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Structured interruptions of therapy: looking for the best protocol
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AIDS 2003; 17(15):2257-2258
Fernando Aiuti; Antonello Giovannetti
From the Department of Allergy and Clinical Immunology 'La Sapienza' University of Rome, Viale dell'Universitˆ 37, 00185 Rome, Italy.
Note from Jules Levin: recently published studies on STIs find what was suspected several years ago when STIs and drug holidays received unwarranted attention and support, that drug resistance can occur and is a risk when stopping therapy. The risk is greater with repeated interruptions. A recently published study from Dybul at the NIH found drug resistance can did develop in a few patients, I think 10%, so the study was stopped for this reason. Patients developing drug resistance were treatment-na•ve and experienced. Recent published articles on interruptions:
Structured Treatment Interruption in Patients with Multidrug-Resistant Human Immunodeficiency Virus
Beware of Drug Holidays before HIV Salvage Therapy
HAART Interruption & Acute HIV Syndrome: Aseptic meningitis and acute HIV syndrome after interruption of antiretroviral therapy: implications for structured treatment interruptions
HAART Interruption & Drug Resistance: Emergence of HIV-1 mutated strains after interruption of highly active antiretroviral therapy in chronically infected patients
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.
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 saquinavir 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.
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