Viral load rebounded to detectable levels within two weeks in every patient participating in a small structured treatment interruption study, published in the 24th January 2003 edition of the journal AIDS.
This study contradicts the findings of an earlier small study, conducted by Dybul and reported in Proceedings of the National Academy of Sciences in 2001. It also further discredits the theory that structured treatment interruptions, or ‘pulsing’ HAART, in chronically infected HIV-positive patients primes the immune system to control HIV without the help of antiretroviral drugs.
Fourteen patients were enrolled to the Swiss-Spanish Intermittent Treatment Trial (SSITT), which involved five cycles of treatment interruptions followed by HAART.
All the patients participating in the trial had been treated with HAART for at least six months. The trial was only open to patients who had a viral load below 50 copies/mL, and patients enrolling to the trial had achieved this for between eleven and 32 months. In addition, patients were required to have a CD4 count above 300 cells/mm3. At baseline participants’ counts ranged between 347-1,269 cells/mm3.
Patients had been treated with a variety of HAART regimens. Seven were taking AZT, 3TC and indinavir; one person was taking AZT, 3TC and nelfinavir; one AZT, 3TC and ritonavir; two people were taking d4T, 3TC and nelfinavir; two patients were taking d4T, ddI and nelfinavir; and, one was prescribed AZT, ddI and nelfinavir.
Study participants underwent four cycles involving a two week treatment break followed by eight weeks of HAART with the identical therapy used before the interruption. The fifth treatment break was longer.
Viral load was measured on the last day on HAART before the treatment break (day zero) and then at days four, eight, twelve and fourteen (the last day of the interruption), during all five treatment breaks. Only people who had an undetectable viral load on day zero were allowed to take a treatment interruption.
During the first treatment interruption, viral load had risen to above 50 copies/mL in five patients by day four; in a total of eight patients by day eight; and, in fourteen people by day fourteen. When the results for all five treatment interruptions were combined, it was found that by day four, nine patients had a viral load above 50 copies/mL; eleven patients by day eight; and, fourteen patients by day twelve. The investigators commented that "the increase in mean viral load at days 8 and 14 compared with that at cycle baseline was highly significant."
Seven patients were prevented from participating in one or more treatment interruptions because they had a detectable viral load on day zero.
The investigators noted that "viral rebound can occur within eight days of STI in a substantial proportion of patients (11 of 14 in our study)." And in a comment which challenged the finding of Dybul’s group, that resistance did not emerge during one week on one week off cycles, they added, "our observations raise concerns that the risk of drug resistance selection during extended periods of cycling may be significantly higher than previously reported."
Seeking to explain the differences observed in this study to that conducted by Dybul, the SSITT investigators speculate that the high rate of rapid rebound noted in their small study was probably related to the potency of the HAART regimens used by their patients. They suggest that the use of an immune modulator such as IL-2 may help patients maintain an undetectable viral load for longer during treatment breaks, as observed in earlier studies.
The study concludes, "our findings clearly demonstrate that significant viral replication can be induced during 1 week structured treatment interruptions, which may increase the risk of the development of drug resistance during long-term cycling…this therapy option still bears considerable risks and should not be considered as a general treatment option at the present time."
Studies to investigate if the use of treatment interruptions are an effective way of priming the immune system to control HIV replication when used in primary HIV infection are underway. Click here for details.
Further information on this website
Fischer M et al. HIV RNA in plasma rebounds within days during structured treatment interruptions. AIDS 17:195 – 199, 2003.
Dybul M et al. Short-cycle structured intermittent treatment of chronic HIV infection with highly active antiretroviral therapy: effects on virologic, immunologic, and toxicity parameters. Proceedings of the National Academy of Sciences, 98 (26): 15161 - 15166, 2001.