Whatever Happened to Structured Treatment Interruptions?
It seems like only yesterday that newsletters and web sites were filled to the brim with research reports about structured treatment interruptions (STIs). These reports on "drug holidays," once full of hope and zeal, now appear scattered and rather lackluster -- a possible indication that STIs are a trend of the past, a highminded theory that failed to pan out in clinical trials.
Fortunately, this isn't the case. STIs, with their potential to boost the immune response to HIV, are still being examined in clinical trials, although fewer studies are now being conducted. The reason for this is simple -- we now have a better sense of which HIV-positive people are most likely to benefit from STIs, along with those who are least likely to benefit. This understanding has led to a more concentrated effort to make sense of these risky treatment options.
STIs in Acute Infection
The potential for STIs during acute HIV infection cannot be overstated in light of legitimate concerns regarding long-term use of antiviral therapies, including toxicities and the possibility of developing drug resistance -- all before treatment is actually needed for the sake of health and survival. Acute infection is loosely defined as the days and weeks that immediately follow HIV's entry into the body. Although studies of STIs in chronic infection show less favorable results, research involving acute infection should continue given recent successes, most notably in a handful of patients receiving care at Massachusetts General Hospital (MGH) in Boston.
Past work at MGH, under the direction of Drs. Bruce Walker and Eric Rosenberg, has shown optimistic results and has led the field in the study of STIs in primary infection. The determination that STIs would work better in acute infection was borne out in early studies looking at HIV-specific cytotoxic lymphocyte (CTL) responses in long-term non-progressors (LTNPs) -- the small percentage of HIV-positive people who live for many years with low viral loads and high CD4 cell counts without the assistance of drug therapy -- compared to chronically infected people who see their viral loads increase and their CD4 cell counts decrease in the absence of therapy. In LTNPs, CTL responses are maintained long after HIV infection is established. Conversely, in chronically infected individuals, the CTL response dwindles shortly after infection is established. Protecting these CTL responses, Drs. Walker and Rosenberg argue, is the key to keeping viral load low and CD4 cells high, perhaps indefinitely, without the need for long-term treatment -- a highly desirable scenario.
The theory behind STIs is to stop treatment at a stage when the CTLs are still in place doing their job. Then, with further interruptions, an auto-immunization may occur with stimulation of the CTLs along with periods of therapy to help keep virus at extremely low levels, hopefully for good. And each time the interruptions occur, the viral load hopefully will become lower for longer periods of time.
The latest information comes from a study by Walker's team looking at 14 people who were HIV antibody-negative but had high HIV viral loads. In other words, HIV was reproducing rapidly in their bodies, but they hadn't yet developed HIV antibodies. All of the participants began treatment prior to, or at the time of, HIV seroconversion and had been on triple-drug therapy for at least eight months before their first STI. The plan was to restart treatment if their viral load exceeded 5,000 copies for three consecutive weeks or if viral load exceeded 50,000 copies at any one time.
During the first 17 days of the first treatment interruption, all participants had increased virus levels, but four people soon saw their levels fall below 5,000 copies. All four have remained off therapy, two of them for two years with viral loads staying below 500. The MGH team noted in a conversation with ACRIA Update that, compared to the first STI, the majority of participants experienced a much slower rebound in viral load during the second STI that would require them to restart therapy. Seven of the fourteen patients have maintained virologic control off therapy following one, two or three STIs. None of the participants who had to restart treatment has had any trouble reducing their viral loads to undetectable levels after any of the interruptions. Although this study is certainly small, it showed that STIs were effective in 50% of the participants -- impressive results in an elegant study that shows promise for auto-immunization.
STIs in Chronic Infection
Is there a chance that chronically infected people -- defined as anybody who has been living with HIV for longer than six months and/or has HIV antibodies detectable in his or her bloodstream -- have a chance at auto-immunization? Unfortunately, the results from small studies in the past have been all over the map in terms of showing the effectiveness of STIs in this population. Remember, HIV-specific CD4 cells are typically destroyed by HIV soon after infection is established. There aren't many of these cells left to protect if therapy isn't started immediately. Still, some researchers believe that STIs can "draw out" those HIV-specific CD4 cells that do remain and, consequently, make them work effectively.
Unfortunately, the largest STI study to date has shown disappointing results in the chronically infected. The Swiss-Spanish Intermittent Treatment Trial (SSITT) now has one year data on 133 patients. These data show that STI may not be a useful strategy for auto-immunization, at least at this stage of infection. Participants in the trial were a relatively healthy bunch to begin with. Before starting antiretroviral therapy, the average viral load was just over 31,000 and the average CD4 count was 388. Participants had been taking HAART for an average of 26 months before their first STI and had undetectable viral loads for approximately 21 of those months. The average CD4 cell count before stopping therapy was 740.
All of the participants completed four STI cycles of eight weeks on treatment, followed by two weeks off. After 40 weeks, treatment would be stopped through week 52, at which time it would be determined how many patients had viral loads below 5,000 copies and, as a result, be able to delay going back on treatment.
The relative viral load rebounds seen during each of the four interruptions were not statistically significant, although higher viral loads were seen to decrease with each successive STI. If virus levels did not go to undetectable within nine weeks of reinitiating therapy following an interruption, participants were removed from the study. Ten were removed after the first interruption, nine after the second, five after the third, and six after the fourth.
Of the 99 participants who had completed all four interruptions as of February 2001, 21 were responders, maintaining viral loads below 5,000 copies. However, five of those responders had viral loads below 5,000 copies before beginning therapy in the first place. So if you subtract those five from the 21 responders, you get an unimpressive 17% overall favorable response. Participants, both responders and non-responders, lost an average of 150 CD4 cells throughout the trial -- not a good thing! These data basically show the failure of STIs in chronically infected individuals. A bit of good news, though: only one participant showed evidence of mutations that would translate into drug resistance as a result of the STI strategy.
The SSITT study showed that people with low viral loads before starting HAART were more likely to respond to the STI strategy. Whether they may have maintained low viral loads without STIs -- or even without treatment -- is impossible to tell. More STI studies in chronic infection -- perhaps with immune modulators such as IL-2 or a therapeutic vaccine -- might provide better results. The SSITT study may also help show that STIs could be useful as a simplification strategy by limiting the amount of time on drugs. If virus levels can be maintained using an intermittent strategy -- continuing interruptions for an undetermined time -- some of the toxicities associated with antiviral therapy might be prevented or delayed. And the exorbitant cost of therapy could be dramatically lowered.
Researchers stress that STIs in acute and chronic populations are not ready for prime time and should only be used in clinical trial settings. As a treatment strategy, STIs continue to have potential, particularly in acute infection, but they also carry considerable risk. The STI story is far from over.
Matt Sharp has been living with AIDS for ten years. Now living in Chicago, he is an AIDS treatment activist with Survive AIDS (formerly ACT UP Golden Gate) and the Coalition for Salvage Therapy.
This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.