HHS Public Access Author manuscript Author Manuscript
Hepatology. Author manuscript; available in PMC 2017 September 01. Published in final edited form as: Hepatology. 2016 September ; 64(3): 999–1000. doi:10.1002/hep.28461.
Novel Quantification of TDF adherence in HIV-hepatitis B coinfected patients with incomplete HBV viral suppression Tammy Chin1, Audrey Lan1, Jennifer Kiser2, Peter L. Anderson2, Keyur Patel3, Hans Tillman3, and Susanna Naggie1 1Division
of Infectious Diseases, Duke University Medical Center, Durham, North Carolina
Author Manuscript
2Department
of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado-Anschutz Medical Campus, Aurora, Colorado
3Division
of Gastroenterology, Duke University Medical Center, Durham, North Carolina
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 HIV/HBV coinfected individuals.1 The authors acknowledged that plasma concentrations of tenofovir do not reflect longer term adherence. Due to 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.2,3
Author Manuscript
An ongoing IRB-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 (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).2,3 Tenofovir, emtricitabine (FTC), and raltegravir were quantified in plasma and TFV-DP and the intracellular form of emtricitabine (FTC-TP) were quantified in dried blood spots, both using a validated LC-MS/MS method.2,3
Author Manuscript
To date we have enrolled two patients. (Table 1) HBV genotyping for both patients was negative for mutations. PID01 had tenofovir and FTC plasma levels suggesting the patient had not taken TDF/FTC in several days prior to the study visit. (Table 1) In DBS, the FTCTP 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
Reprints or correspondence: Susanna Naggie, Div. of Infectious Diseases, Duke University Medical Center, Box 3850, Durham, NC 27710 ([email protected]). Disclosures SN reports receiving research funds to her institution from Gilead Sciences.
Chin et al.
Page 2
Author Manuscript
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 raltegravir, and TFVDP 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. 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 prior year suggesting clinical viral load monitoring does not identify white coat adherence.
Acknowledgments Author Manuscript
These data are complimentary 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 analogue therapy is a sign of poor long term adherence.
References
Author Manuscript
1. Boyd A, Gozlan J, Maylin S, Delaugerre C, Peytavin G, et al. Persistent viremia in HIV-hepatitis B co-infected patients undergoing long-term tenofovir: virologic and clinical implications. Hepatology. 2014; 60(2):497–507. [PubMed: 24752996] 2. Castillo-Mancilla J, Zheng J, Rower J, Meditz A, Gardner EM, et al. Tenofovir, emtricitabine, and tenofovir diphosphate in dried blood spots for determining recent and cumulative drug exposure. AIDS Res Hum Retrov. 2013; 29:384–390. 3. Zheng J, Guida L, Rower C, Castillo-Mancilla J, Meditz A, et al. Quantification of tenofovir and emtricitabine in dried blood spots (DBS) with LC-MS/MS. J Pharmaceut Biomed. 2014; 88:144– 151.
Author Manuscript Hepatology. Author manuscript; available in PMC 2017 September 01.
Author Manuscript
Author Manuscript
BLQ
223
PID01
PID02
8.48
–
Plasma RAL Level (ng/mL)
215
299
DBS TDF-DP Level (fmol/ punch)
HIV RNA quantified from plasma samples drawn for study (Roche TaqMan 2.0 LLQ 20 copies/mL)
*
¶ most recent viral loads from the medical record and as per inclusion criteria,
2216
BLQ
Plasma FTC Level (ng/mL)
BLQ – below the limit of quantification,
Plasma TDF Level (ng/mL)
Patient
0.227
BLQ
DBS FTC-TP Level (pmol/ punch)
Hepatology. Author manuscript; available in PMC 2017 September 01. Published in final edited form as: Hepatology. 2016 September ; 64(3): 999–1000. doi:10.1002/hep.28461.
Novel Quantification of TDF adherence in HIV-hepatitis B coinfected patients with incomplete HBV viral suppression Tammy Chin1, Audrey Lan1, Jennifer Kiser2, Peter L. Anderson2, Keyur Patel3, Hans Tillman3, and Susanna Naggie1 1Division
of Infectious Diseases, Duke University Medical Center, Durham, North Carolina
Author Manuscript
2Department
of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado-Anschutz Medical Campus, Aurora, Colorado
3Division
of Gastroenterology, Duke University Medical Center, Durham, North Carolina
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 HIV/HBV coinfected individuals.1 The authors acknowledged that plasma concentrations of tenofovir do not reflect longer term adherence. Due to 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.2,3
Author Manuscript
An ongoing IRB-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 (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).2,3 Tenofovir, emtricitabine (FTC), and raltegravir were quantified in plasma and TFV-DP and the intracellular form of emtricitabine (FTC-TP) were quantified in dried blood spots, both using a validated LC-MS/MS method.2,3
Author Manuscript
To date we have enrolled two patients. (Table 1) HBV genotyping for both patients was negative for mutations. PID01 had tenofovir and FTC plasma levels suggesting the patient had not taken TDF/FTC in several days prior to the study visit. (Table 1) In DBS, the FTCTP 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
Reprints or correspondence: Susanna Naggie, Div. of Infectious Diseases, Duke University Medical Center, Box 3850, Durham, NC 27710 ([email protected]). Disclosures SN reports receiving research funds to her institution from Gilead Sciences.
Chin et al.
Page 2
Author Manuscript
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 raltegravir, and TFVDP 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. 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 prior year suggesting clinical viral load monitoring does not identify white coat adherence.
Acknowledgments Author Manuscript
These data are complimentary 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 analogue therapy is a sign of poor long term adherence.
References
Author Manuscript
1. Boyd A, Gozlan J, Maylin S, Delaugerre C, Peytavin G, et al. Persistent viremia in HIV-hepatitis B co-infected patients undergoing long-term tenofovir: virologic and clinical implications. Hepatology. 2014; 60(2):497–507. [PubMed: 24752996] 2. Castillo-Mancilla J, Zheng J, Rower J, Meditz A, Gardner EM, et al. Tenofovir, emtricitabine, and tenofovir diphosphate in dried blood spots for determining recent and cumulative drug exposure. AIDS Res Hum Retrov. 2013; 29:384–390. 3. Zheng J, Guida L, Rower C, Castillo-Mancilla J, Meditz A, et al. Quantification of tenofovir and emtricitabine in dried blood spots (DBS) with LC-MS/MS. J Pharmaceut Biomed. 2014; 88:144– 151.
Author Manuscript Hepatology. Author manuscript; available in PMC 2017 September 01.
Author Manuscript
Author Manuscript
BLQ
223
PID01
PID02
8.48
–
Plasma RAL Level (ng/mL)
215
299
DBS TDF-DP Level (fmol/ punch)
HIV RNA quantified from plasma samples drawn for study (Roche TaqMan 2.0 LLQ 20 copies/mL)
*
¶ most recent viral loads from the medical record and as per inclusion criteria,
2216
BLQ
Plasma FTC Level (ng/mL)
BLQ – below the limit of quantification,
Plasma TDF Level (ng/mL)
Patient
0.227
BLQ
DBS FTC-TP Level (pmol/ punch)
