Structured Treatment Interruption: Important Controlled Trial in Monkeys.

The first randomized, controlled study of structured treatment interruption (STI) found that monkeys on a three week on, three week off treatment schedule controlled the virus about as well as those which were on continuous therapy (and therefore received twice as much of the drugs). Also, those in the intermittent-treatment group became able to control virus without treatment for a six-month followup period when the drugs were stopped permanently (after 21 weeks treatment in this study), while those on continuous therapy usually could not. [1]

These results are not automatically applicable to patients, for several reasons:

* This treatment was in macaque monkeys infected with simian immunodeficiency virus (SIV), and treated with an antiretroviral combination which includes an experimental drug (PMPA) currently in human use only in clinical trials, and

* This study began treatment early in infection (six weeks after exposure), shortly after seroconversion had occurred. Most patients are not diagnosed until much later, and it is not known if this strategy would have worked in the animals if treatment had been started late.

On the other hand, the animal test allowed genetically similar individuals to all be infected with the same virus at the same time-making it much easier to see differences in treatment strategy that otherwise would have been hidden by large, unknown variations in disease course caused by these variables.

The researchers also used a new test for HIV-specific immune function--counting the proportion of virus-specific CD8 cells by using flow cytometry to measure which of the cells produce gamma interferon in response to killed virus. This test (called VIR, for virus-specific immune responses) did distinguish the animals that could control the virus from those that could not, while the more common test for HIV-specific immunity (virus-specific CD4 stimulation index) did not distinguish between the groups in this study. (In addition, the new test would appear to be relatively easy to develop for clinical practice, while the stimulation-index test of immune function requires highly trained laboratory staff and would be difficult to make generally available.)

In this controlled trial three groups of animals were compared: five which received no treatment, six which received continuous antiretroviral treatment for 21 weeks, and six which received four cycles of treatment for three weeks, separated by three-week periods without the drugs. The antiretroviral combination used was PMPA, ddI, and hydroxyurea.

This study was done primarily by the RIGHT Institute (Research Institute for Genetic and Human Therapy) in Washington D.C. Franco Lori, M.D., and Julianna Lisziewicz, Ph.D., are the principal authors.

Comment

Human studies of intermittent antiretroviral treatment are happening now. If this approach proves successful in certain identifiable patients, it could at least reduce the cost and toxicity of antiretroviral therapy--and be a significant step toward treatment strategies to assist the immune system to control the virus instead of relying entirely on antiretroviral drugs.

One hopeful sign was a late-breaker report at the Durban AIDS conference by Shoshank R. Joshi, M.D., D.M, Retroviral Physician at MGM hospital in Mumbai, India. [2] Twenty six of his patients took antiretroviral combination therapy (AZT or d4T, plus 3TC, plus saquinavir) on alternate months, because they could not afford continuous treatment. All of these patients had been recently diagnosed, were asymptomatic, and had a CD4 count of over 300 but a viral load over 20,000 when they started the intermittent therapy. At the end of a year, all of them had undetectable viral loads, and had remained asymptomatic and without side effects from the treatment.

References

(1.) Lori F, Lewis MG, Xu J, and others. Control of SIV rebound through structured treatment interruption during early infection. Science. November 24, 2000; volume 290, pages 1591-1593.

(2.) Joshi S, Joshi SS, Vergara PT, and others. Structured interrupted therapy (SIT): Mumbai cohort. XIII International AIDS Conference, Durban, South Africa, July 9-14, 2000 [abstract LbOr10].