treatment-Naive and Treatment-Experienced Patients
Authors:   Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA), Kozal Michael J , Hullsiek Katherine Huppler , Leduc Robert , Novak Richard M , MacArthur Rodger D , Lawrence Jody , Baxter John D 
Published: April 2022

Background HIV-1 protease gene mutations at codon 33 have been associated with resistance to some but not all protease inhibitors (PIs). Little is known about the difference in prevalence of codon 33 mutations and polymorphisms between treatment-naive and treatment-experienced patients, and the effect of codon 33F on PI phenotypic resistance patterns. Methods Baseline genotypes (TRUGENE) from 772 patients participating in two different randomized clinical trials [504 antiretroviral treatment-naive patients and 268 antiretroviral treatment-experienced patients] were evaluated for the presence of protease codon 33 mutations and polymorphisms. Baseline phenotypes (Antivirogram), including fold-change in resistance for 16 antiretroviral drugs, were available for the 268 treatment-experienced patients. Multivariate linear regression models were used to determine factors associated with phenotypic fold-change for PIs. Results The prevalence of codon 33 mutations and polymorphisms was 5.2% in the naive cohort (0.2% 33F, 2.5% 33V, 2.5% 33I) and 34.7% in the experienced cohort (30.2% 33F, 1.5% 33V, 3.0% 33I). In the antiretroviral-experienced cohort (mean = 4.2 prior PIs, 10.6 prior antiretroviral drugs overall), a model adjusting for the presence of specific major protease and multi-PI resistance conferring mutations, the number of other minor PI mutations, prior PI drug exposure (current, prior only, never), and HIV transmission risk factor was used to estimate the phenotypic fold-change in resistance for those with and without mutation 33F. Those with 33F had a significantly higher fold-change for amprenavir (33 vs 19, P<0.0001), ritonavir (162 vs 82, P<0.0001), lopinavir (49 vs 38, P=0.04), and saquinavir (47 vs 41, P=0.02). The presence of the 33F was not a significant predictor of fold change in susceptibility for indinavir or nelfinavir. Conclusions At protease codon 33, the prevalences of polymorphisms 33V and 33I were similar for PI-naive and PI-experienced patients (<3.0%), but the prevalence of 33F was significantly different (0.2% versus 30.2%). In the treatment-experienced cohort, the differences in phenotypic fold-change for amprenavir, lopinavir, saquinavir, and ritonavir between those with and without 33F persist after adjustment for the presence of other major PI mutations and PI drug exposure history. Given the availability of newer PIs that may select for 33F, monitoring for the presence of this mutation should be ongoing for both treatment-naive and treatment-experienced patients.
Incidence of and Risk Factors for Insulin Resistance in Treatment-Naive HIV-Infected Patients 48 Weeks after Starting Highly Active Antiretroviral Therapy
Authors: Palacios Rosario , Merchante Nicolás , Macías Juan , González Mercedes , Castillo Jesús , Ruiz Josefa , Márquez Manuel , Gómez-Mateos Jesús , Pineda Juan A , Santos Jesús 
Published: April 2022

Objectives to assess the incidence and risk factors for insulin resistance (IR) in a cohort of naive HIV-infected patients 48 weeks after satarting highly active antiretroviral therapy (HAART). Design prospective, two centre, observational, cohort study. Methods One-hundred and thirty-seven patients who started HAART and maintained the same regimen for 48 weeks were included. IR was determined by the homeostasis model assessment (HOMA-IR) method. Individuals with a HOMA-IR value >3.8 were defined as insulin resistant. Independent associations with the development of IR at 48 weeks were evaluated. Results Seventeen (12.4%) individuals showed a HOMA-IR value >3.8 at baseline and were excluded for incidence analyses. Fifteen patients developed IR at 48 weeks of HAART, giving an incidence of 13%. Independent predictors of the development or IR were indinavir exposure (β-coefficient 5.45, 95% confidence interval [CI] 1.30–22.8; P=0.02), and hepatitis C virus (HCV) antibody positivity (β-coefficient 5.22, 95% CI 1.34–20.33; P=0.01). The appearance of IR was associated with a higher BMI (β-coefficient 1.72 for each 2 kg/m2 increase, 95% CI 1.54–1.94; P=0.02) and with the presence of lipodystrophy at 48 weeks (β-coefficient 5.59, 95% CI 1.45-21.5; P=0.01). Conclusions HAART induces the development of IR in previously naive non-insulin-resistant HIV-infected individuals, with an incidence of 13% in the first year of therapy. Indinavir exposure, and HCV coinfection are associated with an increased risk of developing IR.
Impact of Lamivudine on the Risk of Liver-Related Death in 2,041 Hbsag- and HIV-Positive Individuals: Results from An Inter-Cohort Analysis
Authors: Puoti Massimo , Cozzi-Lepri Alessandro , Arici Claudio , Moller Nina Friis , Lundgren Jens D , Ledergerber Bruno , Rickenbach Martin , Suarez–Lozano Ignacio , Garrido Myriam , Dabis Francois , Winnock Maria , Milazzo Laura , Gervais Anne , Raffi Francois , Gill John , Rockstroh Juergen , Qurishi Nazifa , Mussini Cristina , Castagna Antonella , Luca Andrea De , Monforte Antonella d'Arminio 
Published: April 2022

Background The impact of lamivudine (3TC) as part of combination antiretroviral therapy (cART) on the risk of liver-related death (LRD) in HIV/hepatitis B virus (HBV)-coinfected patients has not been extensively studied. Methods We performed an analysis involving HIV/HBV-coinfected patients in 13 cohorts who initiated cART. The end–point was LRD – that is, death with concomitant decompensated liver disease (DLD) or hepatocellular carcinoma – as the main cause. Incidence rates of LRD after initiation of cART were expressed as number of events per 100 person–years of follow–up (PYFU). A Poisson regression model adjusted for cohort, gender, mode of HIV transmission, CD4+ T-cell count at cART initiation, liver disease pre–cART, duration of 3TC before cART, and hepatitis C virus was used to assess the association between use of 3TC and risk of LRD. Results We analysed 2,041 patients. Follow–up after starting cART was 7,648 PYFU (5,569 spent on 3TC-containing regimens) with a median per person of 48 months (range: 2–91). Of the total, 217 subjects died; 57 deaths were liver-related resulting in a rate of 7.5 per 1,000 PYFU [95% confidence intervals (CI): 5.6–9.7]. The relative risk of LRD per extra year of 3TC use was 0.73 (95% CI: 0.59–0.90, P=0.004). Conclusion The use of 3TC was associated with a reduced risk of LRD over 4 years of follow–up. This study supports the current view that the use of 3TC as part of cART should be considered in patients who are tested positive for HBsAg.
Defective Synthesis of Granulocyte-Colony Stimulating Factor in Pegylated Interferon-α Treated Chronic Hepatitis C Patients with Declining Leukocyte Counts
Authors: Durante-Mangoni Emanuele , Iardino Patrizia , Utili Riccardo , Adinolfi Luigi E , Ruggiero Giuseppe 
Published: April 2022

Background Pegylated-interferon-α (peg-IFN-α) is the mainstay of treatment for chronic hepatitis C (CHC). Treatment is often complicated by neutropaenia due to inhibition of haematopoiesis. However, there are no data on the kinetics of granulocyte-colony stimulating factor (G-CSF), a major neutrophil growth factor, in this setting. We therefore evaluated G-CSF synthesis in CHC patients on peg-IFN-α treatment. Methods A total of 40 CHC patients were studied. None had pre-existing haematological disorders, or hepatitis B virus or HIV coinfection. For controls, 30 healthy subjects were used. Laboratory examinations, including liver function tests, were performed at baseline and monthly over treatment and follow-up. Serum G-CSF was measured in all patients and controls at baseline and in a subgroup of 20 CHC patients also at weeks 2, 4, 24, 48 and 72 after treatment start. Results CHC patients had a significantly lower pre-treatment neutrophil count (3,256 ±1,197 versus 3,804 ±859; P=0.03). Notwithstanding, they showed lower baseline G-CSF serum levels than healthy controls (16.1 ±6.2 versus 19.4 ±7.5; P=0.048). Consistently, baseline G-CSF levels were poorly correlated with the neutrophil count in CHC patients (r=-0.2; P=0.2). Moreover, serum G-CSF levels did not increase in any of the 20 CHC patients during peg-IFN-α treatment, despite declining neutrophil counts. Conclusions The lower neutrophil counts observed in CHC might be related to an absolute deficiency in G-CSF production. In the human model of neutropaenia induced by peg-IFN-α, we show that endogenous G-CSF levels are not physiologically up-regulated to overcome the decline in neutrophil counts. Our study provides a rationale for the evaluation of recombinant human G-CSF treatment in peg-IFN-α-induced neutropaenia.
A Randomized Trial to Evaluate Continuation versus Discontinuation of Lamivudine in Individuals Failing A Lamivudine-Containing Regimen: The Colate Trial
Authors: Fox Zoe , Dragsted Ulrik B , Gerstoft Jan , Phillips Andrew N , Kjaer Jesper , Mathiesen Lars , Youle Mike , Katlama Christine , Hill Andrew , Bruun Johan N , Clumeck Nathan , Dellamonica Pierre , Lundgren Jens D 
Published: April 2022

Background Lamivudine (3TC) therapy can cause the emergence of M184I/V. Previous studies suggest a higher fidelity of the mutant reverse transcriptase and lower replication capacity of the mutant virus. No data exist from clinical comparative studies evaluating the benefit of M184I/V in patients receiving combination antiretroviral therapy (cART). Methods HIV-1-infected adults failing a 3TC-containing regimen were randomized to continue (On-3TC) or discontinue 3TC (Off-3TC) whilst receiving cART. The primary efficacy measure was the log10 average-area-under-the-curve-minus-baseline reduction in HIV RNA over 48 weeks. Cryopreserved plasma samples from patients with baseline and ≥1 follow-up sample with HIV RNA >500 copies/ml were sequenced for a nucleotide distances substudy. Evolutionary distances were compared between treatment arms and between viruses with and without M184I/V Results The overall 48-week log10 HIV RNA change was -1.4 (95% CI: -1.6, -1.1) for On-3TC ( n=65) and -1.5 (95% CI: -1.7, -1.2) for Off-3TC ( n=66; P=0.51). No difference was seen in the magnitude of the CD4+ T-cell count increases (median increase: 87 vs 76 cells/ml for 3TC vs Off-3TC, respectively). Thirty-seven patients had baseline and follow-up sequencing. Overall, there were 1.2 (95% CI: -2.2, 4.6) more nucleotide substitutions from baseline for Off-3TC patients ( P=0.50), and 10.7 (95% CI: 7.5, 14.0) fewer nucleotide changes in viruses containing M184I/V ( P<0.0001). Conclusion This study found no added virological or immunological benefit of continuing 3TC in patients on cART harbouring M184I/V Evolutionary distances from baseline were larger in viruses that did not contain M184I/V. More discernable benefits may be seen in patients with fewer drug options as potent cART may eclipse a benefit of M184I/V in COLATE.
HIV-1 Infection Alters Gene Expression in Adipose Tissue, Which Contributes to HIV-1/Haart-Associated Lipodystrophy
Authors: Giralt Marta , Domingo Pere , Guallar Jordi P , de la Concepción M Luísa Rodríguez , Alegre Marta , Domingo Joan C , Villarroya Francesc 
Published: April 2022

Background The aetiopathogenic bases of HIV-1-/highly active antiretroviral treatment (HAART)-associated lipodystrophy (HALS) are poorly known, but this syndrome indicates that adipose tissue is highly sensitive to either HIV-1 infection, antiretroviral drugs or their combination. Methods To assess the relative contribution of infection and drugs, we compared the expression of marker genes corresponding to mitochondrial function, adipocyte differentiation and metabolism, and adipokines in subcutaneous adipose tissue from healthy controls, untreated HIV-1-infected patients, and HIV-1-infected patients treated with HAART with or without HALS. Results Subcutaneous adipose tissue from HIV-1-infected patients contained lower concentrations of the mRNA of the mitochondrial DNA-encoded cytochrome c oxidase subunit II than that of controls. These concentrations decreased further in association with HAART. The expression of nuclear genes coding for mitochondrial proteins, peroxisome proliferator-activated receptor-γ, and adipocyte-specific markers was reduced in HIV-1-infected patients, treated or not, with respect to the controls. In contrast, the mRNA concentrations of uncoupling protein-3 and preadipocyte factor-1 increased in lipodystrophic HAART-treated patients. The genes coding for adipokines were strongly affected: tumour necrosis factor-α was upregulated, whereas adiponectin and leptin were downregulated in HIV-1-infected patients, treated or not. Thus, substantial alterations of gene expression were already present when naive patients were compared with controls. Further changes were associated with HAART and with the diagnosis of HALS. Conclusions Disturbances in adipose tissue gene expression are already present in untreated HIV-1-infected patients, thus indicating a role of HIV-1 infection itself in eliciting adipose tissue alterations that are worsened by HAART, which ultimately leads to HALS.
Resistance of Hepatitis C Virus to Ns3–4A Protease Inhibitors: Mechanisms of Drug Resistance Induced by R155Q, A156T, D168A and D168V Mutations
Authors: Courcambeck Jérôme , Bouzidi Mourad , Perbost Régis , Jouirou Besma , Amrani Nolwenn , Cacoub Patrice , Pèpe Gérard , Sabatier Jean-Marc , Halfon Philippe 
Published: April 2022

Background/aims One of the main issues in the development of antiviral therapy is the emergence of drug-resistant viruses. In the case of hepatitis C virus (HCV), selection of drug-resistant mutants was evidenced by in vitro studies on protease inhibitors (PIs); for example, BILN-2061, VX-950 and SCH-6. Four mutations in the HCV protease (R155Q, A156T, D168A and D168V) have been identified in vitro in the HCV replicon system that confer resistance to BILN-2061 (a reference inhibitor). However, the molecular mechanism of drug resistance is still unknown. The aim of this study is to unravel, using an molecular modelling strategy, the structural basis of such molecular mechanism of HCV resistance to PIs. We focused on protease mutations conferring HCV resistance to BILN-2061 and described for the first time such mechanism at a molecular level. Methods The structures of drug-resistant NS3 proteases were obtained by mutation of selected residues (R155Q, A156T, D168A and D168V) and the ternary complexes formed between NS3–4A and BILN-2061 were optimized using GenMol software ( www.3dgenoscience.com ; Genoscience, Marseille, France). Results Two mechanisms were evidenced for viral resistance to BILN-2061. A ‘direct’ resistance mechanism is based on contacts between the mutated R155Q and A156T protease residues and its inhibitor. In the ‘indirect’ resistance mechanism, the mutated D168A/V residue is not in close contact with the drug itself but interacts with other residues connected to the drug. Conclusions These data provide new insights in the understanding of the mechanisms of HCV drug escape, and may allow predicting potential cross-resistance phenomenon with other PIs. This approach can be used as a basis for future rational PI drug design candidates.
The Effect of HIV-1 Resistance Mutations after First-Line Virological Failure on the Possibility to Sequence Antiretroviral Drugs in Second-Line Regimens
Authors: Maggiolo Franco , Ripamonti Diego , Torti Carlo , Arici Claudio , Antinori Andrea , Quiros-Roldan Eugenia , Minoli Lorenzo , Sighinolfi Laura , Nasta Paola , Suter Fredy 
Published: April 2022

Background One of the more vigorous debates in the field of highly active antiretroviral therapy (HAART) is how to start it and what the optimal drug sequence is. Methods A retrospective cohort analysis was performed. The aim was to evaluate which variables could influence the virological response to second-line genotypic-based HAART in patients with virological documented first-line HAART failure. A positive response was defined as a confirmed HIV RNA level <50 copies/ml. Results Two hundred and eight patients were included. Demographic characteristics, risk factors for HIV acquisition, and drugs included in the initial treatment did not significantly influence the considered outcome. According to a multiple logistic model, the presence of thymidine analogue mutations (TAMs) had a negative association with the virological outcome ( P=0.006), whereas the use of a boosted protease inhibitor (PI) in second-line HAART was positively associated with the endpoint ( P=0.001). Patients receiving a genotypic-based second-line HAART containing a boosted PI achieved a viral load <50 copies/ml in a 74.2% of cases compared with 52.2% of those whose therapy did not contain a boosted PI. This difference was statistically significant ( P=0.002) with an odds ratio (OR) of 2.63 and a 95% confidence interval (CI) ranging from 1.46 to 4.76. This last variable positively influenced the outcome even when the analysis was restricted to patients harbouring a virus presenting TAMs. In this case, second-line HAART was successful in 66.7% of cases with an OR of 3.25 and a 95% CI ranging from 1.28 to 8.25 ( P=0.014). Conclusions the wider range of available therapeutic options has made resistance and drug-sequencing considerations a crucial point in selecting first-line HAART. Our data indicate that, by limiting the risk of selecting or accumulating TAMs, it could be possible to save further therapeutic options. In second-line regimens, the higher antiviral effect and genetic barrier of boosted PIs may overcome the limits of the use of NRTI backbones, which retain only a partial effectiveness.