Impact of rilpivirine cross-resistance on long-acting cabotegravir-rilpivirine in low and middle-income countries

In the last 25 years, remarkable progress has been made in the development of better and safer antiretroviral treatment (ART). However, suboptimal adherence to lifelong daily oral treatment remains an important driver of virological failure and increases the risk for transmission and development of drug resistance. There is currently considerable excitement in the therapeutics field at the prospect of long-acting, including oral, injectable, and implantable formulations. On the basis of safety and efficacy data of clinical trials [1–3], long-acting cabotegravir and rilpivirine (CAB/RPV LA) is the first injectable combination approved to treat virologically suppressed adults without history of treatment failure and with no known resistance to either cabotegravir or rilpivirine. Confirmed virological failure (CVF) in these trials was rare; therefore, a pooled analysis was performed to identify baseline risk factors for virological failure [4]. The presence of rilpivirine drug resistance mutations (DRMs), HIV-1 subtype A6/A1 and baseline BMI above 30 kg/m2 were associated with CVF. Accumulation of nonnucleoside reverse transcriptase inhibitors (NNRTIs) DRMs is common in low-and-middle-income countries (LMICs) [5,6]; therefore, predicted rilpivirine cross-resistance was investigated in a South African cohort.

Genotypic sequence data from 277 patients initiating ART and 1372 patients experiencing NNRTI-treatment failure were included for analysis as previously described [7]. Pol sequences were submitted to Stanford HIVdb v9.0 to identify rilpivirine DRMs. The following mutations were included as rilpivirine DRMs (Stanford HIVdb penalty score ≥10): A98G, V100IV, K101EPH, V106I, E138AGKQR, V179DEFL, Y181CFGISV, Y188FL, G190ACEQSTV, H221Y, F227C, and 230IL. Resistance profiles were categorized as susceptible (including potential low-level resistance), intermediate (including low-level resistance), or high-level resistance. Subtyping was performed using the Rega HIV subtyping tool v3.0.

Patients initiating ART (n = 277) had a median age of 34 years (interquartile range (IQR): 29–42) and most were women (58.8%). Two patients (0.6%) presented with a subtype A recombinant virus. At least one NNRTI DRM was detected in 47 patients (17.0%), of whom 34 (12.3%) presented with at least one rilpivirine DRM. Twenty-seven ART initiators (9.7%) presented with predicted intermediate rilpivirine resistance, most often caused by E138A/G (n = 20) and six (2.2%) presented with high-level resistance to rilpivirine, including four with at least two rilpivirine DRMs.

Patients failing NNRTI-based ART (n = 1372) were mostly women (63.6%) with a median age of 37 years (interquartile range: 31–42). Eight patients (0.8%) presented with a subtype A or subtype A recombinant virus. Almost all patients experiencing treatment failure (n = 1305; 95.1%) presented with at least one NNRTI DRM, including 1022 (74.5%) with at least one rilpivirine DRM and 516 (37.6%) with at least two rilpivirine DRMs. Prevalence of rilpivirine DRMs is presented in Fig. 1. Almost three-quarters of patients showed intermediate (28.1%; n = 385) and high-level rilpivirine resistance (44.3%; n = 608).

F1Fig. 1:

Prevalence of rilpivirine drug resistance mutations in 1372 patients failing NNRTI-based treatment.

CAB/RPV LA treatment, with its potential to improve treatment adherence and reduce stigma among other advantages, is a promising addition to the available treatment arsenal [8]. However, this regimen is recommended in virologically suppressed patients without treatment failure or suspected resistance, with the exception of isolated K103N. The assessment of these conditions might be feasible in many resource-rich settings, wherein baseline resistance testing is the norm and viral load monitoring is frequently performed. An Italian study recently showed that only 40% of patients in their cohort would be eligible to switch to CAB/RPV LA, after patients with a detectable viral load, presence of rilpivirine, and/or integrase strand transfer inhibitor mutations or a positive hepatitis B surface antigen result were excluded [9]. Similarly, a French ART-naive cohort showed that 10% of patients had the HIV-1 A1/A6 subtype, rilpivirine, or cabotegravir-associated mutations [10].

Our retrospective analysis indicates that rilpivirine DRMs are common in a setting wherein NNRTI-based treatment was widely implemented. One in 10 patients initiating ART presented with at least one rilpivirine DRM (12.3%). Admittedly, the prevalence of NNRTI pretreatment resistance will likely lessen over time with the widespread roll-out of dolutegravir, which commenced in 2019 in South Africa. However, given the persistence of NNRTI mutations, the large number of patients who have been exposed to NNRTI-based treatment in the past, and the continued large-scale use of NNRTI-based regimens, possible transmission of NNRTI-resistant virus will continue for some time. Although the NADIA trial demonstrated that dolutegravir-based regimens retain activity despite resistance to an NRTI backbone [11], this has yet to be demonstrated for NNRTIs, in two-drug regimens, or for cabotegravir. Rilpivirine cross-resistance was common in patients failing NNRTI-based ART in our cohort with 74.5% of patients presenting with at least one rilpivirine mutation. As viral resuppression on NNRTI-based regimens is not unusual [12,13], the accumulation and archiving of rilpivirine DRMs is of concern. The prevalence of subtype A was very low in our cohort, which was expected in southern Africa where subtype C dominates [14]. Although BMI data were not available in our cohort, obesity is common in South Africa with 41% of women and 11% of men having a BMI above 30 kg/m2[15,16]. Moreover, treatment emergent obesity on ART has rapidly emerged as a clinical concern [17,18].

We acknowledge that our resistance data are not obtained from patients with a suppressed viral load, hence the prevalence of rilpivirine DRMs might be an overestimation. Hermans et al.[13] reported that viremia is common (19.8%) in patients treated with NNRTIs and that many patients (58.5%) were switched late or not at all corroborating the high risk for NNRTI and possibly rilpivirine DRMs in the NNRTI-exposed population. Finally, recent modeling has indicated that the introduction of CAB/RPV LA would only be cost-efficient in patients with a viral load above 1000 copies/ml [19], for which the formulation has not been approved. In addition, patients with detectable viral loads are more at risk of carrying rilpivirine DRMs when they have been exposed to NNRTI-based treatment.

This analysis indicates that rilpivirine DRMs are common in a setting wherein NNRTI-based treatment was recently widely implemented, and has significant implications for operational implementation of CAB/RPV LA. Screening for existing DRMs is logistically and technically challenging in LMICs and could be a barrier to use of CAB/RPV LA.

Acknowledgements

No specific funding was received to perform this research.

Conflicts of interest

W.D.F.V., S.S., and N.C.'s unit is conducting research, investigator-led, with drug donations from ViiV, Merck, Gilead, and J&J, for treatment and PrEP, on long-acting injectables.

W.D.F.V. has accepted honoraria for ad boards and talks for ViiV, Merck, Gilead, and J&J.

N.C. has accepted honoraria from Cipla, Johnson and Johnson, Frontiers Biotech, outside the submitted work.

K.S. and L.H. have no conflicts of interest to declare.

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