Concerns related to cost, inconvenience, and toxicities associated with HAART led researchers to consider interruption of treatment for HIV. For example, a CD4 cell count-driven strategy for treatment interruption was evaluated in the SMART trial, which found an unexpected increase of both opportunistic diseaese and serious cardiovascular events after treatment interruption.

The goal of the present study (ACTG 5102), results of which were published in the April 23, 2008 online edition of PLoS One, was to evaluate fasting metabolic changes associated with interruption of antiretroviral therapy, and relate them to changes in immune activation markers and cardiovascular risk.

ACTG 5102 enrolled 47 HIV-infected subjects on stable antiretroviral therapy with a baseline viral load < 200 copies/mL and CD4 cell count of at least 500 cells/mm3. Participants were randomly assigned to continue antiretroviral therapy for 18 weeks with or without 3 cycles of interleukin-2 (IL-2) (cycle = 4.5 million IU by twice-daiy subcutaneous injection x 5 days every 8 weeks).

After 18 weeks, antiretroviral therapy was discontinued in all patients until the CD4 cell count dropped below 350 cells/mm3. Glucose and lipid parameters were evaluated every 8 weeks initially, and then at weeks 2, 4, 8 and every 8 weeks after treatment interruption. Immune activation were evaluated by flow cytometry and soluble type 2 tumor necrosis factor receptor (TNFR2) levels.

Results

In their conclusion, the authors wrote, "Our data suggests that interrupting antiretroviral therapy does not reduce cardiovascular disease (CVD) risk, as the improvements in lipid parameters are modest and overshadowed by the decreased HDL levels."

In addition, they stated, "Increased immune cell activation and systemic inflammatory responses associated with recrudescent HIV viremia may provide a more cogent explanation for the increased cardiovascular risk associated with treatment interruption and HIV infection."

Discussion

The authors pointed out in the discussion section of their report that over the long term -- although the decrease in total and LDL cholesterol associated with interrupting HAART might be associated with a decreased cardiovascular risk -- "those benefits may be offset by the marked decrease in HDL cholesterol observed."

"Total/HDL cholesterol ratio may more accurately capture the overall cardiac risk as compared to other individual lipoprotein measurements," they continued. "In fact, the total cholesterol to HDL ratio, although improved during the first 4 weeks after interruption, returned to baseline by 8 weeks."

The authors stated that the early benefits seen in triglycerides levels during treatment interruption tended to become less apparent as the duration of the interruption increased.

"Our interpretation of these late lipid changes observed after 24-48 weeks of treatment interruption is that they represent the adverse metabolic effects of unabated HIV replication rather than any residual effect of antiretroviral therapy," they wrote. "These changes are similar to the lipid effects seen in acute and chronic HIV infection in the absence of treatment."

The authors suggested that these lipid abnormalities could be cytokine driven, or mediated directly by HIV replication, or both."

Finally, they wrote, "The net effect of the observed lipid changes would predict little if any improvement in the cardiovascular risk after the discontinuation of antiretroviral therapy."

University of Pennsylvania, Philadelphia, PA; Hennepin County Medical Center, University of Minnesota, MN; Harvard School of Public Health, Boston, MA; University of North Carolina, Chapel Hill, NC; Case Western Reserve University, Cleveland, OH; Social and Scientific Systems Inc, Silver Spring, MD; Frontier Science & Technology Research Foundation, Inc, Amherst, NY; University College Dublin, Dublin, Ireland; Stanford University, Stanford, CA.

4/29/08

Reference
P Tebas, WK Henry, R Matining, and others (ACTG 5102 Trial Investigators). Metabolic and Immune Activation Effects of Treatment Interruption in Chronic HIV-1 Infection: Implications for Cardiovascular Risk. PLoS ONE 3(4): e2021.. April 23, 2006. Available at: http://clinicaltrials.ploshubs.org.