The aim of this study was to determine the efficacy of early tocilizumab treatment for hospitalized patients with COVID-19 disease. Open-label randomized phase II clinical trial investigating ...tocilizumab in patients with proven COVID-19 admitted to the general ward and in need of supplemental oxygen. The primary endpoint of the study was 30-day mortality with a prespecified 2-sided significance level of alpha = 0.10. A post-hoc analysis was performed for a combined endpoint of mechanical ventilation or death at 30 days. Secondary objectives included comparing the duration of hospital stay, ICU admittance and duration of ICU stay and the duration of mechanical ventilation. A total of 354 patients (67% men; median age 66 years) were enrolled of whom 88% received dexamethasone. Thirty-day mortality was 19% (95% CI 14%-26%) in the standard arm versus 12% (95% CI: 8%-18%) in the tocilizumab arm, hazard ratio (HR) = 0.62 (90% CI 0.39-0.98; p = 0.086). 17% of patients were admitted to the ICU in each arm (p = 0.89). The median stay in the ICU was 14 days (IQR 9-28) in the standard arm versus 9 days (IQR 5-14) in the tocilizumab arm (p = 0.014). Mechanical ventilation or death at thirty days was 31% (95% CI 24%-38%) in the standard arm versus 21% (95% CI 16%-28%) in the tocilizumab arm, HR = 0.65 (95% CI 0.42-0.98; p = 0.042). This randomized phase II study supports efficacy for tocilizumab when given early in the disease course in hospitalized patients who need oxygen support, especially when concomitantly treated with dexamethasone.
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We studied changes in bone mineral density (BMD) and bone turnover after initiation of combination antiretroviral therapy (cART) and the contribution of zidovudine/lamivudine (ZDV/3TC) in particular.
...Randomized clinical trial comparing lopinavir/ritonavir(LPV/r) + ZDV/3TC with LPV/r + nevirapine (NVP) in 50 cART-naive men.
Dual energy X-ray absorptiometry (DXA) and quantitative computed tomography scans (QCT) were performed at baseline and 3, 12, and 24 months after cART initiation. Serum 25-hydroxy-vitamin D3, parathyroid hormone (PTH), osteocalcin, and urine deoxypyridinoline (DPD)/creatinine ratio were measured.
BMD decreased rapidly in both femoral neck and lumbar spine after cART initiation. BMD loss during 24 months measured by DXA, but not by QCT, was greater in the ZDV/3TC/LPV/r group compared to the NVP/LPV/r group femoral neck: -6.3% +/- 1.0% (P < 0.0001) compared to -2.3% +/- 0.9% (P = 0.01), between-group P = 0.0006); lumbar spine: -5.1% +/- 0.8% (P < 0.0001) compared to -2.6% +/- 0.7% (P = 0.0006), between-group P = 0.07. Osteocalcin +1.60 +/- 0.32 (P < 0.0001) and +1.81 +/- 0.29 (P < 0.0001) nmol/l and the urine DPD/creatinine ratio +1.35 +/- 0.44 (P = 0.0029) and +1.19 +/- 0.38 nmol/mmol (P = 0.0024) increased in both groups over 24 months, with no significant difference between groups. PTH increased to a greater degree in the NVP/LPV/r group +2.0 +/- 0.31 pmol/l (P < 0.0001) compared to +0.81 +/- 0.33 pmol/l (P = 0.021) in the ZDV/3TC/LPV/r group.
BMD in both femoral neck and lumbar spine decreased rapidly after initiation of cART, in parallel to an increase in bone turnover. The greater bone loss in the ZDV/3TC/LPV/r group compared to the NVP/LPV/r group suggests that ZDV/3TC contributes to this process. The PTH increase does not explain this greater bone loss.
Abstract
Background
The COVIH study is a prospective coronavirus disease 2019 (COVID-19) vaccination study in 1154 people with HIV (PWH), of whom 14% showed reduced antibody levels after primary ...vaccination. We evaluated whether an additional vaccination boosts immune responses in these hyporesponders.
Methods
The primary end point was the increase in antibodies 28 days after additional mRNA-1273 vaccination. Secondary end points included neutralizing antibodies, S-specific T-cell and B-cell responses, and reactogenicity.
Results
Of the 66 participants, 40 previously received 2 doses ChAdOx1-S, 22 received 2 doses BNT162b2, and 4 received a single dose Ad26.COV2.S. The median age was 63 years (interquartile range IQR, 60–66), 86% were male, and median CD4+ T-cell count was 650/μL (IQR, 423–941). The mean S1-specific antibody level increased from 35 binding antibody units (BAU)/mL (95% confidence interval CI, 24–46) to 4317 BAU/mL (95% CI, 3275–5360) (P < .0001). Of all participants, 97% showed an adequate response and the 45 antibody-negative participants all seroconverted. A significant increase in the proportion of PWH with ancestral S-specific CD4+ T cells (P = .04) and S-specific B cells (P = .02) was observed.
Conclusions
An additional mRNA-1273 vaccination induced a robust serological response in 97% of PWH with a hyporesponse after primary vaccination.
Clinical Trials Registration. EUCTR2021-001054-57-N.
An additional 100 µg mRNA-1273 vaccination substantially increased SARS-CoV-2 S1-specific binding antibody levels in people with HIV with a serological hyporesponse after a primary vaccination regimen. This response was observed regardless of the primary vaccination regimen or patient characteristics.
Rahamat‐Langendoen JC, van Vonderen MGA, Engström LJ, Manson WL, van Winkelhoff AJ, Mooi‐Kokenberg EANM. Brain abscess associated with Aggregatibacter actinomycetemcomitans: case report and review of ...literature. J Clin Periodontol 2011; 38: 702–706. doi: 10.1111/j.1600‐051X.2011.01737.x.
Introduction: Aggregatibacter actinomycetemcomitans is considered a major pathogen in localized and generalized aggressive periodontitis. A. actinomycetemcomitans has been found in various extra oral infections and most frequently in endocarditis. We report a patient with multiple brain abscesses due to infection with A. actinomycetemcomitans and review the English language literature related to this subject.
Case report: A 42‐year‐old patient with no underlying medical conditions presented with multiple brain lesions initially thought to be metastatic lesions of a tumour of unknown origin. Findings during drainage and subsequent histopathological conclusions made infection more likely. Culture of drained material remained negative; however, 16S rDNA polymerase chain reaction and sequence analysis on direct material revealed A. actinomycetemcomitans as the causative agent of the infection. The most likely source of infection was the poor dentition of the patient. After repeated drainage of the lesions and antibiotic treatment the patient gradually improved, although cognitive impairment remained.
Conclusions: Our report illustrates that a poor dental condition, notably destructive periodontal disease, can be a risk for life‐threatening extra oral disease, and thus contributes to the total inflammatory burden of the body.
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BFBNIB, CMK, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
BackgroundThe risk of cardiovascular disease in human immunodeficiency virus (HIV)–infected patients is an increasing concern. We studied the changes in vascular properties after the initiation of ...combination antiretroviral therapy (cART) as well as the contribution of different drug classes MethodscART-naive men were randomized to receive either lopinavir/ritonavir (LPV/r) plus zidovudine/lamivudine (ZDV/3TC) (n=19) or LPV/r plus nevirapine (NVP) (n=18). Carotid artery intima-media thickness (C-IMT), arterial stiffness (distensibility coefficients DCs and compliance coefficients CCs of the carotid, femoral, and brachial arteries; carotid elastic modulus; and augmentation index), and markers of endothelial function (soluble vascular cell adhesion molecule sVCAM–1, intercellular adhesion molecule sICAM–1, plasma von Willebrand factor (vWF) antigen, and plasminogen activator inhibitor–1 antigen) and inflammation (high-sensitivity C-reactive protein) were measured before the initiation of cART and after 3, 12, and 24 months of cART ResultsC-IMT increased by 0.061±0.016 mm (P<.001) in the ZDV/3TC/LPV/r arm and by 0.044±0.018 mm (P=.012) in the NVP/LPV/r arm (data are estimated means ± SEs). Femoral artery DC (-1.66±0.78×10-3/kPa P=.035) and CC (-0.11±0.053 mm2/kPa P=.043) decreased in the ZDV/3TC/LPV/r arm and femoral DC decreased in the NVP/LPV/r arm (-1.72±0.85×10-3/kPa P=.046), with no significant difference in C-IMT or arterial stiffness between arms. sVCAM-1, sICAM-1, and vWF levels decreased significantly in both groups ConclusionC-IMT and femoral artery stiffness increased after the initiation of cART, whereas several markers of endothelial function improved, regardless of the composition of cART Trial registrationClinicalTrials.gov identifier: NCT00122226
Approval of drugs in chronic hepatitis C is supported by registration trials. These trials might have limited generalizability through use of strict eligibility criteria. We compared effectiveness ...and safety of real world hepatitis C patients eligible and ineligible for registration trials.
We performed a nationwide, multicenter, retrospective cohort study of chronic hepatitis C patients treated in the real world. We applied a combined set of inclusion and exclusion criteria of registration trials to our cohort to determine eligibility. We compared effectiveness and safety in eligible vs. ineligible patients, and performed sensitivity analyses with strict criteria. Further, we used log binomial regression to assess relative risks of criteria on outcomes.
In this cohort (n = 467) 47% of patients would have been ineligible for registration trials. Main exclusion criteria were related to hepatic decompensation and co-morbidity (cardiac disease, anemia, malignancy and neutropenia), and were associated with an increased risk for serious adverse events (RR 1.45-2.31). Ineligible patients developed significantly more serious adverse events than eligible patients (27% vs. 11%, p< 0.001). Effectiveness was decreased if strict criteria were used.
Nearly half of real world hepatitis C patients would have been excluded from registration trials, and these patients are at increased risk to develop serious adverse events. Hepatic decompensation and co-morbidity were important exclusion criteria, and were related to toxicity. Therefore, new drugs should also be studied in these patients, to genuinely assess benefits and risk of therapy in the real world population.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVES:HIV-infected patients using combination antiretroviral therapy (ART) have an increased cardiovascular risk. We aimed to identify the effects of HIV, ART, and lipodystrophy (LD) on carotid ...artery intima-media thickness (C-IMT), a surrogate measure of atherosclerosis, and arterial stiffness, a marker of cardiovascular risk.
DESIGN:Case-control study of 77 HIV-infected men (55 exposed to ART, 22 ART naive, and 23 with LD) and 52 controls.
METHODS:C-IMT was measured ultrasonically, and arterial stiffness was estimated by distensibility (DC) and compliance (CC) coefficients of the carotid, femoral, and brachial arteries, by the carotid Young elastic modulus and pulse wave velocity.
RESULTS:After adjustment for cardiovascular risk factors, HIV-infected patients had a 0.067 mm (10.8%) greater C-IMT than controls, 13.6% and 29.5% lower DC, and 14.1% and 31% lower CC of the carotid and femoral arteries, respectively, but similar Young elastic modulus and pulse wave velocity. Patients exposed to ART had similar C-IMT compared with ART-naive patients but 25.9% lower DC and 21.7% lower CC of the femoral artery. Arterial properties did not differ between patients with and without LD.
CONCLUSIONS:HIV infection is independently associated with C-IMT and generally increased arterial stiffness. ART use is associated with increased stiffness of the femoral artery.
No randomized study has prospectively followed subcutaneous adipose tissue mitochondrial DNA (mtDNA) changes when starting thymidine nucleoside reverse transcriptase inhibitors (tNRTIs).
The ...Metabolic Effects of DIfferent CLasses of AntiretroviralS study randomized HIV-positive, treatment-naive male participants to start lopinavir/ritonavir (LPVr) with either zidovudine/lamivudine (ZDV/3TC) or nevirapine (NVP).
Regional body fat was assessed by dual energy x-ray absorptiometry and abdominal computed tomography at months 0, 3, 12, 24 and 36. In a molecular substudy, subcutaneous adipose tissue (SAT) biopsies were taken, with mtDNA quantified by quantitative PCR. Data were analyzed using repeated measures linear regression analyses.
Of 50 participants recruited (23 to LPVr/ZDV/3TC), 48 started therapy, and 37 participants (19 on LPVr/ZDV/3TC) enrolled in the substudy. At 36 months, the LPVr/ZDV/3TC group had significantly lower limb fat 6.4 kg (0.26) versus 7.3 kg (0.31), P = 0.017 and a trend toward lower abdominal SAT compared to the LPVr/NVP group 131 cm (6.86) versus 146 cm (6.33), P = 0.097. Over 36 months, mtDNA declined in the LPVr/ZDV/3TC group mtDNA region 1: -190 (95) copies/cell, P = 0.053, region 2: -269 (106) copies/cell, P = 0.016 but not within the LPVr/NVP group region 1: +28 (99) copies/cell, P = 0.78, region 2: +51 (111) copies/cell, P = 0.65, between-group difference P < 0.01 for both measurements. mtDNA was significantly lower in the LPVr/ZDV/3TC group at 36 months.
This is the first randomized study to prospectively demonstrate reductions in SAT mtDNA in patients initiating ZDV/3TC-containing antiretroviral therapy (ART) but not in those initiating nucleoside reverse transcriptase inhibitor-sparing ART containing NVP and protease inhibitor. That reductions in SAT mtDNA were also accompanied by lower limb fat suggests that use of ART not containing ZDV/3TC may help prevent development of peripheral lipoatrophy.
Lipoatrophy is known to be associated with stavudine as part of the treatment for HIV infection, but it is less clear if this serious side effect is also related to other nucleoside reverse ...transcriptase inhibitors like zidovudine. We aimed to determine whether zidovudine-sparing first-line antiretroviral therapy would lead to less lipoatrophy and other metabolic changes than zidovudine-containing therapy.
Fifty antiretroviral therapy-naïve HIV-1 infected men with an indication to start antiretroviral therapy were included in a randomized single blinded clinical trial. Randomisation was between zidovudine-containing therapy (zidovudine/lamivudine+lopinavir/ritonavir) and zidovudine-sparing therapy (nevirapine+lopinavir/ritonavir). Main outcome measures were body composition assessed by computed tomography and dual-energy X-ray absorptiometry scan and lipid profile before and after 3, 12, 24 months of antiretroviral therapy. In the zidovudine/lamivudine+lopinavir/ritonavir group, from 3 months onward limb fat decreased progressively by 684+/-293 grams (estimated mean+/-standard error of the mean)(p = 0.02) up to 24 months whereas abdominal fat increased, but exclusively in the visceral compartment (+21.9+/-8.1 cm(2), p = 0.008)). In contrast, in the nevirapine+lopinavir/ritonavir group, a generalized increase in fat mass was observed. After 24 months no significant differences in high density lipoprotein and total/high density lipoprotein cholesterol ratio were found between both treatment groups, but total and low density lipoprotein cholesterol levels were higher in the nevirapine+lopinavir/ritonavir group (6.1+/-0.2 versus 5.3+/-0.2 and 3.6+/-0.1 versus 2.8+/-0.1 mmol/l respectively, p<0.05). Virologic response and safety were comparable in both groups.
Zidovudine/lamivudine+lopinavir/ritonavir, but not nevirapine+lopinavir/ritonavir in antiretroviral therapy-naïve patients, is associated with lipoatrophy and greater relative intraabdominal lipohypertrophy, suggesting that zidovudine/lamivudine contributes to both these features of lipodystrophy. These findings support to no longer consider zidovudine/lamivudine as one of the preferred possible components of first-line antiretroviral therapy where alternative treatments are available.
ClinicalTrials.gov NCT 00122226.
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