Fracture healing in Human Immunodeficiency Virus positive patients: the HIV in Orthopaedic Skeletal Trauma (HOST) study

Abstract

Background: Human immunodeficiency virus (HIV) has been shown to reduce bone mineral density (BMD), mineralisation and bone turnover. In the HIV-negative population, reduced BMD is associated with delayed bone union and this may also be true in HIV infection. Previous clinical and basic science research has suggested an association between HIV infection and impaired fracture healing. However, the effect of HIV on bone healing is very poorly understood. The aim of this study was to establish whether HIV is a risk factor for the development of delayed bone union or non-union following a fracture.

Methodology: The project aims were addressed with two related clinical studies undertaken at two tertiary referral hospitals in Cape Town, South Africa.

1. HIV in Orthopaedic Skeletal Trauma (HOST) 1 Study: Case-cohort study of participants undergoing fracture surgery: All adult participants with fresh tibia and femur fractures who underwent IM nailing for fracture fixation were eligible for inclusion over a 14-months period. Participants were evaluated at six weeks, and three, six, nine and 12 months post-operatively. The primary outcome was delayed bone union at six months (Radiological Union Score for the Tibia [RUST] score < 9) and the secondary outcome was non-union at months 9 (RUST score < 9).

2. HIV in Orthopaedic Skeletal Trauma (HOST) 2 Study: Matched case-control study of participants presenting with non-unions (RUST < 9) of fractures: Adult participants (cases) with established non-unions of the femur or tibia shaft were recruited over a 14-months period and matched for: a) age; b) sex; c) fracture site; and d) fracture management type, with ‘control’ participants who progressed to fracture union (RUST > 9) within six months of injury. All study participants underwent HIV testing, with measurement of CD4 cell count and viral load and a history of anti-retroviral (ART) therapy if appropriate. Bone healing was assessed by two blinded independent reviewers, using the RUST scoring system. The odds of delayed and non-union by HIV group were estimated and compared using univariate and multivariable logistic regression.

Results: 1. HOST 1 study: A final study population of 358/400 (89.5%) participants, who underwent 395/442 (89.4%) IM nailings were recruited over a 14-month period. All participants were followed up for a minimum of 12 months. 71 participants (71/358, 19.8%) were HIV-positive (83 IM nailings [83/395], 21.0%). HIV was not statistically significantly associated with the development of delayed bone healing following an IM nailing of the tibia or femur in this study population (univariate OR 0.76, [CI 0.37-1.44], p-value=0.417, multivariable OR 1.06 [CI 0.50-2.22], p-value=0.869). However, the HIVpositive participants had a statistically significant lower risk of non-union compared to HIV-negative (univariate OR 0.16 [CI 0.01-0.78], p-value = 0.076, multivariable OR 0.17 [CI 0.01-0.92], p-value = 0.100).

2. HOST 2 study: A total of 57 cases were matched with 57 controls, over a 14month period. The prevalence of HIV among cases was 7% (4/57) and was 15.8% (9/57) among controls, with an overall prevalence of 11.4% (13/114) in the study population. HIV status was not associated with the development of non-union following the management of tibia and femur fractures, on either univariate (OR 0.40 [CI 0.10-1.32], p-value = 0.151) or multivariable (OR 0.86 [CI 0.18-3.73], p-value = 0.831) logistic regression analysis.

Conclusion: The HOST 1 and 2 studies demonstrate that HIV is not associated with the development of delayed union following fracture of the tibia or femur. Additionally, HIV-positive status appears to be associated with a lower risk of developing a non-union. Therefore, fractures sustained in HIV-positive individuals can be managed in the same way as those who are HIV-negative, with no increased risk of delayed or non-union. Future areas of research are indicated to assess the role of ART and CD4 cell count on fracture healing.