Earlier ART may improve HIV clinical outcomes

Early initiation of antiretroviral therapy may decrease both opportunistic disease incidence and serious non-AIDS events, according to new research.

Researchers from the National Centre in HIV Epidemiology and Clinical Research in Sydney, Australia, with a team of international investigators, analyzed data from the Strategies for Management of Antiretroviral Therapy (SMART) study.

Data were compared between patients who received early antiretroviral therapy (the viral suppression group) and the group of patients in whom antiretroviral therapy was deferred until CD4+ counts declined to less than 250 cells per mcL, dubbed the drug conservation group.

The study was supported by grants from the National Institute of Allergy and Infectious Diseases.

The results were published in The Journal of Infectious Diseases.

Treatment groups

Data from patients who were antiretroviral-naive (n=249) or who had not received antiretroviral therapy in the past six months or longer (n=228) were analyzed. Patients were assigned to either the drug conservation group (n=228) or to the viral suppression group (n=249). Clinical outcomes assessed in patients included:

• Opportunistic disease and death from any cause.
• Opportunistic disease, fatal or nonfatal.
• Serious non-AIDS events (cardiovascular, renal and hepatic disease and non–AIDS-defining cancers) as well as non-opportunistic disease deaths.
• The composite of outcomes.

Earlier antiretroviral therapy

According to the researchers, risk reductions for AIDS associated with the earlier use of antiretroviral therapy appeared to be greater than previously estimated.

In a composite of outcomes, 21 events occurred in the drug conservation group. Seven events were in antiretroviral therapy-naive patients, and 14 events occurred in patients who were not taking ART.

Six events were reported in the viral suppression group: two in antiretroviral therapy-naive patients and four in those who were not taking ART.

Patients in the drug conservation group had greater likelihood of adverse outcomes than patients in the viral suppression group. The overall hazard ratio (HR) for the composite of fatal or nonfatal opportunistic disease outcomes and serious non-AIDS events was 4.19 (95% CI, 1.69-10.39) in patients in the drug conservation group vs. patients in the viral suppression group.

The HR for opportunistic disease or death from any cause was 3.47 (95% CI, 1.26-9.56) and was 3.26 (95% CI, 1.04-10.25) for fatal or nonfatal opportunistic disease. For serious non-AIDS event outcomes, the HR was 7.02 (95% CI, 1.57-31.38). – Kirsten H. Ellis

Recent Department of Health and Human Services recommendations for earlier antiretroviral therapy initiation are a reflection of this study and of the consensus of HIV health care providers that opportunistic events related to cardiovascular and cerebrovascular toxicity, neoplasms, and progressive hepatic fibrosis (the latter in HBV and HCV coinfected patients) occur in people with untreated HIV disease at higher CD4 counts (200-350 cells/mm³ than previously recognized. The findings of this and other similar studies of treatment interruption or treatment delay in otherwise asymptomatic HIV infected individuals suggest that intervention in the natural history of HIV disease with earlier institution of antiretroviral therapy should be considered for most patients. Reflecting both these studies and the improved tolerability of current HAART regimens, the USPHS Guidelines Committee in December 2006 formally changed their recommendations for the timing of the initiation of antiretroviral therapy.

– Michael L. Tapper, MD

Infectious Disease News Editorial Advisory Board member

These results further highlight the earlier findings of the SMART study concerning the benefits of antiretroviral therapy in preventing not just HIV-1-related morbidity and mortality, but also other adverse events that historically were not linked to untreated HIV-1 disease, such as cardiovascular disease. Importantly, although drug toxicity is frequently cited as a reason not to initiate antiretroviral therapy in early stages of disease, severe drug toxicities did not emerge as a significant problem in this study. Because patients were followed on study for a mean of 18 months, long-term outcomes were not evaluated. Thus, potential long-term negative consequences or long term positive effects could not be determined. There seems to be little question at this point that earlier initiation of antiretroviral therapy results in lower morbidity and mortality in the short term. Nevertheless, it is not clear whether the cost in terms of expense of medications, impairment of quality of life, and increased drug resistance and toxicities, merits the benefits of earlier intervention. Although the authors conclude that a randomized trial is necessary to address the benefits of earlier initiation of antiretroviral therapy, the feasibility of conducting such a trial in terms of the large numbers of patients and the long period of follow-up that would be necessary to adequately address these issues, is questionable.

– Elizabeth Connick, MD

Infectious Disease News Editorial Advisory Board member

For more information:

• Emery S, Neuhaus JA, Phillips AN, et al. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. J Infect Dis. 2008;197:1133-1144.
• Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents (accessed 3/25/08) at http://www.aidsinfo.nih.gov.