Experimental integrase inhibitor GSK-572 shows continued promise

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The second-generation integrase inhibitor S/GSK1349572, or GSK-572 for short, continues to demonstrate potent antiviral activity – including activity against HIV strains resistant to raltegravir (Isentress) – as it prepares to enter Phase III clinical trials, according to two studies presented this week at the Eighteenth International AIDS Conference in Vienna.


Laboratory and early clinical studies showed that GSK-572, being developed jointly by Shionogi of Japan and ViiV Healthcare, strongly inhibits HIV, has good oral bioavailability when taken once daily without a pharmacoenhancer or 'booster', and appears to have a high genetic barrier to resistance.

The SPRING-1 study, described by Garrett Nichols in a late-breaker presentation on Thursday, is an ongoing, multicentre Phase IIb trial comparing GSK-572 versus the non-nucleoside reverse transcriptase inhibitor efavirenz (Sustiva or Stocrin) in previously untreated individuals.

SPRING-1 included 205 treatment-naive participants randomly assigned in equal numbers to receive 10mg, 25mg or 50mg of GSK-572, or 600mg efavirenz once daily. About two-thirds also received tenofovir/emtricitabine (Truvada), whilst the remainder took abacavir/lamivudine (Kivexa or Epzicom).



Short for logarithm, a scale of measurement often used when describing viral load. A one log change is a ten-fold change, such as from 100 to 10. A two-log change is a one hundred-fold change, such as from 1,000 to 10.

phase III

The third and most definitive stage in the clinical evaluation of a new drug or intervention, typically a randomised control trial with the new intervention compared to an existing therapy or a placebo, in large numbers of participants (typically hundreds or thousands). Trial results are used to evaluate the overall risks and benefits of the drug and provide the information needed for regulatory approval.

phase II

The second stage in the clinical evaluation of a new drug or intervention, in which preliminary data on effectiveness and additional information about safety is collected among a few hundred people with the disease or condition.


A drug that acts against a virus or viruses.


Taking a drug on its own, rather than in combination with other drugs.

Most participants were men, 80% were white and the median age was 37 years. The median CD4 cell count at baseline was 324 cells/mm3, the median viral load was approximately 30,000 copies/ml and about 20% had high viral load – above 100,000 copies/ml.

Results presented at the conference were from a planned interim analysis at 16 weeks. GSK-572 demonstrated "rapid and robust" antiviral activity at all doses; 96% of participants in the 10mg arm, 92% in the 25mg arm and 90% in the 50mg arm achieved viral load below 50 copies/ml, compared with 60% in the efavirenz arm.

What's more, participants taking GSK-572 took a significantly shorter time to reach undetectable viral load than those taking efavirenz. By week 4, 66% of the GSK-572 recipients had viral loads below 50 copies/ml, compared to 16% of the efavirenz recipients. Two participants had confirmed virological failure at week 16.

CD4 cell gains were somewhat higher in the GSK-572 arms, ranging from 153 to 176 cells/mm3, compared with 116 cells/mm3 for efavirenz recipients.

GSK-572 was found to be generally well-tolerated. Between 4 and 8% of participants taking GSK-572 experienced at least moderate side-effects, compared with 18% taking efavirenz. Gastrointestinal symptoms were the most common type of side effect among GSK-572 recipients. No one taking the experimental drug had any serious drug-related adverse events. Serious laboratory abnormalities were rare across the board.

The researchers concluded that GSK-572 demonstrated "potent antiviral activity at all doses explored in this study". The 50mg dose has been selected for further testing in Phase III trials.


In a smaller trial, researchers tested GSK-572 in people who had developed resistance to other antiretroviral drugs, including raltegravir, the sole approved integrase inhibitor.

VIKING is an ongoing open-label, single-arm Phase IIb study looking at the safety and efficacy of GSK-572 in 27 treatment-experienced participants with pre-existing resistance to raltegravir in particular, as well as to any three classes of antiretroviral drugs.

Participants first took 50mg GSK-572 once daily as 'functional monotherapy' (meaning it appeared to be the only active drug in their regimen) for 10 days. Their background regimen was then optimised and they continued on treatment through 24 weeks.

All but two of these participants were men and the average age was 48 years. Compared with SPRING-1, this group had more advanced HIV disease, with a median CD4 cell count of 110 cells/mm3 and about one-quarter having less than 50 cells/mm3. Nearly two-thirds had received a diagnosis of AIDS. They had been on antiretroviral treatment for a median 14 years.

Based on previous studies, the researchers divided participants into two groups depending on type of resistance to raltegravir. People who had developed the Q148 mutation plus secondary changes showed reduced susceptibility to GSK-572, whilst those with either Q148 alone or mutations in the N155 or Y143 pathways showed little or no decrease in GSK-572 activity.

Overall, 78% of participants reached a viral load below 400 copies/ml by day 11, or at least a 0.7 log drop in HIV RNA (average decrease 1.45 log). But response differed substantially based on type of pre-existing resistance. Just 33% of patients with Q148 plus secondary mutations achieved viral suppression (mean decrease 0.72 log) compared with all participants who had N155 and Y143 mutations (mean decrease 1.82 log).

Again, GSK-572 was generally well-tolerated with no serious drug-related side-effects. Participants developed few new integrase resistance mutations and had only minimal changes in susceptibility to GSK-572 at the end of the functional monotherapy phase, indicating a high genetic barrier to resistance.

The researchers concluded that there was a "strong correlation" between viral load decline and baseline changes in susceptibility to GSK-572. These findings suggest that pre-treatment testing for mutations might show which individuals are most likely to benefit from the new drug.

Further information

View abstract and slides on the official conference website, for abstract THLBB205 and MOAB0105.


Arribas J et al. Once-daily S/GSK1349572 as part of combination therapy in antiretroviral naïve adults: rapid and potent antiviral responses in the interim 16-week analysis from SPRING-1 (ING112276). Eighteenth International AIDS Conference, Vienna, abstract THLBB205, 2010.

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). Eighteenth International AIDS Conference, Vienna, abstract MOAB0105, 2010.