title: E138A in HIV-1 reverse transcriptase is more common in subtype C than B: implications for rilpivirine use in resource-limited settings.
abstract: The nonnucleoside reverse transcriptase (RT) inhibitor rilpivirine (RPV) has been co-formulated with emtricitabine and tenofovir disoproxil fumarate for initial therapy of HIV-1-infected individuals. RPV, formulated as a long-acting nanosuspension, will also be assessed for its ability to prevent HIV-1 infection in resource limited settings. In this study, we determined whether any pre-existing genetic differences occurred among different HIV-1 subtypes at residues in RT associated with decreased virologic response to RPV. We found that the E138A substitution occurs more frequently in subtype C (range: 5.9-7.5%) than B (range: 0-2.3%) sequences from both treatment-naïve and -experienced individuals (p<0.01) in 4 independent genotype databases. In one of the databases (Stanford University), E138K and E138Q were also more common in RTI-experienced subtype C sequences (1.0% and 1.1%, respectively) than in subtype B sequences (0.3% and 0.6%, respectively). E138A/K/Q in subtype C decreased RPV susceptibility 2.9-, 5.8-, and 5.4-fold, respectively. Taken together, these data suggest that E138A could impact treatment or prevention strategies that include RPV in geographic areas where subtype C infection is prevalent.
authors.affiliation: University of Pittsburgh School of Medicine, Department of Medicine, Division of Infectious Diseases, Pittsburgh, PA, USA. Electronic address: nps2@pitt.edu.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sluis-Cremer
authors.affiliation: Division of Geographic Medicine and Infectious Disease, Tufts Medical Center, Boston, USA; Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jordan
authors.affiliation: University of Pittsburgh School of Medicine, Department of Medicine, Division of Infectious Diseases, Pittsburgh, PA, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Huber
authors.affiliation: Lancet Laboratories, Johannesburg, South Africa.
authors.forename: Carole L
authors.initials: CL
authors.lastname: Wallis
authors.affiliation: HIV Department, World Health Organization, Geneva, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bertagnolio
authors.affiliation: University of Pittsburgh School of Medicine, Department of Medicine, Division of Infectious Diseases, Pittsburgh, PA, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Mellors
authors.affiliation: Data First Consulting, Belmont, CA, USA.
authors.forename: Neil T
authors.initials: NT
authors.lastname: Parkin
authors.affiliation: BC Centre for Excellence in HIV/AIDS, Vancouver, Canada.
authors.forename: P Richard
authors.initials: PR
authors.lastname: Harrigan
mesh_terms: D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000145:classification / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D020125:Mutation, Missense; D009570:Nitriles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D000068696:Rilpivirine
chemical_list: D019380:Anti-HIV Agents; D009570:Nitriles; D011743:Pyrimidines; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D000068696:Rilpivirine
keywords: E138A; HIV-1; NNRTI; Resistance; Reverse transcriptase; Rilpivirine
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