JAC Advance Access originally published online on June 27, 2008
Journal of Antimicrobial Chemotherapy 2008 62(3):583-586; doi:10.1093/jac/dkn238
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Original research |
Long-term clinical and surrogate marker effects of subcutaneous intermittent interleukin-2 without antiretroviral therapy in HIV-infected patients
1 Department of Infectious Diseases, Vivantes Auguste Viktoria Klinikum, Rubensstr. 125, 12159 Berlin, Germany 2 HIV Clinical Research, Royal Free Hospital, London, UK 3 University of Minnesota, Minneapolis, MN, USA 4 Elton John Centre, Royal Sussex Hospital, University of Brighton, Brighton, UK 5 Department of HIV Medicine, Chelsea and Westminster Hospital, London, UK 6 National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
* Corresponding author. Tel: +49-30-78717533; Fax: +49-30-78715732; E-mail: christian.herzmann{at}web.de
Received 6 March 2008; returned 8 April 2008; revised 21 May 2008; accepted 22 May 2008
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Abstract |
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Objectives: Subcutaneous administration of interleukin-2 (IL-2) has been shown to increase CD4 counts in HIV-infected patients. It remains unclear whether this effect is associated with a clinical benefit.
Patients and methods: We conducted a long-term follow-up in the cohort of the UK-Vanguard study in which three groups of 12 antiretroviral-naive subjects with CD4 cell counts >350 cells/mm3 received no treatment or IL-2 at either 4.5 or 7.5 MIU twice daily in 5 day cycles, respectively.
Results: Mean follow-up was 376 weeks. IL-2 therapy was associated with a higher area under the curve of CD4 cell count change from baseline at week 48 but not thereafter. HIV-RNA levels were unaffected. Highly active antiretroviral therapy (HAART) was initiated after a mean of 172, 175 and 152 weeks in the control group, low-dose and high-dose IL-2 treatment group, respectively, a statistically non-significant difference. There was a tendency to start HAART soon after discontinuation of IL-2 therapy which may have been triggered by the steep decay of CD4 counts. There were two serious adverse events in the control group, seven in the low-dose IL-2 group and eight in the high-dose IL-2 group. No pattern of disease was detected, making an association with IL-2 therapy unlikely.
Conclusions: We could detect neither a benefit of IL-2 therapy after week 48 nor delayed initiation of HAART. This is currently the longest follow-up data comparing IL-2 therapy with no therapy in antiretroviral-naive HIV-infected patients and does not show a persistent benefit of the intervention.
Keywords: immunomodulation , CD4 cell count , HIV viral load , UK Vanguard , long-term follow-up
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Introduction |
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The main challenges of highly active antiretroviral therapy (HAART) for HIV infection remain poor adherence and drug toxicity. Thus, subcutaneous application of interleukin-2 (IL-2) has been evaluated to delay HAART initiation or enhance its efficiency.
IL-2 is secreted by T lymphocytes and is involved in the differentiation and proliferation of CD4 T cells. IL-2 administration results in increased CD4 cell counts.1 However, results are ambiguous regarding the effect on HIV viral load and clinical outcome. In preparation for two large ongoing trials (ESPRIT and SILCAAT), four ‘Vanguard’ pilot studies were conducted.2 A meta-analysis of three of these was published in 2004.3
The UK-Vanguard study was the only trial to evaluate the IL-2 therapy without simultaneous antiretroviral therapy.4 Its purpose was to determine whether the IL-2-associated increase in CD4 T lymphocytes would allow a delayed initiation of antiretroviral therapy. In summary, it showed that intermittent cycles of subcutaneous IL-2 produced significant increases in CD4 cell counts by 24 weeks with no significant effect on HIV-RNA levels.4
The purpose of this analysis was to provide long-term data on clinical outcomes and laboratory surrogate markers of the UK-Vanguard cohort. Our hypothesis was that IL-2-induced CD4 cell count increases could delay the initiation of HAART and potentially reduce clinical events.
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Patients and methods |
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Details of the UK-Vanguard study design, Ethics Committee approval, patient demographics and IL-2 therapy have been published (ClinicalTrials.gov: NCT00000909 [ClinicalTrials.gov] ).4 In brief, 36 subjects were randomized 1:1:1 as controls receiving neither therapy nor placebo, or to receive IL-2 subcutaneously twice daily for 5 consecutive days every 8 weeks at a dose of either 4.5 MIU (referred to as ‘low dose’) or 7.5 MIU (‘high dose’).
As for the UK-Vanguard study analysis, the primary endpoint was the area under the curve (AUC) for CD4 T lymphocyte count change from baseline. The AUC was calculated every 24 weeks from baseline until week 408. For missing measurements, the last value was carried forward. Data were censored with HAART initiation or loss of patients to follow-up. Clinical data on serious adverse events were collected beyond the initiation of HAART.
For control subjects, a virtual date of last IL-2 administration was created at the mean time interval of IL-2 therapy in the two other groups. This allowed us to analyse whether stopping IL-2 therapy led to a rapid CD4 cell decay necessitating HAART.
Data were analysed on an intention-to-treat basis, i.e. measurements were included even if IL-2 dosing had been reduced or discontinued. Pairwise, two-sided comparison between the IL-2 groups (separately and combined) and the control group were carried out, with P < 0.05 indicating statistical significance.
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Results |
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Mean follow-up time was 7.2 years (range: 81–445 weeks). Three patients withdrew consent after 28 weeks; two of these had commenced HAART by then. One of 10 patients in the low-dose group required IL-2 dose reduction; patients received a mean of 6.2 cycles (range 0–12). Six of 11 patients in the high-dose group required IL-2 dose reduction; patients received a mean of 4.7 cycles (range 2–9).
The last dose of IL-2 was administered after a mean time of 75 weeks (range 4 days to 183 weeks). This interval was used as a virtual date of last IL-2 administration for the control group.
There was no significant effect on AUC for HIV-RNA change from baseline.
All groups had similar baseline CD4 lymphocyte counts.4 At 48 weeks, the AUC for CD4 cell count change from baseline was significantly higher in the low-dose IL-2 group (127 cells/mm3) and in the high-dose IL-2 group (128 cells/mm3) compared with the control group (8 cells/mm3; P = 0.018, 0.049 and 0.029 for control versus both treatment groups combined, versus low-dose IL-2 and versus high-dose IL-2, respectively). No significant difference was found at any later follow-up (Figure 1).
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For up to 144 weeks after discontinuation of IL-2, the AUC for CD4 cell count change was significantly smaller in the treatment groups reflecting the decay of CD4 T lymphocytes (Figure 2). Thereafter, HAART was commenced in all but two subjects in the treatment groups, precluding further analysis.
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HAART was initiated at a similar median CD4 cell count of 293, 244 and 213 cells/mm3 in the control group, the low-dose treatment group and the high-dose group, respectively (P = 0.11, 0.44 and 0.08 for control versus combined treatment groups, versus low-dose group and versus high-dose group, respectively).
The mean time to initiation of antiretroviral therapy was similar in all groups: 172 weeks (range 16–366) for control, 175 weeks (range 123–260) for low-dose IL-2 and 152 weeks (range 27–392) for high-dose IL-2 (range 27–392).
The mean interval between the last dose of IL-2 and the first dose of HAART was 90 weeks (range 14–152) in the low-dose IL-2 group and 87 weeks (range 6–262) in the high-dose IL-2 group. In the control group, the mean interval between the virtual last day of IL-2 administration and the first dose of HAART was longer (169 weeks, range 109–291), but the difference was not statistically significant.
Two clinical events occurred in the control group (Kaposi’s sarcoma and hospital admission for diarrhoea).
Seven events occurred in the low-dose IL-2 group (one case each of Kaposi’s sarcoma, Pneumocystis jirovecii pneumonia, non-Hodgkin’s lymphoma with P. jirovecii pneumonia, anal squamous cell carcinoma, diarrhoea, non-viral hepatitis and herpes zoster infection).
There were eight events in the high-dose IL-2 group: one death due to non-Hodgkin’s lymphoma; two cases of pancreatitis; one case each of Kaposi’s sarcoma, pyrexia of unknown origin, pulmonary tuberculosis, bacterial pneumonia, salmonella infection, herpes zoster infection, stroke and non-viral hepatitis.
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Discussion |
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As previously shown, subcutaneous IL-2 therapy resulted in increased CD4 cell counts.1 This increase was significant at week 24 as reported before and at week 48 but not thereafter.4 However, no difference was found between the IL-2 treatment groups (4.5 or 7.5 MIU). This is most likely a dose-related effect and may be explained by the dose reduction required in 6 of 11 patients randomized to the higher dose.3
The duration of the IL-2-associated effect on CD4 cells varies in different studies, but most studies assessed IL-2 in combination with HAART.5,6 In accordance with other trials, higher CD4 counts did not lead to changes of the HIV viral load, possibly due to the inability of IL-2 to induce HIV-1-specific T cell responses.4,7
We did not find any effect of IL-2 on the period of time until HAART was initiated. We therefore could not confirm hopes that the IL-2 treatment might delay the need for antiretroviral therapy. This issue has not been addressed by any other trial and probably will not be addressed in future, given the effectiveness of HAART. Current trials investigating structured HAART interruption with or without IL-2 augmentation led to ambiguous results. The TILT trial found a significantly longer period off HAART when IL-2 was commenced, while the ACTG A5102 study did not find a difference.8,9
As expected, we found a long-lasting decay of CD4 cell counts after IL-2 discontinuation (Figure 2). There seemed to be a tendency to start antiretroviral therapy at a lower CD4 lymphocyte count in the IL-2 groups, but this observation did not reach statistical significance.
When analysing the interval between IL-2 discontinuation and HAART initiation, we had to take the natural progression of HIV in the control group into account. Thus, a virtual date of last IL-2 administration for control subjects was defined at the mean IL-2 treatment interval of all IL-2 patients. HAART was initiated 87 and 90 weeks after the last IL-2 administration in the treatment groups and 169 weeks after the defined virtual date in the control group. Again, the difference was not statistically significant. Although our cohort was too small to allow a definite conclusion, our observations suggest that after IL-2 discontinuation, the CD4 cell numbers declined rapidly even below the therapeutic threshold, triggering the initiation of HAART.
Our trial provides clinical long-term data about IL-2 therapy. Immediate side effects of IL-2 have been reported before.4 Although we found a relatively high number of AIDS-defining events in all groups, we did not detect a specific pattern of events after week 24, making a relationship between IL-2 and adverse clinical events in the long-term improbable. Again, the number of patients was small and larger trials addressing this question are ongoing.
In summary, we found neither a clinical advantage to IL-2 therapy nor did IL-2 treatment delay the initiation of HAART in antiretroviral-naive patients.
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Funding |
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This study was supported by a EUR 7500 grant from the European AIDS Clinical Society to C. H.
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Transparency declarations |
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None to declare.
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Acknowledgements |
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We thank the patients for their participation. Clinical support by the Ian Charleson Day Centre, Royal Free Hospital London, and the HIV Departments of Chelsea and Westminster and Brighton and Sussex University.
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References |
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1 Vento S, Cainelli F, Temesgen Z. Interleukin-2 therapy and CD4+ T cells in HIV-1 infection. Lancet (2006) 367:93–5.[CrossRef][Web of Science][Medline]
2 Emery S, Abrams DI, Cooper DA, et al, ESPRIT Study Group. The evaluation of subcutaneous proleukin (interleukin-2) in a randomised international trial: rationale, design, and methods of ESPRIT. Control Clin Trials (2002) 23:198–220.[CrossRef][Web of Science][Medline]
3 Arduino RC, Nannini EC, Rodriguez-Barradas M, et al, Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT) Vanguard Group; ESPRIT Executive Committee. CD4 cell response to 3 doses of subcutaneous interleukin 2: meta-analysis of 3 Vanguard studies. Clin Infect Dis (2004) 39:115–22. Epub 14 June 2004.[CrossRef][Web of Science][Medline]
4 Youle M, Emery S, Fisher M, et al. A randomised trial of subcutaneous intermittent interleukin-2 without antiretroviral therapy in HIV-infected patients: the UK-Vanguard Study. In: PLoS Clin Trials (2006) 1:e3. Epub 19 May 2006. Erratum in: PLoS Clin Trials 2007; 2: e23.[CrossRef][Medline]
5 Durier C, Capitant C, Lascaux AS, et al. Long-term effects of intermittent interleukin-2 therapy in chronic HIV-infected patients (ANRS 048-079 Trials). Acquir Immune Defic Syndr (2007) 21:1887–97.
6 Vogler MA, Teppler H, Gelman R, et al, AIDS Clinical Trials Group 248 Study Team. Daily low-dose subcutaneous interleukin-2 added to single- or dual-nucleoside therapy in HIV infection does not protect against CD4+ T-cell decline or improve other indices of immune function: results of a randomized controlled clinical trial (ACTG 248). J Acquir Immune Defic Syndr (2004) 36:576–87.[Web of Science][Medline]
7 Venet A, Gougeon ML, Hamonic S, et al, and ANRS 119 Interstart group. Intermittent interleukin-2 therapy induces the expansion of naïve and central memory CD4 T cells and has no impact on HIV-specific T-cell responses in ART-naïve HIV-infected patients: immunological Substudy of the ANRS 119 Interstart Trial. 14th Conference on Retroviruses and Opportunistic Infections 2007. Abstract 395, session 77. http://www.retroconference.org/2007/Abstracts/29807.htm (15 April 2008, date last accessed).
8 Henry K, Katzenstein D, Cherng DW, et al, A5102 Study Team of the AIDS Clinical Trials Group. A pilot study evaluating time to CD4 T-cell count <350 cells/mm(3) after treatment interruption following antiretroviral therapy +/– interleukin 2: results of ACTG A5102. J Acquir Immune Defic Syndr (2006) 42:140–8.[CrossRef][Web of Science][Medline]
9 Angus B, Lampe F, Tambussi G, et al, and TILT trial steering committee. The TILT trial—a pilot trial of ART interruption with and without the use of interleukin-2. 14th Conference on Retroviruses and Opportunistic Infections 2007. Abstract 477, session 86. http://www.retroconference.org/2007/Abstracts/28153.htm (15 April 2008, date last accessed).
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