Dealing with chronic health conditions is never an easy task both for patients and their doctors. Complex treatment regimens, large numbers of pills, side effects and drug interactions are just some of the challenges faced by people taking medications for these conditions. In high-income countries, many people with HIV/AIDS (PHAs) who have received highly active antiretroviral therapy (HAART) face these issues on a daily basis. Not surprisingly, some of these PHAs tire of taking HAART day after day, for many years. As a result, there is much interest in the idea of possibly taking a break from treatment regimens. Such breaks are commonly referred to as "drug holidays" or structured treatment interruptions (STIs).
Most of the studies on drug holidays have been small, not well designed and sometimes short. Despite these shortcomings, some useful information has been collected. Larger and longer trials are either planned or underway, but their results will not be available for another two to three years. Until then, it's clear that drug holidays are not the best way to manage HIV/AIDS. This is because CD4+ counts decrease (sometimes rapidly) and the amount of HIV (viral load) that is produced increases. There may also be less obvious damage to the immune system that resumes when therapy is stopped. Together, these changes increase the risk of developing life-threatening infections. Ironically, in seeking to get away from the demands and stresses of treatment regimens, PHAs on drug holidays require more frequent visits to the clinic to have blood taken for CD4+ and viral load monitoring.
Another issue raised by drug holidays is that of HIV developing resistance against therapy. This issue arises because not all drugs leave the body at the same time. Some drugs, such as efavirenz (Sustiva) and nevirapine (Viramune), remain in circulation at lower levels for a few days than other drugs such as, say, AZT. Some doctors are concerned that during the time of low efavirenz or nevirapine levels it may be easier for HIV to build up resistance to these drugs. Resistance to one member of this class of drugs, called NNRTIs (non-nucleoside reverse transcriptase inhibitors), usually means that a person also is resistant to the other NNRTIs.
If any good immulogic news for drug holidays exists, it has come from people in the very early stages of HIV infection. In these cases, people have received treatment to suppress HIV levels, and then, once suppressed for several months, they take a supervised drug holiday. Overall, results from a small number of subjects suggest a theoretical benefit — possibly better control of HIV by the immune system. However, there is no proof that this strategy delays the decline of the immune system or prolongs survival. Finally, application of this type of intervention is not usually practical because the average person doesn't know exactly when they were exposed to HIV.
Perhaps the people most interested in a drug holiday are those PHAs who have been HIV positive for many years and have been taking HAART for a long time. Unfortunately, the immunologic results of drug holidays in these people are not impressive. All in all, while on a drug holiday, it is clear that their immune systems have not learned how to control HIV. Indeed, results from the largest trial to date (the SSITT study), with more than 100 subjects, have shown no overall benefit. Interestingly, test-tube studies found that the ability of subjects' immune systems to attack HIV increased during the study. However, this improvement did not result in significantly lowered viral loads while off therapy.
In PHAs who have been exposed to several treatment regimens, HIV usually develops resistance to therapy. In these people, despite changing therapies, viral load continues to rise while CD4+ counts fall. Doctors sometimes interrupt therapy for a few months, usually between different regimens. This is done to reduce the pressure on HIV to mutate and decrease its level of resistance. During the break, HIV that is drug resistant tends to be harder to find in blood samples. Once therapy resumes, drug-resistant virus eventually re-emerges.
As many questions about interrupting or stopping HAART remain unanswered, researchers around the world are planning or starting large studies to compare the effect of different drug holiday strategies. Some trials call for fixed periods of on/off therapy (for example, one week on/one week off), while others are more flexible and resuming therapy often depends on CD4+ and viral load levels. Below are short summaries of some of these studies.
REFERENCES
1. Allen TM, Kellehr AD, Zaunders J, et al. STI and beyond: the prospects of boosting anti-HIV immune responses. Trends Immunol 2002 Sep;23(9):456-460.
2. Kane B. Chronic HIV infection: Can anyone afford a drug holiday? Ann Intern Med 2002 Aug 20;137(4):301-4.
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