icon-    folder.gif   Conference Reports for NATAP  
 
  14th CROI
Conference on Retroviruses and Opportunistic Infections Los Angeles, California
Feb 25- 28, 2007
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Gilead Integrase Inhibitor Outdoes New PIs in Salvage Therapy
 
 
  Mark Mascolini
February 28, 2007
14th Conference on Retroviruses and Opportunistic Infections
Los Angeles
 
Elvitegravir (GS-9137), an integrase inhibitor a few development paces behind raltegravir (MK-0518), stopped HIV replication better than protease inhibitor (PI)-based salvage regimens in a 24-week randomized trial described by Andrew Zolopa (Stanford University) at the 14th Conference on Retroviruses [1].
 
The phase 2 study randomized 278 people with one or more PI mutations to (1) one of three elvitegravir doses (20, 50, or 125 mg once daily boosted by 100 mg of ritonavir) plus nucleosides or (2) to a PI plus nucleosides. While 49% in the PI control arm started darunavir, 27% started tipranavir. No one could take a nonnucleoside, but enfuvirtide could be prescribed. About 20% of enrollees did take enfuvirtide.
 
Study participants averaged 11 major and minor protease mutations. The genotypic sensitivity score measured 0 in half of enrollees for all nucleosides in the optimized background regimen (OBR), indicating that these people could expect little or no antiviral activity from nucleosides. Starting viral loads averaged 4.47 to 4.71 log across study arms, with little difference between arms. Baseline average CD4 counts stood at or below 180 cells in all but the 50-mg elvitegravir arm, which started with an average 243 cells.
 
After 8 weeks an independent review panel advised closing the 20-mg elvitegravir arm because of poor virologic response. Those people could jump to the 125-mg dose. At the same time the protocol changed to permit adding darunavir or tipranavir to the elvitegravir arms, and 15% did so. Zolopa did not have a separate analysis for the 85% who never added one of these PIs.
 
After 16 weeks of treatment, when only 4 people had added darunavir or tipranavir to elvitegravir, time-weighted change from baseline viral load (DAVG) measured -1.2 in the PI control arm, -1.5 in the 50-mg elvitegravir arm (a nonsignificant difference, P = 0.09), and -1.7 in the 125-mg elvitegravir arm (P = 0.01). After 24 weeks DAVGs stood at -1.2 in the control arm, -1.4 in the 50-mg elvitegravir arm (not significant), and -1.7 in the high-dose elvitegravir group (P = 0.02). While 51% in the control arm ever had a 2-log (100-fold) drop in viral load by week 24, 69% taking 50 mg of elvitegravir did (P = 0.08), and 76% taking 125 mg did (P = 0.005).
 
Twenty-six people randomized to 125 mg of elvitegravir with no active drugs in the OBR averaged more than a 2-log drop in viral load at week 2, followed by a sharp rebound. Forty-seven people taking high-dose elvitegravir with one or more active nucleosides or with first-time enfuvirtide maintained a 2-log drop through 24 weeks of follow-up.
 
Fewer than 3% in any treatment arm discontinued a drug because of side effects in 24 weeks. Grade 3 or 4 side effect rates proved equivalent across arms at about 15%. About 30% in the PI control arm and the 20-mg elvitegravir arm had a grade 3 or 4 lab abnormality, compared with 21% in both the 50-mg and 125-mg elvitegravir groups.
 
Zolopa and colleagues are still analyzing elvitegravir resistance patterns in people taking the integrase inhibitor with a weak OBR, but Gilead did offer cell study findings on resistance in another conference report [2]. The Gilead team described two divergent pathways to elvitegravir resistance, one hinged on the T66I mutation in viral integrase and one keyed to E92Q. T66I alone trimmed susceptibility to elvitegravir about 15% but did not affect susceptibility to Merck's raltegravir. E92Q caused 30-fold or higher resistance to elvitegravir and about 6-fold resistance to raltegravir. Whether giving 100 mg of ritonavir and no other PI with elvitegravir will foster PI resistance remains unknown.
 
References
1. Zolopa A, Mullen M, Berger D, et al. The HIV integrase inhibitor GS-9137 demonstrates potent ARV activity in treatment-experienced patients. 14th Conference on Retroviruses and Opportunistic Infections. February 25-28, 2007. Los Angeles. Abstract 143LB.
2. Jones G, Ledford RM, Yu F, et al. In vitro resistance profile of HIV-1 mutants selected by the HIV-1 integrase inhibitor, GS-9137 (JTK-303). 14th Conference on Retroviruses and Opportunistic Infections. February 25-28, 2007. Los Angeles. Abstract 627.