Background: Among interleukin-6 inhibitors suggested for use in COVID-19, there are few robust evidences for the efficacy of sarilumab. Herein, we evaluated the efficacy and safety of sarilumab in ...severe COVID-19. Methods: In this phase 3, open-labeled, randomized clinical trial, conducted at 5 Italian hospitals, adults with severe COVID-19 pneumonia (excluding mechanically ventilated) were randomized 2:1 to receive intravenous sarilumab (400 mg, repeatable after 12 h) plus standard of care (SOC) (arm A) or to continue SOC (arm B). Randomization was web-based. As post-hoc analyses, the participants were stratified according to baseline inflammatory parameters. The primary endpoint was analysed on the modified Intention-To-Treat population, including all the randomized patients who received any study treatment (sarilumab or SOC). It was time to clinical improvement of 2 points on a 7-points ordinal scale, from baseline to day 30. We used Kaplan Meier method and log-rank test to compare the primary outcome between two arms, and Cox regression stratified by clinical center and adjusted for severity of illness, to estimate the hazard ratio (HR). The trial was registered with EudraCT (2020-001390-76). Findings: Between May 2020 and May 2021, 191 patients were assessed for eligibility, of whom, excluding nine dropouts, 176 were assigned to arm A (121) and B (55). At day 30, no significant differences in the primary endpoint were found (88% 95% CI 81–94 in arm A vs 85% 74–93, HR 1.07 0.8–1.5 in arm B; log-rank p = 0.50). After stratifying for inflammatory parameters, arm A showed higher probability of improvement than B without statistical significance in the strata with C reactive protein (CRP) < 7 mg/dL (88% 77–96 vs 79% 63–91, HR 1.55 0.9–2.6; log-rank p = 0.049) and in the strata with lymphocytes <870/mmc (90% 79–96) vs (73% 55–89, HR 1.53 0.9–2.7; log-rank p = 0.058). Overall, 39/121 (32%) AEs were reported in arm A and 14/55 (23%) in B (p = 0.195), while serious AEs were 22/121 (18%) and 7/55 (11%), respectively (p = 0.244). There were no treatment-related deaths. Interpretation: The efficacy of sarilumab in severe COVID-19 was not demonstrated both in the overall and in the stratified for severity analysis population. Exploratory analyses suggested that subsets of patients with lower CRP values or lower lymphocyte counts might have had benefit with sarilumab treatment, but this finding would require replication in other studies. The relatively low rate of concomitant corticosteroid use, could partially explain our results. Funding: This study was supported by INMI “Lazzaro Spallanzani” Ricerca Corrente Linea 1 on emerging and reemerging infections, funded by Italian Ministry of Health.
To explore 48 week safety and efficacy of treatment simplification to atazanavir/ritonavir + lamivudine in HIV-infected patients with virological suppression on a stable atazanavir/ritonavir-based ...standard triple regimen.
This was a single-arm pilot study, enrolling 40 patients on atazanavir/ritonavir + two nucleos(t)ide reverse transcriptase inhibitors (NRTIs), without previous treatment failure, with HIV-RNA <50 copies/mL for >3 months and CD4 >200 cells/mm(3). At baseline, patients were switched to 300/100 mg of atazanavir/ritonavir + 300 mg of lamivudine once daily. Laboratory parameters, atazanavir plasma levels, self-reported adherence, quality of life, neurocognitive performance, bone composition and body fat distribution were monitored. Virological failure was defined as HIV-RNA >50 copies/mL on two consecutive determinations or a single level >1000 copies/mL.
After 48 weeks, 4/40 (10%) regimen discontinuations occurred: 1 death (brain haemorrhage), 1 study withdrawal (inadequate atazanavir plasma levels), 1 re-induction with two NRTIs due to pregnancy and 1 virological failure without development of resistance. Seven moderate to severe adverse events were recorded (including four renal colics, possibly treatment-related) in six patients. At week 48, increases in total (mean change +17 mg/dL, P = 0.001), high-density lipoprotein (+6 mg/dL, P < 0.001) and low-density lipoprotein (+8 mg/dL, P = 0.052) cholesterol were observed. The glomerular filtration rate improved (+7 mL/min/1.73 m(2), P < 0.001), as did scores exploring self-reported physical and mental health (+11, P = 0.009 and +13, P < 0.001 on a 0-100 scale), neuropsychological performance (-1 pathological task, P = 0.002) and total bone mineral density (+0.03 g/cm(2), P = 0.026). There were no significant changes in CD4 cell count, bilirubin, atazanavir plasma levels, adherence and body fat distribution over time.
Simplification to atazanavir/ritonavir + lamivudine was apparently safe and associated with rare virological failure, without resistance selection. This strategy deserves further investigation in a randomized trial.
Introduction
The aim of our study was to investigate the potential relationship between liver fibrosis (LF) and cognitive performance in HIV+ patients.
Materials and Methods
We performed a ...cross‐sectional cohort study by consecutively enrolling HIV+ patients during routine outpatient visits at two clinical centres in Italy. Subjects with decompensated liver disease were excluded. All subjects underwent a comprehensive neuropsychological battery exploring memory, attention, psychomotor speed and language; cognitive impairment was defined as at least two abnormal 1.5 SD below the mean for appropriate norms cognitive domains. LF was explored by calculating FIB4 index; in a subgroup of patients, LF was also assessed by transient elastography. Factors associated with cognitive impairment were investigated by logistic regression models.
Results
A total of 413 patients 77% males, median age 46 (IQR 39–52), 17% with past AIDS‐defining events, 19% past IDU, 3% with diabetes, 94% on cART, 90% with HIV RNA <50 copies/mL, 18% co‐infected with HCV were enrolled. Seventeen patients (4%) had FIB4 >3.25 and 14/129 (3%) had liver stiffness >14KPa. Forty‐seven patients (11%) were diagnosed with cognitive impairment. At multivariate analyses patients with FIB4 >1.45 showed a higher risk of cognitive impairment in comparison with those with lower values (OR 2.19, 95% CI 1.02–4.72; p=0.044) after adjusting for education (OR 0.79, 95% CI 0.71–0.88; p<0.001), past IDU (OR 1.69, 95% CI 0.67–4.23; p=0.264), diabetes (OR 2.35, 95% CI 0.62–8.86; p=0.207), HIV RNA <50 copies/mL (OR 0.47, 95% CI 0.19–1.14; p=0.095) and HCV co‐infection (OR 0.88, 95% CI 0.33–2.39; p=0.807). Analyzing any single cognitive domain, a higher risk of abnormal psychomotor speed was associated with fibroscan score >14KPa in comparison with fibroscan score <7KPa (OR 285.07; 95% CI 2.42–33574.06; p=0.020) after adjusting for education (OR 0.54, 95% CI 0.31–0.92; p=0.024), age (for 10 years increase) (OR 2.03, 95% CI 0.55–7.53; p=0.288), past IDU (OR 4.43, 95% CI 0.35–7.57; p=0.526), HIV RNA <50 copies/mL (OR 0.01, 95% CI 0.00–0.18; p=0.003), HIV history (for 1 year increase) (OR 0.96, 95% CI 0.83–1.12; p=0.641), CD4 cells count at nadir (OR 1.10, 95% CI 0.56–2.16; p=0.779), and HCV co‐infection (OR 0.06; 95% CI 0.00–1.93; p=0.113).
Conclusions
In HIV‐infected patients higher LF, estimated through non‐invasive methods, is associated to a higher risk of cognitive impairment.
Introduction
Raltegravir intensification is associated with an increase in 2‐LTR episomal HIV DNA= circles, indicating a persistent low‐level replication, in some individuals in ART with suppressed ...HIV RNA. We aimed at monitoring residual plasma HIV RNA and cellular HIV DNA in virologically suppressed patients switching to a raltegravir‐based regimen.
Materials and Methods
Forty‐six HIV‐infected subjects on PI or NNRTI based‐regimens, with plasma HIV RNA level <40 copies/mL for ≥6 months and CD4 >200 cells/µL for ≥12 months were enrolled. Thirty‐four patients switched to raltegravir‐based regimen (RASTA study group) and 12 continued a PI or NNRTI based‐regimen (control group). Ultrasensitive HIV residual viremia and total PBMC HIV DNA were assessed at baseline (W0), 24 (W24) and 48 (W48) weeks. HIV RNA levels were determined by an ultrasensitive test derived from a commercial real time PCR (limit of detection 5 copies/ml). A real time PCR was used to quantify HIV DNA copy numbers in PBMCs.
Results
At W0, HIV DNA was detected in all patients while at W48 it was detectable in 82.3% of RASTA group vs 100% of controls (p=0.01). The difference between the average values of HIV DNA log10 copies/10°6 CD4 at W0 (median 3.11, IQR 2.70–3.45) and W48 (median 2.87, IQR 2.24–3.38) was statistically significant for RASTA group (p=0.035). Male gender (mean difference −0.37 log10 copies/10°6 PBMC, p=0.023) and previous PI based‐ART (mean difference +0.39 log10 copies/10°6 PBMC, p=0.036) were predictive of HIV DNA level at W0. After adjusting for previous PI based‐ART, male gender was the only variable independently associated with HIV DNA size at W0 (mean difference −0.326 log10 copies/10°6 PBMC, 95% CI −0.641, −0.011 p=0.043). Ultrasensitive HIV‐1 RNA was detectable at W0 in 50% of RASTA group versus 66.7% of controls and at W48 in 32.4% versus 45.5%, respectively. No differences were found between HIV RNA levels at W0 and W48 within and between the two groups.
Conclusions
Switching to raltegravir‐based regimens may be associated with a decrease of HIV reservoir, as measured by total PBMC HIV DNA. A larger sample size is required to confirm this finding.
Introduction
Ageing of HIV‐infected patients led to an increasing rate of osteopenia and osteoporosis. The cause is multifactorial, including virus activity, drug toxicity and host factors. The aim ...of our analysis is to quantify this issue according to our department experience and to evaluate predictors of low BMD.
Materials and Methods
HIV‐1‐infected patients, on stable HAART, were consecutively enrolled in this cross‐sectional study and underwent DEXA. We analyzed the prevalence and evaluated predictors of low BMD in our population.
Results
We collected data from 208 patients, 148 of whom were male, with 49 years median age (IQR 24.1–68.3). About 39% of patients were heterosexuals, 33.7 MSM and 12.5% were IDU, 40.4% were smokers. Caucasians were 93.3%, and 13.9% were co‐infected with HCV virus. Around 6.7% of patients were on their first HAART regimen and all of them started TDF. Their median time of HAART exposure was 1.17 years (IQR 0.8–1.6). Conversely, median time of HAART exposure of multi‐experienced patients was 8.5 years (IQR 3.1–12.0). We stratified DEXA results for patients on first‐line regimen versus multi‐experienced one. We found that 42.9% of patients on first‐line HAART had low BMD of lumbar spine and 7.1% had osteoporosis. Regarding the multi‐experienced group of patients, lumbar spine osteopenia was observed in 36.6% of patients and 15.5% of them had osteoporosis. Median age of patients with low BMD of lumbar spine was 45.6 (IQR 24.1–68.3) for patients on first‐line regimen and 49.8 years for multi‐experienced (IQR 44.2–54.0) regimen. We found similar data for BMD of hip, but no patients in the first group had hip osteoporosis. We also analyzed predictors of low BMD in our population. MSM patients showed a 3.4‐fold higher risk to have osteoporosis of lumbar spine (OR 3.41, CI 1,105–9,269, p=0.03). As expected, we found that non‐Caucasian patients had 13.5‐fold higher risk to have osteoporosis of the hip (OR 13.52, CI 1.5–122.7, p=0.02). Exposure to HAART was also evaluated, but no predictors were found.
Conclusions
Our data confirm how osteoporosis is highly prevalent and occurs earlier in HIV‐infected patients. Antiretrovirals play a crucial role. In our experience loss of BMD can occur within a year of treatment, when almost half of our patients starting TDF had a low BMD. MSM patients have a higher risk to develop spine osteoporosis and non‐Caucasian patients are more likely to have hip osteoporosis. We remark the importance of BMD assessment for HIV‐infected patients especially during their first months of treatment.
Introduction
According to recent evidence about boosted protease inhibitors (PIs/r)‐simplified regimens, the combination of 3TC and DRV/r 800/100 mg could represent a feasible option for optimizing ...antiretroviral therapy (ART) in treatment‐experienced HIV+ patients.
Patients and Methods
We retrospectively evaluated patients switching to 3TC+DRV/r, with at least six months of viral suppression, no resistance mutation to DRV or 3TC and not HBV‐coinfected: incidence of ART discontinuation and of virological failure (VF: 2 consecutive HIV‐RNA determinations>49 cps/mL or a single one≥1000 cps/mL) and the probability of remaining discontinuation‐free during one‐year follow‐up (FU), as well as changes in laboratory parameters at 1, 3, 6 and 12 months were estimated.
Results
We included 94 patients: 74 males, mostly MSM (39.4%), with 49 years old, 9 years of HIV disease, 8 years of ART (median values). Median nadir CD4 count and zenith viral load (log10) were 194 cells/µL and 4.90, respectively. Ten patients were HCV‐coinfected and 38 had at least a previous VF. Seventy‐four patients were on an NRTIs‐based triple regimen (mainly TDF/FTC or 3TC/ABC) whereas 14 on another PI‐based dual therapy (mainly LPV/r). Incidence of treatment discontinuation was 12.4 per 100 patients‐year follow‐up (PYFU), but only 2 patients experienced a VF (3.5 per 100 PYFU). Mean time free from discontinuation was 5 years (95% CI 4–6), with a cumulative one‐year estimated probability of staying on 3TC+DRV/r of 85.9%. At three months, a trend of increased CD4 cells count (+42 cells/µL, p 0.059) was observed, but not confirmed at later time point; an increase of total cholesterol (TC, +17mg/dL, p 0.008) and LDL (+19 mg/dL, p 0.002), and a decreased level of AST and ALT (−2 UI/L, p 0.045; −5 UI/L, p 0.009, respectively) were also detected. Total bilirubin was reduced (−0.71 mg/dL, p 0.038). At 6 and 12 months, alteration of lipid profile was similar, with also an increased TC/HDL ratio (+0.48, p=0.030, at six months) and HDL/LDL ratio (−0.04, p=0.035, at 12 months). A significant decrease in ALT levels (−6 UI/L, 0.013) and a diminishing trend for AST and total bilirubin, as well as a significant increase in renal function (GFR +4mL/min, p 0.048) were observed at 12 months.
Conclusions
These observations on 3TC+DRV/r‐based dual therapy simplification in virologically suppressed patients show a good profile of efficacy and safety. An extended FU time is needed in order to establish the real impact of this promising therapeutic choice.
Facial emotion recognition depends on cortical and subcortical networks. HIV infection of the central nervous system can damage these networks, leading to impaired facial emotion recognition.
We ...performed a cross-sectional single cohort study consecutively enrolling HIV + subjects during routine outpatient visits. Age, gender and education-matched HIV-negative healthy individuals were also selected. Subjects were submitted to a Facial Emotion Recognition Test, which assesses the ability to recognize six basic emotions (disgust, anger, fear, happiness, surprise, sadness). The score for each emotion and a global score (obtained by summing scores for each emotion) were analyzed. General cognitive status of patients was also assessed.
A total of 49 HIV + and 20 HIV - subjects were enrolled. On the Facial Emotion Recognition Test, ANOVA revealed a significantly lower performance of HIV + subjects than healthy controls in recognizing fear. Moreover, fear facial emotion recognition was directly correlated with Immediate Recall of Rey Words. The lower the patients' neurocognitive performance the less accurate they were in recognizing happiness. AIDS-defining events were negatively related to the correct recognition of happiness.
Fear recognition deficit in HIV + patients might be related to the impaired function of neural networks in the frontostriatal system. AIDS events, including non-neurological ones, may have a negative effect on this system. Inclusion of an emotion recognition test in the neuropsychological test battery could help clinicians during the long term management of HIV-infected patients, to better understand the cognitive mechanisms involved in the reduction of emotion recognition ability and the impact of this impairment on daily life.
Introduction
We report interim 24‐weeks efficacy data of ATLAS‐M trial, a phase IV, multicentre, open‐label, randomized study designed to show 48‐weeks, non‐inferior efficacy (margin of −12%) of ...treatment simplification to atazanavir/ritonavir (ATV/r)+lamivudine (3TC) versus maintaining 3‐drugs ATV/r‐based cART.
Methods
Subjects on ATV/r+2 NRTIs, without previous treatment failure (TF), with HIV‐RNA <50copies/mL for >3 months and CD4>200 cells/mm3 for >6 months were eligible. At baseline, patients were randomized to switch to ATV/r+3TC (arm one) or to maintain the original 3‐drug regimen (arm two). Primary endpoint: proportion of patients free of TF at week 48. TF was defined as treatment modification for any reason, including virological failure (VF=two consecutive HIV‐RNA>50 copies/mL or a single value >1000 copies/mL). Enrollment of 266 patients was planned.
Results
A total of 266 patients (78% males, median age 44 years, median CD4 603 cells/µL, 79% treated with a tenofovir‐containing backbone) were enrolled. At the time of analysis, 24 weeks data were available for 84 and 87 patients in arm one and two, respectively. At baseline, subjects in the two arms did not differ for the main characteristics. At 24 weeks, at the intention to treat analysis the proportion of patients free of TF was 91.7% (95% CI 85.8–97.6) and 85.1% (95% CI 77.6–92.6) in arm one and two, respectively (difference +6.6%, 95% CI −2.9/+16.1). VF was observed in two patients randomized to arm one (one at baseline, before treatment simplification) and one to arm two without resistance mutations. Clinical and laboratory adverse events occurred at similar rates in the two arms. At week 24, patients in arm one showed a greater increase in CD4 (mean change +90 vs +10 cells/µL, p=0.007). A greater increase in total cholesterol (+18 vs −2 mg/dL, p<0.001), HDL (+4 vs +0 mg/dL, p=0.001) and LDL (+12 vs +0 mg/dL, p=0.001) was also observed in arm one without differences in other lipid parameters. Renal function showed a significant improvement in arm one (mean change in eGFR +5 vs −2 mL/min/1.73m2 in arm two, p=0.001). No significant differences in bilirubin levels or other laboratory parameters were observed between the two arms.
Conclusions
This interim analysis suggests a 24‐weeks non‐inferior efficacy of treatment simplification to ATV/rit+3TC as compared to continuation of ATV/rit +2 NRTI in virologically suppressed patients. Follow‐up until 48‐weeks is scheduled to confirm these data.
Doc number: 26 Abstract Background: Efavirenz (EFV) administration is still controversial for its high rates of interruption mainly related to central nervous system side effects (CNS-SE). Aim of the ...study was to define if single tablet regimen (STR) as compared to bis-in-die (BID) or once-daily (OD) with âper thousand¥2 pills-a-day EFV formulations reduced the risk of interruption. Methods: Patients starting any cART regimen including EFV + 2NRTIs or switching to EFV + 2NRTIs for simplification after virological suppression were retrospectively selected. Incidence, probability and prognostic factors of interruption by different causes were assessed by survival analysis and Cox regression model. Results: Overall, 553 patients starting EFV-containing regimens were included: 38.2% started BID regimen, 44.5% OD regimens âper thousand¥2 pills and 17.4% STR. The overall proportion of EFV interruption was 37.4% at 4 years; at the same time point, interruptions for virological failure and toxicity were 8.8% and 16.5% (8% for CNS-SE), respectively. Starting EFV co-formulated in STR was associated with lower proportion of overall interruption at 4 years (17.1% vs. 40.6%, p < 0.01). Only one virological failure was observed with STR up to 4 years (1.1% vs. 10.3% in non-STR, p = 0.051). STR also accounted for lower proportion of interruption by patient decision (1.5% vs. 11.8%, p = 0.01). No differences of interruption by overall toxicity and CNS-SE were observed. In multivariable analysis, STR and male gender were associated with lower risk of EFV interruption, while higher CD4 nadir and IDU with higher risk. Conclusions: In our experience, starting EFV co-formulated in STR was associated with lower virological failure and higher adherence, despite a similar proportion of CNS toxicity, thus reducing the risk of treatment interruption. PUBLICATION ABSTRACT
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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