Principles for Switching Antiretroviral Therapy: Determinants of ART Choice

Key Takeaways:

• Various factors need to be considered when contemplating a switch in antiretroviral therapy (ART).
• Toxicity, either long term or immediate, is the most common reason to consider a switch in ART regimen.
• For those who may be reluctant to switch, it can be reassuring to know that if the new ART regimen is not well tolerated, it is typically okay to switch back to the previous well-tolerated regimen when virologically suppressed. 

A vast range of choices exists for antiretroviral therapy (ART) for adults with HIV-1 infection in better resourced and resource-limited countries. Global guidelines have coalesced around the use of second-generation integrase strand transfer inhibitors in first-line treatment, because they are well tolerated and highly potent against HIV with few drug–drug interactions and because they achieve rapid viral suppression. There are, however, many reasons to consider a switch in treatment, both in individuals receiving these currently recommended regimens and in those receiving older therapies.

Recently, a 54-year-old British woman originally from Jamaica transferred her care to our clinic. She was doing well and was stable receiving abacavir/lamivudine and a boosted protease inhibitor. She was switched to this regimen many years ago, having had severe hallucinatory adverse events with an efavirenz-based combination, and she had been noted to have a low estimated glomerular filtration rate with moderate proteinuria. She was hepatitis B immune, and her transfer letter indicated no baseline resistance mutations. She had never received an integrase inhibitor and had not experienced virologic failure since initiating ART. She experienced menopause at 48 years of age and had treated hypertension and type 2 diabetes. She had never smoked and had no other comorbidities. She felt that her HIV medicines were working well, and she was not having any adverse events. Here are some questions that came to my mind as her healthcare professional.

1. Should we consider switching her ART?
2. What are her options for switching?
3. What are the concerns if she declines a switch?

Factors to Consider When Contemplating Switching ART Regimens

Centering the Person With HIV in the Decision
First, it is essential that people with HIV are at the center of the decisions about their care and treatment; no one should switch therapy without careful counseling and an understanding of the risks and benefits of doing so. For people receiving long-term, well-tolerated ART regimens, if the new regimen is not tolerated, the reassuring advice is that, for the most part, it is fine to switch back to the previous regimen when virologically suppressed. Finding the best regimen need not preclude previous regimens, if required.

Change can be unsettling, but most people with HIV understand that evidence evolves and that the role of their healthcare professional, in addition to helping them achieve viral suppression and immune reconstitution, is to maximize long-term health and minimize long-term toxicity associated with ART.

Resistance Considerations
Viral considerations may be important. Transmitted drug resistance is increasingly rare, and acquired resistance (most often due to suboptimal adherence to low barrier regimens) is relatively uncommon. Nonetheless, some individuals struggle to achieve viral suppression, and it may be necessary to switch to regimens with a higher genetic barrier to resistance, including, in some cases, those containing a boosted protease inhibitor. Confirmed resistance also must be considered when choosing a new ART regimen. In addition, understanding the individual ART and HIV-1 RNA history can be helpful; even in the absence of confirmed resistance mutations, these may help us avoid agents that we suspect will have reduced activity.

Considering Dosage Form, Pill Burden, and Coinfections
There are multiple reasons for suggesting a switch in ART regimen in individuals with virologic suppression. For instance, individuals with swallowing problems may require a change in formulation to either liquids, smaller tablets, or injectable agents. Food restrictions around dosing and looking to reduce pill burden, including to single-tablet options, may require consideration when contemplating a switch from some regimens. Coinfections, particularly chronic hepatitis B and others, such as tuberculosis, are important, as they may affect ART choices. Hepatitis B vaccination status is another factor to consider when contemplating an ART switch.

Considering Gender, Age, and Comorbidities
Gender, age, and comorbidities are other important considerations. For individuals considering pregnancy or contraception, pregnant individuals, or individuals approaching menopause, the ART choices may be revised accordingly, depending on evolving evidence. For older people with HIV, agents with lower potential for metabolic or cognitive toxicities, or drug–drug interactions, can be considered, given the likely complications of polypharmacy in people with increasing age-related comorbidities. In addition, for individuals set to receive proton pump inhibitors, chemotherapy for cancer, or immunosuppressants for organ transplantation, we may proactively switch ART regimens (particularly away from ritonavir- or cobicistat-boosted regimens) to avoid potential drug–drug interactions.

Cost Considerations
In certain environments and healthcare systems, cost may play an important role in ART switches, but this should not be the primary reason to switch away from an effective, well-tolerated regimen. Nonetheless, some pragmatism is needed if cost constraints occur.

Avoiding Toxicity
The most common reason for switching HIV therapy is immediate or possible long-term toxicity. Detection of biochemical or metabolic toxicity (for instance, low bone mineral density while receiving tenofovir disoproxil fumarate or hypercholesterolemia while receiving a booster) may be reasons to consider a switch to an alternative ART regimen. Similarly, ART-related symptoms, including sleep or mood disturbance, cognitive issues, weight gain, and nausea or other gastrointestinal problems, are common in people with HIV. Although minor adverse events may be tolerated and may decrease over time, those that persist should warrant a discussion about alternative regimens to improve quality of life.

A switch due to potential toxicity in the long term may be contentious, as the long-term clinical endpoint data are unavailable for many newer ART agents. Nonetheless, in ethical medicinal practice, it is imperative that each component of a combined ART regimen is constantly reviewed in the light of evolving evidence to ascertain and discuss whether its virological contribution is required and whether it is potentially causing any long-term risk.

Individualizing ART Regimens When Making a Switch
It is not sufficient to choose an ART regimen based only on the ability of the agent(s) to bring about rapid viral suppression, but it is equally important to make an individualized choice by understanding the risks associated with each agent on a case-by-case basis and to ascertain the need for each agent before switching the regimen.

In the case of the patient transferring care to my clinic, we discussed the potential for drug–drug interactions and possible increased cardiovascular risk from both her boosted protease inhibitor and abacavir. She appreciated the information and was provided with written information about injectable and oral options for switch. She did not want to attend clinic every 8 weeks for injections and decided to switch to a second-generation integrase inhibitor–based regimen. She has tolerated this well but feels that she has some ART-related weight gain and wants to book another appointment to discuss this.

Your Thoughts?
How would you have managed this patient? Would you have switched her ART? What factors, in your experience, contribute most to decision-making when considering a switch in ART regimen? Join the discussion by leaving a comment.