One of the largest HIV-AIDS treatment trials conducted, has yielded results that cast significant doubt on new experimental strategies to control the progression of the virus through interrupted phases of antiretroviral therapy.
Spearheaded by the National Institutes of Health and funded by the National Institute for Allergy and Infectious Diseases, the initiative brought together 318 clinics and their patients, across 33 countries, and is referred to as Strategies for Management of Anti-Retroviral Therapies (SMART).
Initiated in January 2002, the trial investigated the effects of discontinuing and resuming AIDS therapy based on the levels of CD4+ or T-cells, the white blood cells responsible for fighting infection, that are the primary targets of the HIV strain. Over 5,472 people living with chronic HIV infection volunteered for the programme, and were randomly assigned to one of two groups – Drug Conservation (Interrupted Therapy) and Viral Suppression (Continuous Therapy); on an average, each was observed for up to 16 months.
The independent data and safety monitoring board pulled the plug on the project early this year, when data and research collected from the study, showed increased occurrences of AIDS related events in the Drug Conservation group. Almost 120 volunteers in the Drug Conservation group developed disease progression, as opposed to just 47 in the group that continued treatment. The figures represent a disturbing equation – individuals employing 'stop and start' antiretroviral therapies now appear to be 2.6 times more susceptible to the onset of AIDS or death due to AIDS related illnesses, than their treated counterparts.
Patients in the Viral Suppression group were administered with regular antiretroviral treatment to curb the spread of the virus, while those in the Drug Conservation group received sporadic antiretroviral therapy in an attempt to reduce the extent of the side effects felt, and economise on medication costs. Therapy for the latter, resumed every time tests showed that the CD4+ cell count had fallen below 250 per cubic millimetre of blood, and was suspended when CD4+ levels were above 350 per cubic millimetre. Patients with CD4+ / T-cell counts of 400 or more have immune systems better equipped to fight illness. Incidentally, counts of 800 or more are considered normal for most people.
The study's findings have been published in the November 30 issue of the New England Journal of Medicine; the study also reveals a greater propensity, almost 70% more, towards heart, liver or kidney complications for AIDS patients employing interrupted antiretroviral therapy. Such major events have so far been connected to the side effects of continuous antiretroviral treatment – this discovery is particularly devastating to proponents of the belief that these complications would be seen less frequently, with reduced drug usage.
Interestingly, while 30 volunteers under the group that continued antiretroviral therapy and 55 under the interrupted antiretroviral regimen died, a mere 8 percent of all deaths were the result of illnesses or conditions related to AIDS. Cancer, heart diseases and substance abuse were the foremost causes of death.
Director of the NIAID, Dr. Anthony Fauci, believes that this is the end of the road for interrupted antiretroviral treatment strategies. Not surprisingly, a number of scholars hold that the situation does not merit generalisations; after all, considering the statistics at hand, the number of deaths has been rather low.
Long term survivor and AIDS activist, San Franciscan, Hank Wilson, insists that it is much too early to call the approach a failure. Wilson's own T-cell count has risen from a low of 26 to over 800 with the help of his own interrupted antiretroviral plan. He feels that the data presented needs to be better analysed, factoring in other influences such as the use of cocaine that has been proved to accelerate the proliferation of HIV. It would explain, in some cases, the sudden spurt in HIV activity in the bloodstream after stopping treatment.
In an accompanying article Dr. Judith Currier and Dr. Lindsey Baden of UCLA, note that the results of the SMART trial may have been 'definitive', but continue to maintain that interrupted treatment plans may prove appropriate in situations where HIV infections are detected early on and treated effectively, or during pregnancy for women with high T-cell counts.
Four international centers coordinated the SMART initiative - the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) in Washington, DC; the Medical Research Council Clinical Trials Unit in London; the National Centre in HIV Epidemiology and Clinical Research at the University of New South Wales in Sydney, Australia and the Copenhagen HIV Program in Denmark. The University of Minnesota, Minneapolis, housed the center for managing the data and statistical information on the project.
