| 1. |
- Sundén-Cullberg, Jonas, et al.
(författare)
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Anakinra or tocilizumab in patients admitted to hospital with severe covid-19 at high risk of deterioration (IMMCoVA): A randomized, controlled, open-label trial
- 2023
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 18:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Anakinra and tocilizumab are used for severe Covid-19, but only one previous randomized controlled trial (RCT) has studied both. We performed a multi-center RCT comparing anakinra or tocilizumab versus usual care (UC) for adults at high risk of deterioration.Methods: The study was conducted June 2020 to March 2021. Eligibility required ≥ 5 liters/minute of Oxygen to maintain peripheral oxygen saturation at ≥ 93%, CRP > 70 mg/L, ferritin > 500 μg/L and at least two points where one point was awarded for lymphocytes < 1x 109/L; D-dimer ≥ 0.5 mg/L and; lactate dehydrogenase ≥ 8 microkatal/L. Patients were randomly assigned 1:1:1 to receive either a single dose of tocilizumab (8 mg/kg) or anakinra 100 mg IV QID for seven days or UC alone. The primary outcome was time to recovery.Results: Recruitment was ended prematurely when tocilizumab became part of usual care. Out of a planned 195 patients, 77 had been randomized, 27 to UC, 28 to anakinra and 22 to tocilizumab. Median time to recovery was 15, 15 and 11 days. Rate ratio for recovery for UC vs anakinra was 0.91, 0.47 to 1.78, 95% [CI], p = 0.8 and for UC vs tocilizumab 1.13, 0.55 to 2.30; p = 0.7. There were non-significant trends favoring tocilizumab (and to limited degree anakinra) vs UC for some secondary outcomes. Safety profiles did not differ significantly.Conclusion: Premature closure of trial precludes firm conclusions. Anakinra or tocilizumab did not significantly shorten time to clinical recovery compared to usual care. (IMMCoVA, NCT04412291, EudraCT: 2020-00174824).
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| 2. |
- Ambikan, Anoop T., et al.
(författare)
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Genome-scale metabolic models for natural and long-term drug-induced viral control in HIV infection
- 2022
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Ingår i: Life Science Alliance. - : Life Science Alliance, LLC. - 2575-1077. ; 5:9
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Tidskriftsartikel (refereegranskat)abstract
- Genome-scale metabolic models (GSMMs) can provide novel insights into metabolic reprogramming during disease progression and therapeutic interventions. We developed a context-specific system-level GSMM of people living with HIV (PLWH) using global RNA sequencing data from PBMCs with suppressive viremia either by natural (elite controllers, PLWHEC) or drug-induced (PLWHART) control. This GSMM was compared with HIV-negative controls (HC) to provide a comprehensive systems-level metabo-transcriptomic characterization. Transcriptomic analysis identified up-regulation of oxidative phosphorylation as a characteristic of PLWHART, differentiating them from PLWHEC with dysregulated complexes I, III, and IV. The flux balance analysis identified altered flux in several intermediates of glycolysis including pyruvate, a-ketoglutarate, and glutamate, among others, in PLWHART. The in vitro pharmacological inhibition of OXPHOS complexes in a latent lymphocytic cell model (J-Lat 10.6) suggested a role for complex IV in latency reversal and immunosenescence. Furthermore, inhibition of complexes I/III/IV induced apoptosis, collectively indicating their contribution to reservoir dynamics.
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| 3. |
- Backenius, Erik, 1974-
(författare)
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On Reduction of Substrate Noise in Mixed-Signal Circuits
- 2005
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Microelectronics is heading towards larger and larger systems implemented on a single chip. In wireless communication equipment, e.g., cellular phones, handheld computers etc., both analog and digital circuits are required. If several integrated circuits (ICs) are used in a system, a large amount of the power is consumed by the communication between the ICs. Furthermore, the communication between ICs is slow compared with on-chip communication. Therefore, it is favorable to integrate the whole system on a single chip, which is the objective in the system-on-chip (SoC) approach.In a mixed-signal SoC, analog and digital circuits share the same chip. When digital circuits are switching, they produce noise that is spread through the silicon substrate to other circuits. This noise is known as substrate noise. The performance of sensitive analog circuits is degraded by the substrate noise in terms of, e.g., lower signal-to-noise ratio and lower spurious-free dynamic range. Another problem is the design of the clock distribution net, which is challenging in terms of obtaining low power consumption, sharp clock edges, and low simultaneous switching noise.In this thesis, a noise reduction strategy that focus on reducing the amount of noise produced in digital clock buffers, is presented. The strategy is to use a clock with long rise and fall times. It is also used to relax the constraints on the clock distribution net, which also reduce the design effort. Measurements on a test chip show that the strategy can be implemented in an IC with low cost in terms of speed and power consumption. Comparisons between substrate coupling in silicon-on-insulator (SOI) and conventional bulk technology are made using simple models. The objective here is to get an understanding of how the substrate coupling differs in SOI from the bulk technology. The results show that the SOI has less substrate coupling when no guard band is used, up to a certain frequency that is highly dependent of the chip structure. When a guard band is introduced in one of the analyzed test structures, the bulk resulted in much higher attenuation compared with SOI. An on-chip measurement circuit aiming at measuring simultaneous switching noise has also been designed in a 0.13 µ SOI process.
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| 4. |
- Bergman, Peter, et al.
(författare)
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Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial
- 2021
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 74
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with immunocompromised disorders have mainly been excluded from clinical trials of vaccination against COVID-19. Thus, the aim of this prospective clinical trial was to investigate safety and efficacy of BNT162b2 mRNA vaccination in five selected groups of immunocompromised patients and healthy controls.Methods: 539 study subjects (449 patients and 90 controls) were included. The patients had either primary (n=90), or secondary immunodeficiency disorders due to human immunodeficiency virus infection (n=90), allogeneic hematopoietic stem cell transplantation/CAR T cell therapy (n=90), solid organ transplantation (SOT) (n=89), or chronic lymphocytic leukemia (CLL) (n=90). The primary endpoint was seroconversion rate two weeks after the second dose. The secondary endpoints were safety and documented SARS-CoV-2 infection.Findings: Adverse events were generally mild, but one case of fatal suspected unexpected serious adverse reaction occurred. 72.2% of the immunocompromised patients seroconverted compared to 100% of the controls (p=0.004). Lowest seroconversion rates were found in the SOT (43.4%) and CLL (63.3%) patient groups with observed negative impact of treatment with mycophenolate mofetil and ibrutinib, respectively.Interpretation: The results showed that the mRNA BNT162b2 vaccine was safe in immunocompromised patients. Rate of seroconversion was substantially lower than in healthy controls, with a wide range of rates and antibody titres among predefined patient groups and subgroups. This clinical trial highlights the need for additional vaccine doses in certain immunocompromised patient groups to improve immunity.
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| 5. |
- Chen, Puran, et al.
(författare)
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Real-world assessment of immunogenicity in immunocompromised individuals following SARS-CoV-2 mRNA vaccination : a one-year follow-up of the prospective clinical trial COVAXID
- 2023
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 94
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Tidskriftsartikel (refereegranskat)abstract
- Background: Immunocompromised patients have varying responses to SARS-CoV-2 mRNA vaccination. However, there is limited information available from prospective clinical trial cohorts with respect to long-term immunogenicity-related responses in these patient groups following three or four vaccine doses, and in applicable cases infection.Methods: In a real-world setting, we assessed the long-term immunogenicity-related responses in patients with primary and secondary immunodeficiencies from the prospective open-label clinical trial COVAXID. The original clinical trial protocol included two vaccine doses given on days 0 and 21, with antibody titres measured at six different timepoints over six months. The study cohort has subsequently been followed for one year with antibody responses evaluated in relation to the third and fourth vaccine dose, and in applicable cases SARS-CoV-2 infection. In total 356/539 patients were included in the extended cohort. Blood samples were analysed for binding antibody titres and neutralisation against the Spike protein for all SARS-CoV-2 variants prevailing during the study period, including Omicron subvariants. SARS-CoV-2 infections that did not require hospital care were recorded through quarterly in-person, or phone-, interviews and assessment of IgG antibody titres against SARSCoV-2 Nucleocapsid. The original clinical trial was registered in EudraCT (2021-000175-37) and clinicaltrials.gov (NCT04780659).Findings: The third vaccine dose significantly increased Spike IgG titres against all the SARS-CoV-2 variants analysed in all immunocompromised patient groups. Similarly, neutralisation also increased against all variants studied, except for Omicron. Omicron-specific neutralisation, however, increased after a fourth dose as well as after three doses and infection in many of the patient subgroups. Noteworthy, however, while many patient groups mounted strong serological responses after three and four vaccine doses, comparably weak responders were found among patient subgroups with specific primary immunodeficiencies and subgroups with immunosuppressive medication.Interpretation: The study identifies particularly affected patient groups in terms of development of long-term immunity among a larger group of immunocompromised patients. In particular, the results highlight poor vaccine-elicited neutralising responses towards Omicron subvariants in specific subgroups. The results provide additional knowledge of relevance for future vaccination strategies.
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| 6. |
- Gao, Yu, et al.
(författare)
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Immunodeficiency syndromes differentially impact the functional profile of SARS-CoV-2-specific T cells elicited by mRNA vaccination
- 2022
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Ingår i: Immunity. - : Elsevier. - 1074-7613 .- 1097-4180. ; 55:9, s. 1732-1746.e5
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Tidskriftsartikel (refereegranskat)abstract
- Many immunocompromised patients mount suboptimal humoral immunity after SARS-CoV-2 mRNA vaccination. Here, we assessed the single-cell profile of SARS-CoV-2-specific T cells post-mRNA vaccination in healthy individuals and patients with various forms of immunodeficiencies. Impaired vaccine-induced cell-mediated immunity was observed in many immunocompromised patients, particularly in solid-organ transplant and chronic lymphocytic leukemia patients. Notably, individuals with an inherited lack of mature B cells, i.e., X-linked agammaglobulinemia (XLA) displayed highly functional spike-specific T cell responses. Single-cell RNA-sequencing further revealed that mRNA vaccination induced a broad functional spectrum of spike-specific CD4+ and CD8+ T cells in healthy individuals and patients with XLA. These responses were founded on polyclonal repertoires of CD4+ T cells and robust expansions of oligoclonal effector-memory CD45RA+ CD8+ T cells with stem-like characteristics. Collectively, our data provide the functional continuum of SARS-CoV-2-specific T cell responses post-mRNA vaccination, highlighting that cell-mediated immunity is of variable functional quality across immunodeficiency syndromes.
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| 7. |
- Josephson, Filip, et al.
(författare)
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The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-na
- 2010
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 1432-1041 .- 0031-6970. ; 66:4, s. 349-357
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Tidskriftsartikel (refereegranskat)abstract
- The relation between treatment outcome and trough plasma concentrations of efavirenz (EFV), atazanavir (ATV) and lopinavir (LPV) was studied in a pharmacokinetic/pharmacodynamic substudy of the NORTHIV trial-a randomised phase IV efficacy trial comparing antiretroviral-na < ve human immunodeficiency virus-1-infected patients treated with (1) EFV + 2 nucleoside reverse transcriptase inhibitors (2NRTI) once daily, (2) ritonavir-boosted ATV + 2NRTI once daily or (3) ritonavir-boosted LPV + 2NRTI twice daily. The findings were related to the generally cited minimum effective concentration levels for the respective drugs (EFV 1,000 ng/ml, ATV 150 ng/ml, LPV 1,000 ng/ml). The relation between atazanavir-induced hyperbilirubinemia and virological efficacy was also studied. Drug concentrations were sampled at weeks 4 and 48 and optionally at week 12 and analysed by high-performance liquid chromatography with UV detector. When necessary, trough values were imputed by assuming the reported average half-lives for the respective drugs. Outcomes up to week 48 are reported. No relation between plasma concentrations of EFV, ATV or LPV and virological failure, treatment withdrawal due to adverse effects or antiviral potency (viral load decline from baseline to week 4) was demonstrated. Very few samples were below the suggested minimum efficacy cut-offs, and their predictive value for treatment failure could not be validated. There was a trend toward an increased risk of virological failure in patients on ATV who had an average increase of serum bilirubin from baseline of < 25 mu mol/l. The great majority of treatment-na < ve and adherent patients on standard doses of EFV, ritonavir-boosted ATV and ritonavir-boosted LPV have drug concentrations above that considered to deliver the maximum effect for the respective drug. The results do not support the use of routine therapeutic drug monitoring (TDM) for efficacy optimisation in treatment-na < ve patients on these drugs, although TDM may still be of value in some cases of altered pharmacokinetics, adverse events or drug interactions. Serum bilirubin may be a useful marker of adherence to ATV therapy.
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| 8. |
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| 9. |
- Kamal, Habiba, et al.
(författare)
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The cascade of care for patients with chronic hepatitis delta in Southern Stockholm, Sweden for the past 30 years
- 2024
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Ingår i: Liver international. - : Wiley-Blackwell Publishing Inc.. - 1478-3223 .- 1478-3231. ; 44:1, s. 228-240
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Previous studies have shown suboptimal screening for hepatitis D virus (HDV) among patients with chronic hepatitis B (CHB). This study presents the cascade of care for HDV infection in a major secondary referral centre in Southern Stockholm, Sweden.METHODS: HBsAg+ve patients attending Karolinska University Hospital (KUH) from 1992 to 2022 were identified. The prevalence of anti-HDV and/or HDV RNA positivity, interferon (IFN) therapy and maintained virological responses (MVR) after HDV treatment were assessed. Also, time to anti-HDV testing was analysed in relation to liver-related outcomes with logistic regression.RESULTS: Among 4095 HBsAg+ve persons, 3703 (90.4%) underwent an anti-HDV screening; within a median of 1.8 months (range 0.0-57.1) after CHB diagnosis. This screening rate increased over time, to 97.9% in the last decade. Overall, 310 (8.4%) were anti-HDV+ve, of which 202 (65.2%) were HDV RNA+ve. Eighty-five (42%) received IFN, and 9 (10.6%) achieved MVR at the last follow-up. The predictive factors for anti-HDV screening were Asian origin, diagnosis after the year 2012, HIV co-infection (negative factor) and HBV DNA level < 2000 IU/mL in univariable analysis, while HIV co-infection was the only remaining factor in multivariable analysis. Delayed anti-HDV test >5 years was independently associated with worsened liver-related outcomes (adjusted odds ratio = 7.6, 95% CI 1.8-31.6).CONCLUSION: Higher frequency of HDV screening than previously published data could be seen among CHB patients at KUH in a low-endemic setting. Receiving a delayed screening test seems to be associated with worse outcomes, stressing the need of a strategy for timely HDV diagnosis.
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| 10. |
- Krishnan, Shuba, et al.
(författare)
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Metabolic Perturbation Associated With COVID-19 Disease Severity and SARS-CoV-2 Replication
- 2021
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Ingår i: Molecular & Cellular Proteomics. - : Elsevier BV. - 1535-9476 .- 1535-9484. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- Viruses hijack host metabolic pathways for their replicative advantage. In this study, using patient-derived multiomics data and in vitro infection assays, we aimed to understand the role of key metabolic pathways that can regulate severe acute respiratory syndrome coronavirus-2 reproduction and their association with disease severity. We used multiomics platforms (targeted and untargeted proteomics and untargeted metabolomics) on patient samples and cell-line models along with immune phenotyping of metabolite transporters in patient blood cells to understand viral-induced metabolic modulations. We also modulated key metabolic pathways that were identified using multiomics data to regulate the viral reproduction in vitro. Coronavirus disease 2019 disease severity was characterized by increased plasma glucose and mannose levels. Immune phenotyping identified altered expression patterns of carbohydrate transporter, glucose transporter 1, in CD8+ T cells, intermediate and nonclassical monocytes, and amino acid transporter, xCT, in classical, intermediate, and nonclassical monocytes. In in vitro lung epithelial cell (Calu-3) infection model, we found that glycolysis and glutaminolysis are essential for virus replication, and blocking these metabolic pathways caused significant reduction in virus production. Taken together, we therefore hypothesized that severe acute respiratory syndrome coronavirus-2 utilizes and rewires pathways governing central carbon metabolism leading to the efflux of toxic metabolites and associated with disease severity. Thus, the host metabolic perturbation could be an attractive strategy to limit the viral replication and disease severity.
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| 11. |
- Lundgren, Jan, 1977-
(författare)
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Simulating Behavioral Level On-Chip Noise Coupling
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis, noise coupling simulation is introduced into the behavioral level. Methods andmodels for simulating on-chip noise coupling at the behavioral level in a design flow are presentedand verified for accuracy and validity. Today, designs of electronic systems are becoming denserand more and more mixed-signal systems such as System-on-Chip (SoC) are being devised. Thisraises problems when the electronics components start to interfere with each other. Often, digitalcomponents disturb analog components, introducing noise into the system causing degradation ofthe performance or even introducing errors into the functionality of the system.Today, these effects can only be simulated at a very late stage in the design process, causinglarge design iterations and increased costs if the designers are required to return and makealterations, which may have occurred at a very early stage in the process.This is why the focus of this work is centered on extracting noise coupling simulation modelsthat can be used at a very early design stage, such as at the behavioral level and then follow thedesign through the various design stages. To achieve this, SystemC is selected as a platform andimplementation example for the behavioral level models. SystemC supports design refinement,which means that when designs are being refined and are crossing the design levels, the noisecoupling models can also be refined to suit the current design.This new method of thinking in primarily mixed-signal designs is called Behavioral levelNoise Coupling (BeNoC) simulation and shows great promise in enabling a reduction in the costsof design iterations due to component cross-talk and simplifies the work for mixed-signal systemdesigners.
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| 12. |
- Müller, Thomas R., et al.
(författare)
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Additive effects of booster mRNA vaccination and SARS-CoV-2 Omicron infection on T cell immunity across immunocompromised states
- 2023
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Ingår i: Science Translational Medicine. - 1946-6234 .- 1946-6242. ; 15:704, s. eadg9452-
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Tidskriftsartikel (refereegranskat)abstract
- Suboptimal immunity to SARS-CoV-2 mRNA vaccination has frequently been observed in individuals with various immunodeficiencies. Given the increased antibody evasion properties of emerging SARS-CoV-2 subvariants, it is necessary to assess whether other components of adaptive immunity generate resilient and protective responses against infection. We assessed T cell responses in 279 individuals, covering five different immunodeficiencies and healthy controls, before and after booster mRNA vaccination, as well as after Omicron infection in a subset of patients. We observed robust and persistent Omicron-reactive T cell responses that increased markedly upon booster vaccination and correlated directly with antibody titers across all patient groups. Poor vaccination responsiveness in immunocompromised or elderly individuals was effectively counteracted by the administration of additional vaccine doses. Functionally, Omicron-reactive T cell responses exhibited a pronounced cytotoxic profile and signs of longevity, characterized by CD45RA+ effector memory subpopulations with stem cell-like properties and increased proliferative capacity. Regardless of underlying immunodeficiency, booster-vaccinated and Omicron-infected individuals appeared protected against severe disease and exhibited enhanced and diversified T cell responses against conserved and Omicron-specific epitopes. Our findings indicate that T cells retain the ability to generate highly functional responses against newly emerging variants, even after repeated antigen exposure and a robust immunological imprint from ancestral SARS-CoV-2 mRNA vaccination.
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| 13. |
- Müller, Thomas R., et al.
(författare)
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Memory T cells effectively recognize the SARS-CoV-2 hypermutated BA.2.86 variant
- 2024
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Ingår i: Cell Host and Microbe. - : Elsevier. - 1931-3128 .- 1934-6069. ; 32:2, s. 156-161.e3
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Tidskriftsartikel (refereegranskat)abstract
- T cells are critical in mediating the early control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection. However, it remains unknown whether memory T cells can effectively cross-recognize new SARS-CoV-2 variants with a broad array of mutations, such as the emergent hypermutated BA.2.86 variant. Here, we report in two separate cohorts, including healthy controls and individuals with chronic lymphocytic leukemia, that SARS-CoV-2 spike-specific CD4+ and CD8+ T cells induced by prior infection or vaccination demonstrate resilient immune recognition of BA.2.86. In both cohorts, we found largely preserved SARS-CoV-2 spike-specific CD4+ and CD8+ T cell magnitudes against mutated spike epitopes of BA.2.86. Functional analysis confirmed that both cytokine expression and proliferative capacity of SARS-CoV-2 spike-specific T cells to BA.2.86-mutated spike epitopes are similarly sustained. In summary, our findings indicate that memory CD4+ and CD8+ T cells continue to provide cell-mediated immune recognition to highly mutated emerging variants such as BA.2.86.
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| 14. |
- Narayanan, Aswathy, et al.
(författare)
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Exploring the interplay between antiretroviral therapy and the gut-oral microbiome axis in people living with HIV
- 2024
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Ingår i: Scientific Reports. - 2045-2322. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- The gut and oral microbiome is altered in people living with HIV (PLWH). While antiretroviral treatment (ART) is pivotal in restoring immune function in PLWH, several studies have identified an association between specific antiretrovirals, particularly integrase inhibitors (INSTI), and weight gain. In our study, we explored the differences in the oral and gut microbiota of PLWH under different ART regimens, and its correlation to Body Mass Index (BMI). Fecal and salivary samples were collected from PLWH (n = 69) and healthy controls (HC, n = 80). We performed taxonomy analysis to determine the microbial composition and relationship between microbial abundance and ART regimens, BMI, CD4+T-cell count, CD4/CD8 ratio, and ART duration. PLWH showed significantly lower richness compared to HC in both the oral and gut environment. The gut microbiome composition of INSTI-treated individuals was enriched with Faecalibacterium and Bifidobacterium, whereas non-nucleotide reverse transcriptase inhibitor (NNRTI)-treated individuals were enriched with Gordonibacter, Megasphaera, and Staphylococcus. In the oral microenvironment, Veillonella was significantly more abundant in INSTI-treated individuals and Fusobacterium and Alloprevotella in the NNRTI-treated individuals. Furthermore, Bifidobacterium and Dorea were enriched in gut milieu of PLWH with high BMI. Collectively, our findings identify distinct microbial profiles, which are associated with different ART regimens and BMI in PLWH on successful ART, thereby highlighting significant effects of specific antiretrovirals on the microbiome.Similar content being viewed by others
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| 15. |
- Ray, Shilpa, et al.
(författare)
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Impact of the gut microbiome on immunological responses to COVID-19 vaccination in healthy controls and people living with HIV
- 2023
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Ingår i: npj Biofilms and Microbiomes. - 2055-5008. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Although mRNA SARS-CoV-2 vaccines are generally safe and effective, in certain immunocompromised individuals they can elicit poor immunogenic responses. Among these individuals, people living with HIV (PLWH) have poor immunogenicity to several oral and parenteral vaccines. As the gut microbiome is known to affect vaccine immunogenicity, we investigated whether baseline gut microbiota predicts immune responses to the BNT162b2 mRNA SARS-CoV-2 vaccine in healthy controls and PLWH after two doses of BNT162b2. Individuals with high spike IgG titers and high spike-specific CD4 + T-cell responses against SARS-CoV-2 showed low α-diversity in the gut. Here, we investigated and presented initial evidence that the gut microbial composition influences the response to BNT162b2 in PLWH. From our predictive models, Bifidobacterium and Faecalibacterium appeared to be microbial markers of individuals with higher spike IgG titers, while Cloacibacillus was associated with low spike IgG titers. We therefore propose that microbiome modulation could optimize immunogenicity of SARS-CoV-2 mRNA vaccines.
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| 16. |
- Röshammar, Daniel, 1979, et al.
(författare)
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Non-linear mixed effects modeling of antiretroviral drug response after administration of lopinavir, atazanavir and efavirenz containing regimens to treatment-naive HIV-1 infected patients
- 2011
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 38:6, s. 727-742
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this analysis was to compare three methods of handling HIV-RNA data below the limit of quantification (LOQ) when describing the time-course of antiretroviral drug response using a drug-disease model. Treatment naive Scandinavian HIV-positive patients (n = 242) were randomized to one of three study arms. Two nucleoside reverse transcriptase inhibitors were administrated in combination with 400/100 mg lopinavir/ritonavir twice daily, 300/100 mg atazanavir/ritonavir once a day or 600 mg efavirenz once a day. The viral response was monitored at screening, baseline and at 1, 2, 3, 4, 12, 24, 48, 96, 120, and 144 weeks after study initiation. Data up to 400 days was fitted using a viral dynamics non-linear mixed effects drug-disease model in NONMEM. HIV-RNA data below LOQ of 50 copies/ml plasma (39%) was omitted, replaced by LOQ/2 or included in the analysis using a likelihood-based method (M3 method). Including data below LOQ using the M3 method substantially improved the model fit. The drug response parameter expressing the fractional inhibition of viral replication was on average (95% CI) estimated to 0.787 (0.721-0.864) for lopinavir and atazanavir treatment arms and 0.868 (0.796-0.923) for the efavirenz containing regimen. At 400 days after treatment initiation 90% (76-100) of the lopinavir and atazanavir treated patients were predicted to have undetectable viral levels and 96% (89-100%) for the efavirenz containing treatment. Including viral data below the LOQ rather than omitting or replacing data provides advantages such as better model predictions and less biased parameter estimates which are of importance when quantifying antiretroviral drug response.
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| 17. |
- Vesterbacka, Jan, et al.
(författare)
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Kinetics of microbial translocation markers in patients on efavirenz or lopinavir/r based antiretroviral therapy
- 2013
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 8:1, s. e55038-
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: We investigated whether there are differences in the effects on microbial translocation (MT) and enterocyte damage by different antiretroviral therapy (ART) regimens after 1.5 years and whether antibiotic use has impact on MT. In a randomized clinical trial (NCT01445223) on first line ART, patients started either lopinavir/r (LPV/r) (n = 34) or efavirenz (EFV) containing ART (n = 37). Lipopolysaccharide (LPS), sCD14, anti-flagellin antibodies and intestinal fatty acid binding protein (I-FABP) levels were determined in plasma at baseline (BL) and week 72 (w72).RESULTS: The levels of LPS and sCD14 were reduced from BL to w72 (157.5 pg/ml vs. 140.0 pg/ml, p = 0.0003; 3.13 ug/ml vs. 2.85 ug/ml, p = 0.005, respectively). The levels of anti-flagellin antibodies had decreased at w72 (0.35 vs 0.31 [OD]; p<0.0004), although significantly only in the LPV/r arm. I-FABP levels increased at w72 (2.26 ng/ml vs 3.13 ng/ml; p<0.0001), although significantly in EFV treated patients only. Patients given antibiotics at BL had lower sCD14 levels at w72 as revealed by ANCOVA compared to those who did not receive (Δ = -0.47 µg/ml; p = 0.015).CONCLUSIONS: Markers of MT and enterocyte damage are elevated in untreated HIV-1 infected patients. Long-term ART reduces the levels, except for I-FABP which role as a marker of MT is questionable in ART-experienced patients. Why the enterocyte damage seems to persist remains to be established. Also antibiotic usage may influence the kinetics of the markers of MT.TRIAL REGISTRATION: ClinicalTrials.gov NCT01445223.
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| 18. |
- Vesterbacka, Jan
(författare)
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The role of microbial translocation and gut microbiota in HIV-1 infection
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- HIV-1 infection is characterized by persistent systemic inflammation and immune activation, even in patients receiving effective antiretroviral therapy (ART). Translocation of microbial compounds from a leaky gut to systemic circulation, so called microbial translocation (MT), is a major driver of the immune activation. Additionally, gut microbiota dysbiosis in HIV-1 infected patients further facilitate and fuel MT. The objectives of this thesis were to study: * how different ART regimens and usage of antibiotics affect markers of MT (I, II) * the alternations of gut microbiota during HIV-1 infection and the effect of ART (III,IV) In a clinical randomized trial, HIV-1 infected subjects started ART based on efavirenz (n=37) or ritonavir-boosted lopinavir (n=34). Levels of MT markers and of enterocyte death were elevated at baseline (BL), and MT markers declined until follow up after 72 weeks, but the reduction of anti-flagellin IgG antibodies was significant only in lopinavir treated patients. Levels of Intestinal Fatty Acid Binding Protein (I-FABP) remained unchanged at 72 weeks, but were temporarily increased after one month in efavirenz treated patients. 29 subjects with concomitant use of antibiotics had superior reduction of soluble CD14 (sCD14) levels. These data show that choice of ART and antibiotics usage could affect the kinetics of some MT markers. To further explore the impact of antibiotics usage on MT, we performed a longitudinal study on HIV-1 patients initiating ART without (n=13) or with (n=13) co-trimoxazole (TMP-SMX) as prophylaxis against Pneumocystis jirovecii. Following ART, levels of LPS-binding protein (LBP) were reduced only in the TMP-SMX group, whilst levels of sCD14 declined in both groups after one year. The LBP decrease remained significant in a multivariate analysis model adjusting for co-variates including BL CD4+ T-cell count. This study confirmed that concomitant use of antibiotics and ART in severely immune deteriorated individuals may beneficially influence the kinetics of MT markers. In the third study, the composition of gut microbiota was determined by 16S rRNA sequencing in 28 HIV-1 progressors, 3 Elite controllers (EC) and 9 uninfected controls at BL, and additionally after ten months of ART in 16 subjects. Gut microbiome α-diversity was reduced in HIV-1 infected individuals as compared to controls, and further declined after introduction of ART. At BL, α-diversity was positively correlated with CD4+ T-cell counts, but in contrary several markers of MT/immune activation were inversely correlated. Microbiome of EC had the lowest interindividual variation (ß-diversity), clustering together in PCoA analysis. The bacterial composition at genus level was altered in HIV-1 progressors with higher abundance of Lactobacillus, and depletion of Lachnobacterium, Faecalibacterium and Hemophilus. Thus, this study showed that the alternations of gut microbiota during HIV-1 infection are associated with the level of immune dysfunction, and that almost one year of ART does not restore the shifts in the gut microbiome. In the last work, we studied the gut microbiome of 16 EC in relation to 32 matched ART naive HIV-1 positive individuals and 16 uninfected controls. The number of observed genera and richness indices Chao-1 and ACE were significantly higher in EC as compared to naive patients. The gut microbiota in EC was enriched in genera Succinivibrio, Sutterella, Rhizobium, Delftia, Anaerofilum and Oscillospira, whilst Blautia and Anaerostipes were reduced. Determination of inferred bacterial functionality by PICRUSt analysis revealed that carbohydrate metabolism related genes were depleted in EC. In contrary, pathways related to fatty acid metabolism, PPAR-signaling and lipid biosynthesis proteins were more abundant in EC vs naive. The kynurenine pathway of tryptophan metabolism was altered only during progressive HIV-1 infection, and kynurenine tryptophan (K/T) ratio was inversely associated with gut microbiota richness. This study shows that EC have richer gut microbiota than untreated HIV-1 patients with progressive infection, with a unique bacterial composition and a distinct metabolic profile which may be involved in the control of HIV-1. In summary, data from the studies in my thesis reveal that MT in HIV-1 infection is reduced by ART but also that the choice of ART influences this decline. Additionally, the antibiotics usage may affect the levels of MT. The complexity, composition and functionality of gut microbiota are disturbed in HIV-1 infected individuals with progressive disease, whilst EC have a unique gut microbiota profile that eventually contributes to their control of HIV-1.
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| 19. |
- Vesterbacka, Mark, 1966-, et al.
(författare)
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Selected Papers from NORCHIP '06
- 2008
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Ingår i: IET Computers & Digital Techniques. - Stevenage, UK : The Institution of Engineering and Technology. - 1751-8601 .- 1751-861X. ; 2:4, s. 251-325
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 20. |
- Xu, Xinling, et al.
(författare)
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High seroconversion rate after vaccination with mRNA BNT162b2 vaccine against SARS-CoV-2 among people with HIV - but HIV viremia matters?
- 2022
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Ingår i: AIDS. - : Lippincott Williams & Wilkins. - 0269-9370 .- 1473-5571. ; 36:3, s. 479-481
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Tidskriftsartikel (refereegranskat)abstract
- Our clinical trial of SARS-COV-2 mRNA vaccine in 90 HIV-infected persons on antiviral treatment demonstrated high seroconversion rate and high levels of spike IgG antibodies after two doses of vaccine. The vaccine was well tolerated and not associated with HIV RNA blips. However, the levels of spike IgG antibodies were lower in HIV patients than in healthy controls, especially among those with HIV RNA more than 50 copies/ml at baseline.
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