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

Roger Paredes, Philip L Tzou, Gert van Zyl, Geoff Barrow, Ricardo Camacho, Sergio Carmona, Philip M Grant, Ravindra K Gupta, Raph L Hamers, P Richard Harrigan, Michael R Jordan, Rami Kantor, David A Katzenstein, Daniel R Kuritzkes, Frank Maldarelli, Dan Otelea, Carole L Wallis, Jonathan M Schapiro, Robert W Shafer, Roger Paredes, Philip L Tzou, Gert van Zyl, Geoff Barrow, Ricardo Camacho, Sergio Carmona, Philip M Grant, Ravindra K Gupta, Raph L Hamers, P Richard Harrigan, Michael R Jordan, Rami Kantor, David A Katzenstein, Daniel R Kuritzkes, Frank Maldarelli, Dan Otelea, Carole L Wallis, Jonathan M Schapiro, Robert W Shafer

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.

Conflict of interest statement

Competing Interests: RW Shafer has received research funding during the past two years from Gilead Sciences, Bristol Myers Squibb, Merck Pharmaceuticals and has received consulting fees from ViiV Health Care. PR Harrigan has received grants from, served as an ad hoc advisor to, or spoke at various events sponsored by Abbott, Merck, and Gilead. He has also served as a consultant for ViiV Health Care, and Gilead. DRK has received consulting fees and research support from Gilead, Janssen, Merck and ViiV. JMS has received research support, honorarium or consulting fees from the following: Abbvie, Merck, Gilead Sciences, GlaxoSmithKline, Tibotec-Janssen, BMS, Teva, Virology Education and ViiV Healthcare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Expert panel assessments of 14…
Fig 1. Expert panel assessments of 14 NRTI-associated drug-resistance mutation (DRM) patterns.
Abbreviations: ABC (abacavir), AZT (zidovudine), TDF (tenofovir), 3FTC (lamivudine and emtricitabine), S (susceptible), P (potential low-level resistance), L (low-level resistance), I (intermediate resistance), H (high-level resistance). The diameter of each circle is proportional to the number of experts at the assigned level shown on the Y-axis. The bold dash is the median of the expert assessments. The vertical lines represent the HIVDB version 7.0 interpretations.
Fig 2. Expert panel assessments of 9…
Fig 2. Expert panel assessments of 9 NNRTI-associated drug-resistance mutation (DRM) patterns.
Abbreviations: EFV (efavirenz), ETR (etravirine), RPV (riplivirine), S (susceptible), P (potential low-level resistance), L (low-level resistance), I (intermediate resistance), H (high-level resistance). The diameter of each circle is proportional to the number of experts at the assigned level shown on the Y-axis. The bold dash is the median of the expert assessments. The vertical lines represent the HIVDB version 7.0 interpretations.
Fig 3. Expert panel assessments of 13…
Fig 3. Expert panel assessments of 13 PI-associated drug-resistance mutation (DRM) patterns.
Abbreviations: ATV (boosted atazanavir), DRV (boosted darunavir), LPV (boosted lopinavir), S (susceptible), P (potential low-level resistance), L (low-level resistance), I (intermediate resistance), H (high-level resistance). The diameter of each circle is proportional to the number of experts at the assigned level shown on the Y-axis. The bold dash is the median of the expert assessments. The vertical lines represent the HIVDB version 7.0 interpretations.
Fig 4. Expert panel assessments of 14…
Fig 4. Expert panel assessments of 14 INSTI-associated drug-resistance mutation (DRM) patterns.
Abbreviations: DTG (dolutegravir), EVG (elvitegravir), raltegravir (RAL), S (susceptible), P (potential low-level resistance), L (low-level resistance), I (intermediate resistance), H (high-level resistance). The diameter of each circle is proportional to the number of experts at the assigned level shown on the Y-axis. The bold dash is the median of the expert assessments. The vertical lines represent the HIVDB version 7.0 interpretations.

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