Physician's Weekly Article - Making the Case for Early Antiretroviral Therapy

       New data demonstrate that early initiation of antiretroviral therapy before CD4 counts fall below pre-specified thresholds can significantly improve survival as compared with deferring therapy.

      Although antiretroviral therapy has helped reduce AIDS complications and deaths among patients with HIV, the optimal time to begin therapy in asymptomatic patients is still uncertain. Current guidelines recommend that treatment begin for asymptomatic patients when they have CD4 counts of less than 350 cells/mm³. “Although antiretroviral therapy is clearly life-saving for patients with AIDS, there are also side effects to consider,” says Paul E. Sax, MD. “In the late 1990s, many clinicians put asymptomatic HIV patients on treatment early, but the drugs available at that time were much more toxic. As a result, in the early 2000s, clinicians changed their approach, often holding off on using antiretroviral therapy for as long as possible.”

      New Data Emerging

      Until recently, there has been a lack of data regarding timing of the initiation of antiretroviral therapy. Several studies have compared patients with similar CD4 counts who either initiated or deferred antiretroviral therapy, but they did not have the statistical power and methods to examine outcome differences. In 2006, a subgroup analysis of the Strategies for Management of Antiretroviral Therapy (SMART) trial found that deferring antiretroviral therapy until CD4 counts fell below 250 cells/mm³ increased the risk of progression to AIDS or death when compared with initiating therapy when CD4 counts were higher than 350 cells/mm³. “The SMART trial was primarily designed to determine the effects of continuous versus intermittent therapy, but in some ways, it also investigated the issue of early-versus-deferred therapy,” says Dr. Sax. “Findings from this trial and other data in the last 5 years have shown that early antiretroviral treatment can lead to better responses to therapy and preserve immune function.”

      In the April 1, 2009 online issue of the New England Journal of Medicine, researchers in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) examined 17,517 asymptomatic HIV-infected patients in the United States and Canada from 1996 to 2005. None of the patients had undergone previous antiretroviral therapy. Participants were stratified into two groups, those with counts ranging between 351 cells/mm³ and 500 cells/mm³ and those with counts higher than 500 cells/mm³, at the initiation of antiretroviral therapy. The relative risk of death was assessed for patients who initiated therapy early—when the CD4 count was above each of the two thresholds of interest—and for patients who deferred therapy until the CD4 count fell below the thresholds.

      In the first NA-ACCORD analysis, researchers observed a 69% increase in the risk of death when patients with CD4 counts between 351 cells/mm³ and 500 cells/mm³ deferred therapy (Table 1). The second analysis, which analyzed patients who initiated therapy when their CD4 counts were higher than 500 cells/mm³, revealed a 94% increased risk of death for the deferred-therapy group. Older age, a history of injection-drug use, and the presence of hepatitis C virus infection were also identified independent risk factors for death in patients with HIV (Table 2). “The NA-ACCORD study provides some of the strongest data suggesting that early treatment is better,” Dr. Sax says.

      Important Implications

      Despite the positive findings from NA-ACCORD, Dr. Sax warns that more data are needed. “We must be cautious when interpreting observational data despite efforts to control for confounders,” he says. “The NA-ACCORD data do not provide definitive proof that we should be starting antiretroviral therapy in all patients with HIV infection. More data from randomized, prospective clinical trials are required.” At least three such studies are either ongoing or planned; meanwhile, the supportive evidence for the benefits of earlier therapy continues to increase.

      Dr. Sax says that if an asymptomatic patient with HIV and a CD4 count of more than 500 cells/mm³ wished to start antiretroviral therapy 5 years ago, “most experienced clinicians could have made an excellent case as to why treatment should be deferred. Today, if a similar patient was eager to start, clinicians should be ready and willing to prescribe therapy, so long as it’s understood that ongoing careful monitoring for side effects is critical for a treatment that could last decades.”

      The benefits of initiating antiretroviral therapy earlier after HIV infection must still be weighed against the potential adverse effects of treatment, says Dr. Sax. “Newer antiretroviral therapies are more potent, have fewer side effects, and can be taken less frequently than previous drug regimens. However, the potential side effects of long-term antiretroviral therapy are still unknown. Advancing our understanding of the role of HIV infection in inflammation and immune activation may support the practice of earlier treatment for HIV. Furthermore, patients who go on antiretroviral therapy early are less likely to transmit the virus to others. From a personal and public health perspective, this is important because getting patients on therapy earlier may help slow the HIV epidemic.”

      Paul E. Sax, MD, has disclosed to Physician’s Weekly that he has served as an advisor or consultant to, and has received grants for educational activities from Abbott Laboratories, Bristol-Myers Squibb, Gilead Sciences, Tibotec, and Pfizer. He has also received grants for clinical research and educational activities and served as an advisor or consultant to Merck and GlaxoSmithKline.