Continued antiretroviral therapy reduces bone mineral density in SMART study

A sub-study of the SMART trial has found greater losses of bone mineral density in people who stayed on continuous antiretroviral therapy, compared to those who periodically interrupted their treatment. The study also found that people on continuous treatment were almost five times more likely to experience a serious fracture during the follow-up period than those who interrupted treatment.

HIV-positive individuals generally have lower bone-mineral density than their HIV-negative peers. There is conflicting evidence about the relationship between antiretroviral treatment and long-term HIV infection as contributing causes, and the question continues to be investigated. Investigators from the SMART study presented findings from a body composition sub-study in a poster at the 48^th Interscience Conference on Antimicrobial Agents and Chemotherapy in Washington DC on Monday.

The SMART study was designed to compare the outcomes of continuous antiretroviral treatment versus therapy involving treatment interruptions. Participants were randomised to either take their antiretrovirals continually or, if their viral load was undetectable, to discontinue treatment when their CD4 cell count was above 350 cells/mm³, recommencing treatment when it fell to around 200 cells/mm³. The study was terminated early when it was found that patients who interrupted treatment were more likely to have both HIV-related and non-HIV-related illnesses.

A total of 275 patients in the SMART study were prospectively enrolled in a sub-study designed to evaluate the impact of antiretroviral treatment on bone mineral density; data was available on 214 of these patients. Between May 2002 and January 2006, 98 of these patients took continuous antiretroviral treatment with the remaining 116 patients interrupting their treatment according to the study protocol. The two groups of patients were very similar, with an average age of about 44 years; ethnic backgrounds were fairly evenly represented and about 20% were women. A significant number smoked (41% in the interruption group and 51% in the continuous group). Several large studies have shown that smokers suffer more bone mineral loss as they age.

Over the four-year course of the sub-study, patients on continuous therapy received antiretroviral treatment for 93% of the follow-up time, compared with 37% in the treatment interruption group. The majority of the time off treatment occurred in the first year of the study.

Bone mineral density (BMD) was checked at baseline and then annually in the hip and spine using a technique called dual-energy X-ray absorptiometry (DEXA). BMD in the spine was also checked using a CT scan.

Overall, spine BMD steadily declined in the continuous-therapy group. In the treatment-interruption group, it increased over the first year, when the greatest number of participants were off therapy. It declined after that but still remained higher than the levels of those on continuous therapy. Although the differences fell below statistical significance at further time points (due to the declining numbers with follow-up data available, as well as the gradually decreasing differences themselves), the overall longitudinal difference (summed over time) remained significant.

Compared to patients who interrupted their antiretroviral therapy, those who took antiretroviral treatment continuously experienced a 0.9% decline in bone mineral density in the hip each year, a 2.9% decline in density in the spine (as measured by CT scan), and a 0.4% fall in density in the spine (as measured by DEXA). In the spine (as measured by DEXA), the difference in BMD favoured the interrupted-therapy group by 1.7% at year 1 (p = 0.003) and 1.2% over the entire period (p = 0.05). In the hip, the differences were 1.3% at year 1 (p = 0.002) and 1.4% over the duration (p = 0.002).

Although differences between outcomes were observed in people on different antiretroviral agents, the study was not powered to evaluate such differences.

In the larger SMART study, grade 4 bone fractures occurred at a rate of 0.13 per 100 person-years in patients who took their treatment all the time, versus 0.03 per 100 person-years in those who interrupted therapy (hazard ratio 4.9, 95% confidence interval 1.1 – 22.5, p = 0.04).

The investigators concluded that "continuous antiretroviral therapy contributes to bone mineral density loss and may increase the risk of fractures" relative to intermittent antiretroviral treatment. However, they stress that interrupting HIV treatment is not recommended, as the SMART study showed that it increases the risk of both HIV disease progression and death.