Structured Treatment Interruptions for the Management of HIV Infection [Lori F and Lisziewicz J JAMA 2001;286:2981] The authors provide a review of Structured Treatment Interruption (STI), a philosophy of treatment that initially generated interest with the "Berlin patient" [NEJM 1999;340:1683]. This patient was treated during acute HIV syndrome, cycled on and off therapy, and has now gone four years off therapy with good virologic control. The forms of STI in this review were its use for virologic control in the acute HIV infection, for virologic control after successful HAART therapy in chronically infected patients, and as a salvage therapeutic strategy. These tactics are summarized in the table below, along with relevant studies in the following table:

Acute infection: The major study is the Boston cohort reported by Walker and colleagues, which is prospective and uncontrolled with treatment interruption after successful virologic suppression with HAART initiated during the acute phase of infection. Patients are retreated when the plasma viral load exceeds 5,000 c/mL. Results of this study are promising in terms of progressive increases in the number of patients with a sustained response that correlates with an expansion in the T-cell mediated immune response to HIV.

Chronic HIV with viral suppression: The largest study is the Swiss-Spanish cohort in which participants with good virologic control were switched to a regimen of 8 weeks on HAART with two weeks off for four cycles and then retreated only when the viral load rebound exceeded 5,000 c/mL. Results in this trial showed a sustained virologic suppression of 12 weeks or longer in only 9 of 54 patients; there were no favorable sustained responses in those with a baseline viral load exceeding 100,000 c/mL. This study showed improved cellular immune responses in some participants, and this correlated with the duration of virologic control. The authors conclude by this and other studies with smaller sample sizes that STI during chronic infection shows potential for reconstitution of the immune system for HIV-specific response, but the outcome in any individual patient is difficult to predict and virologic rebound is associated with rapid consumption of HIV-specific T cells. Another trial format is the NIH protocol in which 12 participants who responded to HAART are treated with one week on and one week off this regimen. The potential safety of this strategy was suggested by observations that discontinuation of HAART is usually accompanied by virologic rebound after more than one week. The anecdotal experience with 12 patients now followed for over one year seems to show sustained virologic and CD4 cell count responses despite the 50% reduction in total drug administration, with the benefits of cost reduction, relief from pill burden and reduction in side effects of drugs. Nevertheless, this is still considered "experimental."

STI during virologic failure: The theory here is that discontinuation of patients who have failed therapy and have resistant virus will have conversion to wild-type virus that is more easily treated if the selective pressure of HAART is suspended. Two major studies have explored this issue, the Frankfort cohort and the San Francisco cohort, both summarized above. In essence, both studies show that there is conversion to drug-sensitive virus at weeks 6-8, but there is also a rapid decline in the CD4 cell count and persistence of the resistant strain as a minority species. The conclusion is that "STI in patients with failing therapies has not been met with great success."

Future of STI: The fundamental question that the authors raise regarding STI is when to restart therapy after viral rebound. They suggest that this should possibly be the same criteria for starting patients on therapy when they are treatment naïve. With regard to other strategies to augment STI, they emphasize the potential role of "immune system modulation" as with hydroxyurea, mycophenolic acid, interleukin 2 or HIV vaccines.

Comment: This is an interesting and scholarly review of one of the most topical issues in HIV management. In brief, the use of STI for acute infection appears promising, use in chronically infected patients who have achieved virologic control has been disappointing, and the use of this strategy for regenerating sensitive strains after virologic failure in chronically infected patients appears to be fundamentally flawed in both concept and practice. With regard to the second category, chronically infected patients who have good virologic control, the authors suggestion is actually quite different than the protocols that have tested the thesis: they suggest the use of STI for "pulse therapy" in which the guidance for retreatment is based not on virologic rebound or some arbitrary period of treatment suspension, but rather on the CD4 cell count with or without viral load according to currently accepted guidelines for managing treatment-naïve patients. There are, in fact, practically no studies to address the issue in this context other than the favorable report by J. Gallant in a retrospective review of the Moore Clinic experience as presented at ICAAC [Abstract 673]. The interest in immune stimulation is also keen, but in the U.S. the major interest at the moment appears to be in IL-2.
posted 1/14/2002

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