February 1, 2000
Viral load changes were reviewed from over 1,000 patients in ACTG 343, 368, and 359. The study compared outcomes in people who followed a "typical response" pattern after initiating HAART, to outcomes of people who followed a "variant response" pattern. A "typical response" pattern is defined as achieving significant viral suppression after four weeks of therapy, and having an HIV RNA below 200 after 24 weeks. In this group, the initial decrease in HIV RNA is marked by a steep decline in detectable levels of HIV RNA. A "variant response" pattern is characterized by a slower decline of HIV RNA levels, with evidence of some increase in HIV RNA (viral rebound) after four weeks of drug therapy.
For trial participants without prior antiretroviral therapy, the average time it took to get to HIV RNA <200 was four weeks, if the initial HIV RNA was less than 100,000. This same decrease took an average of nine weeks if the initial HIV RNA was greater than 100,000. 74 percent of people without prior therapy followed the "typical response" and had a good result after 24 weeks (ACTG 343). However, for people with prior treatment failure, (in ACTG 368) only 66% followed the "typical response". In ACTG 359, which included the most heavily pre-treated people, only 22% had the typical quick-sustained decrease in HIV RNA.
The most significant implication of this study was that when virologic failure occurred, it did so rapidly, and was not related to the initial HIV RNA in people with prior therapy, nor predicted by how quickly the HIV RNA initially decreased. This means that it will be difficult to identify people when they just begin to fail a regimen in order to consider adding a drug, or intensifying their regimen. Dr. Mellors concluded that, "Most failures are characterized by sharp, unexpected rebounds in HIV RNA after being 'on-track' [following a 'typical response' pattern] for suppression."
An interesting question from the audience was whether or not the level of adherence during initiation of HAART appeared to have an impact on the early virologic response pattern. The answer was that the level of adherence was not a good predictor of response type (i.e., "typical" vs. "variant").
In a more recent group of 161 people treated with protease inhibitor-containing regimens in 1998, the percent of people achieving an HIV RNA of less than 500 was almost twice as high in the group with this genetic variation, 82% versus 48%. The differences could not be accounted for by other factors including level of HIV RNA at start of treatment. While this type of genetic test is not routinely performed, it might, in the future, be another factor to consider, in the difficult question of when to start treatment.
The thymus, a small gland in the chest, which decreases in function with age, is the source of new T cells, those able to respond to new infections, or naive cells. Using some sophisticated markers, it was found that the drug-resistant virus appeared to be unable to cause as much infection in lymphocytes, or T cells, in the thymus, as in the blood. Thus, in spite of high levels of HIV RNA in the blood, evidence of significant production of healthy new T cells was seen from the thymus. This would support the concept that it may be better to stay on a failing regimen, if few treatment options are available, rather that stop all treatment. A clinical trial is needed to prove the clinical benefits of this approach.
Those on protease inhibitor-containing regimen showed a 43% decline in the risk of disease progression. This outcome suggests that people with very low CD4 counts benefit from potent antiviral therapy, even when viral load remains detectable. (These clinical findings support the observations of the above study, slide 453.) It still needs to be determined, from further studies, whether non-protease inhibitor-containing regimens will show similar benefit, and what are the long-term risks of developing resistant strains of HIV to the drugs being used, due to the incomplete suppression of HIV RNA .
This study asked if switching from a combination therapy, including a protease inhibitor, to ABC, 3TC + ZDV, would provide the same level of viral suppression -- without the lipid side affects commonly ascribed to protease inhibitors. One half of the people in the study continued on their current protease inhibitor-containing regimen (79) and one half were randomized to switch to the three NRTI combination (84). There were five people in the continuation group versus nine in the switch group who experienced increases in HIV RNA. (All had HIV RNA <50 at the time of the randomization.) Of concern, is that most of the people who had viral rebound, in the three-NRTI group, developed significant drug-resistant mutations, but 7/9 had good suppression of HIV RNA when their treatment was changed back to a protease inhibitor-containing regimen. There was a significant decrease in cholesterol observed in the group switched to three NRTIs, and a trend towards deceased triglycerides. This study was not designed to study the effect of the switch on lipodystrophy. So, while the majority of people stayed well suppressed, there was a concerning number of people who did not.
The theory is that, due to very good viral suppression in people on HAART, their immune system's response to HIV actually diminishes, because there is not enough HIV virus present to elicit such a response. A structured interruption, or stopping HAART for a brief period of time, and then restarting with the same drug combination, would theoretically allow for a "controlled" increase in HIV and strengthen the immune system's response to HIV. The stopping and restarting of drugs -- repeatedly over time -- might generate a strong enough HIV-specific immune response, to allow for stopping HAART, as a sufficient HIV-specific immune response might be able control viral replication without antiviral drug therapy.
All people in this trial had HIV RNA levels below 50, and CD4 counts above 300. The trial was designed to stop HAART for two weeks, then restart HAART for eight weeks, and repeat this cycle four times, in 120 people. Very preliminary data was presented on the first 99 people, after the first cycle only. No real conclusions can be drawn from the information presented as to the possible outcome of this study, nor the long-term efficacy of structured interruptions. One reassuring aspect, though, is that, to date, most patients in the study appear to be able to regain viral suppression to undetectable levels using the same drug combinations they were on before the structured interruption. This infers that drug resistant strains of the virus are not being created during the structured interruption.
However, some people rebounded to over 1,000,000 copies of HIV RNA in two weeks, and the researchers did not tell us what happened to T cell counts during the two-week stop period. Others researchers have observed very significant decreases in CD4 counts, even during short periods of treatment interruption. In addition, while some improvements were noted in a few measures of immune response to HIV, others were not.
| Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here. |