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IAS 2011: New Integrase Inhibitor Dolutegravir Looks Potent and Well-tolerated


The next-generation HIV integrase inhibitor dolutegravir (S/GSK1349572) suppressed HIV viral load as well as efavirenz (Sustiva) but caused fewer side effects in a study of treatment-naive patients, researchers reported at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2011) last week in Rome.

Jan van Lunzen from University Medical Center in Hamburg-Eppendorf presented findings from SPRING-1, a multinational Phase 2b trial comparing dolutegravir vs efavirenz as first-line antiretroviral therapy.

Prior studies have shown that dolutegravir (being developed by Shionogi and ViiV Healthcare) can be administered once-daily, unlike the sole approved integrase inhibitor, raltegravir (Isentress), which must be taken twice-daily. Further, dolutegravir does not require a booster, as does another experimental once-daily integrase inhibitor, elvitegravir

SPRING-1 included 205 patients starting HIV treatment for the first time. The study is designed to last 96 weeks; data from a planned 48-week interim analysis were presented in Rome.

Most participants (86%) were men, more than two-thirds were white, the median age was 37 years, and the mean CD4 count was 324 cells/mm3. About 20% had high baseline viral load (> 10,000 copies/mL).

Participants were randomly assigned to receive 10 mg, 25 mg, or 50 mg dolutegravir, or else 600 mg efavirenz, all once-daily, in combination with either tenofovir/emtricitabine (Truvada) or abacavir/lamivudine (Epzicom).


  • An unusual 16-week analysis showed that dolutegravir produced rapid HIV suppression, lowering viral load faster than efavirenz.
  • At 16 weeks, 90% to 96% of dolutegravir recipients had undetectable viral load (< 50 copies/mL), compared with 58% of efavirenz recipients.
  • Participants receiving dolutegravir experienced sustained viral suppression, but efavirenz recipients caught up by week 24.
  • The 48-week response rates were 88% to 91% in the dolutegravir arms compared with 82% in the efavirenz arm, not a statistically significant difference.
  • An ultrasensitive assay showed that 53% of people taking 50mg dolutegravir and 60% taking efavirenz had viral loads < 2 copies/mL.
  • There was a trend toward larger CD4 cell gains in the combined dolutegravir arms compared with the efavirenz arm (231 vs 174 cells/mm3), but the difference did not reach statistical significance.
  • The difference in efficacy was largely driven by the better tolerability of dolutegravir.
  • Overall, dolutegravir recipients experienced fewer moderate or worse side effects than efavirenz recipients (8% vs 20%, respectively):
    • central nervous system or psychiatric symptoms (0% vs 6%, respectively);
    • skin rash (0% vs 4%, respectively).
  • 2 people taking dolutegravir and 4 people taking efavirenz dropped out due to side effects (1% vs 8%, respectively).
  • Serious adverse events were also less common in the dolutegravir arm (5% vs 8%, respectively).
  • No integrase mutations were detected in the 3 participants who experienced virological failure on dolutegravir through week 48 (none of whom were taking the highest dose).

While grade 3 or higher laboratory abnormalities were uncommon, some participants taking dolutegravir experienced small changes in serum creatinine, a potential indicator of impaired kidney function. Changes were noted soon after starting the drug, but they did not progress and there was no difference in glomerular filtration rate (GFR). Van Lunzen explained that dolutegravir appears to inhibit creatinine secretion in the proximal renal tubules.

Looking at blood lipids, there were no notable changes in the dolutegravir arms compared with an increase in total and LDL "bad" cholesterol in the efavirenz arm, leading van Lunzen to describe dolutegravir as "lipid friendly." Triglyceride levels fell among dolutegravir recipients whilst rising among efavirenz recipients.

The 50 mg dolutegravir dose was chosen for further evaluation in Phase 3 studies. The developers are also working on a coformulated single-tablet regimen containing the new drug.



J van Lunzen, F Maggiolo, B Phung, et al. Rapid, robust and sustained antiviral response with once-daily (QD) dolutegravir (DTG, S/GSK1349572), a next generation integrase inhibitor (INI) in combination therapy in antiretroviral-naive adults: 48 week results from SPRING­1 (ING112276). 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2011). Rome, July 17-20, 2011. Abstract TUAB0102.