An Update on Structured Treatment Interruptions: Possibilities & Pitfalls
Ever since CRIA Update published its first review of the hope -- and hype -- surrounding structured treatment interruptions (STIs) six months ago, there has been a great demand among readers to remain up-to-date regarding this highly experimental treatment approach. This article discusses the results of studies reported since CRIA Update ran the original article in the Spring 2000 issue.
The list of possible reasons why someone on anti-HIV therapy might want to go on an STI continues to grow:
Immune Restoration: New Data
As mentioned above, STIs to boost HIV-specific T-cell activity hold a great deal of promise. One way to look for HIV-specific activity of the immune system is to see what happens to viral load during an STI. Researchers believe that, if HIV-specific T-cells are present, the rebound in viral load that occurs during the STI should be lower than the viral load seen before therapy was started in the first place. According to a study reported at the 4th International Workshop on HIV Drug Resistance and Treatment Strategies this past summer in Sitges, Spain, this appears to be the case.
In the study, ten HIV-infected patients who had an average pre-therapy viral load of more than 10,000 copies/mL received a four-drug anti-HIV drug combination consisting of indinavir (Crixivan), ritonavir (Norvir), d4T (Zerit), and 3TC (Epivir). Patients who had undetectable viral loads (less than 20 copies/mL) for at least 32 weeks were permitted to undergo a series of three STIs. After the last cycle, in which therapy was stopped indefinitely, half the patients had a virus level that was significantly lower than their pre-therapy viral load. What's more, the low viral loads seen in these patients persisted for more than eight months before having to restart therapy again.
Early results from a second, still-ongoing study -- reported at the 13th International AIDS Conference -- are also intriguing. The study is being conducted in Spain and Switzerland and is the largest STI study currently ongoing anywhere in the world. Patients taking a protease inhibitor-based regimen with a viral load below 50 copies/mL and a CD4+ count above 300 cells/mm3 are undergoing a series of two-week STIs. Each STI is followed by an eight-week course of therapy. After 40 weeks of these cycles (four cycles in total), treatment is discontinued until viral load increases to levels above 5,000 copies/mL, regardless of how long this takes. Approximately 120 patients have already been enrolled in the study.
If HIV-specific T-cells were becoming increasingly more active with each STI, viral load should peak at a lower level during each STI. However, this was not the case in this study. On average, each two-week STI resulted in a viral load increase of 1,000 copies/mL. But something interesting happened as well -- after the first STI, 24% of the patients did not experience any rebound in viral load. After the fourth STI, 14% did not experience any rebound in viral load and an additional 28% are seeing their viral loads creep up at a very slow rate.
A few warning flags have been raised in this study as well. First, some patients have seen their viral loads increase at a rapid rate -- sometimes to levels above 100,000 copies -- during the STIs. Second, more than 7% of patients were unable to bring their viral loads back down to undetectable levels upon restarting therapy after an STI. Both of these findings underscore the potential risks of STIs and need to be studied much more carefully in the months to come.
The Potential of Pulsed Therapy
There was also an interesting report in Durban from Dr. Anthony Fauci's lab at the National Institutes of Health (NIH). In this ongoing study, patients are receiving Crixivan, Norvir, Zerit, and Epivir using one of two highly unorthodox dosing schedules: seven days on therapy followed by seven days off therapy, or two days on therapy followed by five days off therapy. With almost ten weeks of "pulsed" therapy under their belts, most of the patients are doing extraordinarily well. All four of the patients who began the seven days on/seven days off schedule have an undetectable viral load (<500 copies/mL). Of the three patients who began the two days on/five days off dosing regimen, two had undetectable viral loads at the time data were presented by Dr. Fauci's team.
Of course, there's no telling what these results really mean. For starters, the number of patients enrolled in this study is very small. Second, the length of time these patients have been followed is incredibly short. However, these early results are promising and represent a radical departure from the current standard of care. More data from this study -- and other "pulsed" therapy studies in development -- are eagerly awaited.
STIs in Treatment Failure
As discussed at the beginning of this article, using STIs to help "switch" drug-resistant HIV to drug-sensitive "wild-type" virus is of major interest among researchers. Veronica Miller, Ph.D., a researcher in Frankfurt, has found that 26/39 (66%) patients resistant to as many as eight drugs saw their virus switch to wild-type virus during a 12-week STI. Upon restarting therapy, these patients experienced, on average, a 2.6 log reduction in their viral loads. Among the 13 patients who did not see a shift in their drug-resistant virus, the average viral load reduction upon restarting therapy was only 1.02 log. Also of interest was Dr. Miller's finding that patients who switched from drug-resistant to wild-type virus were more likely to see an increase in viral load and decrease in T-cell counts during the STI.
Dr. Miller recently reported follow-up data involving patients who completed the 12-week STI and restarted therapy. Unfortunately, most patients -- regardless of whether or not they experienced a drug-resistant-to-wild-type switch -- saw their viral load rebound within three months of restarting therapy. According to Dr. Miller, there was no "statistically significant" difference between these two groups of patients. In other words, while there was a slower viral load rebound among patients who experienced a switch, this may have been due to chance.
What's more, Dr. Miller has found that some patients who are failing therapy and initiate an STI actually experience rapid disease progression. In a recent study involving 165 multi-drug resistant patients with a history of low T-cells, those who initiated an STI were much more likely to experience a new AIDS-related illness than those who remained on a "failing" regimen. Thus, even though a rebounding viral load indicates that a regimen is no longer doing all that it should, therapy is still offering some benefit.
Like the possible use of STIs to boost the immune system and, perhaps, to reduce side effects and make treatment more economically feasible, knowing how and when to use STIs in patients experiencing treatment failure remains uncertain. More research is definitely needed and, luckily, much research is currently underway.
Tim Horn is the executive editor of The PRN Notebook, published by Physicians' Research Network in New York, and a member of CRIA's Research Advisory Committee.
This article was provided by AIDS Community Research Initiative of America. It is a part of the publication CRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.