By Ronald Baker, PhD

At the 14th CROI in Los Angeles last week, Andrew Zolopa of Stanford University presented 24-week results of a trial of the novel oral experimental integrase inhibitor elvitegravir (EVG; aka GS 9137). Integrase inhibitors are a new class of antiretrovirals that have shown early promise as potent and safe drugs in the treatment of HIV infections.

The data presented at the 14th CROI by Dr. Zolopa demonstrated significant reductions in viral load among HIV-treatment-experienced patients receiving 125 mg EVG boosted with 100 mg ritonavir, compared to those receiving a boosted protease inhibitor (PI), each in combination with an optimized background regimen (OBR).

The trial was designed to assess the activity and safety of elvitegravir at three different ritonavir-boosted doses among 278 antiretroviral-experienced HIV patients, an HIV patient population in need of effective and safe new therapies.

The current study is an ongoing, partially-blinded, randomized 48-week Phase II clinical trial designed to evaluate the non-inferiority of once-daily EVG versus ritonavir (RTV)-boosted comparator HIV protease inhibitors (CPI/r) that were chosen by the investigators.

The primary endpoint of the trial was the mean HIV RNA level (viral load) at 24 weeks.

The study protocol required patients to have HIV RNA of at least 1,000 copies/mL and at least one protease inhibitor mutation. There was no CD4 T cell count entry criterion. At baseline, participants had a mean HIV viral load of 4.59 log10 copies/mL, a mean CD4 cell count of 185 cells/microliter and a median of 11 PI mutations

Study participants were randomized to receive either 20, 50 or 125 mg EVG once-daily boosted with 100 mg RTV or CPI/r, all in combination with an optimized background regimen of two or more nucleos(t)ides (NRTIs) with or without the fusion inhibitor enfuvirtide (Fuzeon).

When the data safety monitoring board (DSMB) reviewed the trial data at eight weeks, they recommended closure of the 20 mg dose EVG arm due to poor virologic response. Those patients were then offered the opportunity to join the 125 mg EVG arm.

At the same time, the study protocol was amended to allow the use of the PIs darunavir (Prezista) or tipranavir (Aptivus) in the EVG study arms. This was done because new had data emerged showing no adverse interactions between these two PIs and EVG (when the trial began, these data were not available). Fifteen percent (15%) of patients in the EVG 50 and 125 mg arms added either tipranavir or darunavir prior to week 24 of the study; 37% of patients in the CPI/r arm who experienced virologic failure switched to open label EVG.

Following 16 weeks of treatment, there was a significant change in the HIV RNA levels. The PI control arm demonstrated a mean viral load reduction of -1.2 log10 copies/mL. The mean viral load reduction in the ritonavir-boosted EVG 50 mg dose arm was -1.4 log10 copies/mL (not statistically superior). The mean viral load decrease in the EVG 125 mg dose arm was -1.7 log10 copes/mL, which represented a statistically superior drop (P= 0.01).

Changes in Mean HIV RNA Level and CD4 Cell Count at 16 vs 24 Weeks

At 16 weeks, using an intent to treat analysis where missing equals failure, 38 percent (27/71) of patients in EVG 50 mg arm and 40 percent (29/73) of patients in the EVG 125 mg arm achieved HIV RNA less than 50 copies/mL compared to 30 percent (19/63) of patients in the CPI/r arm of the study.

At 24 weeks, 32 percent (23/71) of patients in the EVG 50 mg arm and 36 percent (26/73) of patients in the EVG 125 mg arm achieved HIV RNA less than 50 copies/mL compared to 27 percent (17/63) of patients in the CPI/r arm.

At 16 weeks, mean increases in CD4 cell count among patients receiving 50 mg and 125 mg of EVG were 52 and 61 cells/microliter versus 28 cells/microliter for the comparator arm.

At 24 weeks, the increase in CD4 cells was also similar across the arms (53 and 57 versus 53 cells/microliter, respectively). These differences were not statistically significant.

Outcomes in Patients on the EVG 125 mg Dose Receiving Active Drugs in Background Regimen

In patients receiving the EVG 125 mg dose, the durability of the response to EVG related directly to the presence of active drugs in the optimized background regimen. When the background regimen had no active drugs, the mean HIV RNA level declined -0.7 log10 copies/mL (week 24). In contrast, forty-seven patients receiving 125 mg EVG who also received enfuvirtide for the first time or had at least one active NRTI in their background regimen, experienced more than a -2.1 log10 drop in HIV RNA level (P=0.001).

Safety

Patients across all arms tolerated EVG well. Few patients in any arm discontinued the study due to adverse events (see Table).

Treatment-related grade 3 or 4 adverse side effects, laboratory abnormalities or discontinuations of study drugs showed no relationship to EVG dosing. Further, the incidence of grade 3 or 4 laboratory abnormality was similar in the 50 mg and 125 mg EVG arms compared to the CPI/r arm (21%, 21% and 30%, respectively).

Summary of Adverse Events and Laboratory Abnormalities

Zolopa and others. 14th CROI. February 2007. Abstract 143LB.

Conclusions

Based on the findings reviewed here, Dr. Zolopa presented the following conclusions:

• EVG 50 mg and 125 mg arms met the primary endpoint of non-inferiority for DAVG (Time -weighted average change in HIV from baseline)

• EVG 125 mg dose demonstrated potency (>2 log10 decrease) within 2 weeks

• When combined with active background drug, potency was durable

• No difference in incidence or severity of adverse events between CPI (comparator protease inhibitor) and the EVG arms

• No dose relationship in Grade 3 or 4 adverse events, laboratory abnormalities, or study drug discontinuation for the EVG arms

The next step in the clinical development of EVG will be to evaluate the 125 mg dose in the presence of an optimized background regimen (with at least one, preferably more, active drugs).

Dr. Zolopa and colleagues are continuing to investigate the resistance patterns of EVG in patients receiving the drug in combination with a weak optimized background regimen.

However, researchers at Gilead Sciences presented a second paper at the 14th CROI that offers more insight into EVG resistance. In the conclusion to their study, the authors write, "Selection of HIV-1 in vitro with GS-9137 [elvitegravir] resulted in the emergence of a T66I IN [HIV-1 integrase] mutation and subsequently additional IN mutations.

"Site-directed mutant viruses carrying the T66I mutation showed reduced susceptibility to GS 9137, but remained susceptible to other IN inhibitors, including MK-0518 [ratelgravir from Merck].

"In contrast, site-directed mutant viruses with E92Q demonstrated both resistance to GS 9137 and evidence of cross-resistance to MK-0518.

"All the IN inhibitor mutants remained fully susceptible to ART drugs of other classes."

Stanford Univ, CA, US; Mt Sinai Sch of Med, New York, NY, US; NorthStar Medical Center, Chicago, IL, USA; Light Source Med, Los Angeles, CA, US; Southwest CARE, Santa Fe, NM, US; and Gilead Sci, Foster City, CA, US.

03/06/07

References

A R Zolopa, M Mullen D Berger, and others. The HIV integrase inhibitor GS-9137 demonstrates potent ARV activity in treatment-experienced patients. 14th CROI. February 25-28, 2007. Los Angeles. Abstract (oral) 143LB.

G Jones, R Ledford, F Yu, and others (Gilead Sciences, Foster City, CA). Resistance Profile of HIV-1Mutants in vitro Selected by the HIV-1 integrase inhibitor, GS-9137 (JTK-303). 14th CROI. February 25-28, 2007. Los Angeles. Abstract (poster) 627.

Gilead Sciences. Gilead announces 24-week results from phase II study of investigational HIV integrase inhibitor GS 9137. Press Release. March 1, 2007.

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