Comprehensive analysis of gastrointestinal side effects in COVID-19 patients undergoing combined pharmacological treatment with azithromycin and hydroxychloroquine: a systematic review and network meta-analysis

Abstract

During the COVID-19 pandemic, several drugs were repositioned and combined to quickly find a way to mitigate the effects of the infection. However, the adverse effects of these combinations on the gastrointestinal tract are unknown. We aimed investigate whether Hydroxychloroquine (HD), Azithromycin (AZ), and Ivermectin (IV) used in combination for the treatment of COVID-19, can lead to the development of gastrointestinal disorders. This is a systematic review and network meta-analysis conducted using Stata and Revman software, respectively. The protocol was registered with PROSPERO (CRD42023372802). A search of clinical trials in Cochrane Library databases, Embase, Web of Science, Lilacs, PubMed, Scopus and Clinicaltrials.gov conducted on November 26, 2023. The eligibility of the studies was assessed based on PICO criteria, including trials that compared different treatments and control group. The analysis of the quality of the evidence was carried out according to the GRADE. Six trials involving 1,686 COVID-19 patients were included. No trials on the association of HD or AZ with IV met the inclusion criteria, only studies on the association between HD and AZ were included. Nausea, vomiting, diarrhea, abdominal pain and increased transaminases were related. The symptoms of vomiting and nausea were evaluated through a network meta-analysis, while the symptom of abdominal pain was evaluated through a meta-analysis. No significant associations with these symptoms were observed for HD, AZ, or their combination, compared to control. Low heterogeneity and absence of inconsistency in indirect and direct comparisons were noted. Limitations included small sample sizes, varied drug dosages, and potential publication bias during the pandemic peak. This review unveils that there are no associations between gastrointestinal adverse effects and the combined treatment of HD with AZ in the management of COVID-19, as compared to either the use of a control group or the administration of the drugs individually, on the other hand, highlighting the very low or low certainty of evidence for the evaluated outcomes. To accurately conclude the absence of side effects, further high-quality randomized studies are needed.

Keywords:

• Gastrointestinal effects
• COVID-19
• SARS-CoV-2
• risk
• meta-analysis

Acknowledgments

The authors gratefully acknowledge Dr. Paulo Sergio Marques dos Santos (mathematician and statistician at the Parnaíba Delta Federal University), who reviewed an early draft of the manuscript and provided non-binding comments and analyses. The authors gratefully acknowledge the comments of the Editor and the external reviewers selected by the Editor who were anonymous to the authors.

Declaration of interest

Considering the challenges presented by the Covid-19 pandemic and its significant effects on global health, we decided to direct our research to investigate the impact of the use of the main medicines indicated for Covid-19 in Brazil on the gastrointestinal tract. Our research group has been dedicated, over the years, to the study of the gastrointestinal tract, which motivated us to explore this particular perspective in light of the current pandemic scenario.

J.V.R. Medeiros and L.A.D. Nicolau conceived the study. G. Pacheco, A.L.F. Lopes and A.S. Teres designed the study. G. Pacheco and A.L.F. Lopes selected the articles and extracted data. A.P. Oliveira appraised the articles. G. Pacheco, A.L.F. Lopes, A.S. Teles, L.D.B. Lima, M.L.P. Souza analyzed and interpreted the data. A.S. Teles reviewed the statistical analyzes. G. Pacheco, A.L.F. Lopes, A.P. Oliveira, W.R.M. Corrêa, L.A.D. Nicolau, A.S. Teles and L.D.B. Lima contributed to the writing of the final version of the manuscript. All authors agreed with the results and conclusions of this article. J.V.R. The responsibility for the preparation and content of this manuscript rests only with the authors, and the conclusions and interpretations expressed are entirely those of the authors and not of any institution or commercial entity. The authors have not participated in and do not anticipate participation in any legal, regulatory, or advocacy proceedings related to the contents of the article.