Dolutegravir superior to raltegravir for treatment-experienced people with HIV

The once-daily HIV integrase inhibitor dolutegravir demonstrated better efficacy than twice-daily raltegravir for previously treated people with HIV, with fewer study withdrawals due to virological failure and less emergent drug resistance, researchers reported on Wednesday at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Kuala Lumpur. Results were published concurrently in The Lancet online edition.

Pedro Cahn of Fundacion Huesped in Buenos Aires and fellow investigators with the SAILING trial compared dolutegravir, a next-generation integrase inhibitor being developed by ViiV Healthcare, against raltegravir (Isentress), the sole approved integrase agent, for people with extensive drug resistance. 

This phase 3 study included 724 individuals on failing antiretroviral therapy with ongoing viral replication. Participants showed evidence of resistance to two or more antiretroviral drug classes – with half showing resistance to at least three classes – but had not previously used integrase inhibitors.

About 70% of study participants were men, half were white, about 40% were of African descent and the median age was about 43 years; 16% were co-infected with hepatitis B or C. At baseline the median CD4 count was approximately 200 cells/mm³ and 30% had HIV viral load above 50,000 copies/ml. 

Participants were randomly assigned (1:1) to take 50mg once-daily dolutegravir or 400mg twice-daily raltegravir for 48 weeks, both in combination with an investigator-selected background regimen of no more than two drugs, at least one of which was still fully active.

About 20% included the potent protease inhibitor darunavir (Prezista) and had no primary protease resistance mutations, while the remainder either did not use darunavir or did so with these viral mutations. The number of participants using darunavir was capped in the protocol so as not to mask the effect of dolutegravir. 

Six people in the dolutegravir group and four in the raltegravir group either never started study drugs or were otherwise excluded at study sites, leaving a modified intent-to-treat population of 354 and 361 participants in the two arms. Study completion rates were high at 84% and 78%, respectively.

Overall, dolutegravir was statistically superior, with 71% of participants in the dolutegravir group and 64% in the raltegravir group achieving HIV RNA below 50 copies/ml at week 48 in a modified intent-to-treat analysis (p=0.03). Response rates were similar in a per protocol or 'as-treated' analysis, 73 vs 66%, respectively. 

Half as many people in the dolutegravir group experienced protocol-defined virologic failure – either virologic non-response or viral rebound – compared with the raltegravir group at 48 weeks: 6 vs 12%, respectively. Participants taking dolutegravir were also significantly less likely to have new integrase inhibitor resistance mutations, 1 vs 5%.

CD4 cell gains were similar in both the dolutegravir and raltegravir arms at 162 and 153 cells/mm³, respectively. 

Turning to subgroup analyses, dolutegravir and raltegravir worked about equally well for patients with lower baseline viral load (<50,000 copies/ml), with 48-week response rates of 75 and 71%, respectively. But dolutegravir performed better for those with high viral load, 62 vs 47%.

Likewise, dolutegravir and raltegravir performed similarly for people who also used darunavir with no primary resistance mutations, 69 vs 70%, respectively. Among those not benefiting from fully active darunavir, however, dolutegravir again proved superior, 71 vs 62%. 

Dolutegravir and raltegravir were both safe and well tolerated. About one-in-five participants experienced drug-related side-effects (20 and 23%, respectively), with gastrointestinal symptoms being most frequent.

Two people taking dolutegravir (<1%) and four taking raltegravir (1%) experienced serious drug-related adverse events, with similar rates of discontinuation due to adverse events in both arms (3 and 4%, respectively). 

Grade 3 and 4 laboratory abnormalities were generally uncommon. Participants taking dolutegravir had a larger average increase in serum creatinine (11.1 vs 5.1 mcmol/l), which Cahn explained was not due to kidney impairment but rather to the drug's effect on a renal transporter. Some people who also took atazanavir (Reyataz) experienced bilirubin elevations.

"Dolutegravir once-daily has higher virologic efficacy when compared with raltegravir twice-daily in a treatment-experienced, integrase inhibitor-naive population," the researchers concluded. "Dolutegravir statistical superiority was driven by fewer withdrawals due to lack of efficacy, lower number of protocol-defined virologic failures and lower treatment emergent resistance." 

These findings suggest that dolutegravir represents "a potential new drug in the integrase inhibitor class that will add to our treatment armamentarium", Cahn told reporters.

Dolutegravir has been submitted for licensing in the United States and European Union and is likely to receive marketing approval in the second half of 2013.