TFV-DP in DBS is strongly associated with virologic suppression in PLWH on TDF-based therapy and is associated with certain participant characteristics. Further research is required to evaluate this drug adherence and exposure measure in clinical practice.

O ral preexposure prophylaxis (PrEP) using coformulated tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) has proven effective in preventing HIV infection in high-risk individuals (1-7). Unfortunately, PrEP efficacy has not been consistent across all studies, mostly due to variations in drug adherence (8)(9)(10). Multiple studies have demonstrated that sustained drug adherence and exposure are the main factors that determine success in PrEP (1, 5). However, despite its importance, no gold standard measure of antiretroviral adherence is currently available in routine clinical practice, and adequately quantifying adherence continues to be a challenge.Plasma and intracellular tenofovir (TFV) and TFV-diphosphate (TFV-DP) levels have been shown to be powerful markers of adherence to PrEP (1, 5, 11). In particular, TFV-DP in red blood cells (RBCs), measured using dried blood spots (DBS), was found to be a strong marker of cumulative adherence to TDF-FTC and highly predictive of PrEP efficacy in men who have sex with men (MSM) (5,7,12). This is due to the uniquely long intracellular half-life (17 days) of TFV-DP in RBCs (and DBS), which leads to high accumulation with optimal adherence, so that adherence gradients can be estimated. This is informative about cumulative TDF dosing (adherence) over an extended period (6). However, because of its long half-life, TFV-DP in DBS is unable to discriminate between patterns of recent versus remote dosing and cannot adequately detect variations in very recent dosing. Similar to TFV, FTC (the other component of the currently approved PrEP regimen) is also phosphorylated and trapped inside RBCs as FTC-triphosphate (FTC-TP) (13), with the advantage that it can be simultaneously quantified in DBS, along with TFV-DP. Although the pharmacokinetics of TFV-DP in DBS have been defined (6), our current knowledge about the disposition of FTC-TP in this matrix is limited. In addition, it remains unknown whether FTC-TP in DBS can provide adherence information complementary to that provided by TFV-DP.In this study, we aimed to characterize the pharmacokinetics of FTC-TP in DBS and to evaluate its utility as a marker of recent dosing with TDF-FTC.

BackgroundTenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is associated with viral suppression in persons living with HIV (PLWH) taking tenofovir disoproxil fumarate (TDF). However, its value as a predictor of future viremia remained unknown.MethodsBlood for plasma viral load (VL) and TFV-DP in DBS were collected (up to 3 visits within 48 weeks) in PLWH on TDF. TFV-DP cut points were selected using logistic prediction models maximizing the area under the receiver operation characteristic curve, and estimated adjusted odds ratio (aOR) of future viremia (≥20 copies/mL) were compared to the highest TFV-DP category.ResultsAmong all 451 participants in the analysis, aOR of future viremia for participants with TFV-DP <800 and 800 to <1650 fmol/punch were 4.7 (95% CI, 2.6–8.7; P < .0001) and 2.1 (95% CI, 1.3–3.3; P = .002) versus ≥1650 fmol/punch, respectively. These remained significant for participants who were virologically suppressed at the time of the study visit (4.2; 95% CI, 1.5–12.0; P = .007 and 2.2; 95% CI, 1.2–4.0; P = .01).ConclusionsTFV-DP in DBS predicts future viremia in PLWH on TDF, even in those who are virologically suppressed. This highlights the utility of this biomarker to inform about adherence beyond VL.Clinical Trials Registration. NCT02012621.

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Delavirdine mesylate (DLV) is a potent nonnucleoside reverse transcriptase inhibitor with activity specific for human immunodeficiency virus type 1. In the present phase I/II study we evaluated the safety, toxicity, pharmacokinetics, and antiretroviral activities of two-drug and three-drug combinations of DLV and conventional doses of nucleoside analogs compared with those of both DLV monotherapy and two-drug nucleoside analog therapy. A total of 85 human immunodeficiency virus type 1 infected patients with CD4 counts of 100 to 300 cells per mm3 were enrolled in two periods: in the first period patients were randomized to receive either zidovudine (ZDV) plus didanosine (group 1) or ZDV plus didanosine plus escalating doses (400 to 1,200 mg/day) of DLV (group 2). In the second period, patients were randomized to receive either 1,200 mg of DLV alone per day (group 3) or ZDV plus 1,200 mg of DLV per day (group 4). DLV demonstrated good oral bioavailability at all five doses tested. The major toxicity was a transient mild rash which appeared in 44% of all DLV recipients. Overall, group 2 patients demonstrated more sustained improvements in CD4 counts, percent CD4 cells, branched DNA levels, p24 antigen levels, and virus titers in plasma than group 1, 3, or 4 patients. The magnitude of the response correlated with the intensity of prior nucleoside analog treatment, the non-syncytium-inducing or syncytium-inducing viral phenotype at baseline, and the presence of a wild-type codon at amino acid position 215 in the baseline reverse transcriptase genotype. Despite a transient rash, DLV therapy was well tolerated. Combination therapy with DLV and nucleoside analogs appears promising, with the three-drug combination appearing to be more potent that either two-drug combinations or monotherapy.