Model informed dosing of hydroxycholoroquine in COVID-19 patients: Learnings from the recent experience, remaining uncertainties and gaps.

AIMS: In the absence of a commonly agreed dosing protocol based on pharmacokinetic (PK) considerations, the dose and treatment duration for hydroxychloroquine (HCQ) in COVID-19 disease currently vary across national guidelines and clinical study protocols. We have used a model-based approach to explore the relative impact of alternative dosing regimens proposed in different dosing protocols for hydroxychloroquine in COVID-19. METHODS: We compared different PK exposures using Monte Carlo simulations based on a previously published population pharmacokinetic model in patients with rheumatoid arthritis, externally validated using both independent data in lupus erythematous patients and recent data in French COVID-19 patients. Clinical efficacy and safety information from COVID-19 patients treated with HCQ were used to contextualize and assess the actual clinical value of the model predictions. RESULTS: Literature and observed clinical data confirm the variability in clinical responses in COVID-19 when treated with the same fixed doses. Confounding factors were identified that should be taken into account for dose recommendation. For 80% of patients, doses higher than 800 mg day on day 1 followed by 600 mg daily on following days might not be needed for being cured. Limited adverse drug reactions have been reported so far for this dosing regimen, most often confounded by co-medications, comorbidities or underlying COVID-19 disease effects. CONCLUSION: Our results were clear, indicating the unmet need for characterization of target PK exposures to inform HCQ dosing optimization in COVID-19. Dosing optimization for HCQ in COVID-19 is still an unmet need. Efforts in this sense are a prerequisite for best benefit/risk balance.

Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study.

Large studies on bedaquiline used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) are lacking. This study aimed to evaluate the safety and effectiveness of bedaquiline-containing regimens in a large, retrospective, observational study conducted in 25 centres and 15 countries in five continents.428 culture-confirmed MDR-TB cases were analysed (61.5% male; 22.1% HIV-positive, 45.6% XDR-TB). MDR-TB cases were admitted to hospital for a median (interquartile range (IQR)) 179 (92-280) days and exposed to bedaquiline for 168 (86-180) days. Treatment regimens included, among others, linezolid, moxifloxacin, clofazimine and carbapenems (82.0%, 58.4%, 52.6% and 15.3% of cases, respectively).Sputum smear and culture conversion rates in MDR-TB cases were 63.6% and 30.1%, respectively at 30 days, 81.1% and 56.7%, respectively at 60 days; 85.5% and 80.5%, respectively at 90 days and 88.7% and 91.2%, respectively at the end of treatment. The median (IQR) time to smear and culture conversion was 34 (30-60) days and 60 (33-90) days. Out of 247 culture-confirmed MDR-TB cases completing treatment, 71.3% achieved success (62.4% cured; 8.9% completed treatment), 13.4% died, 7.3% defaulted and 7.7% failed. Bedaquiline was interrupted due to adverse events in 5.8% of cases. A single case died, having electrocardiographic abnormalities that were probably non-bedaquiline related.Bedaquiline-containing regimens achieved high conversion and success rates under different nonexperimental conditions.

Comparison of effectiveness and safety of imipenem/clavulanate- versus meropenem/clavulanate-containing regimens in the treatment of MDR- and XDR-TB.

No large study to date has ever evaluated the effectiveness, safety and tolerability of imipenem/clavulanate versus meropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to compare the therapeutic contribution of imipenem/clavulanate versus meropenem/clavulanate added to background regimens to treat MDR- and XDR-TB cases.84 patients treated with imipenem/clavulanate-containing regimens showed a similar median number of antibiotic resistances (8 versus 8) but more fluoroquinolone resistance (79.0% versus 48.9%, p<0.0001) and higher XDR-TB prevalence (67.9% versus 49.0%, p=0.01) in comparison with 96 patients exposed to meropenem/clavulanate-containing regimens. Patients were treated with imipenem/clavulanate- and meropenem/clavulanate-containing regimens for a median (interquartile range) of 187 (60-428) versus 85 (49-156) days, respectively.Statistically significant differences were observed on sputum smear and culture conversion rates (79.7% versus 94.8%, p=0.02 and 71.9% versus 94.8%, p<0.0001, respectively) and on success rates (59.7% versus 77.5%, p=0.03). Adverse events to imipenem/clavulanate and meropenem/clavulanate were reported in 5.4% and 6.5% of cases only.Our study suggests that meropenem/clavulanate is more effective than imipenem/clavulanate in treating MDR/XDR-TB patients.

Effectiveness and safety of meropenem/clavulanate-containing regimens in the treatment of MDR- and XDR-TB.

No large study has ever evaluated the efficacy, safety and tolerability of meropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to evaluate the therapeutic contribution, effectiveness, safety and tolerability profile of meropenem/clavulanate added to a background regimen when treating MDR- and XDR-TB cases.Patients treated with a meropenem/clavulanate-containing regimen (n=96) showed a greater drug resistance profile than those exposed to a meropenem/clavulanate-sparing regimen (n=168): in the former group XDR-TB was more frequent (49% versus 6.0%, p<0.0001) and the median (interquartile range (IQR)) number of antibiotic resistances was higher (8 (6-9)versus 5 (4-6)). Patients were treated with a meropenem/clavulanate-containing regimen for a median (IQR) of 85 (49-156) days.No statistically significant differences were observed in the overall MDR-TB cohort and in the subgroups with and without the XDR-TB patients; in particular, sputum smear and culture conversion rates were similar in XDR-TB patients exposed to meropenem/clavulanate-containing regimens (88.0% versus 100.0%, p=1.00 and 88.0% versus 100.0%, p=1.00, respectively). Only six cases reported adverse events attributable to meropenem/clavulanate (four of them then restarting treatment).The nondifferent outcomes and bacteriological conversion rate observed in cases who were more severe than controls might imply that meropenem/clavulanate could be active in treating MDR- and XDR-TB cases.

Development, validation and clinical use of a LC-MS/MS method for the simultaneous determination of the nine main antituberculosis drugs in human plasma.

The treatment of tuberculosis, in particular the multi-drug resistant tuberculosis, remains a challenge mainly because of the therapy duration and the pharmacokinetic variability of the drugs included in the regimen. The monitoring of antituberculosis drugs is a recent tool that could improve the outcome of patients. We developed a LC-MS/MS method allowing the simultaneous quantification of the four first-line drugs (isoniazid, rifampicin, pyrazinamide and ethambutol), a metabolite of isoniazid (acetylisoniazid) and the five main second-line drugs (rifabutin, levofloxacin, moxifloxacin, linezolid and bedaquiline). An isotopologue standard was used for each drug. The protein precipitation was performed with acetonitrile and the separation was carried out using an EC-18 column and a gradient elution. The validated ranges for each drug were adapted to monitor the plasma concentration at 2 h (peak) and 6 h to evaluate their enteric absorption. The intermediate precision (CV) and the trueness at the limit of quantification were ≤ 10.1% and ≤ 10.7%, respectively. Preliminary data were obtained for 12 patients. The results showed that 38% of the patients had infra-therapeutic levels for both rifampicin and isoniazid, that the leading cause of an impaired oral absorption seemed to be malabsorption and that the effective concentrations for rifampicin were in the lower range of the therapeutic interval.

Evaluation and Modelling of the Performance of an Automated SARS-CoV-2 Antigen Assay According to Sample Type, Target Population and Epidemic Trends.

The Lumipulse® G SARS-CoV-2 Ag assay performance was evaluated on prospectively collected saliva and nasopharyngeal swabs (NPS) of recently ill in- and outpatients and according to the estimated viral load. Performances were calculated using RT-PCR positive NPS from patients with symptoms ≤ 7 days and RT-PCR negative NPS as gold standard. In addition, non-selected positive NPS were analyzed to assess the performances on various viral loads. This assay yielded a sensitivity of 93.1% on NPS and 71.4% on saliva for recently ill patients. For NPS with a viral load > 103 RNA copies/mL, sensitivity was 96.4%. A model established on our daily routine showed fluctuations of the performances depending on the epidemic trends but an overall good negative predictive value. Lumipulse® G SARS-CoV-2 assay yielded good performance for an automated antigen detection assay on NPS. Using it for the detection of recently ill patients or to screen high-risk patients could be an interesting alternative to the more expensive RT-PCR.

Performance of Xpert MTB/RIF Ultra for diagnosis of pulmonary and extra-pulmonary tuberculosis, one year of use in a multi-centric hospital laboratory in Brussels, Belgium.

Among the challenges in controlling tuberculosis, a rapid and accurate diagnostic test for the detection of Mycobacterium tuberculosis complex (MTBc) and its resistance to first line therapies is crucial. We evaluated the performance of the Xpert MTB/RIF Ultra assay (Xpert Ultra) for the rapid detection of MTBc and rifampicin resistance (RR) in 1120 pulmonary and 461 extra-pulmonary clinical specimens and compared it with conventional phenotypic techniques. The Xpert Ultra assay detected MTBc in 223 (14.1%) samples with an overall sensitivity and specificity, using culture as the "gold standard", of 91.1% (95% CI, 85.6-95.1) and 94.5% (95% CI, 93.1-95.6), respectively. The sensitivity of the Xpert Ultra test for smear-negative extra-pulmonary specimens was high (87.1%), even higher than with smear-negative pulmonary specimens (81.8%). But this enhanced sensitivity came with a low overall specificity of smear-negative extra-pulmonary specimens (66.7%). For 73 patients, 79/1423 (3.4%) negative mycobacterial culture samples were found to be positive with Xpert Ultra. Clinical data was necessary to correctly interpret potential false-positive results, especially trace-positive results. Sensitivity of the Xpert Ultra to detect RR compared to drug susceptibility testing was 100% (95% CI, 29.2-100) and specificity was 99.2% (95% CI, 95.8-100). We concluded that the Xpert Ultra test is able to provide a reliable TB diagnosis within a significantly shorter turnaround time than culture. This is especially true for paucibacillary samples such as smear-negative pulmonary specimens and extra-pulmonary specimens.

Dolutegravir as a trigger for DRESS syndrome?

Dolutegravir is an increasingly-used second-generation human immunodeficiency virus integrase strand transfer inhibitor. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome has been described in several patients treated with raltegravir but to our knowledge, there is no previous report of DRESS syndrome associated with dolutegravir.

Is systematic screening and treatment for latent tuberculosis infection in HIV patients useful in a low endemic setting?

OBJECTIVES: A decreasing incidence of tuberculosis (TB) among HIV patients has been documented in high-income settings and screening for tuberculosis is not systematically performed in many clinics (such as ours). Our objectives are to evaluate whether a same decline of incidence was seen in our Belgian tertiary center and to evaluate whether systematic screening and prophylaxis of tuberculosis should remain part of routine practice. METHODS: Between 2005 and 2012, the annual incidence of tuberculosis among adult HIV patients was measured. The impact of demographic characteristics and CD4 nadir on the incidence of active TB was evaluated. RESULTS: Among the 1167 patients who entered the cohort, 42 developed active TB with a significant decrease of annual incidence from 28/1000 patient-years in 2005 to 3/1000 patient-years in 2012. Among the 42 cases, 83% were of sub-Saharan origin. Median CD4 cell count upon HIV diagnosis was significantly lower in TB cases and 60% had a nadir CD4 below 200/µl. Thirty-six percent of incident TB occurred within 14 days after HIV diagnosis. CONCLUSION: A significant decline of TB incidence in HIV patients was observed. Incident TB occurred mainly in African patients, with low CD4 upon HIV diagnosis. A significant proportion of TB cases were discovered early in follow-up which probably reflects TB already present upon HIV diagnosis. In a low endemic setting, exclusion of active TB upon HIV diagnosis remains a priority and screening for LTBI should focus on HIV patients from high risk groups such as migrants from endemic regions, especially in patients with low CD4 nadir.

Immune Activation by Mycobacterium tuberculosis in HIV-Infected and -Uninfected Subjects.

INTRODUCTION: This study investigates the influence of Mycobacterium tuberculosis infection on immune activation biomarkers, both in HIV-infected and -uninfected subjects. METHODS: Forty-eight treatment-naive HIV-infected patients and 74 HIV-uninfected subjects were recruited and divided into groups according to their M. tuberculosis infection status: latent tuberculosis infection (LTBI), active tuberculosis (TB), and no evidence of M. tuberculosis infection. The expression of cellular markers CD38 and HLA-DR on circulating CD8 T lymphocytes and the plasmatic levels of soluble markers interleukin-6, sCD14, and D-Dimer were measured and compared between groups. The HIV-infected patients with no evidence of M. tuberculosis or with LTBI who initiated antiretroviral treatment were tested again for these biomarkers once viral suppression was reached. RESULTS: In both HIV-infected and -uninfected groups, patients with TB had higher levels of immune activation markers than subjects with LTBI and with no evidence of M. tuberculosis. Among the HIV-uninfected subjects, no significant difference in biomarker level was found between those presenting LTBI and those with no evidence of M. tuberculosis. The effect of LTBI on activation biomarkers in the HIV-infected groups was inconclusive because of the small number of individuals in the HIV+/LTBI group. sCD14 and D-Dimer levels were significantly higher in the TB-only group than in the HIV-only group. DISCUSSION: Although TB is associated with an increase in biomarkers of immune activation, the effect of LTBI is less evident. Further investigation is warranted, and according to our results, soluble markers may offer greater sensitivity for the evaluation of M. tuberculosis-associated immune activation than cellular markers.

Meropenem/clavulanate and linezolid treatment for extensively drug-resistant tuberculosis.

The combination of meropenem with clavulanate has high antimycobacterial activity in vitro against extensively drug-resistant Mycobacterium tuberculosis strains. We report the successful use of this combination in association with linezolid in the management of an advanced extensively drug-resistant tuberculosis disease with complex second-line drug resistance in a 14-year-old teenager.