New integrase inhibitor dolutegravir helps treatment-experienced people on failing therapy

Dolutegravir superior to raltegravir in integrase inhibitor-naive patients
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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 monotherapy.



A person who has previously taken treatment for a condition. Treatment-experienced people may have taken several different regimens before and may have a strain of HIV that is resistant to multiple drug classes.

integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase, which is an HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected. Blocking integrase prevents HIV from replicating.

host cell

A host cell is a living cell invaded by, or capable of being invaded by, an infectious agent (such as a bacterium or a virus).


immune reconstitution inflammatory syndrome (IRIS)

A collection of inflammatory disorders associated with paradoxical worsening (due to the ‘waking’ and improvement of the immune system) of pre-existing infectious processes following the initiation of antiretroviral therapy.


gastrointestinal (GI) symptoms

Relating to or affecting the gut, stomach or bowel. GI symptoms include diarrhoea, abdominal pain (cramps), constipation, gas in the gastrointestinal tract, nausea, vomiting and GI bleeding. Among several possible causes of GI symptoms are infections and antiretroviral medicines.


Dolutegravir (formerly S/GSK1349572), being developed by ViiV/Shionogi, was submitted for regulatory approval in Europe, Canada and the US in late 2012.

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 (Isentress), in treatment-experienced people on failing therapy.

The study 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 integrase drugs.

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 participants receiving 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, respectively.

Fewer people on dolutegravir were virological non-responders (15 vs 24%), they had fewer protocol-defined 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".


Pozniak A et al. Dolutegravir vs raltegravir in ART-experienced, integrase-naive subjects: 24-week interim results from SAILING (ING111762). 20th Conference on Retroviruses and Opportunistic Infections, Atlanta, abstract 179LB, 2013.

View abstract 179LB on the conference website.