Excess Risk of Opportunistic Disease and Death Remains after Reinitiating HAART following Treatment Interruption

By Liz Highleyman

Recent studies -- including the large international SMART trial -- have shown that continued HIV replication and lower CD4 cell counts are associated with a variety of "non-AIDS-related" conditions -- including cardiovascular disease and cancer -- well before the CD4 cell count falls into the opportunistic infection (OI) "danger zone" below 200 cells/mm3.

As previously reported, SMART included 5472 HIV positive participants with a CD4 cell count above 350 cells/mm3 at baseline who were randomly assigned to either stay on continuous antiretroviral therapy, or else to interrupt treatment when their CD4 count was above 350 cells/mm3, resuming when it fell below 250 cells/mm3.

Interim results showed that participants who interrupted HAART not only were at higher risk of AIDS-related OIs and death, but also had a higher rate of serious cardiovascular, liver, and kidney disease. Based on these findings, the study was halted prematurely in January 2006 and patients in the treatment interruption arm were encouraged to start or reinitiate continuous therapy.

Now, in the September 2, 2008 Annals of Internal Medicine, investigators have reported that while the excess risk of death decreased after patients resumed treatment, it may not be fully reversed to the level of those who stayed on continuous therapy.

Results

• 18 months after the recommendation to reinitiate continuous therapy, mean CD4 cell counts were significantly lower -- by an average of 152 cells/mm3 -- in the former treatment interruption arm compared with the initial continuous therapy arm (P < 0.001).

• The proportion of follow-up time spent with a CD4 cell count of 500 cells/mm3 or higher and a viral load of 400 copies/mL or lower was 29% for participants initially assigned to the treatment interruption arm and 66% for those initially randomized to continuous therapy.

• Participants who restarted continuous therapy after treatment interruption experienced rapid viral load decline, and 89.7% achieved HIV RNA levels <400 copies/mL after 6 months.

• However, CD4 cell counts in the former treatment interruption group remained an average of 140 cells/mm3 below the baseline level after 6 months.

• The hazard ratio for opportunistic disease or death in the treatment interruption versus the initial continuous therapy arm decreased after reinitiating continuous treatment, falling from 2.5 to 1.4; P = 0.033 for difference).

• However, the former treatment interruption arm remained at slightly higher risk of opportunistic disease or death 18 months after going on continuous therapy.

The investigators concluded that, "Reinitiating continuous antiretroviral therapy in patients previously assigned to episodic treatment reduced excess risk for opportunistic disease or death, but excess risk remained."

They acknowledged, however, that "follow-up was too short to assess the full effect of switching from episodic to continuous antiretroviral therapy."

The authors attributed the residual excess risk in the former treatment interruption arm to some patients failing to reinitiate continuous therapy as advised, and to slow CD4 cell recovery among those who did go on continuous treatment.

"Episodic antiretroviral therapy, as used in the SMART study, should be avoided," they recommended.

10/24/08

Reference
WM El-Sadr, B Grund, J Neuhaus, and others (SMART Study Group). Risk for opportunistic disease and death after reinitiating continuous antiretroviral therapy in patients with HIV previously receiving episodic therapy: a randomized trial. Annals of Internal Medicine 149(5): 289-299. September 2, 2008. (Abstract). Summary for patients.