Preclinical in vivo assessment of the activity of AZD7442 anti-SARS-CoV-2 monoclonal antibodies against Omicron sublineages.

Therapeutic monoclonal antibodies have been successful in protecting vulnerable populations against SARS-CoV-2. However, their effectiveness has been hampered by the emergence of new variants. To adapt the therapeutic landscape, health authorities have based their recommendations mostly on in vitro neutralization tests. However, these do not provide a reliable understanding of the changes in the dose-effect relationship and how they may translate into clinical efficacy. Taking the example of EvusheldTM (AZD7442), we aimed to investigate how in vivo data can provide critical quantitative results and project clinical effectiveness. We used the Golden Syrian hamster model to estimate 90 % effective concentrations (EC90) of AZD7442 in vivo against SARS-CoV-2 Omicron BA.1, BA.2 and BA.5 variants. While our in vivo results confirmed the partial loss of AZD7442 activity for BA.1 and BA.2, they showed a much greater loss of efficacy against BA.5 than that obtained in vitro. We analyzed in vivo EC90s in perspective with antibody levels measured in a cohort of immunocompromised patients who received 300 mg of AZD7442. We found that a substantial proportion of patients had serum levels of anti-SARS-CoV-2 spike protein IgG above the estimated in vivo EC90 for BA.1 and BA.2 (21 % and 92 % after 1 month, respectively), but not for BA.5. These findings suggest that AZD7442 is likely to retain clinical efficacy against BA.2 and BA.1, but not against BA.5. Overall, the present study illustrates the importance of complementing in vitro investigations by preclinical studies in animal models to help predict the efficacy of monoclonal antibodies in humans.

Cotrimoxazole Prophylaxis is Not Associated with a Higher Occurrence of Atazanavir Treatment Failure: Analysis of Worldwide Pharmacovigilance Data.

[Background: Cotrimoxazole is the main antibiotic used in HIV-infected patients for the prophylaxis of opportunistic infections. This antibiotic is prescribed in patients receiving antiretroviral agents (ART) such as Atazanavir (ATV), a protease inhibitor used with other ART classes. The objective of this study was to compare HIV treatment failure (HIVTF) in HIV-infected patients treated concomitantly with ATV and cotrimoxazole to those of patients treated only with ATV. MATERIALS AND METHODS: This is a comparative analysis of the safety data of HIVTF available with ATV in the WHO International Pharmacovigilance database "VigiBase®". We used the SMQ (Standardized MedDRA Querie) to identify all the terms corresponding to HIVTF. We presented results as a percentage or an adjusted Reporting Odds Ratio (aROR) with a 95% confidence interval (95% CI). RESULTS: A total of 116 cases of HIVTF (2.2%) were reported with ATV among the 5196 individual case safety reports (ICSR) included in the analysis. The proportion of HIV-infected patients who presented ATV treatment failure (ATVTF) was lower (2.6%, 3/116) when cotrimoxazole was concomitant (aROR was 0.5 with a 95%CI from 0.2 to 1.7). Only 10 of 273 ICSRs (3.7%) were reported from Africa concerning the use of cotrimoxazole prophylaxis concomitantly with ATV. CONCLUSION: This study did not show a higher occurrence of ATVTF when cotrimoxazole was concomitant. These results reinforce the place of concomitant use of ATV with cotrimoxazole in the management of HIV treatment.

Higher Atazanavir Plasma Exposure in Rats is Associated with Gut Microbiota Changes Induced by Cotrimoxazole.

BACKGROUND: Cotrimoxazole (TMP-SMX) is concomitantly used as a primary prophylaxis of opportunistic infections with antiretroviral agents, such as Atazanavir (ATV). Results from an ex vivo study showed changes in intestinal absorption of ATV when rats were pretreated with TMP-SMX. The objective of this in vivo study is to determine the effect of TMP-SMX on the pharmacokinetics of ATV in rats. We also studied changes in gut microbiota induced by TMP-SMX. METHODS: We used the non-compartment analysis to compare the pharmacokinetics of ATV in a parallel group of rats treated with a low or therapeutic dose of TMP-SMX for nine days to untreated control rats. Gut microbiota was characterized using qPCR and High Throughput Sequencing of 16S rDNA. RESULTS: Rats treated with TMP-SMX showed a much broader exposure to ATV compared to the control group (AUC0-8h (ng.mL-1.h), 25975.9±4048.7 versus 2587.6±546.9, p=0.001). The main observation regarding the gut microbiota was a lower proportion of enterobacteria related to the administration of TMP-SMX. Moreover, the Total Gastrointestinal Transit Time (TGTT) was longer in the TMP-SMX treated group. CONCLUSION: Concomitant administration of TMP-SMX and ATV significantly increased ATV exposure in rats. This increase could be the result of a prolonged TGTT leading to an increase in the intestinal residence time of ATV favoring its absorption. Gut microbiota changes induced by TMP-SMX could be at the origin of this prolonged TGTT. If demonstrated in humans, this potential interaction could be accompanied by an increase in the adverse effects of ATV.