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

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.

Intracellular Tenofovir-Diphosphate and Emtricitabine-Triphosphate in Dried Blood Spots Following Tenofovir Alafenamide: The TAF-DBS Study.

BACKGROUND: Tenofovir alafenamide (TAF), in combination with FTC, was recently approved for PrEP in the United States. The objective of this study was to assess the relationship between tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) in dried blood spots (DBS) with adherence to TAF/FTC. METHODS: TAF-DBS was a randomized, crossover clinical study of TFV-DP in DBS, following directly observed dosing of 33%, 67%, or 100% of daily TAF (25 mg)/FTC (200 mg). Healthy volunteers were randomized to 2 different, 12-week dosing regimens, separated by a 12-week washout. DBS were collected weekly. TFV-DP and FTC-TP were extracted from two 7-mm punches and assayed with LC-MS/MS. RESULTS: Thirty-seven participants (17 female, 7 African American, and 6 Hispanic) were included. TFV-DP exhibited a mean half-life of 20.8 days (95% confidence interval: 19.3 to 21.3). The slope for TFV-DP versus dosing arm was 1.14 (90% confidence interval: 1.07 to 1.21). The mean (SD) TFV-DP after 12 weeks was 657 (186), 1451 (501), and 2381 (601) fmol/2 7-mm punches for the 33%, 67%, and 100% arms. The following adherence interpretations are proposed: <450 fmol/punches, <2 doses/wk; 450-949 fmol/punches, 2-3 doses/wk; 950-1799 fmol/punches, 4-6 doses/wk; and ≥1800 fmol/punches, 7 doses/wk. FTC-TP was quantifiable for 1 week after drug cessation in 50%, 92%, and 100% of participants in the 33%, 67%, and 100% arms, respectively. CONCLUSION: TFV-DP in DBS after TAF/FTC exhibited a long half-life and was linearly associated with dosing, similar to its predecessor tenofovir disoproxil fumarate. FTC-TP was quantifiable for up to 1 week after drug cessation. Together, these moieties provide complementary measures of cumulative adherence and recent dosing for TAF/FTC.

Brief Report: Higher ART Adherence Is Associated With Lower Systemic Inflammation in Treatment-Naive Ugandans Who Achieve Virologic Suppression.

BACKGROUND: Residual systemic inflammation persists despite suppressive antiretroviral therapy (ART) and is associated with non-AIDS clinical outcomes. We aimed to evaluate the association between ART adherence and inflammation in Ugandans living with HIV who were predominantly receiving nevirapine-based ART with a thymidine analog backbone and were virologically suppressed by conventional assays. METHODS: Plasma concentrations of interleukin-6 (IL-6), D-dimer, soluble (s)CD14, sCD163, and the kynurenine/tryptophan ratio, in addition to CD8 T-cell activation, were measured at baseline and 6 months after ART initiation in treatment-naive adults who achieved an undetectable plasma HIV RNA (<400 copies/mL) at their 6-month visit. Adherence was measured through medication event monitoring system and calculated as the ratio of observed/prescribed device openings per participant. We fit adjusted linear regression models to estimate the association between ART adherence and the log-transformed plasma concentrations of inflammatory biomarkers. RESULTS: We evaluated 282 participants (median age, 35 years; 70% women). The median (interquartile range) adherence was 93% (84-98). In the adjusted analyses, for every 10% increase in average ART adherence, we found a 15% [P < 0.0001; 95% confidence interval (CI), -21.0 to -7.9], 11% (P = 0.017; 95% CI, -18.3 to -2.0), and 3% (P = 0.028; 95% CI, -5.0 to -0.3) decrease in IL-6, D-dimer, and sCD14, respectively. CONCLUSIONS: Higher ART adherence was associated with lower levels of biomarkers of inflammation, immune activation, and coagulopathy among Ugandans living with HIV who achieved viral suppression shortly after ART initiation. This suggests that ART adherence could have biological consequences beyond viral suppression. Whether ART adherence optimization in virologically suppressed individuals could reduce residual inflammation remains unknown.

Brief Report: Adherence Biomarker Measurements in Older and Younger HIV-Infected Adults Receiving Tenofovir-Based Therapy.

BACKGROUND: Concentrations of tenofovir (TFV) in hair and tenofovir diphosphate (TFV-DP) in dried blood spots (DBSs) as measures of cumulative exposure have been primarily studied in younger, HIV-uninfected individuals taking preexposure HIV prophylaxis. Data on these measures among older HIV-infected individuals are limited. METHODS: We evaluated longitudinal TFV and TFV-DP concentrations in hair and DBS, respectively, from HIV-infected adults. Multivariable model variables included age group (18-35 and 60 years and older), creatinine clearance (CrCl), hematocrit (TFV-DP), and gray hair color (TFV). RESULTS: Baseline hair TFV and DBS TFV-DP were moderately correlated [r = 0.5 (0.2 to 0.7); P = 0.001] across both age groups [younger (N = 23) and older (N = 22)]. In adjusted models, CrCl was associated with increases of 15.9% (7.4% to 25.0%); P = 0.0006, and 5.7% (-0.2% to 11.9%); P = 0.057 for TFV in hair and TFV-DP in DBS, respectively, for every 20-mL/min CrCl decrease. Although older age (versus younger age) was univariately associated with increased TFV hair levels, older age was not significantly associated with higher concentrations in hair [-1.4% (-26.7% to 32.7%); P = 0.93] or DBS [4.0% (-14.1% to 25.9%); P = 0.68] after adjustment. Similarly, gray color was not significantly associated with higher TFV levels in hair [27.6% (-11.1% to 83.0%; P = 0.18)] in adjusted models. In both adjusted and unadjusted models of TFV-DP levels in DBS, a 1% hematocrit increase was associated with a 3.3% (0.2% to 6.5%) TFV-DP increase (P = 0.04). CONCLUSIONS: Cumulative drug exposure measures (hair and DBS) were comparable in younger and older HIV-infected individuals on TFV-based therapy after adjustment for renal function.