BACKGROUND: Coronavirus disease 2019 (COVID-19) is a respiratory virus that has afflicted millions of individuals in the United States. A few medications have been determined to be beneficial for outpatient treatment. The medications in use against mild-to-moderate COVID-19 in the outpatient setting during the study period are nirmatrelvir-ritonavir, remdesivir, molnupiravir, and bebtelovimab. Proper assessment and treatment of patients with mild-to-moderate COVID-19 in the outpatient setting is critical to reducing rates of disease progression and hospitalization.
OBJECTIVE: This study aimed to evaluate the appropriateness of the prescribing by internal medicine physicians for mild-to-moderate Coronavirus disease 2019 (COVID-19) infections based on the National Institutes of Health (NIH) guideline-directed COVID-19 outpatient treatment options.
METHODS: This is a retrospective chart review examining the outpatient treatment of mild-to-moderate COVID-19 by internal medicine physicians between February 2022 and August 2022. Patients were eligible if they were 18 years or older, had a positive home or polymerase chain reaction (PCR) test, completed a telehealth visit within 7 days of the positive test, and were prescribed either nirmatrelvir-ritonavir, remdesivir, molnupiravir, or bebtelovimab for COVID-19 treatment. The primary end point was the appropriateness of COVID-19 treatment in the outpatient setting based on NIH guidelines, patient characteristics, and prescribing information for the medications. The secondary end point was hospitalization within 30 days of initiation of outpatient COVID-19 treatment. The presence or absence of a clinical pharmacist consultation at the time of prescribing was recorded as a process measure.
RESULTS: A total of 376 encounters were assessed, of which 226 were included and analyzed. A total of 210 participants (93%) received nirmatrelvir-ritonavir. The remaining participants received molnupiravir or bebtelovimab. Overall, guideline-concordant treatment for mild-to-moderate COVID-19 was prescribed for 200 participants (88%). Among patient characteristics, only glomerular filtration rate (GFR) had a statistically significant difference between groups prescribed medication for the treatment of mild-to-moderate COVID-19. Fifty-six participants (25%) received clinical pharmacist consultation. Three participants were hospitalized for COVID-19 within 30 days of receiving an appropriately prescribed medication for treatment. Nirmatrelvir-ritonavir was the only medication potentially prescribed inappropriately due to lack of being renally dose adjusted and the extensive drug-drug interactions.
CONCLUSIONS: Nirmatrelvir-ritonavir was the most prescribed medication for the treatment of mild-to-moderate COVID-19, consistent with its position as first-line therapy and widespread accessibility. The study results will inform future educational opportunities, such as in-service presentations and handouts, that may improve the prescribing of outpatient treatment for mild-to-moderate COVID-19 moving forward.

BACKGROUND: The current World Health Organization (WHO) pediatric tuberculosis dosing guidelines lead to suboptimal drug exposures. Identifying factors altering the exposure of these drugs in children is essential for dose optimization. Pediatric pharmacokinetic studies are usually small, leading to high variability and uncertainty in pharmacokinetic results between studies. We pooled data from large pharmacokinetic studies to identify key covariates influencing drug exposure to optimize tuberculosis dosing in children.
RESULTS: We used nonlinear mixed-effects modeling to characterize the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide, and investigated the association of human immunodeficiency virus (HIV), antiretroviral therapy (ART), drug formulation, age, and body size with their pharmacokinetics. Data from 387 children from South Africa, Zambia, Malawi, and India were available for analysis; 47% were female and 39% living with HIV (95% on ART). Median (range) age was 2.2 (0.2 to 15.0) years and weight 10.9 (3.2 to 59.3) kg. Body size (allometry) was used to scale clearance and volume of distribution of all 3 drugs. Age affected the bioavailability of rifampicin and isoniazid; at birth, children had 48.9% (95% confidence interval (CI) [36.0%, 61.8%]; p < 0.001) and 64.5% (95% CI [52.1%, 78.9%]; p < 0.001) of adult rifampicin and isoniazid bioavailability, respectively, and reached full adult bioavailability after 2 years of age for both drugs. Age also affected the clearance of all drugs (maturation), children reached 50% adult drug clearing capacity at around 3 months after birth and neared full maturation around 3 years of age. While HIV per se did not affect the pharmacokinetics of first-line tuberculosis drugs, rifampicin clearance was 22% lower (95% CI [13%, 28%]; p < 0.001) and pyrazinamide clearance was 49% higher (95% CI [39%, 57%]; p < 0.001) in children on lopinavir/ritonavir; isoniazid bioavailability was reduced by 39% (95% CI [32%, 45%]; p < 0.001) when simultaneously coadministered with lopinavir/ritonavir and was 37% lower (95% CI [22%, 52%]; p < 0.001) in children on efavirenz. Simulations of 2010 WHO-recommended pediatric tuberculosis doses revealed that, compared to adult values, rifampicin exposures are lower in most children, except those younger than 3 months, who experience relatively higher exposure for all drugs, due to immature clearance. Increasing the rifampicin doses in children older than 3 months by 75 mg for children weighing <25 kg and 150 mg for children weighing >25 kg could improve rifampicin exposures. Our analysis was limited by the differences in availability of covariates among the pooled studies.
CONCLUSIONS: Children older than 3 months have lower rifampicin exposures than adults and increasing their dose by 75 or 150 mg could improve therapy. Altered exposures in children with HIV is most likely caused by concomitant ART and not HIV per se. The importance of the drug-drug interactions with lopinavir/ritonavir and efavirenz should be evaluated further and considered in future dosing guidance.
BACKGROUND: ClinicalTrials.gov registration numbers; NCT02348177, NCT01637558, ISRCTN63579542.

BACKGROUND: Since the beginning of the COVID-19 pandemic, therapeutic options for treating COVID-19 have been investigated at different stages of clinical manifestations. Considering the particular impact of COVID-19 in the Americas, this document aims to present recommendations for the pharmacological treatment of COVID-19 specific to this population.
METHODS: Fifteen experts, members of the Brazilian Society of Infectious Diseases (SBI) and the Pan-American Association of Infectious Diseases (API) make up the panel responsible for developing this guideline. Questions were formulated regarding prophylaxis and treatment of COVID-19 in outpatient and inpatient settings. The outcomes considered in decision-making were mortality, hospitalisation, need for mechanical ventilation, symptomatic COVID-19 episodes, and adverse events. In addition, a systematic review of randomised controlled trials was conducted. The quality of evidence assessment and guideline development process followed the GRADE system.
RESULTS: Nine technologies were evaluated, and ten recommendations were made, including the use of tixagevimab + cilgavimab in the prophylaxis of COVID-19, tixagevimab + cilgavimab, molnupiravir, nirmatrelvir + ritonavir, and remdesivir in the treatment of outpatients, and remdesivir, baricitinib, and tocilizumab in the treatment of hospitalised patients with severe COVID-19. The use of hydroxychloroquine or chloroquine and ivermectin was discouraged.
CONCLUSIONS: This guideline provides recommendations for treating patients in the Americas following the principles of evidence-based medicine. The recommendations present a set of drugs that have proven effective in the prophylaxis and treatment of COVID-19, emphasising the strong recommendation for the use of nirmatrelvir/ritonavir in outpatients as the lack of benefit from the use of hydroxychloroquine and ivermectin.

The Australian National COVID-19 Clinical Evidence Taskforce was established in March 2020 to maintain up-to-date recommendations for the treatment of people with coronavirus disease 2019 (COVID-19). The original guideline (April 2020) has been continuously updated and expanded from nine to 176 recommendations, facilitated by the rapid identification, appraisal, and analysis of clinical trial findings and subsequent review by expert panels.
In this article, we describe the recommendations for treating non-pregnant adults with COVID-19, as current on 1 August 2022 (version 61.0). The Taskforce has made specific recommendations for adults with severe/critical or mild disease, including definitions of disease severity, recommendations for therapy, COVID-19 prophylaxis, respiratory support, and supportive care.
The Taskforce currently recommends eight drug treatments for people with COVID-19 who do not require supplemental oxygen (inhaled corticosteroids, casirivimab/imdevimab, molnupiravir, nirmatrelvir/ritonavir, regdanvimab, remdesivir, sotrovimab, tixagevimab/cilgavimab) and six for those who require supplemental oxygen (systemic corticosteroids, remdesivir, tocilizumab, sarilumab, baricitinib, casirivimab/imdevimab). Based on evidence of their achieving no or only limited benefit, ten drug treatments or treatment combinations are not recommended; an additional 42 drug treatments should only be used in the context of randomised trials. Additional recommendations include support for the use of continuous positive airway pressure, prone positioning, and endotracheal intubation in patients whose condition is deteriorating, and prophylactic anticoagulation for preventing venous thromboembolism. The latest updates and full recommendations are available at www.covid19evidence.net.au.

OBJECTIVE: Nirmatrelvir in association with ritonavir (PAXLOVID™, Pfizer) is an antiviral agent targeting the 3-chymotrypsin-like cysteine protease enzyme (3C-like protease or Mpro) which is a key enzyme of the viral cycle of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This combination with a well-known pharmacokinetic enhancer leads to a high risk for drug-drug interactions in a polymedicated elected population for treatment. The aim of this work was to provide recommendations on behalf of the national French society of pharmacology (French Society of Pharmacology and Therapeutics; SFPT), by suggesting optimal and pragmatic therapeutic strategies if nirmatrelvir/ritonavir is to be given together with drugs commonly used, in order to ensure secured physicians\' prescription.
METHODS: Six clinical pharmacologists search the scientific literature to provide a first draft of recommendations. Thereafter, twelve other clinical pharmacologists verified the recommendations and proposed modifications. The final draft was then validated by all 18 participants.
RESULTS: Five distinct recommendations were issued: i) contra-indications, ii) \"PAXLOVID™ not recommended with the comedication\", iii) \"PAXLOVID™ possible whether the comedication is discontinued\", iv) \"PAXLOVID™ possible only after an expert advice\" and v) \"PAXLOVID™ possible without modification of the associated treatment\". The final document comprises recommendations for 171 drugs/therapeutic classes aiming to secure prescription. In complex situations, clinicians are advised to contact their pharmacology department to obtain specific recommendations on the management of drug-drug interactions with nirmatrelvir/ritonavir.
CONCLUSIONS: These recommendations intend to be a help for clinicians willing to prescribe nirmatrelvir/ritonavir and to prevent drug-drug interactions leading to adverse drug reactions or loss of efficacy. They constitute a guideline for primary care situations. Of course, some complex situations may require expert advices and here, again, clinical pharmacologists are at the forefront in providing therapeutic advice.

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OBJECTIVE: Molnupiravir is a newer oral antiviral drug that has recently received emergency use authorization (EUA) in USA, UK and India. We aim to conduct an update on our previous systematic review to provide practical clinical guideline for using molnupiravir in patients with COVID-19.
METHODS: We systematically searched the electronic database of PubMed, MedRxiv and Google Scholar until January 5, 2022, using key MeSH keywords.
RESULTS: Final result of phase 3 study in 1433 non-hospitalized COVID-19 patients showed a significant reduction in composite risk of hospital admission or death (absolute risk difference, -3.0% [95% confidence interval {CI}, -5.9 to -0.1%]; 1-sided P = 0.02) although with a non-significant 31% relative risk reduction (RRR). RRR for death alone was 89% (95% CI, 14 to 99; P-value not reported). Number needed to treat to prevent 1 death or 1 hospitalization or death composite appears to be closely competitive to other agents having EUA in people with COVID-19. However, cost-wise molnupiravir is comparatively cheaper compared to all other agents.
CONCLUSIONS: Molnupiravir could be a useful agent in non-pregnant unvaccinated adults with COVID-19 who are at increased risk of severity including hospitalization. However, it is effective only when used within 5-days of onset of symptoms. A 5-days course seems to be safe without any obvious short-term side effects.

BACKGROUND: We aimed to determine how emerging evidence over the past decade informed how Ugandan HIV clinicians prescribed protease inhibitors (PIs) in HIV patients on rifampicin-based tuberculosis (TB) treatment and how this affected HIV treatment outcomes.
METHODS: We reviewed clinical records of HIV patients aged 13 years and above, treated with rifampicin-based TB treatment while on PIs between1st-January -2013 and 30th-September-2018 from twelve public HIV clinics in Uganda. Appropriate PI prescription during rifampicin-based TB treatment was defined as; prescribing doubled dose lopinavir/ritonavir- (LPV/r 800/200 mg twice daily) and inappropriate PI prescription as prescribing standard dose LPV/r or atazanavir/ritonavir (ATV/r).
RESULTS: Of the 602 patients who were on both PIs and rifampicin, 103 patients (17.1% (95% CI: 14.3-20.34)) received an appropriate PI prescription. There were no significant differences in the two-year mortality (4.8 vs. 5.7%, P = 0.318), loss to follow up (23.8 vs. 18.9%, P = 0.318) and one-year post TB treatment virologic failure rates (31.6 vs. 30.7%, P = 0.471) between patients that had an appropriate PI prescription and those that did not. However, more patients on double dose LPV/r had missed anti-retroviral therapy (ART) days (35.9 vs 21%, P = 0.001).
CONCLUSIONS: We conclude that despite availability of clinical evidence, double dosing LPV/r in patients receiving rifampicin-based TB treatment is low in Uganda\'s public HIV clinics but this does not seem to affect patient survival and viral suppression.

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A life-threatening respiratory illness (COVID-19) due to severe acute respiratory syndrome (SARS)-CoV-2 coronavirus was first described in December 2019 in Wuhan (China), rapidly evolving into a pandemic. In the first phase, when the viral replication plays a pivotal pathogenetic role, antiviral drugs could be crucial in limiting viral-induced organ damage. Unfortunately, there are no specific antivirals of proven efficacy for COVID-19, and several drugs have been repurposed to face this dramatic pandemic. In this paper we review the studies evaluating lopinavir/ritonavir association (LPV/r) use in COVID-19, and previously in SARS and Middle East respiratory syndrome (MERS). We searched PubMed to identify all relevant clinical and laboratory studies published up to 15 May 2020; the guidelines on the use of LPV/r in COVID-19 were further directly searched on the website of the main international scientific societies and agencies. Available evidence is currently scarce and of low quality. The recommendations issued for COVID-19 vary from positions clearly against the use of LPV/r to other positions that are more favorable. In our opinion, despite the controversial results of an important randomized clinical trial, and some recommendations, clinicians should not abandon the use of LPV/r for the treatment of COVID-19, possibly using this drug inside a prospective randomized trial, waiting for the results of the numerous ongoing trials evaluating its efficacy.