Understanding TMC114 power against resistant HIV
Mark Mascolini for NATAP.org
This years ICAAC afforded a 24-week look at results of the POWER 2 trial pitting TMC114/ritonavir against a standard PI salvage regimen in people with plentiful PI experience. But wait. Havent we already heard 24-week POWER 2 results? Or was that POWER 1?
Both, as it turns out. In February 2005, at the Conference on Retroviruses, Richard Haubrich spelled out findings on 497 people enrolled in either POWER 1 or 2 . Twenty-six weeks later, Christine Katlama gave a more focused look at POWER 1 results, but still only 24 weeks worth . At ICAAC, 46 weeks after Haubrichs talk, Timothy Wilkin from the University of California, San Diego, homed in on a still-maturing 24-week data set from POWER 2 . Perhaps Tibotec, maker of this potent PI, will unveil 48-week data at next Februarys Retrovirus conference.
Both POWER studies randomised people with triple-class experience and at least one major PI mutation to take one of four TMC114/ritonavir doses or the best-feasible PI-based control regimen. The protocols blinded researchers to the TMC114 dose. Wilkins POWER 2 enrollees had more advanced HIV infection than their POWER 1 counterparts (Table 1), but the two study groups had similar PI experience and equivalent resistance to PIs.
Table 1: Differences between POWER 1 and POWER 2 studies of TMC114/r
|POWER 1||POWER 2|
|Design||Randomised, partially blinding, dose-finding phase 2b, international trial|
|Eligibility||Adults, 3-class experienced, currently taking PI, >1 primary PI mutation|
|Follow-up||24 weeks||24 weeks|
|N (n on TMC114/r)||318 (225)||278 (225)|
|Baseline values (on TMC114 vs control)|
|Mean HIV RNA||4.5 vs 4.4||4.7 vs 4.6|
|Median CD4||172 vs 197||99 vs 113|
|Mean PI duration (yr)||6 vs 6||6 vs 6|
|Mean PIs used||4 vs 4||4 vs 4|
|Median no. of 1° and 2° PI mutations||8 vs 8||8 vs 8|
|24-week outcomes 600.100mg twice daily vs control|
|Mean drop HIV RNA||2.13 vs 0.63 *||1.7 vs 0.3 *|
|<50 copies/mL (%)||53 vs 18 **||39 vs 7 *|
|<50 copies/mL (%) in T-20 naive T-20||63 vs 21||64 vs 7 *|
|<50 with no T-20 (%)||56 vs 19||30 vs 4|
|<50 with =3 primary mutations at baseline (%)||59 vs 9||35 vs 7|
|<50 with 0 active drugs||17 vs 0||8 vs 0|
* P < 0.001; ** P < 0.01
The more advanced disease in POWER 2 than in POWER 1 may figure in the more modest 24-week virologic response-a 1.7-log copies/mL drop with the highest dose of TMC114/ritonavir (600/100 mg twice daily) in POWER 2 versus 2.13 log copies/mL in POWER 1. Also, a lower proportion in POWER 2 than in POWER 1 (39% versus 53%) had a 24-week viral load under 50 copies/mL in an intent-to-treat analysis. Both responses in the TMC114 groups handily exceeded 24-week RNA wanings in the control arms.
People in POWER 2 also got less from 600/100 mg of TMC114/ritonavir than POWER 1 enrollees if they had three or more primary mutations, if they did not mix the fusion inhibitor enfuvirtide into their regimen, or if they had no other active agent in their background regimen (Table). But among enfuvirtide-naive people starting that drug, POWER 2 participants did as well as POWER 1 enrollees. By all these measures, TMC114/ritonavir worked much better than control PI regimens. Phase 3 studies will use the 600/100-mg twice-daily dose.
Daniel Berger from Chicagos Northstar Medical Center detailed side effect findings in POWER 2, reporting that 8% quit the TMC114/ritonavir arms because of side effects versus 4% in the control arm . The primary reason for the between-arm difference appears to be that people dropped out of the control group because of virologic failure before they could quit because of side effects. By week 24 the virologic failure dropout rate measured 47% with standard PI salvage regimens versus 9% with TMC114/ritonavir.
More than one quarter of POWER 2 participants taking the new PI had grade 3 or 4 problems (32% in the 600/100-mg arm), and 15% had a serious adverse event (9% in the 600/100-mg arm). Rash was the most common clinical problem with TMC114/ritonavir, affecting 5%. AST elevations, in 4%, were the most frequent lab abnormality.
Mark Mascolini writes about HIV infection.
- Katlama C, Berger D, Bellos N, et al. Efficacy of TMC114/r in 3-class experienced patients with limited treatment options: 24-week planned interim analysis of 2 96-week multinational dose-finding trials. 12th Conference on Retroviruses and Opportunistic Infections. February 22-25, 2005. Boston. Abstract 164LB.
- Katlama C, Carvalho MTM, Cooper D, et al. TMC114/r outperforms investigator-selected PI(s) in 3-class-experienced patients: week 24 primary efficacy analysis of POWER 1 (TMC114-C213). 3rd IAS Conference on HIV Pathogenesis and Treatment. July 24-27, 2005. Rio de Janeiro. Abstract WeOaLB0102.
- Wilkin T, Haubrich R, Steinhart CR, et al. TMC114/r superior to standard of care in 3-class-experienced patients: 24-wks primary analysis of the Power 2 study (C202). 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-413.
- Berger DS, Bellos N, Farthing C, et al. TMC114/r in 3-class-experienced patients: 24-wk primary safety analysis of the Power 2 study (C202). 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-1094.