SMART study reaffirms that HIV replication is harmful, even at CD4 counts above 350

Uncontrolled HIV replication is associated with a higher risk of serious illness and death even when the CD4 cell count is above the currently recommended threshold for starting treatment - 350 cells/mm³ - according to a new analysis of the SMART study of structured treatment interruption published in the April 15^th edition of the Journal of Infectious Diseases.

In addition, the analysis showed that the greater risk of serious illness and death in the treatment interruption was also associated with a greater period spent living with a CD4 cell count below 350 cells/mm³.

Taken together, say the authors, the findings "support consideration of initiating ART before even moderate levels of immunodeficiency develop," although they recommend that a large randomised trial still needs to be conducted to answer the question of when is the optimal time to start antiretroviral treatment.

The SMART study compared two antiretroviral treatment (ART) strategies in HIV-infected adults with CD4 counts > 350 cells/mm³. The viral suppression (VS) strategy entailed continuous use of ART to maximally suppress HIV replication. By contrast, the CD4 count-guided ART interruption strategy, also designated drug conservation (DC), involved stopping ART when CD4 counts was above 350 cells/mm³ and re-initiating ART when CD4 counts fell below 250 cells cells/mm³.

The study reported an increased risk of serious opportunistic diseases (OD) and all-cause mortality in HIV-infected patients on CD4 count-guided ART interruption by comparison with HIV-infected patients on continuous ART.

The majority of the excess risk of disease or death in SMART was associated with lower CD4 counts and higher HIV RNA loads during follow-up in patients on ART interruption. However the reasons or mechanisms underlying this effect remained unknown. In order to address this issue, the SMART study group has now assessed the rates and predictors of OD/death and the relative risk (RR) in DC versus VS groups as a function of the latest CD4 cell count and HIV RNA level.

Details of the study design and study participants have already been reported by the SMART study group (New England Journal of Medicine 355: 2283-2296, 2006). During a mean of 16 months of follow-up, DC patients spent more time with a latest CD4 cell count 3 (for DC vs. VS, 31% vs. 8%) and with a latest HIV RNA level > 400 copies/ml (71% vs. 28%) and had a higher rate of OD/death (3.4 vs. 1.3/100 person-years) than VS patients.

For periods of follow-up with a CD4 cell count above 350 cells/mm³, rates of OD/death were similar in the two groups (5.7 vs. 4.6/100 person-years). The rates of OD/death were higher in DC versus VS patients (2.3 vs. 1.0/100 person-years; RR, 2.3 [95% confidence interval, 1.5–3.4]) for periods with the latest CD4 cell count of 350 cells/mm³ or greater. This increased risk of disease or death is explained by the higher HIV RNA levels in the DC group despite the higher CD4 counts.

These findings are significant for two reasons. First, uncontrolled HIV replication even at higher CD4 cell counts appears to be an important cause of pathology which has not been hitherto appreciated. Second, the current treatment guidelines which emphasise deferring ART at higher CD4 counts are probably resulting in an unnecessary burden of disease and death on the fragile public health systems in resource-poor countries. This probably compromises the ability of these countries to confront other challenges due to malaria, tuberculosis, and a legion of other diseases.

A companion paper in the same issue by the SMART study group reports on the lower relative risk of serious illness or death in those who started treatment with a CD4 cell count above 350 cells/mm³.