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  11th IAS Conference on HIV Science 18-21 July 2021
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CAB + RPV Failure Risk Factor in 10% of Large French Cohort
  IAS 2021, 11th IAS Conference on HIV Science, July 18-21, 2021
Mark Mascolini
One in 10 antiretroviral-naive people in a 4200-person French HIV cohort had 1 pretreatment virologic risk factor for virologic failure of monthly or every-2-month cabotegravir plus rilpivirine (CAB + RPV) [1]. Only 0.4% of the group had two virologic failure risk factors before starting CAB + RPV, but 2 baseline risk factors carried a much higher risk of virologic failure.
Multivariable analysis across 3 phase 3 trials of long-acting CAB + RPV—the injectable combination of an integrase inhibitor and a nonnucleoside—determined that 1.25% of participants (13 of 1039) naive to CAB + RPV had confirmed virologic failure [2]. Four variables raised odds of virologic failure with CAB + RPV: RPV resistance mutations before treatment began (odds ratio [OR] 37.24), HIV-1 subtype A6/A1 (OR 6.59), lower log2 post hoc week 8 RPV trough concentration (OR 4.17), and higher pretreatment body mass index (OR 1.13).
Among people with no baseline (pretreatment) risk factors, 3 of 732 (0.41%) had confirmed virologic failure, as did only 1 of 272 (0.37%) with any one baseline risk factor [2]. But the researchers saw confirmed virologic failures in 9 of 35 people (26%) with two or more baseline risk factors.
The new study aimed to calculate the prevalence of baseline virologic risk factors for CAB + RPV failure in a large group of antiretroviral-naive people with HIV [1]. The analysis involved people at three big Parisian academic hospitals who had reverse transcriptase and integrase sequences available between 2010 and 2020. The investigators analyzed these viral sequences for RPV and CAB resistance-associated mutations by combining the French ANRS algorithm (www.hivfrenchresistance.org) and the IAS-USA list [3].
The Paris team evaluated 4212 HIV-1 sequences from 4212 antiretroviral-naive people with both reverse transcriptase and integrase sequences available. About one third of viral sequences came from people with HIV-1 subtype B (39%) or circulating recombinant form (CRF)02_AG (32%), while 5% were subtype A and 3% subtype C. In the subtype A group, 86% of sequences (186 sequences) came from subtype A6/A1 virus.
Prevalence of CAB resistance mutations stood at 16.2%, but that rate fell to 3.2% when the researchers excluded the L74I polymorphism. CAB resistance mutation prevalence was higher in non-B than B HIV-1 subtypes (21.5% vs 7.7%, P < 0.0001). The ANRS algorithm determined that only 31 sequences (0.74%) from these 4212 antiretroviral-naive people were resistant to CAB.
Prevalence of RPV resistance mutations measured 14.3%, with no prevalence difference between B and non-B subtypes. The ANRS algorithm figured that 6.2% of sequences were resistant to RPV before treatment began, with significantly higher resistance prevalence in non-B than in B virus (7.4% vs 4.2%, P < 0.0001).
Of the 4212 total HIV-1 sequences, 183 (4.3%) were subtype A6/A1. Among the 261 sequences resistant to RPV, 17 (6.5%) were subtype A6/A1.
Among all 4212 sequences, 427 (10.1%) had 1 baseline (pretreatment) virologic risk factor for virologic failure of CAB + RPV. Only 0.4% of all sequences had 2 pretreatment virologic risk factors for virologic failure of CAB + RPV. Four sequences (0.09% of 4212) proved resistant to both RPV and CAB. Among all 4212 sequences, 17 subtype A6/A1 sequences (0.4%) were resistant to RPV.
The Paris investigators believe their findings underline “the need for checking the cumulative genotypic resistance profile and viral subtype” before starting CAB + RPV in both antiretroviral-naive people and those with an undetectable viral load with their current antiretroviral combination “in order to limit the potential risk of virologic failure and the emergence of resistance.”
1. Charpentier C, Storto A, Soulie C, et al. Prevalence of baseline virological risk factors of increased virological failure to CAB+RPV among ARV-naive patients. IAS 2021, 11th IAS Conference on HIV Science, July 18-21, 2021. Abstract OAB0303.
2. Cutrell AG, Schapiro JM, Perno CF, et al. Exploring predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: a multivariable analysis. AIDS. 2021;35:1333-1342. doi: 10.1097/QAD.0000000000002883. https://journals.lww.com/aidsonline/Fulltext/2021/07150/
3. Wensing AM, Calvez V, Ceccherini-Silberstein F, et al. 2019 update of the drug resistance mutations in HIV-1. Top Antivir Med. 2019;27:111-121. PMID: 31634862. https://pubmed.ncbi.nlm.nih.gov/31634862/