Structured interruptions of therapy: looking for the best protocol
Aiuti, Fernando; Giovannetti, Antonello
From the Department of Allergy and Clinical Immunology ‘La Sapienza’ University of Rome, Viale dell'Università 37, 00185 Rome, Italy.
See also p. F33
Correspondence to F. Aiuti, Department of Allergy and Clinical Immunology ‘La Sapienza’ University of Rome, Rome, Italy.
Received: 18 June 2003; accepted: 26 June 2003.
The advent of highly active antiretroviral therapy (HAART) has dramatically modified the clinical course of HIV infection in a large proportion of infected individuals, leading to a significant reduction in the incidence of both AIDS-associated opportunistic infections and deaths . However, in spite of the elevated potency of current antiretroviral regimens, infectious HIV-1 continues to replicate and to reside latently in resting memory lymphocytes as well as in other reservoirs . A life-long therapy that maximally suppresses virus replication is therefore required to maintain immune reconstitution. Unfortunately HAART is burdened by a number of limitations such as elevated long-term toxicity, emergence of drug resistant viruses, scarce adherence to complicated regimens, and elevated economic costs. Since immune responses against HIV, reduced during HAART , can influence viral control, immunological augmentation has been proposed as an alternative therapeutic approach to HIV infection .
Anecdotal cases, suggesting immune boosting after discontinuation of therapies , have favoured the concept of strategic interruptions of therapy (STI) as a tool capable of reducing the limitations of HAART. A large number of clinical trials, based on protocols varying widely with regard to the number and the duration of STI, have therefore been initiated in the setting of either acute or chronic HIV infection. STI is also currently under investigation in the context of failing antiretroviral therapy where it is conceivable that it may reestablish a dominant population of drug sensitive virus . The most promising data regarding STI comes from studies involving subjects with treated acute infection in which stimulated HIV-specific CD4 helpers and CD8 cytotoxic responses resulted in plasma viraemia rebounds that became smaller with successive interruptions . On the contrary, in chronically infected HIV patients a clear-cut beneficial effect of STI on viraemic control was more difficult to demonstrate since the virus rebounded in basically all of the patients. In fact, with the notable exception of data reported by Dybul et al. showing no relapse of virus replication in a 1-week-on–1-week-off STI , all other data have indicated that STI initiated during chronic HIV infection, although relatively safe, was generally unable to significantly modify the pre-HAART equilibrium between cellular immunity and viral replication, nor was it able to lower the viral load set point [9,10].
In this issue of AIDS, Ananworanich et al. report planned interim results from the ongoing Staccato study. In this trial, 600 patients with HAART-induced viral suppression had to be randomized to one of three arms: fixed short STI (1 week on therapy, 1 week off therapy); CD4 cell count guided pulse therapy; and continuous therapy. The rationale of the STI arm was based on the observation that after discontinuation of antiretroviral therapy, the viral rebound is not immediate and therefore patients were expected to remain aviraemic with stable CD4 cell counts. Unfortunately, the study by Ananworanich et al. does not support this hypothesis as a high proportion of patients, largely exceeding the expected acceptable limit of 10%, showed HIV RNA concentrations > 500 copies/ml. For this reason the week on – week off arm of the Staccato study has been prematurely terminated. These data are in conflict with what was previously reported by Dybul et al. and are therefore of great concern regarding this strategic approach.
The apparently deluding results of the study by Ananworanich et al. could induce the reader to consider the STI as an intrinsically failing strategy. It is now evident that some of the early optimistic hypotheses on the beneficial effects of STI should be, in the light of recent evidence, carefully reconsidered. The overall message coming from the largely negative results of clinical trials designed to explore the feasibility of STI is that patients eligible for discontinuation of therapy must be accurately selected on the basis of multiple virological and immunological parameters. Multivariate analysis from previous reports identified pretreatment CD4 cell count nadir and plasma HIV RNA levels as predictors of treatment response. Other crucial factors are represented by the HAART regimen prior to starting STI as well as by the history of antiretroviral usage. It is reasonable to hypothesize that only patients with a good immune control of HIV replication, naive for antiretroviral drugs before starting HAART and currently in therapy with powerful combinations of drugs, will have the best outcomes on STI.
Although not clearly evident, there exists a number of differences between the Dybul and Ananworanich studies that have determined the contrasting results, and it is extremely important to characterize these discrepancies, defining their exact role before drawing any conclusion. Patients enrolled in the two studies were on different pre-study HAART regimens and this may represent a major confounding factor. As known, the antiretroviral drugs show individual profiles in terms of potency, pharmacokinetics (half-life) and susceptibility to mutations conferring resistance. In the study by Ananworanich et al., a consistent proportion of failing patients was on saquinavir plus ritonavir whereas in the Dybul study only one patient was treated with raquinavir while the remaining patients were mainly on an indinavir plus ritonavir regimen. Moreover, in the study by Dybul et al., 70% of patients had a history of interleukin-2 therapy and a high CD4 T-cell count nadir prior to starting STI. For these important reasons caution is warranted in interpreting such conflicting results of these two very similar studies.
In conclusion, with the failure of the ‘autovaccination’ hypothesis and considering the significant risk of the emergence of drug resistant viruses following STI, it is tempting to speculate that STI, far from being considered as a general tool to decrease the disadvantages related to the chronic use of antiretroviral drugs, must be proposed only to selected and well characterized patients displaying multiple favourable immunological and virological parameters. Only large randomized clinical trials could tell us what kind of STI offers the best advantages for patients with chronic HIV infection.
1. Palella FJ, Jr., Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med
2. Furtado MR, Callaway DS, Phair JP, Kunstman KJ, Stanton JL, Macken CA, et al. Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. N Engl J Med
3. Pitcher CJ, Quittner C, Peterson DM, Connors M, Koup RA, Maino VC, et al. HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nature Med
4. Papasavvas E, Ortiz GM, Gross R, Sun J, Moore EC, Heymann JJ, et al. Enhancement of human immunodeficiency virus type 1-specific CD4 and CD8 T cell responses in chronically infected persons after temporary treatment interruption. J Infect Dis
5. Lisziewicz J, Rosenberg E, Lieberman J, Jessen H, Lopalco L, Siliciano R, et al. Control of HIV despite the discontinuation of antiretroviral therapy. N Engl J Med
6. Miller V, Sabin C, Hertogs K, Bloor S, Martinez-Picado J, D'Aquila R, et al. Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure. AIDS
7. Rosenberg ES, Altfeld M, Poon SH, Phillips MN, Wilkes BM, Eldridge RL, et al. Immune control of HIV-1 after early treatment of acute infection. Nature
8. Dybul M, Chun TW, Yoder C, Hidalgo B, Belson M, Hertogs K, et al. Short-cycle structured intermittent treatment of chronic HIV infection with highly active antiretroviral therapy: effects on virologic, immunologic, and toxicity parameters. Proc Natl Acad Sci USA
9. Oxenius A, Price DA, Gunthard HF, Dawson SJ, Fagard C, Perrin L, et al. Stimulation of HIV-specific cellular immunity by structured treatment interruption fails to enhance viral control in chronic HIV infection. Proc Natl Acad Sci USA
10. Fagard C, Oxenius A, Gunthard H, Garcia F, Le Braz M, Mestre G, et al
. A prospective trial of structured treatment interruptions in human immunodeficiency virus infection. Arch Intern Med
HIV; antiretroviral therapy; strategic treatment interruption; drug resistance; immune response
© 2003 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.