Foundations of ART Management in Heavily Treatment–Experienced Patients

The SWITCHMRK study may be considered a cautionary tale of between-class switches.²⁶ This was a study published in 2010, when RAL became available as the first-in-class, well-tolerated INSTI. At that time, we had many patients who were stable and virologically suppressed on boosted PIs. These regimens were, at the time, more complex and associated with some toxicity. SWITCHMRK-1 and -2 randomized patients to stay on their boosted PI regimen (LPV/RTV plus 2 NRTIs) or switch to RAL plus 2 NRTIs.

These studies were stopped early because of a higher rate of virologic failure in the switch group. When the predictors of failure were analyzed, it was very clear that those who had a history of earlier virologic failure at any time before they ultimately became suppressed on their current boosted PI–based regimen were at higher risk of failing with the RAL-based regimen.

This is illustrated in the table. Among those with no previous virologic failure, approximately 90% in both groups remained virologically suppressed with HIV-1 RNA <50 copies/mL. However, among those who experienced previous viral failure and received RAL, only 77% remained suppressed, whereas those who remained on the boosted PI–based regimen had a similar outcome to those with no virologic failure in their history.

We learned from this study that between-class switches need to be done with caution, particularly if the new regimen does not include a drug with a high barrier to resistance.

Since SWITCHMRK, several studies have reinforced the concept that switching to a new regimen containing a drug with a high barrier to resistance can be done safely in patients with some underlying viral resistance. The BRAAVE 2020 study investigated a switch to BIC/FTC/TAF in patients with stable virologic suppression on a regimen that included 2 NRTIs and a third agent—first-generation INSTIs, boosted PIs, and NNRTIs.²⁷ The results documented very high rates of virologic suppression at Weeks 24 and 48. The primary endpoint at 24 weeks is shown in the right figure in the slide.

A high level of virologic suppression was maintained with both the switch regimen and the original regimen even among those who had underlying NRTI resistance in the form of M184V. The reason for this was because they were going to a new drug with a high barrier to resistance, in this case, BIC.

This pooled analysis of 6 phase III studies included more than 2000 individuals who were virologically suppressed and switched their regimen to BIC/FTC/TAF.²⁸ Among these, 10% had M184V, documented either by the proviral DNA genotypic resistance testing or by treatment history. In addition, some patients had NNRTI resistance, some had PI resistance, and a small number had resistance to INSTIs.

As we saw in BRAAVE 2020, high levels of virologic suppression were maintained regardless of whether M184V (and other resistance) was present or not. This study emphasizes that a high-barrier drug will remain active even if only 1 of the NRTIs in the regimen is fully active.

380-4030 studied a switch to BIC/FTC/TAF in virologically suppressed patients receiving DTG plus 2 NRTIs.²⁹ A total of 25% of these patients had underlying NRTI resistance. After the switch to BIC/FTC/TAF, >90% remained virologically suppressed, a rate similar to those who remained on their stable DTG regimens. 

Virologic suppression was also evaluated based on underlying resistance. Overall virologic response rates were very high, in the range of 90% even in those who had underlying resistance; very similar to that obtained if there was no NRTI resistance.^29,30 If we look at other NRTI resistance, including K65R (tenofovir resistance), thymidine analogue mutations, unspecified RT mutations, or M184V with or without other resistance mutations, we still see very high rates of virologic suppression. 

Once again, these data suggest that switching from a regimen including 1 agent with a high barrier to resistance to another regimen with an agent with a similarly high barrier can be effective in virologically suppressed patients, even in the setting of underlying resistance.

Modifying ART regimens in patients with virologic suppression may be done for many reasons, including convenience, tolerability, drug–drug interactions, and others.

Before a planned switch is implemented, it is very important that we carefully consider the presence of documented or inferred underlying drug resistance to inform our decision.

Many studies illustrate that suppression can be maintained when simplifying to a regimen that includes an agent with a high genetic barrier to resistance—such as a second-generation INSTIs—even when underlying resistance to NRTIs is present.