The World Health Organization (WHO) recommends that countries implement pharmacovigilance and collect information on active drug safety monitoring (aDSM) and management of adverse events.The aim of ...this prospective study was to evaluate the frequency and severity of adverse events to anti-tuberculosis (TB) drugs in a cohort of consecutive TB patients treated with new (
bedaquiline, delamanid) and repurposed (
clofazimine, linezolid) drugs, based on the WHO aDSM project. Adverse events were collected prospectively after attribution to a specific drug together with demographic, bacteriological, radiological and clinical information at diagnosis and during therapy. This interim analysis included patients who completed or were still on treatment at time of data collection.Globally, 45 centres from 26 countries/regions reported 658 patients (68.7% male, 4.4% HIV co-infected) treated as follows: 87.7% with bedaquiline, 18.4% with delamanid (6.1% with both), 81.5% with linezolid and 32.4% with clofazimine. Overall, 504 adverse event episodes were reported: 447 (88.7%) were classified as minor (grade 1-2) and 57 (11.3%) as serious (grade 3-5). The majority of the 57 serious adverse events reported by 55 patients (51 out of 57, 89.5%) ultimately resolved. Among patients reporting serious adverse events, some drugs held responsible were discontinued: bedaquiline in 0.35% (two out of 577), delamanid in 0.8% (one out of 121), linezolid in 1.9% (10 out of 536) and clofazimine in 1.4% (three out of 213) of patients. Serious adverse events were reported in 6.9% (nine out of 131) of patients treated with amikacin, 0.4% (one out of 221) with ethionamide/prothionamide, 2.8% (15 out of 536) with linezolid and 1.8% (eight out of 498) with cycloserine/terizidone.The aDSM study provided valuable information, but implementation needs scaling-up to support patient-centred care.
We investigated the efficacy of a switch to dolutegravir plus lamivudine in aviremic individuals without evidence of persistent lamivudine resistance-associated mutations in baseline proviral DNA ...population sequencing.
Open-label, single-arm, 48-week pilot trial. HIV-1 infected adults, naïve to integrase inhibitors, with CD4+ above 350 cell/μL and fewer than 50 HIV-1 RNA copies per mL the year prior to study entry switched to dolutegravir plus lamivudine. Participants were excluded if baseline proviral DNA population genotyping detected lamivudine resistance-associated mutations. To detect resistance minority variants, proviral DNA next-generation sequencing was retrospectively performed from baseline samples. Primary efficacy endpoint was proportion of participants with fewer than 50 HIV-1 RNA copies per mL at week 48. Safety and tolerability outcomes were incidence of adverse events and treatment discontinuations. ART-PRO is registered with ClinicalTrials.gov, NCT03539224.
41 participants switched to dolutegravir plus lamivudine, 21 with lamivudine resistance mutations in historical plasma genotypes. Baseline next-generation sequencing detected lamivudine resistance mutations (M184V/I and/or K65R/E/N) over a 5% threshold in 15/21 (71·4%) and 3/20 (15%) of participants with and without history of lamivudine resistance, respectively. At week 48, 92·7% of participants (38/41) had fewer than 50 HIV-1 RNA copies per mL. There were no cases of virologic failure. Three participants with historical lamivudine resistance were prematurely discontinued from the study (2 protocol violations, one adverse event). Ten participants (4 in the group with historical lamivudine resistance) had a transient viral rebound, all resuppressed on dolutegravir plus lamivudine. There were 28 drug-related adverse events, only one leading to discontinuation.
In this pilot trial, dolutegravir plus lamivudine was effective in maintaining virologic control despite past historical lamivudine resistance and presence of archived lamivudine resistance-associated mutations detected by next generation sequencing. Further studies are needed to confirm our results.
Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III PI16/00837-PI16/00678.
Few clinical trials and cohort studies have evaluated the efficacy of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in people with HIV (PWH) with preexisting M184V/I or other ...nucleos(t)ide reverse transcriptase inhibitor (NRTI) resistance-associated mutations (RAMs). Real-world data are also scarce.
Retrospective review of treatment-experienced patients who started B/F/TAF in a cohort of PWH. HIV-RNA less than 50 copies/ml was analyzed at 48 weeks in an intention-to-treat (ITT) analysis (missing=failure) and per protocol analysis (patients with missing data or changes for reasons other than virological failure were excluded). Results were compared in patients with and without previous NRTI-RAMs.
Five hundred and six PWH were included (16.2% women). Median age and time with HIV infection were 52.3 and 18.9 years, respectively. At baseline, viral load was less than 50 copies/ml in 440 patients (86.6%). Overall, 69 (13.6%) participants had documented preexisting NRTI-RAMs: 57 (11.2%) M184V/I and 30 (5.9%) tenofovir RAMs. In the ITT analysis, 83% (420/506) had HIV-RNA less than 50 copies/ml 82.2% (359/437) and 88.4% (61/69) in persons without and with NRTI-RAMs, respectively ( P = 0.2). In the per protocol analysis 94.2% (420/445) had HIV-RNA less than 50 copies/ml 94.4% (359/380) vs. 93.8% (61/65); P = 0.2. A total of 61 participants were excluded from the per protocol analysis (23 missing data, 19 discontinued B/F/TAF because of toxicity, 13 for other reasons, and 6 died).
Switching to B/F/TAF is well tolerated and effective in the real-world setting, even in patients with preexisting NRTI RAMs, such as M184V and RAMs conferring resistance to tenofovir. These results confirm the robustness of this combination.
Abstract
Background
In the ART-PRO pilot trial there were no virological failures through 48 weeks of treatment with dolutegravir plus lamivudine in suppressed individuals with and without archived ...lamivudine resistance-associated mutations (RAMs) detected through next-generation sequencing (NGS) but without evidence of lamivudine RAMs in baseline proviral DNA population sequencing.
Objectives
To present 96 week results from ART-PRO.
Methods
Open-label, single-arm pilot trial. At baseline, all participants switched to dolutegravir plus lamivudine. Participants were excluded if proviral DNA population genotyping detected lamivudine RAMs. To detect resistance minority variants, proviral DNA NGS was retrospectively performed from baseline samples. For this analysis the efficacy endpoint was the proportion of participants with <50 HIV-1 RNA copies/mL at week 96. Safety and tolerability outcomes were incidence of adverse events and treatment discontinuations.
Results
Forty-one participants were included, 21 with lamivudine RAMs in historical plasma RNA genotypes. Baseline proviral DNA NGS detected lamivudine RAMs (M184V/I and/or K65R/E/N) above a 5% threshold in 71.4% (15/21) and 15% (3/20) of participants with and without history of lamivudine resistance, respectively. At 96 weeks, 90.2% of participants achieved the efficacy endpoint. Between week 48 and 96 there was one discontinuation due to consent withdrawal and no discontinuations related to adverse events. Two participants had a transient viral rebound, both re-suppressed on dolutegravir plus lamivudine. Through week 96, there were no virological failures.
Conclusions
In this pilot trial, dolutegravir plus lamivudine maintained virological suppression at 96 weeks despite historical lamivudine resistance and persisting archived minority lamivudine RAMs.
Endothelial Activation and Stress Index (EASIX) predict death in patients undergoing allogeneic hematopoietic stem cell transplantation who develop endothelial complications. Because coronavirus ...disease 2019 (COVID-19) patients also have coagulopathy and endotheliitis, we aimed to assess whether EASIX predicts death within 28 days in hospitalized COVID-19 patients.
We performed a retrospective study on COVID-19 patients from two different cohorts derivation (
= 1,200 patients) and validation (
= 1,830 patients). The endpoint was death within 28 days. The main factors were EASIX (lactate dehydrogenase
creatinine)/thrombocytes and aEASIX-COVID (EASIX
age), which were log
-transformed for analysis.
Log
-EASIX and log
-aEASIX-COVID were independently associated with an increased risk of death in both cohorts (
< 0.001). Log
-aEASIX-COVID showed a good predictive performance for 28-day mortality both in the derivation cohort (area under the receiver-operating characteristic = 0.827) and in the validation cohort (area under the receiver-operating characteristic = 0.820), with better predictive performance than log
-EASIX (
< 0.001). For log
aEASIX-COVID, patients with low/moderate risk (<6) had a 28-day mortality probability of 5.3% 95% confidence interval (95% CI) = 4-6.5%, high (6-7) of 17.2% (95% CI = 14.7-19.6%), and very high (>7) of 47.6% (95% CI = 44.2-50.9%). The cutoff of log
aEASIX-COVID = 6 showed a positive predictive value of 31.7% and negative predictive value of 94.7%, and log
aEASIX-COVID = 7 showed a positive predictive value of 47.6% and negative predictive value of 89.8%.
Both EASIX and aEASIX-COVID were associated with death within 28 days in hospitalized COVID-19 patients. However, aEASIX-COVID had significantly better predictive performance than EASIX, particularly for discarding death. Thus, aEASIX-COVID could be a reliable predictor of death that could help to manage COVID-19 patients.
Abstract
Objectives
To evaluate whether the negative impact of tenofovir on telomere length (TL) is due to immune reconstitution interference or inhibition of telomerase.
Methods
One hundred and ...twenty-eight long-term aviraemic HIV adults treated with tenofovir-containing (n = 79) or tenofovir-sparing regimens (n = 49) were recruited to compare the following: TL in whole blood, PBMCs, CD4+ T cells and CD8+ T cells by quantitative PCR (qPCR); telomerase activity in PBMCs, CD4+ cells and CD8+ T cells using the TRAPeze RT Telomerase Detection Kit; and T cell maturational subset distribution by flow cytometry.
Results
In an adjusted analysis, participants treated with tenofovir for at least 4 years had shorter TL in CD8+ T cells (P = 0.04) and lower telomerase activity in CD4+ (P = 0.012) and CD8+ T cells (P = 0.023). Tenofovir treatment was also associated with lower proportions of recent thymic emigrant (RTE) CD4+ cells (P = 0.031) and PD1 marker expression (P = 0.013).
Conclusions
In long-term aviraemic HIV adults, the inhibition of telomerase by tenofovir could explain telomere shortening in CD8+ T cells. There is no telomere shortening in the CD4+ compartment and the decrease in telomerase activity could be explained both by the inhibition by tenofovir and by the lower proportion of RTE CD4+cells.
Abstract
Background
Previously selected lamivudine resistance-associated mutations (RAMs) may remain archived within the proviral HIV-DNA.
Objectives
To evaluate the ability of proviral DNA ...genotyping to detect lamivudine RAMs in HIV-1 virologically suppressed participants; the correlation between Sanger and next generation sequencing (NGS); and predictive factors for detection of lamivudine RAMs in proviral DNA.
Methods
Cross-sectional study of participants on stable antiretroviral therapy and suppressed for ≥1 year. Analysis of proviral DNA was performed by Sanger sequencing in whole blood and by NGS in PBMCs.
Results
We analysed samples from 102 subjects (52 with and 50 without lamivudine RAMs in historical plasma RNA-genotypes). Among participants with previous lamivudine resistance, Sanger sequencing detected RAMs in 26.9%. Detection rates significantly increased using NGS: 47.9%, 64.6%, 75% and 87.5% with the 20%, 10%, 5% and 1% thresholds, respectively. As for participants without historical lamivudine resistance, Sanger detected the RAMs in 1/49 (2%), and NGS (5% threshold) in 8/45 (17.8%). Multivariate models fitted to the whole population revealed that having a history of lamivudine resistance was a risk factor for detection of lamivudine RAMs by NGS. Among participants with historical lamivudine resistance, multivariate analysis showed that a longer time since HIV diagnosis was associated with persistence of archived mutations by NGS at thresholds of >10% OR 1.10 (95% CI: 1.00–1.24) and >5% OR 1.16 (95% CI: 1.02–1.32).
Conclusions
Proviral DNA Sanger sequencing does not detect the majority of historical lamivudine RAMs. NGS increases the sensitivity of detection at lower thresholds, although the relevance of these minority populations with lamivudine RAMs needs further evaluation.
Background: Previous epigenome-wide association studies have shown that HIV infection can disrupt the host DNA methylation landscape. However, it remains unclear how antiretroviral therapy (ART) ...affects the HIV-induced epigenetic modifications. Methods: 184 individuals with HIV from the NEAT001/ANRS143 clinical trial (with pre-ART and post-ART samples 96 weeks of follow-up) and 44 age-and-sex matched individuals without HIV were included. We compared genome-wide DNA methylation profiles in whole blood between groups adjusting for age, sex, batch effects, and DNA methylation-based estimates of leucocyte composition. Findings: We identified 430 differentially methylated positions (DMPs) between HIV+ pre-ART individuals and HIV-uninfected controls. In participants with HIV, ART initiation modified the DNA methylation levels at 845 CpG positions and restored 49.3% of the changes found between HIV+ pre-ART and HIV-uninfected individuals. We only found 15 DMPs when comparing DNA methylation profiles between HIV+ post-ART individuals and participants without HIV. The Gene Ontology enrichment analysis of DMPs associated with untreated HIV infection revealed an enrichment in biological processes regulating the immune system and antiviral responses. In participants with untreated HIV infection, DNA methylation levels at top HIV-related DMPs were associated with CD4/CD8 ratios and viral loads. Changes in DNA methylation levels after ART initiation were weakly correlated with changes in CD4+ cell counts and the CD4/CD8 ratio. Interpretation: Control of HIV viraemia after 96 weeks of ART initiation partly restores the host DNA methylation changes that occurred before antiretroviral treatment of HIV infection. Funding: NEAT-ID Foundation and Instituto de Salud Carlos III, co-funded by European Union.
Previous epigenome-wide association studies have shown that HIV infection can disrupt the host DNA methylation landscape. However, it remains unclear how antiretroviral therapy (ART) affects the ...HIV-induced epigenetic modifications.
184 individuals with HIV from the NEAT001/ANRS143 clinical trial (with pre-ART and post-ART samples 96 weeks of follow-up) and 44 age-and-sex matched individuals without HIV were included. We compared genome-wide DNA methylation profiles in whole blood between groups adjusting for age, sex, batch effects, and DNA methylation-based estimates of leucocyte composition.
We identified 430 differentially methylated positions (DMPs) between HIV+ pre-ART individuals and HIV-uninfected controls. In participants with HIV, ART initiation modified the DNA methylation levels at 845 CpG positions and restored 49.3% of the changes found between HIV+ pre-ART and HIV-uninfected individuals. We only found 15 DMPs when comparing DNA methylation profiles between HIV+ post-ART individuals and participants without HIV. The Gene Ontology enrichment analysis of DMPs associated with untreated HIV infection revealed an enrichment in biological processes regulating the immune system and antiviral responses. In participants with untreated HIV infection, DNA methylation levels at top HIV-related DMPs were associated with CD4/CD8 ratios and viral loads. Changes in DNA methylation levels after ART initiation were weakly correlated with changes in CD4+ cell counts and the CD4/CD8 ratio.
Control of HIV viraemia after 96 weeks of ART initiation partly restores the host DNA methylation changes that occurred before antiretroviral treatment of HIV infection.
NEAT-ID Foundation and Instituto de Salud Carlos III, co-funded by European Union.
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