Proviral DNA Resistance Testing: Uses and Limitations When Switching ART

Key Takeaways

• Proviral DNA genotypic resistance tests may add useful information for switching ART when a complete clinical history is not available, including when considering a switch to long-acting agents.
  • However, the results must be interpreted with caution because the test may miss clinically relevant, archived resistance mutations.

There are many situations in which someone receiving suppressive antiretroviral therapy (ART) may need or want to switch to a different HIV regimen. Examples where a switch may be required include treatment-related toxicity or intolerability, development of comorbidities, and pregnancy planning. In many countries, the recent emergence of a long-acting, injectable treatment option may be increasing interest in switching ART for people who have had difficulty with daily oral therapy or who prefer the convenience of an every-2-month option.

The most important goal when switching ART in people with viral suppression on their current regimen is maintaining viral suppression. To achieve this goal, it is critical that healthcare professionals assess for any potential history of virologic failure and/or drug resistance that could impair the efficacy of the switch regimen. 

Switching in the Absence of ART History: The Role of Proviral DNA Resistance Testing
A careful evaluation of an individual’s treatment history will reveal if the person has ever experienced virologic failure on any of the drugs you are considering in the switch regimen as well as any detected resistance to those drugs. However, it is sometimes the case that a complete treatment history is not available, perhaps because the person moved without a transfer of medical records or experienced a previous disruption in care. In these cases, we have a tool that can assist in detecting archived drug resistance in the setting of viral suppression: proviral DNA genotypic resistance testing. This test is not difficult to perform. Unlike standard plasma HIV-1 RNA drug resistance testing, proviral DNA sequencing examines HIV proviruses that have integrated into the chromosomes of peripheral blood mononuclear cells. Because proviral DNA reflects an archive of the viral mutations that emerge over the course of infection, it can provide a historical record of drug resistance mutations. 

However, proviral DNA resistance testing is not without its limitations. The main drawback as described in expert guidelines from the US Department of Health and Human Services and the European AIDS Clinical Society is sensitivity. The test can identify resistance associated mutations present in ≥10% of proviral species, but it may not detect all relevant archived mutations. Specificity is also a limitation in that the test can detect mutations that are clinically irrelevant. Therefore, the results must be interpreted with caution. If relevant resistance associated mutations are identified, they should be considered as present and should be incorporated into the identification of an optimal switch regimen. By contrast, the absence of detectable resistance should not be interpreted as absolute assurance that such resistance is not present. This limitation underscores the importance of making every effort to obtain all previous clinical records whenever possible. 

Proviral DNA Resistance Testing When Considering a Switch to Long-Acting ART
What role does proviral DNA genotypic resistance testing play when considering a switch more specifically to long-acting cabotegravir (CAB) plus rilpivirine (RPV)? First, it is helpful to consider that long-acting injectable CAB plus RPV is indicated as a complete HIV switch regimen for people who are hepatitis B immune, with virologic suppression on their current ART, no history of treatment failure, and no known or suspected resistance to either CAB or RPV. In addition, clinical trials have demonstrated that switching to long-acting CAB plus RPV is safe and highly effective, with a very low ~1.4% absolute risk of virologic failure.

However, this regimen does appear to have a slightly lower genetic barrier to resistance vs daily oral HIV therapies that include a second-generation integrase inhibitor (INSTI; ie, bictegravir [BIC] or dolutegravir [DTG]), as there have been cases of virologic failure with the emergence of INSTI resistance.

Based on the recommended regimens in most national and international guidelines, many candidates interested in a switch to long-acting CAB plus RPV are likely to be currently receiving a daily, oral 3-drug regimen containing BIC or DTG. Therefore, when switching from these regimens to long‑acting CAB plus RPV, we are effectively decreasing the genetic barrier to resistance of the regimen. In addition, multivariable analyses have demonstrated that the strongest predictive factor for virologic failure after switching to long‑acting CAB plus RPV is the presence of archived RPV resistance associated mutations at baseline, with incidence rate ratios for confirmed virologic failure of 21.7-25.7, depending on the analysis. 

For these reasons, it is even more crucial that we have as much information as possible regarding the potential past history of virologic failure and/or drug resistance when considering a switch from BIC-based or DTG-based 3-drug, daily oral therapy to long-acting injectable CAB plus RPV. As in the general clinical scenario of switching ART with viral suppression, proviral DNA resistance testing may provide useful information here if a complete clinical history is unavailable. If the test reveals archived RPV resistance associated mutations or CAB resistance associated mutations, a switch to long-acting CAB plus RPV would not be advised. If the test does not identify any RPV resistance associated mutations or any INSTI resistance associated mutations, this can provide some reassurance that the switch may be effective; however, as noted, the limited sensitivity of proviral DNA resistance testing does not guarantee that such mutations are not present, and caution is warranted.

Your Thoughts?
Have you incorporated proviral DNA resistance testing when switching ART in your clinical practice, and in which clinical scenarios? How about specifically when switching to long-acting agents? Join the discussion and share your experiences by posting a comment.