ICAAC 2012: Dolutegravir HIV Regimen Superior to Atripla, Fewer Stop Due to Side Effects

The experimental integrase inhibitor dolutegravir combined with abacavir/lamivudine (Epzicom) demonstrated statistically superior antiviral efficacy compared with the popular Atripla single-tablet regimen for first-line HIV treatment, largely because fewer people stopped using the former due to side effects, researchers reported this week at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) this week in San Francisco.

Integrase inhibitors work by preventing HIV from inserting its genetic material into a host cell's chromosomes, a necessary step in viral replication. Dolutegravir  (formerly S/GSK1349572), being jointly developed by Shionogi and ViiV Healthcare, has so far shown promising outcomes for both treatment-experienced and previously untreated individuals.

Sharon Walmsley, MD, from the University Health Network in Toronto presented the latest findings from the SINGLE (ING114467) study, a multinational Phase 3 trial comparing the safety and efficacy and safety of 50 mg once-daily dolutegravir plus abacavir/lamivudineversus once-daily Atripla (efavirenz/tenofovir/emtricitabine coformulation).

SINGLE enrolled 833 treatment-naive participants who were randomly allocated (1:1) to receive the 2 regimens. Most (84%) were men, about two-thirds were white, and the median age was 35 years. At baseline, the median viral load was approximately 50,000 copies/mL (with 32% > 100,000 copies/mL) and the median CD4 T-cell count was about 337 cells/mm³ (with 14% < 200 cells/mm³).

Results

• 88% of dolutegravir/abacavir/lamivudine recipients achieved viral load < 50 copies/mL at 48 weeks, compared with 81% of Atripla recipients in an intent-to-treat "snapshot" analysis.
• Although the trial was designed to show non-inferiority, statistical analysis showed that the dolutegravir regimen actually performed significantly better than Atripla (P = 0.003).
• Response to dolutegravir/abacavir/lamivudineandAtripla was similar for people with baseline viral loads above and below 100,000 copies/mL and for those with CD4 counts above or below 200 cells/mm³.
• Dolutegravir/abacavir/lamivudine was associated with a significantly larger gain in CD4 cells (267 vs 208 cells/mm³, respectively).
• Dolutegravir/abacavir/lamivudine also suppressed HIV more rapidly than Atripla (28 vs 84 days, respectively), but the clinical relevance of this findings is unclear.
• In each arm, 4% of participants experience protocol-defined virological failure, and 3% discontinued the study for this reason.
• No one in the dolutegravir/abacavir/lamivudine arm developed integrase or reverse transcriptase drug resistance mutations, while 1 person taking Atripla developed a NRTI mutation and 4 developed NNRTI mutations.
• Just 2% of participants in the dolutegravir/abacavir/lamivudinearm stopped treatment early due to side effects compared with 10% in the Atripla arm.
• The difference was mainly due to psychiatric symptoms (<1% vs 4%, respectively) and nervous system symptoms (0% vs 3%, respectively) associated with efavirenz.
• Gastrointestinal symptoms were the most common adverse event in the dolutegravir/abacavir/lamivudinearm, but frequency was the same in both arms (17%-18% for diarrhea, 14% for nausea).
• Insomnia was the only adverse event reported more often with the dolutegravir regimen(15% vs 10%).
• There were no deaths in dolutegravir/abacavir/lamivudineand 2 deaths in the Atripla arm, neither of which were considered related to the drug.
• People in the dolutegravir/abacavir/lamivudinearm saw an initial rise in serum creatinine -- a potential signal of kidney toxicity -- but this soon plateaued; little change in kidney function was observed in the Atripla arm.

Dolutegravir plus abacavir/lamivudine"was highly effective and better tolerated through 48 weeks" than the Atripla single-tablet regimen, the researchers concluded.

Walmsley said that the better performance of the dolutegravir regimen was driven by its better tolerability, as Atripla recipients were more likely to discontinue treatment prematurely due to adverse events or death. An expert in the audience noted that the Atripla discontinuation rate appeared to be higher in SINGLE than in prior studies.

Walmsley also explained that the early rise in serum creatinine is thought to be due to dolutegravir's inhibition of creatinine secretion in the kidneys, not a true reflection of kidney toxicity.

ViiV Healthcare indicated in a media statement that findings from SINGLE and three other phase III trials -- SPRING-2 (also treatment-naive) and VIKING-3 and SAILING (both treatment-experienced) -- are expected to be submitted to regulatory agencies to support approval of dolutegravir. ViiV also owns abacavir and lamivudine, and a single-tablet regimen is in the works.

9/14/12

Reference

S Walmsley, A Antela, N Clumeck, et al. Dolutegravir (DTG; S/GSK1349572) + Abacavir/Lamivudine Once Daily Statistically Superior to Tenofovir/Emtricitabine/Efavirenz: 48-Week Results - SINGLE (ING114467). 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012). San Francisco. September 9-12, 2012. Abstract H-556b.

Other Source

ViiV Healthcare. Dolutegravir (DTG; S/GSK1349572) + Abacavir/Lamivudine Once Daily Statistically Superior to Tenofovir/Emtricitabine/Efavirenz: 48-Week Results - SINGLE (ING114467). Media statement. September 10, 2012.