The Body PRO Covers: The 9th Conference on Retroviruses and Opportunistic Infections

Treatment Interruption (Poster Session 72)

February 25, 2002

  • SSITT: A Prospective Trial of Treatment Interruptions in HIV Infection
    Abstract 528-M
    Authored by B. Hirschel1, C. Fagard1, A. Oxenius2, H. Gunthard3, and F. Garcia4 for the Swiss HIV Cohort Study (1Geneva, Switzerland; 2Oxford, UK; 3Zürich, Switzerland; and 4Barcelona, Spain)
    View the original abstract

The benefits of STIs, or Structured Treatment Interruptions have been the subject of a lot of criticism. Small-scale studies have resulted in disappointments and conflicting information. Nevertheless many clinicians are reluctant to completely abandon this idea. So seems that STIs are here to stay -- at least for a while.

It is hard to predict if larger and longer clinical trials in STIs are going to result in better outcomes. But the reality for now is that with the treatment options we currently have, many patients are going to continue to request treatment interruptions from their physicians, whether we clinicians agree with them or not. That is why I welcome any study that can shed some light on a better way to structure them.

The concept that re-exposure to HIV during planned treatment interruption may stimulate anti-HIV immunity (autovaccination) has been looked at in subjects with acute seroconversion. In those studies, subjects who started treatment soon after initial infection, and then stopped this treatment, it was noted that while the viral load returned, it settled at lower levels, especially after a few cycles of treatment and stopping. (See "Use of Structured Treatment Interruptions in Primary Infections," Abstract 421, ICAAC 2001).

In another study, also presented at ICCAC 2001, stopping treatment also led to a strengthening of the HIV-specific CD8 T-cell response, and a diminution of the CD4 T-cell response. Also, no resistance mutations emerged and patients resuming therapy had a quick virologic response with no treatment failures. (See "Structured Treatment Interruptions (STI) in Patients Receiving HAART Since Primary HIV-1 Infection (PHI): Spontaneous Control of Viremia in Almost Half of Cases After the First Two Cycles Off Therapy," Abstract 1908 ICAAC 2001).

What appears clear is that autovaccination does not appear to improve HIV-related immunity in a chronically-infected patient. (See "Predictors of Virologic and Immunologic Success Post Treatment Interruption (TI) in Patients with Chronic HIV Infection," Abstract 1909, ICAAC 2001.) That is why I was surprised to see this poster by the European group.

In this study, 133 patients who were chronically infected at the start of HAART, with a CD4 >300 and viral suppression <50 copies/mL for at least six months, were enrolled. None of those patients were on an NNRTI regimen. Subjects underwent four cycles of STIs (two weeks off, eight weeks on), after which they discontinued therapy at week 40. Patients were allowed to restart therapy if pre-determinate levels of HIV-RNA and CD4 cells were exceeded.

For this study "rebound" was defined as an HIV-RNA >200 copies/mL. "Response" was defined as an HIV-RNA < 5000 copies/mL at 52 weeks. Eighty-eight out of 133 patients had a rebound after the first two weeks of interrupted treatment. High viral load and low CD4 counts pre-ART predicted patients that would rebound. Only 17 percent of the patients (23/133) responded at 52 weeks (HIV-RNA <5,000 copies/mL). 110 patients did not respond, 44 of those with HIV-RNA >5,000 at 52 weeks. The lack of rebound during the periods of interruptions predicted patients that would respond at 52 weeks. At 96 weeks, the predictive factors of response were initiation of ART within two years of infection and a baseline HIV-RNA of <4.05 log copies/mL. Factors that were non-predictive were pre-ART CD4 cells, CD4 cells at initiation of STIs or type of treatment at study entrance.

The investigators concluded that STIs are not enough to obtain low viremia without antiretroviral therapy. They noticed CD4 cell counts decreased, particularly in the first 12 weeks without treatment. Only 40 percent of patients remained off treatment after a median follow up exceeding one year.

In summary, this study shared more evidence on the lack of effectiveness of structured treatment interruptions to enhance virologic and immunologic responses and specific anti-HIV immunity.

Because there was no control arm, we cannot predict what otherwise would have been the outcome for a similar cohort of patients after 96 weeks. There is also no information on what happened with those patients if they were put back on ART (i.e., will their CD4 cells increase again to pre-study baseline?). Therefore, we cannot comment if those patients are actually worse now than before they started treatment. We do know that they are not better, and that they did not appear to have developed better anti-HIV immunity. That is not necessarily a completely bad thing, since those patients were taken off medications for a significant amount of time, decreasing the morbidity and side effects related to treatments, and reducing cost of therapy.

One of the best studies and presentations addressing this issue was dictated by Dr. Joel Gallant. (See "Long-Term Effects of Treatment Interruptions: 18-Month Evaluation of a Controlled Trial in >300 HIV-Positive Patients," Abstract 1910, ICAAC 2001.)

When we are confronting the dilemma of treatment interruption in a chronically-infected patient, we need to define the goals for that approach; is it to improve the immunologic profile of patients on treatment? Or is it simply to reduce overall drug exposure, thereby reducing cost and toxicity? Other concerns are the potential for HIV to spread further in the body, the increased risk for patients to infect a sexual partner, and the potential development of resistance.

This is not the last we are going to hear about treatment interruptions in chronically infected patients. More studies are currently underway to better elucidate any potential benefits of this treatment strategy. In the meantime, our best approach is to wait until these issues are better sorted out.

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