Collaborative update of a rule-based expert system for HIV-1 genotypic resistance test interpretation

PLoS One. 2017 Jul 28;12(7):e0181357. doi: 10.1371/journal.pone.0181357. eCollection 2017.

Abstract

Introduction: HIV-1 genotypic resistance test (GRT) interpretation systems (IS) require updates as new studies on HIV-1 drug resistance are published and as treatment guidelines evolve.

Methods: An expert panel was created to provide recommendations for the update of the Stanford HIV Drug Resistance Database (HIVDB) GRT-IS. The panel was polled on the ARVs to be included in a GRT report, and the drug-resistance interpretations associated with 160 drug-resistance mutation (DRM) pattern-ARV combinations. The DRM pattern-ARV combinations included 52 nucleoside RT inhibitor (NRTI) DRM pattern-ARV combinations (13 patterns x 4 NRTIs), 27 nonnucleoside RT inhibitor (NNRTI) DRM pattern-ARV combinations (9 patterns x 3 NNRTIs), 39 protease inhibitor (PI) DRM pattern-ARV combinations (13 patterns x 3 PIs) and 42 integrase strand transfer inhibitor (INSTI) DRM pattern-ARV combinations (14 patterns x 3 INSTIs).

Results: There was universal agreement that a GRT report should include the NRTIs lamivudine, abacavir, zidovudine, emtricitabine, and tenofovir disoproxil fumarate; the NNRTIs efavirenz, etravirine, nevirapine, and rilpivirine; the PIs atazanavir/r, darunavir/r, and lopinavir/r (with "/r" indicating pharmacological boosting with ritonavir or cobicistat); and the INSTIs dolutegravir, elvitegravir, and raltegravir. There was a range of opinion as to whether the NRTIs stavudine and didanosine and the PIs nelfinavir, indinavir/r, saquinavir/r, fosamprenavir/r, and tipranavir/r should be included. The expert panel members provided highly concordant DRM pattern-ARV interpretations with only 6% of NRTI, 6% of NNRTI, 5% of PI, and 3% of INSTI individual expert interpretations differing from the expert panel median by more than one resistance level. The expert panel median differed from the HIVDB 7.0 GRT-IS for 20 (12.5%) of the 160 DRM pattern-ARV combinations including 12 NRTI, two NNRTI, and six INSTI pattern-ARV combinations. Eighteen of these differences were updated in HIVDB 8.1 GRT-IS to reflect the expert panel median. Additionally, HIVDB users are now provided with the option to exclude those ARVs not considered to be universally required.

Conclusions: The HIVDB GRT-IS was updated through a collaborative process to reflect changes in HIV drug resistance knowledge, treatment guidelines, and expert opinion. Such a process broadens consensus among experts and identifies areas requiring further study.

MeSH terms

  • Anti-HIV Agents / pharmacology*
  • Benzoxazines / pharmacology
  • Dideoxynucleosides / pharmacology
  • Drug Resistance, Viral / genetics
  • Genotype
  • HIV-1 / drug effects*
  • HIV-1 / genetics*
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Lamivudine / pharmacology
  • Lopinavir / pharmacology
  • Nelfinavir / pharmacology
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Ritonavir / pharmacology
  • Zidovudine / pharmacology

Substances

  • Anti-HIV Agents
  • Benzoxazines
  • Dideoxynucleosides
  • Heterocyclic Compounds, 3-Ring
  • Reverse Transcriptase Inhibitors
  • Lopinavir
  • Lamivudine
  • Zidovudine
  • dolutegravir
  • Nelfinavir
  • efavirenz
  • Ritonavir
  • abacavir