Tenofovir Diphosphate in Dried Blood Spots and HIV-1 Resistance in South Africa

Overview

Journal AIDS Res Ther

Publisher Biomed Central

Specialty Infectious Diseases

Date 2023 Sep 13

PMID 37705102

Authors

Y Singh

J Castillo-Mancilla

R Madimabe

L Jennings

C M Ferraris

R N Robbins

P L Anderson

R H Remien

C Orrell

Affiliations

Soon will be listed here.

Abstract

Background: Suboptimal antiretroviral (ART) adherence can lead to virologic failure with consequent HIV-1 resistance. Tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is a powerful biomarker of cumulative adherence, predictive of future viremia. It has been associated with resistance in Persons With HIV (PWH) in South Africa and the US. We explored the relationship of TFV-DP concentrations with antiretroviral drug resistance at the time of treatment failure in SA.

Methods: Adult PWH from health clinics in Cape Town, South Africa on efavirenz-based first-line ART containing tenofovir disoproxil fumarate (TDF) with an undetectable (< 50 copies/mL) HIV-1 viral load (VL) were prospectively enrolled in an observational cohort for 12 months. Monthly study visits included blood collection for HIV-1 VL and DBS for TFV-DP. The first confirmed viral breakthrough (VB) > 400 copies/mL triggered HIV-1 genotyping at the subsequent visit. An electronic adherence (EA) device monitored ART adherence in real-time, estimated as a percent for the 30-days prior to VB. Wilcoxon rank sum test was used to compare median [IQR] TFV-DP by genotype outcome.

Results: Of 250 individuals, (n = 195, 78% women), 21 experienced VB, with a median of 5 [4;7] months on study, and a median EA of 33.3 [13.3;53.3]%. Demographic characteristics between those with and without VB were similar. Median VL at VB was 4.0 [3.2;4.5] log copies/mL. TFV-DP concentrations trended down towards the VB visit. Median TFV-DP concentrations were significantly higher in those HIV-1 genotype did not amplify due to being virally suppressed at the subsequent visit (n = 10; 380 [227-661] fmol/punch, p = 0.035; EA 45 [24.9; 59.2]%); than in those who were successfully genotyped with evidence of drug resistance (n = 5, 241 [150-247] fmol/punch, EA 20 [6.7;36.7]%) and in individuals who did not have resistance (n = 3, 39.9 [16.6; 93.9] fmol/punch; EA 33.3 [16-38]%). Three genotype collections were not done. Only non-nucleoside reverse transcriptase inhibitor-associated mutations were identified on resistance testing. (K103N, E138K, Y118H).

Conclusion: TFV-DP in DBS showed a step-wise inverse relationship with VB and drug resistance, with evidence of low cumulative ART adherence in PWH who developed antiretroviral resistance. Monitoring TFV-DP concentrations could be a valuable tool for predicting future VB and future resistance.

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References

Orrell C, Cohen K, Mauff K, Bangsberg D, Maartens G, Wood R . A Randomized Controlled Trial of Real-Time Electronic Adherence Monitoring With Text Message Dosing Reminders in People Starting First-Line Antiretroviral Therapy. J Acquir Immune Defic Syndr. 2015; 70(5):495-502. DOI: 10.1097/QAI.0000000000000770. View

Castillo-Mancilla J, Brown T, Erlandson K, Palella Jr F, Gardner E, Macatangay B . Suboptimal Adherence to Combination Antiretroviral Therapy Is Associated With Higher Levels of Inflammation Despite HIV Suppression. Clin Infect Dis. 2016; 63(12):1661-1667. PMC: 5146724. DOI: 10.1093/cid/ciw650. View

Castillo-Mancilla J, Musinguzi N, Asiimwe S, Siedner M, Orrell C, Bangsberg D . High residual inflammation despite HIV viral suppression: Lessons learned from real-time adherence monitoring among people with HIV in Africa. HIV Med. 2021; 23(5):465-473. DOI: 10.1111/hiv.13200. View

Castillo-Mancilla J, Edwards J, Brijkumar J, Moosa M, Zhao Y, Ofotokun I . Tenofovir diphosphate levels in dried blood spots are associated with virologic failure and resistance to first-line therapy in South Africa: a case-control cohort study. J Int AIDS Soc. 2021; 24(12):e25849. PMC: 8673924. DOI: 10.1002/jia2.25849. View

Yager J, Coyle R, Coleman S, Ellison L, Zheng J, Bushman L . Moderately High Tenofovir Diphosphate in Dried Blood Spots Indicates Drug Resistance in Viremic Persons Living with HIV. J Int Assoc Provid AIDS Care. 2019; 18:2325958219888457. PMC: 6873269. DOI: 10.1177/2325958219888457. View

Kristofich M, Anderson P, Castillo-Mancilla J . Beyond HIV viral load: application of pharmacologic measures to identify ART adherence mismatch. Ther Adv Infect Dis. 2021; 8:20499361211010596. PMC: 8127751. DOI: 10.1177/20499361211010596. View

Ammassari A, Trotta M, Shalev N, Marconi P, Antinori A . Beyond virological suppression: the role of adherence in the late HAART era. Antivir Ther. 2012; 17(5):785-92. DOI: 10.3851/IMP2084. View

Breuer E, Stoloff K, Myer L, Seedat S, Stein D, Joska J . The validity of the Substance Abuse and Mental Illness Symptom Screener (SAMISS) in people living with HIV/AIDS in primary HIV care in Cape Town, South Africa. AIDS Behav. 2014; 18(6):1133-41. DOI: 10.1007/s10461-014-0698-y. View

Mansky L, Pearl D, Gajary L . Combination of drugs and drug-resistant reverse transcriptase results in a multiplicative increase of human immunodeficiency virus type 1 mutant frequencies. J Virol. 2002; 76(18):9253-9. PMC: 136424. DOI: 10.1128/jvi.76.18.9253-9259.2002. View

10.

Deschamps A, Van Wijngaerden E, Denhaerynck K, de Geest S, Vandamme A . Use of electronic monitoring induces a 40-day intervention effect in HIV patients. J Acquir Immune Defic Syndr. 2006; 43(2):247-8. DOI: 10.1097/01.qai.0000246034.86135.89. View

11.

Castillo-Mancilla J, Haberer J . Adherence Measurements in HIV: New Advancements in Pharmacologic Methods and Real-Time Monitoring. Curr HIV/AIDS Rep. 2018; 15(1):49-59. PMC: 5876155. DOI: 10.1007/s11904-018-0377-0. View

12.

Williams A, Amico K, Bova C, Womack J . A proposal for quality standards for measuring medication adherence in research. AIDS Behav. 2012; 17(1):284-97. PMC: 3434290. DOI: 10.1007/s10461-012-0172-7. View

13.

Musinguzi N, Castillo-Mancilla J, Morrow M, Byakwaga H, MaWhinney S, Burdo T . Antiretroviral Therapy Adherence Interruptions Are Associated With Systemic Inflammation Among Ugandans Who Achieved Viral Suppression. J Acquir Immune Defic Syndr. 2019; 82(4):386-391. PMC: 6820698. DOI: 10.1097/QAI.0000000000002148. View

14.

Smith R, Villanueva G, Probyn K, Sguassero Y, Ford N, Orrell C . Accuracy of measures for antiretroviral adherence in people living with HIV. Cochrane Database Syst Rev. 2022; 7:CD013080. PMC: 9309033. DOI: 10.1002/14651858.CD013080.pub2. View

15.

Charpentier C, Peytavin G, Le M, Joly V, Cabras O, Perrier M . High virological suppression regardless of the genotypic susceptibility score after switching to a dolutegravir-based regimen: week 48 results in an observational cohort. J Antimicrob Chemother. 2018; 73(6):1665-1671. DOI: 10.1093/jac/dky062. View

16.

Castillo-Mancilla J, Zheng J, Rower J, Meditz A, Gardner E, Predhomme J . Tenofovir, emtricitabine, and tenofovir diphosphate in dried blood spots for determining recent and cumulative drug exposure. AIDS Res Hum Retroviruses. 2012; 29(2):384-90. PMC: 3552442. DOI: 10.1089/AID.2012.0089. View

17.

Morrow M, MaWhinney S, Coyle R, Coleman S, Gardner E, Zheng J . Predictive Value of Tenofovir Diphosphate in Dried Blood Spots for Future Viremia in Persons Living With HIV. J Infect Dis. 2019; 220(4):635-642. PMC: 6639595. DOI: 10.1093/infdis/jiz144. View

18.

Anderson P, Liu A, Castillo-Mancilla J, Gardner E, Seifert S, McHugh C . Intracellular Tenofovir-Diphosphate and Emtricitabine-Triphosphate in Dried Blood Spots following Directly Observed Therapy. Antimicrob Agents Chemother. 2017; 62(1). PMC: 5740314. DOI: 10.1128/AAC.01710-17. View

19.

Mansky L . HIV mutagenesis and the evolution of antiretroviral drug resistance. Drug Resist Updat. 2003; 5(6):219-23. DOI: 10.1016/s1368-7646(02)00118-8. View

20.

Reinius M, Wettergren L, Wiklander M, Svedhem V, Ekstrom A, Eriksson L . Development of a 12-item short version of the HIV stigma scale. Health Qual Life Outcomes. 2017; 15(1):115. PMC: 5450123. DOI: 10.1186/s12955-017-0691-z. View