Effect of covariates on virological response
The rate of virological response (≥ 1 log10 copies/ml HIV-1 RNA decrease) did not appear to be affected by baseline HIV-1 RNA levels or number of primary PI mutations at baseline; response rates were similar among these respective subgroups in all TMC114/r dosage groups (Table 2). However, the small subgroup numbers limited statistical power. Greater susceptibility (using an exploratory cut-off of fold-change < 4 recommended by regulatory authorities) to TMC114 improved the virological response, although the effect was most noted at lower doses.
Inclusion of enfuvirtide and a greater number of sensitive NRTI or ART in the optimized background regimen markedly increased the proportion of patients having ≥ 1.0 log10 copies/ml reduction in HIV-1 RNA at week 24 (Table 2). A lower response rate was observed for patients with none or one sensitive ART in their optimized background regimen versus those with two or more. Patients using enfuvirtide for the first time had a greater response than those not receiving enfuvirtide.
Through 24 weeks, the incidence of adverse events of all grades regardless of causality was comparable between TMC114/r and CPI arms. No relationship with TMC114/r dose was observed for any adverse event. When excluding enfuvirtide-associated injection-site reactions, the following adverse events (of any grade, any causality and occurring in ≥ 10% of patients) occurred mostly at similar rates in the TMC114/r treatment groups and CPI arm: headache, nausea, diarrhea, fatigue, upper respiratory tract infection, insomnia and pyrexia. Mean exposure to study medication was longer for the TMC114/r arm than for the CPI arm (32 versus 20 weeks). There was a limited number of individual grade 3 or 4 adverse events recorded (Table 3).
Adverse events led to treatment discontinuation in 8% (18/225) of TMC114/r recipients and 4% (2/53) of CPI recipients. The discontinuation rate was similar in all TMC114/r groups (7–9%), and all events were isolated except two cases each of elevated lipase and gamma-glutamyl transpeptidase. Overall, 15% (33/225) of TMC114/r and 8% (4/53) of CPI patients reported one or more serious adverse event, the most common being pneumonia (in 2% and 4% of TMC114/r and CPI arms, respectively). Occurrences of serious adverse events ranged from 9% (5/57) with 600/100 mg twice daily group to 23% (13/56) with 800/100 mg once daily and were not dose related. Six TMC114/r patients died during the study. All deaths were considered by the investigator to be unrelated (five) or doubtfully related (one) to study medication.
Grade 3 or 4 triglyceride elevations were more common in the two groups receiving TMC114 twice daily than in the other groups (Table 3). However, mean triglyceride levels decreased in all treatment groups. Week-24 triglycerides reductions were 0.6–2.0 mmol/l for the TMC114/r groups compared with 0.5 mmol/l for the CPI group. Collection of long-term safety data from this study is ongoing.
Despite previous exposure to a median of 11 ART and broad PI cross-resistance, 62% of patients who received TMC114/r 600/100 mg twice daily had ≥ 1.0 log10 copies/ml HIV-1 RNA reduction, and 39% had HIV-1 RNA < 50 copies/ml at week 24. In contrast, 14% and 7%, respectively, of CPI recipients achieved the same endpoints. These differences were statistically significant and are clinically relevant. The study confirmed a dose–response relationship for virological efficacy with TMC114/r. These results, plus those from pharmacokinetic/pharmacodynamic analyses (pooled POWER 1 and 2) , validate the selection and regulatory approval of TMC114/r 600/100 mg twice daily for use in treatment-experienced patients.
Advances in ART therapy have led to the availability of safe, convenient and effective treatments capable of reducing HIV-1 RNA to < 50 copies/ml in most treatment-naive individuals . Virological suppression after virological failure of the initial regimen remains achievable , but options for more drug-experienced patients are limited owing to cross-resistance. For patients with extensive drug resistance, use of enfuvirtide, combined with existing NRTI and PI, produced improved responses in another trial , but the maximal viral suppression rate remained suboptimal. Results from this study and from POWER 1  suggest that TMC114/r provides a valuable treatment option for patients with significant ART resistance.
Subgroup analyses, albeit with small sample sizes, demonstrated that a greater number of active antiretroviral drugs (including NRTI and enfuvirtide) in the optimized background regimen was associated with better virological outcomes in all treatment groups. Enfuvirtide-naive patients receiving enfuvirtide had improved virological suppression rates. Overall responses to CPI regimens containing enfuvirtide were low. The incremental benefit of first-time enfuvirtide use in this study was more pronounced than was seen in the POWER 1 study, where patients had more favourable baseline characteristics . Taken together, these findings underscore the value of using two or more active antiretroviral drugs in treatment-experienced patients and suggest a new treatment paradigm of achieving < 50 copies/ml in most patients with advanced HIV-1-treatment failure.
In this 24-week analysis, incidence of adverse events was similar with the TMC114/r and CPI arms, even though the drug exposure was shorter with the CPI arm. Despite this potential bias against TMC114/r, adverse events were similar for all treatments. No differences in the incidence of laboratory abnormalities were noted, nor was there a dose–response relationship for adverse events or laboratory abnormalities. Therefore, the improved HIV-1 RNA reduction with higher doses of TMC114/r did not occur at the expense of patient safety and therapy tolerability.
In conclusion, the combination of TMC114/r 600/100 mg twice daily with an optimized background regimen over 24 weeks was effective for these treatment-experienced HIV-1-infected patients whose virus carried multiple PI-resistance mutations. These data suggest that TMC114/r will help to bridge the gap between the different treatment goals defined for treatment-experienced and treatment-naive patients, moving from previously accepted goals of partial and transient HIV-1 RNA reduction, with maintenance of immunological function, to a more effective and durable strategy of achieving complete viral suppression.
We would like to thank the patients and their families for their participation and support during this study. Special thanks go to Peter Shalit, Koen de Backer, Marie-Pierre de Béthune, Sandra de Meyer, Martine de Pauw, Frederic Godderis, Richard Hoetelmans, Jasmine Kestemont, Andreas Koester, Wim Parys, Monika Peeters, Vanitha Sekar, Sabrina Spinosa-Guzman, Paul Stoffels, Tony Vangeneugden, Hilde Walgraeve and the TMC114 study team for their contributions. The authors would also like to acknowledge Gardiner-Caldwell Communications, for assistance in outline preparation and collating author contributions.
Study contributors. In addition to the authors, the POWER 2 study group included the following investigators and contributors to the design, conduct or analysis of the study: B. Barnett, J. Baxter, G. Beatty, S. Becker, N. C. Bellos, C. Borkert, D. Brand, S. Brown, A. Burnside, A. Collier, E. de Jesus, R. Liporace, C. Farthing, J, Feinberg, I. Frank, M. Frank, J. Gathe, S. Green, J. Hernandez, D. Jayaweera, J Jemsek, H. Katner, D. Kuritzkes, A. LaMarca, J. Lennoz, M. Markowitz, S. Marlowe, D. McMahon, S. Miles, C. Martorell, R. L. Murphy, R. Anderson Myers, R. Nahass, W. O'Brien, V. Perez, K. Patterson, B. Rashbaum, A. Roberts, P. J. Ruane, R. Salata, P. Salvato, S. Schneider, T. Campbell, M. Sension, K. Squires, C. Steinhart, R. Stryker, P. Wolfe, M. Wohlfeiler, B. Yangco, M. Yin, C. Zorrilla, and J. Zurlo (North America); P. Cahn, I. Cassetti and M. Losso (Argentina).
Sponsorship: Financial assistance to support this service was provided by Tibotec and their employees collected the data.
Potential conflict of interest and financial disclosures: On behalf of Richard Haubrich, the University of California, San Diego has received funding to support research conduct and consulting for the POWER 2 study. Richard Haubrich received research support from GlaxoSmithKline and Pfizer. He has also acted as consultant and/or received honorarium from Bristol-Myers Squibb, Monogram Bio, Tanox, Roche, Abbott, Boehringer Ingleheim, Gilead and Virco. Jeffrey Nadler has received research support from Boehringer Ingleheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hoffmann-La Roche, Incyte, Merck, Pfizer, Schering-Plough, Tanox and Tibotec. He has also acted as consultant and/or contributed on Scientific Advisory Boards for Bristol-Myers Squibb, GlaxoSmithKline, Monogram Bio, Tanox, Tibotec and Virco, and been involved in a Speakers' Bureau for Gilead and Virco. Michael Saag has been a consultant and been involved in a Speakers' Bureau for Achillion Pharmaceutical, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Panacos, Pfizer/Agouron, Progenics, Roche Laboratories, Tanox, Tibotec/Virco, Trimeris, Vertex and ViroLogic. He has also received research support from Gilead Sciences, GlaxoSmithKline, Panacos, Pfizer/Agouron, Roche Laboratories, Serono and Tibotec. Timothy Wilkin has served as an ad hoc consultant or received honoraria from Tibotec and Merck. He has received research support from Tibotec and Boehringer-Ingleheim. Dan Berger, Philippe Chiliade, Amy Colson, Marcus Conant, Joel Gallant and Gerald Pierone all have no contractual obligations, restrictions or conflicts of interest to disclose. Ben van Baelen, Marie-Pierre de Béthune, Andreas Koester, Wim Parys, Vanitha Sekar and Eric Lefebvre are all current employees of Tibotec. All authors have reviewed and approved the final draft of the manuscript.
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Keywords:© 2007 Lippincott Williams & Wilkins, Inc.
TMC114; darunavir; protease inhibitor; HIV; efficacy; treatment-experienced; safety