Research Initiative Treatment Action (RITA!); Vol 5, No. 5 December 1999
Paul Simmons, RN, ACRN
In 1996, virologist David Ho made a stunning announcement. At the World AIDS Conference in Vancouver, he asserted that antiretroviral therapy might cure HIV infection. American physicians were already prone to treating HIV more aggressively than their European counterparts. Now, inspired by the possibility of a cure, they intensified the effort, starting patients on multi-drug regimens as soon as the infection was diagnosed. Researchers call this practice of early, aggressive treatment, "hit hard, hit early." But as dawn rises on a new millennium, the light reveals it as a failing paradigm.
No data exist to show that individuals with early stage HIV infection will benefit clinically in the long-term by starting antiviral therapy now. In the absence of data, "hit hard, hit early" relies upon four assumptions for the strength of its recommendation. Specifically, it assumes the following:
It is clear from these assumptions that the paradigm of early treatment is neither irrational nor corrupt. But the assumptions are troubled. Some were fragile from the start. Others have emerged as false.
To cure HIV, highly active antiretroviral therapy (HAART) would have to penetrate all compartments of infection and stop all viral replication. Investigation has proven that it does neither.
Three reports, all published in 1997, demonstrate conclusively that HAART fails to clear all virus from the body, even when therapy is started soon after infection.1 These reports also found evidence that viral replication persists in the presence of drug. If the next century brings a cure for HIV (see "A vision of the normal: Will the new millennium bring a cure for HIV?" page 5 of this issue), it will not come in the form of a standard antiretroviral regimen.
Early treatment claims to preserve a healthy immune system. But studies of the natural history of HIV infection show that clinically-relevant immunity is rarely impaired until the CD4 cell count has fallen to 350 or lower.2 In fact, the immune system usually holds the most serious opportunistic infections (OIs) in check until the CD4 count is down to 200 or below.3 Moreover, survival time often extends beyond even critical immune suppression. In a study of gay men, thirty percent of those with fewer than 50 CD4 cells were still alive after 2 years.4
In AIDS Clinical Care, Mario Schechter, MD, and Lee Harrison, MD, write, "The CD4 cell counts at which OIs tend to occur in patients on therapy and patients who are not are therapy are similar. ... These data suggest that CD4 cell counts are excellent markers for the short-term risk of developing an OI, and that waiting for a CD4 count to decline to about 350 cells/mm3 may not be harmful for many patients."5
Hitting hard and early is supposed to delay the emergence of drug resistance. In early HIV infection, most researchers believe the viral population is relatively homogenous and therefore more susceptible to antivirals. But even if this is true--and some investigators have disputed it--it ignores an important clinical reality. By imposing selective pressure on the virus, especially in a setting of partial adherence, early antiviral therapy may actually speed the selection of drug-resistant mutants.
Data presented in early 1999 indicate that the virologic success of HAART depends on patients taking their drugs at least 95% of the time.6 That is an extraordinary level of adherence that many patients are unlikely to sustain. For example, a study published in the July issue of the Archives of Internal Medicine found that the rate of drug failure rebound exceeded fifty percent after only one year among those attending an outpatient clinic at Johns Hopkins University.7
Fine in theory, the early initiation of therapy for the prevention of drug resistance has often proven unrealistic in practice. Moreover, another strategy exists for preventing resistance: delay the drugs and the selective pressure they apply until there is a clinical need for therapy.
According to "hit hard, hit early," undertaking HAART while the CD4 count is high improves the patient's ability to tolerate therapy. But at least one large trial suggests that may not be so. The ICONA8 study, in which more than twenty-five hundred patients are enrolled, finds no statistically significant relationship between baseline CD4 cell count and the risk of withdrawing from therapy for a drug-related toxicity.9
Clearly, when given to patients in late stage disease or to those experiencing an opportunistic illness, antiviral therapy has the power to prolong life and improve its quality.10 It is no coincidence that AIDS-related deaths in the United States declined rapidly following the introduction of HAART. But late stage disease is not early stage disease.
To date, no one has undertaken a large, prospective study to demonstrate a clinical benefit from the early initiation of HAART, and it appears unlikely that anyone will do so. The pharmaceutical industry has no interest in a study if the results take people off drug. The federal research consortiums, claiming either a lack of resources or volunteers, have no plans to launch a trial to determine the benefit, if any, of early therapy.
Unsurprisingly, "hit hard, hit early" is loosing intellectual support. In an October issue of AIDS Clinical Care, the authors write, "Our basic premise is that overly simplistic models of the pathogenesis of HIV infection and antiretroviral therapy have been used to develop the current guidelines."
Andrew Phillips, MD, of the Royal Free Medical School states the objection to "hit hard, hit early" directly. He told an October meeting of the British HIV Association, "Given the current evidence, there would appear to be no compelling case for starting therapy with a CD4 count above 200 unless the patient is particularly committed to starting therapy or is experiencing symptomatic illness."
1 Science, 14:178, p. 1291, November 14, 1997; Science, 14:278, p. 1295, November 14, 1997; Proceedings of the National Academy of Science, 94:24, p. 13193, November 25, 1999.
2 Textbook of AIDS Medicine, 2nd ed., p. 49, 1999.
3 Ibid.
4 Journal of Infectious Diseases, 1995 Apr;171(4):829-36.
5 AIDS Clinical Care, 11:10, p. 79, 1999.
6 6th Conference on Retroviruses and Opportunistic Infections, Abstract 92, 1999.
7 Archives of Internal Medicine, 159, p. 1771, 1999.
8 Issues of Italian Cohort Naive Antiretroviral (ICONA).
9 Cited in "Review of HIV cohort studies suggest no advantage to starting therapy in asymptomatic persons with CD4 count above 200," www.hivandhepatitis.com.
10 New England Journal of Medicine, 338, p. 853, 1998.
Paradigm: an example or model.
Early stage: refers to HIV-infected individuals with 500 or more CD4 T cells.
Natural history: the course of HIV infection when left untreated.
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Copyright © 1999 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org
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