GSK572 (dolutegravir): second-generation integrase inhibitor
Simon Collins, HIV i-Base
Results from a phase 2b dose finding study of the Shionogi/GSK(ViiV) integrase compound S/GSK1349572 (GSK572, dolutegravir) were also presented as a late breaker. 
Approximately 200 HIV-positive people were randomised 1:1:1:1 to 10mg, 25mg or 50mg of GSK572 or efavirenz 600mg once-daily, plus either tenofovir/FTC or abacavir/3TC.
As with other integrase inhibitors, GSK572 produced more rapid viral load reductions compared to efavirenz (66% vs 18% at week 4, p <0.001 and >90% vs 60% by week 16) though baseline viral load was originally very low (approximately 30,000 copies/mL) with only 26% particpicants >100,000 copies/mL. Other baseline characteristics included being largely male (86%) and white (80%), with mean CD4 count of 324 cells/mm3.
There were more side effects reported in the efavirenz arm, including more discontinuations, with GSK572 no safety concerns over this short period. Onepatient in each arm was defined as a virologic failure at week 16. No integrase mutations were seen in the GSK572 patient and the efavirenz patient suppressed by week 24. The only defined serious drug-related adverse event was an attempted suicide on the efavirenz arm. Median CD4 (IQR) increases from baseline to week 16 were similar, in favour of GSK572 +165 (88242) vs +116 (66226) cells/mm3. Grade 3/4 laboratory abnormalities were <10% in all arms with no relationship to dose. Efavirenz had a greater negative impact on lipids (increases in triglycerides, total and LDL cholesterol).
The degree to which people who already have resistance to raltegravir could benefit from GSK572 was addressed in results from an ongoing 24-week phase 2b study in 27 patients with resistance to raltegravir, presented by Joe Eron. 
Raltegravir is associated with three primary resistance pathways: Y143, N155 and Q148H (>10-fold) with the accumulation of mutations associated with higher resistance and reduced impact of impaired fitness. For inclusion in the study, integrase resistance required Q148H/K/R alone or with one or more Q148-associated mutation, N155H and/or Y143Hwith or without additional mutations. Participants discontinued raltegravir and substituted GSK572 50mg once-daily while continuing their failing regimen to Day 11 when the background regimen was optimised, and 572 continued. Phenotypic susceptibility to GSK572 was then compared to virological responses. The primary endpoint was suppression to <400 copies/mL or a >0.7 log reduction in viral load at day 11 with change in viral load as a secondary endpoint.
By day 11, 21/27 participants either reduced viral load to <400 copies/mL or had a >0.7 log drop in viral load. Response rates differed by baseline genotype: 16/16 with N155H or Y143H or Q148 single mutant pathways; 3/4 with Q148 plus one mutation; 0/5 with Q148 plus >2 mutations; 2/2 other. See Table 1.
Table 1: Viral load response by baseline genotypic mutations
|All participants||21/27 (78%)||1.45 (SD 0.76)|
|Q148H/K/R + >
Q148-associated mutation at L74, E138 or G140 (n=9)
|3/9 (33%)||0.72 (SD 0.63)|
|All other genotypes from N155H and
Y143H pathways (n=18)
|18/18 (100%)||1.82 (SD 0.53)|
There was a positive correlation between baseline sensitivity to GSK572 and change in viral load at day 11 (correlation r=0.79, p <0.001). GSK572 was well tolerated: the most frequent side effects were diarrhoea (n=3) and insomnia (n=3), two subjects experienced an SAE considered unrelated to study drug.
Details of phenotypic and genotypic changes during this study were presented in a separate poster by Bonaventura Clotet. 
Over the short study period, there was little evidence of new integrase-associated mutations or a reduction in sensitivity to GSK572. However, one person with mixed Y143+Q148 mutations at baseline had a susceptibility to GSK572 change from FC=6.49 at baseline to FC=38 at day 11. The day 11 genotypic changes included both wild-type to mutant L74I/M, E138E/A and mutant Y143H to Y143Y. Another patient without genotypic resistance changes had susceptibility increase from FC=21 to FC=40. Full details are included in the poster, also available online. 
These early results highlight the promise of integrase inhibitors as a class both for naive and experienced patients. Picking an early time point and a patient group with low baseline viral load will produce promising results if the study endpoint is percentage of patients below 50 copies/mL.
While GSK572 retained activity in many of these patients with low-level resistance, integrase mutations have the potential to rapidly accumulate and this was most significant for the 148 pathway.  People currently unsuppressed on raltegravir-containing regimens may want to switch to a combination that with not jeopardise their option to use this pipeline compound.
While the 50mg dose has apparently been selected for further development, it would be important to know whether higher doses would be able to overcome more extensive integrase resistance.
Unless otherwise stated, all references are to the Programme and Abstracts of the 17th International AIDS Conference, 18-23 July 2010, Vienna.
- Nichols G et al. Once-daily S/GSK1349572 as part of combination therapy in antiretroviral naive adults: rapid and potent antiviral responses in the interim 16-week analysis from SPRING-1 (ING112276). Oral late breaker THLBB205. http://pag.aids2010.org/Abstracts.aspx?SID=1990&AID=17600
- Eron J et al. Activity of a next generation integrase inhibitor (INI), S/GSK1349572, in subjects with HIV exhibiting raltegravir resistance: initial results of VIKING study (ING112961). Oral abstract MOAB0105. http://pag.aids2010.org/Abstracts.aspx?SID=631&AID=12762
- Clotet B et al. HIV integrase genotypic and phenotypic changes between Day1 and Day11 in subjects with raltegravir (RAL) resistant HIV treated with S/GSK1349572: results of VIKING study (ING112961). Poster abstract TUPE0130. http://pag.aids2010.org/Abstracts.aspx?AID=15484
- Integrase inhibitor resistance and cross-resistance: weighing viral fitness and the option to benefit from second-generation compounds. HTB August 2008. https://i-base.info/htb/602