Impact of Tenofovir-Based Pre-exposure Prophylaxis on Biomarkers of Bone Formation, Bone Resorption, and Bone Mineral Metabolism in HIV-Negative Adults.

BACKGROUND: Pre-exposure prophylaxis (PrEP) with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) reduces the risk of HIV seroconversion but may promote bone mineral density (BMD) decline. The mechanisms of BMD decline with FTC/TDF remain unclear, and studies in HIV-positive individuals have been confounded by the effects of HIV and concomitant antiretroviral medications. We evaluated the impact of FTC/TDF on biomarkers of bone remodeling and bone mineral metabolism in HIV-negative men and women enrolled in the Partners PrEP Study. METHODS: In a random sample of HIV-negative participants randomized to FTC/TDF PrEP (n = 50) or placebo (n = 50), serum parathyroid hormone (PTH), bone biomarkers (C-telopeptide, procollagen 1 intact N-terminal propeptide, and sclerostin), and plasma fibroblast growth factor 23 were measured at baseline and month 24, and the percentage change was compared between groups. In a complementary analysis, we compared the change in biomarkers between participants with and without a 25% decline in glomerular filtration rate (GFR) on FTC/TDF. RESULTS: Baseline characteristics were similar between the groups (median age, 38 years; 40% women). Vitamin D insufficiency was common, but baseline GFR and PTH were in the normal range. We observed a significantly greater percent increase in serum C-telopeptide in participants randomized to FTC/TDF vs placebo (P = .03), suggesting an increase in bone remodeling. We observed no differences in the other biomarkers, or in a separate analysis comparing participants with and without a decline in GFR. CONCLUSIONS: Increased bone remodeling may mediate the BMD decline observed with tenofovir-containing PrEP and antiretroviral therapy, independent of a TDF-mediated decrease in kidney function.

Folic acid supplementation and chronic kidney disease progression.

In contrast to prior studies demonstrating no benefit or even increased harm from B vitamin supplementation in patients with chronic kidney disease, a large randomized trial from China recently demonstrated small but statistically significant reductions in the risk of first stroke and chronic kidney disease progression with the addition of folic acid to enalapril in adults with hypertension. Differences in the study population and study intervention may explain these discordant results.

HIF stabilization by prolyl hydroxylase inhibitors for the treatment of anemia in chronic kidney disease.

The treatment of anemia with erythropoiesis-stimulating agents and iron supplementation has become the standard of care in patients with chronic kidney disease. Because of the risks associated with this approach, hypoxia inducible factor stabilizing prolyl hydroxylase inhibitors were developed as a potential treatment alternative. In recent phase 2 trials, these agents raised hemoglobin in a predictable and controlled manner and improved markers of iron metabolism. More experience is needed to establish long-term efficacy, tolerability, and safety, and to determine whether their use is associated with lower iron requirements.

Fibroblast growth factor receptor 4: the missing link between chronic kidney disease and FGF23-induced left ventricular hypertrophy?

Serum phosphorus and the regulatory hormone fibroblast growth factor 23 have been strongly linked to cardiovascular morbidity and mortality in patients with chronic kidney disease. A recent study identified fibroblast growth factor receptor 4 as the primary receptor mediating the effect of fibroblast growth factor 23 on left ventricular hypertrophy, providing new mechanistic insights and a potential therapeutic target to reduce cardiovascular morbidity in chronic kidney disease.

Short communication: Inadequate vitamin D exacerbates parathyroid hormone elevations in tenofovir users.

Parathyroid hormone (PTH) elevations are associated with reduced bone mineral density and adverse health outcomes and have been reported in patients with HIV infection. We aimed to examine the impact of vitamin D status and tenofovir (TDF) use on PTH levels among HIV-infected patients receiving combination antiretroviral therapy (cART). Demographics, medication and supplement use, and clinical data, including 25-hydroxyvitamin D [25(OH)D] and PTH, were collected on 45 HIV-infected men on ART. Suboptimal vitamin D status was defined as 25(OH)D < 30 ng/ml. The relationship between antiretroviral agents, suboptimal 25(OH)D, and PTH levels was examined. Among subjects with suboptimal vitamin D status, PTH values greater than or equal to the ULN (87 pg/ml) were more common among TDF users than nonusers: 41% versus 0% (p = 0.018); and median PTH was higher in TDF users: 80 pg/ml versus 55 pg/ml (p = 0.02). Among TDF users, PTH was higher in the group with suboptimal 25(OH)D (p = 0.045). Multivariable linear regression showed that PTH was independently and directly related to TDF use (p = 0.017) and inversely related to 25(OH)D (p = 0.017). PTH was not related to the estimated glomerular filtration rate (p = 0.9). In this cross-sectional study of HIV-infected men on ART, the use of TDF and the level of 25(OH)D were independently associated with PTH levels. Because TDF is a potent and widely used antiretroviral drug, information about cofactors that may exacerbate its side effects is of significant clinical value.