Interaction of CYP3A4 with the inhibitor cobicistat: Structural and mechanistic insights and comparison with ritonavir.

Cobicistat is a derivative of ritonavir marketed as a pharmacoenhancer for anti-HIV therapy. This study investigated the interaction of cobicistat with the target protein, drug-metabolizing cytochrome P450 3A4 (CYP3A4), at the molecular level using spectral, kinetic, functional, and structural approaches. It was found that, similar to ritonavir, cobicistat directly coordinates to the heme via the thiazole nitrogen but its affinity and the binding rate are 2-fold lower: 0.030 µM and 0.72 s-1, respectively. The newly determined 2.5 Å crystal structure of cobicistat-bound CYP3A4 suggests that these changes arise from the inability of cobicistat to H-bond to the active site S119 and establish multiple stabilizing contacts with the F-F' connecting fragment, which becomes disordered upon steric clashing with the bulky morpholine moiety. Nonetheless, cobicistat inhibits recombinant CYP3A4 as potently as ritonavir (IC50 of 0.24 µM vs 0.22 µM, respectively) due to strong ligation to the heme and formation of extensive hydrophobic/aromatic interactions via the phenyl side-groups. To get insights into the inhibitory mechanism, the K257 residue, known to be solely and irreversibly modified by the reactive ritonavir metabolite, was substituted with alanine. Neither this nor control K266A mutation changed the extent of time-dependent inhibition of CYP3A4 by cobicistat and ritonavir, suggesting the existence of alternative inactivation mechanism(s). More importantly, K257 was found to be functionally important and contributed to CYP3A4 allosterism, possibly by modulating protein-ligand interactions through conformational dynamics.

Effectiveness and Tolerability of Dual Therapy with Dolutegravir Plus Darunavir/cobicistat in Treatment-Experienced Patients with HIV: A 144-Week Follow-Up.

BACKGROUND: A dual regimen with dolutegravir plus cobicistat-boosted darunavir (DTG+DRV/c) is a promising alternative for patients with human immunodeficiency virus (HIV) with resistance or intolerance to nucleoside reverse transcriptase inhibitors, especially those with a history of treatment failure. MATERIALS AND METHODS: We included all treatment-experienced patients with HIV who switched to the DTG+DRV/c regimen at a tertiary university hospital. We assessed the regimen's effectiveness, safety, and tolerability through serial laboratory data and clinical findings. The primary endpoint was the proportion of patients with plasma HIV-RNA levels <50 copies/mL at week 144 post-switch. The secondary endpoints were safety and tolerability assessments. RESULTS: Our retrospective analysis involved 40 patients. The leading reasons for switching to DTG+DRV/c were treatment failure in 17 patients (42.5%), simplification after multiple previous regimens in 15 (37.5%), and adverse drug reactions in 8 (20.0%). Among the 17 patients in the treatment failure group, we observed enhanced viral suppression and improved CD4+ T-cell counts after initiating the dual regimen. In the non-treatment failure group (23 patients), viral suppression and CD4+ T-cell levels were consistently maintained. No significant alterations in renal function, liver function, glucose levels, or lipid profiles were observed post-switch. High tolerability was observed, with 34/40 patients (85.0%) responding well to the regimen. However, six patients discontinued treatment before reaching the 144-week mark. CONCLUSION: Our findings confirm that DTG+DRV/c is an effective and well-tolerated switch therapy regimen for treatment-experienced patients with HIV, with sustained benefits observed for up to 144 weeks of follow-up. This regimen showed adaptability across different patient groups and demonstrated virological and immunological improvements, particularly in patients with a history of treatment failure.

Outcome of Darunavir-Cobicistat-Based Regimens in HIV-Infected People Who Have Experienced Virological Failure.

Objective: To evaluate the virological outcome of darunavir-cobicistat (DRVc)-based regimens in adults living with HIV who had experienced virological failure (VF) on any previous drug combination. Methods: This was a retrospective cohort study (CSLHIV Cohort) of adults living with HIV who started a DRVc-based regimen with HIV-RNA >50 copies/mL after VF on any previous drug combination. Data on demographics, antiretroviral treatment since HIV diagnosis, and immunological and metabolic parameters from baseline (start of DRVc) to 48 weeks were analyzed in order to assess the cumulative proportion of those who achieved virological success (VS), defined as at least one instance of HIV-RNA <50 copies/mL within 12 months from baseline. Follow-up lasted from the start of the DRVc-based regimen (baseline) to the first instance of HIV-RNA <50 copies/mL, last available visit, or loss to follow-up or death, whichever occurred first. Univariate and multivariate Cox proportional-hazard regression models were used to identify baseline factors associated with VS. Results: A total of 176 individuals were included, and 120 (68.2%) achieved <50 HIV-RNA copies/mL within 12 months since baseline. On multivariate analysis, baseline HDL cholesterol was independently associated with the occurrence of VS (adjusted HR 1.021, 95% CI 1.004-1.038; p=0.014). Among the 120 subjects with VS, 27 (22.5%) had had VF during a median follow-up of 20.8 months since the first undetectable HIV-RNA. Resistance testing after VF was available in two cases, which harboured the HIV variant-bearing protease inhibitor-resistance mutations D30N, I50V, and N88D. During a median follow-up of 38.4 months, 65 of 176 (36.9%) individuals discontinued DRVc for any reason (37 of 120, 30.8%) and achieved VS vs. 28 of 56 (50%) without VS (p=0.019). Time to discontinuation was longer in people with VS (41.5 vs. 23.0 months, p=0.0007). No statistically significant changes were observed in immunological or lipid profiles during follow-up. Conclusion: Most individuals in this study achieved VS within 12 months from the beginning of a DRVc-based regimen; therefore, this treatment represent a viable option for people who have experienced VF on other regimens.

Distinct Lipidomic Profiles between People Living with HIV Treated with E/C/F/TAF or B/F/TAF: An Open-Label Prospective Cohort Study.

INTRODUCTION: Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) has been increasingly replaced by bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in the treatment of human immunodeficiency virus (HIV) owing to its more favorable pharmacokinetics and fewer drug-drug interactions. However, the effect of this switch on plasma lipids and lipidomic profiles remains poorly characterized. METHODS: HIV infected patients on an E/C/F/TAF regimen were recruited into the study and followed up every 12 weeks. Participants were divided into E/C/F/TAF and B/F/TAF groups depending on whether they were switched to B/F/TAF during follow-up. Clinical information and blood samples were collected at 0, 12, and 24 weeks, and lipidomic analysis was performed using liquid chromatography mass spectrometry. RESULTS: No significant differences were observed between the groups at baseline. At week 24, patients switched to B/F/TAF had lower triglyceride [mmol/L; 1.23 (0.62) versus 2.03 (0.75), P = 0.001] and very low-density lipoprotein cholesterol [mmol/L; 0.64 (0.26) versus 0.84 (0.32), P = 0.037) compared with patients who continued E/C/F/TAF therapy. Small decrease from baseline in Framingham general cardiovascular risk score (FRS) was observed in the B/F/TAF arm [week (W) 0: 2.59 (1.57) versus W24: 2.18 (1.01), P = 0.043]. Lipidomic analysis indicated that E/C/F/TAF treatment increased the levels of several diglycerides (DGs), triacylglycerols (TAGs), and lyso-phosphatidylcholines (LPCs), whereas switching to B/F/TAF led to increased sphingolipids and glycerophospholipids. After adjusting for demographic and clinical parameters, only DG (16:0/18:2), DG (18:2/22:6), DG (18:3/18:2), DG (20:5/18:2), TAG (18:3/18:2/21:5), TAG (20:5/18:2/22:6), and LPC (22:6) were found to be significantly associated with FRS (regression coefficient of 0.17-6.02, P < 0.05). Most of these FRS associate lipid species were significantly elevated in individuals treated with E/C/F/TAF instead of individuals treated with B/F/TAF. CONCLUSION: E/C/F/TAF promotes the accumulation of lipid species closely associated with cardiovascular disease (CVD) risk among people living with HIV, whereas B/F/TAF has a decreased impact on CVD-related lipid profile and is associated with lower CVD risk. A graphical abstract is available with this article. TRIAL REGISTRATION: ClinicalTrials.gov; identifier, NCT06019273.

Broad-spectrum antiviral activity of two structurally analogous CYP3A inhibitors against pathogenic human coronaviruses in vitro.

Coronaviruses pose a permanent risk of outbreaks, with three highly pathogenic species and strains (SARS-CoV, MERS-CoV, SARS-CoV-2) having emerged in the last twenty years. Limited antiviral therapies are currently available and their efficacy in randomized clinical trials enrolling SARS-CoV-2 patients has not been consistent, highlighting the need for more potent treatments. We previously showed that cobicistat, a clinically approved inhibitor of Cytochrome P450-3A (CYP3A), has direct antiviral activity against early circulating SARS-CoV-2 strains in vitro and in Syrian hamsters. Cobicistat is a derivative of ritonavir, which is co-administered as pharmacoenhancer with the SARS-CoV-2 protease inhibitor nirmatrelvir, to inhibit its metabolization by CPY3A and preserve its antiviral efficacy. Here, we used automated image analysis for a screening and parallel comparison of the anti-coronavirus effects of cobicistat and ritonavir. Our data show that both drugs display antiviral activity at low micromolar concentrations against multiple SARS-CoV-2 variants in vitro, including epidemiologically relevant Omicron subvariants. Despite their close structural similarity, we found that cobicistat is more potent than ritonavir, as shown by significantly lower EC50 values in monotherapy and higher levels of viral suppression when used in combination with nirmatrelvir. Finally, we show that the antiviral activity of both cobicistat and ritonavir is maintained against other human coronaviruses, including HCoV-229E and the highly pathogenic MERS-CoV. Overall, our results demonstrate that cobicistat has more potent anti-coronavirus activity than ritonavir and suggest that dose adjustments could pave the way to the use of both drugs as broad-spectrum antivirals against highly pathogenic human coronaviruses.

Synthetic and Clinical Perspectives of Evotaz: An Overview.

Viruses cause a variety of diseases in the human body. Antiviral agents are used to prevent the production of disease-causing viruses. These agents obstruct and kill the virus's translation and replication. Because viruses share the metabolic processes of the majority of host cells, finding targeted medicines for the virus is difficult. In the ongoing search for better antiviral agents, the USFDA approved EVOTAZ, a new drug discovered for the treatment of Human Immunodeficiency Virus (HIV). It is a once-daily (OD) fixed-dose combination of Cobicistat, a cytochrome P450 (CYP) enzyme inhibitor, and Atazanavir, a protease inhibitor. The combination drug was created in such a way that it can inhibit both CYP enzymes and proteases at the same time, resulting in the virus's death. The drug is not effective in children under the age of 18; however, it is still being studied for various parameters. This review article focuses on EVOTAZ's preclinical and clinical aspects, as well as its efficacy and safety profiles.

Serotonin Syndrome Triggered by an Interaction Between Opioid Analgesics and Cobicistat: A Challenging Diagnostic Case Report.

Serotonin syndrome is a clinically diagnosed disorder that may occur secondary to medications that increase the release of endogenous serotonin, impair the reuptake of serotonin from the synaptic cleft, are direct serotonin receptor agonists, or increase the sensitivity of the postsynaptic serotonin receptor. In this case report, we describe the diagnosis of serotonin syndrome in a 60-year-old immunocompromised male. This case is unique, as many of the medications associated with the development of serotonin syndrome in this patient are not typically thought of as being associated with serotonin syndrome, though, in this clinical context, they combined to produce a profound pro-serotonergic effect.

A Randomized Trial of Dolutegravir Plus Darunavir/Cobicistat as a Switch Strategy in HIV-1-Infected Patients With Resistance to at Least 2 Antiretroviral Classes.

Background: Suppressed patients with drug-resistant HIV-1 require effective and simple antiretroviral therapy to maintain treatment adherence and viral suppression. Methods: This randomized, open-label, noninferiority, multicenter pilot study involved HIV-infected adults who met the following criteria: confirmed HIV-1 RNA <50 copies/mL for ≥6 months preceding the study randomization, treatment with at least 3 antiretroviral drugs, and a history of drug resistance mutations against at least 2 antiretroviral classes but remaining fully susceptible to darunavir (DRV) and integrase inhibitors. Participants were randomized 1:1 to switch to dolutegravir (DTG; 50 mg once per day) plus DRV boosted with cobicistat (DRV/c; 800/150 mg once per day; 2D group) or continue with their baseline regimen (standard-of-care [SOC] group). The primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL at week 48 relative to time to loss of virologic response, with a noninferiority margin set at -12.5%. Virologic failure was defined as confirmed HIV-1 RNA ≥50 copies/mL or a single determination of HIV-1 RNA >50 copies/mL followed by antiretroviral therapy discontinuation. Results: Forty-five participants were assigned to the 2D group and 44 to the SOC group. Time to loss of virologic response showed no difference in the proportion maintaining HIV-1 RNA <50 copies/mL at week 48: 39 of 45 (86.7%; 95% CI, 73.21%-94.95%) in the 2D group vs 42 of 44 (95.4%; 95% CI, 84.53%-99.44%) in the SOC group (log-rank P = .159) with an estimated difference of -8.7 (95% CI, -22.72 to 5.14). Only 2 (4.5%) in the SOC group experienced virologic failure, and 3 participants from the 2D group experienced adverse events leading to treatment discontinuation. Conclusions: In suppressed patients with at least 2 resistant antiretroviral classes, noninferiority could not be demonstrated by fully active DRV/c plus DTG. Nevertheless, there were no unexpected adverse events or virologic failure. DRV/c plus DTG may be considered a once-daily therapy option only for well-selected patients. Clinical Trials Registration. ClinicalTrials.gov (NCT03683524).

Pharmacokinetic boosting of olaparib: A randomised, cross-over study (PROACTIVE-study).

BACKGROUND: Pharmacokinetic (PK) boosting is the intentional use of a drug-drug interaction to enhance systemic drug exposure. PK boosting of olaparib, a CYP3A-substrate, has the potential to reduce PK variability and financial burden. The aim of this study was to investigate equivalence of a boosted, reduced dose of olaparib compared to the non-boosted standard dose. METHODS: This cross-over, multicentre trial compared olaparib 300 mg twice daily (BID) with olaparib 100 mg BID boosted with the strong CYP3A-inhibitor cobicistat 150 mg BID. Patients were randomised to the standard therapy followed by the boosted therapy, or vice versa. After seven days of each therapy, dense PK sampling was performed for noncompartmental PK analysis. Equivalence was defined as a 90% Confidence Interval (CI) of the geometric mean ratio (GMR) of the boosted versus standard therapy area under the plasma concentration-time curve (AUC0-12 h) within no-effect boundaries. These boundaries were set at 0.57-1.25, based on previous pharmacokinetic studies with olaparib capsules and tablets. RESULTS: Of 15 included patients, 12 were eligible for PK analysis. The GMR of the AUC0-12 h was 1.45 (90% CI 1.27-1.65). No grade ≥3 adverse events were reported during the study. CONCLUSIONS: Boosting a 100 mg BID olaparib dose with cobicistat increases olaparib exposure 1.45-fold, compared to the standard dose of 300 mg BID. Equivalence of the boosted olaparib was thus not established. Boosting remains a promising strategy to reduce the olaparib dose as cobicistat increases olaparib exposure Adequate tolerability of the boosted therapy with higher exposure should be established.

Switch from a ritonavir to a cobicistat containing antiretroviral regimen and impact on tacrolimus levels in a kidney transplant recipient.

BACKGROUND: Solid-organ transplantation due to end-stage organ disease is increasingly performed in people living with HIV. Despite improved transplant outcomes, management of these patients remains challenging due to higher risk for allograft rejection, infection and drug-drug interactions (DDIs). Complex regimens for multi-drug resistant HIV-viruses may cause DDIs particularly if the regimen contains drugs such as ritonavir or cobicistat. CASE PRESENTATION: Here we report on a case of an HIV-infected renal transplant recipient on long-term immunosuppressive therapy with mycophenolate mofetil and tacrolimus dosed at 0.5 mg every 11 days due to the co-administration of a darunavir/ritonavir containing antiretroviral regimen. In the presented case the pharmacokinetic booster was switched from ritonavir to cobicistat for treatment simplification. A close monitoring of tacrolimus drug levels was performed in order to prevent possible sub- or supratherapeutic tacrolimus trough levels. A progressive decrease in tacrolimus concentrations was observed after switch requiring shortening of tacrolimus dosing interval. This observation was unexpected considering that cobicistat is devoid of inducing properties. CONCLUSIONS: This case highlights the fact that the pharmacokinetic boosters ritonavir and cobicistat are not fully interchangeable. Therapeutic drug monitoring of tacrolimus is warranted to maintain levels within the therapeutic range.

Pharmacokinetic Boosting of Kinase Inhibitors.

(1) Introduction: Pharmacokinetic boosting of kinase inhibitors can be a strategy to enhance drug exposure and to reduce dose and associated treatment costs. Most kinase inhibitors are predominantly metabolized by CYP3A4, enabling boosting using CYP3A4 inhibition. Kinase inhibitors with food enhanced absorption can be boosted using food optimized intake schedules. The aim of this narrative review is to provide answers to the following questions: Which different boosting strategies can be useful in boosting kinase inhibitors? Which kinase inhibitors are potential candidates for either CYP3A4 or food boosting? Which clinical studies on CYP3A4 or food boosting have been published or are ongoing? (2) Methods: PubMed was searched for boosting studies of kinase inhibitors. (3) Results/Discussion: This review describes 13 studies on exposure boosting of kinase inhibitors. Boosting strategies included cobicistat, ritonavir, itraconazole, ketoconazole, posaconazole, grapefruit juice and food. Clinical trial design for conducting pharmacokinetic boosting trials and risk management is discussed. (4) Conclusion: Pharmacokinetic boosting of kinase inhibitors is a promising, rapidly evolving and already partly proven strategy to increase drug exposure and to potentially reduce treatment costs. Therapeutic drug monitoring can be of added value in guiding boosted regimens.

Elabela-apelin-12, 17, 36/APJ system promotes platelet aggregation and thrombosis via activating the PANX1-P2X7 signaling pathway.

The elabela-apelin/angiotensin domain type 1 receptor-associated protein (APJ) system is an important regulator in certain thrombosis-related diseases such as atherosclerosis, myocardial infarction, and cerebral infarction. Our previous reports have revealed that apelin exacerbates atherosclerotic lesions. However, the relationship between the elabela-apelin/APJ system and platelet aggregation and atherothrombosis is unclear. The results of the present study demonstrate that elabela and other endogenous ligands such as apelin-12, -17, and -36 induce platelet aggregation and thrombosis by activating the pannexin1(PANX1)-P2X7 signaling pathway. Interestingly, the diuretic, spironolactone, a novel PANX1 inhibitor, alleviated elabela- and apelin isoforms-induced platelet aggregation and thrombosis. Significantly, two potential antithrombotic drugs were screened out by targeting APJ receptors, including the anti-HIV ancillary drug cobicistat and the traditional Chinese medicine monomer Schisandrin A. Both cobicistat and Schisandrin A abolished the effects of elabela and apelin isoforms on platelet aggregation, thrombosis, and cerebral infarction. In addition, cobicistat significantly attenuated thrombosis in a ponatinib-induced zebrafish trunk model. Overall, the elabela-apelin/APJ axis mediated platelet aggregation and thrombosis via the PANX1-P2X7 signaling pathway in vitro and in vivo. Blocking the APJ receptor with cobicistat/Schisandrin A or inhibiting PANX1 with spironolactone may provide novel therapeutic strategies against thrombosis.

Iatrogenic Cushing's Syndrome: The Result of Cobicistat and Glucocorticoid Interaction in an HIV Patient After Bariatric Surgery.

Cobicistat, used as a pharmacokinetic booster in therapeutic combination with human immunodeficiency virus (HIV) protease inhibitors and integrase inhibitors, is a strong inhibitor of cytochrome P450 3A4 (CYP3A4). Since most glucocorticoids are metabolized by the isoenzyme of the cytochrome P450 pathway, their plasma concentrations can be highly increased in the presence of cobicistat-boosted darunavir, with subsequent risk of iatrogenic Cushing's syndrome (ICS) and secondary adrenal insufficiency. We report a case of a 45-year-old man with HIV-hepatitis C virus co-infection treated with raltegravir and darunavir/cobicistat since 2019. In May 2021, he underwent a sleeve gastrectomy due to morbid obesity (BMI: 50.9 kg/m2) with multiple comorbidities. Four months after surgery, he was diagnosed with asthma and was started on inhaled budesonide, which was later changed to fluticasone propionate. At the 12-month postoperative visit, the patient referred proximal muscle weakness and asthenia, and suboptimal weight loss (excess weight loss of 39%) and high blood pressure were documented. Moon facies, buffalo hump, and abdominal large vinous striae were evident on physical examination. Laboratory studies showed impaired glucose metabolism and hypokalemia. Cushing's syndrome was suspected and further investigation confirmed its iatrogenic origin. The diagnosis of ICS and consequent secondary adrenal insufficiency due to an interaction between the darunavir/cobicistat combination and budesonide/fluticasone was established. Darunavir/cobicistat therapy was replaced by dolutegravir/doravirine dual therapy, inhaled corticoid was switched to beclomethasone, and glucocorticoid substitutive therapy was introduced. This is a particular case of overt ICS due to cobicistat-inhaled corticosteroid interaction in a superobese patient, developed after he underwent bariatric surgery. The presence of morbid obesity, combined with the rarity of this pharmacological complication in individuals taking cobicistat, made the correct diagnosis even more challenging. A meticulous review of pharmacologic habits and potential interactions is essential to avoid serious harm to patients.

Immune recovery among Romanian HIV/AIDS patients receiving darunavir/ritonavir or darunavir/cobicistat regimens in cART management: A three-year study.

Approximately two-thirds of Romanian HIV patients were parenterally infected with the F subtype of HIV in early childhood. They are now in the context of immunological aging, with immunosuppression posing an additional challenge in developing the most effective and well-tolerated regimens. The risk of an improper immune recovery is higher in these patients than in newly diagnosed patients. The primary goal of this retrospective study was to conduct a comparative analysis of the immune recovery, measured at three time points, on 462 HIV-infected patients who were registered at the "Matei Bals National Institute of Infectious Diseases", Bucharest, Romania, between 2018 and 2021, as follows: darunavir (DRV) 600 mg plus ritonavir (RTV) 100 mg (twice daily) was given to 384 patients, while DRV 800 mg plus cobicistat (COBI) 150 mg was given to 78 patients (once daily). The immune response was assessed by counting T lymphocytes, CD4 count cells/mm3, and the CD4/CD8 lymphocyte count ratio. Additionally, the study assessed the relationship between the immune and virological responses to therapy. Using various statistical tests, the results revealed that the immune response is normal in both groups, but with a statistically significant difference (p < 0.05) for the DRV/c group. Statistical associations between RNA viral plasma load and immune response (CD4 count and CD4/CD8 ratio) were assessed at all three visits and showed an insignificant association for the first two time points; however, at the final visit, the outcomes changed and reached statistical significance for both groups.

Pharmacokinetic boosting of osimertinib with cobicistat in patients with non-small cell lung cancer: The OSIBOOST trial.

INTRODUCTION: Exposure to osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for treatment of non-small cell lung cancer (NSCLC) and a sensitizing EGFR mutation, can be substantially below average. We evaluated whether plasma levels could be boosted by co-administration of cobicistat, a strong Cytochrome P450 3A-inhibitor. METHODS: This was a pharmacokinetic, proof-of-concept clinical trial (the OSIBOOST trial, NCT03858491). NSCLC-patients with osimertinib were eligible if their steady state osimertinib plasma trough concentration was low (≤195 ng/mL). On day 1, the area under the plasma curve (AUC0-24,ss) of osimertinib and its metabolite (AZ5104) was calculated using a limited sampling strategy (four samples). Cobicistat co-treatment (150 mg, once daily) was started on day 2. Between day 22-26, a second AUC was determined. Cobicistat dose could be escalated if the osimertinib trough concentration was still ≤ 195 ng/mL, in the absence of toxicity. Primary endpoint was the increase in osimertinib exposure, secondary endpoint was toxicity. Cobicistat could be continued during the expanded access phase, with follow-up (2-4 months) of the boosting effect. RESULTS: The mean baseline osimertinib trough concentration for the eleven enrolled patients was 154 ng/mL. In all patients, cobicistat addition led to an increase in osimertinib exposure. Mean increase in total AUC0-24ss (AUC osimertinib + AUC AZ5104) was 60%, (range 19%-192%). The boosting effect was consistent over time. No grade ≥ 2 toxicity was observed. CONCLUSION: Pharmacokinetic boosting of osimertinib with cobicistat in patients with NSCLC is feasible without increasing toxicity, although the degree of boosting is variable.

Approved HIV reverse transcriptase inhibitors in the past decade.

HIV reverse transcriptase (RT) inhibitors are the important components of highly active antiretroviral therapies (HAARTs) for anti-HIV treatment and pre-exposure prophylaxis in clinical practice. Many RT inhibitors and their combination regimens have been approved in the past ten years, but a review on their drug discovery, pharmacology, and clinical efficacy is lacking. Here, we provide a comprehensive review of RT inhibitors (tenofovir alafenamide, rilpivirine, doravirine, dapivirine, azvudine and elsulfavirine) approved in the past decade, regarding their drug discovery, pharmacology, and clinical efficacy in randomized controlled trials. Novel RT inhibitors such as islatravir, MK-8504, MK-8507, MK8583, IQP-0528, and MIV-150 will be also highlighted. Future development may focus on the new generation of novel antiretroviral inhibitors with higher bioavailability, longer elimination half-life, more favorable side-effect profiles, fewer drug-drug interactions, and higher activities against circulating drug-resistant strains.

SARS-CoV-2 Infection-Of Music and Mechanics of Its Spikes! A Perspective.

The COVID-19 pandemic has been inflicted upon humanity by the SARS-CoV-2 virus, the latest insidious incarnation of the coronaviruses group. While in its wake intense scientific research has produced breakthrough vaccines and cures, there still exists an immediate need to further understand the origin, mechanobiology and biochemistry, and destiny of this virus so that future pandemics arising from similar coronaviruses may be contained more effectively. In this Perspective, we discuss the various evidential findings of virus propagation and connect them to respective underpinning cellular biomechanical states leading to corresponding manifestations of the viral activity. We further propose avenues to tackle the virus, including from a "musical" vantage point, and contain its relentless strides that are currently afflicting the global populace.

Low Incidence and Brief Duration of Gastrointestinal Adverse Events with Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) Over 96 Weeks: Post hoc Analyses of AMBER and EMERALD.

Gastrointestinal intolerance has been associated with ritonavir-boosted protease inhibitors. This post hoc analysis evaluated gastrointestinal adverse events of interest (AEOIs; diarrhea, nausea, abdominal discomfort, flatulence [MedDRAv21]) through Wk96 among patients enrolled in the phase 3 AMBER (treatment-naïve) and EMERALD (virologically suppressed) studies of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg. 362 and 763 patients initiated D/C/F/TAF in AMBER and EMERALD, respectively. All D/C/F/TAF-related gastrointestinal AEOIs were grade 1/2 in severity; none were serious. Across studies, incidence of D/C/F/TAF-related diarrhea and nausea were each ≤5% in Wk1 (≤1% post-Wk2); prevalence of each decreased to <5% post-Wk2. In each study, there was 1 case of D/C/F/TAF-related abdominal discomfort during Wk1 and none thereafter. Incidence of D/C/F/TAF-related flatulence was <1% throughout. Median duration of D/C/F/TAF-related gastrointestinal AEOIs was 16.5 (AMBER) and 8.5 (EMERALD) days. In conclusion, in treatment-naïve and virologically suppressed patients, incidences and prevalences of D/C/F/TAF-related gastrointestinal AEOIs were low and tended to present early.

The FDA-Approved Drug Cobicistat Synergizes with Remdesivir To Inhibit SARS-CoV-2 Replication In Vitro and Decreases Viral Titers and Disease Progression in Syrian Hamsters.

Combinations of direct-acting antivirals are needed to minimize drug resistance mutations and stably suppress replication of RNA viruses. Currently, there are limited therapeutic options against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and testing of a number of drug regimens has led to conflicting results. Here, we show that cobicistat, which is an FDA-approved drug booster that blocks the activity of the drug-metabolizing proteins cytochrome P450-3As (CYP3As) and P-glycoprotein (P-gp), inhibits SARS-CoV-2 replication. Two independent cell-to-cell membrane fusion assays showed that the antiviral effect of cobicistat is exerted through inhibition of spike protein-mediated membrane fusion. In line with this, incubation with low-micromolar concentrations of cobicistat decreased viral replication in three different cell lines including cells of lung and gut origin. When cobicistat was used in combination with remdesivir, a synergistic effect on the inhibition of viral replication was observed in cell lines and in a primary human colon organoid. This was consistent with the effects of cobicistat on two of its known targets, CYP3A4 and P-gp, the silencing of which boosted the in vitro antiviral activity of remdesivir in a cobicistat-like manner. When administered in vivo to Syrian hamsters at a high dose, cobicistat decreased viral load and mitigated clinical progression. These data highlight cobicistat as a therapeutic candidate for treating SARS-CoV-2 infection and as a potential building block of combination therapies for COVID-19. IMPORTANCE The lack of effective antiviral treatments against SARS-CoV-2 is a significant limitation in the fight against the COVID-19 pandemic. Single-drug regimens have so far yielded limited results, indicating that combinations of antivirals might be required, as previously seen for other RNA viruses. Our work introduces the drug booster cobicistat, which is approved by the FDA and typically used to potentiate the effect of anti-HIV protease inhibitors, as a candidate inhibitor of SARS-CoV-2 replication. Beyond its direct activity as an antiviral, we show that cobicistat can enhance the effect of remdesivir, which was one of the first drugs proposed for treatment of SARS-CoV-2. Overall, the dual action of cobicistat as a direct antiviral and a drug booster can provide a new approach to design combination therapies and rescue the activity of compounds that are only partially effective in monotherapy.

Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Versus Dolutegravir/Abacavir/Lamivudine in Antiretroviral-Naive Adults (SYMTRI): A Multicenter Randomized Open-Label Study (PReEC/RIS-57).

BACKGROUND: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) is the reference for combination therapy based on protease inhibitors due to its efficacy, tolerability, and convenience. Head-to-head randomized comparisons between D/C/F/TAF and combination therapy based on integrase inhibitors in antiretroviral-naive patients are lacking. METHODS: Adult (>18 years old) human immunodeficiency virus-infected antiretroviral-naive patients (HLA-B∗5701 negative and hepatitis B virus negative), with viral load (VL) ≥500 c/mL, were centrally randomized to initiate D/C/F/TAF or dolutegravir/abacavir/lamivudine (DTG/3TC/ABC) after stratifying by VL and CD4 count. Clinical and analytical assessments were performed at weeks 0, 4, 12, 24, and 48. The primary endpoint was VL <50 c/mL at week 48 in the intention-to-treat (ITT)-exposed population (US Food and Drug Administration snapshot analysis, 10% noninferiority margin). RESULTS: Between September 2018 and 2019, 316 patients were randomized and 306 patients were included in the ITT-exposed analysis (151 D/C/F/TAF and 155 DTG/3TC/ABC). Almost all (94%) participants were male and their median age was 35 years. Forty percent had a baseline VL >100 000 copies/mL, and 13% had <200 CD4 cells/µL. Median weight was 73 kg and median body mass index was 24 kg/m2. At 48 weeks, 79% (D/C/F/TAF) versus 82% (DTG/3TC/ABC) had VL <50 c/mL (difference, -2.4%; 95% confidence interval [CI], -11.3 to 6.6). Eight percent versus four percent experienced virologic failure but no resistance-associated mutations emerged. Four percent versus six percent had drug discontinuation due to adverse events. In the per-protocol analysis, 94% versus 96% of patients had VL <50 c/mL (difference, -2%; 95% CI, -8.1 to 3.5). There were no differences in CD4 cell count or weight changes. CONCLUSIONS: We could not demonstrate the noninferiority of D/C/F/TAF relative to DTG/ABC/3TC as initial antiretroviral therapy, although both regimens were similarly well tolerated.