Clinic Institute of Infectious Diseases and Immunology, Institut dInvestigacions Biomèdiques August Pi i Sunyer, Hospital Clinic, Faculty of Medicine, University of Barcelona, Spain
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Abstract |
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Keywords: hydroxyurea, mycophenolate mofetil, structured treatment interruptions
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Introduction |
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Failure of structured therapy interruption to enhance an effective specific HIV-1 immunological response |
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Role of hydroxyurea as adjuvant to HAART |
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In order to evaluate the clinical immunosuppressive drug effect on viral dynamics, we conducted a randomized controlled study of STI with cycles of HAART or HAART plus HU.14 Treatment interruptions were scheduled on five cycles of 2 weeks off treatment, but continuing HU during the last two cycles. This schedule allowed us to determine the HU effect, comparing the viral dynamics between cycles on and off HU. First, if HU could inhibit the initial wave of HIV rebound originating from reservoirssuch as quiescent lymphocytes, macrophages or dendritic cellsin which the drug has been shown as an effective monotherapy,11 the effect of HU should be observed even when HU was stopped. Second, HU could slow the subsequent wave of viral replication driven by activated lymphocytes by virtue of its cytostatic effects. Therefore, control of viral replication should only be observed if HU was maintained.
Although no major differences were observed in neutralizing activity, lymphoproliferative and cytotoxic HIV-specific responses between groups, the increase in the doubling time of viral load rebound was strongly correlated with the lymphoproliferative response as previously described in other STI trials. No major differences were obtained in viral rebound after the first three HAART interruptions. Conversely, when HU was maintained after HAART interruption the viral load was one log lower than previous HU-STI cycles and in addition lower than in the HAART group. This fact strongly supports the hypothesis of the effectiveness of HU as a cytostatic drug and argues against a potential role of HU in reservoirs.
Most importantly, HU significantly increases the proportion of patients who achieve control of viral replication (eight out of nine patients maintained a viral load <5000 copies/mL) after five cycles of STI and after 48 weeks continuously off HAART and despite a baseline viral load of 4.6 log copies/mL.
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Role of mycophenolate mofetil as adjuvant to HAART |
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We conducted a randomized trial to evaluate the effect of MMF on plasma and tonsillar tissue viral load and on immune response during and after an STI study.16 Patients treated for at least 1 year with an abacavir-containing regimen were randomized to receive or not MMF with HAART for 4 months before treatment interruptions. We hypothesized that MMF could affect viral rebound, especially in MMF-treated patients whose T cell proliferation capacity significantly diminished.
A multiple in vitro assay after the MMF dose was used to evaluate the capacity of the patient sera to inhibit the proliferation of a T cell line. It was observed that patients treated with MMF had a remarkable reduction in the size of dividing CD4 T cells and also in viral set-point after HAART interruption. This effect was mainly observed in those patients who maintained an inhibitory capacity of lymphocyte proliferation (>60%) for at least >4 h after MMF.
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Other scenarios |
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In another setting, MMF was used as part of salvage therapy and added as a single drug to a rescue-HAART regimen containing abacavir in heavily pre-treated patients harbouring multiple drug mutations.18 An important viral load reduction (>0.5 log) was obtained in those patients in whom the carbovir (the active antiviral metabolite of abacavir) deoxyguanosine triphosphate ratio was increased due to the inhibition of inosine monophosphate dehydrogenase and depletion of guanosine nucleotides.
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Conclusions |
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Recent data suggest that initiation of HAART during acute infection is associated with long-term control of virus replication after therapy discontinuation, due to preservation of HIV-specific T cell clones.4 The use of ciclosporin A and probably other immunosuppressive drugs reduced the number of activated CD4 cells that support massive virus production, and may prevent sequestration of CD4 T cells into lymphoid tissue, which is the place of antigen presentation and productive HIV infection. This could have an impact on the milieu of quiescent T cells containing competent replicative viruses. However, it is not known whetherby establishing a new immunological set-point that may affect the rate of disease progressionthese approaches will clinically benefit long-term infection,.
In the chronic stage of infection, the STI strategy allows us to control viral replication in 20% of patients. However, the use of HU and MMF showed the significant improvement in viral dynamics after HAART interruption mainly because of cytostatic and immune properties which did not have a deleterious effect on HIV-specific responses. This approach could also have an indirect impact on the latent reservoir pool, strikingly diminishing the pool of activated T cells. It was demonstrated that MMF reduced the isolation of the virus from the T cell peripheral pool and also from lymphoid tissue, decreasing the release rate of virus from reservoirs. Studies focusing on the correct measure of viral load in reservoirs are needed.
Optimal candidates, exact drug, dosage, duration of therapy and the optimum time to initiate it within the natural course of infection are questions that need to be answered in the context of large clinical trials. Although no major drug toxicity was reported in trials using different drugs, the long-term safety in terms of opportunistic infections and development of lymphoproliferative diseases are a major concern.
The strategy for using drugs that interfere with the HIV life-cycle, acting on the target cells of HIV rather than on viral enzymes, offers the advantage of avoiding the development of antiretroviral drug-resistant HIV mutants. Caution is required when combining HAART and cytostatic drugs in HIV-1 infection until the impact and long-term safety have been further investigated in larger clinical trials.
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Acknowledgements |
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FIPSE, a non-profit Foundation including: Spanish Ministry of Health, Abbott Laboratories, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Merck Sharp and Dohme and Roche.
RIS, Red Temática Cooperativa de Grupos de Investigación en Sida del Fondo de Investigación Sanitaria (Fondo de Investigación Sanitaria de la Seguridad Social).
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Footnotes |
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References |
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2
.
Kahn, J. O. & Walker, B. D. (1998). Acute human immunodeficiency virus type 1 infection. New England Journal of Medicine 339, 339.
3 . Giorgi, J. V., Liu, Z., Hultin, L. E. et al. (1999). Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or viral chemokine coreceptor usage. Journal of Infectious Diseases 179, 85970.[CrossRef][ISI][Medline]
4 . Rosenberg, E. S., Altfeld, M., Poon, S. H. et al. (2000). Immune control of HIV-1 after early treatment of acute infection. Nature 407, 5236.[CrossRef][ISI][Medline]
5
.
Davey, R., Bhat, N., Yoder, Ch. et al. (1999). HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proceedings of the National Academy of Sciences, USA 96, 1510914.
6 . García, F., Plana, M., Ortiz, G. M. et al. (2001). The virological and immunological consequences of structured treatment interruptions in chronic HIV-1 infection. AIDS 15, F2940.[CrossRef][ISI][Medline]
7
.
Fagard, C., Oxenius, A., Günthard, H. et al. (2003). A prospective trial of structured treatment interruptions in human immunodeficiency virus infection. Archives of Internal Medicine 163, 12206.
8
.
Lieberman, J., Shankar, P., Manjunath, N. et al. (2001). Dressed to kill? A review of why antiviral CD8 T lymphocytes fail to prevent progressive immunodeficiency in HIV-1 infection. Blood 98, 166774.
9 . García, F., Plana, M., Mestre, G. et al. (2002). Immunological and virological factors at baseline may predict response to structured therapy interruption in early stage chronic HIV-1 infection. AIDS 16, 17615.[CrossRef][ISI][Medline]
10 . Douek, D. C., Brenchley, J., Betts, M. et al. (2002). HIV preferentially infects HIV-specific CD4+ T cells. Nature 417, 958.[CrossRef][ISI][Medline]
11
.
Lori, F., Lewis, M. G., Xu, J. et al. (2000). Control of SIV rebound through structured treatment interruptions during early infection. Science 290, 15913.
12 . Lori, F., Malykh, A. G., Cara, A. et al. (1994) Hydroxyurea as an inhibitor of human immunodeficiency virus-type 1 replication. Science 266, 8015.[ISI][Medline]
13 . Hellinger, J. A., Iwane, M. K., Smith, I. J. et al. (2000). A randomized study of the safety and antiretroviral activity of hydroxyurea combined with didanosine in persons infected with human immunodeficiency virus type 1. Journal of Infectious Diseases 181, 5407.[CrossRef][ISI][Medline]
14 . García, F., Plana, M., Arnedo, M. et al. (2003). A cytostatic drug improves control of HIV-1 replication during structured treatment interruptions: a randomized study. AIDS 17, 4351.[CrossRef][ISI][Medline]
15 . Chapuis, A., Rizzardi, P., D'Agostino, C. et al. (2000). Effects of mycophenolic acid on human immunodeficiency virus infection in vitro and in vivo. Nature Medicine 6, 7628.[CrossRef][ISI][Medline]
16 . García, F., Plana, M., Arnedo, M. et al. (2003). The addition of mycophenolate mophetil (MMF) to HAART in early stage HIV-infected patients is associated with a probable decrease in viral reservoir size. In Programs and Abstracts of the Tenth Conference on Retroviruses and Opportunistic Infections, Boston, MA, 2003. Abstract 656, p. 292. Foundation for Retrovirology and Human Health, Alexandria, VA, USA.
17
.
Rizzardi, G. P., Harari, A., Capiluppi, B. et al. (2002). Treatment of primary HIV-1 infection with cyclosporin A coupled with highly active antiretroviral therapy. Journal of Clinical Investigation 109, 6818.
18 . Margolis, D., Kewn, S., Coull, J. et al. (2002). The addition of mycophenolate mofetil to antiretroviral therapy including abacavir is associated with depletion of intracellular deoxyguanosine triphosphate and a decrease in plasma HIV-1 RNA. Journal of Acquired Immune Deficiency Syndromes 31, 459.[Medline]