Benefit of starting HIV treatment early outweighs the risk of toxicities, SMART study shows

Tom Egwang
Published: 14 April 2008

Starting antiretroviral therapy at a CD4 cell count above 350 - the current threshold for starting treatment - reduced the risk of serious illness and death compared to later treatment, according to the findings of a subgroup analysis of the SMART treatment interruption trial published in the 15th April edition of the Journal of Infectious Diseases.

Current treatment guidelines in Europe and the United States recommend deferring antiretroviral therapy (ART) in asymptomatic adult patients until the CD4 count falls below 350 cells/mm3 or has reached less than 200 cells/mm3 in resource-poor countries. These recommendations were based on the results of nonrandomised studies and expert opinions.

The guidelines were formulated based on earlier concerns about the risk/benefit ratio of starting ART earlier and the fact that AIDS-defining clinical events were rare at higher CD4 counts. There were fears that any benefits of early ART could be compromised by toxicities, cost-effectiveness, quality of life issues, adherence, and drug resistance.

An increasing body of evidence now suggests that these guidelines must be revisited. First, data from clinical studies indicate that the risk of AIDS persists at CD4 counts >500 cells/mm3. Second, even in patients with high CD4 counts, the risk of AIDS or death decreases with the initiation of ART by comparison with those who are not on ART. Finally, the risk of serious non-AIDS-related diseases and cancers is lower at higher CD4 counts.

The Strategies for Management of Antiretroviral Therapy (SMART) Study Group conducted in 318 international sites in 33 countries has addressed this issue. Its primary finding - that treatment interruption was associated with an increased risk of serious illness and death - was published in the New England Journal of Medicine in 2006, and a range of other findings have been presented at international conferences over the past five years.

The SMART study randomised participants with CD4 cell counts above 350 cells/mm3 to continuous use of ART (the viral suppression, or VS, strategy) or to discontinue treatment until the CD4 cell count fell below 250 cells/mm3. Some participants were antiretroviral-naive when they entered the study.

For the present study, the SMART Study Group undertook a subgroup analysis of the larger trial in which clinical outcomes were compared between participants who initiated ART in the trial with CD4 counts above 350 cells/mm3 and HIV-infected patients who deferred ART until the CD4 counts had declined to <250 cells/mm3.

The sub-study analysed 477 patients, 249 of them treatment-naive on entry to the study. The patients were followed for a mean of 18 months with periodic clinical and laboratory monitoring for CD4 counts and HIV-1 RNA loads.

The following clinical outcomes were assessed: (i) opportunistic disease (OD) or death from any cause (OD/death); (ii) OD (fatal or nonfatal); (iii) serious non-AIDS events (cardiovascular, renal, and hepatic disease plus non–AIDS-defining cancers) and non-OD deaths; and (iv) the composite outcomes of OD and serious non-AID events.

Twenty one and 6 OD and non-AIDS events occurred in the DC and VS groups, respectively. Hazard ratios for DC versus VS by outcome category were as follows: OD/death, 3.47 (P = 0.02); OD (fatal or nonfatal), 3.26 (P = 0.04); serious non-AIDS events, 7.02 (P = 0.01); and the composite outcomes, 4.19 (P = 0.002). Thus, early initiation of ART at CD4 cell counts > 350 cells/mm3 reduced HIV-related deaths and disease.

The authors say these findings require urgent validation in a large, randomised clinical trial. An accompanying editorial makes the point that such a study should unequivocally establish that the benefit of early ART initiation is large enough to justify the costs. Such a study would also provide unique opportunities to unravel the mechanisms underlying the beneficial effects of early ART initiation on non-AIDS events.

A companion report in the same edition of the journal provides further evidence to support earlier treatment. The analysis shows that even at CD4 cell counts above 350 cells/mm3, uncontrolled viral replication in individuals who had interrupted therapy was associated with an increased risk of serious illness or death, as was a greater duration of time spent living with a CD4 cell count below 350 cells/mm3.

Reference

The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. Major clinical outcomes in antiretroviral therapy (ART)–naive participants and in those not receiving ART at baseline in the SMART study. Journal of Infectious Diseases 197:1133 - 1144, 2008.

Hughes MD, Ribaudo HR. The search for data on when to start treatment for HIV infection. Journal of Infectious Diseases 197:1084-1086, 2008.

Related news selected from other sources

More editors' picks on starting treatment >