Ujjwal Neogi1, Amanda Häggblom2, Kamalendra Singh3, Leonard C Rogers3, Shwetha D Rao4, Wondwossen Amogne5, Eugen Schülter6, Maurizio Zazzi7, Eddy Arnold8, Stefan G Sarafianos3, Anders Sönnerborg9. 1. Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm 141 86, Sweden ujjwal.neogi@ki.se. 2. Unit of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden. 3. Departments of Molecular Microbiology & Immunology and Biochemistry, Christopher Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA. 4. Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm 141 86, Sweden. 5. Addis Ababa University, Addis Ababa, Ethiopia. 6. Institute of Virology, University of Cologne, Cologne, Germany. 7. Department of Medical Biotechnologies, University of Siena, Siena, Italy. 8. Department of Chemistry and Chemical Biology and Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ 08854, USA. 9. Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm 141 86, Sweden Unit of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden.
Abstract
OBJECTIVES: The use of the NNRTI rilpivirine in low- and middle-income countries (LMICs) is under debate. The main objective of this study was to provide further clinical insights and biochemical evidence on the usefulness of rilpivirine in LMICs. PATIENTS AND METHODS: Rilpivirine resistance was assessed in 5340 therapy-naive and 13,750 first-generation NNRTI-failed patients from Europe and therapy-naive HIV-1 subtype C (HIV-1C)-infected individuals from India (n = 617) and Ethiopia (n = 127). Rilpivirine inhibition and binding affinity assays were performed using patient-derived HIV-1C reverse transcriptases (RTs). RESULTS: Primary rilpivirine resistance was rare, but the proportion of patients with >100,000 HIV-1 RNA copies/mL pre-ART was high in patients from India and Ethiopia, limiting the usefulness of rilpivirine as a first-line drug in LMICs. In patients failing first-line NNRTI treatments, cross-resistance patterns suggested that 73% of the patients could benefit from switching to rilpivirine-based therapy. In vitro inhibition assays showed ∼ 2-fold higher rilpivirine IC50 for HIV-1C RT than HIV-1B RT. Pre-steady-state determination of rilpivirine-binding affinities revealed 3.7-fold lower rilpivirine binding to HIV-1C than HIV-1B RT. Structural analysis indicated that naturally occurring polymorphisms close to the NNRTI-binding pocket may reduce rilpivirine binding, leading to lower susceptibility of HIV-1C to rilpivirine. CONCLUSIONS: Our clinical and biochemical findings indicate that the usefulness of rilpivirine has limitations in HIV-1C-dominated epidemics in LMICs, but the drug could still be beneficial in patients failing first-line therapy if genotypic resistance testing is performed.
OBJECTIVES: The use of the NNRTI rilpivirine in low- and middle-income countries (LMICs) is under debate. The main objective of this study was to provide further clinical insights and biochemical evidence on the usefulness of rilpivirine in LMICs. PATIENTS AND METHODS: Rilpivirine resistance was assessed in 5340 therapy-naive and 13,750 first-generation NNRTI-failed patients from Europe and therapy-naive HIV-1 subtype C (HIV-1C)-infected individuals from India (n = 617) and Ethiopia (n = 127). Rilpivirine inhibition and binding affinity assays were performed using patient-derived HIV-1C reverse transcriptases (RTs). RESULTS: Primary rilpivirine resistance was rare, but the proportion of patients with >100,000 HIV-1 RNA copies/mL pre-ART was high in patients from India and Ethiopia, limiting the usefulness of rilpivirine as a first-line drug in LMICs. In patients failing first-line NNRTI treatments, cross-resistance patterns suggested that 73% of the patients could benefit from switching to rilpivirine-based therapy. In vitro inhibition assays showed ∼ 2-fold higher rilpivirine IC50 for HIV-1C RT than HIV-1B RT. Pre-steady-state determination of rilpivirine-binding affinities revealed 3.7-fold lower rilpivirine binding to HIV-1C than HIV-1B RT. Structural analysis indicated that naturally occurring polymorphisms close to the NNRTI-binding pocket may reduce rilpivirine binding, leading to lower susceptibility of HIV-1C to rilpivirine. CONCLUSIONS: Our clinical and biochemical findings indicate that the usefulness of rilpivirine has limitations in HIV-1C-dominated epidemics in LMICs, but the drug could still be beneficial in patients failing first-line therapy if genotypic resistance testing is performed.
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