Drug-drug interactions when treating HIV-related metabolic disorders

ABSTRACT

Introduction: Drug-drug interactions (DDI) between antiretroviral drugs and drugs for the treatment of metabolic disturbances in people living with human immunodeficiency virus (HIV) (PLWH) have represented a problem of paramount importance in the recent times. The problem has been mainly driven by sharing common metabolizing pathways. This problem has classically been worsened by the frequent use of pharmacokinetic boosters to enhance protease inhibitors and some integrase inhibitors plasma levels.

Areas covered: This article focuses on the interactions between antiretroviral drugs and those drugs used to treat metabolic disturbances which frequently appear in PLWH. These include dyslipidemia, diabetes mellitus, hyperuricemia, and finally, drugs for the treatment of overweight and clinical obesity. References from PubMed, Embase, or Web of Science, among others, were reviewed.

Expert opinion: The advent of safer drugs, in terms of DDI, in the antiretroviral and the metabolic field,such as non-boosted antiretrovirals and drugs with divergent metabolizing paths. Besides, learning by the caregivers on how to decrease and manage DDI, together with the extensive use of online updated DDI databases, has undoubtedly minimized the problem. The foreseeable increase in the burden of HIV-associated comorbidities and their associated treatments anticipates further complexities in the management of DDI in PLWH.

KEYWORDS:

• HIV infection
• people living with HIV
• combination antiretroviral therapy
• drug-drug interactions
• lipid-lowering agents
• statins
• fibrates
• ezetimibe
• biguanides
• sulphonylureas
• glitazones
• glinides
• DPP-4 inhibitors
• Alpha-glucosidase inhibitors
• allopurinol
• weight-lowering agents

Article highlights

• Metabolic complications are common in people living with HIV (PLWH)

• Drug-drug interactions (DDI) between cART and drugs for the treatment of metabolic disturbances in PLWH have represented a problem of increasing importance in the recent times.

• Protease inhibitors (PI) and the boosting agents ritonavir (RTV) and cobicistat (COB) have the greatest potential for DDI with other drugs.

• Simvastatin, lovastatin and atorvastatin are the most likely to interact with antiretrovirals whereas pravastatin and pitavastatin have the least interaction potential among statins.

• No clinically significant DDI are expected when fibrates are co-administrated with new antiretroviral drugs.

• Ezetimibe is only affected by OATP1B1 inducer or inhibitors whereas evolocumab is not likely to have DDI with antiretrovirals.

• Metformin DDI are produced by inhibition of transporters (OCT and MATE) which can be inhibited by cobicistat, bictegravir and dolutegravir.

• DDI between antiretrovirals and most of the oralantidiabetic agents have not been studied.

• Repaglinide cannot be co-administered with ATV.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work has been partially funded by Instituto de Salud Carlos III [FIS PI13/0796, PI14/0700, PI14/0063, PI016/0503, PI17/0420 & PI17/0498], Ministerio de Sanidad, Politica Social e Igualdad [EC11-293], Programa de Suport als Grups de Recerca AGAUR [2014 SGR 250, 2017 SGR 948], and Red de Investigación en SIDA [RD012/0017/0014, RD12/0017/0005] integrated in the National RDI Plan and cofinanced by the ISCIII-Subdirección General de Evaluación and FEDER; FEDER (Fondo Europeo de desarrollo Regional; otra manera de hacer Europa) and by the Gilead Fellowship Program (I Convocatoria de Proyectos de Investigación en VIH y Hepatitis 2013, [GLD 1300168], and II Convocatoria de Proyectos de Investigación en VIH y Hepatitis [GLD 2014/00923]. The funding sources were not involved in the design of the study, in the collection and analysis of data or in writing the report. All authors had access to the data used and the lead author reviewed the full data report. The full study data were available to all authors. The decision to submit the paper for publication was made by P Domingo.