HIV Drug Resistance Among Individuals Failing Tenofovir/Lamivudine and Dolutegravir First Line Regimen in Brazil

NCT04453436 | Active Not Recruiting FDA Drug

• 1 other identifier: SPARC-8
• Study Type: observational
• Target: 2,500
• Locations: 1 country
• Sites: 1

Brief Summary

Brazil was the first middle-income country to provide free and universal access to antiretroviral drugs to HIV infected individuals. Since 2014 local guidelines recommend that all HIV infected individuals be started on therapy regardless of CD4 count. Since January 2017, all patients are started on a DTG containing triple regimen. As of November 2018, 170,000 individuals were receiving DTG through the public health system. It is a public health priority to evaluate the risk of virologic failure and the subsequent development of INSTI resistance in these real-life settings. Our preliminary data from Brazil indicated a high virologic failure rate of 8% after 18 months of treatment TL+D. Our central hypothesis is that TDR may be associated and contribute to virologic failure with DTG in clinical practice. To test this central hypothesis, we will identify PLWH failing DTG containing regimens in Brazil. The insights generated with these studies will contribute to a more effective use of second generation INSTI in the future.

Conditions

HIV; Drug; Resistance

Keywords

HIV; treatment; resistance

Outcome Measures

Primary Outcomes (1)

• HIV RNA Viral Load

  Number of individuals with HIV viral load above detections limits during first line treatment with Tenofovir/3TC + Dolutegravir

  24 weeks

Secondary Outcomes (2)

• HIV reverse transcriptase resistance mutations

  24 weeks

• HIV integrase resitance mutations

  24 weeks

Study Arms (2)

Virologic failure

Viral load above detection limits at window period

Drug: Tenofovir Disoproxil

Virologic Success

Viral load bellow detection limits at window period

Drug: Tenofovir Disoproxil

Interventions

Tenofovir Disoproxil DRUG

Genotipic resistance test

Also known as: Lamivudine, Dolutegravir

Virologic Success; Virologic failure

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

2,500 HIV positive Brazilian

You may qualify if:

• Patints starting first line anti HIV treatment with Tenofovir/laimudine + Dolutegravir
• No previous antiretroviral treatment
• ≥ 18 ≤ 65 y.o

You may not qualify if:

• Not to be able to understand and sign the informed consent form

Sponsors & Collaborators

• Federal University of São Paulo: lead
• Gilead Sciences: collaborator

Study Sites (1)

Laboratório de Retrovirologia, EP2

São Paulo, São Paulo, 04039-032, Brazil

Location

Related Publications (24)

• Clotet B, Feinberg J, van Lunzen J, Khuong-Josses MA, Antinori A, Dumitru I, Pokrovskiy V, Fehr J, Ortiz R, Saag M, Harris J, Brennan C, Fujiwara T, Min S; ING114915 Study Team. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet. 2014 Jun 28;383(9936):2222-31. doi: 10.1016/S0140-6736(14)60084-2. Epub 2014 Apr 1.

  PMID: 24698485 BACKGROUND

• Raffi F, Jaeger H, Quiros-Roldan E, Albrecht H, Belonosova E, Gatell JM, Baril JG, Domingo P, Brennan C, Almond S, Min S; extended SPRING-2 Study Group. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2013 Nov;13(11):927-35. doi: 10.1016/S1473-3099(13)70257-3. Epub 2013 Sep 25.

  PMID: 24074642 BACKGROUND

• Walmsley S, Baumgarten A, Berenguer J, Felizarta F, Florence E, Khuong-Josses MA, Kilby JM, Lutz T, Podzamczer D, Portilla J, Roth N, Wong D, Granier C, Wynne B, Pappa K. Brief Report: Dolutegravir Plus Abacavir/Lamivudine for the Treatment of HIV-1 Infection in Antiretroviral Therapy-Naive Patients: Week 96 and Week 144 Results From the SINGLE Randomized Clinical Trial. J Acquir Immune Defic Syndr. 2015 Dec 15;70(5):515-9. doi: 10.1097/QAI.0000000000000790.

  PMID: 26262777 BACKGROUND

• Orrell C, Hagins DP, Belonosova E, Porteiro N, Walmsley S, Falco V, Man CY, Aylott A, Buchanan AM, Wynne B, Vavro C, Aboud M, Smith KY; ARIA study team. Fixed-dose combination dolutegravir, abacavir, and lamivudine versus ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate and emtricitabine in previously untreated women with HIV-1 infection (ARIA): week 48 results from a randomised, open-label, non-inferiority, phase 3b study. Lancet HIV. 2017 Dec;4(12):e536-e546. doi: 10.1016/S2352-3018(17)30095-4. Epub 2017 Jul 17.

  PMID: 28729158 BACKGROUND

• Cahn P, Pozniak AL, Mingrone H, Shuldyakov A, Brites C, Andrade-Villanueva JF, Richmond G, Buendia CB, Fourie J, Ramgopal M, Hagins D, Felizarta F, Madruga J, Reuter T, Newman T, Small CB, Lombaard J, Grinsztejn B, Dorey D, Underwood M, Griffith S, Min S; extended SAILING Study Team. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet. 2013 Aug 24;382(9893):700-8. doi: 10.1016/S0140-6736(13)61221-0. Epub 2013 Jul 3.

  PMID: 23830355 BACKGROUND

• Malet I, Subra F, Charpentier C, Collin G, Descamps D, Calvez V, Marcelin AG, Delelis O. Mutations Located outside the Integrase Gene Can Confer Resistance to HIV-1 Integrase Strand Transfer Inhibitors. mBio. 2017 Sep 26;8(5):e00922-17. doi: 10.1128/mBio.00922-17.

  PMID: 28951475 BACKGROUND

• Das AT, Berkhout B. How Polypurine Tract Changes in the HIV-1 RNA Genome Can Cause Resistance against the Integrase Inhibitor Dolutegravir. mBio. 2018 Apr 10;9(2):e00006-18. doi: 10.1128/mBio.00006-18. No abstract available.

  PMID: 29636435 BACKGROUND

• Wijting IEA, Lungu C, Rijnders BJA, van der Ende ME, Pham HT, Mesplede T, Pas SD, Voermans JJC, Schuurman R, van de Vijver DAMC, Boers PHM, Gruters RA, Boucher CAB, van Kampen JJA. HIV-1 Resistance Dynamics in Patients With Virologic Failure to Dolutegravir Maintenance Monotherapy. J Infect Dis. 2018 Jul 24;218(5):688-697. doi: 10.1093/infdis/jiy176.

  PMID: 29617822 BACKGROUND

• Darcis G, Berkhout B. Human Immunodeficiency Virus Resistance to Dolutegravir: Are We Looking in the Wrong Place? J Infect Dis. 2018 Nov 5;218(12):2020. doi: 10.1093/infdis/jiy474. No abstract available.

  PMID: 30085190 BACKGROUND

• Wijting IEA, Lungu C, Rijnders BJA, van der Ende ME, Pham HT, Mesplede T, Pas SD, Voermans JJC, Schuurman R, van de Vijver DAMC, Boers PHM, Gruters RA, Boucher CAB, van Kampen JJA. Reply to Darcis and Berkhout. J Infect Dis. 2018 Nov 5;218(12):2020-2021. doi: 10.1093/infdis/jiy475. No abstract available.

  PMID: 30085047 BACKGROUND

• World Health Organization. Updated Recommendations on First-Line and Second-Line Antiretroviral Regimens and Post-Exposure Prophylaxis and Recommendations on Early Infant Diagnosis of HIV: Interim Guidance. Geneva: World Health Organization; 2018 (WHO/CDS/HIV/18.18). Licence: CC BY.; 2018.

  BACKGROUND

• Phillips AN, Cambiano V, Nakagawa F, Revill P, Jordan MR, Hallett TB, Doherty M, De Luca A, Lundgren JD, Mhangara M, Apollo T, Mellors J, Nichols B, Parikh U, Pillay D, Rinke de Wit T, Sigaloff K, Havlir D, Kuritzkes DR, Pozniak A, van de Vijver D, Vitoria M, Wainberg MA, Raizes E, Bertagnolio S; Working Group on Modelling Potential Responses to High Levels of Pre-ART Drug Resistance in Sub-Saharan Africa. Cost-effectiveness of public-health policy options in the presence of pretreatment NNRTI drug resistance in sub-Saharan Africa: a modelling study. Lancet HIV. 2018 Mar;5(3):e146-e154. doi: 10.1016/S2352-3018(17)30190-X. Epub 2017 Nov 22.

  PMID: 29174084 BACKGROUND

• World Health Organization. Transition to new antiretrovirals in HIV programmes: Policy brief. WHO/HIV/2017.20. 2017.

  BACKGROUND

• Mantovani NP, Azevedo RG, Rabelato JT, Sanabani S, Diaz RS, Komninakis SV. Analysis of transmitted resistance to raltegravir and selective pressure among HIV-1-infected patients on a failing HAART in Sao Paulo, Brazil. J Clin Microbiol. 2012 Jun;50(6):2122-5. doi: 10.1128/JCM.00539-12. Epub 2012 Mar 7.

  PMID: 22403424 BACKGROUND

• Hemelaar J, Gouws E, Ghys PD, Osmanov S; WHO-UNAIDS Network for HIV Isolation and Characterisation. Global trends in molecular epidemiology of HIV-1 during 2000-2007. AIDS. 2011 Mar 13;25(5):679-89. doi: 10.1097/QAD.0b013e328342ff93.

  PMID: 21297424 BACKGROUND

• Inocencio LA, Pereira AA, Sucupira MC, Fernandez JC, Jorge CP, Souza DF, Fink HT, Diaz RS, Becker IM, Suffert TA, Arruda MB, Macedo O, Simao MB, Tanuri A. Brazilian Network for HIV Drug Resistance Surveillance: a survey of individuals recently diagnosed with HIV. J Int AIDS Soc. 2009 Sep 18;12:20. doi: 10.1186/1758-2652-12-20.

  PMID: 19765271 BACKGROUND

• Arruda MB, Boullosa LT, Cardoso CC, da Costa CM, Alves CR, de Lima ST, Kaminski HT, Aleixo AW, Esposito AO, Cavalcanti AM, Riedel M, Couto-Fernandez JC, Ferreira SB, de Oliveira IC, Portal LE, Wolf HH, Fernandes SB, de M C Pardini MI, Feiteiro MV, Tolentino FM, Diaz RS, Lopes GI, Francisco RB, Veras NM, Pires AF, Franchini M, Mesquita F, Tanuri A; HIV-BResNet. Brazilian network for HIV Drug Resistance Surveillance (HIV-BresNet): a survey of treatment-naive individuals. J Int AIDS Soc. 2018 Mar;21(3):e25032. doi: 10.1002/jia2.25032.

  PMID: 29504269 BACKGROUND

• Brindeiro RM, Diaz RS, Sabino EC, Morgado MG, Pires IL, Brigido L, Dantas MC, Barreira D, Teixeira PR, Tanuri A; Brazilian Network for Drug Resistance Surveillance. Brazilian Network for HIV Drug Resistance Surveillance (HIV-BResNet): a survey of chronically infected individuals. AIDS. 2003 May 2;17(7):1063-9. doi: 10.1097/00002030-200305020-00016.

  PMID: 12700457 BACKGROUND

• Sabino EC, Shpaer EG, Morgado MG, Korber BT, Diaz RS, Bongertz V, Cavalcante S, Galvao-Castro B, Mullins JI, Mayer A. Identification of human immunodeficiency virus type 1 envelope genes recombinant between subtypes B and F in two epidemiologically linked individuals from Brazil. J Virol. 1994 Oct;68(10):6340-6. doi: 10.1128/JVI.68.10.6340-6346.1994.

  PMID: 8083973 BACKGROUND

• De Sa Filho DJ, Sucupira MC, Caseiro MM, Sabino EC, Diaz RS, Janini LM. Identification of two HIV type 1 circulating recombinant forms in Brazil. AIDS Res Hum Retroviruses. 2006 Jan;22(1):1-13. doi: 10.1089/aid.2006.22.1.

  PMID: 16438639 BACKGROUND

• Sucupira MC, Munerato P, Silveira J, Santos AF, Janini LM, Soares MA, Diaz RS. Phenotypic susceptibility to antiretrovirals among clades C, F, and B/F recombinant antiretroviral-naive HIV type 1 strains. AIDS Res Hum Retroviruses. 2013 Jun;29(6):880-6. doi: 10.1089/AID.2012.0259. Epub 2013 Mar 8.

  PMID: 23398474 BACKGROUND

• Quashie PK, Oliviera M, Veres T, Osman N, Han YS, Hassounah S, Lie Y, Huang W, Mesplede T, Wainberg MA. Differential effects of the G118R, H51Y, and E138K resistance substitutions in different subtypes of HIV integrase. J Virol. 2015 Mar;89(6):3163-75. doi: 10.1128/JVI.03353-14. Epub 2014 Dec 31.

  PMID: 25552724 BACKGROUND

• Han YS, Mesplede T, Wainberg MA. Differences among HIV-1 subtypes in drug resistance against integrase inhibitors. Infect Genet Evol. 2016 Dec;46:286-291. doi: 10.1016/j.meegid.2016.06.047. Epub 2016 Jun 25.

  PMID: 27353185 BACKGROUND

• Cid-Silva P, Margusino-Framinan L, Balboa-Barreiro V, Martin-Herranz I, Castro-Iglesias A, Pernas-Souto B, Llibre JM, Poveda E. Initial treatment response among HIV subtype F infected patients who started antiretroviral therapy based on integrase inhibitors. AIDS. 2018 Jan 2;32(1):121-125. doi: 10.1097/QAD.0000000000001679.

  PMID: 29112068 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

plasma sample

MeSH Terms

Interventions

Tenofovir; Lamivudine; dolutegravir

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Zalcitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Dideoxynucleosides

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Target Duration: 24 Months
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor, Paulista School of Infectious Diseases, Federal University of Sao Paulo

Study Record Dates

• First Submitted: June 27, 2020
• First Posted: July 1, 2020
• Study Start: September 1, 2023
• Primary Completion: December 31, 2024
• Study Completion: October 1, 2025
• Last Updated: August 8, 2025

Record last verified: 2025-02

Locations

BR (1)