To stop or not to stop: That is the question, but what is the answer?

Combination antiretroviral therapy has dramatically altered the natural history of infection by HIV. This has been clearly documented in clinical trials as well as population-bases studies [1–5]. Despite earlier enthusiasm, it is now clear that currently available regimens are not able to eradicate HIV infection in the short term. The question remains whether this strategy could lead to eradication of HIV infection over a period of many years or even decades [6–8]. As a result, antiretroviral therapy in the early 2000s should be regarded as a long-term, possibly life-long proposition. In this context, maintaining a high level of adherence to the regimen has become critically important [9]. Unfortunately, this is often compromised because of the complex nature of the regimens, lifestyle issues, and co-morbidities. Furthermore, with continued exposure to antiretroviral therapy, patients have begun to experience a variety of new and previously unexpected adverse effects, including redistribution of body fat, insulin resistance, diabetes, hypercholesterolemia, hypertriglyceridemia, osteopenia and osteoporosis [10–12]. More recently there has been increasing concern that some of these adverse effects may be associated with increased risk for cardiovascular morbidity [13]. A variety of therapeutic strategies has emerged to try to facilitate long-term successful management of HIV infection. Several approaches have been explored in an attempt to facilitate adherence through the simplification of therapy such as decreasing dose scheduling to twice and once daily [14]. Pharmacokinetic boosting of protease inhibitors has also allowed simplification of regimens and, in some instances, increasing drug exposure to overcome mild to moderate levels of resistance. Deferring initiation of therapy in chronically infected individuals has also been proposed to minimize treatment-related morbidity without compromising long-term therapeutic effectiveness. This objective can be achieved as long as treatment is initiated before the CD4 cell count decreases to less than 200 × 106/l, among AIDS-free patients [15–18]. Another approach that has been proposed to possibly reduce drug exposure, promote adherence, and decrease pill fatigue involves various kinds of treatment interruption [19]. When considering the role of treatment interruptions, it is important to differentiate their potential role in several distinct clinical settings. For patients who initiated therapy during acute seroconversion, treatment interruption has been postulated to enhance HIV specific immune response and, as a result, allow better control of viral replication in the absence of continued therapy [20,21]. Cases of apparent control on HIV viremia in the absence of antiretroviral therapy have been reported in patients treated during acute infection who discontinued therapy after having an undetectable viral load (plasma viral load < 50 copies/ml) for several months [20,21]. This remains an attractive hypothesis that should be explored further in prospective controlled clinical trials. Until such results are available, this intervention (as well as the initiation of treatment during acute infection) should be regarded as experimental in nature. At the other extreme of the spectrum, the effect of treatment interruptions has been explored in the setting of advanced treatment failure. Early observational data suggested that type of strategy could lead to re-establishment of predominantly wild-type virus in the peripheral circulation [22] and to a rapid decline in the detectability of resistant virus in the circulation [23]. In some patients, interruption of a failing regimen was associated with an enhanced, short-term response following re-institution of antiretroviral therapy [24]. Longer follow-up of such patients has been rather disappointing in that antiviral responses appear to be transient and the initial decrease in CD4 cell counts associated with rebound of viral replication during the treatment interruption, cannot be predictably recovered with re-institution of therapy [25]. Given that the CD4 cell count dictates disease progression in this particular group of patients, the ultimate role of this intervention in this setting remains unclear. Prospective clinical trials are currently underway to better define the role of treatment interruptions in this setting. Until such results are available, the systematic use of treatment interruptions in patients presenting with rebound viral replication and evidence of resistance cannot be recommended. Treatment interruption in chronically infected individuals without virologic failure has been explored from a variety of standpoints. Perhaps the earliest form of treatment interruption pertains to those patients who, in the course of chronic long-term management, stopped treatment because of issues of toxicity or the development of intercurrences, which precluded continuation of therapy. The work by Taffe et al. in this issue of AIDS provides some insight into this particular treatment interruption modality [26]. Not surprisingly, Taffe and colleagues found that short-term interruptions of antiretroviral therapy in the order of up to 3 months within the Swiss HIV cohort study were quite common. Of the 4720 persons included in the analysis, 1125 (24%) had one interruption in therapy and 174 (4%) had two or more interruptions. Of note, the authors were not able to detect an increased risk of HIV-associated morbidity or mortality during the follow-up time in this patient population. An important limitation of this work relates to its ability to precisely define the reasons or circumstances leading to interrupting therapy in a given individual. Furthermore, there may be biases operating on the part of the physicians recommending treatment interruptions to patients that are somehow perceived to be at a lesser risk of disease progression based on characteristics that are not captured by the analysis. Another important limitation relates to the relatively short observation period following the treatment interruption, which may limit our ability to detect differences in long-term outcome between groups. Obviously, further prospective evaluation of this issue will be required before precise guidelines can be developed regarding the best way to incorporate single treatment interruptions in clinical practice. Various forms of structured treatment interruptions scheduled at specific time points with specific thresholds for re-initiation of therapy have been explored in chronically infected patients initially to boost HIV specific immune responses [27–29] and more recently to try to decrease overall drug exposure in an attempt to reduce drug-related morbidity and drug costs [30]. Comparison between these types of studies has been complicated by to the heterogeneity in the types of the triggers for stopping and re-initiating therapy. Strategies have varied from very flexible to very rigid guidelines with the re-institution of treatment at fixed intervals, varying between months to weekly periods on and off treatment. The efficacy of this approach has yet to be determined. Furthermore, there are unanswered concerns regarding the potential negative effects of using structured treatment interruptions or even pulse therapy as such an approach may expose the patient (and the virus) to differential drug levels due to varying half-life of the medications in the regimen, which ultimately may promote premature selection of resistance [30]. There are other references from meetings. There is some concern, as well, that recurrent rebound of viral replication may re-seed viral reservoirs, which ultimately may conspire against eradication of HIV infection with currently available treatment strategies [29]. Finally, the use of structured treatment interruptions or even pulse therapy in this setting assumes that less drug will be associated with less toxicity, less drug-related cost, and improved adherence while preserving overall outcomes. All of these represent critical assumptions that need to be tested in long-term strategy trials. Pending the results of such studies, structured treatment interruptions or pulsed therapy of chronic HIV infection cannot be recommended. Considerable effort has focused on trying to characterize the potential role of treatment interruptions in patients with acute HIV infection, treatment failure, or chronic infection. A clear answer to this important issue has not yet emerged. Whether to stop or not to stop treatment in any given setting remains unclear. Current therapeutic guidelines do not adequately address this issue, which occurs frequently in the clinic [31–33]. With Taffe et al. we concur that, at this time, treatment interruptions should be regarded as an experimental procedure that whenever possible should be undertaken in the context of carefully designed prospective clinical trial under the supervision of experienced investigators. There may never be a clear answer when to interrupt therapy, but hopefully unlike Hamlet's tragic demise [34], our dilemma will end with the availability of simpler and more efficacious or even possibly curative treatments. `‘To be, or not to be, that is the Question: Whether ‘tis Nobler in the minde to suffer The Slings and Arrowes of outragious Fortune, Or to take Armes against a Sea of troubles, And by opposing end them: to dye, to sleepe No more; and by a sleepe, to say we end The Heart-ake, and the thousand Naturall shockes That Flesh is heyre too?’' William Shakespeare, 1623

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