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Second-Generation INSTIs
Keeping It Simple With Second-Generation INSTIs

Released: October 27, 2023

Don E Smith
Don E Smith, MD, FRCP (London) FAChSHM
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Key Takeaways
  • Second-generation INSTIs have simplified initiating and switching ART regimens, even when considering baseline CD4+ cell count and HIV-1 RNA, presence of resistance, or other patient-specific factors.

Initiating and switching antiretroviral therapy (ART) regimens used to be a complex process. There were several factors to consider such as baseline CD4+ cell counts and HIV-1 RNA, resistance genotypes, and comorbidities while selecting drug combinations with sufficient potency yet acceptable toxicity. The era of second-generation integrase strand transfer inhibitors (INSTIs), such as bictegravir (BIC) and dolutegravir (DTG), has radically changed that mindset.

Treating HIV in Australia

In Australia, we are fortunate that the cost of antiretrovirals (ARVs) is fully subsidized by the federal government, meaning we, as healthcare professionals, are free to select treatment based on evidence rather than cost or insurance status.

Treatment initiation has never been so simple. Second-generation INSTIs are now the predominant backbone of therapy. I tell new patients, “You have a virus that is slowly rotting your immune system and will kill you. If you take 1 tablet per day, that will never happen. You can live a normal life—with the same opportunities for work, unprotected sex, having a family as previously—can you do that?” Almost all patients say “yes,” so it is no surprise to me that 98% of people living with HIV receiving treatment are virologically suppressed in Australia.

Second-Generation INSTIs

2-Drug Regimens

Requiring 3 different ARVs to suppress the virus has been a long-standing dogma that has been overturned. Several clinical trials (eg, GEMINI 1 and GEMINI 2) and cohort studies have confirmed the effectiveness of the 2-drug combination DTG/lamivudine (3TC) in people who are treatment naive. Two-drug regimens can be considered in patients who are interested but not recommended in patients with high HIV-1 RNA (>500,000 copies/mL) or hepatitis B virus coinfection.

ARV Resistance

As transmitted drug resistance is rare in Australia, there is really no need to wait for these results before starting therapy.

In addition, among those with transmitted drug resistance and treatment failure, treatment options can be simplified to once-daily regimens comprising 1-2 tablets. This is an important point as most patients develop resistance from medication nonadherence.

Some approaches that I use to simplify ART regimens based on the presence of resistance include the following:

  • If no current or archived ARV resistance: consider either a 2-drug regimen like DTG/3TC or a preferred 3-drug regimen
  • If nucleos(t)ide reverse transcriptase inhibitor or nonnucleoside reverse transcriptase inhibitor resistance present: consider BIC or DTG with tenofovir alafenamide (TAF) and emtricitabine (FTC) (tenofovir disoproxil fumarate could also be considered if TAF is unavailable)
  • If multiclass resistance present, including a single INSTI mutation: consider darunavir/cobicistat/FTC/TAF plus DTG

Empowering Patients

Simplifying ART can be considered for many people who are stable on their current ART regimens. During regular monitoring visits, it is important to take the opportunity to assess whether your patient’s current treatment still meets the needs. By doing this, you can reassess any adverse events and changes in preferences and discuss other treatments, including newer treatment options such as injectable ART.

Keep It Simple

Practicing the “keep it simple” mindset lets people living with HIV maintain viral suppression and remain in control of their HIV care, allowing ART modifications with changing preferences. The simplicity of current regimens can empower patients. Their HIV infection is no longer a constant and present threat but more of an inactive past issue that is easy to keep at bay in the background. I believe this mindset has helped many Australians remain virologically suppressed, and I suspect that will continue with our ongoing efforts of keeping it simple.

Your Thoughts?

In your practice, what strategies do you use to simplify ART regimens for people with HIV? Join the discussion by posting a comment.