Pharmacokinetics of dolutegravir with and without darunavir/cobicistat in healthy volunteers (vol 74, pg 149, 2019)

Background:Dolutegravir combined with darunavir/cobicistat is a promising NRTI-sparing and/or salvage strategy for the treatment of HIV-1 infection. Methods:This Phase I, open-label, 57 day, crossover, pharmacokinetic (PK) study, enrolled healthy volunteers aged 18-65 years, who were randomized to one of two groups. Group 1 received dolutegravir (50 mg) once daily for 14 days followed by a 7 day washout, then a 14 day dolutegravir/darunavir/cobicistat (DTG/DRV/COBI) once-daily co-administration period followed by a 7 day washout and finally a 14 day period of darunavir/cobicistat (800/150 mg) once daily. Group 2 followed the same sequence starting with darunavir/cobicistat and concluding with dolutegravir. Each group underwent intensive PK sampling over 24 h on day 14 of each drug period and DTG/DRV/COBI concentrations were measured using validated LC-MS/MS methods. Results:Twenty participants completed all PK phases. Thirteen were female and median age and BMI were 33.5 years and 27 kg/m2. Dolutegravir geometric mean ratios (GMR, DTG/DRV/COBI versus dolutegravir alone) and 90% CI for Cmax, AUC0-24 and C24 were 1.01 (0.92-1.11), 0.95 (0.87-1.04) and 0.9 (0.8-1.0), respectively. Darunavir GMR (DRV/COBI/DTG versus darunavir/cobicistat alone) and 90% CI for Cmax, AUC0-24 and C24 were 0.90 (0.83-0.98), 0.93 (0.86-1.00) and 0.93 (0.78-1.11), respectively. No grade 3 or 4 adverse events or laboratory abnormalities were observed. Conclusions:Concentrations of dolutegravir and darunavir, when boosted with cobicistat, decreased by <10% during co-administration, suggesting this combination can be prescribed safely in the treatment of HIV-1, with no adjustment to current guideline-recommended dosages

Improvement of ALT decay kinetics by all-oral HCV treatment: Role of NS5A inhibitors and differences with IFN-based regimens

Background: Intracellular HCV-RNA reduction is a proposed mechanism of action of direct-acting antivirals (DAAs), alternative to hepatocytes elimination by pegylated-interferon plus ribavirin (PR). We modeled ALT and HCV-RNA kinetics in cirrhotic patients treated with currently-used all-DAA combinations to evaluate their mode of action and cytotoxicity compared with telaprevir (TVR)+PR. Study design: Mathematical modeling of ALT and HCV-RNA kinetics was performed in 111 HCV-1 cirrhotic patients, 81 treated with all-DAA regimens and 30 with TVR+PR. Kinetic-models and Cox-analysis were used to assess determinants of ALT-decay and normalization. Results: HCV-RNA kinetics was biphasic, reflecting a mean effectiveness in blocking viral production &gt;99.8%. The first-phase of viral-decline was faster in patients receiving NS5A-inhibitors compared to TVR+PR or sofosbuvir+simeprevir (p&lt;0.001), reflecting higher efficacy in blocking assembly/secretion. The second-phase, noted \u3b4 and attributed to infected-cell loss, was faster in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.27 vs 0.21 d-1, respectively, p = 0.0012). In contrast the rate of ALT-normalization, noted \u3bb, was slower in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.17 vs 0.27 d-1, respectively, p&lt;0.001). There was no significant association between the second-phase of viral-decline and ALT normalization rate and, for a given level of viral reduction, ALT-normalization was more profound in patients receiving DAA, and NS5A in particular, than TVR+PR. Conclusions: Our data support a process of HCV-clearance by all-DAA regimens potentiated by NS5A-inhibitor, and less relying upon hepatocyte death than IFN-containing regimens. This may underline a process of "cell-cure" by DAAs, leading to a fast improvement of liver homeostasis

Level of agreement between frequently used cardiovascular risk calculators in people living with HIV

Objectives The aim of the study was to describe agreement between the QRISK2, Framingham and Data Collection on Adverse Events of Anti‐HIV Drugs (D:A:D) cardiovascular disease (CVD) risk calculators in a large UK study of people living with HIV (PLWH). Methods PLWH enrolled in the Pharmacokinetic and Clinical Observations in People over Fifty (POPPY) study without a prior CVD event were included in this study. QRISK2, Framingham CVD and the full and reduced D:A:D CVD scores were calculated; participants were stratified into ‘low’ ( 20%) categories for each. Agreement between scores was assessed using weighted kappas and Bland–Altman plots. Results The 730 included participants were predominantly male (636; 87.1%) and of white ethnicity (645; 88.5%), with a median age of 53 [interquartile range (IQR) 49–59] years. The median calculated 10‐year CVD risk was 11.9% (IQR 6.8–18.4%), 8.9% (IQR 4.6–15.0%), 8.5% (IQR 4.8–14.6%) and 6.9% (IQR 4.1–11.1%) when using the Framingham, QRISK2, and full and reduced D:A:D scores, respectively. Agreement between the different scores was generally moderate, with the highest level of agreement being between the Framingham and QRISK2 scores (weighted kappa = 0.65) but with most other kappa coefficients in the 0.50–0.60 range. Conclusions Estimates of predicted 10‐year CVD risk obtained with commonly used CVD risk prediction tools demonstrate, in general, only moderate agreement among PLWH in the UK. While further validation with clinical endpoints is required, our findings suggest that care should be taken when interpreting any score alone

Functional antibody and T-cell immunity following SARS-CoV-2 infection, including by variants of concern, in patients with cancer: the CAPTURE study

Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study (NCT03226886) integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2-positive, 94 were symptomatic and 2 patients died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies, 82% had neutralizing antibodies against WT, whereas neutralizing antibody titers (NAbT) against the Alpha, Beta, and Delta variants were substantially reduced. Whereas S1-reactive antibody levels decreased in 13% of patients, NAbT remained stable up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment-specific, but presented compensatory cellular responses, further supported by clinical. Overall, these findings advance the understanding of the nature and duration of immune response to SARS-CoV-2 in patients with cancer

Depression, lifestyle factors and cognitive function in people living with HIV and comparable HIV-negative controls

We investigated whether differences in cognitive performance between people living with HIV (PLWH) and comparable HIV-negative people were mediated or moderated by depressive symptoms and lifestyle factors. METHODS: A cross-sectional study of 637 'older' PLWH aged ≥ 50 years, 340 'younger' PLWH aged < 50 years and 276 demographically matched HIV-negative controls aged ≥ 50 years enrolled in the Pharmacokinetic and Clinical Observations in People over Fifty (POPPY) study was performed. Cognitive function was assessed using a computerized battery (CogState). Scores were standardized into Z-scores [mean = 0; standard deviation (SD) = 1] and averaged to obtain a global Z-score. Depressive symptoms were evaluated via the Patient Health Questionnaire (PHQ-9). Differences between the three groups and the effects of depression, sociodemographic factors and lifestyle factors on cognitive performance were evaluated using median regression. All analyses accounted for age, gender, ethnicity and level of education. RESULTS: After adjustment for sociodemographic factors, older and younger PLWH had poorer overall cognitive scores than older HIV-negative controls (P < 0.001 and P = 0.006, respectively). Moderate or severe depressive symptoms were more prevalent in both older (27%; P < 0.001) and younger (21%; P < 0.001) PLWH compared with controls (8%). Depressive symptoms (P < 0.001) and use of hashish (P = 0.01) were associated with lower cognitive function; alcohol consumption (P = 0.02) was associated with better cognitive scores. After further adjustment for these factors, the difference between older PLWH and HIV-negative controls was no longer significant (P = 0.08), while that between younger PLWH and older HIV-negative controls remained significant (P = 0.01). CONCLUSIONS: Poorer cognitive performances in PLWH compared with HIV-negative individuals were, in part, mediated by the greater prevalence of depressive symptoms and recreational drug use reported by PLWH

Regression models to explore independent factors associated with intima-media thickness (pIMT).

a<p>Logistic regression model: pathological intima-media thickness (pIMT) defined as IMT>1 mm analysed as categorical variable.</p>b<p>Linear regression model: mean IMT analysed as a continuous variable –plaque excluded from the analysis.</p><p>NOTE: HAART, highly active antiretroviral therapy; PI, protease inhibitors; HOMA-IR, homeostasis model assessment of insulin resistance.</p><p>OR, odds ratio – AOR, adjusted odds ratio.</p>*<p>Adjusted for Framingham risk score and HOMA-IR;</p>**<p>Mutually adjusted for all of the parameters tested in the univariate model.</p

Different peripheral T-cell immune phenotypes according to the degree of carotid intima-media thickness.

<p><b>A–B.</b> Activated CD8+ T-cells were defined by the expression of CD38, whereas memory activated CD8+ T-cells were defined by the co-expression of CD45R0 and CD38. <b>A.</b> nIMT and pIMT HIV+ patients exhibited similar number of CD8+CD38+ T-cells. <b>B.</b> pIMT patients had significantly higher memory activated CD8+CD38+CD45R0+ T-cells in comparison to nIMT patients (p = .038). <b>C–D.</b> Apoptotic T-cells were defined by the expression of CD95 on CD4+ and CD8+ cells. As compared to nIMT, pIMT patients exhibited a significantly higher number of CD4+CD95+ cells (p = .01) (<b>C</b>), and CD8+CD95+ T-cells (p = .003) (<b>D</b>). <b>E.</b> CD127 expression on CD4+ T-cells was similar between the nIMT and pIMT groups. <b>F.</b> A non-significant trend towards greater number of CD8+CD127+ cells was observed among pIMT patients as compared to nIMT patients (p = .08).</p

T-cell immunosenescence according to the degree of intima-media thickness.

<p><b>A.</b> A non-significant tendency towards reduced early differentiated memory (CD28+CD57−) CD4+ T-cell numbers was observed for pIMT patients in comparison to nIMT patients (p = .09). <b>B.</b> No differences were observed in early differentiated memory CD8+ CD28+CD57− T-cells between the two study groups. <b>C–D.</b> The number of late-differentiated memory (CD28–CD57+) CD4+ (<b>C</b>) and CD8+ (<b>D</b>) T-cells was comparable between nIMT and pIMT groups. <b>E–F.</b> We observed no difference in CD4+CD28+CD57+ (<b>E</b>) and CD8+CD28+CD57+ (<b>F</b>) T-cells between the nIMT and pIMT groups. <b>G.</b> No major difference in CD4+CD28–CD57− T-cells were observed between nIMT and pIMT patients. <b>H.</b> Compared to nIMT patients, pIMT patients tended to have lower number of CD8+CD28–CD57− cells (p = .06).</p

Markers of Inflammation, endothelial cell activation, microbial translocation and anti-CMV IgG according to the degree of intima-media thickness.

<p><b>A.</b> IL-6 plasma levels were increased in pIMT patients in comparison to nIMT patients, albeit not-reaching significance (p = .08). <b>B–F.</b> When nIMT patients were compared to pIMT patients, no differences in TNF-α (<b>B</b>), s-VCAM-1 (<b>C</b>) hs-C-reactive protein (hs-CRP) (<b>D</b>) plasma levels were detected. <b>E.</b> nIMT and pIMT patients exhibited similar plasma levels of lipopolysaccharide (LPS). <b>F.</b> pIMT patients showed significantly higher circulating levels of sCD14 in comparison to nIMT patients (p = .046). <b>G.</b> nIMT and pIMT patients displayed comparable levels of anti-CMV IgG.</p

Effects of tuberculosis and/or HIV-1 infection on COVID-19 presentation and immune response in Africa

Here the authors describe outcomes of SARS-CoV-2 infection in an African setting of high HIV-1 and tuberculosis prevalence. They find that tuberculosis is a common co-morbidity in patients admitted to hospital with COVID-19 and that the immune response to SARS-CoV-2 is adversely affected by co-existent HIV-1 and tuberculosis