Novel quantification of tenofovir disoproxil fumarate adherence in human immunodeficiency virus/hepatitis B coinfected patients with incomplete hepatitis B virus viral suppression
Authors: Tammy C. Wong, Audrey Lan, Jennifer J. Kiser, Peter L. Anderson, Keyur Patel, Hans Tillman, Susanna Naggie
Journal: Hepatology (2016)

Potential conflict of interest: Dr. Tillmann consults for Novartis and Novo Nordisk. He owns stock in AbbVie, Abbott, Gilead, Regeneron, Celldex, and Regulus. Dr. Kiser is on the speakers' bureau for Astellas and received grants from Janssen. Dr. Anderson received grants from Gilead. Dr. Naggie advises and received grants from Gilead. Dr. Patel advises Gilead. To the Editor: We read with interest the article by Boyd et al. addressing patterns of suboptimal response to tenofovir disoproxil fumarate (TDF)‐based therapies in human immunodeficiency virus (HIV)/hepatitis B virus (HBV) coinfected individuals.1 The authors acknowledged that plasma concentrations of tenofovir do not reflect longer‐term adherence. Because of intracellular phosphorylation, monitoring intracellular drug levels of tenofovir‐diphosphate (TFV‐DP) can provide long‐term assessments of adherence given the 17‐day half‐life of TFV‐DP in red blood cells (RBCs).2 An ongoing institutional review board–approved study in the Duke HIV Clinic is assessing adults with HIV/HBV coinfection who were on a stable TDF‐containing antiretroviral regimen and had (1) evidence of HBV viral suppression (<357 IU/mL) and new HBV‐DNA detection and evidence of persistent HIV‐RNA suppression (<50 copies/mL for >6 months) or (2) persistent HBV‐DNA detection and evidence of long‐term HIV‐RNA suppression for >2 consecutive years. Plasma and dried blood spot (DBS) were collected at time of consent. Drugs were measured in plasma and DBS at the University of Colorado Antiviral Pharmacology Laboratory (previously described).2 Tenofovir, emtricitabine (FTC), and raltegravir (RAL) were quantified in plasma, and TFV‐DP and the intracellular form of emtricitabine (FTC‐TP) were quantified in DBSs, both using a validated liquid chromatography tandem mass spectrometry method.2 To date, we have enrolled 2 patients (Table 1). HBV genotyping for both patients was negative for mutations. PID01 had tenofovir and FTC plasma levels suggesting that the patient had not taken TDF/FTC in several days before the study visit (Table 1). In DBS, the FTC‐TP concentration was below the limit of quantification (BLQ), and TFV‐DP concentration was 299 fmol/punch. FTC‐TP has a short half‐life in RBCs and is therefore a measure of short‐term adherence similar to plasma levels. The TFV‐DP concentration is consistent with a TDF/FTC dosing pattern of approximately 2 doses per week. Patient PID02 had plasma and DBS concentrations that were quantifiable for tenofovir, FTC, and RAL, and TFV‐DP and FTC‐TP, respectively, suggesting recent dosing. Again, the TFV‐DP concentration would suggest a dosing pattern of approximately 2 doses of TDF/FTC per week. Table 1 - Assessment of Intracellular and Plasma Drug Levels and Corresponding Viral Outcomes Patient Plasma TDF Level (ng/mL) Plasma FTC Level (ng/mL) Plasma RAL Level (ng/mL) DBS TDF‐DP Level (fmol/punch) DBS FTC‐TP Level (pmol/punch) Most Recent HIV Viral Loadc (copies/mL) CD4 Count (cells/mm3) Most Recent HBV Viral Loadc (IU/mL) PID01a BLQ BLQ N/A 299 BLQ <20 670 20,000 PID02a 223 2,216 8.48 215 0.227 <20 480 300,000 PID02b 103 469 346 — — N/A N/A N/A PID02b 80.8 326 407 — — N/A N/A N/A aAt time of enrollment.bBefore enrollment date from clinic repository.cMost recent viral loads from the medical record and as per inclusion criteria.Abbreviation: N/A, not applicable. The pattern of quantifiable plasma concentrations, but low TFV‐DP intracellular concentrations, is consistent with "white coat adherence." To further investigate this, HIV RNA was quantified in the study samples, which did not coincide with an HIV clinic visit. Indeed, both samples had evidence of low‐level HIV viremia. Neither patient had evidence of HIV viremia on clinical testing in the previous year, suggesting clinical viral load monitoring does not identify white coat adherence. These data are complementary to the work presented by Boyd et al., providing a measure of long‐term adherence that spot plasma levels cannot. These data further support the concern expressed by the authors that lack of HBV viral control on TDF nucleoside analog therapy is a sign of poor long‐term adherence.