Sub-Epidemics Explain Localized High Prevalence of Reduced Susceptibility to Rilpivirine in Treatment-Naive HIV-1 Infected Patients: Subtype- & Geographic Compartmentalization of Baseline Resistance Mutations

OBJECTIVE:

The latest NNRTI rilpivirine is indicated for HIV-1 patients initiating antiretroviral treatment, but the extent of genotypic rilpivirine resistance in treatment-naïve patients outside clinical trials is poorly defined.

STUDY DESIGN:

This retrospective observational study of clinical data from Belgium and Portugal evaluates genotypic information from HIV-1 drug-naive patients obtained for the purpose of drug resistance testing. Rilpivirine resistance-associated mutations (RPV-RAMs) were defined based on clinical trials, phenotypic studies and expert-based resistance algorithms. Viral susceptibility to rilpivirine alone and to the single-tablet regimen was estimated using expert-based resistance algorithms.

RESULTS:

In 4631 HIV-1 treatment-naive patients infected with diverse HIV-1 subtypes, major RPV-RAMs were detected in 4.6% while complete viral susceptibility to rilpivirine was estimated in 95% of patients. Subtype C and F1 infected patients displayed the highest levels of reduced viral susceptibility at baseline, respectively 13.2% and 9.3%, mainly due to subtype- and geographic-dependent occurrence of RPV-RAMs E138A and A98G as natural polymorphisms. Strikingly, a founder effect in Portugal resulted in a 138A prevalence of 13.2% in local subtype C-infected treatment-naive patients. The presence of transmitted drug resistance did not impact our estimates.

CONCLUSION:

Rilpivirine is the first HIV-1 inhibitor for which, in absence of transmitted drug resistance, intermediate or high-level genotypic resistance can be detected in treatment-naive patients. The extent of rilpivirine susceptibility in treatment-naive patients differs depending on the HIV-1 subtype and on the dynamics of local compartmentalized epidemics. The highest prevalence of reduced susceptibility was found to be 15.7% in Portuguese subtype C-infected treatment-naive patients. In this context, even in the absence of TDR, drug resistance testing at baseline should be considered extremely important before starting treatment with this NNRTI.

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By:   Theys K1, Van Laethem K2,3, Gomes P4,5, Baele G6, Pineda-Peña AC7,8, Vandamme AM7,9, Camacho RJ10, Abecasis AB11.

• 1KU Leuven - University of Leuven, Rega Institute for Medical Research, Leuven, Belgium ; kristof.theys@rega.kuleuven.be.
• 2KU Leuven - University of Leuven, Rega Institute for Medical Research, Leuven, Belgium.
• 3University Hospitals Leuven, AIDS Reference Laboratory, Leuven, Belgium ; kristel.vanlaethem@uzleuven.be.
• 4LMCBM, SPC, HEM , Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal.
• 5Instituto Superior de Ciências da Saúde Sul, Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Lisbon, Portugal ; gomes.perpetua@gmail.com.
• 6KU Leuven - University of Leuven, Rega Institute for Medical Research, Leuven, Belgium ; Guy.Baele@rega.kuleuven.be.
• 7Universidade NOVA de Lisboa, Institute for Hygiene and Tropical Medicine, Global Health and Tropical Medicine, Lisbon, Portugal.
• 8Universidad del Rosario, Fundación Instituto de Inmunología de Colombia (FIDIC), Molecular Biology and Immunology Department, Bogota, Colombia ; andreapinedap@gmail.com.
• 9KU Leuven - University of Leuven, Rega Institute for Medical Research, Leuven, Belgium ; annemie.vandamme@uzleuven.be.
• 10KU Leuven - University of Leuven, Rega Institute for Medical Research, Leuven, Belgium ; RicardoJorge.Camacho@rega.kuleuven.be.
• 11Universidade NOVA de Lisboa, Institute for Hygiene and Tropical Medicine, Global Health and Tropical Medicine, Lisbon, Portugal ; ana.abecasis@ihmt.unl.pt. 

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