Adherence Measured Using Electronic Dose Monitoring is Associated with Emergent Antiretroviral Resistance and Poor Outcomes in People with Human Immunodeficiency Virus/AIDS and Multidrug-Resistant Tuberculosis

Abstract

Background: Medication adherence is known to challenge treatment of human immunodeficiency virus (HIV)/AIDS and multidrug-resistant tuberculosis (MDR-TB). We hypothesized that adherence using electronic dose monitoring (EDM) would identify an antiretroviral therapy (ART) adherence threshold for emergent ART resistance and predict treatment outcomes in patients with MDR-TB and HIV on ART and bedaquiline-containing TB regimens.

Methods: A prospective cohort of adults with MDR-TB and HIV on ART and initiating MDR-TB treatment with bedaquiline were enrolled at a public hospital in KwaZulu-Natal, South Africa (PRAXIS Study). Participants received separate EDM devices that measure adherence to bedaquiline and ART (nevirapine or lopinavir/ritonavir). Adherence was calculated cumulatively over 6 months. Participants were followed through completion of MDR-TB treatment. HIV genome sequencing was performed at baseline and 2 and 6 months on samples with HIV RNA ≥1000 copies/mL.

Results: From November 2016 through February 2018, 198 persons with MDR-TB and HIV were enrolled and followed (median, 17.2 months; interquartile range, 12.2-19.6). Eleven percent had baseline ART resistance mutations, and 7.5% developed emergent ART resistance at 6 months. ART adherence was independently associated with ART resistance and mortality. Modeling identified a significant (P < .001), linear association between ART adherence and emergent resistance, suggesting a strong association without a specific threshold.

Conclusions: Our findings highlight the need for ART resistance testing, especially in patients with MDR-TB and HIV, which is currently not the standard of care in resource-limited settings. Despite short follow-up duration, reduced ART adherence was significantly associated with emergent resistance and increased mortality.

Clinical trials registration: NCT03162107.

Keywords: South Africa; antiretroviral adherence; electronic dose monitoring; emergent resistance; patients with HIV/AIDS and multidrug-resistant tuberculosis.

Conflict of interest statement

Potential conflicts of interest. M. R. O. reports payment or honoraria from Otsuka and the France Foundation and being a board member for fightcovidafrica.org. Richard J. Lessells reports grants or contracts from the NIH and an International epidemiology Databases to Evaluate AIDS (IeDEA) subaward to the University of KwaZulu-Natal from the Universität Bern outside of the submitted work. C. O. reports salary from the University of Cape Town and the Desmond Tutu Health Foundation, honoraria for consulting on an expert panel for ViiV, honoraria for consulting on an expert panel for Merck Sharp & Dohm Corp., a subsidiary of the Merck & Co., Inc. (MSD), and is a member of Data Safety and Monitoring Board for Standard versus double dose dolutegravir in patients with HIV-associated tuberculosis: a phase 2 non-comparative randomised controlled (RADIANT-TB) trial (DSMB for RADINAT TB) and Data Safety Monitoring Board for Zidovudine, lamivudine and dolutegravir (AXD) Relative to Tenofovir, lamivudine and dolutegravir (TXD) in Second Line Antiretroviral Therapy (ARTIST) Trial: a randomized control trial (DSMB chair for ARTIST). J. C. M. B. reports grants or contracts from the NIH paid to the Albert Einstein College of Medicine outside the scope of this work. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Enrollment flowchart showing number of patients screened, enrolled, and included in the analysis. *One patient died 11 days after enrollment and had not initiated treatment; 1 patient was enrolled but subsequently was found to be ineligible. Abbreviations: ART, antiretroviral therapy; DR, drug resistant; DST, Drug sensitive; HIV, human immunodeficiency virus; MTB, Mycobacterium Tuberculosis; TB, tuberculosis.

Figure 2.

Kaplan-Meier analysis comparing survival probabilities across 4 levels of antiretroviral adherence (≤60%, 60%–80%, 80%–95%, >95%) by log-rank test.

Figure 3.

Bar graph showing the percentage of participants who developed resistance emergence at different deciles* of adherence. *Less than 50% adherence was used as a cutoff because of the small number of participants in deciles below 50%.

Figure 4.

Likelihood of emergent resistance at 6 months by percent adherence.* Effect plot of continuous association of percent treatment adherence with emergent resistance measured at 6 months using a logistic model with cubic splines indicating predicted probability (solid line) and the 95% confidence interval (shaded area). The P for linearity = .20** and P for association <.0001. **A P for linearity suggests the association is linear. Abbreviations: ART, antiretroviral therapy.