Lancet: Dolutegravir Works as Well as Raltegravir for First-time HIV Treatment

The next-generation HIV integrase inhibitor dolutegravir worked as well as raltegravir (Isentress), an approved drug in this class, for treatment-naive people in the Phase 3 SPRING-2 trial, according to a report published in the January 8, 2013, advance edition of The Lancet.

Integrase inhibitors prevent HIV from inserting its genetic material into host cells. Because they do not interfere with known human cellular processes, they have fewer toxicities than some other types of antiretroviral drugs.

Dolutegravir (formerly S/GSK1349572), being developed by ViiV Healthcare and Shionogi, is a once-daily integrase inhibitor that does not require pharmacokinetic boosting. In early studies it was well-tolerated, had low potential for drug interaction, and had a distinct resistance profile.

The drug has demonstrated potent antiviral activity and a good safety profile in both treatment-experienced and treatment-naive patients in Phase 3 clinical trials. In December ViiV announced that it has requested approval of dolutegravir in the U.S., Canada, and Europe.

As described in the recent Lancet report and presented at theInternational AIDS Conference (AIDS 2012) this past July, the SPRING-2 trial (ING113086) is a multicenter, double-blind, non-inferiority study comparing once-daily dolutegravir versus twice-daily raltegravir for previously untreated people. The primary endpoint was response at 48 weeks, but the study will continue through 96 weeks.

Starting in October 2010, Francois Raffi from the University of Nantes in France and colleagues enrolled 822 participants in Australia, Canada, Europe, and the U.S. who had not been not previously treated for HIV.

About 85% were men, a similar proportion were white, and the median age was 36 years. At baseline 28% had HIV viral load above 100,000 copies/mL and the median CD4 T-cell count was about 360 cells/mm³, with about 12% having < 200 cells/mm³. About 10% had hepatitis C coinfection and 2% had hepatitis B.

Participants were randomly assigned (1:1) to receive 50 mg once-daily dolutegravir or 400 mg twice-daily raltegravir, both in combination with an investigator-selected dual nucleoside/nucleotide reverse transcriptase inhibitor backbone of either tenofovir/emtricitabine (the drugs in Truvada), chosen by 60%, or abacavir/lamivudine (the drugs in Epzicom), chosen by 40%.

Results

• At 48 weeks, 88% of participants taking dolutegravir achieved HIV RNA < 50 copies/mL, compared with 85% in the raltegravir arm.
• The adjusted difference between the 2 arms was 2.5% in favor of dolutegravir, well within the predetermined 10% non-inferiority margin.
• Response rates in the 2 arms were similar regardless of viral load:

o   Low (<100,000 copies/mL): 90% with dolutegravir vs 89% with raltegravir;

o   High (>100,000 copies/mL): 82% vs 75%, respectively.

• Response rates were similar with tenofovir/emtricitabine and abacavir/lamivudine.
• Dolutegravir suppressed HIV somewhat faster, with 85% of dolutegravir recipients and 79% of raltegravir recipients achieving undetectable viral load by 8 weeks.
• An exploratory analysis showed a higher response rate in the dolutegravir arm for people with low baseline CD4 cell counts, though few patients had advanced immunosuppression.
• Participants in both groups experienced a median CD4 cell gain of 230 cells/mm³ at 48 weeks.
• 5% of dolutegravir recipients and 8% of raltegravir recipients experienced protocol-defined virological failure.
• No patients with virological failure had treatment-emergent integrase- or NRTI- resistance mutations in the dolutegravir arm, while 1 person did so in the raltegravir arm.
• Both regimens were generally well-tolerated with similar safety profiles in both arms.
• Few participants in either arm had drug-related serious adverse events (1% or less), and 2% of people in both groups discontinued treatment due to adverse events.
• The most common side effects were nausea (14% with dolutegravir vs 13% with raltegravir), headache (12% in both arms), nasopharyngitis (11% vs 12%), and diarrhea (11% in both arms).
• There were no clinically significant changes in fasting lipid profiles in either group.
• Serum creatinine increased in both treatment groups by 2 week, but thereafter remained stable through 48 weeks.
• However, no patients in either arm had grade 3 or 4 creatinine elevation and none discontinued treatment due to kidney-related events.
• Two people in each treatment arm had ALT increases at least 5-10 times the upper limit of normal and met liver-related stopping criteria; 1 person in each group had possible drug-induced liver injury with hypersensitivity reaction or rash.

"Taken together," the study authors wrote, "the results of this study suggest that dolutegravir 50 mg once daily, in combination with either tenofovir/emtricitabine or abacavir/lamivudine, is well tolerated and highly effective as initial treatment for treatment of adults with HIV infection, and is an alternative to a twice-daily raltegravir regimen."

Changes in serum creatinine among people taking dolutegravir were "not regarded as clinically significant," and were attributed to the drug's inhibition of tubular secretion of creatinine in the kidneys without affecting glomerular filtration, they explained.

The researchers acknowledged that a limitation of this trial was the low numbers of women and people of color, and they recommended that "[f]uture studies should assess the efficacy and safety [of dolutegravir] in patients excluded from this study, and then more generally in a diverse (ie, resource-limited) health-care setting."

Based on these findings, they concluded, "The non-inferior efficacy and similar safety profile of dolutegravir compared with raltegravir means that if approved, combination treatment with once-daily dolutegravir and fixed-dose nucleoside reverse transcriptase inhibitors would be an effective new option for treatment of HIV-1 in treatment-naive patients."

Commentary

In an accompanying editorial, Laura Waters and Tristan Barber from the Central and North West London NHS Foundation Trust noted that it is difficult to know, based on the small numbers in this trial, how well dolutegravir will work for individuals with advanced disease.

"The high genetic barrier [to resistance] of dolutegravir is particularly appealing, and whether this characteristic will enable us to use this drug as we use protease inhibitors -- eg, combined with another drug, or even as monotherapy -- is clearly something that should be explored," they wrote.

ViiV/Shionogi are working on a coformulation of dolutegravir with abacavir/lamivudine, which would add a fourth single-tablet regimen after Atripla (efavirenz/tenofovir/emtricitabine), Complera (rilpivirine/tenofovir/emtricitabine), and Stribild, the recently approved 4-in-1 pill containing tenofovir/emtricitabine plus Gilead's new integrase inhibitor elvitegravir, boosted with cobicistat.

"Single-tablet regimens have definite advantages and, not surprisingly, are preferred to regimens with several pills, as shown in patient surveys; however, data are scarce to support an advantage in effectiveness of single-pill regimens compared with use of separate drug components," Waters and Barbar wrote. "At a time when high levels of effectiveness are assumed and safety expected, alternative differentiators such as cost-effectiveness, convenience, patients' preferences, and quality of life, will need to be considered."

1/11/13

References

F Raffi, A Rachlis, H-J Stellbrink, et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. The Lancet. January 8, 2013 (Epub ahead of print).

LJ Waters and TJ Barber. Dolutegravir for Treatment of HIV: SPRING Forwards? (Commentary). The Lancet. January 8, 2013 (Epub ahead of print).