Interest in structured treatment interruptions (STIs) (sometimes mistakenly called drug holidays) continues to increase. Though research in this area is relatively new and so far inconclusive, many people are already taking unplanned or unstructured treatment interruptions due to problems with drug side effects, treatment failure and adherence problems.
During unstructured interruptions, people are not closely monitored for viral load and CD4+ cell counts. The interruption follows no particular plan. However, people taking STIs are usually tested very frequently for viral load, CD4+ cell count and sometimes resistance. This way, when they're ready to restart therapy, the decision can be made based on data and the achievement of goals while minimizing the risks.
Early results have recently been reported from several STI studies, but it's still too early to know how safe or effective an STI treatment strategy may be. STIs are now being studied in three different scenarios:
Primary or chronic/established HIV infection in people with well-controlled viral replication.
AdvertisementThe goal in either group is to improve the natural immune response against HIV, hopefully making it possible to control viral replication with less aggressive treatment. In primary infection (someone infected very recently, from a few days to a few months), the body usually mounts a vigorous immune response against HIV. Over time, though, this response often fades. In chronic/established HIV infection (someone living with HIV for at least a year), this natural immune response is often very weak or missing altogether. In both cases, the decline is thought to be associated with the success of anti-HIV therapies, which dramatically reduces the amount of new virus being produced. Because of this lowered viral activity, the immune system sees less and less of the virus and thus does less to mount a defense against it. By periodically permitting HIV to replicate, an STI permits the immune system to once again "see" and react against the virus, perhaps resulting in a strong natural anti-HIV response.
Chronic/established HIV infection in people who have developed resistance to all or most of the available antiviral drugs.
The potential goal of STI here is to replace drug-resistant virus with non-resistant virus, called "wild type." This might restore a person's sensitivity to drugs that had previously become ineffective due to resistance and allow the drugs to work again, at least temporarily.
Chronic/established HIV infection in people who have become physically or psychologically intolerant to currently available anti-HIV drugs.
The goal of STI in this context is give the person -- mind, body and spirit -- a chance to rest and recover from the stress of anti-HIV therapy. Some people develop bothersome side effects to anti-HIV drugs, either quickly or after years of use. Side effects such as liver and kidney problems can become serious, even life-threatening, and limit a person's ability to use the drugs. Other effects, such as lipodystrophy, may have unknown long-term consequences in addition to their visible impact. Many also develop psychological obstacles. Over time, it gets more difficult to adhere to the regimen. Whether the cause is physical or psychological, intolerance of the drugs will cripple their ability to aid in the fight against HIV. While these factors may affect only a portion of people on treatment at any moment, over time they are likely to effect everyone who hopes to live out a normal life span with HIV.
STIs in Scenario #1
A Boston study followed 15 people with primary infection treated with HAART for over a year. Seven took an STI and their viral loads and CD4+ cell counts were measured weekly. Their immune response to HIV, or HIV-specific cytotoxic lymphocyte (CTL), was also measured. HIV-specific CTLs are cells that target and destroy HIV-infected cells.
At the start of their STIs, the seven participants had low-level CTL responses and undetectable viral loads. During the STIs, all saw their HIV levels increase, as expected, so they restarted HAART. Everyone also experienced increases in HIV-specific CTL responses after the STI.
Three of the seven went on to a second and third cycle of STI, and with each cycle they had higher HIV-specific CTL responses. After each STI, the returning levels of viral load were lower than in the previous STI and it often took longer for viral load to reappear. This suggests that the improved HIV-specific CTLs were at least partly effective in controlling HIV replication.
Chronic Infection: A Barcelona study followed 26 people with HIV levels below 50 copies for over two years. Fourteen continued on HAART while the other twelve took an STI. Among the twelve, five had two courses of interleukin-2 (IL-2, Proleukin) while on HAART; the other seven took their same HAART regimen as before their STIs. Those on STIs were closely checked for viral load (every two days to determine the rate of increase in HIV levels).
This study was designed for people to restart HAART either after 30 days of interruption or when their viral loads went above 3,000 copies HIV RNA. They then took their HAART regimens for three more months before taking another STI.
During the first STI, two had no detectable HIV levels during the 30-day period. However, on the second STI, only one person continued to have undetectable (below 50 copies HIV RNA) HIV levels during the 30 days off therapy. In most, HIV levels increased after 14 or 15 days off therapy during the first and second STI. The percentage of CD4+ and CD8+ cells did not change during the STIs. There was no difference between people who used IL-2 and those who did not.
Early results found little or no improvement in the immune response to HIV and all participants experienced significant increases in HIV levels during STIs. However, it is possible that more cycles of STIs are needed before the immune system can mount a stronger response against HIV.
The largest study to date involving STI is the Swiss-Spanish Intermittent Treatment Trial, currently enrolling 120 people with CD4+ cell counts above 300 with viral loads under 50 copies HIV RNA for at least six months. The study design involves alternating between two weeks off HAART and eight weeks on, for a total of four cycles. After 40 weeks, anti-HIV therapy will be stopped indefinitely until a person's viral load increases to 5,000 copies HIV RNA, when therapy is then restarted.
Early results from this study involve 96 people who had one STI, 54 people a second and 23 a third STI. All had viral load increases during the STI. So far, there's no indication that the viral load set point is lower or that there are any significant changes in CD4+ cell counts with each STI.
All of these studies have found that when people restart HAART, viral loads decrease and, in almost all cases, go back to under 50 copies HIV RNA. This suggests that participants are not developing anti-HIV drug resistance. However, people should be cautious with efavirenz (Sustiva) and nevirapine (Viramune) when undertaking an STI since these drugs remain in the bloodstream far longer than other anti-HIV drugs. Researchers recommend that they be stopped two to three days before stopping other drugs when initiating an STI.
STIs in Scenario #2
A Frankfurt study of people who had developed resistance to most or all currently approved anti-HIV drugs reported that three-quarters of them shifted from multi-drug resistant virus to wild type virus during the STI. Groups in London and San Francisco have duplicated this observation.
The San Francisco study followed 18 people who had developed resistance to protease inhibitors and nucleoside analogue drugs. During the STI, all experienced decreases in CD4+ cell counts (an average of about 100 cells) and increases in HIV levels (about a ten-fold increase). Sixteen of the eighteen shifted from protease inhibitor-resistant virus to protease inhibitor-sensitive virus during the STI, although seven retained some degree of resistance to the nucleoside analogue drugs.
However, when using extremely sensitive techniques, researchers found that about half the participants had very low levels of drug-resistant HIV. In others words, they did not find protease inhibitor-resistant virus in blood when using standard tests but did find it when using extremely sensitive tests. Since no participant had restarted therapy when these results were presented, the significance of these findings is unknown.
STIs in Scenario #3
Little research has yet been conducted on the use of STIs for combatting physical or psychological intolerance of drug regimens. However, this scenario probably reflects the most common form of "unstructured" interruption in which people simply stop treatment to recover from side effects and give themselves a rest. There is some work underway to create observational databases of the experiences of such people.
These early studies primarily looked at the potential risks rather than the benefits of STIs. They suggest that, at least in the short-term, there's a low risk for developing drug-resistant HIV. However, decreases in CD4+ cell counts to pre-treatment levels and increases in HIV levels in some people suggest the need for frequent and careful monitoring, particularly if the resulting CD4+ count falls into the ranges with increased risk of opportunistic infections (under 200 for some OIs, under 100 for others). When this occurs, people should resort to earlier strategies of treatment, such as Bactrim for preventing pneumocystis pneumonia.
Numerous STI studies are planned for the near future. They will explore different lengths of STIs and different lengths of time on therapy as well as possibly using therapies, like IL-2 and therapeutic vaccines, that affect the immune system.
More results will be available soon that will help determine the role of this strategy in treating people with HIV. Project Inform, the Foundation for AIDS and Immune Research (FAIR) and the Treatment Action Group (TAG) will convene a second workshop on STIs in the fall of 2000. At this meeting, new results, ideas and observations will be discussed and incorporated into future studies.
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