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JAC Advance Access originally published online on September 8, 2008
Journal of Antimicrobial Chemotherapy 2008 62(6):1374-1378; doi:10.1093/jac/dkn377
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

A randomized, controlled study evaluating an induction treatment strategy in which enfuvirtide was added to an oral, highly active antiretroviral therapy regimen in treatment-experienced patients: the INTENSE study

Bonaventura Clotet1,*, Amedeo Capetti2, Luis E. Soto-Ramirez3, Jose M. Gatell4, Lucy Rowell5, Miklos Salgo6 and Jonathan M. Schapiro7

1 Hospital Universitari Germans Trias i Pujol and irsiCaixa Foundation, Ctra. de Canyet s/n, 08916 Barcelona, Spain 2 L. Sacco' Hospital, Via G. B. Grassi 74, Milan, Italy 3 Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Vasco de Quiroga 15, Colonia Seccion XVI, Tlalpan, CP 14000, Mexico DF, Mexico 4 Clinical Institute of Medicine and Dermatology, Hospital Clinic, University of Barcelona, Villarroel, 170, 08036 Barcelona, Spain 5 Roche, Welwyn, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, UK 6 Roche, 340 Kingsland Avenue, Nutley, NJ 07110, USA 7 National Hemophilia Center, Sheba Medical Center, Tel Hashomer, Israel

* Corresponding author. Tel: +34-93-465-6374; Fax: +34-93-465-3968; E-mail: BClotet{at}irsicaixa.es

Received 27 May 2008; returned 28 June 2008; revised 31 July 2008; accepted 10 August 2008


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Objectives: The aim of the study was to compare the efficacy and safety of induction with the addition of enfuvirtide to a newly designed oral, highly active antiretroviral therapy (HAART) regimen versus HAART alone followed by a maintenance phase wherein participants were randomized to either continue/discontinue enfuvirtide while maintaining HAART or continue HAART alone (NCT00487188 [ClinicalTrials.gov] ).

Methods: Participants with HIV-1 RNA ≥1000 copies/mL, CD4 count ≥200 cells/mm3 and genotype sensitivity score ≥2 (excluding enfuvirtide) were randomized 2:1 to enfuvirtide+HAART or HAART alone and assessed every 4 weeks. Participants achieving <50 copies/mL on two consecutive visits by week 24 entered a maintenance phase wherein those receiving enfuvirtide+HAART underwent another randomization 1:1 to maintain enfuvirtide+HAART or discontinue enfuvirtide; those receiving HAART alone continued their regimen. Virological and immunological endpoints were analysed at weeks 24 and 48.

Results: At 24 weeks, 20/31 (65%) participants in the enfuvirtide+HAART arm versus 8/16 (50%) participants in the HAART arm achieved <50 copies/mL. Median time to achieving <50 copies/mL was 57 versus 141 days in the enfuvirtide+HAART and HAART arms (P = 0.048). Withdrawals were similar between groups. In the maintenance phase, at 48 weeks, 14/19 (74%) in the original enfuvirtide+HAART arm (regardless of second randomization) versus 4/8 (50%) in the HAART arm had <50 copies/mL. During maintenance, there were two virological failures in the enfuvirtide+HAART continuation arm, one in the enfuvirtide discontinuation arm and none in the HAART arm.

Conclusions: Although limited by small participant numbers, these results suggest that treatment with enfuvirtide added to HAART may be an option for many patients.

Keywords: antiretroviral , HAART , HIV


   Introduction
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Enfuvirtide, the first available fusion inhibitor, was found to significantly improve virological responses when added to an optimized background regimen in triple-class, experienced HIV-1-infected patients.1–3 When this study was initiated in 2005, there were few agents available for treatment-experienced patients, and enfuvirtide was felt to be an ideal candidate to study in an ‘induction’ model of highly active antiretroviral therapy (HAART) by virtue of its novel mechanism of action. Previously, in a small study of HIV-infected, antiretroviral-naive patients,4 the addition of enfuvirtide to a HAART regimen was shown to significantly increase the viral decay rate within the first 6 days of treatment when compared with HAART alone, with an estimated 22% increase in antiretroviral potency. These findings suggested that induction of an early viral response by adding enfuvirtide to a new optimized HAART regimen in treatment-experienced patients could provide benefits as well. Although a highly effective agent when used in combination with HAART, long-term treatment with enfuvirtide has been limited by its tolerability.1,2 The INTENSE study (ClinicalTrials.gov registry number NCT00487188 [ClinicalTrials.gov] ) was intended as a ‘proof of concept’ study to compare the efficacy and safety of adding enfuvirtide for a short period to a newly designed HAART regimen including at least two active agents (standard of care) with HAART alone in treatment-experienced patients failing their current regimen.


   Methods
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Participants and study design

HIV-1 infected adults (≥18 years) with HIV RNA levels ≥1000 copies/mL on their current regimen were enrolled in this open-label Phase IIIb/IV study conducted in 20 centres in Spain, Italy, Mexico, the USA, France and Germany [see Supplementary data for entry criteria, available at JAC Online (http://jac.oxfordjournals.org/)]. Participants were randomized 2:1 to receive enfuvirtide+HAART or HAART alone [induction phase; intent-to-treat (ITT1)]; stratification was based on the number of active antiretroviral agents [genotype sensitivity score (GSS) of 2 versus >2] to be included in the HAART regimen and the use/non-use of any new/permitted antiretrovirals available through expanded access programmes (see Supplementary data for randomization protocol). Participants achieving a viral load of <50 copies/mL on two consecutive visits by week 24 that was confirmed by week 28 were classified as responders and entered a maintenance phase (ITT2). Those in the enfuvirtide+HAART arm were re-randomized 1:1 to maintain enfuvirtide+HAART or to discontinue enfuvirtide while those receiving HAART alone continued their treatment. Participants not achieving <50 copies/mL by week 24 were permitted to revise their HAART regimen and to continue with or without enfuvirtide and were followed for safety. A change in HAART during maintenance was allowed only for toxicity or for virological failure (HIV RNA ≥400 copies/mL confirmed on two subsequent visits).

A HAART regimen of three to five active agents was selected from approved/new/permitted agents based on prior treatment history, screening GSS and any prior resistance data. Enfuvirtide (90 mg) was administered twice daily by subcutaneous injection.

Study assessments and endpoints

Clinical and laboratory assessments, measurement of CD4 counts and quantification of HIV RNA were performed every 4 weeks through 48 weeks. The final follow-up visit was at 52 weeks. Participants experiencing virological failure were followed for safety and efficacy through 48 weeks.

Primary efficacy endpoints included the proportions of participants achieving viral loads of <50 copies/mL at 24 and 48 weeks and the time to loss of viral response from entry of the maintenance phase. Secondary endpoints included the time to achievement of <50 copies/mL, the proportion of participants achieving <400 copies/mL and changes from baseline in viral loads and in CD4 counts at both weeks 24 (after the induction phase) and 48 (after the maintenance phase; see Supplementary data for statistical analysis). The safety endpoints included all pneumonias, serious adverse events (SAEs) and AIDS-defining category C events that were considered serious or fatal, as well as premature withdrawals due to safety at 24 weeks (all randomized participants receiving at least one study medication) and at 48 weeks.

Ethics

The study was conducted in accordance with the Declaration of Helsinki and with Institutional Review Board approval. Written informed consent was obtained from all participants.


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Induction phase

Because of slow enrolment, study recruitment was stopped after 1 year (31 October 2006; n = 47). Two participants randomized to receive enfuvirtide+HAART withdrawn prior to receiving enfuvirtide were included in the enfuvirtide+HAART arm for the ITT1 analysis and in the HAART arm for the safety analysis. Baseline demographics and clinical parameters were balanced (n = 31, enfuvirtide+HAART; n = 16, HAART; Table 1). By week 24, 20/31 (65%) participants in the enfuvirtide+HAART group had achieved <50 copies/mL compared with 8/16 (50%) of those receiving HAART alone (Table 2). The relative risk for achieving <50 copies/mL in the enfuvirtide+HAART arm was 1.409 (95% confidence interval 0.712–2.79). Induction with enfuvirtide led to a significantly lower median time to achieving <50 copies/mL (57 versus 141 days in the enfuvirtide+HAART and HAART arms, respectively; P = 0.048). Four participants remained in the study without achieving a response (see details in the Supplementary data).


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  		Table 1. Participant baseline demographics and clinical parameters

 


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  		Table 2. Efficacy analyses at weeks 24 and 48

 
Discontinuations at week 24 were comparable [9/29 (31%) for enfuvirtide+HAART and 7/18 (39%) for HAART]. These included 1/18 (6%) in the HAART arm for lack of virological response versus none in the enfuvirtide+HAART arm and 1/18 (6%) versus 5/29 (17%) for safety reasons, respectively. In the enfuvirtide+HAART arm, 3/29 (10%) participants had four SAEs (one each of anaemia, rhabdomyolysis and renal failure unrelated to treatment and one injection site reaction probably treatment related) while 3/18 (17%) in the HAART arm had five events (one each of parotitis, post-operative wound infection and hepatic failure and two gastrointestinal disorders all unrelated to treatment).

Maintenance phase

Because of the limited enrolment, the enfuvirtide arms were combined in the analysis of the maintenance phase (ITT2) population for 27 participants in total (n = 10, enfuvirtide continuation arm; n = 9, enfuvirtide discontinuation arm; n = 8, HAART alone). The enfuvirtide+HAART arm had a somewhat lower median baseline viral load compared with the HAART alone arm (Table 1). In the maintenance phase, 14/19 (74%) had <50 copies/mL HIV RNA in the combined enfuvirtide+HAART arm regardless of second randomization [7/10 (70%) in the continuation arm and 7/9 (78%) in the discontinuation arm] compared with 4/8 (50%) in the HAART arm (Table 2). During the maintenance phase, three participants in the enfuvirtide+HAART arm had virological failures (two in the enfuvirtide+HAART continuation arm and one in the enfuvirtide discontinuation arm) compared with none in the HAART arm. There were two withdrawals due to adverse events in the enfuvirtide+HAART continuation arm (hepatic dysfunction and pneumonia/respiratory failure leading to death, both unrelated to treatment) and two non-safety withdrawals (one each in the enfuvirtide+HAART and enfuvirtide discontinuation arms); the HAART arm had no withdrawals. Three SAEs were reported as the causes of the withdrawals described above.


   Discussion
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In this study, an induction strategy in which enfuvirtide was added for a limited period of time to a newly designed HAART regimen showed a trend toward improved virological responses, with 65% of participants achieving <50 copies/mL compared with 50% in the HAART alone arm. In the maintenance phase, 74% of participants had <50 copies/mL at 48 weeks compared with 50% in the HAART arm. Because these comparisons did not reach statistical significance and the study was arbitrarily terminated, interpretation of these results is severely limited. However, participants receiving enfuvirtide+HAART in the induction phase did achieve <50 copies/mL significantly more rapidly than those in the HAART arm. The high dropout rate precluded a meaningful analysis of the combined induction/maintenance strategy (using ITT1 as the denominator).

The response with enfuvirtide in this study is similar to studies showing reductions in viral loads when an additional agent was added to HAART.5–7 Intensification after the initiation of a HAART regimen has been demonstrated to lower the frequency of intermittent viraemic episodes,6 decrease the occurrence of antiretroviral resistance mutations,8 increase CD4 counts9 and reduce the percentages of activated CD45 and CD85,9 cells. Moreover, intensification of a HAART regimen after long-term therapy has been reported to accelerate the decay of the latent HIV reservoir from a median t1/2 of 31 to 10 months.6

The results of this study, combined with other published studies,5–7 suggest that when an additional agent, particularly of another class such as enfuvirtide, is used concurrently with HAART for a limited time period patients can rapidly achieve undetectable HIV RNA levels. Although enfuvirtide is a highly potent agent in combination with an optimized HAART regimen, the need for twice-daily injections and the potential for injection site reactions are often deterrents to its use. A potential benefit of an induction strategy is that HIV resistance to enfuvirtide is unlikely to develop with this relatively brief use, thereby preserving its future activity for patients who subsequently develop multiclass-resistant HIV.

The ability to draw firm conclusions in this study was limited by the small numbers of participants because of slow participant enrolment, largely due to the established use of enfuvirtide in more advanced diseases and the availability of newer options that did not require injection, and the high discontinuation rate. Another limitation was that participants achieving <50 copies/mL early were required to maintain their suppression longer and were at greater risk of experiencing virological failure during the maintenance phase. Nonetheless, these results are promising and suggest that a limited treatment interval with enfuvirtide in addition to HAART may be an option that could benefit many patients.


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This study was sponsored by Roche. Funding for editorial support was provided by Roche.


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B. C. has served as a consultant on advisory boards, speakers' bureaus and in the conduct of clinical trials with Roche, Boehringer-Ingelheim, Abbott, Bristol-Myers Squibb, Glaxo SmithKline, Gilead, Tibotec, Merck and Pfizer. L. R. and M. S. are employees of Hoffmann-La Roche, Inc. M. S. owns stock in Roche via the employee participation programme. J. M. S. has received research support, honoraria or consulting fees from Abbott, Bayer, Merck, Roche, Gilead, Pfizer, Monogram Biosciences, Tibotec, Siemens, Ambrillia and BMS. All other authors: none to declare.

Editorial support, including assistance with preparation of the first draft and styling of the manuscript, was provided by Linda Whetter, PhD, of Zola Associates.


   Supplementary data
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Supplementary data are available at JAC Online (http://jac.oxfordjournals.org/).


   References
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1 Lalezari JP, Henry K, O'Hearn M, et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med (2003) 348:2175–85.[Abstract/Free Full Text]

2 Lazzarin A, Clotet B, Cooper D, et al. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med (2003) 348:2186–95.[Abstract/Free Full Text]

3 Nelson M, Arasteh K, Clotet B, et al. Durable efficacy of enfuvirtide over 48 weeks in heavily treatment-experienced HIV-1-infected patients in the T-20 versus optimized background regimen only 1 and 2 clinical trials. J Acquir Immune Defic Syndr (2005) 40:404–12.[CrossRef][Web of Science][Medline]

4 Molto J, Ruiz L, Valle M, et al. Increased antiretroviral potency by the addition of enfuvirtide to a four-drug regimen in antiretroviral-naive, HIV-infected patients. Antivir Ther (2006) 11:47–51.[Web of Science][Medline]

5 Havlir DV, Strain MC, Clerici M, et al. Productive infection maintains a dynamic steady state of residual viremia in human immunodeficiency virus type 1-infected persons treated with suppressive antiretroviral therapy for five years. J Virol (2003) 77:11212–9.[Abstract/Free Full Text]

6 Ramratnam B, Ribeiro R, He T, et al. Intensification of antiretroviral therapy accelerates the decay of the HIV-1 latent reservoir and decreases, but does not eliminate, ongoing virus replication. J Acquir Immune Defic Syndr (2004) 35:33–7.[CrossRef][Web of Science][Medline]

7 Louie M, Hogan C, Di Mascio M, et al. Determining the relative efficacy of highly active antiretroviral therapy. J Infect Dis (2003) 187:896–900.[CrossRef][Web of Science][Medline]

8 McColl DJ, Margot NA, Wulfsohn M, et al. Patterns of resistance emerging in HIV-1 from antiretroviral-experienced patients undergoing intensification therapy with tenofovir disoproxil fumarate. J Acquir Immune Defic Syndr (2004) 37:1340–50.[CrossRef][Web of Science][Medline]

9 Kolber MA, Saenz MO, Tanner TJ, et al. Intensification of a suppressive HAART regimen increases CD4 counts and decreases CD8+ T-cell activation. Clin Immunol (2008) 126:315–21.[CrossRef][Web of Science][Medline]


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