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 of Hospital Universitari Germans Trias i Pujol, Barcelona, presented a subgroup analysis from the FLAMINGO trial comparing dolutegravir versus ritonavir-boosted darunavir (Prezista) in people new to antiretroviral therapy (ART).
This multicentre, 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 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 50mg dolutegravir or 800/100mg darunavir/ritonavir, both once daily. In addition, they received investigator-selected NRTIs, with 67% using tenofovir/emtricitabine (Truvada) and 33% using abacavir/lamivudine (Kivexa).
Results from the primary analysis, presented last month at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 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. Dolutegravir's advantage was particularly notable amongst 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 amongst 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 drop-outs 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, Clotet said (90 vs 81% for <50; 89 vs 92% for >50 years).
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 favouring 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-tolerated new option for first-line HIV treatment."
Dolutegravir vs other regimens
Approval of dolutegravir was based in part on favourable first-line therapy results from two randomised controlled trials: SINGLE trial, 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 50mg once-daily dolutegravir had non-inferior efficacy and similar tolerability compared to 400mg 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 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 one 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 two trials that directly compared dolutegravir against efavirenz or raltegravir, along with data from 46 randomised controlled trials comparing the latter two drugs against other agents, to estimate dolutegravir's comparative efficacy. They ran the analyses both adjusted and non-adjusted 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, also in Eviplera). Efficacy was similar to that of the other integrase inhibitors, raltegravir and elvitegravir (part of the Stribild co-formulation). Dolutegravir was also associated with higher CD4 cell gains than most comparators.
"Overall, meta-analysis estimates show dolutegravir is comparable to or more effective than all guideline-recommended third-agent options for first-line treatment of HIV-1-infected patients," the researchers concluded.
The future of dolutegravir
In an editorial accompanying the SPRING-2 report in The 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 might include NRTI-sparing regimens, ART without pharmacokinetic boosting and even dolutegravir monotherapy, they suggested.
In the shorter term, ViiV announced last week that it has requested US regulatory approval of a new single-tablet regimen containing dolutegravir, abacavir and lamivudine. A European regulatory application has also been submitted, according to the company. This combination, taken as separate pills, worked well in the aforementioned trials. If approved, the new co-formulation will offer the first one-pill, once-daily regimen that does not contain tenofovir/emtricitabine (as does Gilead's trio of Atripla, Complera/Eviplera and Stribild), which could be particularly beneficial for people with, or at risk for, kidney disease or osteoporosis.
Clotet B et al. Once-daily dolutegravir versus darunavir/ritonavir in antiretroviral naive subjects: 48 week subgroup analyses from FLAMINGO. 14th European AIDS Conference, Brussels, abstract PS4/6, 2013. View abstract on the conference website.
Patel D 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, Brussels, abstract PS7/7, 2013. View abstract on the conference website. Abstract PE7/7.
Raffi F et al. 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. The Lancet Infectious Diseases, 13(11):927-935, November 2013.
Boyd M, Cooper D SPRING-2 the future of antiretroviral therapy. The Lancet Infectious Diseases, 13(11):908-909, November 2013.