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Simplifying to 2-Drug ART: Safety and Tolerability Considerations

Darcy Wooten, MD

Associate Professor of Medicine
Division of Infectious Diseases and Global Public Health
Department of Medicine
University of California, San Diego
San Diego, California

Darcy Wooten, MD, has no relevant financial relationships to disclose.

View ClinicalThoughts from this Author

Released: December 23, 2022

Key Takeaways

  • Two-drug antiretroviral therapy regimens are effective, safe, and tolerable across a range of patients.
  • Although it is important to be aware of limitations to their use, 2-drug regimens can be considered for antiretroviral therapy simplification in many people with HIV, even among those with substantial medical complexity.

Two-drug antiretroviral therapy (ART) regimens continue to be a nice simplification strategy for people with HIV. Thisapproach can be helpful in situations where multiple comorbidities and drug–drug interactions make ART selection challenging.

As 2-drug ART becomes more prevalent, it is important to consider not only efficacy data, but also safety and tolerability data when selecting these regimens for your patients. Here I will review recent updates from IDWeek and HIV Glasgow 2022 on 2-drug ART, with a focus on safety and tolerability.

Cabotegravir Plus Rilpivirine

Safety Outcomes by Race
At IDWeek 2022, Paul and colleagues shared results from a pooled analysis from FLAIR and ATLAS-2M of 937 participants who received long-acting (LA) cabotegravir (CAB) plus rilpivirine (RPV). Data were stratified by self-reported race (76% White, 16% Black, 4% Asian, 4% other races). Rates of grade 3 or higher adverse events were low across all groups and only very rarely led to discontinuation. No differences in injection site pain were observed; this adverse event occurred in 20% of participants on average, lasting 2-7 days and very rarely leading to discontinuation.

Although there are still opportunities to improve recruitment of underrepresented and marginalized individuals into clinical trials, these data are reassuring that this regimen is safe, effective, and well-tolerated across a diverse patient population.

Neuropsychiatric Effects
Integrase strand transfer inhibitors have been associated with neuropsychiatric adverse events.

A post hoc analysis of ATLAS, FLAIR, and ATLAS-2M assessing drug-related neuropsychiatric effects was presented by Elliot and colleagues at HIV Glasgow 2022.

Through 48 weeks, 9% of patients who received injectable LA CAB plus RPV experienced neuropsychiatric effects compared with 2% of patients who remained on oral therapy. Fewer than 1% of symptoms were characterized as grade 3 or higher or led to withdrawal. Most neuropsychiatric effects (eg, headache, dizziness) resolved within 1 week, whereas other less common effects (eg,
insomnia, abnormal dreams, anxiety, depressive disorders) resolved after several weeks into therapy.

These data are reassuring, but it will be important to see how these effects manifest in real-world experience.

Positive Hepatitis B Core Antibody
Finally, at IDWeek 2022, Welford and colleagues presented a case series describing hepatitis B virus (HBV) in patients switched to injectable LA CAB plus RPV. Of 38 patients with hepatitis B core antibody (anti-HBc) positivity and hepatitis B surface antigen (HBsAg) negativity, 3 patients developed low-level HBV viremia after they switched ART. Two of the patients were switched back to a tenofovir-containing regimen, and the third patient opted to continue with LA CAB plus RPV because of their challenges with daily oral ART. 

Although the significance of low-level HBV viremia in these patients is unclear, it has been linked with worse outcomes in patients with chronic HBV infection who are HBsAg positive. Additional data are needed to understand whether switching patients to LA CAB plus RPV is safe for those who have a positive anti-HBc and negative HBsAg.  


Chronic Kidney Disease
The 2-drug dolutegravir (DTG)/RPV regimen is a convenient single-tablet regimen that is especially suited for individuals with chronic kidney disease (CKD), as it does not require any renal dose adjustments. A prospective, open-label switch study of 35 patients suppressed on ART with CKD (mean estimated glomerular filtration rate 26-47 mL/min/1.73 m2) was presented by Kwakwa and colleagues at IDWeek 2022. The study included participants who are usually underrepresented in clinical trials; 97% of patients were Black, 94% of patients were older than 50 years of age, and patients had an average of 4 comorbidities. Most patients were receiving an ART regimen of 3 pills per day prior to switching to DTG/RPV. All patients maintained viral suppression at Week 24. 

No serious adverse events or discontinuations due to adverse events occurred. In addition, participants reported higher adherence rates and improvement in HIV treatment satisfaction with DTG/RPV compared with their baseline regimen.

The data affirm that DTG/RPV is a safe and well-tolerated regimen, including for individuals who are medically complex with multiple comorbidities. When considering this regimen for a switch strategy, it is important to be cognizant of the food requirement for RPV, as well as the limitations with acid-reducing medications. 

Two-drug ART is a relatively new paradigm shift in HIV treatment that has been effective, safe, and tolerable across a range of patients with substantial medical complexity. Although it is important to be aware of its limitations (eg, presence of relevant resistance mutations, chronic HBV infection, and key drug‒drug and drug‒food interactions), these 2-drug regimens can provide many patients with additional and streamlined options for simplification.

Your Thoughts?
How does tolerability affect how you consider suggesting switches to 2-drug regimens for HIV treatment? Join the discussion by posting a comment. 

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