Dolutegravir combo beats Atripla for effectiveness and tolerability

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

Sharon Walmsley from the University Health Network in Toronto presented the latest findings from the SINGLE (ING114467) study, a multinational phase III trial comparing the safety and efficacy and safety of 50mg once-daily dolutegravir plus abacavir/lamivudine versus once-daily Atripla (efavirenz/tenofovir/emtricitabine co-formulation).

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

After 48 weeks of treatment, 88% of dolutegravir/abacavir/lamivudine recipients achieved viral load below 50 copies/mL, 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/lamivudine and Atripla was similar for people with baseline viral loads above and below 100,000 copies/mL and for people with CD4 counts above or below 200 cells/mm³.

Dolutegravir/abacavir/lamivudine also suppressed HIV more rapidly than Atripla (28 vs 84 days, respectively) and was associated with a significantly larger gain in CD4 cells (267 vs 208 cells/mm³, respectively), but the clinical relevance of these 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, but one person taking Atripla developed a nucleoside analogue reverse transcriptase inhibitor mutation and four developed NNRTI mutations.

Walmsley noted that the better performance of the dolutegravir regimen was largely driven by its better tolerability, as Atripla recipients were more likely to discontinue treatment prematurely due to adverse events or death.

Just 2% of participants in the dolutegravir/abacavir/lamivudine arm stopped treatment early due to side-effects compared with 10% in the Atripla arm. This 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 side-effect in the dolutegravir/abacavir/lamivudine arm, but the frequency was the same with both regimens (22%). Insomnia was the only side-effect seen more often with the dolutegravir regimen (15 vs 10%). Dolutegravir has been associated with headache in other studies, but that was not observed in SINGLE. There were two 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. Walmsley explained that this is thought to be due to dolutegravir's inhibition of creatinine secretion in the kidneys. Little change in kidney function was observed in the Atripla arm, despite tenofovir's known association with kidney problems in a small proportion of patients.

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

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 plans to market dolutegravir in a fixed-dose tablet combined with abacavir and 3TC.

Walmsley S et al. Dolutegravir (DTG; S/GSK1349572) + abacavir/lamivudine once daily statistically superior to tenofovir/emtricitabine/efavirenz: 48-week results - SINGLE (ING114467). 52^nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract H-556b, 2012. View the abstract on the conference website.