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Structured Treatment Interruptions (STIs)

by Bill Valenti, MD

A study by Parish et al provides some insight into the real world of stopping and restarting treatment.1 The study assessed the durability of treatment interruptions, factors predicting CD4+ cell count decline and treatment resumption, an estimate of the time to CD4+ cell count decline to < 200 cells/mm3, and virologic response to resumption of HAART.

This was an uncontrolled, prospective, observational chart review of 62 patients who, after physician consultation, agreed to stop HAART. Patients were not included if they had CDC-defined AIDS; did not intend to resume antiretroviral treatment based on decreasing CD4 or increasing viral load; or had developed an AIDS-defining infection.

The most common reasons for stopping treatment were: patient did not meet current recommendations for initiating treatment (44%);
nonadherence (18%); drug toxicity (18%); and virologic failure (5%).

Pretreatment viral loads were available for 36 patients. The investigators found good correlation with average viral loads during treatment interruption, suggesting that during treatment interruption, viral loads rebound to close to pretreatment levels and not to higher, more aggressive rebounds.

During the follow-up period, 16 patients resumed therapy (26%) and 46 did not (74%). The differences between the 2 groups were:

" A shorter median duration of treatment interruption in the resumers (33 vs 64 weeks)
" A lower CD4+ cell count among resumers when measured off-treatment (316 vs 495 cells/mm3)
" A higher plasma HIV-1 RNA level among resumers when measured off-treatment (141,200 vs 22,511 copies/mL)

Factors during treatment interruption that were significantly associated with resuming therapy were the average and the maximum viral loads, the size of the rebound in HIV-1 RNA, the lowest CD4+ cell count (nadir), and the absolute change in CD4+ cell count. The estimated time taken for the CD4+ cell count to fall below 200 cells/mm3 was significantly shorter for HAART resumers vs nonresumers.

There are many reasons why STI generates such interest, including management of treatment side effects. Still unproven is the concept that STI improves immune system function or boosts the immune system.

Recently, two studies reviewed this concept in patients with primary HIV infection, and in patients with chronic infection. Miro et al studied 12 patients who started treatment within 90 days of onset of symptoms of primary HIV infection and who, after at least 1 year of therapy, began cyclical treatment interruptions.2 Three subjects had viral loads below 5000 copies/mL during the treatment interruptions; in only two of these patients was the plasma HIV-1 RNA level in the range of 1000 copies/mL or less. This is in contrast to earlier work by Altfield and Rosenberg which suggested that STIs in primary infection might result in immunologic control of viremia.3,4 The differences between the two studies may be due to differences in patient selection and the difficulty in identifying primary HIV infection early enough. See also comments by Dr. Bruce Walker on this matter online at: <http://www. iapac.org/conferences/sessions01/reuters.html>

The results of a study of STI in patients with chronic HIV infection were also disappointing. Hoffmann et al5 showed that:

" STIs in chronically infected patients who had detectable plasma viral loads had no real effect on HIV-specific immunity
" STIs in chronically infected patients resulted in an initial decrease in HIV-specific T-cell immune responses, followed by an increase back to or above baseline

Other studies that have attempted to identify predictors of success or failure with STI have also been disappointing.6 For example, stable CD4 T-lymphocyte counts on therapy were not predictive of stability with STI in patients who were showing evidence of virologic failure on treatment (median viral load = 3.38 log10 copies/mL; ~2400 copies). In a small, retrospective study of STI in 16 patients, during the first 6 months off therapy the mean CD4+ cell count dropped precipitously at a rate of 46.2 cells/mm3 per month before slowing to a rate of 10.2 cells/mm3 per month.

Based on these results, STI to stimulate the immune system is still not ready for prime time clinically. It is difficult to predict the likely outcome of stopping therapy in any individual patient whose treatment regimen appears to be failing. Clinicians should approach treatment interruptions cautiously after full discussion with the patient and with a clear plan for both monitoring the patient and resuming therapy based on changes in CD4 count, viral load, and clinical symptoms.

Dr. Bill Valenti is the Founding Medical Director of the Community Health Network, a community-based medical clinic for HIV/AIDS in Rochester, NY, where he continues to see patients. He is also Clinical Associate Professor of Medicine at the University of Rochester School of Medicine. He has been involved in AIDS treatment, research, and policy since the early 1980s.

REFERENCES

1. Parish MA, Tarwater P, Raines C, Higgins M, Gallant JE. Treatment discontinuation in patients with marginal indications for HAART. Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, 2001, Chicago. [Abstract I-673]

2. Miro JM, Plana M, Ortiz GM, et al. 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. Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, 2001, Chicago. [Abstract I-1908]

3. Altfeld M, Walker BD. Less is more? STI in acute and chronic HIV-1 infection. Nat Med. 2001;7:881884.

4. Rosenberg ES, Altfeld M, Poon SH, et al. Immune control of HIV-1 after early treatment of acute infection. Nature. 2000;407:523526.

5. Hoffmann C, Mayer W, Wolf E, et al. Enhancement of HIV-specific immune response during structured treatment interruptions (STIs) in chronic infection depends on baseline viral load. Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, 2001, Chicago. [Abstract I-1907]

6. Mussini C, Bugarini R, Perno C, et al. Virological and immunological effects of discontinuation of antiretroviral therapy in HIV-positive patients with virological failure and a CD4 count above 500 cells/mL. Program and abstracts of the 1st IAS Conference on HIV Pathogenesis and Treatment, July 811, 2001, Buenos Aires, Argentina. [Abstract 110]

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