Research Institute for Genetic and Human Therapy (RIGHT) at IRCCS Policlinico S. Matteo, P. le Golgi, 2-27100 Pavia, Italy, and 2233 Wisconsin Avenue, Suite 503, Washington, DC 20007, USA
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Abstract |
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Introduction |
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Therefore, there is an unmet need for alternative therapies to continuous HAART. Along with the development of additional drugs, the possibility of using different administration schedules has been hypothesized. In particular, structured treatment interruptions (STI), consisting of alternating on and off cycles of HAART, have recently been investigated in: (i) primary HIV infection (PHI); (ii) chronic infection; (iii) virological failure; and (iv) in conjunction with adjuvant therapy. In this review, clinical data on the use of STI in these different settings are presented.
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STI during PHI: the concept of autovaccination |
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Autovaccination is therefore based on the concept of inducing controlled viral rebound, thus utilizing the autologous virus as antigen to stimulate HIV-specific immune responses (Figure 1). Two strategies might be envisaged. (i) To resume drug treatment as soon as HIV reappears in the plasma. This would require frequent monitoring of the viral load, and might be applied in research settings involving a limited number of patients. (ii) To cycle HAART according to a pre-determined fixed schedule, selecting a schedule that will not allow uncontrolled viral replication (such as a 13 week HAART interruption), thus avoiding frequent viral load determinations. This strategy would make STI feasible for studies involving large numbers of patients, and applicable in clinical practice.
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STI during chronic infection |
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Figure 2 illustrates how STI do not seem to reduce the extent of viral rebound and change the viral load set-point during chronic infection. Probably, STI are not sufficient to stimulate a proper immune response in chronically infected patients,11,19,20 and the autologous virus can only transiently mobilize HIV-specific T cells. This hypothesis has been confirmed recently.8,2126 CD8 T cell responses improve during STI; however, this increase does not correlate with viral control.2123 In addition, a study evaluating CTL responses during STI in chronic infection has shown that the increase in CTL responses was probably related to the expansion of responses already present in the lymph nodes.8 It has also been shown that CD4 T cells specific for HIV antigens are more frequently infected by HIV, and an increase in the number of CD4-infected T cells was observed after STI.24 Furthermore, CD4 T cell proliferative responses were inhibited in the presence of high viraemia during STI.25,26 This might be caused by the rapid depletion of T cells during uncontrolled viral replication,27 thus limiting the ability of STI strategies to induce immune-mediated viral control during chronic HIV infection. Lack of viral control during chronic infection might also be due to changes of the viral quasi-species, and this would render immune control of viral replication increasingly problematic after each STI cycle.28,29
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STI after virological failure |
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Adjuvant therapy for STI |
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A very exciting possibility is represented by the potential combined strategy of STI and an HIV vaccine inducing an HIV-specific T-cell-mediated immune response. By using such a combination, autologous (by STI) and heterologous (by vaccine) viruses (as antigen) might synergize to increase HIV-specific immune responses, most likely eliciting a broader response (Figure 3). Our group and others are exploring the possibility of using HIV vaccines and STI in combination as a therapeutic technique to extend drug-free periods during the management of HIV infection. Vaccine candidates have been designed for therapeutic vaccination, such as HIV-1 Immunogen, poxvirus-based vaccines or DermaVir.4143 In addition, vaccines conceived for prevention44,45 might be tested. Autologous and heterologous antigens might indeed act synergically to enhance HIV-specific immune responses.
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Conclusions |
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In our opinion, STI might represent a valid alternative to continuous HAART in acute as well as in chronically HIV-infected patients. However, the results available to date are not sufficient to recommend the use of this strategy in everyday practice, since the individual results are still unpredictable and the potential hazards are not fully known. In order to evaluate the potential of STI, and clarify the overall risk/benefit ratio, large, controlled and randomized clinical trials are necessary. Many of these trials are presently ongoing.46
Based on the above considerations, it could be hypothesized that the immune system itself might become a fourth drug as part of the arsenal to efficiently control HIV replication. However, until further studies confirm the safety and efficacy of STI, clinicians and patients should refrain from using this therapeutic scheme. Ultimately, the use of therapeutic vaccines, or a combination of STI and therapeutic vaccines, will be a safer and more reproducible approach to induce HIV-specific immune responses in infected individuals.
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Acknowledgements |
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Footnotes |
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References |
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