By Liz Highleyman

Evidence has accumulated over the past several years showing that antiretroviral treatment interruption guided by CD4 cell count is a risky strategy that can lead to a higher risk of both AIDS-defining opportunistic illnesses and serious conditions such as cardiovascular disease that are not traditionally considered HIV-related, but may be due to inflammation and other abnormalities associated with ongoing viral replication.

Researchers initially explored structured treatment interruption in an effort to spare patients some of the side effects, inconvenience, and costs of life-long therapy. But most studies to date have demonstrated few such benefits, especially given the development of more tolerable and easier to use drugs.

The latest analysis from the large SMART trial, however, indicates that continuous HAART may increase the risk of bone loss (osteopenia, or the more serious osteoporosis). Data were presented this week in a late-breaking poster at the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC) this week in Washington, DC.

Research looking at bone mineral density (BMD) in people with HIV has produced conflicting results. Several studies have shown that HIV positive people have lower BMD compared with the general population, but it is not clear whether this is related to HIV infection itself, antiretroviral therapy, an accelerated aging process, or other unknown factors.

Briefly, the SMART study 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 (the "viral suppression" arm), or to interrupt treatment when their CD4 count was above 350 cells/mm3, resuming when it fell below 250 cells/mm3 (the "drug conservation" arm). The study was halted prematurely in January 2006 after interim results showed that people who periodically stopped therapy had both a higher rate of AIDS-related opportunistic infections or death and serious heart, liver, and kidney disease.

The substudy presented at ICAAC included 275 SMART participants, of whom 214 had sufficient available bone data (98 in the continuous therapy arm, 116 in the treatment interruption arm). Most (81%) were men, the median age was 44 years, and about 45% smoked (a known risk factor for bone loss).

Hip and spine BMD were measured annually using dual-energy x-ray absorptiometry (DEXA), and trabecular BMD of the spine was assessed using quantitative computed tomography (CT). The investigators used longitudinal models to compare BMD changes in the 2 arms, and assessed the incidence of reported fractures in the study as a whole. Further, they evaluated associations between BMD decline and cumulative antiretroviral drug use in the continuous therapy arm.

At baseline, 12% of the patients had osteoporosis, median t-scores (a standard measure of bone density) were -0.5 for the femur, -0.9 for the spine by CT, and -0.7 for the spine by DEXA. Participants were followed for a mean of 2.4 years.

Results

• In the continuous therapy group, patients received ART for 93% of total follow-up time, compared with 37% in the treatment interruption group.

• In the continuous therapy group, femur BMD declined by 0.9% per year, spine BMD by CT declined by 2.9% per year, and spine BMD by DEXA decreased by 0.4% annually.

• BMD decreases were significantly smaller in the treatment interruption group, especially during the first year when most were not yet on therapy.

• Over the entire follow-up period, the estimated differences in BMD changes in the treatment interruption group compared with the continuous therapy group were:

• Femur: 1.4% (P = 0.002);

• Spine by CT: 2.9% (P = 0.01);

• Spine by DEXA: 1.2% (P = 0.05).

• No consistent significant associations were observed between BMD decline and use of specific antiretroviral drugs.

• In the study as a whole, during a mean 2.8 years of follow-up, 10 of 2753 patients in the continuous therapy arm and 2 of 2720 in the treatment interruption group reported fractures as grade 4 adverse events.

• The rate of fractures was nearly 5 times higher in the continuous therapy arm compared with the treatment interruption arm (0.13 vs 0.03 per 100 person-years; hazard ratio 4.9; P = 0.04).

Based on the results of this analysis, the researchers concluded that, "Continuous antiretroviral therapy is associated with decline in BMD and possibly more fractures relative to intermittent, CD4-guided antiretroviral therapy."

Given the now-obvious detrimental effects of treatment interruption, however, they emphasized that "Intermittent antiretroviral therapy is not recommended due to increased risk of AIDS and death observed in the SMART study."

Univ. of Minnesota, Minneapolis, MN; St. Vincent's Hosp. and Univ. of NSW, Sydney, Australia.

10/31/08

Reference
B Grund and A Carr (for INSIGHT/SMART Study Group). Continuous Antiretroviral Therapy (ART) Decreases Bone Mineral Density: Results from the SMART Study. 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract H-2312a.