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New Data, New Insights, and New Treatment Strategies -- The Latest on Strategic Treatment Interruptions: An Expert Interview With Roy M. Gulick, MD, MPH


Editor's Note:
The success of highly active antiretroviral therapy (HAART) makes it possible to achieve long-term virologic suppression. Although this is good news, the long-term use of any drug may carry an additional risk of adverse events. The important questions regarding which agents or regimens to start with, and what to switch to, have evolved over time to include the parameters introduced by long-term adverse events. At the 13th Conference on Retroviruses and Opportunistic Infections (CROI) in Denver, Colorado, several studies addressed the use of strategic treatment interruptions to reduce adverse effects of antiretroviral therapy. To explore the data and clinical significance of these studies, Mary Anderson, PhD, Clinical Editor of Medscape HIV/AIDS, spoke with Dr. Roy Gulick, Associate Professor of Medicine at Weill Medical College of Cornell University; Director of the Cornell Clinical Trials Unit; and Associate Attending Physician at New York Presbyterian Hospital, New York, NY. In the clinical setting, Dr. Gulick is an expert in the treatment of HIV disease; in the experimental arena, he is an expert in designing and conducting clinical trials of antiretroviral therapy. He has been a coinvestigator on many of the seminal trials in this area, and has coauthored over 70 articles. Dr Gulick is Vice-chair of Optimization of the Antiretroviral Therapy (OPART) Committee of the AIDS Clinical Trials Group (ACTG).

Medscape: Using "strategic" or "planned" treatment interruptions after a period of virologic suppression has theoretical benefit in terms of reducing treatment cost and/or toxicities. On Tuesday, February 7, 2006, at CROI, results from several studies that investigated continuous vs intermittent therapy for HIV infections were reported. The SMART study gained the most press attention before and during the conference; the results of that trial and others appeared to offer conflicting results. Obviously, there were some differences in the design of these trials, which might preclude cross-study comparisons. But what were the common themes that emerged in terms of risks and benefits of continuous vs intermittent therapy, and what were some of the key features of the differences in the designs of these trials (such as thresholds for stopping or restarting therapy, baseline characteristics, CD4+ cell count, nadir, definitions of failure, etc.) that might account for the apparent differences?

Dr. Gulick: The use of antiretroviral therapy certainly has been associated with delaying disease progression and a survival benefit. A still-open question in the field is: What is the best time to start antiretroviral therapy? More recently, given the side effects of the drugs, there has been interest in safe ways to stop therapy or to develop strategies that may include coming off therapy for certain periods of time. Given the balance of the good effects of the medications, and the negative effects, such as inconvenience and treatment toxicity, people have looked for safe ways to reduce the use of antiretroviral drugs. This has stimulated a lot of interest over the last several years, and this recent CROI was really the first meeting at which we saw large randomized studies from around the world that investigated different ways of trying to allow patients to come off antiretroviral therapy.

If we group these studies into categories, we can say that there were 2 structured treatment interruption (STI) approaches to try to allow people to come off medications. The first broad category is an intermittent approach based on protocol-defined time intervals, whereby patients who were taking antiretroviral therapy came off their medications at prespecified periods of time. Different studies looked at different ways of doing this: There was the W-O-W-O (week-on, week-off) strategy, which was employed in the Staccato study[1] and conducted in Thailand and Switzerland. The French-sponsored Window study looked at 8 weeks off and 8 weeks on therapy.[2] The third variation was the Trivacan study,[3] which was conducted in Western Africa and looked at 4 months on and 2 months off therapy. The final variation on the fixed-duration STI approach was the Italian study known as ISS PART,[4] which looked at STIs of different durations. There were 5 courses of treatment interruptions: The first was 1 month off therapy, followed by 3 months on therapy, then STIs of 1 month, 2 months, 2 months, 3 months, and 3 months, with a 3-month period on therapy after each STI. These 4 studies represent the defined-interval intermittent approach to therapy.

The other major strategy that's been looked at in these studies is a CD4+ cell count-guided approach. In this approach, patients take therapy until CD4+ cell counts exceed a certain level and then stop the therapy. After CD4+ cell counts fall over time, therapy is restarted based on protocol-defined CD4+ cell counts. What the intermittent approach and the CD4+ cell-guided approach have in common is ultimately to allow patients to come off medications for some period of time. Again the underlying thought was that this strategy could reduce the side effects and inconvenience of the medications.

Data from all of these studies were presented at the meeting, and although there were some themes that could be discerned, I must say that it's not crystal-clear in some cases as to what the take-home messages were, if indeed there were any take-home messages at all. The studies vary in terms of the numbers of patients that were enrolled, the areas of the world where the studies were conducted, and the specifics, such as the CD4+ cell cutoffs for starting or stopping therapy, and whether the patients had virologic suppression when they interrupted therapy; so it's rather complicated to sort through. But I think one can discern several themes.

In terms of the intermittent approach (that is, prespecifying certain amounts of time that people go on and off therapy), a definitive answer came from the Staccato study[1]. Staccato is a study of 558 patients who were randomized to: (1) the week-on, week-off (WOWO) approach; (2) a CD4+ cell-guided approach in which patients continued antiretroviral therapy until their CD4+ cell counts went over 350/mcL, and then stopped therapy, and only restarted when the CD4+ cell counts went below 350/mcL; or (3) continuous therapy -- that is the standard of care. Importantly, the week-on, week-off arm of the study was stopped early because of inferior performance, and that strategy is no longer recommended.

An Italian study, the ISS-PART,[4] compared 2 strategy groups: one had frequent stopping of therapy (1, 2, or 3 months), interspersed with 3-month periods of being on therapy and the other took continuous antiretroviral therapy. The conclusion of that study was that the intermittent therapy strategy was associated with the selection of drug resistance mutations. The investigators concluded that this was not an acceptable strategy because of the selection of drug resistance. Two other studies found different results: The Window study,[9] which was the French-sponsored study of intermittent therapy (8 weeks off, 8 weeks on), essentially concluded that there was no difference between that approach and continuous therapy -- they demonstrated that the STI strategy was noninferior based on the number of patients whose CD4+ cell count fell to < 300 cells/mcL (4% in the STI group vs 2% in the continuous group). Finally, the Trivacan study[3] had a strategy arm with the 4-month-on, 2-month-off approach, and they also concluded that essentially there were no major differences between that approach and continuous treatment so far and planned to continue the STI and continuous arms in active follow-up.

So what do we have in terms of intermittent therapy? It appears that shorter periods of coming on and off therapy may be associated with risks such as clinical progression or increased resistance, although it's fair to say that not all of the studies found that, and so this strategy continues to be explored.

The other major strategy tested of implementing an STI was CD4+ cell-guided therapy, and again we had some results that suggest different conclusions. The ACTG 5170 study[5] enrolled 167 patients, all of whom had CD4+ cell counts > 350 cells/mcL prior to starting antiretrovirals and at the time of entry into the study. ACTG 5170 was a single-arm pilot study of simply stopping the antiretroviral therapy and describing what occurred; it was one of the smaller STI studies presented. There were very few clinical events, so the investigators concluded that this strategy appeared to be safe in this population of patients.

As I mentioned, the Staccato study[1] had an arm that was week-on, week-off and that was stopped early, but they too had a CD4+ cell-guided arm, which had patients on therapy who continued until their CD4+ cell counts went to > 350 cells/mcL, and then stopped until they went to < 350 cells/mcL -- the predefined point to restart therapy. On the basis of their findings, the investigators concluded that the STI arm (compared with the standard arm) was associated with no difference in new AIDS-associated illnesses, but more HIV-related disease (eg, candidiasis, thrombocytopenia, acute retroviral syndrome), less treatment-related toxicity (eg, diarrhea, neuropathy, hypercholesterolemia), no difference in virologic failure or HIV RNA levels after restarting treatment, no difference in the emergence of drug resistance, but lower CD4+ cell counts, and of course noted that the patients who went off their medications had less exposure to antiretrovirals. In other words, there appeared to be trade-offs comparing the STI and continuous strategies.

The 2 CD4+ cell-guided strategy studies that generated the most interest were the Trivacan study[3] and the SMART study.[12] On the STI arm of the Trivacan trial, patients on antiretroviral therapy stopped when their CD4+ cell counts went to > 350 cells/mcL but didn't restart treatment until the CD4+ cell counts dropped to < 250 cells/mcL. The SMART study,[6] which is the largest study of all of these by far, was quite similar in design to the Trivacan trial. This was a study of 5472 HIV-infected people from around the world, the vast majority of whom were on therapy and were randomized to either continue their medications long term or to undergo the CD4+ cell-guided STI strategy (where they continued therapy until CD4+ cell counts went to > 350 cells/mcL, stopped, and then only restarted therapy when CD4+ cell counts fell to < 250 cells/mcL). The SMART study was stopped early in the fall of 2005 because of a significantly higher rate of clinical events and death that occurred in the group that stopped medications -- that is, the group that underwent CD4+ cell-guided stopping of antiretroviral therapy.

A very important result from the SMART study was that the group that had the STI had higher rates of HIV disease progression and death, as a combined endpoint, and also each of those events independently; that is, they had higher rates of death and higher rates of HIV disease progression. Surprisingly, patients in the STI arm also had higher rates of serious complications that included cardiovascular events such as myocardial infarction, end-stage renal disease, and hepatic cirrhosis. So all in all, it looked like the risk was higher in the SMART study for the group that was undergoing STI in every subgroup that they looked at, whether it was by demographics (eg, gender, race/ethnicity), prestudy CD4+ cell count, or nadir CD4+ cell count, and whatever endpoints they evaluated, including the individual components of HIV disease progression, death, or other important clinical events, they always concluded that the STI arm was inferior to the continuous group. The SMART data and safety monitoring board (DSMB) reviewed this data and stopped the STI arm of the study early, and on the basis of these results, the SMART study investigators concluded that this strategy cannot be recommended.

How do we synthesize all of this information? What is clear is that the CD4+ cell count must be very important in terms of the association with increased events, both HIV events and, importantly, other clinical events. So it looks as though allowing people to drop to < 250 CD4+ cells/mcL increases the risk for clinical events. It's interesting that the conclusions were different in the 2 studies that focused on stopping therapy at higher CD4+ cell counts; the ACTG descriptive study[5] and the Staccato study[1] both focused on a CD4+ cell count of 350 cells/mcL as the trigger for resuming antiretroviral therapy, while Trivacan and SMART restarted therapy at a CD4+ cell count of 240 cells/mcL. So if you take a step back, these studies confirm something we've known for a long time: CD4+ cell counts are important in determining the risk for clinical events.

Medscape: Could you comment on how these results might translate into a clinical situation? In terms of treatment, is this approach really off the table for right now?

Dr. Gulick: There is continued interest on the part of patients and providers in safe ways to stop or to hold antiretroviral medications. I think the bulk of the evidence here says that one must be very careful about that strategy, depending on what the CD4+ cell count is. One way of putting it is to say that the best way to decrease the amount of time on antiretroviral therapy is to delay starting it in the first place. I think this reinforces the point that we need to use medications when they're needed, and perhaps not start too early, because the bulk of the evidence here is that once a person starts, they should continue on antiretrovirals, both for the benefits in terms of HIV disease, and again, as suggested by the SMART study, the benefits in terms of reducing other end-organ complications, such as cardiovascular, renal, and hepatic toxicities.

Just to complicate the issue, there were additional data[7] presented at the conference suggesting that starting antiretroviral therapy earlier (ie, at a higher CD4+ cell count) was associated with the development of fewer side effects than starting later (ie, at a lower CD4+ cell count). These observations suggest that we need to assess carefully the risks and benefits for an individual and support further clinical research to investigate these critical issues.