Research Director (HIV and Infectious Diseases)
Hospital La Paz. IdiPAZ.
José R. Arribas, MD, has disclosed that he has received consulting fees from Aelix, Gilead Sciences, Janssen, Merck, Teva, and ViiV Healthcare and funds for research support from Gilead Sciences, Merck, and ViiV Healthcare.
How to safely switch ARVs in virologically suppressed patients without a complete history of virologic failures and/or resistance test results remains an unresolved issue in HIV treatment. The complexity of such cases increases when switching away from a boosted PI–based regimen to drugs with a lower genetic barrier to resistance (eg, NNRTIs or first-generation INSTIs) or when reducing the total number of drugs as in the dual regimens dolutegravir (DTG)/lamivudine (3TC), DTG/rilpivirine (RPV), or long-acting cabotegravir (CAB) plus RPV, the latter of which is anticipated but not yet approved.
A decade ago, results of the SWITCHMRK studies taught clinicians to be careful when considering ART modification in the context of virologic suppression. In SWITCHMRK 1 and 2, patients switching from lopinavir (LPV)/ritonavir (RTV) to raltegravir (RAL) while maintaining a backbone of at least 2 NRTIs were more likely to lose virologic suppression if they had a history of virologic failure or if the LPV/RTV-based therapy was not their first regimen. The take-home message? Don’t switch from high genetic barrier to low genetic barrier regimens if the activity of background NRTIs cannot be guaranteed.
The question then remains: What course of action is best when necessary mutational information is unavailable? The most prudent approach is to avoid switching ART in these circumstances. However, this strategy is untenable when there is an important reason to modify therapy such as elimination of an adverse event or presentation of a new comorbidity.
Performing Proviral DNA Testing
One approach to mitigate the potential impact of a missing patient history is to perform “virus archeology” by means of proviral DNA testing. This type of resistance testing aims to identify mutations in cell-associated proviral DNA and so can be done in the absence of detectable plasma HIV-1 RNA.
In theory, if historical RNA genotyping indicated the presence of M184V, this mutation should be archived in proviral DNA and detectable years later, even in the setting of virologic suppression. Unfortunately, in practice, historical mutations are not always detected by proviral DNA testing because it lacks sensitivity and is subject to sampling limitations, only distinguishing mutations that represent at least 10% to 20% of the total viral population. This contrasts with plasma genotyping, which tests for mutations in the setting of active viral replication uniformly distributed in a sample. Another disadvantage of proviral DNA testing is its detection of mutations that might not be clinically relevant; such sequences can be archived in defective viruses, which constitute most of the viral reservoir.
These limitations are recognized both by EACS and DHHS ART guidelines in their recommendations about how to interpret the results of proviral DNA testing. So far, no study has shown that performing proviral DNA genotyping improves patient outcomes when switching ARVs in virologically suppressed patients.
Maintaining the Genetic Barrier to Resistance
Another approach is to switch the regimen without decreasing its overall genetic barrier to resistance. For example, if a patient needed to modify boosted darunavir (DRV) plus emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) because of renal or bone adverse events, switching to DRV/cobicistat (COBI)/FTC/tenofovir alafenamide (TAF) should alleviate the toxicities associated with boosted TDF without increasing the risk of regimen failure. This exact switch was successful in the EMERALD trial, even in participants with a history of virologic failure, which makes sense because boosted DRV plus FTC/TDF should have a genetic barrier similar to DRV/COBI/FTC/TAF.
Another consideration: What if we also want to avoid the boosting drug because of drug–drug interactions? Could dual therapy be an option in this setting? The trials that tested DTG/3TC, DTG/RPV, and long-acting CAB plus RPV for maintenance of virologic suppression excluded participants with a history of virologic failure. Consequently, these regimens should not be considered if there is suspected archived resistance to any component of the regimen.
By contrast, accumulating evidence suggests that switching to a second-generation INSTI (ie, DTG or bictegravir [BIC]) plus 2 NRTIs might not need the guarantee that both NRTIs are fully active. Results from Studies 380-1878, 380-1844, and 380-4030 suggest that BIC/FTC/TAF and DTG plus FTC/TAF are effective treatment options for virologically suppressed patients, including those with evidence of archived NRTI resistance.
Interested in Learning More?
To hear more about incorporating the latest data and guidance into ART selection for your patients, including those with virologic suppression, view this CME-certified video module featuring case-based discussions among me and my colleagues, Alexandra Calmy, MD, FMH, PhD; Jean-Michel Molina, MD, PhD; and Laura Waters, MD.