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      Relationship between HIV viral suppression and multidrug resistant tuberculosis treatment outcomes

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          Abstract

          The impact of HIV viral suppression on multidrug resistant tuberculosis (MDR-TB) treatment outcomes among people with HIV (PWH) has not been clearly established. Using secondary data from a cluster-randomized clinical trial among people with MDR-TB in South Africa, we examined the effects of HIV viral suppression at MDR-TB treatment initiation and throughout treatment on MDR-TB outcomes among PWH using multinomial regression. This analysis included 1479 PWH. Viral suppression (457, 30.9%), detectable viral load (524, 35.4%), or unknown viral load (498, 33.7%) at MDR-TB treatment initiation were almost evenly distributed. Having a detectable HIV viral load at MDR-TB treatment initiation significantly increased risk of death compared to those virally suppressed (relative risk ratio [RRR] 2.12, 95% CI 1.11–4.07). Among 673 (45.5%) PWH with a known viral load at MDR-TB outcome, 194 (28.8%) maintained suppression, 267 (39.7%) became suppressed, 94 (14.0%) became detectable, and 118 (17.5%) were never suppressed. Those who became detectable (RRR 11.50, 95% CI 1.98–66.65) or were never suppressed (RRR 9.28, 95% CI 1.53–56.61) were at significantly increased risk of death (RRR 6.37, 95% CI 1.58–25.70), treatment failure (RRR 4.54, 95% CI 1.35–15.24), and loss to follow-up (RRR 7.00, 95% CI 2.83–17.31; RRR 2.97, 95% CI 1.02–8.61) compared to those who maintained viral suppression. Lack of viral suppression at MDR-TB treatment initiation and failure to achieve or maintain viral suppression during MDR-TB treatment drives differences in MDR-TB outcomes. Early intervention to support access and adherence to antiretroviral therapy among PWH should be prioritized to improve MDR-TB treatment outcomes.

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          A note on robust variance estimation for cluster-correlated data.

          There is a simple robust variance estimator for cluster-correlated data. While this estimator is well known, it is poorly documented, and its wide range of applicability is often not understood. The estimator is widely used in sample survey research, but the results in the sample survey literature are not easily applied because of complications due to unequal probability sampling. This brief note presents a general proof that the estimator is unbiased for cluster-correlated data regardless of the setting. The result is not new, but a simple and general reference is not readily available. The use of the method will benefit from a general explanation of its wide applicability.
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            Consistent Covariance Matrix Estimation with Cross-Sectional Dependence and Heteroskedasticity in Financial Data

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              Bedaquiline: a review of human pharmacokinetics and drug-drug interactions.

              Bedaquiline has recently been approved for the treatment of pulmonary multidrug-resistant tuberculosis (TB) as part of combination therapy in adults. It is metabolized primarily by the cytochrome P450 isoenzyme 3A4 (CYP3A4) to a less-active N-monodesmethyl metabolite. Phase I and Phase II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant TB have assessed the pharmacokinetics and drug-drug interaction profile of bedaquiline. Potential interactions have been assessed between bedaquiline and first- and second-line anti-TB drugs (rifampicin, rifapentine, isoniazid, pyrazinamide, ethambutol, kanamycin, ofloxacin and cycloserine), commonly used antiretroviral agents (lopinavir/ritonavir, nevirapine and efavirenz) and a potent CYP3A inhibitor (ketoconazole). This review summarizes the pharmacokinetic profile of bedaquiline as well as the results of the drug-drug interaction studies.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: SupervisionRole: Writing – review & editing
                Role: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: SupervisionRole: ValidationRole: Writing – review & editing
                Role: ValidationRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: Editor
                Journal
                PLOS Glob Public Health
                PLOS Glob Public Health
                plos
                PLOS Global Public Health
                Public Library of Science (San Francisco, CA USA )
                2767-3375
                6 May 2024
                2024
                : 4
                : 5
                : e0002714
                Affiliations
                [1 ] School of Nursing, Johns Hopkins University, Baltimore, Maryland, United States of America
                [2 ] Center for Infectious Disease and Nursing Innovation, Johns Hopkins University, Baltimore, Maryland, United States of America
                [3 ] Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
                [4 ] National Department of Health, Tuberculosis Control and Management, Pretoria, Gauteng, South Africa
                [5 ] KwaZulu-Natal Department of Health, Tuberculosis Programme, Pietermaritzburg, KwaZulu-Natal, South Africa
                Chinese Academy of Medical Sciences and Peking Union Medical College, CHINA
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0002-8834-1795
                https://orcid.org/0009-0009-0943-4116
                https://orcid.org/0000-0001-9013-5256
                Article
                PGPH-D-23-01695
                10.1371/journal.pgph.0002714
                11073678
                38709764
                7a20ed6a-edb3-4e74-868d-b175ff1a344b
                © 2024 Geiger et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 30 August 2023
                : 5 January 2024
                Page count
                Figures: 1, Tables: 4, Pages: 12
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: NIAID R01AI104488-02
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: NIAID K24AI150349
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100006108, National Center for Advancing Translational Sciences;
                Award ID: TL1 TR003100
                Award Recipient :
                This work was supported by the National Institute of Allergy and Infectious Disease [NIAID R01AI104488-02; ClinicalTrials.gov Identifier NCT02129244; PI Jason Farley]. KG received funding from the National Center for Advancing Translational Sciences grant number TL1 TR003100. KED is supported by NIAID K24AI150349. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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