- Category: Approved HIV Drugs
- Published on Friday, 25 October 2013 00:00
- Written by Liz Highleyman
The recently approved HIV integrase inhibitor dolutegravir (Tivicay) provides at least equivalent antiviral efficacy and better tolerability compared with approved antiretroviral drugs for treatment-naive people, according to data reported at the 14th European AIDS Conference last week in Brussels and in the current edition of Lancet Infectious Diseases.
Bonaventura Clotet form Hospital Universitari Germans Trias i Pujol presented a subgroup analysis from the FLAMINGO trial comparing dolutegravir versus ritonavir-boosted darunavir (Prezista) in people new to antiretroviral therapy (ART).
This multicenter, open-label, non-inferiority study enrolled 484 treatment-naive adults with HIV. Most participants (85%) were men, a majority were white, 23% were black, and the median age was 34 years. At baseline the median CD4 T-cell count was 395 cells/mm3 and one-quarter had high viral load (HIV RNA >100,000 copies/mL).
Participants were randomly assigned to receive 50 mg dolutegravir or 800/100 mg darunavir/ritonavir, both once-daily. In addition they received investigator-selected NRTIs, with 67% using tenofovir/emtricitabine (Truvada) and 33% using abacavir/lamivudine (Epzicom).
Results from the primary analysis, presented last month at the Interscience Conference on Antimicrobial Agents and Chemotherapy, showed that 90% of people taking dolutegravir and 83% taking darunavir/ritonavir achieved undetectable viral load in a snapshot analysis, with dolutegravir meeting the criteria for statistical superiority. CD4 cell gains were the same in both arms at 210 cells/mm3. Fewer people in the dolutegravir arm discontinued due to adverse events (1% vs 4%) and serious drug-related adverse events were rare (one vs none).
Clotet's late-breaker presentation at EACS focused on pre-specified subgroups stratified by baseline viral load and CD4 count, NRTI backbone used, and demographic factors (age, sex, and race).
- Dolutegravir's advantage was particularly notable among people with high viral load, with a 48-week response rate of 93% compared to 70% in the darunavir/ritonavir arm.
- The difference was smaller among people with lower viral load, 88% vs 87%, respectively.
- The larger difference in the high viral load strata was mainly driven by lower likelihood of virological non-response (7% vs 18%) and fewer dropouts due to adverse events (0% vs 7%) in the dolutegravir arm.
- Response rates for people with CD4 counts above and below 350 cells/mm3 were similar to those seen in the primary analysis as a whole (88% vs 80% for <350; 91% vs 84% for >350).
- Response rates were comparable for younger and older patients (90% vs 81% for <50; 89% vs 92% for >50 years).
- Response rates for men (91% vs 85%) and for white patients (91% vs 84%) were similar to the overall primary analysis; rates were lower for women (84% vs 73%) and black patients (85% vs 77%), but with the same pattern of differences favoring dolutegravir.
- There were no differences according to NRTIs used (90% vs 85% with Kivexa; 90% vs 81% with Truvada).
- Overall, side effects in the subgroups were similar to those observed in the analysis as a whole, with most subgroups reporting more adverse events in the darunavir/ritonavir arm.
- There were no significant differences in adverse events leading to withdrawal by subgroup.
- Dolutegravir recipients experienced smaller rises in LDL "bad" cholesterol.
- Some people taking dolutegravir had small increases in serum creatinine, attributed to the drug's effect on a transporter protein.
Based on these findings the researchers concluded,"Dolutegravir provide a potent and well-tolerate new option for first-line HIV treatment."
Dolutegravir vs Other Regimens
Approval of dolutegravir was based in part on favorable first-line therapy results from 2 randomized controlled trials: SINGLE, which tested dolutegravir plus abacavir/lamivudine against Atripla (efavirenz/tenofovir/emtricitabine single tablet regimen), and SPRING-2, comparing dolutegravir against raltegravir (Isentress), the first approved integrase inhibitor.
The extended 96-week analysis from SPRING-2,published in the November 2013 issue of Lancet Infectious Diseases, showed that 50 mg once-daily dolutegravir had non-inferior efficacy and similar tolerability compared to 400 mg twice-daily raltegravir, both taken with either tenofovir/emtricitabine or abacavir/lamivudine.
At 96 weeks, 81% of dolutegravir recipients and 76% of raltegravir recipients had viral load below 50 copies/mL, not a significant difference. Median CD4 cell increases were also similar (276 and 264 cells/mm3). Virological non-response was less common in the dolutegravir group (5% vs 10%, respectively). None of the dolutegravir recipients who experienced virological failure had new integrase or NRTI resistance mutations.
Just 2% of participants in each treatment arm discontinued due to adverse events, with none in the dolutegravir group and 1 in the raltegravir group doing so between weeks 48 and 96; no drug-related serious adverse events occurred during this period.
As presented in a poster at last week's EACS meeting, ViiV Healthcare/GlaxoSmithKline researchers performed a systematic review and "network meta-analysis" to indirectly compare dolutegravir against current preferred first-line regimens.
It is not practical to compare new therapies against every possible competitor, especially older regimens used by fewer people. The researchers therefore used results from the 2 trials that directly compared dolutegravir against efavirenz or raltegravir, along with data from 46 other randomized controlled trials comparing the latter 2 drugs against other agents, to estimate dolutegravir's comparative efficacy. They ran the analyses both adjusted and unadjusted for which NRTI backbone was used.
They found that dolutegravir was significantly more likely to lead to viral suppression than the boosted protease inhibitors atazanavir (Reyataz), darunavir (this analysis did not include FLAMINGO) or lopinavir/ritonavir (Kaletra), as well as the NNRTI rilpivirine (Edurant). Efficacy was similar to that of the other integrase inhibitors, raltegravir and elvitegravir (part of the Stribild coformulation). Dolutegravir was also associated with higher CD4 cell gains than most comparators.
"Overall, meta-analysis estimates show dolutegravir is comparable to or more effective that all guideline-recommended third-agent options for first-line treatment of HIV-1-infected patients," the researchers concluded.
In an editorial accompany the SPRING-2 report in Lancet Infectious Diseases,Mark Boyd and David Cooper from the Kirby Institute of the University of New South Wales speculated about how dolutegravir might alter standard antiretroviral treatment and provide more options in resource-limited settings. Possibilities could include NRTI-sparing regimens, ART without pharmacokinetic boosting, and even dolutegravir monotherapy, they suggested.
In the nearer term, ViiV announced this week that it has requested U.S. regulatory approval of a new single-tablet regimen containing dolutegravir, abacavir, and lamivudine. If approved, it will offer the first 1 pill/once-daily regimen that does not contain tenofovir, which will be particularly beneficial for people with or at risk for kidney disease or osteoporosis.
B Clotet, MS Khuong, A Antinori, et al. Once-daily dolutegravir versus darunavir/ritonavir in antiretroviral naive subjects: 48 week subgroup analyses from FLAMINGO. 14th European AIDS Conference (EACS 2013). Brussels. October 16-19, 2013. Abstract PS4/6.
DA Patel, SJ Snedecor, WY Tang, et al. 48-Week efficacy of dolutegravir relative to commonly used 3rd agents in treatment-naive HIV-1-infected patients: a systematic review and network meta-analysis. 14th European AIDS Conference (EACS 2013). Brussels. October 16-19, 2013. Abstract PE7/7.
F Raffi, H Jaegaer, E Quiros-Roldan, et al (SPRING-2 Study Group). Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infectious Diseases 13(11):927-935. November 2013.
MA Boyd and DA Cooper. SPRING-2 the future of antiretroviral therapy. Lancet Infectious Diseases 13(11):908-909. November 2013.
ViiV Healthcare. ViiV Healthcare Announces US Regulatory Submission for a Single-tablet Regimen Combining Dolutegravir with Abacavir and Lamivudine for People Living with HIV. Press release. October 22, 2013.