Lower Cumulative Antiretroviral Exposure in People Living With HIV and Diabetes Mellitus

Abstract

Objective: People living with HIV (PLWH) are living longer and developing more non-AIDS comorbidities, which negatively impact antiretroviral therapy (ART) adherence. Tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is a novel pharmacologic measure of cumulative ART adherence that is predictive of viral suppression and future viremia. However, the relationship between non-AIDS comorbidities and this adherence measure is unknown. We aimed to evaluate the association between 3 non-AIDS comorbidities (diabetes mellitus (DM), hypertension, and hyperlipidemia) and TFV-DP in DBS in PLWH. Methods: Blood for TFV-DP in DBS and HIV viral load was prospectively collected from PLWH on tenofovir disoproxil fumarate for up to 3 times over 48 weeks. Non-AIDS comorbidities were recorded. Mixed effect multivariable linear regression models were used to estimate the changes in TFV-DP concentrations in DBS according to the presence of comorbidities and to estimate the percent differences in TFV-DP concentrations between these groups. Results: A total of 1144 person-visits derived from 523 participants with available concentrations of TFV-DP in DBS were included in this analysis. In univariate analysis, no significant association between non-AIDS comorbidities (categorized as having 0, 1, 2, or 3 comorbidities) and the concentrations of TFV-DP in DBS was observed (P = 0.40). Participants who had DM had 25% lower (95% confidence interval: −36% to −12%; P < 0.001) TFV-DP in DBS than participants without DM after adjusting for age, gender, race, body mass index, estimated glomerular filtration rate, CD4+ T-cell count, hematocrit, ART class, patient-level medication regimen complexity index, and 3-month self-reported adherence. Conclusions: Diabetic PLWH have lower concentrations of TFV-DP in DBS compared with those without DM. Further research is required to identify the clinical implications and biological mechanisms underlying these findings.

Higher medication complexity in persons with HIV is associated with lower tenofovir diphosphate in dried blood spots

“…Second, a more complex medication regimen has the potential for more drug‐drug interactions, which could theoretically impact TFV‐DP concentrations; however, interactions of this magnitude are not likely 34,35 . Third, a more complex medication regimen is a marker for more comorbidities, which could influence drug concentrations, as was previously observed in this cohort in PWH and diabetes mellitus 36 . Finally, patients who are nonadherent to ART may be more likely to require prophylactic medications for opportunistic infections, which in turn would increase the pMRCI.…”

Tenofovir-silver nanoparticles conjugate ameliorates neurocognitive disorders and protects ultrastructural and cytoarchitectonic properties of the prefrontal cortex in diabetic rats

“…Tenofovir disoproxil fumarate (TDF) is commonly used for pre-exposure prophylaxis alone or in combination with other antiretroviral drugs as post-exposure prophylaxis [46,47]. Despite TDF's low CNS-penetration rate, studies have reported its neurotoxic effect and diabetic and neurocognitive implications [11,12,19]. Silver nanoparticles have been shown to cross the blood-brain barrier independent of dosage and route of administration [48,49].…”

“…In addition, a 25% reduction in the TDF concentration was observed in dried blood spots of people with diabetes mellitus compared with non-diabetic control adults [12]. Long-term administration of NRTIs, especially TDF, is associated with metabolic disorders, diabetes mellitus, and systemic and organ toxicity [13,14].…”

“…However, TDF is ranked as a low central nervous system (CNS)-penetration drug considering its physicochemical characteristics, cerebrospinal fluid concentration, and effectiveness in the CNS [ 9 - 11 ]. More so, a 25% reduction in the TDF concentration was observed in dried blood spots of people with diabetes mellitus compared with non-diabetic control (NC) adults [ 12 ]. Besides, long-term administration of NRTIs, especially TDF, is associated with metabolic disorders, diabetes mellitus, and systemic and organ toxicity [ 13 , 14 ].…”

“…Despite the benefits of TDF in HIV management and control, studies have proposed its dose modification in people living with diabetes mellitus and HIV due to its low CNS penetration and neurotoxicity [ 11 , 12 ]. For these reasons, using the nano-delivery system to navigate TDF via the bloodbrain barrier and improving its CNS concentration while minimizing its neurotoxic effects would provide immense therapeutic benefits.…”