Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING Study

Joseph J Eron, Bonaventura Clotet, Jacques Durant, Christine Katlama, Princy Kumar, Adriano Lazzarin, Isabelle Poizot-Martin, Gary Richmond, Vincent Soriano, Mounir Ait-Khaled, Tamio Fujiwara, Jenny Huang, Sherene Min, Cindy Vavro, Jane Yeo, VIKING Study Group, Sharon L Walmsley, Joseph Cox, Jacques Reynes, Philippe Morlat, Daniel Vittecoq, Jean-Michel Livrozet, Pompeyo Viciana Fernández, Jose M Gatell, Edwin Dejesus, Jerome Devente, Jacob P Lalezari, Lewis H McCurdy, Louis A Sloan, Benjamin Young, Anthony Lamarca, Trevor Hawkins, Joseph J Eron, Bonaventura Clotet, Jacques Durant, Christine Katlama, Princy Kumar, Adriano Lazzarin, Isabelle Poizot-Martin, Gary Richmond, Vincent Soriano, Mounir Ait-Khaled, Tamio Fujiwara, Jenny Huang, Sherene Min, Cindy Vavro, Jane Yeo, VIKING Study Group, Sharon L Walmsley, Joseph Cox, Jacques Reynes, Philippe Morlat, Daniel Vittecoq, Jean-Michel Livrozet, Pompeyo Viciana Fernández, Jose M Gatell, Edwin Dejesus, Jerome Devente, Jacob P Lalezari, Lewis H McCurdy, Louis A Sloan, Benjamin Young, Anthony Lamarca, Trevor Hawkins

Abstract

Background: Dolutegravir (DTG; S/GSK1349572), a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, has limited cross-resistance to raltegravir (RAL) and elvitegravir in vitro. This phase IIb study assessed the activity of DTG in HIV-1-infected subjects with genotypic evidence of RAL resistance.

Methods: Subjects received DTG 50 mg once daily (cohort I) or 50 mg twice daily (cohort II) while continuing a failing regimen (without RAL) through day 10, after which the background regimen was optimized, when feasible, for cohort I, and at least 1 fully active drug was mandated for cohort II. The primary efficacy end point was the proportion of subjects on day 11 in whom the plasma HIV-1 RNA load decreased by ≥0.7 log(10) copies/mL from baseline or was <400 copies/mL.

Results: A rapid antiviral response was observed. More subjects achieved the primary end point in cohort II (23 of 24 [96%]), compared with cohort I (21 of 27 [78%]) at day 11. At week 24, 41% and 75% of subjects had an HIV-1 RNA load of <50 copies/mL in cohorts I and II, respectively. Further integrase genotypic evolution was uncommon. Dolutegravir had a good, similar safety profile with each dosing regimen.

Conclusion: Dolutegravir 50 mg twice daily with an optimized background provided greater and more durable benefit than the once-daily regimen. These data are the first clinical demonstration of the activity of any integrase inhibitor in subjects with HIV-1 resistant to RAL.

Figures

Figure 1.
Figure 1.
Study design. Subjects received dolutegravir (DTG) 50 mg once daily (cohort I) or DTG 50 mg twice daily (cohort II). In both cohorts, subjects were allocated to 1 of 2 groups on the basis of integrase genotype at screening, to ensure a broad representation of genotypes and a range of phenotypic susceptibility. Cohort II subjects were required to have ≥1 fully active antiretroviral therapy in an optimized background regimen (OBR). Abbreviation: RAL, raltegravir. aQ148H/K/R plus changes in L74, E138, or G140. bSubjects remained on failing background regimen from day 1 to day 10.
Figure 2.
Figure 2.
Dolutegravir (DTG) fold-change (FC) in 50% inhibitory concentration at baseline, by integrase (IN) mutational pathway at baseline.

References

    1. Powderly WG. Integrase inhibitors in the treatment of HIV-1 infection. J Antimicrob Chemother. 2010;65:2485–8.
    1. Markowitz M, Nguyen B-Y, Gotuzzo E, et al. and the Protocol 004 Part II Study Team. Rapid and durable antiretroviral effect of the HIV-1 integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr. 2007;46:125–33.
    1. Steigbigel RT, Cooper DA, Kumar PN, et al. for the BENCHMRK Study Teams. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med. 2008;359:339–54.
    1. Mbisa JL, Martin SA, Cane PA. Patterns of resistance development with integrase inhibitors in HIV. Infect Drug Resist. 2011;4:65–76.
    1. DeJesus E, Berger D, Markowitz M, et al. for the 183–0101 Study Team. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J Acquir Immune Defic Syndr. 2006;43:1–5.
    1. Zolopa AR, Berger DS, Lampiris H, et al. Activity of elvitegravir, a once-daily integrase inhibitor, against resistant HIV type 1: results of a phase 2, randomized, controlled, dose-ranging clinical trial. J Infect Dis. 2010;201:814–22.
    1. Cooper DA, Steigbigel RT, Gatell JM, et al. for the BENCHMRK Study Teams. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med. 2008;359:355–65.
    1. DeJesus E, Cohen C, Elion R, et al. for the 183-0101 Study Team. First report of raltegravir (RAL, MK-0518) use after virologic rebound on elvitegravir (EVT, GS 9137) [abstract TUPEB032] 2007 Poster presented at: 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, Australia, 22–25 July.
    1. Marinello J, Marchand C, Mott BT, Bain A, Thomas CJ, Pommier Y. Comparison of raltegravir and elvitegravir on HIV-1 integrase catalytic reactions and on a series of drug-resistant integrase mutants. Biochemistry. 2008;47:9345–54.
    1. Garrido C, Villacian J, Zahonero N, et al. Broad phenotypic cross-resistance to elvitegravir in HIV-infected patients failing on raltegravir-containing regimens. Antimicrob Agents Chemother. 2012 56:2873–8.
    1. van Lunzen J, Maggiolo F, Arribas JR, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis. 2012;12:111–8.
    1. Sato A, Seki T, Kobayashi M, et al. In vitro passage of drug resistant HIV-1 against a next generation integrase inhibitor (INI), S/GSK1349572. 2009 Poster presented at: 49th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy Meeting, San Francisco, CA, 12–15 September Abstract H-932.
    1. Seki T, Kobayashi M, Wakasa-Morimoto C, et al. S/GSK1349572 is a potent next generation HIV integrase inhibitor and demonstrates a superior resistance profile substantiated with 60 integrase mutant molecular clones. 2010 Poster presented at: 17th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 16–19 February Abstract 555.
    1. National Institutes of Allergy and Infectious Diseases, Division of Acquired Immunodeficiency Syndrome. Division of AIDS table for grading the severity of adult and pediatric adverse events. NIAID DAIDS Regulatory Support Center. December 2004, with clarification published on August 2009. . Accessed 9 January 2012.
    1. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry: antiretroviral drugs using plasma HIV RNA measurements—clinical considerations for accelerated and traditional approval. 2002. Silver Spring, MD: Center for Drug Evaluation and Research. . Accessed 19 September 2012.
    1. Lovern M, Underwood M, Nichols G, Song I. PK/PD modeling supports dose escalation decision in VIKING. 2010 Poster P182 presented at: 10th International Congress on Drug Therapy in HIV Infection, Glasgow, United Kingdom, 7–11 November. J t AIDS Soc 2010; 13(suppl 4):P182.
    1. Kobayashi M, Yoshinaga T, Seki T, et al. In vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother. 2011;55:813–21.
    1. Underwood MR, Huang J, Dudas K, et al. Multiple mutations and replicative capacity: HIV integrase resistance analysis for raltegravir (RAL) resistant virus isolates while under pressure with dolutegravir (DTG, S/GSK1349572) therapy. 2011 Poster presented at: International HIV & Hepatitis Virus Drug Resistance Workshop, Los Cabos, Mexico, 7–11 June Abstract 1.
    1. Vavro C, Dudas K, Hasan S, Huang J, Yeo J, Underwood M. Dolutegravir treatment of HIV subjects with raltegravir resistance: integrase resistance evolution in Cohort II of the VIKING study [abstract 5] 2012 Abstract presented at: International HIV & Hepatitis Virus Drug Resistance Workshop, Sitges, Spain, 5–9 June.
    1. Winters MA, Lloyd RM, Jr, Shafer RW, Kozal MJ, Miller MD, Holodniy M. Development of elvitegravir resistance and linkage of integrase inhibitor mutations with protease and reverse transcriptase resistance mutations. PLoS One. 2012;7:e40514.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever