The next-generation integrase
inhibitor dolutegravir proved more beneficial than raltegravir (Isentress) for
treatment-experienced people with resistance to two or more antiretroviral drug
classes, researchers reported in a poster presented at the 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013) last week in Atlanta.
Although novel antiretroviral agents and treatment
strategies are no longer the primary focus of the retroviruses conference,
there is still a need for new and better options for people with extensive
treatment experience and highly resistant HIV.
Integrase inhibitors work by preventing HIV from inserting its genetic
material into host cell chromosomes. Because they do not interfere with known
human cellular processes, they tend to have low toxicity. Their completely
different mechanism remains active against virus that has developed resistance
to older drug classes, for example, due to prior use of suboptimal drugs or functional
Dolutegravir (formerly S/GSK1349572), being developed by ViiV/Shionogi,
was submitted for regulatory approval in Europe, Canada and the US in late
Dolutegravir is taken once daily, does not requiring
pharmacokinetic boosting and has stacked up favourably against existing drugs
in the long-term VIKING trials of treatment-experienced patients and
the SPRING and SINGLE studies of previously untreated individuals.
At this year's meeting, Anton Pozniak from the Chelsea and Westminster Hospital in London presented findings from the phase III SAILING study,
evaluating dolutegravir versus the sole approved integrase inhibitor, raltegravir
treatment-experienced people on failing therapy.
included 715 participants with ongoing viral replication despite being on
treatment. Unlike VIKING, which tested dolutegravir in treatment-experienced patients with
pre-existing raltegravir resistance mutations as well as resistance to any
three antiretroviral classes, SAILING compared the two integrase inhibitors in
people who had developed resistant to two or more classes but had never used
About two-thirds of
participants were men, half were white, about 40% were of
African descent; the median age was about 42 years. The median CD4 cell
count was approximately 200 cells/mm3, 30% had high
baseline viral load (>50,000 copies/ml) and 15% were co-infected with
hepatitis B or C. They had been on antiretroviral therapy for a median
of about six years and half were resistant to three or more drug classes.
Participants were randomised to receive either 50mg once-daily dolutegravir or 400mg twice-daily raltegravir for 48 weeks, along with an
investigator-selected background regimen that included no more than two other agents,
one of which was fully active.
In a planned interim analysis at 24 weeks, 79% of
dolutegravir achieved undetectable viral load (<50
copies/ml) compared with 70% of those taking raltegravir, reaching the
threshold for statistical superiority. The difference was greater (70 vs 53%)
among people with high baseline viral load, but was not significant among
participants taking darunavir (Prezista, 80
vs 81%). Median CD4 cell gains were similar at 99 and 93 cells/mm3,
people on dolutegravir were virological non-responders (15 vs 24%), they had
virologic failures (4 vs 9%) and they were less likely to have evidence of integrase
inhibitor resistance after treatment failure (0.6 vs 2.8%).
Dolutegravir was generally safe and well tolerated, with about 20% of
participants in both arms reporting drug-related adverse events; 2% of
dolutegravir recipients and 4% of raltegravir recipients discontinued treatment
due to adverse events. Gastrointestinal symptoms were the most common
side-effects, occurring with similar frequency in both groups. People with
hepatitis B or C co-infection were more likely to experience liver enzyme flares
attributed to immune reconstitution inflammatory syndrome (IRIS).
Dolutegravir "demonstrated superior
efficacy" to raltegravir, with differences driven by a lower rate of
virological failure in patients on dolutegravir, the researchers concluded. The
dose studied "was well tolerated with a wide variety of background
regimens in treatment-experienced subjects".