# HIV-1 cross-resistance to second-generation non-nucleoside reverse transcriptase inhibitors among individuals failing antiretroviral therapy in Cameroon: implications for the use of long-acting treatment regimens in low- and middle-income countries

## TL;DR

This study finds high cross-resistance to second-generation HIV drugs in Cameroon due to prior use of older drugs, suggesting the need for alternative treatment strategies in low- and middle-income countries.

## Contribution

The study provides new evidence on cross-resistance patterns to second-generation NNRTIs in a low- and middle-income country context.

## Key findings

- 77.18% of individuals had resistance-associated mutations to second-generation NNRTIs.
- Y181C was the most common major resistance mutation for second-generation NNRTIs.
- Patients failing first-line treatment had higher resistance prevalence than those on second-line regimens.

## Abstract

Several long-acting antiretroviral treatment regimens contain second-generation non-nucleoside reverse transcriptase inhibitors (2ndGenNNRTI). As first-generation NNRTIs (1stGenNNRTI) exhibit some cross-resistance with 2ndGenNNRTI, we sought to evaluate the rate of acquired cross-resistance to 2ndGenNNRTI and its determinants at treatment failure in a typical low- and middle-income country (LMIC) such as Cameroon.

A facility-based cross-sectional study was conducted among patients failing first-/second-line regimens between 2019 and 2023 in Cameroon. HIV-1 Sanger sequencing was performed on plasma and resistance-associated mutations (RAMs) to etravirine, rilpivirine and doravirine were interpreted using HIVdb program v.9.5.0 (HIVdb penalty scores were,  ≥60, high resistance; 15–59, intermediate resistance and  <15, susceptible) and the IAS-USA 2022 list.

Overall, 653 individuals previously exposed to 1stGenNNRTI were enrolled [median (IQR) age 39 (26–46) years and viraemia 59 370 (10 442–244 916) copies/mL]. Importantly, 361 participants were on 1stGenNNRTI-based first-line and 292 on protease inhibitor-based second-line regimen. NNRTIs RAMs were found in up to 90.64% of individuals, with 36.45% having more than three RAMs. Concerning 2ndGenNNRTIs, 77.18% of individuals harboured RAMs conferring high or intermediate-level resistance, with the predicted efficacy of etravirine, doravirine and rilpivirine being 47.17%, 33.23% and 32.31%, respectively. Major 2ndGenNNRTIs RAMs were driven by Y181C (23.74%), K101E (8.57%), Y188L (8.42%) and H221Y (8.42%), while minor RAMs were A98G (18.83%), G190A (18.68%) and P225H (14.70%). A higher prevalence of RAMs was observed in those failing first-line versus second line (81.71% versus 71.57%, respectively, P < 0.001), driven predominantly by the difference in doravirine-RAMs [first line (72.85%) versus second line (59.58%), P < 0.001].

Among patients failing treatment in Cameroon, there is a high-level of cross-resistance to 2ndGenNNRTI due to wide exposure to 1stGenNNRTI. Thus, in LMICs sharing similar programmatic features, the use of NNRTI-sparing regimens should be prioritized as a public health approach, while second-generation-NNRTI long-acting regimens should be guided by genotyping or for clients without previous exposure to NNRTIs.