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Study Finds Increased Fractures in First 2 Years after Starting Antiretroviral Treatment

HIV positive individuals appear to have significantly increased risk of bone fractures during the first 2 years after beginning antiretroviral therapy (ART), but the risk returned to baseline levels thereafter, according to a study published in the November 2012 issue of the journal AIDS.

Several studies and clinical reports have shown that bone mineral density (BMD) decreases significantly upon starting ART. Moreover, HIV positive men have been shown to experience fractures at a younger age than HIV negative men.

Michael Yin of Columbia University and others looked at the incidence of fractures in over 4600 HIV positive individuals in the AIDS Clinical Trials Group (ACTG) Longitudinal-Linked Randomized Trial cohort, made up of participants from 26 HIV treatment studies; most were treatment-naive when they enrolled in these studies.

The average age in the cohort was 39 years, 48% were white, 29% were black, and 83% were men. Participants had relatively advanced HIV disease, with a baseline CD4 T-cell count of 242 cells/mm³ and a nadir or lowest-ever count of 187 cells/mm³. Nearly 40% were smokers, 4% had hepatitis B virus (HBV) coinfection, and 10% had hepatitis C virus (HCV) coinfection.

Results

• A total of 116 fractures were reported among 106 participants (2.3%), 67 of them among people who were treatment-naive at enrollment.
• Average time to first fracture was just over 2 years.
• Baseline incidence of fractures was 0.40 per 100 person-years (PY) among all participants, and 0.38 per 100 PY among those who were treatment-naive.
• Among treatment-naive people starting therapy, the risk of fractures within the first 2 years after ART initiation was 0.53 per 100 PY.
• After 2 years, however, the rate decreased to 0.30 per 100 PY.
• Traditional risk factors like smoking, HBV or HCV coinfection, and corticosteroid use increased the risk of fractures.
• Current and lowest-ever CD4 count were not significant predictors of fractures.
• Use of specific antiretroviral drugs was not associated with additional risk.

"Fracture rates were higher within the first 2 years after ART initiation, relative to subsequent years," the researchers concluded. "However, continuation of ART was not associated with increasing fracture rates in these relatively young HIV-positive individuals."

This study and others suggest loss of bone mineral density and increased risk of fractures are significant risk factors associated with the start of ART. This risk seems to be highest during the first 2 years after starting antiretrovirals and declines thereafter.

While the biological mechanism for this is not fully understood, the study’s authors suggest 2 possible explanations. First, the decrease in risk over time might be a reflection of overall improvement in health with more time on ART. It is also possible that increased study visits and clinical vigilance in the short term after treatment initiation might have identified more fractures.

Furthermore, several factors known to increase the risk of bone loss and fractures are common among people with HIV. These include smoking, HCV coinfection, alcohol and drug use, and corticosteroid use. There is likely an additive risk for people on antiretrovirals. Of note, only about 20% of participants in this analysis used tenofovir (Viread, also in the Atripla, Complera, and Stribild coformulations), which is now one of the most commonly used HIV drugs and has been linked to bone loss. It is also noteworthy that other studies have found higher rates of fractures among people with HIV in general, not only those on ART.

The study’s authors note that this cohort was generally young, with an average age of 39 years. Risk of fractures increases with age. Therefore, fracture rates would be expected to be higher among older people with HIV, particularly post-menopausal women.

The authors also note that although the bone loss was similar in the near term among those starting antiretrovirals and corticosteroids, the risk of fracture is higher among those initiating corticosteroids. The authors argue that this apparent discrepancy suggests the need for further study of the "micro-architecture" of bones during this acute loss of BMD.

12/14/12

Reference

M Yin, M Kendall, X Wu, et al. Fractures after antiretroviral initiation.AIDS 26(17):2175-2184. November 13, 2012