Low Body Weight in Females Is a Risk Factor for Increased Tenofovir Exposure and Drug-Related Adverse Events

Abstract

Treatment with tenofovir sometimes leads to non-reversible kidney and/or bone diseases. Factors associated with these drug-related adverse events are poorly characterized. Our objective was to investigate such factors in patients treated long term with daily tenofovir. One-hundred Caucasian HIV-positive patients with basal creatinine clearance >80 mL/min treated with tenofovir for at least 6 months and with at least one assessment of tenofovir plasma trough concentrations were considered. Tenofovir-associated adverse events were defined as the appearance of pathological proteinuria, worsening of renal function or bone demineralization. By multivariate regression analysis, we found that serum creatinine (p = 0.003) and body weight (p = 0.002) were the factors independently associated with plasma tenofovir concentrations. In particular, women with body weight<50 kg had significantly higher plasma tenofovir concentrations than those weighting >50 Kg (160±93 vs.71±52 ng/mL, p<0.001). High tenofovir plasma trough concentrations and the age of the patients were independently associated with the development of drug-related kidney and bone toxicity. In this retrospective study we have shown that HIV-infected women with low body weight are at risk to be exposed to high tenofovir plasma trough concentrations, ultimately resulting in a significant hazard to develop long-term tenofovir complications.

Determinants of bone diseases in tenofovir-treated HIV patients

“…We also extended the findings by Bedimo et al [1] by recognizing that bone disease was significantly associated with the duration of TDF therapy but not with TDF plasma trough concentrations. The latter finding seems to argue against a potential contribution of TDF overexposure on the development of bone diseases, at variance with findings in HIV-infected patients experiencing TDF-related kidney complications [2,3]. This may be eventually related to the fact that, at variance with kidney diseasesin which a direct mechanism linked to the selective accumulation of TDF within renal -4 -tubular cells has been identified [6][7][8] -TDF is only one of the risk factors for bone loss, and its effect may be eventually diluted by the presence of other clinical covariates (such as, patients' sex, age, diet, body mass index, etc) known to play a key pathogenetic role in bone diseases [4,5].…”

“…Furthermore, the Authors documented that, at variance with HCV, HIV infection was associated also with altered bone turnover, as documented by increased telopeptide X (CTX) and osteocalcin (OC) serum concentrations. Here we intend to extend these findings by assessing the potential contribution of TDF overexposure on bone diseases, in consideration of the recently reported associations between high TDF plasma concentrations and the development of kidney impairment [2,3].…”

Incidence of stage 3 chronic kidney disease and progression on tenofovir-based regimens

“…Although gender differences in TDF levels could not be assessed in the previous study, 10% incremental decreases in body mass index were also associated with a 1.04-fold higher TDF AUC [42]. In a report by Gervasoni and colleagues as well as Msango et al, low body mass index, particularly in HIV-positive women, was associated with higher risk of both TDF-related nephrotoxicity and bone toxicity [22, 43]. …”

Concentrations of Pro-Inflammatory Cytokines Are Not Associated with Senescence Marker p16INK4a or Predictive of Intracellular Emtricitabine/Tenofovir Metabolite and Endogenous Nucleotide Exposures in Adults with HIV Infection

“…Inflammation may also affect intracellular enzymes responsible for the metabolism of NRTIs [16]. While FTC is relatively non-toxic, kidney and bone toxicity with TFV are well-described adverse effects of the drug [17], and may potentially be related to drug concentrations [5, 18]. These toxicities are particularly critical in the aging population, as renal function and bone mass density decline occur naturally in this population, and TDF may compound these adverse effects.…”