NIH 7-Day On-Off Trial May Reduce Drug Side Effects, Cost; Why It's Not Ready for Use.

On December 4 researchers at the U.S. National Institute of Allergy and Infectious Diseases published an early report of their 7-day-on/7-day-off trial of antiretrovirals. (1) This study found that a handful of selected patients, with a selected antiretroviral regimen, were able to use the drugs intermittently, with a schedule of 7 days on and 7 days off. They were able to maintain viral suppression for 32-68 weeks so far, with only half the drug use and clearly reduced side effects. The researchers emphasize that this regimen is not ready for use outside of controlled clinical trials. The reasons are explained in the article, but not in most news reports.

The Purpose of the Trial

The goal of this trial is to see if it is possible to maintain HIV suppression with a reduced amount of antiretroviral drugs, in order to reduce toxicity and cost. There is no effort in this study to improve the treatment by allowing some return of the virus in order to stimulate the body's immune system against it.

Instead, this trial started with the observation that when HIV is very well suppressed by antiretrovirals, and the treatment is interrupted, it usually takes 2-3 weeks for detectable virus to return. Since there is so little HIV replication in that first week (assuming, of course, that the virus had been very well controlled when treatment was stopped), there should be little chance for the virus to develop resistance in that first week off the drugs. Then the treatment would be started again, keeping the virus suppressed. So far it seems to be working in this 10-patient proof-of-concept trial.

Cholesterol decreased 22% in this study, and triglycerides decreased 51%, after 24 weeks of intermittent treatment -- probably because patients had less exposure to the drugs. The researchers do not expect much change in lipodystrophy, however.

Comment: Why It's Not Ready to Use

We are concerned that people may start trying treatment interruptions without medical advice, in cases when it is entirely inappropriate for them. Here are some facts to consider:

* First and most important, all the volunteers in this trial had very well suppressed virus before they began. Viral load had to be below 500 copies for more than six months, and below 50 copies when they started the trial; also, they had to have a CD4 count of greater than 300. If someone tried this intermittent schedule when their virus was not suppressed, the whole idea of this trial would not apply. Instead, the frequent interruptions would cause periods of inadequate drug levels while the virus was replicating -- excellent conditions for the development of viral resistance.

* Also, all the volunteers in this trial received a four-drug regimen "selected to provide potent antiretroviral therapy with a high genetic barrier to the development of drug resistance" -- d4T, 3TC, indinavir, and a small dose of ritonavir (mainly to keep the indinavir in the blood longer). As an extra precaution, the last dose of ritonavir before each treatment interruption was not given, in order to clear the indinavir from the body faster.

* In addition, a research study can test viral load and other blood levels frequently, to detect treatment failure. Once a patient waited only three extra days to resume treatment (10 days instead of 7), and as a result had a viral load of over 3,000 copies. He was able to continue the study and regain viral suppression, but this case illustrates that control of HIV with this treatment schedule may leave little room for error.

* We still need to know whether this schedule works in longer-term use, whether it works in more advanced patients, and whether it can be used with other antiretroviral regimens. But the proof-of-concept trial suggests that when more is known, intermittent treatment might significantly reduce both cost and toxicity of antiretroviral therapy, and help to make it available in developing countries where cost is a major obstacle.

References

(1.) Dybul M, Chun T, Yoder C, and others. 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 USA, Early Edition online (December 4, 2001).