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 52nd Interscience Conference on
Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco.
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
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
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,
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.
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
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.
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.