Viral failure on CAB/RPV-LA: overcoming drug resistance with second-generation INSTIs

13 April 2025. Related: Journal scan, Early access, Treatment strategies, Drug resistance.

Simon Collins, HIV i-Base

One of the major current limitations on wider use of long-acting cabotegravir/rilpivirine injections (CAB/RPV-LA) is the unpredictable risk of virological failure with two-class resistance, despite excellent adherence. This includes concerns about the loss of integrase inhibitors for future ART.

Even though this risk of virological failure in these settings is low, the loss of integrase inhibitors as a class, often also with resistance to NNRTIs, leaves limited choices, largely dependent on PIs.

In a letter to the journal AIDS, Giguère Pierre and colleagues from the University of Ottowa report a case series of five people who responded to bictegravir/emtricitabine/TAF (B/F/TAF), despite developing drug resistance mutations against both cabotegravir and rilpivirine on two-monthly injections. [1]

These five cases were all on INSTI-based ART before switching to CAB/RPV-LA, none were subtype B (one with subtype AG and one with A) and BMI ranged from 25 to 37. All had major mutations associated with both NNRTI and integrase inhibitor drug classes, although the specific integrase mutations had minimal phenotypic impact on drug susceptibility to bictegravir. See Table 1.

Viral rebound was generally detected early while viral load was >1000 to <10,000 copies/mL but included one case of rebound to >90,000 copies/mL which also included the most complex drug resistance.

After switching to B/F/TAF, these cases suppressed viral load to <20 copies/mL, which has been sustained from 6 to 18 months.

Importantly, the genotype resistance profiles supported the likely activity of second-generation INSTIs. For example, 148R on its own has minimal impact on susceptibility to bictegravir and even combined with 138K/148R is only associated with 2-5 fold reduced susceptibility. Similarly, Q148H/K/R reduces susceptibility to cabotegravir by 5-fold but has minimal impact on bictegravir. Multiple mutation complexes however are more difficult to predict and may have more significant impact on phenotypic sensitivity to bictegravir. One participant reported a single G118R mutation that is usually only reported with viral failure on dolutegravir and which might have developed on earlier ART but not been detected at baseline. [2]

The publication also reviews the limited evidence for using second-generation INSTIs reported in other reports, including successfully using dolutegravir-based ART.

Table 1. Responses to Biktarvy in people with INSTI and NNRTI drug resistance on CAB/RPV-LA

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This report highlights the importance of early detection of viral rebound and the potential for drug resistance tests to enable subsequent viral suppression with bictegravir-based ART.

Most reports on choice of ART in cases of virological failure on CAB/RPV-LA report resuppression using a cautious approach with a change to protease inhibitor-based ART. [3]

It would be very helpful if ViiV and others could perhaps publish greater details on all such cases of viral breakthroughs. This would include resistance data and responses to subsequent ART. This data set would be invaluable – and might already be ongoing or have been done.

These detailed results might provide more confidence and awareness that the INSTI class might not be lost for future treatment. 

However, bictegravir and dolutegravir might produce different results. A meta-analysis of 33 studies of CAB/RPV-LA included rates of viral failure of approximately 1% but in the 19/33 with resistance data, roughly 40% to 70% included integrase inhibitor mutations with cross resistance to dolutegravir. [4] 

This was also the focus of an excellent presentation at CROI 2025 by Professor Saye Khoo who discussed viral failure on CAB/RPV-LA as “a low incidence (roughly 1.6% over three years) but high consequence event.” [5]

He also commented that having two or more of the four recognised risk factors for viral failure also excludes many people who could potentially still benefit from injectable ART, especially as the two highest risks were RPV mutations at baseline and having subtype A1/A6. Although low drug levels are commonly reported as a factor, this might be related to variability between injection techniques as well as individual pharmacokinetics.

Although this presentation referred to the use of oral INSTIs to resuppress viral load in 10 participants in the OPERA study using monthly injections, it is notable that neither the choice of INSTI, nor the viral outcomes were reported. [6]

References

1. Giguère P et al. Bictegravir/emtricitabine/tenofovir alafenamide after virologic failure to cabotegravir/rilpivirine. correspondence. AIDS 39(6):p 777-779 May 01 2025. | DOI: 10.1097/QAD.0000000000004133
   https://journals.lww.com/aidsonline/fulltext/2025/05010/bictegravir_emtricitabine_tenofovir_alafenamide.20.aspx
2. Stanford HIV Drug Resistance Database. INSTI Resistance Notes.
   https://hivdb.stanford.edu/dr-summary/resistance-notes/INSTI
3. van Welzen BJ et al. Virological Failure After Switch to Long-Acting Cabotegravir and Rilpivirine Injectable Therapy: An In-depth Analysis. Clin Infect Dis. 2024 Jul 19;79(1):189-195. doi: 10.1093/cid/ciae016.
   https://pmc.ncbi.nlm.nih.gov/articles/PMC11259215
4. Perez Navarro A et al. Virologic failure and emergent integrase strand transfer inhibitor drug resistance with long acting cabotegravir for HIV treatment: A meta-analysis. Clin Infect Dis. 2024 Dec 26:ciae631. doi: 10.1093/cid/ciae631.
   pubmed.ncbi.nlm.nih.gov/39724249
5. Khoo S. CROI 2025. Long-Acting InSTI Strategies: Understanding the Risks for Failure and Resistance. Oral abstract O49.
   https://www.croiconference.org/abstract/3942-2025-s (abstract)
   https://watch.croiwebcasts.org/2025croi/ap/54304 (webcast)
6. Hsu RK et al. Real-World Effectiveness of Cabotegravir + Rilpivirine vs Standard of Care Oral Regimens in the US. CROI 2024. Poster abstract 623.
   https://www.croiconference.org/abstract/real-world-effectiveness-of-cabotegravir-rilpivirine-vs-standard-of-care-oral-regimens-in-the-us (abstract)
   https://www.croiconference.org/wp-content/uploads/sites/2/posters/2024/623.pdf (poster)