Important new integrase inhibitor approved

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Post by David Menadue28 Feb 2014

Dolutegravir (DTG, brand name Tivicay®) is an integrase inhibitor that was approved in 2014 by the Therapeutic Goods Administration for use as an HIV antiretroviral (ARV) drug.

Dolutegravir was given Pharmaceutical Benefits Scheme listing as an s100 drug on April 1st 2014. (See Treatments Update below for more on integrase inhibitors.)

Results from five separate clinical trials support the effectiveness of DTG in suppressing HIV replication.  It joins raltegravir (RAL, brand name Isentress®) and elvitegravir (EVG, brand name Vitekta®) as the other currently approved integrase inhibitors.

Useful first-line treatment
Three recent trials (the SINGLE Study, the SPRING-2 Study and the FLAMINGO trial) involved treatment-naive people living with HIV. Between them, the studies indicate that DTG is either superior or non-inferior to efavirenz, raltegravir and boosted darunavir in people who commence treatment with it as part of their HIV drug combination. It appears to have a favourable side effects profile and a superior lipids profile. It also has a high genetic barrier to the development of HIV resistance.

Effective for treatment resistance
The SAILING Study investigated the use of DTG compared with AL in 719 PLHIV who had previously received HIV ARVs (but who had not used any integrase inhibitors). These treatment experienced patients all had resistance to at least two classes of HIV ARVs, and 49% at commencement of the trial had resistance to three ARV drug classes. At 24 weeks, 79% of people receiving DTG compared with 70% of the RAL arm had achieved an ‘undetectable’ viral load. Patients receiving DTG had a slightly better increase in CD4 cell increases (144 versus 106 cells/mm³). Fewer participants discontinued due to development of resistance (0.6% in DTG arm versus 10.6% in RAL arm) and there were no major side effects.

Similar results were found in the VIKING-3 Study which demonstrated that DTG is effective in successfully treating people who have failed other integrase inhibitor regimes.

Dosing is in a small tablet (50mg DTG) once daily for both treatment-experienced and naive patients and its high genetic barrier to resistance makes it an attractive alternative. It affects lipids less than both Atripla® and darunavir/r and has significantly less central nervous system side effects than EFV.

References
Tivicay® (dolutegravir) Tablets Product Information atwww.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2014-PI-01200-1 last amended 17 Jan 2014.

Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A, et al. (2013) Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 369(19):1807-18. Available at www.natap.org/2013/HIV/nejmoa1215541.pdf

Raffi F, Jaeger H, Quiros-Roldan E, Albrecht H, Belonosova E, et al. (2013) Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomiseddouble-blind, non-inferiority trial. Lancet Infect Dis. 13(11):927-35. Available atwww.natap.org/2013/HIV/PIIS1473309913702573.pdf

Feinberg J, Clotet B, Khuong MA, et al. Once-daily dolutegravir is superior to darunavir/ritonavir in antiretroviral naive adults: 48 week results from FLAMINGO (ING114915). 53rd ICAAC Interscience Conference on Antimicrobial Agents and Chemotherapy. September 10-13, 2013. Denver. Abstract H-1464a. Summarised atwww.natap.org/2013/ICAAC/ICAAC_24.htm

Cahn P, Pozniak AL, Mingrone H, Shuldyakov A, Brites C, et al. (2013) 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. 382(9893):700-8. Summarised at www.jwatch.org/na31638/2013/07/22/sailing-dolutegravir-outperforms-raltegravir-treatment

Nichols G, Lazzarin A, Maggiolo F, et al. Phase 3 assessment of dolutegravir (DTG) 50 mg twice daily in HIV-1-infected subjects with raltegravir (RAL) and/or elvitegravir (EVG) resistance in VIKING-3: week 24 results of all 183 patients enrolled. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur. Abstract TULBPE19. Summarised at www.natap.org/2013/IAS/IAS_28.htm

Castagna A, Maggiolo F, Penco G, Wright D, Mills A, et al. (2014) Dolutegravir in Antiretroviral-Experienced Patients With Raltegravir- and/or Elvitegravir-Resistant HIV-1: 24-Week Results of the Phase III VIKING-3 Study. J Infect Dis. published online Jan 19. Available at jid.oxfordjournals.org/content/early/2014/01/19/infdis.jiu051.long