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Good Response and Resistance Record
in Naive and Experienced Starting Dolutegravir
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20th International AIDS Conference, July 20-25, 2014, Melbourne
From abstract below: ".....In treatment naïve studies where DTG was given with 2NRTIs, no subject developed resistance to either DTG or the background therapy through 96 weeks (SPRING-2, SINGLE) or 48 weeks (FLAMINGO). In patients with a history of at least 2 class-resistance but INI-naïve (SAILING), those receiving DTG plus 2NRTIs over 48 weeks did not experience PDVF (0/32), even when both NRTIs were not fully active"
Mark Mascolini
No one starting the integrase inhibitor dolutegravir with two nucleoside/nucleotides (NRTIs) in three clinical trials enrolling antiretroviral-naive people had evidence of emergent dolutegravir or NRTI mutations [1]. Virologic failure proved more frequent with raltegravir than dolutegravir in SAILING, a randomized trial that enrolled people with HIV resistant to two antiretroviral classes.
Dolutegravir is a potent integrase inhibitor licensed for antiretroviral-naive or integrase inhibitor-experienced people 12 years old or older. To look more closely at rates of virologic failure and emergent resistant virus with dolutegravir regimens, ViiV Healthcare researchers examined findings from three randomized trials that enrolled antiretroviral-naive people (SPRING-2, SINGLE, and FLAMINGO) and one trial that enrolled people with two-class resistance but naive to integrase inhibitors (SAILING).
In all four studies, researchers performed genotypic and phenotypic resistance testing before treatment began and upon virologic failure. They excluded people with baseline resistance from the three treatment-naive studies and used baseline resistance to select background regimens in SAILING.
Dolutegravir proved virologically superior to efavirenz at week 96 of SINGLE and superior to darunavir/ritonavir at week 48 in FLAMINGO. In the three trials enrolling antiretroviral-naive people starting dolutegravir plus two NRTIs, virus resistant to dolutegravir or the NRTIs (tenofovir/emtricitabine or abacavir/lamivudine) did not emerge through 48 weeks of treatment in FLAMINGO or through 96 weeks in SPRING-2 or SINGLE.
In the SAILING trial of double-class-experienced but integrase inhibitor-naive people, dolutegravir proved virologically superior to raltegravir at 48 weeks (71% versus 64% below 50 copies, P = 0.03). Among people with virologic failure at week 48, integrase-related mutations arose in 1% randomized to dolutegravir versus 5% randomized to raltegravir, a significant difference (P = 0.003). Virus resistant to background drugs emerged in 1% assigned to dolutegravir and 3% assigned to raltegravir.
Among SAILING participants who entered the trial with primary protease inhibitor mutations, 48-week sub-50-copy response rates were 85% with dolutegravir and 67% with raltegravir (difference 18.6%, 95% confidence interval 5.0 to 32.2). Among people who took only NRTIs with their integrase inhibitor in SAILING, none of 32 randomized to dolutegravir versus 7 of 32 (22%) randomized to raltegravir had protocol-defined virologic failure at week 48.
Among SAILING participants who entered the trial with an M184V mutation conferring resistance to lamivudine or emtricitabine and taking those NRTIs in the trial, none of 13 had virologic failure with a dolutegravir regimen, compared with 4 of 12 randomized to raltegravir. Phenotyping indicated that the second NRTI was active in 10 of the 13 people randomized to dolutegravir and in all 12 randomized to raltegravir. In the dolutegravir arm, the 3 other people had two or more NRTI thymidine analog mutations (TAMs) when starting the dolutegravir regimen.
Among all people entering SAILING with TAMs, 48-week virologic failure occurred in 10 of 164 assigned to dolutegravir and 17 of 166 assigned to raltegravir (6% versus 10%). Among people taking a ritonavir-boosted protease inhibitor with dolutegravir or raltegravir in SAILING, 18 of 300 randomized to dolutegravir versus 36 of 305 randomized to raltegravir had protocol-defined virologic failure at week 48 (6% versus 12%).
The ViiV investigators noted that further studies with more participants and longer follow-up are needed to confirm the SAILING findings.
Reference
1. Demarest J, Underwood M, St Clair M, et al. DTG-containing regimens are active in INI-naive patients with a history of NRTI resistance. AIDS 2014. 20th International AIDS Conference. July 20-25, 2014. Melbourne. Abstract TUAB0104.
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Program Abstract
Background: Dolutegravir (DTG) has exhibited potent antiviral efficacy in Phase 3 studies of more than n=1800 integrase inhibitor(INI)-naïve patients. These international studies evaluated the activity of DTG-based regimens in the context of different HIV-1 subtypes and treatment history.
Methods: Virologic outcome of patients enrolled in the SPRING-2, SINGLE, FLAMINGO, and SAILING studies of DTG-based regimens was evaluated. Screening PI, NNRTI, and NRTI resistance was performed for patients enrolling in SAILING. In all studies, genotypic and phenotypic resistance testing was performed with the Baseline and time of failure samples for patients experiencing protocol defined virologic failure (PDVF).
Results: In treatment naïve studies where DTG was given with 2NRTIs, no subject developed resistance to either DTG or the background therapy through 96 weeks (SPRING-2, SINGLE) or 48 weeks (FLAMINGO). In patients with a history of at least 2 class-resistance but INI-naïve (SAILING), those receiving DTG plus 2NRTIs over 48 weeks did not experience PDVF (0/32), even when both NRTIs were not fully active. In contrast, several subjects receiving RAL plus 1-2NRTIs experienced PDVF (7/32, 22%). In SAILING subjects for whom the background regimen included 3TC/FTC in the presence of mutation M184V, 0/13 had failure with DTG + a second NRTI. For 10 of these subjects, the second NRTI was active (by phenotype); for 3 of these subjects, the second NRTI was used in the presence of 2 or more thymidine-analog mutations. For RAL subjects who received 3TC/FTC plus a second NRTI in the presence of M184V, 4/12 (33%) had PDVF; in all of these cases the second NRTI was active by phenotype.
Conclusions: DTG-based regimens showed substantial and durable antiviral activity in INI-naïve patients. No treatment-naïve subject receiving DTG+2NRTIs developed resistance to either DTG or the background therapy through 96 or 48 weeks. In the SAILING study of patients failing therapy with at least 2-class resistance, there was no evidence of an increased risk of virologic failure for subjects receiving DTG + 2 NRTIs, even in the presence of NRTI resistance. Further studies and longer follow-up are planned to confirm these findings.
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