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AIDS 2014: Dolutegravir Demonstrates Good Efficacy Despite Resistance

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Antiretroviral regimens containing the recently approved HIV integrase inhibitor dolutegravir (Tivicay) demonstrated high rates of viral suppression even in treatment-experienced people who were resistant to NRTIs. Among people starting treatment for the first time, no resistance was detected through 96 weeks, according to study findings presented at the 20th International AIDS Conference last week in Melbourne.

Modern antiretroviral therapy (ART) is highly effective and generally well-tolerated, but novel agents -- especially those in newer drug classes -- can offer important options for people such as those with resistance to existing drugs and those who have difficulty tolerating specific side effects.

Jim Demarest of ViiV Healthcare and colleagues performed a post-hoc combined analysis looking at virological outcomes among participants enrolled in Phase 3 trials of dolutegravir-based regimens. The SPRING-2, SINGLE, and FLAMINGO studies looked at previously untreated people, while SAILING enrolled treatment-experienced patients with resistance to at least 2 drug classes who had not yet used integrase inhibitors.

All the treatment-naive studies performed resistance testing at baseline and excluded people who were resistant to study drugs. In SAILING, resistance to 2 or more drug classes was an inclusion criterion, and baseline resistance testing was used to select an optimized background regimen. All studies called for additional resistance testing if participants experienced virological failure (either failure to achieve viral suppression or viral rebound while on treatment).

The first 3 trials found that dolutegravir plus 2 nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs) worked as well as or better than the older integrase inhibitor raltegravir (Isentress), the non-nucleoside reverse transcriptase inhibitor efavirenz (Sustiva), and the boosted protease inhibitor darunavir (Prezista), respectively.

SAILING showed that dolutegravir bested raltegravir in treatment-experienced people; in this study 71% of participants assigned to receive dolutegravir plus a background regimen achieved virological suppression (50 copies/ml) at 48 weeks, compared with 64% of those assigned to take raltegravir.

Results

  • In the treatment-nave trials, no study participants developed emergent resistance to either dolutegravir or the background drugs through 48 or 96 weeks of follow-up.
  • Among SAILING participants who experienced protocol-defined virological failure, there was significantly less emergent drug resistance in the dolutegravir arm than in the raltegravir arm; integrase inhibitor resistance was detected in 1% and 5%, respectively, while resistance to background drugs was seen in 1% and 3%.
  • Response rates were similar for SAILING participants who either had never used boosted darunavir (67% in the dolutegravir arm vs 60% in the raltegravir arm) or had done so and had no primary protease inhibitor resistance mutations (69% vs 70%, respectively).
  • Among darunavir users with primary protease mutations, however, dolutegravir performed significantly better (86% vs 67%).
  • Among people who included any protease inhibitor in their regimen, half as many experienced treatment failure in the dolutegravir arm compared with the raltegravir arm (6% vs 12%).
  • Among the 32 SAILING participants who received dolutegravir with only 2 NRTIs, none experienced protocol-defined virological failure, even if both of their background NRTIs were not fully active due to resistance; in contrast, 22% of participants assigned to take raltegravir plus 2 NRTIs did experience virological failure.
  • SAILING included 25 participants whose background regimen included lamivudine (Epivir) or emtricitabine (Emtriva, also in several coformulations) and who had the M184V viral mutation, which confers resistance to these drugs.
  • None of these patients in the dolutegravir arm experienced virological failure -- even if their second NRTI also appeared to be compromised by thymidine-analog resistance mutations -- compared with one-third of those taking raltegravir.

"Dolutegravir-based regimens showed substantial and durable antiviral activity" in integrase inhibitor-naive patients, the researchers concluded. "The resistance profile for dolutegravir will be defined further by use in clinical practice and additional clinical trials."

The U.S. Food and Drug Administration is currently evaluating a fixed-dose coformulation containing dolutegravir plus abacavir/lamivudine (the drugs in Epzicom or Kivexa). If this is approved, it will be the first 1-pill/once-daily regimen that does not contain tenofovir DF (Viread), which some people wish to avoid due to its risk of kidney and bone toxicity.

7/29/14

Reference

J Demarest, M Underwood, M St Clair, et al. DTG-containing regimens are active in INI-naive patients with a history of NRTI resistance. 20th International AIDS Conference. Melbourne, July 20-25 2014. Abstract TUAB0104.