The great debate raging within the practice of HIV medicine is over what one should hope to accomplish by interrupting highly active antiretroviral therapy ( HAART ) . The particular goal will shape the duration of an interruption and the measure used to decide when to restart therapy.
Supporters of alternative approaches offered data from very small groups of patients to bolster their positions at the 8th Annual Retroviral Conference in Chicago, Feb. 4-8.
Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases ( NIAID ) at NIH, laid out three reasons why people are considering structured interruptions of therapy in treating HIV.
One is the hope that virus which has mutated resistance to drugs will be less fit when those drugs are removed. Given adequate time, the mutant virus may fade away and the original wild type virus will reestablish itself. Wild type virus would be more vulnerable to the drugs, though it seems likely that given enough time, drug-resistant mutants will reemerge.
The "auto-immunization" approach theorizes that low levels of HIV do not adequately stimulate the immune system to suppress the virus. Removing therapy and allowing the viral load to grow may stimulate an immune response. Then therapy is restarted. Repeating this cycle may result in better control of the virus by T-cells and antibodies and allow for greater periods of time off of all therapy.
Fauci supports a third approach. Given the limitations of current drugs to suppress HIV and the toxicities associated with those drugs, his goal is simply "to get people off therapy for a well-defined period of time." He calls it Structured Interruption of Therapy ( SIT ) and he has tried a couple of variations.
For patients on HAART, the most successful cycle has been one of seven days off therapy and seven days back on. A number of studies have shown that with an undetectable viral load and the exponential growth of the virus, it takes more than a week for it to multiply enough to reach detectable levels.
Fauci says that on the seven-day cycle, "the virus does not rebound, there is no negative impact on the immune system, and we have not seen the emergence of any resistance." He cautions that it is only ten patients and none have been on this cycle for more than 44 weeks. "But it does tell you that it is at least feasible to pursue that."
He says that most patients really want a break from the therapy. "It's a big deal to patients if you don't have to take drugs fifty percent of the time."
Another caveat is that these interruptions have only been tried with drugs that have a short half-life, so as not to promote drug mutation resistance as the blood levels trail off. Fauci's NIH team does not interrupt use of Sustiva ( efavirenz ) , or abacavir, and on regimens that use low dose ritonavir to enhance retention of protease inhibitors, they stop the ritonavir a day before the other drugs.
He says, "the adherence problem is no worse and perhaps better than with people who are on continuous therapy." Fauci expects that there will be a decline in lipid and other metabolic side effects simply because total exposure to drug is less. However, it will take a longer time to see any physical changes in patients, and his current study does not have a large enough number of patients to produce solid answers.
Bruce Walker's group at Massachusetts General Hospital presented data on 14 patients who began therapy during acute infection. That is the very brief window of about 90 days between exposure to HIV and seroconversion, the development of antibodies that show up on the standard elisa screening test for HIV.
They were on HAART for at least a year with undetectable viral load before trying a structured interruption to stimulate an immune response. When they stopped taking their drugs, all of the patients showed a dramatic increase in viral load, most passing 50,000 copies. But once they were exposed to enough virus, the immune system kicked in, lowering and controlling the virus with no help from drugs.
Four patients were able to control the virus at below 400 copies on the first interruption. The other ten patients required another cycle or two on and off therapy and all could control the virus at a viral load of a few thousand copies or less after four cycles. Some of these patients continue to control viral replication after more than a year off of drugs.
Walker performed a number of sophisticated tests and found that "early treatment prevented or impaired viral diversification." The immune system was better able to contain a narrow range of virus. By contrast, patients with chronic infection had a more diverse pool of virus, a more diverse immune response, and were less able to control the infection.
Marty Markowitz, a leading researcher at the Aaron Diamond AIDS Research Center in New York, had much less success with strategic interruptions. Patients who started therapy during chronic infection generally had inconsistent control of the virus when they went off therapy, and repeated cycles on and off drugs did not necessarily generate better immune control of the virus.
However, some patients were able to go off therapy for weeks or months at a time, sometimes with significant control of viral replication. They were able to restart therapy and attain the same level of viral suppression that they had prior to their last interruption.
SHAPING A PARADIGM
No one has yet put together a grand strategy for staging interruptions. Part of the equation must be a patient's CD4 count, as T-cells will start to be destroyed soon after therapy is stopped and the virus rebounds. The higher the count above the warning line of 200 T-cells, the more flexibility a patient has to take a chance and still rebuild whatever T-cells are lost during an interruption.
Five to 15 percent of patients "will control viremia when you stop therapy," without any further cycling of interruptions, says Fauci. They are, generally but perhaps not exclusively, patients who started therapy during acute infection.
So perhaps it makes sense to begin a first interruption under Walker's guidelines of letting HIV rebound to see the viral set point where the immune system controls replication. His criteria for restarting is a single viral load above 50,000 copies, or greater than 5,000 copies for three consecutive weeks, numbers that he admits are arbitrary.
Two or three cycles should give an indication of whether the immune system is learning to better control the viremia it is exposed to. Most patients will learn that they will not be able to go an extended period of time without therapy, but the only way to learn those limits is to try.
Patients who have developed drug-resistant virus might want to try an extended interruption of six months to see if the mutant will revert to an easier to treat wild type variation of HIV. Unfortunately, most patients with resistant virus have had relatively low CD4 counts and cannot afford to spend that much time off therapy without severely depleting their T-cells. Some experienced patients have had success building up those counts with IL-2 therapy and then were able to take an extended interruption.
Finally, it appears that Fauci's seven-day cycle off and on therapy is safe and well tolerated by patients with low or undetectable viral loads. It is unclear whether patients with advanced disease can use this strategy.
TPAN 2001 Drug Guide
The 2001 edition of Positively Aware's Drug Guide, 2001: A Drug Odyssey, is now available at the Test Positive Aware Network office, 1258 W. Belmont, and other locations around Chicago.
This year's drug guide, the fifth published by TPAN, includes information on HIV drugs, opinions from community activists and HIV specialists, an index of 2000 Positively Aware articles and a calendar of TPAN's events and programs.
Positively Aware is published bi-monthly, with a Spanish-language version published quarterly.