Optimizing Antiviral Therapy for COVID-19 With Learned Pathogenic Model

COVID-19 together with variants have caused an unprecedented amount of mental and economic turmoil with ever increasing fatality and no proven therapies in sight. The healthcare industry is racing to find a cure with multitude of clinical trials underway to access the efficacy of repurposed antivirals, however the much needed insights into the dynamics of pathogenesis of SARS-CoV-2 and corresponding pharmacology of antivirals are lacking. This paper introduces systematic pathological model learning of COVID-19 dynamics followed by derivative free optimization based multi objective drug rescheduling. The pathological model learnt from clinical data of severe COVID-19 patients treated with Remdesivir could additionally predict immune T cells response and resulted in a dramatic reduction in Remdesivir dose and schedule leading to lower toxicities, however maintaining a high virological efficacy.

Letermovir for the compassionate therapeutic use of cytomegalovirus infection

Purpose Data on the efficacy, dosing and safety of letermovir for the compassionate therapeutic use of CMV infections are limited. Methods Clinical and virological efficacy of letermovir was assessed in a retrospective single-centre study of patients who received letermovir for the compassionate therapeutic use of CMV infections. Results Letermovir initiation yielded prompt treatment response in 7 out of 9 patients (77.7%). Conclusion Letermovir may be an effective and well tolerated option in the compassionate treatment of CMV infections, although recurrence of CMV and emergence of resistance may be issues.

Rilpivirine plus cobicistat-boosted darunavir as a two-drug switch regimen in HIV-infected, virologically suppressed subjects on steady standard three-drug therapy: a randomized, controlled, non-inferiority trial (PROBE 2)

Background We explored the combination of rilpivirine plus cobicistat-boosted darunavir [a two-drug regimen (2DR)] when switching from standard triple combined ART. Methods In this randomized, open-label, non-inferiority trial, participants had an HIV-RNA <50 copies/mL on a stable (>6 months) three-drug regimen. The primary endpoint was proportion with HIV-RNA <50 copies/mL at Week 24 (snapshot algorithm), with a –12% non-inferiority margin. ClinicalTrials.gov: NCT04064632. Results One hundred and sixty patients were allocated (1:1) to 2DR or to continue current ART (CAR). At Week 24, 72 (90.0%) of participants with 2DR and 75 (93.8%) with CAR maintained HIV-RNA <50 copies/mL [difference −3.75% (95% CI = −11.63 to 5.63)], confirming non-inferiority. Non-inferiority was confirmed considering an HIV-RNA >50 copies/mL (0% for 2DR; 3.7% for CAR; 95% CI = −0.4 to 7.9). Four patients reported adverse events not leading to treatment discontinuation (one patient in the 2DR group and three patients in the CAR group); eight subjects discontinued therapy in the 2DR group and three in the CAR group. With 2DR, lipid serum concentrations increased, but differences were statistically significant only for tenofovir disoproxil fumarate-containing CAR and in 2DR patients receiving a pre-switch regimen including tenofovir disoproxil fumarate. Median bone stiffness decreased in the CAR group from 86.1 g/cm2 (IQR = 74–98) to 83.2 g/cm2 (IQR = 74–97) and increased in the 2DR group from 84.9 g/cm2 (IQR = 74–103) to 85.5 g/cm2 (IQR = 74–101). The reduction within the CAR group was significant (P = 0.043). Conclusions Once-daily rilpivirine plus cobicistat-boosted darunavir is an effective 2DR that combines a high virological efficacy with a potential to avoid major NRTI toxicities.

Efficacy of intermittent short cycles of integrase inhibitor-based maintenance ART in virologically suppressed HIV patients

Background Several studies have shown that NNRTI/PI-based triple therapy could be safely administered as a 4 days (4D) or 5 days (5D) a week maintenance strategy. We report here our experience of using an integrase inhibitor (INSTI)-based 4D/5D regimen in virologically suppressed HIV patients. Methods This cohort study enrolled adult patients on ART with viral load (VL) <50 copies/mL for >1 year, who switched to an INSTI-based triple regimen given 4D/5D a week. The primary endpoint was the virological efficacy rate at Week (W) 48, with virological failure defined as confirmed VL ≥50 copies/mL. Results A total of 73 patients were included (n = 28 for 4D, n = 45 for 5D): 54 men (74%), median (IQR) age 51 (45–57) years, ART duration 10 (6–18) years and duration of viral suppression 5 (2–9) years at baseline. As of 25 March 2019, the median follow-up was 21 (14–35) months, with a total of 161 patient-years of follow-up; all patients had reached the W24 visit, 66 (90%) W48 and 34 (47%) W96. Four patients discontinued the strategy: virological failure (n = 2) at W60 and W67, respectively, switch for renal toxicity (n = 1) at W28 and switch to rilpivirine/dolutegravir (n = 1) at W65. Overall the rate of virological success (95% CI) was 100% (94%–100%) at W24 and W48 and 93.7% (79.8%–98.2%) at W96. Conclusions While waiting for the final results of the large randomized QUATUOR ANRS-170 study, our real-life results suggest that the use of an intermittent maintenance triple-drug regimen given as a weekend (2 or 3 days) off is as effective with an INSTI-based regimen as with a PI or an NNRTI.

Cohort profile: The Observational cohort for the study of DOlutegravir in Antiretroviral Combination REgimens (ODOACRE)

PurposeThe Observational cohort for the study of DOlutegravir in Antiretroviral Combination REgimens (ODOACRE) cohort was established in Italy in 2016 to evaluate the overall efficacy and tolerability of dolutegravir (DTG)-based antiretroviral (ARV) regimens in clinical practice.ParticipantsThe ODOACRE cohort enrols all adult HIV-1-infected patients, both treatment-naïve and treatment-experienced, starting a DTG-based ARV regimen, in 11 clinical centres in Italy from 2014.Findings to dateIn recent years, various works by the ODOACRE cohort have been produced, demonstrating the high efficacy and tolerability of DTG-based ARV regimens in clinical practice, both in ART-naïve (in the setting of acute HIV-1 infection and late presenters patient) and experienced patients. We confirmed the virological efficacy of DTG-based regimens and we evaluated predictors of virological failure. We investigated cause of discontinuation and evaluated tolerability and metabolic profile of the regimens. Within these investigations, we explored particularly the use of DTG in simplification in two-drug regimen with either rilpivirine or lamivudine. We also compared DTG-based regimens with other integrase inhibitors in clinical practice.Future plansTo continue to study long-term efficacy and tolerability of DTG-based regimens is the purpose of the ODOACRE cohort.