IAPAC Monthly - Vol. 8, No. 2, January 2002
Anne A. Oplinger

A critical long-term study to determine which of two common HIV treatment strategies ultimately is better began in early January 2002 at 21 US and Australian clinical trial sites. SMART, or Strategies for Management of Antiretroviral Therapies, will eventually enroll 6,000 people who will be monitored for up to nine years. The study is being conducted by the Community Programs for Clinical Research on AIDS (CPCRA), a network of community-based researchers funded by the US National Institute of Allergy and Infectious Diseases (NIAID).

People with HIV and their physicians can take one of two approaches when tackling the disease. They may either suppress the virus as much as possible from the outset by continually using strong antiviral drugs or delay drug therapy until CD4+ T cells (immune system cells that are the primary target of HIV and that are a key indicator of immune system health) fall below a critical level.

"There is no doubt that people living with HIV/AIDS have benefited greatly from the introduction of highly active antiretroviral therapy (HAART) and other advances during the mid-1990s," noted Anthony S. Fauci, the Director of the NIAID. "However, it is also undeniable that these powerful drugs cause serious side effects .... To strike a balance between adequately aggressive treatment and minimal adverse side effects, we need hard data. SMART promises to provide just that kind of information to physicians and their patients."

HIV/AIDS treatment guidelines developed in the mid-1990s favored the "hit-hard-early" strategy. In the short term, this strategy often leads to a less debilitating course of AIDS. As a result, death and disability from HIV/AIDS have declined sharply in the United States and other developed countries.

However, the drug regimens are expensive, difficult to follow and frequently cause a host of serious side effects after long-term use. Moreover, HIV may become resistant to one or more of the drugs, thereby making them ineffective. For these reasons, current HIV treatment guidelines do not recommend starting HAART as early as former guidelines did. "There are many unanswered questions about the most appropriate use of anti-viral therapy," said Karin Klingman, a medical officer in the NIAID's Division of AIDS and member of the SMART protocol team. "We simply do not know when the best time is to begin therapy after infection; when to switch from one treatment to another; or which of several key factors best predicts how the disease will progress."

It is hoped SMART will answer these questions.

SMART differs from previous AIDS treatment clinical trials in several ways. For example, although the effectiveness and toxicity of various anti-HIV therapies have been studied, this is the first study to do so over a prolonged period. SMART will compare two distinct treatment approaches and will follow enrollees for an average of seven years. In addition, while most AIDS treatment trials measure indirect indicators of AIDS development, such as the amount of virus or number of CD4+ T cells in the blood, SMART will measure clinical events such as progression to full-blown disease or to death, which take longer to occur.

"The study's length is one reason for our great emphasis on patient and physician education both prior to enrollment and throughout the study," Klingman said. SMART's enrollment criteria are broad - teenagers as well as adults are eligible - so the findings will be applicable to as many people as possible, she added.

In the first year, study investigators will enroll 1,000 HIV infected people and randomly assign them to either a "go slow" or a "hit-hard-early" treatment strategy. The hit-hard-early strategy (in which drugs are used to suppress HIV levels to low or undetectable levels) is recommended in guidelines employed by many physicians in the United States. Study participants in the go-slow arm of the study will agree not to take antiviral drugs unless their CD4+ T -cell count drops below 250 per cubic millimeter (mm³), and then they will take the drugs only until their CD4+ T -cell counts rebound above 350. The long-term feasibility of the study will be evaluated after the first year. Based on a favorable outcome, an additional 5,000 people will be enrolled over the next three years.

To take advantage of the wealth of information predicted to come from such a large and lengthy trial, the SMART study will incorporate several sub-studies. One such sub-study, which examines treatment effects on the heart, is the first of its kind. Another will examine whether and how treatment changes body fat distribution and bone density - significant side effects of HAART - in enrollees in each group.

"Reliable evidence from randomized trials is needed to assess the risks and benefits of the strategies evaluated in SMART. The successful completion of this study will provide ground-breaking information on how to approach treatment of HIV disease," said Wafaa El-Sadr, a Principal Investigator and Co-Chair of the SMART study team.

Anne A. Oplinger is a science writer at the US National Institute of Allergy and Infectious Diseases (NIAID) Office of Communications and Public Liaison. She may be contacted at aoplinger@nih.gov.

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