Nothing is perfect: the safety issues of integrase inhibitor regimens

ABSTRACT

Introduction

Since the administration of the first integrase strand transfer inhibitor (INSTI) in 2007, most international treatment guidelines consider INSTI-based regimens to be the preferred antiretroviral combinations for HIV-1-infected patients as a result of their safety and efficacy profile. INSTIs are generally well tolerated, and reported rates of discontinuation due to drug-related adverse events (AEs) have been very low to date. However, recent reports indicate that physicians should be aware of potential INSTI-related AEs to ensure good clinical practice.

Areas covered

The authors performed a critical review of the safety issues affecting INSTIs based on published evidence from original studies and new data from researchers.

Expert opinion

Almost all antiretroviral drugs, including INSTIs, are associated with undesirable AEs. Dolutegravir in particular has been associated with more frequent AEs such as neuropsychiatric disorders, neural tube defect in newborns, and weight gain. Data with bictegravir in routine practice are still scarce. While this association and its clinical relevance are not clear, physicians should be alert to the appearance of the aforementioned AEs and others in the future. In the meantime, INSTIs continue to be the preferred option in guidelines on antiretroviral therapy.

KEYWORDS:

• Adverse events
• antiretroviral therapy
• HIV
• integrase strand transfer inhibitors
• safety

Article highlights

• INSTI-based regimens are considered the preferred option for initiation of ART in all international guidelines. They are generally well tolerated, and reported rates of discontinuation due to drug-related AEs have been very low to date.

• Dolutegravir has been associated with more frequent AEs such as neuropsychiatric disorders, neural tube defect in newborns, and weight gain in relation to the other members of the INSTI group. The exception is bictegravir, which probably induces similar toxicity in relation to weight gain and neuropsychiatric effects, even though data from patient-reported outcomes (PROs) related to neuropsychiatric events from RCTs showed differences in favor of this agent. More data are needed to define the toxicity of bictegravir in routine clinical practice.

• Dolutegravir was associated with development of neural tube defects, although the number of cases of periconceptional exposure to this agent is currently insufficient to confirm the association. Actually, there are differences in the recommendations given by international guidelines.

• The mechanism of weight gain with INSTIs is under study, as is its impact on metabolic disease.

• Cabotegravir is a new member of this group and is currently in advanced phases of development as a long-acting agent. No specific AEs have been reported in clinical trials, except for local reactions

This box summarizes key points contained in the article.

Declaration of interest

D Podzamczer has received research grants and/or honoraria for advisories and/or conferences From Gilead Sciences, janssen-Cilag, Merck Sharp & Dome and ViiV Healthcare. JM Tiraboschi has received research grants and/or honoraria for advisories and/or conferences From Gilead Sciences, janssen-Cilag, Merck Sharp & Dome and ViiV Healthcare. The authors have no other 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

A reviewer on this manuscript has disclosed that they served on an advisory board of ViiV for dolutegravir in dual therapy in 2018. Another reviewer on this manuscript has disclosed that they are an advisor on the Antiretroviral Pregnancy Registry and am currently undertaking a study on the use and safety of dolutegravir in pregnancy (funded by ViiV). All other peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.