Cabenuva is Not Recommended for Patients with Y181Y/C and H221H/Y Resistance Mutations
A patient with resistance-associated mutations (RAMs) including Y181Y/C and H221H/Y should not receive Cabenuva (cabotegravir and rilpivirine) due to demonstrated resistance to rilpivirine, which is a key component of Cabenuva. 1, 2
Understanding the Patient's Resistance Profile
The patient's genotype results show:
- Resistance to rilpivirine (Edurant) due to Y181Y/C and H221H/Y mutations 2
- Resistance to etravirine (Intelence) due to V106V/I, Y181Y/C, and H221H/Y mutations 2
- Resistance to nevirapine (Viramune) due to Y181Y/C mutation 2
- Possible resistance to doravirine (Pifeltro) and efavirenz (Sustiva) 2, 3
Why Cabenuva is Contraindicated
- Cabenuva contains rilpivirine as one of its two active components 1
- The patient's virus shows resistance to rilpivirine due to Y181Y/C and H221H/Y mutations 2
- Cross-resistance has been observed among NNRTIs, and the Y181C mutation specifically confers resistance to rilpivirine 2, 4
- The H221H/Y mutation further contributes to rilpivirine resistance 2, 4
Evidence for Cross-Resistance
- The FDA drug label for doravirine explicitly states that "treatment-emergent doravirine resistance-associated substitutions can confer cross resistance to efavirenz, etravirine, nevirapine, and rilpivirine" 2
- Y181C is a major NNRTI resistance mutation that affects multiple drugs in this class 2, 4
- When multiple NNRTI mutations are present (as in this case with V106V/I, Y181Y/C, H221H/Y), cross-resistance is more likely 4
Alternative Treatment Options
For patients with NNRTI resistance, guidelines recommend:
- Integrase strand transfer inhibitor (InSTI)-based regimens without rilpivirine, such as dolutegravir or bictegravir with appropriate NRTIs 1
- Boosted protease inhibitor-based regimens, such as darunavir/ritonavir with appropriate NRTIs 1
- For patients with complex treatment history and multidrug resistance, therapy with at least 2 fully active drugs from different antiretroviral drug classes is recommended 1
- Newer agents like ibalizumab, fostemsavir, or lenacapavir may be considered for patients with limited treatment options 1, 5
Clinical Implications
- Using Cabenuva in this patient would effectively be using monotherapy with cabotegravir, as the rilpivirine component would be ineffective 2, 4
- Monotherapy is strongly discouraged as it leads to rapid development of additional resistance 1
- Adding a single active drug to a failing regimen is not recommended (evidence rating: AIIa) 1
- Resistance testing should guide the selection of an appropriate alternative regimen 1
Common Pitfalls to Avoid
- Do not assume that long-acting formulations will overcome resistance issues - the same resistance principles apply regardless of drug delivery method 1
- Do not use Cabenuva without confirming susceptibility to rilpivirine, especially in patients with prior NNRTI exposure 1, 2
- Remember that the Y181C mutation is one of the most common NNRTI resistance mutations and significantly impacts rilpivirine effectiveness 4, 6
- Avoid underestimating the impact of mixed mutations (indicated by Y/C notation), as these still represent resistant viral populations 2, 4