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Drug Resistance Testing Before LA ART
Why I Recommend Drug Resistance Testing Prior to Long-Acting Injectable ART Initiation

Released: July 18, 2023

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Key Takeaways
  • Before initiating LA injectable ART, healthcare professionals should complete resistance testing to inform medical decision-making.
  • I believe proviral DNA testing should be considered for patients with suppressed HIV-1 RNA prior to initiating LA ART.

Long-acting (LA) injectable antiretroviral therapy (ART), including LA cabotegravir plus rilpivirine (CAB + RPV), is a desirable regimen for some people living with HIV who may not want to continue taking pills every day. Those interested in LA ART, however, should have an extensive review of their prior antiretroviral therapy and resistance testing conducted before starting these agents.

Recently, I was involved in the care of a person living with HIV that was virologically suppressed using bictegravir (BIC)/tenofovir alafenamide (TAF)/emtricitabine(FTC), with documented low-level resistance to RPV demonstrated only on the proviral DNA genotype. Here’s how we approached treatment.

A Patient Case
A 30-year-old cisgender male diagnosed with HIV 2 years ago presented to the clinic for a follow-up visit and shared his interest in LA ART. He had started with BIC/TAF/FTC daily and had confirmed virologic suppression since the initiation of therapy.

Despite demonstrating adherence to the oral ART, the patient stated that he would like to switch to LA therapy because of his work schedule and his dislike of the daily reminder of HIV that comes with taking ART daily. The patient was unable to obtain RNA resistance testing with HIV-1 RNA <50 copies/mL, so we completed resistance testing using proviral DNA genotyping.

Results from the proviral DNA testing demonstrated the following resistance mutations.

  • Nucleos(t)ide reverse-transcriptase inhibitors (NRTIs): No resistance-associated mutations (RAMs) were identified.
  • Nonnucleoside-reverse transcriptase inhibitors (NNRTIs): A98G, V35T, E36A, T39D, S48T, V60I, T200A, V245Q, T2856A, E291D, V292I, and K311R.
  • Protease inhibitors (PIs): T12A, E35D, R41K, D60E, I62V, L63P, and I93L.
  • Integrase strand transfer inhibitors (INSTIs): No RAMs were identified.

Stanford University’s HIV Drug Resistance Database did not identify significant resistance to the PIs, NRTIs, or INSTIs, but it did identify NNRTI resistance with potential low-level resistance to etravirine, doravirine, efavirenz, and RPV and intermediate resistance to nevirapine.

The database then provided the following interpretation: “This virus is predicted to have low-level reduced susceptibility to [rilpivirine]. The use of the combination of CAB [+] RPV should be considered relatively contraindicated.”

Determining the Best Therapy
LA CAB + RPV has been demonstrated to be noninferior to oral ART in patients who are virologically suppressed and offers an opportunity for some people living with HIV to eliminate their pill burden. Virologic failure is generally highest among patients who have ≥2 of the following baseline variables: RPV drug-resistance mutations, HIV-1 subtype A6/A1, and/or a baseline BMI >30 kg/m2.

The case patient’s BMI was <30 kg/m2 and, although we did not have confirmation of the HIV subtype, it would be unlikely that he has the A6/A1 subtype. Therefore, he had only 1 baseline risk factor for virologic failure: The RPV RAMs we identified by resistance testing. In patients who have ≤1 of these baseline risk factors, the risk of virologic failure is generally <2%.

Furthermore, a recent study demonstrated that 5% more high-frequency and 14% more low-frequency drug-resistance mutations were detected with use of proviral DNA genotyping compared with standard HIV RNA genotyping in adults recently diagnosed with HIV who are ART naive. It is unclear if these additional mutations have any impact on clinical response and development of future resistance. The theoretical concern is that exposure to RPV may lead to potential viral rebound. 

After discussing the proviral DNA resistance testing results and recommending that the patient avoid LA CAB + RPV alone because of increased risk of viral rebound in the setting of low-level RPV resistance, he ultimately decided to continue his oral ART with BIC/TAF/FTC. However, he continues to express interest in LA injectable ART, and he will consider it in the future if other options become available. 

As highlighted above, a case like this should prompt healthcare professionals to consider using proviral DNA genotyping prior to initiating LA injectable ART in patients with undetectable HIV-1 RNA.

Your Thoughts?
Before initiating LA injectable CAB + RPV, are you currently performing proviral DNA testing for patients with undetectable HIV-1 RNA? Join in the conversation by answering the polling question and posting a comment below.