October 26, 2002
Over the past two years, there has been increased interest in stopping antiretroviral therapy to potentially avoid toxic side effects from the medications or to improve immune responses to HIV itself. Various strategies include drug holidays, structured treatment interruptions and pulse therapy.
Drug holidays are when patients need a single break either for a definite or indefinite time period for any number of reasons. Sometimes, these may be for convenience, such as during a vacation or for a planned surgery or when someone simply needs a break for mental or physical health. Some providers have recommended a "holiday" in the setting of multi-drug resistance in the hope that the wild-type virus would re-appear and reinitiating therapy would help suppress the virus.
A structured treatment interruption is a set time on and off antiretroviral therapy -- for example seven days off/on or two months on/one month off, etc. The hope is that this interruption may help stimulate a patient's immune response, particularly HIV-1 specific immunity and, over time, result in suppressed plasma HIV viral loads while the patient is off antiretroviral therapy.
Pulse therapy is when a patient takes antiretroviral therapy based upon their CD4 T-cell count, such as staying on therapy until your CD4 T-cell count is greater than 500 cells/µl and then stopping antiretroviral therapy. When the CD4 T-cell count declines to around 300-350 cells/µl the individual restarts antiretroviral therapy. Some individuals may be able to stay off antiretroviral therapy for a long time and potentially avoid metabolic complications or reverse any toxicities they may have already experienced. All of the strategies I just mentioned are still investigational.
Dr. Woodward and colleagues presented a poster (abstract 456) entitled "Supervised Treatment Interruption (STI) in an Urban Clinical Practice: A Prospective Analysis." Unlike most structured treatment interruptions, they did not have a planned schedule for the interruption. They really followed a pulse regimen, re-initiating antiretroviral therapy based upon the person's CD4 T-cell response or plasma HIV viral load (VL) response. Dr. Woodward and colleagues are attempting to address an extremely important question -- can patients who began antiretroviral therapy based upon previous treatment guidelines to begin treatment with a CD4 T-cell count less than 500 cells/µl stop therapy and then resume again once their CD4 T-cell count reaches around 350 cells/µl (i.e., the current recommendations for when to start therapy)?
The researchers enrolled ten patients who either previously had a good response to treatment interruption in the past or who met their inclusion criteria. They defined a previous good response as an individual who had greater than 1 log viral load decrease in rebound viremia during a treatment interruption as compared to that person's previously known baseline viral load prior to therapy. Inclusion criteria included a viral load less than 400 copies/ml, "good adherence" and "robust" CD4 T-cell response. The structured treatment interruptions were planned and supervised by the healthcare provider. All structured treatment interruptions were greater than seven days. Charts were abstracted for baseline demographics, antiretroviral therapy regimens, treatment duration, viral load, CD4 T-cell counts, structured treatment interruption duration and any illness during the structured treatment interruption.
The mean age of the ten patients was 36 years with 50 percent female, 30 percent Hispanic, 30 percent black, 30 percent white and 10 percent Asian. Mean baseline CD4 T-cell count was 450 cells/µl and viral load was 106,991 copies/ml. Of the seven out of ten patients with data at four weeks off antiretroviral therapy, the mean viral load was 1.38 log below their baseline. Seven out of the ten patients maintained a viral load less than 5,000 copies/ml for more than eight weeks off antiretroviral therapy (mean 27 weeks with one patient being off for more than two years). Four patients out of seven with data during more than one structured treatment interruption showed an increase in time to reach 5,000 copies/ml. None of the patients developed resistance mutations during interruption.
This study is obviously limited by the small sample size. The individual responses on such a small number are essentially meaningless especially without immunologic assays evaluating HIV-1 specific responses. Also, although their providers followed the patients "prospectively," the patients were not enrolled in a clinical trial with pre-determined clinic visits. Hence, not all of the subjects had laboratory values at four weeks, etc. It is unclear to me whether the patients' visits and labs were recorded prospectively or were collected retrospectively afterwards.
As the authors noted, they chose a biased population with six of the ten previously stopping antiretroviral therapy without adverse consequences. They also did not have pre-determined target values for CD4 T-cell counts or viral load in order to discontinue or begin antiretroviral therapy which makes it difficult to make any interpretation of when "structured treatment interruption" could be offered to a patient.
They were able to report that the patients did well overall, with patients being able to stay off antiretroviral therapy for a median of 11 weeks (range 4-107 weeks) and without any patient developing resistant mutations that could limit future options. Other advantages to the patients included being off therapy with reduced pill burden and potential side effects from the medications. The benefit of this and other similar small studies is that it supports the need for a larger randomized clinical trial with definitive cut-offs for CD4 T-cell counts and HIV viral loads to be conducted before this becomes standard practice.