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Efficacy of TMC114/r in Treatment-Experienced HIV Patients: Factors Influencing Outcome in the Pooled 24-Week Analysis of POWER 1, 2 and 3
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Reported by Jules Levin
Presented at the 12th Annual Conference of the British HIV Association (BHIVA), 29 March-1 April 2006, Brighton, UK.
...Multivariate analyses showed that baseline FC, number of sensitive NRTIs and concomitant use of ENF (Fuzeon) correlated with response..... Baseline median TMC114 FC >10 was only found for patients having >/= 10 PI resistance-associated mutations...this study analysis found that patients with fold-change of 10 or less to TMC114 at baseline experienced -2.08 log viral load reductions, patients with TMC114 fold-change of 10 to 40 had -1.08 log viral load reductions, and patients found with 40 or more fold-change to TMC114 had -0.76 log viral load reductions.... Whether patients were taking TMC114 or CPI, patients with 0 susceptible sensitive NRTIs had less benefit (-1.27 log viral load reduction if taking TMC114) than patients sensitive to 1 NRTI (-1.67 log viral load reduction if taking TMC114) and patients sensitive to 2 or more NRTIs achieved more benefit (-2.15 log viral load reduction if taking TMC114)....The greatest benefit of ENF use was observed in the subgroup of patients with no other susceptible ARVs in their OBR: 43% of patients using ENF for the first time achieved a VL of <50 copies/mL, compared to 26% of those who did not use ENF.... At Week 24, 49% and 44% of TMC114/r patients using ENF (naively) and not using ENF, respectively, achieved a VL of <50 copies/mL compared to 16% and 11% of control patients, respectively.....
Other baseline prognostic factors
The baseline VL and baseline genotype (number of primary PI mutations) were also predictors of the efficacy of TMC114/r.
TMC114 retained efficacy at high (>100,000 copies/mL) baseline VLs: the reduction in VL from baseline was 1.57, 1.65 and 2.07 log10 copies/mL for TMC114/r patients with baseline VLs of 220,000, 20,000-2100,000, and >100,000 copies/mL, respectively.
TMC114 was still effective even in the presence of 34 primary PI mutations. The reduction in VL from baseline was 2.00, 1.88 and 1.42 log10 copies/mL for TMC114/r patients with 22, 3, or 34 primary PI mutations, respectively. Regardless of whether patients had 1, 2 or 33 primary PI mutations at baseline, responses observed with TMC114/r were consistently higher than in the control group (data not shown).
Authors- Pozniak A,1 Saag M,2 Bellos N,3 Chiliade P,4 Grinsztejn B,5 Molina J-M,6 Katlama C,7 De Meyer S,8 Vangeneugden T,8 Lefebvre E,9 Hill A10
1Chelsea and Westminster Hospital, London, UK; 2University of Alabama, AL, USA; 3Southwest Infectious Disease Associates, Dallas, TX, USA; 4Whitman-Walker Clinic, Washington, DC, USA; 5Instituto de Pesquisa Clinica Evandro Chagas-Fiocruz, Brazil; 6Hopital St-Louis, Division of Clinical Microbiology and Infectious Diseases, Paris, France; 7Hopital Pitie-Salpetriere, Paris, France; 8Tibotec BVBA, Mechelen, Belgium; 9Tibotec Inc., Yardley, PA, USA; 10University of Liverpool, Liverpool, UK
The present analysis focuses on the pooled Week 24 efficacy results of the TMC114/r 600/100mg bid dose in POWER 1, 2 and 3, and the CPI results from POWER 1 and 2, to examine what factors were predictors of the efficacy of TMC114/r in the studied patient population.
The rationale for pooling the data from these trials was based on the similarities between the trials, including patient baseline disease characteristics, TMC114/r dosing, site selection, inclusion/exclusion criteria, and efficacy and safety outcomes.2-5
ABSTRACT
Aim: Data from the randomised, protease inhibitor (PI)-controlled POWER 1 and 2 (TMC114-C213 and C202) and the open-label roll-over study, POWER 3 (TMC114-C215/C208), were pooled to examine factors contributing to the efficacy of TMC114 with low-dose ritonavir (TMC114/r) in treatment-experienced HIV patients.
Methods: Patients randomised to receive TMC114/r 600/100mg bid (n=458) or
control PI(s) (CPI, n=124) were included in this analysis. Regimens were optimized using 32 NRTIs with or without enfuvirtide (ENF).Week 24 efficacy data were analysed by baseline viral load (VL), TMC114 EC50 fold change (FC), concomitant and previous ENF use, number of IAS-USA primary PI mutations, and number of sensitive NRTIs and CPI(s).
Results:
Overall, baseline mean VL was 4.6 log10 copies/mL, median CD4 count was
128 cells/mm3 and 73% had 33 primary PI mutations.
Overall baseline median TMC114 FC was 3.5, 4.9 and 3.2 for POWER 1, 2 and 3, respectively. HIV RNA <50 copies/mL was reached by 42% of TMC114/r patients, 24% with a susceptible CPI, and 7% with a resistant CPI.
Multivariate analyses showed that baseline FC, number of sensitive NRTIs and concomitant use of ENF (Fuzeon) correlated with response.
Subgroup analysis showed baseline FC was highly predictive of virological outcome:
-- 50, 25 and 13% of TMC114/r patients with baseline FC 40 respectively reached HIV RNA <50 copies/mL.
All subgroup analyses showed a higher proportion of responders in the TMC114/r group compared to control, regardless of concomitant ENF use.
Conclusions: TMC114 FC was the strongest predictor of regimen efficacy. The
magnitude of the incremental benefit for all other factors was determined by baseline TMC114 susceptibility. TMC114/r 600/100mg bid was uniformly superior to CPI, regardless of CPI predicted activity.
RESULTS
Of the 458 TMC114/r 600/100mg bid patients included in this analysis, 131 were enrolled in the POWER 1 and 2 studies and 327 were from POWER 3. A total of 377 patients had reached Week 24 at the time of this analysis.
The PIs used in the control arms were lopinavir (36%), saquinavir (35%), fosamprenavir or amprenavir (34%), atazanavir (17%), indinavir (2%) and nelfinavir (1%).
Overall, mean baseline VL was 4.6 log10 copies/mL, median CD4 count was 128 cells/mm3, and 73% of patients had three or more primary PI mutations. Median baseline phenotypic TMC114 FC was 3.5, 4.9 and 3.2 in POWER 1, 2 and 3 respectively; for all CPIs, median phenotypic FC was >10 (range 0.1-359.5).
Virological responses in the TMC114/r treatment group were consistently higher than for patients receiving CPIs to which they were susceptible or resistant at Week 24 (Table 1), even where control patients were fully susceptible to their investigator-selected PI(s).
Table 1. Virological responses at Week 24 for patients receiving TMC114/r 600/100mg bid or CPI(s) in POWER 1, 2 and 3.
Impact of baseline TMC114 FC on virological response
In multivariate analyses, baseline phenotypic TMC114 FC was the strongest of all prognostic variables, with a p-value <0.0001 after adjusting for other baseline prognostic factors such as VL, CD4 cell count, number of susceptible NRTIs in the OBR, use of ENF, and treatment group.
For all virological efficacy parameters, the responses were better in the subgroup of patients with a lower baseline phenotypic TMC114 FC (Table 2). The majority of patients had TMC114 FC values below or equal to 10.
Table 2. Effect of baseline TMC114 FC on Week 24 virological responses for patients receiving TMC114/r 600/100mg bid.
For patients receiving TMC114/r, the reduction in VL from baseline was greater for patients with TMC114 FC (Figure 1). This trend was consistent across all three trials for all patients.
Reductions in VL were consistently higher than those of the control group, regardless of TMC114 FC subgroup. By Week 24, the mean change in VL from baseline for all control patients was -0.48 log10 copies/mL, and for control patients with TMC114 FC
Baseline median TMC114 FC >10 was only found for patients having >/= 10 PI resistance-associated mutations. 7 In line with the above results, in terms of effect of baseline TMC114 FC on virological response, the response rate was reduced if patients had >/= 10 PI resistance-associated mutations at baseline.
Figure 1. Effect of baseline TMC114 FC on the change in log10 VL from baseline at Week 24 in patients who received TMC114/r 600/100mg bid.
Impact of background therapy on virological response
The greatest virological responses were obtained in the presence of two or more susceptible ARVs in the OBR (Table 3), which is consistent with expectations for the studied patient population.
Table 3. Effect of concomitant use of any susceptible ARV in the OBR in patients receiving TMC114/r 600/100mg bid or CPI(s).
Responses of patients receiving TMC114/r were consistently higher than those observed for patients receiving CPI(s), even where patients had limited or no susceptibility to ARVs (Figure 2).
The use of ENF was similar between the TMC114/r and control groups in terms of the proportion of patients receiving ENF, and whether they were ENF-naive or not. At Week 24, 49% and 44% of TMC114/r patients using ENF (naively) and not using ENF, respectively, achieved a VL of <50 copies/mL compared to 16% and 11% of control patients, respectively.
Figure 2. Effect of number of susceptible ARVs in the OBR on the change in log10 VL from baseline at Week 24.
ARV = 0 = no susceptible AVRs in OBR; susc. = susceptible
For TMC114/r patients, incremental benefit of concomitant ENF use was analysed according to the number of susceptible NRTIs used in the OBR. The greatest benefit of ENF use was observed in the subgroup of patients with no other susceptible ARVs in their OBR: 43% of patients using ENF for the first time achieved a VL of <50 copies/mL, compared to 26% of those who did not use ENF. The proportion of patients achieving a VL of <50 copies/mL was
greater for those with at least one susceptible NRTI in their OBR: 53% for ENF-naive patients and 51% for patients not using ENF (Figure 3).
Figure 3. Proportion of TMC114/r 600/100mg bid patients reaching a VL of <50 copies/mL at Week 24 according to ENF use and number of susceptible NRTIs and ARVs in the OBR (ITT-TLOVR)
Author Conclusions
Virological responses of patients receiving TMC114/r 600/100mg bid were consistently higher than those of patients receiving CPIs, regardless of the susceptibility of the CPIs.
Baseline phenotypic TMC114 FC was the strongest predictor of response, indicating that TMC114 is the main driver of the efficacy of the regimen. The virological response was greatest for patients with FC
For the 440 patients treated with TMC114/r 600/100mg bid in the POWER 1, 2 and 3 trials, baseline PI resistance determined the additional benefits of the background ARVs used.
For patients with baseline phenotypic TMC114 resistance levels below 10-fold (n=308, 70%), log10 reduction in HIV RNA at Week 24 was strongest for those with either susceptible NRTIs or using ENF in the background treatment. There was no additional benefit for using ENF naively together with susceptible NRTIs in this subgroup.
For those with TMC114 phenotypic resistance levels above 10-fold (n=132, 30%), there were only marginal additional efficacy benefits for using both susceptible NRTIs and ENF (first use) in the background regimen.
These data indicate that TMC114 provides a substantial reduction in VL and an increase in CD4 counts in treatment-experienced HIV patients.
References
1. De Meyer S, et al. Antimicrob Agents Chemother 2005;49:2314-21.
2. Katlama C, et al. 3rd IAS Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, Brazil, July 24-27, 2005. Abstract WeOaLB0.102.
3. Wilkin T, et al. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy,Washington, DC, USA, December 16-19 2005. Abstract 2860.
4. Grinsztejn B, et al. 3rd IAS Conference on HIV Pathogenesis and Treatment; Rio de Janeiro, Brazil, July 24-27, 2005. Abstract WePeLB6.201.
5. Berger D, et al. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy,Washington, DC, USA, December 16-19 2005. Abstract H-1094.
6. D'Aquila T, et al. Top HIV Med 2003;11:92-6.
7. Johnson VA, et al. Top HIV Med 2004;12:119-24.
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