Summary Background The phase 3 LUME-Lung 1 study assessed the efficacy and safety of docetaxel plus nintedanib as second-line therapy for non-small-cell lung cancer (NSCLC). Methods Patients from 211 ...centres in 27 countries with stage IIIB/IV recurrent NSCLC progressing after first-line chemotherapy, stratified by ECOG performance status, previous bevacizumab treatment, histology, and presence of brain metastases, were allocated (by computer-generated sequence through an interactive third-party system, in 1:1 ratio), to receive docetaxel 75 mg/m2 by intravenous infusion on day 1 plus either nintedanib 200 mg orally twice daily or matching placebo on days 2–21, every 3 weeks until unacceptable adverse events or disease progression. Investigators and patients were masked to assignment. The primary endpoint was progression-free survival (PFS) by independent central review, analysed by intention to treat after 714 events in all patients. The key secondary endpoint was overall survival, analysed by intention to treat after 1121 events had occurred, in a prespecified stepwise order: first in patients with adenocarcinoma who progressed within 9 months after start of first-line therapy, then in all patients with adenocarcinoma, then in all patients. This trial is registered with ClinicalTrials.gov , number NCT00805194. Findings Between Dec 23, 2008, and Feb 9, 2011, 655 patients were randomly assigned to receive docetaxel plus nintedanib and 659 to receive docetaxel plus placebo. The primary analysis was done after a median follow-up of 7·1 months (IQR 3·8–11·0). PFS was significantly improved in the docetaxel plus nintedanib group compared with the docetaxel plus placebo group (median 3·4 months 95% CI 2·9–3·9 vs 2·7 months 2·6–2·8; hazard ratio HR 0·79 95% CI 0·68–0·92, p=0·0019). After a median follow-up of 31·7 months (IQR 27·8–36·1), overall survival was significantly improved for patients with adenocarcinoma histology who progressed within 9 months after start of first-line treatment in the docetaxel plus nintedanib group (206 patients) compared with those in the docetaxel plus placebo group (199 patients; median 10·9 months 95% CI 8·5–12·6 vs 7·9 months 6·7–9·1; HR 0·75 95% CI 0·60–0·92, p=0·0073). Similar results were noted for all patients with adenocarcinoma histology (322 patients in the docetaxel plus nintedanib group and 336 in the docetaxel plus placebo group; median overall survival 12·6 months 95% CI 10·6–15·1 vs 10·3 months 95% CI 8·6–12·2; HR 0·83 95% CI 0·70–0·99, p=0·0359), but not in the total study population (median 10·1 months 95% CI 8·8–11·2 vs 9·1 months 8·4–10·4; HR 0·94, 95% CI 0·83–1·05, p=0·2720). Grade 3 or worse adverse events that were more common in the docetaxel plus nintedanib group than in the docetaxel plus placebo group were diarrhoea (43 6·6% of 652 vs 17 2·6% of 655), reversible increases in alanine aminotransferase (51 7·8% vs six 0·9%), and reversible increases in aspartate aminotransferase (22 3·4% vs three 0·5%). 35 patients in the docetaxel plus nintedanib group and 25 in the docetaxel plus placebo group died of adverse events possibly unrelated to disease progression; the most common of these events were sepsis (five with docetaxel plus nintedanib vs one with docetaxel plus placebo), pneumonia (two vs seven), respiratory failure (four vs none), and pulmonary embolism (none vs three). Interpretation Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinum-based therapy, especially for patients with adenocarcinoma. Funding Boehringer Ingelheim.
The face of hepatitis C virus (HCV) therapy is changing dramatically. Direct-acting antiviral agents (DAAs) specifically targeting HCV proteins have been developed and entered clinical practice in ...2011. However, despite high sustained viral response (SVR) rates of more than 90%, a fraction of patients do not eliminate the virus and in these cases treatment failure has been associated with the selection of drug resistance mutations (RAMs). RAMs may be prevalent prior to the start of treatment, or can be selected under therapy, and furthermore they can persist after cessation of treatment. Additionally, certain DAAs have been approved only for distinct HCV genotypes and may even have subtype specificity. Thus, sequence analysis before start of therapy is instrumental for managing DAA-based treatment strategies. We have created the interpretation system geno2phenoHCV (g2pHCV) to analyse HCV sequence data with respect to viral subtype and to predict drug resistance. Extensive reviewing and weighting of literature related to HCV drug resistance was performed to create a comprehensive list of drug resistance rules for inhibitors of the HCV protease in non-structural protein 3 (NS3-protease: Boceprevir, Paritaprevir, Simeprevir, Asunaprevir, Grazoprevir and Telaprevir), the NS5A replicase factor (Daclatasvir, Ledipasvir, Elbasvir and Ombitasvir), and the NS5B RNA-dependent RNA polymerase (Dasabuvir and Sofosbuvir). Upon submission of up to eight sequences, g2pHCV aligns the input sequences, identifies the genomic region(s), predicts the HCV geno- and subtypes, and generates for each DAA a drug resistance prediction report. g2pHCV offers easy-to-use and fast subtype and resistance analysis of HCV sequences, is continuously updated and freely accessible under http://hcv.geno2pheno.org/index.php. The system was partially validated with respect to the NS3-protease inhibitors Boceprevir, Telaprevir and Simeprevir by using data generated with recombinant, phenotypic cell culture assays obtained from patients' virus variants.
Effective control of HIV-1 infection in humans is achieved using combinations of antiretroviral therapy (ART) drugs. In humanized mice (hu-mice), control of viremia can be achieved using either ART ...or by immunotherapy using combinations of broadly neutralizing antibodies (bNAbs). Here we show that treatment of HIV-1–infected hu-mice with a combination of three highly potent bNAbs not only resulted in complete viremic control but also led to a reduction in cell-associated HIV-1 DNA. Moreover, lowering the initial viral load by coadministration of ART and immunotherapy enabled prolonged viremic control by a single bNAb after ART was withdrawn. Similarly, a single injection of adeno-associated virus directing expression of one bNAb produced durable viremic control after ART was terminated. We conclude that immunotherapy reduces plasma viral load and cell-associated HIV-1 DNA and that decreasing the initial viral load enables single bNAbs to control viremia in hu-mice.
Abstract Background Acute epididymitis is a common infectious disease of unknown etiology in about 30% of cases with guidelines based on studies published >15 yr ago. Objective To investigate the ...etiology of acute epididymitis using state-of-the-art methods and to provide rational data for antimicrobial therapy and clinical management. Design, setting, and participants Between 2007 and 2013, 237 patients (150 antimicrobially naive and 87 antibiotically pretreated) with acute epididymitis underwent comprehensive investigation comprising microbiologic cultures, polymerase chain reaction (PCR) for sexually transmitted infections (STIs), 16S ribosomal DNA (rDNA) analysis, and PCR detection of 23 viruses. Clinical management followed international guidelines. Outcome measures and statistical analysis Etiology, clinical management, and outcome after 3 mo were assessed. Results and limitations A causative pathogen, predominantly Escherichia coli (56%), was identified in 132 antibiotic-naive patients (88%) and 44 pretreated patients (51%); 16S rDNA analysis increased the detection rate by 10%. STIs were present in 34 cases (14%) (25 patients with Chlamydia trachomatis ) and were not restricted to a specific age group. Enteroviruses were found in only two patients (1%). In naive patients, cultured bacteria were susceptible to fluoroquinolones and group 3 cephalosporins in >85% of cases (preateted patients: 42% and 67%, respectively). Primary empirical therapy was continued in 88% of naive patients for 11 d and in 77% of pretreated patients for 13 d with indwelling urinary catheters, rendering patients as high risk for switching. Only six patients (2.5%) underwent semicastration. Prostate-specific antigen levels halved within 3 mo, except in patients who were antibiotic naive and without detected pathogens. Study limitations included a lack of susceptibility testing in cases of STIs. Conclusions Even in antimicrobially pretreated patients, acute epididymitis is mainly of bacterial origin. STIs are not limited to patients aged <35 yr. Viral epididymitis seems a rare condition. Current guideline recommendations on empirical antimicrobial therapy are adequate. Patient summary Patients with acute epididymitis should receive appropriate diagnostics and antimicrobial therapy for safe conservative management.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents a global health emergency. To improve the understanding of the systemic component of SARS-CoV-2, we investigated if viral load ...dynamics in plasma and respiratory samples are associated with antibody response and severity of coronavirus disease 2019 (COVID-19). SARS-CoV-2 RNA was found in plasma samples from 14 (44%) out of 32 patients. RNAemia was detected in 5 out of 6 fatal cases. Peak IgG values were significantly lower in mild/moderate than in severe (0.6 (interquartile range, IQR, 0.4-3.2) vs. 11.8 (IQR, 9.9-13.0), adjusted
= 0.003) or critical cases (11.29 (IQR, 8.3-12.0), adjusted
= 0.042). IgG titers were significantly associated with virus Ct (Cycle threshold) value in plasma and respiratory specimens ((ß = 0.4, 95% CI (confidence interval, 0.2; 0.5),
< 0.001 and ß = 0.5, 95% CI (0.2; 0.6),
= 0.002). A classification as severe or a critical case was additionally inversely associated with Ct values in plasma in comparison to mild/moderate cases (ß = -3.3, 95% CI (-5.8; 0.8),
= 0.024 and ß = -4.4, 95% CI (-7.2; 1.6),
= 0.007, respectively). Based on the present data, our hypothesis is that the early stage of SARS-CoV-2 infection is characterized by a primary RNAemia, as a potential manifestation of a systemic infection. Additionally, the viral load in plasma seems to be associated with a worse disease outcome.
BIBF 1120 is an oral, potent angiokinase inhibitor targeting receptors of the vascular endothelial growth factors, platelet-derived growth factors, and fibroblast growth factors. This phase I, ...accelerated titration study assessed the maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamic effects of BIBF 1120.
Sixty-one patients with advanced cancers received BIBF 1120 in successive cohorts. Twenty-five received 50 to 450 mg once daily and 36 received 150 to 300 mg twice daily in 4-week treatment courses interspersed by 1 week of washout. Dynamic contrast-enhanced magnetic resonance imaging assessed antiangiogenic effect in 42 patients.
Most frequent BIBF 1120-related adverse events were mostly mild to moderate (Common Toxicity Criteria grade 1-2) nausea (68.9%), vomiting (45.9%), and diarrhea (44.3%). The majority of dose-limiting adverse events of Common Toxicity Criteria grade 3 or 4 were reversible liver enzyme elevations. The maximum tolerated dose was 250 mg of BIBF 1120 for once and twice daily dosing. BIBF 1120 was absorbed moderately fast (t(max) = 1-3 hours at steady state), with no deviation from dose linearity and no decrease of exposure over time. The gMean terminal half-life was from 13 to 19 hours. One complete and two partial responses occurred in patients with renal cell cancer (n = 2) and colorectal cancer (n = 1). Dynamic contrast-enhanced magnetic resonance imaging showed a significant reduction in tumor blood flow in 55% of evaluable patients.
BIBF 1120 dosed continuously displayed a favorable safety and pharmacokinetics profile, and first efficacy signals were observed. Twice daily dosing permitted increased drug exposure without additional toxicity. Two hundred milligrams BIBF 1120 twice daily is the recommended dose for phase II monotherapy studies.
Highlights • EVs and HPeVs infecting healthy people in Côte d’Ivoire were characterized. • EV serotypes belonging to EV group A–C were identified. • Rarely reported worldwide EV strains have been ...isolated. • Children less than 5 years were the most affected from both infections. • The first data about HPeV infections in a sub-Saharan African country are reported.
The increased use of antiretroviral therapy (ART) has decreased mortality and morbidity of HIV-1 infected people but increasing levels of HIV drug resistance threatens the success of ART regimens. ...Conversely, late presentation can impact treatment outcomes, health costs, and potential transmission of HIV.
To describe the patterns of transmitted drug resistance (TDR) and acquired drug resistance (ADR) in HIV-1 infected patients followed in Europe, to compare its patterns in late presenters (LP) vs non-late presenters (NLP), and to analyze the most prevalent drug resistance mutations among HIV-1 subtypes.
Our study included clinical, socio-demographic, and genotypic information from 26,973 HIV-1 infected patients from the EuResist Integrated Database (EIDB) between 1981 and 2019.
Among the 26,973 HIV-1 infected patients in the analysis, 11,581 (42.9%) were ART-naïve patients and 15,392 (57.1%) were ART-experienced. The median age was 37 (IQR: 27.0-45.0) years old and 72.6% were males. The main transmission route was through heterosexual contact (34.9%) and 81.7% of patients originated from Western Europe. 71.9% of patients were infected by subtype B and 54.8% of patients were classified as LP. The overall prevalence of TDR was 12.8% and presented an overall decreasing trend (
for trend < 0.001), the ADR prevalence was 68.5% also with a decreasing trend (
for trend < 0.001). For LP and NLP, the TDR prevalence was 12.3 and 12.6%, respectively, while for ADR, 69.9 and 68.2%, respectively. The most prevalent TDR drug resistance mutations, in both LP and NLP, were K103N/S, T215rev, T215FY, M184I/V, M41I/L, M46I/L, and L90M.
Our study showed that the overall TDR (12.8%) and ADR (68.5%) presented decreasing trends during the study time period. For LP, the overall TDR was slightly lower than for NLP (12.3 vs 12.6%, respectively); while this pattern was opposite for ADR (LP slightly higher than NLP). We suggest that these differences, in the case of TDR, can be related to the dynamics of fixation of drug resistance mutations; and in the case of ADR with the more frequent therapeutic failure in LPs.
Despite a large number of antiretroviral drugs targeting HIV-1 protease for inhibition, mutations in this protein during the course of patient treatment can render them inefficient. This emerging ...resistance inspired numerous computational studies of the HIV-1 protease aimed at predicting the effect of mutations on drug binding in terms of free binding energy ΔG, as well as in mechanistic terms. In this study, we analyze ten different protease-inhibitor complexes carrying major resistance-associated mutations (RAMs) G48V, I50V, and L90M using molecular dynamics simulations. We demonstrate that alchemical free energy calculations can consistently predict the effect of mutations on drug binding. By explicitly probing different protonation states of the catalytic aspartic dyad, we reveal the importance of the correct choice of protonation state for the accuracy of the result. We also provide insight into how different mutations affect drug binding in their specific ways, with the unifying theme of how all of them affect the crucial drug binding regions of the protease.
Sub-Saharan Africa is endemic for intestinal parasites and distinguished for the largest burden of HIV cases. Blastocystis sp. is one of the most common protists infecting humans but its role in ...human disease is still controversial. Aim of this study was to investigate the prevalence of Blastocystis sp. in HIV positive and negative adults in Ghana and its association with immune status and other risk factors.
122 HIV positive outpatients and 70 HIV negative blood donors from the Komfo Anokye Teaching Hospital in Kumasi, Ghana, were included in the present study. Demographic, clinical and laboratory data were collected and HIV positive patients distinguished for CD4+ T cell count <200 cells/μl (n = 54) and >200 cells/μl (n = 68). A Blastocystis's phylogenetic analysis was performed to determine sample subtype (ST).
The prevalence of Blastocystis sp. in adult HIV positive individuals was lower than in HIV negative persons (6.6% vs. 20.0%, p = 0.008) and Blastocystis sp. ST1 was the most prevalent strain. Within HIV positive participants, the prevalence of Blastocystis sp. was lower in those individuals with CD4+ T cell count <200 cells/μl than in patients with higher CD4+ T cell count (1.9% vs. 10.3%, p = 0.076). Multiple regression analysis revealed that Blastocystis sp. was inversely associated with an obese Body Mass Index (BMI) in HIV negative persons (p = 0.040). Presence of Blastocystis sp. was correlated with higher CD4+ T cell count in HIV positive participants (p = 0.049).
It is largely reported that people living with HIV (PLHIV) in Africa are affected from parasite infections and that co-infections may adversely impact on their immune status, accelerating progress to AIDS and worsening gastrointestinal manifestations. Differently, in this study Blastocystis sp. was associated with a better immune status jointly with a healthy body weight while it seems to be reduced with the progression of HIV infection. This data agree with recent suggestions that Blastocystis sp. can represent a component of the healthy gut microbiota.
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