To investigate resistance-associated substitutions (RASs) as well as retreatment efficacies in a large cohort of European patients with failure of glecaprevir/pibrentasvir.
Patients were identified ...from three European Resistance Reference centres in Spain, Italy and Germany. Sequencing of NS3, NS5A and NS5B was conducted and substitutions associated with resistance to direct antiviral agents were analysed. Clinical and virological parameters were documented retrospectively and retreatment efficacies were evaluated.
We evaluated 90 glecaprevir/pibrentasvir failures 3a (n = 36), 1a (n = 23), 2a/2c (n = 20), 1b (n = 10) and 4d (n = 1). Ten patients were cirrhotic, two had previous exposure to PEG-interferon and seven were coinfected with HIV; 80 had been treated for 8 weeks. Overall, 31 patients (34.4%) failed glecaprevir/pibrentasvir without any NS3 or NS5A RASs, 62.4% (53/85) showed RASs in NS5A, 15.6% (13/83) in NS3 and 10% (9/90) in both NS5A and NS3. Infection with HCV genotypes 1a and 3a was associated with a higher prevalence of NS5A RASs. Patients harbouring two (n = 34) or more (n = 8) RASs in NS5A were frequent. Retreatment was initiated in 56 patients, almost all (n = 52) with sofosbuvir/velpatasvir/voxilaprevir. The overall sustained virological response rate was 97.8% in patients with end-of-follow-up data available.
One-third of patients failed glecaprevir/pibrentasvir without resistance. RASs in NS5A were more prevalent than in NS3 and were frequently observed as dual and triple combination patterns, with a high impact on NS5A inhibitor activity, particularly in genotypes 1a and 3a. Retreatment of glecaprevir/pibrentasvir failures with sofosbuvir/velpatasvir/voxilaprevir achieved viral suppression across all genotypes.
Abstract
Background
Antiretroviral drug resistance mutations remain a major cause of treatment failure.
Objectives
To evaluate the impact of NRTI resistance mutations on virological effectiveness of ...elvitegravir-containing regimens.
Materials and methods
We selected treatment-experienced HIV-1-infected patients starting elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF), with at least one protease/reverse transcriptase genotype available before switching and at least one HIV-1 RNA viral load (VL) measurement during follow-up. The primary endpoint was virological failure (VF), defined as one VL value of ≥1000 copies/mL or two consecutive VL values of >50 copies/mL.
Results
We included 264 ART regimens: 75.6% male, median (IQR) age 47 years (39–53), 7 years (3–16) of HIV infection, nadir CD4+ 247 cells/mm3 (105–361), 81.5% with VL ≤50 copies/mL and 11.7% with at least one NRTI mutation at baseline. Eleven (5.2%) VFs occurred in virologically suppressed patients versus eight (15.1%) in viraemic patients. The estimated probability of VF at 48 weeks with versus without any NRTI mutation was 7.4% (95% CI 2.3–12.5) versus 3.8% (2.1–5.5) in virologically suppressed patients and 66.7% (39.5–93.9) versus 11.2% (6.5–15.9) (P<0.001) in viraemic patients. The only predictor of VF was time on therapy (per 1 year more, adjusted HR 1.14, 95% CI 1.02–1.27, P=0.024) in viraemic patients.
Conclusions
A switch to E/C/F/TDF or E/C/F/TAF is safe for virologically suppressed patients without documented NRTI resistance, but not recommended in viraemic patients with a history of NRTI resistance. Although we did not detect a detrimental effect of past NRTI resistance in virologically suppressed patients, a fully active regimen remains preferred in this setting due to possible rebound of drug-resistant virus in the long term.
Background
Since the beginning of the coronavirus disease 2019 (COVID‐19) pandemic, an increasing number of chilblain‐like lesions (ChLL) have been increasingly reported worldwide. To date, the ...causal link between ChLL and SARS‐CoV‐2 infection has not been unequivocally established.
Methods
In this case series, we present demographic, clinical, laboratory, and histopathological information regarding 27 young patients with a clinical diagnosis of ChLL who referred to the Dermatology Unit of Papa Giovanni XXIII Hospital, Bergamo, Italy, from 1 April 2020 to 1 June 2020.
Results
The mean age was 14.2 years, and 21 patients (78%) experienced mild systemic symptoms a median of 28 days before the onset of cutaneous lesions. ChLL mostly involved the feet (20 patients – 74%). Among acral lesions, we identified three different clinical patterns: (i) chilblains in 20 patients (74%); (ii) fixed erythematous macules in 4 children (15%); (iii) erythrocyanosis in 3 female patients (11%). Blood examinations and viral serologies, including parvovirus B19, cytomegalovirus (CMV), Epstein‐Barr virus (EBV), and coxsackievirus were normal in all. Three patients (11%) underwent nasopharyngeal swab for RT‐PCR for SARS‐CoV‐2 showing only 1 positive. Histopathological examinations of 7 skin biopsies confirmed the clinical diagnosis of chilblains; vessel thrombi were observed only in 1 case. Our findings failed to demonstrate the direct presence of SARS‐CoV‐2 RNA in skin biopsies, both with real‐time polymerase chain reaction (RT‐PCR) and RNAscope in situ hybridization (ISH).
Limitations
Limited number of cases, unavailability of laboratory confirmation of COVID‐19 in all patients, potential methodological weakness, and latency of skin biopsies in comparison to cutaneous lesions onset.
Conclusions
These observations may support the hypothesis of an inflammatory pathogenesis rather than the presence of peripheral viral particles. Although, we could not exclude an early phase of viral endothelial damage followed by an IFN‐I or complement‐mediated inflammatory phase. Further observations on a large number of patients are needed to confirm this hypothesis.
Objectives Genomic surveillance of Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) is crucial for virulence, drug-resistance monitoring, and outbreak containment. Methods ...Genomic analysis on 87 KPC-Kp strains isolated from 3 Northern Italy hospitals in 2019-2021 was performed by whole genome sequencing (WGS), to characterize resistome, virulome, and mobilome, and to assess potential associations with phenotype resistance and clinical presentation. Maximum Likelihood and Minimum Spanning Trees were used to determine strain correlations and identify potential transmission clusters. Results Overall, 15 different STs were found; the predominant ones included ST307 (35, 40.2%), ST512/1519 (15, 17.2%), ST20 (12, 13.8%), and ST101 (7, 8.1%). 33 (37.9%) KPC-Kp strains were noticed to be in five transmission clusters (median number of isolates in each cluster: 5 3-10), four of them characterized by intra-hospital transmission. All 87 strains harbored Tn4401a transposon, carrying bla.sub.KPC-3 (48, 55.2%), bla.sub.KPC-2 (38, 43.7%), and in one case (1.2%) bla.sub.KPC-33, the latter gene conferred resistance to ceftazidime/avibactam (CZA). Thirty strains (34.5%) harbored porin mutations; of them, 7 (8.1%) carried multiple Tn4401a copies. These strains were characterized by significantly higher CZA minimum inhibitory concentration compared with strains with no porin mutations or single Tn4401a copy, respectively, even if they did not overcome the resistance breakpoint of 8 ug/mL. Median 2 (IQR:1-2) virulence factors per strain were detected. The lowest number was observed in ST20 compared to the other STs (p<0.001). While ST307 was associated with infection events, a trend associated with colonization events could be observed for ST20. Conclusions Integration of genomic, resistance score, and clinical data allowed us to define a relative diversification of KPC-Kp in Northern Italy between 2019 and 2021, characterized by few large transmission chains and rare inter-hospital transmission. Our results also provided initial evidence of correlation between KPC-Kp genomic signatures and higher MIC levels to some antimicrobial agents or colonization/infection status, once again underlining WGS's importance in bacterial surveillance. Keywords: K. pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp), WGS, Genomic epidemiology, Antimicrobial resistance (AMR)
Dual therapy (DT) with boosted protease inhibitors (bPIs) plus lamivudine has been shown to be superior to bPI monotherapy in virologically suppressed patients despite previous selection of the ...lamivudine resistance M184V mutation. We compared the virological efficacy of lamivudine-based DT in patients with and without a history of M184V detection.
We retrospectively analyzed patients with HIV-RNA ≤50 copies/mL switching to DT with at least 1 previous resistance genotype in the ARCA database. Time to virological failure (VF; HIV-RNA ≥200 copies/mL or 2 consecutive HIV-RNA >50 copies/mL) and to treatment discontinuation (TD) was analyzed by survival analysis.
Four hundred thirty-six patients switching to lamivudine plus bPIs (70%) or integrase inhibitors (30%) were included. Patients with M184V (n = 87) were older, had lower nadir CD4+ cell count, longer duration of antiretroviral therapy and of virologic suppression, and higher rate of hepatitis C virus infection compared with patients without M184V. The 3-year probability of remaining free from VF was 91.9% (95% confidence interval CI, 86.6-97.2) without M184V and 87.8% (95% CI, 78.4-97.2) with M184V (
= .323). The time to TD did not differ between groups. Multivariate analysis adjusting for baseline variables differing between groups also did not detect M184V as being associated with VF or TD; however, the 3-year probability of remaining free of viral blips (isolated HIV-RNA 51-199 copies/mL) was 79.8% (95% CI, 67.8%-91.8%) with M184V vs 90.1% (95% CI, 84.0%-96.2%) without M184V (
= .016).
Previous selection of M184V did not increase the risk of VF or TD with lamivudine-based DT but was associated with a higher probability of viral blips.
Objectives
The aim was to evaluate the evolution of transmitted HIV‐1 drug resistance (TDR) prevalence in antiretroviral therapy (ART)‐naïve patients from 2006 to 2016.
Methods
HIV‐1 sequences were ...retrieved from the Antiviral Response Cohort Analysis (ARCA) database and TDR was defined as detection of at least one mutation from the World Health Organization (WHO) surveillance list.
Results
We included protease/reverse transcriptase sequences from 3573 patients; 455 had also integrase sequences. Overall, 68.1% of the patients were Italian, the median CD4 count was 348 cells/μL interquartile range (IQR) 169–521 cells/μL, and the median viral load was 4.7 log10 HIV‐1 RNA copies/mL (IQR 4.1–5.3 log10 copies/mL). TDR was detected in 10.3% of patients: 6% carried mutations to nucleos(t)ide reverse transcriptase inhibitors (NRTIs), 4.4% to nonnucleos(t)ide reverse transcriptase inhibitors (NNRTIs), 2.3% to protease inhibitors (PIs), 0.2% to integrase strand transfer inhibitors (INSTIs) and 2.1% to at least two drug classes. TDR declined from 14.5% in 2006 to 7.3% in 2016 (P = 0.003): TDR to NRTIs from 9.9 to 2.9% (P = 0.003) and TDR to NNRTIs from 5.1 to 3.7% (P = 0.028); PI TDR remained stable. The proportion carrying subtype B virus declined from 76.5 to 50% (P < 0.001). The prevalence of TDR was higher in subtype B vs. non‐B (12.6 vs. 4.9%, respectively; P < 0.001) and declined significantly in subtype B (from 17.1 to 8.8%; P = 0.04) but not in non‐B subtypes (from 6.1 to 5.8%; P = 0.44). Adjusting for country of origin, predictors of TDR were subtype B adjusted odds ratio (AOR) for subtype B vs. non‐B 2.91; 95% confidence interval (CI) 1.93–4.39; P < 0.001, lower viral load (per log10 higher: AOR 0.86; 95% CI 0.75–0.99; P = 0.03), site in northern Italy (AOR for southern Italy/island vs. northern Italy, 0.61; 95% CI 0.40–0.91; P = 0.01), and earlier calendar year (per 1 year more recent: AOR 0.95; 95% CI 0.91–0.99; P = 0.02).
Conclusions
The prevalence of HIV‐1 TDR has declined during the last 10 years in Italy.
To compare continuous highly active antiretroviral therapy with a CD4 cell count-driven structured treatment interruption (STI) strategy. The primary end-point was the proportion of subjects ...maintaining CD4 cell count > 400 x 10 cells/l. Secondary end-points were to identify the dynamic and predictive variables of CD4 cell loss.
The BASTA study is a randomized, controlled, prospective trial. Patients with CD4 cell counts > 800 x 10 cells/l were enrolled and the immunological threshold to resume therapy was set to the lower normal limit of CD4 cells for HIV-uninfected adults.
Sixty-nine patients were randomized and followed for 64 weeks. At baseline, all had undetectable plasma HIV RNA and their mean CD4 cell count was 1077 x 10 cells/l. None of the patients showed a disease progression or any AIDS-defining event. At each time point, the proportion of subjects in the STI group that had a CD4 cell count < 400 x 10 cells/l was not statistically different from the control group. In all cases, the 95% confidence interval for this difference was smaller than +/-10%. However, 57% of patients with nadir CD4 cell count 200-350 x 10 cells/l reached a CD4 cell count < 400 x 10 cells/l. This was statistically different (P = 0.02) from the nearly 90% of patients with a nadir CD4 cell count 350-500 x 10 cells/l who maintained a CD4 cell count of > 400 x 10 cells/l.
Prolonged STI in patients with fully suppressed virus and marked immune reconstitution is generally safe. The main predictor of CD4 cell decline is the nadir CD4 cell count. Pulse therapy warrants further careful prospective evaluation to investigate virological and clinical outcomes over a very long period.
Highlights • Multicentre study for the standardization of CMV, EBV and BKV quantification. • The accuracy measured ranged from 58.6% to 89.6%. • Low variability were observed between 15 Italian ...laboratories. • No false positive results were obtained.
The authors assessed the predictive capacity of 3 rule-based algorithms (Bergamo, Stanford University, Rega Institute) for HIV genotypic interpretation. A total of 1132 postgenotypic regimens in 533 ...patients were considered. The genotypic sensitivity score (GSS) was strongly associated (P < .0001) with the virologic outcome (1 log HIV-RNA reduction). The 3 algorithms had a highly significant prediction efficiency. The Bergamo algorithm receiver-operating characteristic curve area under the curve (AUC) for the prediction of ≥1 log HIV-RNA reduction was 0.753 (95% confidence interval, 0.725-0.781), testifying that the prediction was significantly different (P < .0001) from simple chance. The AUCs obtained by the 2 other systems were similar (0.752 Stanford; 0.741 Rega). The predictive capacity of the algorithms was not influenced by the type of antiviral drugs used. The 3 considered rule-based algorithms for the interpretation of HIV genotypic resistance yield congruent results and may effectively predict the virologic outcome of rescue therapy. Their use may help clinicians in interpreting mutational patterns and in making therapeutic choices.
PDF
