Major drug resistance mutations to HIV-1 protease inhibitors (PI) among patients exposed to PI class failing antiretroviral therapy in São Paulo State, Brazil

Autoři: Giselle de Faria Romero Soldi aff001;  Isadora Coutinho Ribeiro aff001;  Cintia Mayumi Ahagon aff001;  Luana Portes Ozório Coelho aff001;  Gabriela Bastos Cabral aff001;  Giselle Ibette Silva López Lopes aff001;  João Leandro de Paula Ferreira aff001;  Luís Fernando de Macedo Brígido aff001aff001
Působiště autorů: Núcleo de Doenças de Vinculação Sanguínea ou Sexual, Laboratório de Retrovírus, Centro de Virologia, Instituto Adolfo Lutz, São Paulo, São Paulo, Brazil aff001
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223210



Protease inhibitors (PI) are especially important in salvage therapy. Previous treatment failure with a PI containing regimen may elicit resistance mutations, reducing PI susceptibility and limiting treatment options. The aim of this study was to describe major PI mutations among patients exposed to at least one PI to evaluate predictors of mutation emergence and the impact of subtypes on resistance.


Partial HIV-1 pol sequences (Sanger Sequencing) from patients exposed to PI with virological failure were genotyped from January 2014 to December 2017. Drug resistance mutations (DRM), antiretroviral susceptibility (GSS) and subtypes, along clinical and laboratory parameters, were evaluated using logistic regression to access the predictors of mutation emergence.


In 27.5% (466/1696) of the cases at least one major PI mutations was identified, most commonly M46 (14.7%), V82 (13.8%) and I54 (13.3%). Mutations to NRTI and NNRTI were observed in 69.6% and 59.9%, respectively, of the 1696 sequences. Full activity to darunavir was predicted in 88% (1496/1696), but was only 57% among those with at least one PI-DRM. Subtype C sequences had less major PI-DRMs (10%, 9/87) compared to B (28%, 338/1216) or F (35%, 58/168) (p <0.001) but adjusted analysis suggested that this association is not independent from a shorter treatment time and fewer regimens (OR 0.59, Confidence Interval 95: 0.2–2.5, p = 0.48). Subtype F, together with NRTI mutations and longer time on treatment was associated to presence of PI-DRM, to a lower darunavir GSS and to mutations at codon I50.


Among patients with PI-DRM, full activity to darunavir was compromised in almost half of the cases and efforts to detect failure at earlier time are warranted, particularly for HIV-1 subtype F that showed association to the emergence of resistance, with potential impact in protease inhibitors sequencing. Furthermore, NRTI mutations may serve as an indicative of sufficient adherence to allow PI-DRM emergence.

Klíčová slova:

Antimicrobial resistance – Genotyping – HIV-1 – Microbial mutation – Mutation databases – Viral load – Protease inhibitors


1. PATON Nicholas I. et al. Assessment of Second-Line Antiretroviral Regimens for HIV Therapy in Africa. New England Journal Of Medicine, [s.l.], v. 371, n. 3, p.234–247, 17 jul. 2014. New England Journal of Medicine (NEJM/MMS). 25014688

2. A BOYD Mark et al. Baseline HIV-1 resistance, virological outcomes, and emergent resistance in the SECOND-LINE trial: an exploratory analysis. The Lancet Hiv, [s.l.], v. 2, n. 2, p.42–51, feb. 2015. Elsevier BV.

3. MATSUDA Elaine Monteiro et al. High Prevalence of Drug Resistance Mutations Among Patients Failing First-Line Antiretroviral Therapy and Predictors of Virological Response 24 Weeks After Switch to Second-Line Therapy in São Paulo State, Brazil. Aids Research And Human Retroviruses, [s.l.], v. 34, n. 2, p.156–164, feb. 2018. Mary Ann Liebert Inc. 28969448

4. LÓPEZ-CORTÉS Luis F. et al. Effectiveness of Ritonavir-Boosted Protease Inhibitor Monotherapy in Clinical Practice Even with Previous Virological Failures to Protease Inhibitor-Based Regimens. Plos One, [s.l.], v. 11, n. 2, p.1–12, 12 feb. 2016. Public Library of Science (PLoS).

5. UNAIDS. Infográficos—Brasil. 2017. Disponível em: <>. Acessoem: 14 feb. 2019

6. BRÍGIDO L. F. M. et al. Southern Brazil HIV Type 1 C Expansion into the State of São Paulo, Brazil. Aids Research And Human Retroviruses, [s.l.], v. 27, n. 3, p.339–344, mar. 2011. Mary Ann Liebert Inc. 20950149

7. COELHO Luana Portes Ozorio et al. Prevalence of HIV-1 transmitted drug resistance and viral suppression among recently diagnosed adults in São Paulo, Brazil. Archives Of Virology, [s.l.], p.1–8, 20 dec. 2018. Springer Nature. 28980078

8. HEMELAAR Joris et al. Global and regional molecular epidemiology of HIV-1, 1990–2015: a systematic review, global survey, and trend analysis. The Lancet Infectious Diseases, [s.l.], v. 19, n. 2, p.143–155, feb. 2019. Elsevier BV. 30509777

9. THOMSON Michael M. et al. Rapid Expansion of a HIV-1 Subtype F Cluster of Recent Origin Among Men Who Have Sex With Men in Galicia, Spain. Jaids Journal Of Acquired Immune Deficiency Syndromes, [s.l.], v. 59, n. 3, p.49–51, mar. 2012. Ovid Technologies (Wolters Kluwer Health).

10. DELGADO Elena et al. Phylogeny and Phylogeography of a Recent HIV-1 Subtype F Outbreak among Men Who Have Sex with Men in Spain Deriving from a Cluster with a Wide Geographic Circulation in Western Europe. Plos One, [s.l.], v. 10, n. 11, p.1–8, 24 nov. 2015. Public Library of Science (PLoS).

11. RHEE Soo-yon et al. HIV-1 pol mutation frequency by subtype and treatment experience: extension of the HIVseq program to seven non-B subtypes. Aids, [s.l.], v. 20, n. 5, p.643–651, mar. 2006. Ovid Technologies (Wolters Kluwer Health). 16514293

12. ORTIZ Roberto et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. Aids, [s.l.], v. 22, n. 12, p.1389–1397, jul. 2008. Ovid Technologies (Wolters Kluwer Health). 18614861

13. MOLINA Jean-michel et al. Once-Daily Atazanavir/Ritonavir Compared With Twice-Daily Lopinavir/Ritonavir, Each in Combination With Tenofovir and Emtricitabine, for Management of Antiretroviral-Naive HIV-1-Infected Patients: 96-Week Efficacy and Safety Results of the CASTLE Study. Jaids Journal Of Acquired Immune Deficiency Syndromes, [s.l.], v. 53, n. 3, p.323–332, mar. 2010. Ovid Technologies (Wolters Kluwer Health). 20032785

14. GUIMARÃES, Paula Morena de Souza et al. Transmitted Drug Resistance Among Recently Diagnosed Adults and Children in São Paulo, Brazil. Aids Research And Human Retroviruses, São Paulo, v. 31, n. 12, p.1219–1224, dec. 2015. Mary Ann Liebert Inc. 25826640

15. RYOM L et al. Highlights of the 2017 European AIDS Clinical Society (EACS) Guidelines for the treatment of adult HIV-positive persons version 9.0. Hiv Medicine, [s.l.], v. 19, n. 5, p.309–315, 1 mar. 2018. Wiley. 29493093

16. UNITED STATES DEPARTMENT OF HEALTH AND HUMAN SERVICES. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. 2018. Disponível em: <>. Access: 10 jan. 2019.

17. CLUTTER Dana S. et al. HIV-1 drug resistance and resistance testing. Infection, Genetics And Evolution, [s.l.], v. 46, p.292–307, dec. 2016. Elsevier BV.

18. SHAFER Robert W. Human Immunodeficiency Virus Type 1 Drug Resistance Mutations Update. The Journal Of Infectious Diseases, [s.l.], v. 216, n. 9, p.843–846, 15 sep. 2017. Oxford University Press (OUP).

19. A THOMPSON Jennifer et al. Evolution of Protease Inhibitor Resistance in Human Immunodeficiency Virus Type 1 Infected Patients Failing Protease Inhibitor Monotherapy as Second-line Therapy in Low-income Countries: An Observational Analysis Within the EARNEST Randomized Trial. Clinical Infectious Diseases, [s.l.], v. 68, n. 7, p.1184–1192, 28 jul. 2018. Oxford University Press (OUP).

20. FILY F. et al. HIV-1 drug resistance testing at second-line regimen failure in Arua, Uganda: avoiding unnecessary switch to an empiric third-line. Tropical Medicine & International Health, [s.l.], v. 23, n. 10, p.1075–1083, oct. 2018. Wiley.

21. CID-SILVA Purificación et al. Initial treatment response among HIV subtype F infected patients who started antiretroviral therapy based on integrase inhibitors. Aids, [s.l.], v. 32, n. 1, p.121–125, jan. 2018. Ovid Technologies (Wolters Kluwer Health). 29112068

22. GROSSMAN et al. Genetic variation at NNRTI resistance-associated positions in patients infected with HIV-1 subtype C. Aids, London, v. 18, n. 6, p.909–915, apr. 2004 doi: 10.1097/00002030-200404090-00008 15060438

23. COUTSINOS D. et al. Template Usage Is Responsible for the Preferential Acquisition of the K65R Reverse Transcriptase Mutation in Subtype C Variants of Human Immunodeficiency Virus Type 1. Journal Of Virology, [s.l.], v. 83, n. 4, p.2029–2033, 10 dec. 2008. American Society for Microbiology. 19073730

24. PALMA A. C. et al. HIV-1 protease mutation 82M contributes to phenotypic resistance to protease inhibitors in subtype G. Journal Of Antimicrobial Chemotherapy, [s.l.], v. 67, n. 5, p.1075–1079, 13 feb. 2012. Oxford University Press (OUP). 22331593

25. PARASKEVIS Dimitrios et al. Molecular characterization of HIV-1 infection in Northwest Spain (2009–2013): Investigation of the subtype F outbreak. Infection, Genetics And Evolution, [s.l.], v. 30, p.96–101, mar. 2015. Elsevier BV. 25527396

Článek vyšel v časopise


2019 Číslo 10