Increase in bone turnover markers in HIV patients treated with tenofovir disoproxil fumarate combined with raltegravir or efavirenz

Abstract

Introduction: Accelerated bone loss and osteoporosis are multifactorial comorbidities related to HIV and its treatments; however, their mechanisms remain elusive. Identifying HIV treatments that are differentially linked to osteoporosis risk, and clinical factors associated with HIV-related osteoporosis may enable optimizing anti-retroviral treatment (ART) and anti-osteoporosis therapy in preventing or treating this debilitating complication. This study aims to evaluate the dynamics of bone turnover markers after initiation of two commonly used antiretroviral regimens.

Methods: A prospective matched cohort study. Thirty treatment-naïve male patients (mean age 40 ± 10y) who initiated treatment with truvada (tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)) + raltegravir or TDF/FTC + efavirenz were included in the study. Control group included 15 treatment-naive HIV patients. Serum morning fasting level of P1NP and CTX were measured 0, 1, 6, and 12 months after treatment initiation in the two study groups, and at 0, 6 and 12 months in the control group.

Results: In both treatment groups, but not in the control group, both markers increased significantly over time with no difference in BTM between patients treated with raltegravir or efavirenz. Levels of P1NP were statistically higher at 6 and 12 months after treatment initiation in both treatment groups compared to the controls, while CTX during treatment increased in both treatment groups but was significantly higher only in the raltegravir treatment group after 12 months. The ratio of area under the curve of P1NP/CTX correlated with CD4 increment.

Conclusions: Treatment initiation with raltegravir or efavirenz combined with TDF/FTC is associated with increased bone turnover. Thus, therapy that optimize bone turnover is needed to reduce bone loss at this vulnerable period and improve long-term bone health.

Keywords: CTX; Efavirenz; HIV; P1NP; Raltegravir; Tenofovir/emtricitabine.

Fig. 1

CD4 T cell dynamics during the study period. **CD4 levels were significantly higher before treatment initiation in the control group (control vs RAL p < 0.001, control vs EFV p = 0.002). CD4 levels increased significantly in the raltegravir/TDF + FTC [RAL] C in each time point-1, 6, 12 in comparison to treatment initiation (p = 0.009, p = 0.004, p < 0.001 respectively). CD4 levels increased significantly in the efavirenz/TDF/FTC [EFV] in each time point-1, 6, 12 in comparison to treatment initiation (p < 0.001, p = 0.003, p < 0.001 respectively). Bars indicate SD.

Fig. 2

HIV viral load changes during the study period.

Fig. 3

P1NP levels during the study period. P1NP level increased significantly in the raltegravir/TDF/FTC [RAL] group after 6 and 12 months of treatment in comparison to treatment initiation (6 months vs treatment initiation p = 0.006, 12 months vs treatment initiation p = 0.006) and to the control group (RAL vs control 6 months p = 0.002, RAL vs control 12 months p = 0.01). P1NP level increased significantly in the efavirenz/TDF/FTC [EFV] after 6 and 12 months of treatment compared to treatment initiation (6 months vs treatment initiation p = 0.001, 12 months vs treatment initiation p = 0.001) and the control group (EFV vs control 6 months p = 0.005, EFV vs control 12 months p = 0.001). P1NP levels were significantly higher in the efavirenz/TDF/FTC group in comparison to raltegravir/TDF/FTC [RAL] after 1 months of treatment. p = 0.004, but not at other time points (6 months p = 0.3, 12 months p = 0.7). Bars indicate SD.

Fig. 4

CTX levels during the study period. CTX levels increased significantly in the raltegravir/TDF/FTC [RAL] in 12 months of treatment in comparison to treatment initiation (p = 0.5). CTX levels increased significantly in the raltegravir/TDF/FTC [RAL] at 12 months of treatment in comparison to the control group (untreated patients) (p = 0.02).There was no significant difference in CTX levels between RAL vs EFV in any of time points 0, 1, 6, 12 (p = 0.26, p = 0.6, p = 0.22, p = 0.53 respectively). Bars indicate SD.