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BMD Loss in HIV TDF PrEP - 2 studies
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BMD Loss in HIV- Men Participating in a TDF PrEP Clinical Trial in San Francisco
Jules Levin
CROI 2011 March 2 Boston
Albert Liu*1,2, E Vittinghoff2, R Irby2, K Mulligan2, D Sellmeyer3, K Mayer4, M Thompson5, R Gvetadze6, L Grohskopf7, and S Buchbinder1,2
1San Francisco Dept of Publ Hlth, CA, US; 2Univ of California, San Francisco, US; 3Johns Hopkins Univ Sch of Med, Baltimore, MD, US; 4Fenway Hlth, Boston, MA, US; 5AIDS Res Consortium of Atlanta, GA, US; 6Northrop Grumman, Atlanta, GA, US; and 7CDC, Atlanta, GA, US
Background: Several pre exposure prophylaxis (PrEP) trials are evaluating regimens containing tenofovir disoproxil fumarate (TDF) in HIV- individuals for HIV prevention. Little is known about the effect of daily TDF on bone mineral density (BMD) in this population.
Methods: From 2005 to 2007, 200 HIV- men who have sex with men (MSM) enrolled in San Francisco in a double-blind, randomized trial evaluating the safety of daily oral TDF vs placebo. Half began the study drug after a 9-month delay to evaluate changes in risk behavior with pill use. Longitudinal DEXA bone densitometry was performed in 184 men at baseline, 9 or 12 months, and 24 months. Linear mixed models were used to assess effects of TDF on percentage change in BMD. A secondary workup including thyroid-stimulating hormone, testosterone, urine calcium/creatinine, 25-OH vitamin D, and parathyroid hormone, was performed in men with low BMD (Z score ²2.0 at the total spine, total hip, or femoral neck) or a ³5% decrease from baseline.
Results:
Median age was 40 years; 77% were white, 7% Latino or Hispanic, 5% African American, and 5% Asian or Pacific Islander.
Body mass index (BMI) was slightly higher in the TDF group at baseline; otherwise there were no significant differences between groups.
In the intention-to-treat analysis, there was a 1.1% net decrease in mean BMD in the TDF vs pre-treatment or placebo group at the femoral neck (95% CI 0.4 to 1.9%, p = 0.004) and a 0.8% net decline at the total hip (95%CI 0.3 to 1.3%, p = 0.003); at the L2 to L4 spine, there was a non to significant trend towards an adverse effect (0.7% decline, 95%CI -0.1 to 1.5%, p = 0.11).
Results were similar after adjustment for baseline BMD, BMI, race, age, and baseline creatinine clearance.
Declines in BMD in the TDF group were most prominent during the first 12 to 15 months of treatment.
Overall, 13% vs 6% participants experienced ³5% loss of BMD at the femoral neck in the TDF vs placebo groups (p = 0.13). Evaluations performed in 27 men revealed 2 with vitamin D deficiency and 2 with hypogonadism.
In all, 10 participants reported fractures during follow-up: 6 in the TDF group and 4 in the placebo group (p = 0.75); all were trauma-related and assessed as not related to study drug.
Conclusions: TDF use resulted in a small but statistically significant decline in BMD at the total hip and femoral neck in HIV- men participating in a PrEP trial. Larger studies with longer follow-up are needed to determine the trajectory of these BMD changes and any association with clinical fractures.
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Effects of FTC/TDF on Bone Mineral Density in Seronegative Men from 4 Continents: DEXA Results of the Global iPrEx Study
Kathleen Mulligan*1, D Glidden1, P Gonzales2, M-E Ramirez-Cardich3, A Liu1,4, S Namwongprom5, P Chodacki6, L Mendon¨a7, V McMahan8, R Grant1,8, and iPrEx Study Team
1Univ of California, San Francisco, US; 2Investigaciones Medicas en Salud, Lima, Peru; 3Assn Civil Impacta Salud y Ed, Lima, Peru; 4San Francisco Dept of Publ Hlth, CA, US; 5Chiang Mai Univ, Thailand; 6Desmond Tutu HIV Fndn, Cape Town, South Africa; 7Federal Univ of Rio de Janeiro, Brazil; and 8Gladstone Inst of Virology and Immunology, San Francisco, CA, US
Background: Oral emtricitabine/tenofovir (FTC/TDF) pre-exposure prophylaxis (PrEP) decreases HIV acquisition among men who have sex with men (MSM). Initiation of TDF has been associated with decreases in bone mineral density in HIV+ people. HIV infection itself, host response to HIV, and other antiretroviral drugs may also contribute to bone loss in HIV- populations. The effect of the combination of FTC/TDF on bone mineral density in the absence of HIV infection is not known.
Methods: DEXA scans of the hip and spine were performed at baseline and 24-week intervals in a substudy of iPrEx, an international randomized, double-blind, placebo-controlled trial of FTC/TDF PrEP in MSM. Data are reported as the mean (SE) difference of change since enrollment in the FTC/TDF vs placebo groups; p values were based on a linear mixed model.
Results: We enrolled 503 participants (247 randomized to FTC/TDF and 256 to placebo) in this optional substudy (Peru n = 221, Thailand n = 95, US n = 71, South Africa n = 61, Brazil n = 55) with variable periods of follow-up. Mean body mass index was 23.5 (0.2) kg/m2; 18% were Caucasian, 13% black, 20% Asian, 49% mixed race; 52% were of Hispanic or Latino; 48% of subjects were age 18 to 24 years and likely still accruing bone mass. At baseline, 36% had low bone mineral density (Z-score <-1) in the spine and 18% in the hip. There were no differences between randomization groups in baseline bone mineral density or percentage with low bone mineral density. Percentage changes in bone mineral density at weeks 24 (n = 418), 48 (n = 268), and 72 (n = 126) are shown below. Bone mineral density tended to increase in the placebo arm and decrease in the FTC/TDF arm, resulting in modest (-0.7 to -1.0%) but statistically significant differences between the groups by week 24. There were no differences between the groups in bone fractures (p = 0.56) or the incidence of low bone mineral density using WHO or International Society for Clinical Densitometry criteria.
Mean (SE) percent change in bone mineral density from enrollment
Conclusions: In this large, diverse group of HIV- MSM, there were small but significant decreases in bone mineral density in those randomized to FTC/TDF relative to placebo, suggesting an effect of FTC/TDF on bone mass in the absence of HIV infection.
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