Switching ART in Patients With Prior Resistance

Key Takeaways:

• In patients with virologic suppression and no resistance to integrase inhibitors, recent data support antiretroviral therapy switch strategies with dolutegravir plus emtricitabine or lamivudine/tenofovir, or with bictegravir plus emtricitabine/tenofovir even with nucleos(t)ide reverse-transcriptase resistance.
• In patients with virologic failure, switch strategies may not be as effective because resistance to the integrase strand transfer inhibitor is possible.

In the past few years, we have transformed our understanding of how to treat patients with HIV who have virologic suppression and multidrug resistance. However, before optimizing antiretroviral therapy (ART) in patients receiving older regimens, the first step is to carefully review their treatment history and know which therapies they have previously taken. It also is critical to know the results of any prior resistance testing to learn the history of their HIV drug resistance.

Often, patients whose HIV was multiclass resistant in the early 2000s have achieved viral suppression with raltegravir plus darunavir, sometimes combined with etravirine, maraviroc, and/or nucleoside inhibitors. Some patients still are receiving these complex regimens, but several recent studies suggest we can effectively switch patients from these regimens to newer regimens containing antivirals with higher barriers to resistance. Below, I describe these trials and what we have learned from them about optimizing ART in patients with and without virologic suppression.

Switching to Dolutegravir in Patients With Virologic Failure
One of the most important studies evaluating ART switching is NADIA, which enrolled patients with HIV receiving a non-nucleoside reverse-transcriptase inhibitor with emtricitabine or lamivudine/tenofovir for ≥6 months with virologic failure. Patients first were randomized to receive dolutegravir or ritonavir-boosted darunavir and subsequently randomized to receive lamivudine/tenofovir or lamivudine/zidovudine. At baseline, >90% of patients had intermediate or high levels of resistance to lamivudine, and >50% had intermediate or high levels of resistance to tenofovir. Approximately 50% of patients had baseline K65R/N mutations, and approximately 85% had M184V/I mutations.

Switching to dolutegravir plus 2 nucleoside reverse-transcriptase inhibitors (NRTIs) was noninferior to switching to ritonavir-boosted darunavir plus 2 NRTIs regardless of baseline characteristics and randomized NRTIs. The dolutegravir was certainly every bit as good virologically, as there were similar rates of virologic rebound. However, 9 of the 235 patients who received dolutegravir developed treatment-emergent resistance. So, a downside to switching ART to this regimen in patients with virologic failure is the risk of dolutegravir resistance.

Switching to Dolutegravir in Patients With Virologic Suppression
The 2SD study enrolled patients with viral suppression receiving a second-line regimen of boosted protease inhibitor plus 2 nucleoside inhibitors to switch to dolutegravir plus 2 nucleoside inhibitors or continue their original therapy. They could not have received an integrase inhibitor previously. Baseline resistance data were not collected, but previous studies of second-line therapy in sub-Saharan Africa have found that NRTI resistance is common with patients maintaining virologic suppression if receiving a drug with a high barrier to resistance.

The 2SD study found that switching to dolutegravir was noninferior, and there were no reports of resistance to the study drugs, at least based on the presentation of the study at the 2022 Conference on Retroviruses and Opportunistic Infections (which has not yet been published or peer reviewed). This suggests it is safe to switch ART to dolutegravir plus 2 nucleoside inhibitors in patients who have maintained virologic suppression on a boosted protease inhibitor plus NRTIs even in populations where nucleoside resistance is common. These results are very encouraging and contrast with what we have learned with first-generation integrase inhibitors, most notably raltegravir.

Switching to Bictegravir in Patients With Virologic Suppression
If the switching strategy works for dolutegravir plus 2 nucleoside inhibitors in patients who have maintained virologic suppression, does it work with bictegravir/emtricitabine/tenofovir in this same population?

Although there are fewer data with bictegravir/emtricitabine/tenofovir, a pooled analysis of 2034 patients with baseline viral suppression (182 with the preexisting M184V mutation) found that switching to this regimen was noninferior and there was no treatment-emergent resistance—hence, losing the full activity of emtricitabine does not seem to impact the switching strategy. Other studies of patients with baseline viral suppression who switched to bictegravir/emtricitabine/tenofovir are BRAAVE 2020 and Study 380-4030. Both of these trials showed that baseline NRTI resistance does not predict virologic failure when switching to a bictegravir-based regimen.

From these data, I believe we can use either of these switching strategies in patients with virologic suppression and NRTI resistance, with no apparent virologic failure if they continue to be adherent to their regimen. However, among patients with current virologic failure, there is a risk of emergent integrase strand transfer inhibitor drug resistance, and healthcare professionals should do this with caution.

Your Thoughts?
Have you switched ART regimens for any of your patients with virologic suppression and a history of multidrug resistance? Join the discussion by posting in the comments section below.