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Dolutegravir Effective at 24/48 Weeks in People With Integrase Inhibitor Mutations
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7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur
Mark Mascolini
After 24 weeks, 69% of people who started twice-daily dolutegravir with mutations conferring resistance to other integrase inhibitors (INI) had a viral load below 50 copies [1]. After 48 weeks, 56% had a sub-50-copy viral load. Half of study participants who had two or more primary INI mutations had a sub-50-copy load at week 24.
Dolutegravir at a dose of 50 mg daily is effective for people with INI-susceptible virus. Researchers designed VIKING 3 to test dolutegravir at a dose of 50 mg twice daily in people with INI mutations conferring resistance to raltegravir or elvitegravir. All study participants had a viral load above 500 copies and had a record of resistance to raltegravir and/or elvitegravir, the two licensed integrase inhibitors. All participants had resistance to two or more antiretroviral classes.
In a functional monotherapy phase, study participants began dolutegravir (50 mg twice daily) and continued the other antiretrovirals in the regimen (except raltegravir or elvitegravir) for 1 week. On day 8 they continued dolutegravir and replaced other drugs with an optimized background regimen that had an overall susceptibility score (OSS) at or above 1 as determined by Monogram Biosciences. The week-24 population included all 183 patients recruited; the week-48 population included 114 people who reached 48 weeks by the time of the data cutoff.
Two thirds of study participants (68%) had INI resistance mutations detectable at screening, and most had resistance to two or more nucleosides (75%), one or more nonnucleosides (70%), and two or more protease inhibitors (62%). Only 55 of 183 people (30%) were able to find a fully active protease inhibitor for their regimen. Most second and third active antiretrovirals in the dolutegravir regimen were nucleosides. Median baseline CD4 count stood at 140 (range 19 to 1110), and participants had taken antiretrovirals for a median 13 years (range 0.3 to 25).
Viral load fell by an average 1.4 log (25-fold) after 7 days of functional monotherapy. After 24 weeks of treatment, 126 of 183 people (69%) had a viral load below 50 copies. After 48 weeks, 64 of 114 (56%) had a sub-50 viral load. There were 50 virologic nonresponders (27%) at week 24 and 44 (39%) at week 48. Through 48 weeks, 6 of 183 people (3%) discontinued treatment because of adverse events. There were two serious drug-related adverse events--hyperbilirubinemia, elevated ALT, and drug eruption in a patient taking dolutegravir with etravirine, and grade 2 syncope in another patient.
At week 24 sub-50-copy response rates were 78% with no primary INI mutations, 100% with changes at position T66, 75% with changes at Y143, 88% with changes at N155, 50% with two or more primary INI mutations, 59% with a Q148 change plus one secondary mutation, and 24% with Q148 plus two or more secondary mutations. Multivariate analysis identified two factors highly associated with smaller viral load declines with dolutegravir: (1) Q148 changes plus two or more secondary INI mutations, and (2) baseline fold change in dolutegravir susceptibility.
Virologic response rates were 82% for people with a 4-fold or lower change in susceptibility to dolutegravir at baseline, 56% in people with a fold change between 4 and 10, and 11% in people with a fold change above 10. Background regimen OSS was not associated with virologic response.
Reference
1. 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.
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