RESUMO
Background: An in silico screen was performed to identify FDA approved drugs that inhibit SARS-CoV-2 main protease (Mpro), followed by in vitro viral replication assays, and in vivo pharmacokinetic studies in mice. These studies identified atovaquone as a promising candidate for inhibiting viral replication. Methods: A 2-center, randomized, double-blind, placebo-controlled trial was performed among patients hospitalized with COVID-19 infection. Enrolled patients were randomized 2:1 to atovaquone 1500 mg BID versus matched placebo. Patients received standard of care treatment including remdesivir, dexamethasone, or convalescent plasma as deemed necessary by the treating team. Saliva was collected at baseline and twice per day for up to 10 days for RNA extraction for SARS-CoV-2 viral load measurement by quantitative reverse-transcriptase PCR. The primary outcome was the between group difference in log-transformed viral load (copies/mL) using a generalized linear mixed-effect models of repeated measures from all samples. Results: Of the 61 patients enrolled; 41 received atovaquone and 19 received placebo. Overall, the population was predominately male (63%) and Hispanic (70%), with a mean age of 51 years, enrolled a mean of 5 days from symptom onset. The log10 viral load was 5.25 copies/mL vs. 4.79 copies/mL at baseline in the atovaquone vs. placebo group. Change in viral load did not differ over time between the atovaquone plus standard of care arm versus the placebo plus standard of care arm. Pharmacokinetic (PK) studies of atovaquone plasma concentration demonstrated a wide variation in atovaquone levels, with an inverse correlation between BMI and atovaquone levels, (Rho -0.45, p = 0.02). In post hoc analysis, an inverse correlation was observed between atovaquone levels and viral load (Rho -0.54, p = 0.005). Conclusion: In this prospective, randomized, placebo-controlled trial, atovaquone did not demonstrate evidence of enhanced SARS-CoV-2 viral clearance compared with placebo. However, based on the observed inverse correlation between atovaquone levels and viral load, additional PK-guided studies may be warranted to examine the antiviral effect of atovaquone in COVID-19 patients.
RESUMO
Objective: Half of the people living with HIV (PLWH) with hepatitis C virus (HCV) remain untreated for HCV. We examined predictors of HCV linkage to care among PLWH and the impact of HIV lost to care. Design and methods: We conducted a retrospective review of PLWH/HCV from our HIV clinics between 2014 and 2017, and examined predictors of HCV linkage to care. We used the Kaplan-Meier method to estimate the probability of HIV retention and HCV linkage over time. Results: Of 615 PLWH/HCV, 34% linked to HCV care and 21% were cured. Higher odds of linkage to HCV care were among blacks (adjusted odds ratio [aOR]: 2.95, 95% confidence interval [CI]: 1.59, 5.47), prior injection drug users (IDUs; aOR: 2.89, 95% CI: 1.39, 6.01), Medicare (aOR: 3.09, 95% CI: 1.56, 6.11), and cirrhotics (aOR: 2.80, 95% CI: 1.52, 5.14). Reduced odds for linkage were in active IDU (aOR: 0.16, 95% CI: 0.05, 0.45) and those seen by an advanced practice provider (aOR: 0.53, 95% CI: 0.30, 0.92). The main reason for failure to link to HCV care was lost to HIV care. At 3 years, the overall probability of being retained in HIV care was 53%; among those who had an HCV evaluation visit, it was 75% vs. 41% with no HCV evaluation visit. Accounting for loss to follow-up, PLWH/HCV had a 65% probability of having an HCV evaluation at 3 years.
RESUMO
A recent Phase 3 study of newly diagnosed glioblastoma (GBM) demonstrated the addition of tumor treating fields (TTFields) to temozolomide (TMZ) after combined radiation/TMZ significantly increased survival and progression free survival. Preliminary data suggested benefit with both methylated and unmethylated O-6-methylguanine-DNA methyl-transferase (MGMT) promoter status. To date, however, there have been no studies to address the potential interactions of TTFields and TMZ. Thus, the effects of TTFields and TMZ were studied in vitro using patient-derived GBM stem-like cells (GSCs) including MGMT expressing (TMZ resistant: 12.1 and 22GSC) and non-MGMT expressing (TMZ sensitive: 33 and 114GSC) lines. Dose-response curves were constructed using cell proliferation and sphere-forming assays. Results demonstrated a ⩾10-fold increase in TMZ resistance of MGMT-expressing (12.1GSCs: IC50=160µM; 22GSCs: IC50=44µM) compared to MGMT non-expressing (33GSCs: IC50=1.5µM; 114GSCs: IC50=5.2µM) lines. TTFields inhibited 12.1 GSC proliferation at all tested doses (50-500kHz) with an optimal frequency of 200kHz. At 200kHz, TTFields inhibited proliferation and tumor sphere formation of both MGMT GSC subtypes at comparable levels (12.1GSC: 74±2.9% and 38±3.2%, respectively; 22GSC: 61±11% and 38±2.6%, respectively; 33GSC: 56±9.5% and 60±7.1%, respectively; 114 GSC: 79±3.5% and 41±4.3%, respectively). In combination, TTFields (200kHz) and TMZ showed an additive anti-neoplastic effect with equal efficacy for TTFields in both cell types (i.e., ± MGMT expression) with no effect on TMZ resistance. This is the first demonstration of the effects of TTFields on cancer stem cells. The expansion of such studies may have clinical implications.
