Quality assessment of oral antimalarial and antiretroviral medicines used by public health systems in Sahel countries.

Malaria and Human Immunodeficiency Virus infections are among the top 10 causes of death in low income countries. Furthermore, many medicines used in these treatment areas are substandard, which contributes to the high death rate. Using a monitoring system to identify substandard and falsified medicines, the study aims to evaluate the quality of antimalarial and antiretroviral medicines in Sahel countries, assessing site conditions, compliance of medicines with pharmacopoeia tests, formulation equivalence with a reference medicine, and the influence of climate on quality attributes. Ultra Performance Liquid Chromatography methods for eight active pharmaceutical ingredients were validated following the International Conference for Harmonization guideline for its detection and quantification. Quality control consists of visual inspections to detect any misinformation or imperfections and pharmacopeial testing to determine the quality of pharmaceutical products. Medicines which complied with uniformity dosage units and dissolution tests were stored under accelerated conditions for 6 months. Artemether/Lumefantrine and Lopinavir/Ritonavir formulations failed uniformity dosage units and disintegration tests respectively, detecting a total of 28.6% substandard medicines. After 6 months stored under accelerated conditions (40 °C // 75% relative humidity) simulating climatic conditions in Sahel countries, some medicines failed pharmacopeia tests. It demonstrated the influence of these two factors in their quality attributes. This study emphasizes the need of certified quality control laboratories as well as the need for regulatory systems to maintain standards in pharmaceutical manufacturing and distribution in these countries, especially when medicines are transported to rural areas where these climatic conditions are harsher.

Effect of Carbamazepine on Darunavir Trough Concentrations: When the Dose Can Make the Difference-A Case Study.

BACKGROUND: Carbamazepine (CBZ) is an antiseizure medication known to induce the expression of cytochrome P4503A metabolic enzymes. Here, we describe a man living with HIV who underwent several changes in the daily dose of CBZ, which resulted in different induction effects on darunavir trough concentrations. METHODS: A 59-year-old man with HIV, successfully undergoing maintenance antiretroviral treatment with darunavir/cobicistat once daily (combined with raltegravir), was prescribed CBZ for recurrent trigeminal neuralgia. Over subsequent months, the patient underwent various changes in the doses (from 200 to 800 mg/d) and trough concentrations (from 3.6 to 18.0 mg/L) of CBZ, guided by clinical response to trigeminal neuralgia. RESULTS: A highly significant inverse association was observed between darunavir trough concentration and both CBZ dose or trough concentration (coefficient of determination >0.75, P < 0.0001). Ultimately, the darunavir dose was increased to 600 mg twice daily with ritonavir and dolutegravir to ensure optimal antiretroviral coverage, anticipating potential further uptitration of CBZ doses. CONCLUSIONS: The impact of CBZ on boosted darunavir exposure seemed to be dose- and concentration-dependent. The management of such drug-drug interactions in daily practice was facilitated through therapeutic drug monitoring. This case underscores the importance of a multidisciplinary approach that incorporates both antiretroviral and nonantiretroviral comedications contributing to the optimal management of polypharmacy in individuals living with HIV.

Nirmatrelvir/ritonavir treatment of patients with COVID-19 taking tacrolimus: case series describing the results of drug-drug interactions.

Nirmatrelvir/ritonavir is a novel drug combination that is authorized by the Food and Drug Administration for the treatment of coronavirus disease 2019 (COVID-19). Ritonavir is a cytochrome P450 3A inhibitor and a P-glycoprotein inhibitor that increases the plasma concentration of tacrolimus and other medications. We describe the cases of two patients treated with nirmatrelvir/ritonavir: a patient who had undergone kidney transplantation and another with a history of hematopoietic stem cell transplantation. Toxic concentrations of tacrolimus were induced in both. This case series highlights the risk associated with the concomitant administration of tacrolimus and nirmatrelvir/ritonavir.

Clinical effectiveness of nirmatrelvir plus ritonavir on the short- and long-term outcome in high-risk children with COVID-19.

This study investigated the clinical effectiveness of nirmatrelvir plus ritonavir (NMV-r) on short-term outcome and the risk of postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) among pediatric patients with coronavirus disease 2019 (COVID-19). This retrospective cohort study used the TriNetX research network to identify pediatric patients between 12 and 18 years with COVID-19 between January 1, 2022 and August 31, 2023. The propensity score matching (PSM) method was used to match patients receiving NMV-r (NMV-r group) with those who did not receive NMV-r (control group). Two cohorts comprising 633 patients each (NMV-r and control groups), with balanced baseline characteristics, were identified using the PSM method. During the initial 30 days, the NMV-r group showed a lower incidence of all-cause hospitalization, mortality, or ED visits (hazard ratio [HR] = 0.546, 95% confidence interval [CI]: 0.372-0.799, p = 0.002). Additionally, the NMV-r group had a significantly lower risk of all-cause hospitalization compared with the control group (HR = 0.463, 95% CI: 0.269-0.798), with no deaths occurring in either group. In the 30-180-day follow-up period, the NMV-r group exhibited a non-significantly lower incidence of post-acute sequelae of SARS-CoV-2 infection (PASC), encompassing symptoms such as fatigue, cardiopulmonary symptoms, pain, cognitive impairments, headache, dizziness, sleep disorders, anxiety, and depression, compared to the control group. This study underscores the potential effectiveness of NMV-r in treating high-risk pediatric patients with COVID-19, demonstrating significant reductions in short-term adverse outcomes such as emergency department visits, hospitalization, or mortality within the initial 30-day period. Additionally, NMV-r shows promise in potentially preventing the development of PASC.

Effectiveness of Nirmatrelvir-Ritonavir for the Prevention of COVID-19-Related Hospitalization and Mortality: A Systematic Literature Review.

BACKGROUND: Nirmatrelvir/ritonavir (NMV/r) is an oral antiviral drug used to treat mild-to-moderate coronavirus disease 2019 (COVID-19) in patients aged 12 years or older at high risk of progression to severe disease (eg, hospitalization and death). Despite being the preferred option for outpatient treatment in the majority of countries worldwide, NMV/r is currently underutilized in real-world clinical practice. AREAS OF UNCERTAINTY: As numerous real-world studies have described patient outcomes following treatment with NMV/r, this systematic literature review provides a comprehensive summary of evidence on NMV/r effectiveness against hospitalization and mortality further organized by clinically meaningful categories, such as acute versus longer-term follow-up, age, underlying health conditions, and vaccination status, to help inform health care decision making. DATA SOURCES: We searched Embase and PubMed (December 22, 2021-March 31, 2023) and congress abstracts (December 1, 2021-December 31, 2022) for reports describing NMV/r effectiveness. THERAPEUTIC ADVANCES: In total, 18 real-world studies met final selection criteria. The evidence showed that NMV/r significantly reduced postinfection risk of all-cause and COVID-19-related hospitalization and mortality in both acute (≤30 days) (21%-92%) and longer-term (>30 days) (1%-61%) follow-up. The reduction in postinfection risk was higher when treatment was received within 5 days of symptom onset. Real-world effectiveness of NMV/r treatment was observed regardless of age, underlying high-risk conditions, and vaccination status. CONCLUSION: The systematic literature review findings demonstrated the effectiveness of NMV/r against hospitalization and mortality during the Omicron period among individuals at high risk of progression to severe COVID-19 disease.

In-vitro and in-vivo assessment of nirmatrelvir penetration into CSF, central nervous system cells, tissues, and peripheral blood mononuclear cells.

Three years after SARS-CoV-2 emerged as a global infectious threat, the virus has become endemic. The neurological complications such as depression, anxiety, and other CNS complications after COVID-19 disease are increasing. The brain, and CSF have been shown as viral reservoirs for SARS-CoV-2, yielding a potential hypothesis for CNS effects. Thus, we investigated the CNS pharmacology of orally dosed nirmatrelvir/ritonavir (NMR/RTV). Using both an in vitro and an in vivo rodent model, we investigated CNS penetration and potential pharmacodynamic activity of NMR. Through pharmacokinetic modeling, we estimated the median CSF penetration of NMR to be low at 18.11% of plasma with very low accumulation in rodent brain tissue. Based on the multiples of the 90% maximal effective concentration (EC90) for SARS-CoV-2, NMR concentrations in the CSF and brain do not achieve an exposure level similar to that of plasma. A median of only 16% of all the predicted CSF concentrations in rats were > 3xEC90 (unadjusted for protein binding). This may have implications for viral persistence and neurologic post-acute sequelae of COVID-19 if increased NMR penetration in the CNS leads to decreased CNS viral loads and decreased CNS inflammation.

Clinical assessment of momelotinib drug-drug interactions via CYP3A metabolism and transporters.

Momelotinib-approved for treatment of myelofibrosis in adults with anemia-and its major active metabolite, M21, were assessed as drug-drug interaction (DDI) victims with a strong cytochrome P450 (CYP) 3A4 inhibitor (multiple-dose ritonavir), an organic anion transporting polypeptide (OATP) 1B1/1B3 inhibitor (single-dose rifampin), and a strong CYP3A4 inducer (multiple-dose rifampin). Momelotinib DDI perpetrator potential (multiple-dose) was evaluated with CYP3A4 and breast cancer resistance protein (BCRP) substrates (midazolam and rosuvastatin, respectively). DDI was assessed from changes in maximum plasma concentration (Cmax), area under the concentration-time curve (AUC), time to reach Cmax, and half-life. The increase in momelotinib (23% Cmax, 14% AUC) or M21 (30% Cmax, 24% AUC) exposure with ritonavir coadministration was not clinically relevant. A moderate increase in momelotinib (40% Cmax, 57% AUC) and minimal change in M21 was observed with single-dose rifampin. A moderate decrease in momelotinib (29% Cmax, 46% AUC) and increase in M21 (31% Cmax, 15% AUC) were observed with multiple-dose rifampin compared with single-dose rifampin. Due to potentially counteracting effects of OATP1B1/1B3 inhibition and CYP3A4 induction, multiple-dose rifampin did not significantly change momelotinib pharmacokinetics compared with momelotinib alone (Cmax no change, 15% AUC decrease). Momelotinib did not alter the pharmacokinetics of midazolam (8% Cmax, 16% AUC decreases) or 1'-hydroxymidazolam (14% Cmax, 16% AUC decreases) but increased rosuvastatin Cmax by 220% and AUC by 170%. Safety findings were mild in this short-term study in healthy volunteers. This analysis suggests that momelotinib interactions with OATP1B1/1B3 inhibitors and BCRP substrates may warrant monitoring for adverse reactions or dose adjustments.

Proof-of-concept studies with a computationally designed Mpro inhibitor as a synergistic combination regimen alternative to Paxlovid.

As the SARS-CoV-2 virus continues to spread and mutate, it remains important to focus not only on preventing spread through vaccination but also on treating infection with direct-acting antivirals (DAA). The approval of Paxlovid, a SARS-CoV-2 main protease (Mpro) DAA, has been significant for treatment of patients. A limitation of this DAA, however, is that the antiviral component, nirmatrelvir, is rapidly metabolized and requires inclusion of a CYP450 3A4 metabolic inhibitor, ritonavir, to boost levels of the active drug. Serious drug-drug interactions can occur with Paxlovid for patients who are also taking other medications metabolized by CYP4503A4, particularly transplant or otherwise immunocompromised patients who are most at risk for SARS-CoV-2 infection and the development of severe symptoms. Developing an alternative antiviral with improved pharmacological properties is critical for treatment of these patients. By using a computational and structure-guided approach, we were able to optimize a 100 to 250 µM screening hit to a potent nanomolar inhibitor and lead compound, Mpro61. In this study, we further evaluate Mpro61 as a lead compound, starting with examination of its mode of binding to SARS-CoV-2 Mpro. In vitro pharmacological profiling established a lack of off-target effects, particularly CYP450 3A4 inhibition, as well as potential for synergy with the currently approved alternate antiviral, molnupiravir. Development and subsequent testing of a capsule formulation for oral dosing of Mpro61 in B6-K18-hACE2 mice demonstrated favorable pharmacological properties, efficacy, and synergy with molnupiravir, and complete recovery from subsequent challenge by SARS-CoV-2, establishing Mpro61 as a promising potential preclinical candidate.

Effectiveness of nirmatrelvir-ritonavir versus azvudine for adult inpatients with severe or critical COVID-19.

BACKGROUND: In China, both nirmatrelvir-ritonavir (Paxlovid) and azvudine have been granted approval to treat adult SARS-CoV-2-infected patients with moderate symptoms. Information about the clinical effect of the two available agents among inpatients with severe or critical COVID-19 is scarce. PURPOSE: To compare the clinical outcomes of Paxlovid and azvudine among adult inpatients with severe or critical COVID-19. METHOD: We conducted a retrospective cohort study in two large medical centres after the epidemic control measures were lifted in China. A new propensity score matched-inverse probability of treatment weighting cohort was constructed to evaluate the in-hospital all-cause mortality, hospital length of stay, Sequential Organ Failure Assessment (SOFA) score and safety. RESULTS: A total of 955 individuals were in the cohort. The antiviral therapy strategies were decided by the senior physician and the supplies of the pharmacy. A total of 451 patients were in the Paxlovid group, and 504 patients were in the azvudine group. Compared with Paxlovid, the effects of azvudine on in-hospital all-cause mortality were not significantly different, and the OR (95% CI) was 1.084 (0.822 to 1.430), and the average hospital length of stay of patients discharged alive was also similar in the azvudine group, and the difference (day) and (95% CI) was 0.530 (-0.334 to 1.393). After 7 days of therapy, the degree of decline in the SOFA score was greater in the Paxlovid group than in the azvudine group (p<0.001). The change in glomerular filtration rate was not significantly different (p=0.824). CONCLUSION: Paxlovid and azvudine had similar effectiveness on in-hospital all-cause mortality and hospital length of stay. Compared with the azvudine group, after 7 days of therapy, the degree of decline in SOFA score was significantly higher in the Paxlovid group. These findings need to be verified in larger prospective studies or randomised controlled trials.

Nirmatrelvir and ritonavir combination against COVID-19 caused by omicron BA.2.2 in the elderly: A single-center large observational study.

BACKGROUND: Since coronavirus 2019 (COVID-19) swept the world, a variety of novel therapeutic and prevention strategies have been developed, among which nirmatrelvir-ritonavir is highly recommended. We intended to assess the effectiveness and safety of nirmatrelvir-ritonavir in the elderly mild-to-moderate COVID-19 population caused by the omicron BA.2.2 variant in real-world settings. METHODS: An observational study was conducted retrospectively to review the outcomes of mild-to-moderate COVID-19 patients admitted between April 26 and June 30, 2022. Patients' baseline characteristics were collected and assessed. Participants in the intervention group were administered nirmatrelvir-ritonavir in addition to standard care, whereas those in the control group only received standard care. The primary outcome was the duration between the initial positive reverse-transcription polymerase chain reaction (RT-PCR) test and the subsequent conversion to a negative result. RESULTS: The analysis included 324 patients who were administered nirmatrelvir-ritonavir and an equal number of control patients. The patient characteristics in both groups were evenly matched. The average duration from the initial positive RT-PCR to negative conversion was similar in both groups (16.2 ± 5.0 vs. 16.1 ± 6.3 days, p = .83). Control patients exhibited slower conversion in comparison to patients who received nirmatrelvir-ritonavir treatment within 10 days of symptom onset. CONCLUSIONS: These findings suggest that administering nirmatrelvir-ritonavir within 10 days of symptom onset could potentially reduce the time it takes for SARS-CoV-2-infected patients to negative RT-PCR results, thereby expanding the current usage guidelines for nirmatrelvir-ritonavir.

Adaptative Strategy of Immunosuppressive Drugs Dosage Adjustments When Combined With Nirmatrelvir/Ritonavir in Solid Organ Transplant Recipients With COVID-19.

Nirmatrelvir/ritonavir is a promising option for preventing severe COVID-19 in solid organ transplant recipients with SARS-CoV-2 infection. However, concerns have arisen regarding potential drug interactions with calcineurin inhibitors (CNI). This two-phase multicentre retrospective study, involving 113 patients on tacrolimus and 13 on cyclosporine A, aimed to assess the feasibility and outcomes of recommendations issued by The French societies of transplantation (SFT) and pharmacology (SFPT) for CNI management in this context. The study first evaluated adherence to recommendations, CNI exposure, and clinical outcomes. Notably, 96.5% of patients on tacrolimus adhered to the recommendations, maintaining stable tacrolimus trough concentrations (C0) during nirmatrelvir/ritonavir treatment. After reintroduction, most patients experienced increased C0, with 42.9% surpassing 15 ng/mL, including three patients exceeding 40 ng/mL. Similar trends were observed in cyclosporine A patients, with no COVID-19-related hospitalizations. Moreover, data from 22 patients were used to refine the reintroduction strategy. Modelling analyses suggested reintroducing tacrolimus at 50% of the initial dose on day 8, and then at 100% from day 9 as the optimal approach. In conclusion, the current strategy effectively maintains consistent tacrolimus exposure during nirmatrelvir/ritonavir treatment, and a stepwise reintroduction of tacrolimus may be better suited to the low CYP3A recovery.

A validated method for simultaneous quantification of four antiretrovirals in dried blood spot and plasma using LC-MS/MS: Application to efavirenz therapeutic drug monitoring in pregnant patients.

INTRODUCTION: The specific physiological background induced by pregnancy leads to significant changes in maternal pharmacokinetics, suggesting potential variability in plasma concentrations of antiretrovirals. Pregnant HIV patients exposed to subtherapeutic doses, particularly in the last trimester of the pregnancy, have higher chances to transmit the infection to their children. Therefore, the therapeutic drug monitoring of antiretrovirals in HIV pregnant patients would be of great value. OBJECTIVES: This study aimed to develop and validate a sensitive liquid chromatograph tandem mass spectrometry (LC-MS/MS) method for simultaneous quantification of efavirenz, raltegravir, atazanavir, and ritonavir in dried blood spots (DBS) and plasma. DESIGN AND METHODS: The analytes were extracted from the DBS punch and plasma with a mixture of methanol:zinc sulfate 200 mM (50:50, v/v) and 100 % methanol, respectively. For the chromatographic separation a Shim-pack® C18, 4.6 mm × 150 mm, 5 µm column was used. Detection was performed in a 3200-QTRAP® mass spectrometer, with a run time of 6 min. RESULTS: The assay was linear in the range of 15-1,000 ng/mL for raltegravir, 50-10,000 ng/mL for both atazanavir and ritonavir, 50-5,000 ng/mL for efavirenz. Precision and accuracy at these concentrations were less than 15 % for all analytes. Raltegravir, atazanavir, and ritonavir were stable for seven days at 23 °C and 40 °C, whereas efavirenz was stable for twenty-four hours at the same conditions. CONCLUSIONS: The method was successfully applied to quantify efavirenz in DBS samples obtained from HIV-1 infected pregnant volunteers under antiretroviral therapy. The concentrations of efavirenz in DBS and plasma were comparable according to Passing-Bablok regression and Bland-Altman analysis.

Joint analysis of vaccination effectiveness and antiviral drug effectiveness for COVID-19: a causal inference approach.

OBJECTIVES: This study aims to estimate the causal effects of oral antivirals and vaccinations in the prevention of all-cause mortality and progression to severe COVID-19 in an integrative setting with both antivirals and vaccinations considered as interventions. METHODS: We identified hospitalized adult patients (i.e. aged 18 or above) in Hong Kong with confirmed SARS-CoV-2 infection between March 16, 2022, and December 31, 2022. An inverse probability-weighted (IPW) Andersen-Gill model with time-dependent predictors was used to address immortal time bias and produce causal estimates for the protection effects of oral antivirals and vaccinations against severe COVID-19. RESULTS: Given prescription is made within 5 days of confirmed infection, nirmatrelvir-ritonavir is more effective in providing protection against all-cause mortality and development into severe COVID-19 than molnupiravir. There was no significant difference between CoronaVac and Comirnaty in the effectiveness of reducing all-cause mortality and progression to severe COVID-19. CONCLUSIONS: The use of oral antivirals and vaccinations causes lower risks of all-cause mortality and progression to severe COVID-19 for hospitalized SARS-CoV-2 patients.

COVID-19 Rebound After VV116 vs Nirmatrelvir-Ritonavir Treatment: A Randomized Clinical Trial.

Importance: With the widespread use of anti-SARS-CoV-2 drugs, accumulating data have revealed potential viral load rebound after treatment. Objective: To compare COVID-19 rebound after a standard 5-day course of antiviral treatment with VV116 vs nirmatrelvir-ritonavir. Design, Setting, and Participants: This is a single-center, investigator-blinded, randomized clinical trial conducted in Shanghai, China. Adult patients with mild-to-moderate COVID-19 and within 5 days of SARS-CoV-2 infection were enrolled between December 20, 2022, and January 19, 2023, and randomly allocated to receive either VV116 or nirmatrelvir-ritonavir. Interventions: Participants in the VV116 treatment group received oral 600-mg VV116 tablets every 12 hours on day 1 and 300 mg every 12 hours on days 2 through 5. Participants in the nirmatrelvir-ritonavir treatment group received oral nirmatrelvir-ritonavir tablets with 300 mg of nirmatrelvir plus 100 mg of ritonavir every 12 hours for 5 days. Participants were followed up every other day until day 28 and every week until day 60. Main Outcomes and Measures: The primary outcome was viral load rebound (VLR), defined as a half-log increase in viral RNA copies per milliliter compared with treatment completion. Secondary outcomes included a reduction in the cycle threshold value of 1.5 or more, time until VLR, and symptom rebound, defined as an increase of more than 2 points in symptom score compared with treatment completion. The primary outcome and secondary outcomes were analyzed using the full analysis set. Sensitivity analyses were conducted using the per protocol set. Adverse events were analyzed using the safety analysis set. Results: The full analysis set included 345 participants (mean [SD] age, 53.2 [16.8] years; 175 [50.7%] were men) who received VV116 (n = 165) or nirmatrelvir-ritonavir (n = 180). Viral load rebound occurred in 33 patients (20.0%) in the VV116 group and 39 patients (21.7%) in the nirmatrelvir-ritonavir group (P = .70). Symptom rebound occurred in 41 of 160 patients (25.6%) in the VV116 group and 40 of 163 patients (24.5%) in the nirmatrelvir-ritonavir group (P = .82). Viral whole-genome sequencing of 24 rebound cases revealed the same lineage at baseline and at viral load rebound in each case. Conclusions and Relevance: In this randomized clinical trial of patients with mild-to-moderate COVID-19, viral load rebound and symptom rebound were both common after a standard 5-day course of treatment with either VV116 or nirmatrelvir-ritonavir. Prolongation of treatment duration might be investigated to reduce COVID-19 rebound. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2200066811.

Paxlovid use is associated with lower risk of cardiovascular diseases in COVID-19 patients with autoimmune rheumatic diseases: a retrospective cohort study.

BACKGROUND: Paxlovid has been shown to be effective in reducing mortality and hospitalization rates in patients with coronavirus disease 2019 (COVID-19). It is not known whether Paxlovid can reduce the risk of cardiovascular diseases (CVD) in COVID-19-surviving patients with autoimmune rheumatic diseases (AIRDs). METHODS: TriNetX data from the US Collaborative Network were used in this study. A total of 5,671,395 patients with AIRDs were enrolled between January 1, 2010, and December 31, 2021. People diagnosed with COVID-19 were included in the cohort (n = 238,142) from January 1, 2022, to December 31, 2022. The Study population was divided into two groups based on Paxlovid use. Propensity score matching was used to generate groups with matched baseline characteristics. The hazard ratios (HRs) and 95% confidence intervals of cardiovascular outcomes, admission rate, mortality rate, and intensive care unit (ICU) admission rate were calculated between Paxlovid and non-Paxlovid groups. Subgroup analyses on sex, age, race, autoimmune diseases group, and sensitivity analyses for Paxlovid use within the first day or within 2-5 days of COVID-19 diagnosis were performed. RESULTS: Paxlovid use was associated with lower risks of cerebrovascular complications (HR = 0.65 [0.47-0.88]), arrhythmia outcomes (HR = 0.81 [0.68-0.94]), ischemic heart disease, other cardiac disorders (HR = 0.51 [0.35-0.74]) naming heart failure (HR = 0.41 [0.26-0.63]) and deep vein thrombosis (HR = 0.46 [0.24-0.87]) belonging to thrombotic disorders in AIRD patients with COVID-19. Compared with the Non-Paxlovid group, risks of major adverse cardiac events (HR = 0.56 [0.44-0.70]) and any cardiovascular outcome mentioned above (HR = 0.76 [0.66-0.86]) were lower in the Paxlovid group. Moreover, the mortality (HR = 0.21 [0.11-0.40]), admission (HR = 0.68 [0.60-0.76]), and ICU admission rates (HR = 0.52 [0.33-0.80]) were significantly lower in the Paxlovid group than in the non-Paxlovid group. Paxlovid appears to be more effective in male, older, and Black patients with AIRD. The risks of cardiovascular outcomes and severe conditions were reduced significantly with Paxlovid prescribed within the first day of COVID-19 diagnosis. CONCLUSIONS: Paxlovid use is associated with a lower risk of CVDs and severe conditions in COVID-19-surviving patients with AIRD.

A global phase II randomized trial comparing oral taxane ModraDoc006/r to intravenous docetaxel in metastatic castration resistant prostate cancer.

STUDY AIM: ModraDoc006, an oral formulation of docetaxel, is co-administered with the cytochrome P450-3A4 and P-glycoprotein inhibitor, ritonavir (r): ModraDoc006/r. The preliminary efficacy and safety of oral ModraDoc006/r was evaluated in a global randomized phase II trial and compared to the current standard chemotherapy regimen of intravenous (i.v.) docetaxel and prednisone. METHODS: 103 mCRPC patients, chemotherapy-naïve with/without abiraterone and/or enzalutamide pretreated, with adequate organ function and evaluable disease per RECIST v1.1 and PCWG3 guidelines were randomized 1:1 into two cohorts. In Cohort 1, 49 patients received docetaxel 75 mg/m2 i.v. every 3 weeks (Q3W). In Cohort 2, 52 patients received ModraDoc006/r; 21 patients with a starting dose of ModraDoc006 30 mg with ritonavir 200 mg in the morning and ModraDoc006 20 mg with ritonavir 100 mg in the evening (30-20/200-100 mg) bi-daily-once-weekly (BIDW) on Days 1, 8, and 15 of a 21-day cycle. To alleviate tolerability, the starting dose was amended to ModraDoc006/r 20-20/200-100 mg in another 31 patients. All patients received prednisone 10 mg daily. Primary endpoint was rPFS. RESULTS: There was no significant difference in rPFS between the 2 arms (p = 0.1465). Median rPFS was 9.5 months and 11.1 months (95% CI) for ModraDoc006/r and i.v. docetaxel, respectively. Partial response was noted in 44.1% and 38.7% measurable disease patients, and 50% decline of PSA was seen in 23 (50%) and 26 (56.5%) evaluable cases treated with ModraDoc006/r and i.v. docetaxel, respectively. The safety profile of ModraDoc006/r 20-20/200-100 mg dose was significantly better than i.v. docetaxel, with mild (mostly Grade 1) gastrointestinal toxicities, no hematologic adverse events, and neuropathy and alopecia incidence of 11.5% and 25%, respectively. CONCLUSIONS: ModraDoc006/r potentially represents a widely applicable, convenient, effective, and better tolerated oral taxane therapy option for mCRPC. Further investigation of ModraDoc006/r in a large randomized trial is warranted.

Drugs and natural products for the treatment of COVID-19 during 2020, the first year of the pandemic.

This work aimed to show which treatments showed efficacy against coronavirus disease 2019 (COVID-19); therefore, the results of 37 clinical trials started in 2020 and completed in 2021 are reviewed and discussed here. These were selected from databases, excluding vaccines, computational studies, in silico, in vitro, and those with hyperimmune sera from recovered patients. We found 34 drugs, one vitamin, and one herbal remedy with pharmacological activity against symptomatic COVID-19. They reduced mortality, disease progression, or recovery time. For each treatment, the identifier and type of trial, the severity of the disease, the sponsor, the country where the trial was conducted, and the trial results are presented. The drugs were classified according to their mechanism of action. Several drugs that reduced mortality also reduced inflammation in the most severe cases. These include some that are not considered anti-inflammatory, such as Aviptadil, pyridostigmine bromide, anakinra, imatinib, baricitinib, and bevacizumab, as well as the combination of ivermectin, aspirin, dexamethasone, and enoxaparin. Nigella sativa seeds with honey have also been reported to have therapeutic activity. On the other hand, tofacitinib, novaferon with ritonavir, and lopinavir were also effective, as well as in combination with antiviral therapies such as danoprevir with ritonavir. The natural products colchicine and Vitamin D3 were only effective in patients with mild-to-moderate COVID-19, as was hydroxychloroquine. Drug repositioning has been the main tool in the search for effective therapies by expanding the pharmacological options available to patients.

El objetivo del presente trabajo fue conocer qué tratamientos mostraron efectividad contra COVID-19, para lo cual se revisan y discuten los resultados de 37 estudios clínicos iniciados durante 2020 y concluidos en 2021. Estos fueron seleccionados de bases de datos, excluyendo vacunas, estudios computacionales, in silico, in vitro y con sueros hiperinmunes de pacientes recuperados. Se documentaron 34 fármacos, una vitamina y un remedio herbolario, con actividad farmacológica ante COVID-19 sintomático. Estos redujeron la mortalidad, el progreso de la enfermedad, o el tiempo de recuperación. Para cada tratamiento se presenta identificador y tipo de estudio, la gravedad de la enfermedad, patrocinador, país donde se realizó, así como sus resultados. Los fármacos se clasificaron de acuerdo con su mecanismo de acción. Varios fármacos que redujeron la mortalidad también disminuyeron la inflamación en los casos más graves. Esto incluyendo algunos no considerados antiinflamatorios, como el aviptadil, el bromuro de piridostigmina, el anakinra, el imatinib, el baricitinib y el bevacizumab, así como la combinación de ivermectina, aspirina, dexametasona y enoxaparina. También se reportaron con actividad terapéutica las semillas de Nigella sativa con miel. Además, resultaron efectivos el tofacitinib, el novaferón con ritonavir y lopinavir, así como los antivirales en terapias combinadas como el danoprevir con ritonavir. Los productos naturales colchicina y vitamina D3, solo tuvieron actividad en los pacientes en estado leve a moderado de la COVID-19, así como la hidroxicloroquina. El reposicionamiento de fármacos fue la principal herramienta para buscar terapias efectivas ampliando las opciones farmacológicas accesibles a los pacientes.

The host-targeted antiviral drug Zapnometinib exhibits a high barrier to the development of SARS-CoV-2 resistance.

Host targeting antiviral drugs (HTA) are directed against cellular mechanisms which can be exploited by viruses. These mechanisms are essential for viral replication, because missing functions cannot be compensated by the virus. However, this assumption needs experimental proof. Here we compared the HTA Zapnometinib (ZMN), with direct acting antivirals (DAA) (Remdesivir (RDV), Molnupiravir (MPV), Nirmatrelvir (NTV), Ritonavir (RTV), Paxlovid PAX)), in terms of their potency to induce reduced drug susceptibilities in SARS-CoV-2. During serial passage of δ-B1.617.2 adaptation to all DAAs occurred, while the inhibitory capacity of ZMN was not altered. Known single nucleotide polymorphisms (SNPs) responsible for partial resistances were found for RDV, NTV and PAX. Additionally, the high mutagenic potential of MPV was confirmed and decreased drug efficacies were found for the first time. Reduced DAA efficacy did not alter the inhibitory potential of ZMN. These results show that ZMN confers a high barrier towards the development of viral resistance and has the potential to act against partially DAA-insensitive viruses.

A combination of nirmatrelvir and ombitasvir boosts inhibition of SARS-CoV-2 replication.

Antiviral therapeutics are highly effective countermeasures for the treatment of coronavirus disease 2019 (COVID-19). However, development of resistance to antivirals undermines their effectiveness. Combining multiple antivirals during patient treatment has the potential to overcome the evolutionary selective pressure towards antiviral resistance, as well as provide a more robust and efficacious treatment option. The current evidence for effective antiviral combinations to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication is limited. Here, we demonstrate a combination of nirmatrelvir with ombitasvir, to jointly bring about potent inhibition of SARS-CoV-2 replication. We developed an in vitro 384- well plate cytopathic effect assay for the evaluation of antiviral combinations against Calu-3 cells infected with SARS-CoV-2 and found, that a combination of ombitasvir and nirmatrelvir was synergistic; thereby decreasing the nirmatrelvir IC50 by approx. 16-fold. The increased potency of the nirmatrelvir-ombitasvir combination, over nirmatrelvir alone afforded a greater than 3 log10 reduction in viral titre, which is sufficient to fully prevent the detection of progeny SARS-CoV-2 viral particles at 48 h post infection. The mechanism of this potentiated effect was shown to be, in-part, due to joint inhibition of the 3-chymotrypsin-like protease via a positive allosteric modulation mechanism.