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
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
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,
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
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%,
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
"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."
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.