Introduction

Integrase strand transferase inhibitor (INSTI) drugs like raltegravir (RAL), elvitegravir (ELV), and dolutegravir (DTG), are effective and well-tolerated in HIV treatment, but long-term sustainability data is limited.

Aim

To evaluate the performance of different INSTI-based regimens in a large Italian cohort of people living with HIV (PLWH)

Patient Profile

Participants in the MaSTER cohort who initiated an INSTI-based regimen either at baseline (after diagnosis) or following a regimen switch between 2009 and 2017

Methods

• Retrospective analysis of INSTI-based cART in PLWH:
  • Study population: 24,000+ PLWH from the MaSTER cohort initiating INSTI therapy between 2009-2017.

• Investigated reasons for interrupting treatment and factors associated with interruption
• Compared outcomes for RAL, ELV, and DTG-based regimens
• Performance of cART INSTI-based regimens, overall and stratified by INSTI type (RAL vs ELV vs DTG), using the metrics of efficacy, safety and convenience that together constituted the ‘‘durability’’ of the INSTI-based regimen.

Defining interruption metrics and evaluating regimen durability:

• Efficacy interruption: Virological failure (>50 HIV-RNA copies/ml at least 6 months after therapy initiation).
• Safety interruption: Laboratory alterations (grades 3-4) or clinical progression.
• Convenience interruption: Reasons related to tolerability or practicality.
• Overall and stratified evaluation of cART INSTI-based regimen durability based on efficacy, safety, and convenience metric

Result

• A total of 8173 participants within the MaSTER cohort initiated INSTI-based cART regimens between the years 2009 and 2017. The demographic composition primarily comprised males (72.6%) and those with prior cART experience (83.0%).
• The mean age at treatment initiation was 49.7 years.

• 34% of participants interrupted their first INSTI-based regimen
• Across all three INSTI-based therapies, safety concerns emerged as the most frequently reported reason for treatment interruption (20% of all interruptions).

Associations with treatment interruption for the metrics of durability

• Individuals aged 50+ had higher risk (HR: 1.14).
• Non-virally suppressed at baseline had higher risk (HR: 1.25).

• 3-drug therapy vs. 2-drug therapy had higher risk (HR: 1.21).
• Initiating therapy later (2012-2017) had higher risk (HR: 1.43-1.78), and HCV/HBV positivity had higher risk (HR: 1.15).

Associations with Increased Risk of Treatment Interruption for Efficacy

• Later diagnosis year was associated with higher risk (HR: 1.25).
• Longer time between diagnosis and therapy start had higher risk (HR: 1.26).
• Baseline Viral Suppression: Non-virally suppressed at baseline had significantly higher risk (HR: 4.34).
• Past experience with cART medication was associated with higher risk (HR: 2.05).

Associations with Lower Risk of Treatment Interruption for Convenience

• Individuals aged 50+ had lower risk than those under 50 (HR: 0.65).
• Males had lower risk than females (HR: 0.69).
• Shorter time between diagnosis and treatment start had lower risk (HR: 0.90).

Associations with Higher Risk of Treatment Interruption for Convenience

• People who inject drugs (PWID) had higher risk than heterosexual individuals (HR: 1.49).
• Initiating newer INSTI-based therapies (2012-2017) had higher risk than earlier cohorts (2009-2011) (HR: 1.66-1.97).

Associations with Increased Risk of Treatment Interruption for Safety

• Individuals aged 50+ had higher risk than those under 50 (HR: 1.51).
• Non-virally suppressed at baseline had higher risk (HR: 1.17).
• 3-drug therapy vs. 2-drug therapy had higher risk (HR: 1.23).
• Initiating therapy later (2012-2014) had higher risk than earlier cohorts (HR: 1.83) and having hepatitis (HCV or HBV) was associated with higher risk (HR: 1.19).

Associations with Lower Risk of Treatment Interruption for Safety

• Later diagnosis year was associated with lower risk (HR: 0.91).
• Higher CD4 count (>500 cells) had lower risk (HR: 0.86).
• Shorter time between diagnosis and treatment start had lower risk (HR: 0.90).

 Treatment Interruption Stratified by Therapy Type

• Higher hazards of interruption due to convenience for DTG & RAL
• Lower hazards of interruption for all metrics when on EVG.
• RAL increased risk of interruption for durability with increasing diagnosis year.
• DTG & EVG increased risk of interruption for convenience with later initiation cohorts (2012-2017)

Conclusion

• One-third of PLWH in this study interrupted their first INSTI-based regimen, with decreasing frequency in the subsequent three-year periods mainly due to safety concerns
• The primary cause of treatment interruption was toxicity-related events, occurring at a moderate frequency and accounting for approximately 20% of all discontinuations within the study population. Notably, individuals experiencing these events switched to DTG-based regimens.
• Several factors increased the risk of interruption, including previous cART use, non-viral suppression, and low CD4+ count.
• DTG appeared to be more durable than RAL and ELV, but longer follow-up is needed for confirmation.

Reference

Eur. J. Med. Res.2023; 28:292.