Physiologically-Based Pharmacokinetic Modeling to Support the Clinical Management of Drug-Drug Interactions With Bictegravir

Bictegravir is equally metabolized by cytochrome P450 (CYP)3A and uridine diphosphate-glucuronosyltransferase (UGT)1A1. Drug-drug interaction (DDI) studies were only conducted for strong inhibitors and inducers, leading to some uncertainty whether moderate perpetrators or multiple drug associations can be safely coadministered with bictegravir. We used physiologically-based pharmacokinetic (PBPK) modeling to simulate DDI magnitudes of various scenarios to guide the clinical DDI management of bictegravir. Clinically observed DDI data for bictegravir coadministered with voriconazole, darunavir/cobicistat, atazanavir/cobicistat, and rifampicin were predicted within the 95% confidence interval of the PBPK model simulations. The area under the curve (AUC) ratio of the DDI divided by the control scenario was always predicted within 1.25-fold of the clinically observed data, demonstrating the predictive capability of the used modeling approach. After the successful verification, various DDI scenarios with drug pairs and multiple concomitant drugs were simulated to analyze their effect on bictegravir exposure. Generally, our simulation results suggest that bictegravir should not be coadministered with strong CYP3A and UGT1A1 inhibitors and inducers (e.g., atazanavir, nilotinib, and rifampicin), but based on the present modeling results, bictegravir could be administered with moderate dual perpetrators (e.g., efavirenz). Importantly, the inducing effect of rifampicin on bictegravir was predicted to be reversed with the concomitant administration of a strong inhibitor such as ritonavir, resulting in a DDI magnitude within the efficacy and safety margin for bictegravir (0.5-2.4-fold). In conclusion, the PBPK modeling strategy can effectively be used to guide the clinical management of DDIs for novel drugs with limited clinical experience, such as bictegravir

Mycobacterium-avium -Pneumonie bei HIV-negativem Patienten

Zusammenfassung: Ein 79-jähriger Patient mit kurativ behandeltem Lungenkarzinom wurde wegen Fieber, Atemnot und Husten zugewiesen. Eine Antibiotikatherapie zur Pneumoniebehandlung brachte keine Besserung, und radiologisch war die Pneumonie progredient. Ein Erreger konnte nicht gefunden werden. Erst unter einer Steroidtherapie bei vermuteter kryptogener Pneumonitis normalisierten sich die Entzündungszeichen und die Symptomatik war rückläufig. Nach 3-wöchiger Kultivierung konnten im Eintrittssputum Mycobacterium avium Complex (MAC) gefunden und eine MAC-Pneumonie diagnostiziert werde

Long-term outcome after SARS-CoV-2 infection in healthcare workers: a single centre cohort study

BACKGROUND: Long-term symptoms after acute COVID-19 are highly debated. Nevertheless, data on long-term symptoms of COVID-19 in healthcare workers are scarce. METHODS: We assessed frequency and risk factors of persisting symptoms in a retrospective cohort of healthcare workers infected with SARS-CoV-2. RESULTS: Persistent symptoms at 3 and 12 months were reported by 26.5% and 13.5% of participants, respectively. Most commonly reported symptoms were fatigue, impaired sense of taste or smell and general weakness. A history of depression or state of exhaustion, pre-existing lung disease and older age were associated with persisting symptoms. CONCLUSION: Our study shows that a relevant proportion of healthcare workers with mild COVID-19 report persisting symptoms over 3 and 12 months. Although in the majority of cases symptoms are mild, this study highlights the need for further research into causes and therapy

Impact of Obesity on the Drug-Drug Interaction Between Dolutegravir and Rifampicin or Any Other Strong Inducers

BACKGROUND: Obesity is increasingly prevalent among people with HIV. Obesity can impact drug pharmacokinetics and consequently the magnitude of drug-drug interactions (DDIs) and, thus, the related recommendations for dose adjustment. Virtual clinical DDI studies were conducted using physiologically based pharmacokinetic (PBPK) modeling to compare the magnitude of the DDI between dolutegravir and rifampicin in nonobese, obese, and morbidly obese individuals. METHODS: Each DDI scenario included a cohort of virtual individuals (50% female) between 20 and 50 years of age. Drug models for dolutegravir and rifampicin were verified against clinical observed data. The verified models were used to simulate the concurrent administration of rifampicin (600 mg) at steady state with dolutegravir (50 mg) administered twice daily in normal-weight (BMI 18.5-30 kg/m(2)), obese (BMI 30-40 kg/m(2)), and morbidly obese (BMI 40-50 kg/m(2)) individuals. RESULTS: Rifampicin was predicted to decrease dolutegravir area under the curve (AUC) by 72% in obese and 77% in morbidly obese vs 68% in nonobese individuals; however, dolutegravir trough concentrations were reduced to a similar extent (83% and 85% vs 85%). Twice-daily dolutegravir with rifampicin resulted in trough concentrations always above the protein-adjusted 90% inhibitory concentration for all BMI groups and above the 300 ng/mL threshold in a similar proportion for all BMI groups. CONCLUSIONS: The combined effect of obesity and induction by rifampicin was predicted to further decrease dolutegravir exposure but not the minimal concentration at the end of the dosing interval. Thus, dolutegravir 50 mg twice daily with rifampicin can be used in individuals with a high BMI up to 50 kg/m(2)

Carriage of Staphylococcus aureus Among Injection Drug Users: Lower Prevalence in an Injection Heroin Maintenance Program Than in an Oral Methadone Program

Abstract Objectives: To compare the prevalence of Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) carriage among injection drug users (IDUs) treated in an injection heroin maintenance program with that among IDUs treated in an oral methadone program, and to determine predictors of S. aureus carriage. Design: Survey. Setting: Two opiate maintenance programs at a psychiatrie university clinic. Participants: A volunteer sample consisting of 94 (74%) of 127 IDUs treated in an injection opiate maintenance program with at least twice daily injections of heroin, and 70 (56%) of 125 IDUs treated in an oral methadone program. Results: Addicts treated in the intravenous heroin substitution program had a significantly lower overall rate of S. aureus carriage (37 of 94 [39.4%] vs 42 of 70 [60%]; P = .009) and a significantly lower rate of nasal carriage (21 of 94 [22.3%] vs 30 of 70 [42.9%]; P = .005) than did addicts treated in the oral methadone program. Being treated in the oral methadone program was the only independent predictor of S. aureus carriage (odds ratio, 2.27; 95% confidence interval, 1.19-4.31; P=.012). All S. aureus isolates were susceptible to oxacillin. Conclusions: The regular use of needles under aseptic conditions did not increase the rate of S. aureus carriage among IDUs. Further studies are necessary to investigate whether the lower rate of S. aureus carriage among IDUs treated with intravenous heroin leads to a lower incidence of S. aureus infections in these patient

Effect of Antiretroviral Therapy on Apoptosis Markers and Morphology in Peripheral Lymph Nodes of HIV-Infected Individuals

Background:: CD4+ T cell depletion and destruction and the involution of the lymphoid tissue are hallmarks of HIV infection. Although the underlying mechanisms are still unclear, apoptosis appears to play a central role. The objective of this study was to investigate the effect of antiretroviral therapy on the lymph node tissue, particularly with respect to morphology and apoptosis. Patients and Methods:: Between 1997 and 1999, two inguinal lymph nodes were excised from 31 previously untreated individuals who were in an early stage of HIV infection, the first one prior to treatment and the second after 16 to 20 months of treatment. Paraffin sections were investigated for lymph node architecture, distribution of cellular and viral markers, apoptosis, and expression of apoptotic key molecules which indirectly reflect apoptotic processes. Results:: After 16-20 months of antiretroviral therapy, a significant decrease in highly activated HIV-driven immune response was observed in the lymph node tissue as a marked reduction in follicular hyperplasia, a normalization of the follicular dendritic cell network, a significant increase in the number of CD4+ T cells, and a significant decrease in the number of CD8+ T cells. The expression of several proapoptotic (Fas, TRAIL, and active caspase 3) and antiapoptotic (Bcl-2 and IL-7Rα) molecules that were reconstituted in the tissues during therapy resembled their expression in lymph nodes of HIV-negative individuals. Limitations of the study are (a) the lack of untreated patients in the late stages, (b) for ethical reasons, the lack of a control group with untreated patients, and (c) for methodological reasons, the restriction of sequential measurements of apotpotic markers to one-third of the patients. Conclusion:: Antiretroviral therapy initiated in the early stages in HIV infection may halt the irreversible destruction of the lymph node tissue and may partially normalize apoptotic processe

Genotypic and phenotypic resistance testing of HIV-1 in routine clinical care

Data on genotypic and phenotypic resistance testing of HIV-1 in the routine clinical setting are lacking. In a retrospective single-center study, all patients (n=102) for whom genotypic resistance typing (GRT) and phenotypic resistance typing (PRT) were performed during the calendar year 2002 were examined. GRT and PRT results were concordant for 79% of the drugs, being highest for nevirapine (92%) and lowest for didanosine (57%). Concordance of results for protease inhibitors was lowest for lopinavir (78%) and highest for indinavir (88%). Discordant results for lamivudine were observed in 16% of patients; 90% of these results corresponded to high-level resistance by PRT and susceptibility by GRT. Overall, HIV loads were lower and CD4+ cell counts higher after therapy following resistance testing, but a significant association with the number of active drugs as predicted by GRT or PRT could not be identified. In a subgroup of 43 patients with virological failure under antiretroviral therapy and sufficient follow-up data, HIV loads were significantly lower after 3 and 6months. More patients with HIV loads <400/ml had 2 or more active drugs according to PRT (21/29 [75%]) than according to GRT ([15/29 [52%]; p=0.109. This was also found for HIV loads <50/ml (PRT 16/22 [72%], GRT 10/22 [42%]; p=0.103), although the differences were not statistically significant. There was no discernable difference between GRT and PRT in the clinic-based population, but the numbers of resistance tests performed are not sufficient to draw definitive conclusion