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TB drugs and ARVs decrease mortality in people with HIV

In patients with HIV and multidrug-resistant tuberculosis, the use of antiretroviral therapy (ART) and more effective anti-tuberculosis drugs was associated with lower odds of death, Infectious Diseases Advisor reports according to the results of a study. Patients with HIV infection and receiving treatment for multidrug-resistant tuberculosis treatment are at increased risk for mortality, but the extent to which ART and tuberculosis medications affect this risk is not clear. Investigators led by Dr Gregory Bisson at the Perelman School of Medicine, the University of Pennsylvania, therefore aimed to evaluate how these treatments altered mortality risk in HIV-positive adults with multidrug-resistant tuberculosis.

To do so, they employed an individual patient data meta-analysis of 11,920 adults aged ≥18 years with confirmed or presumed multidrug-resistant tuberculosis initiating tuberculosis treatment between the years 1993 and 2016. Of these patients, 25% were HIV-positive and receiving ART, 7% were HIV-positive and not receiving ART, and 15% had extensively drug-resistant tuberculosis. By using the HIV-negative patients as a reference, the adjusted odds ratio of death was found to be 2.4 (95% CI, 2.0-2.9) for all patients with HIV infection, 1.8 (95% CI, 1.5-2.2) for HIV-positive patients receiving ART, and 4.2 (95% CI, 3.0-5.9) for HIV-positive patients with no or unknown ART. For those patients with HIV, the use of at least one World Health Organisation Group A drug and specific use of moxifloxacin, levofloxacin, bedaquiline, or linezolid were associated with significantly decreased odds of death.

The investigators noted several limitations of their research, including the fact that 17% of patients were lost to follow-up. Although these patients were similar to those who were not lost to follow-up in terms of most clinical and treatment characteristics, the investigators report that “differential rates of death among patients with HIV after becoming lost could have introduced bias into our results.” Data on CD4 counts, ART regimen types, timing of ART initiation, treatment adherence, and precise time of disease onset were also unavailable; therefore, variability in these factors could not be analysed and residual confounding in HIV-specific analyses might also be present. Missing data represents another limitation, but the investigators did employ a multiple imputation approach that reduces bias compared with complete case analysis. The study was also not designed to examine changes in the association between HIV and mortality over time, and children were excluded. Furthermore, inclusion of data was dependent on investigators’ willingness to participate, most of the data for HIV-positive patients came from South Africa, and studies published since the dataset was assembled were not included; hence, the results may not be generalisable to all settings.

According to the investigators, this study does indicate that ART and high-quality anti-tuberculosis drugs reduce deaths due to multidrug-resistant tuberculosis in adults living with HIV. They added that “a substantial proportion of deaths in patients with HIV occur early after initiation of treatment for multidrug-resistant tuberculosis, and odds of these early deaths are reduced by use of ART and Group A tuberculosis medications.”

Abstract
Background: HIV-infection is associated with increased mortality during multidrug-resistant tuberculosis treatment, but the extent to which the use of antiretroviral therapy (ART) and anti-tuberculosis medications modify this risk are unclear. Our objective was to evaluate how use of these treatments altered mortality risk in HIV-positive adults with multidrug-resistant tuberculosis.
Methods: We did an individual patient data meta-analysis of adults 18 years or older with confirmed or presumed multidrug-resistant tuberculosis initiating tuberculosis treatment between 1993 and 2016. Data included ART use and anti-tuberculosis medications grouped according to WHO effectiveness categories. The primary analysis compared HIV-positive with HIV-negative patients in terms of death during multidrug-resistant tuberculosis treatment, excluding those lost to follow up, and was stratified by ART use. Analyses used logistic regression after exact matching on country World Bank income classification and drug resistance and propensity-score matching on age, sex, geographic site, year of multidrug-resistant tuberculosis treatment initiation, previous tuberculosis treatment, directly observed therapy, and acid-fast-bacilli smear-positivity to obtain adjusted odds ratios (aORs) and 95% CIs. Secondary analyses were conducted among those with HIV-infection.
Findings: We included 11 920 multidrug-resistant tuberculosis patients. 2997 (25%) were HIV-positive and on ART, 886 (7%) were HIV-positive and not on ART, and 1749 (15%) had extensively drug-resistant tuberculosis. By use of HIV-negative patients as reference, the aOR of death was 2·4 (95% CI 2·0–2·9) for all patients with HIV-infection, 1·8 (1·5–2·2) for HIV-positive patients on ART, and 4·2 (3·0–5·9) for HIV-positive patients with no or unknown ART. Among patients with HIV, use of at least one WHO Group A drug and specific use of moxifloxacin, levofloxacin, bedaquiline, or linezolid were associated with significantly decreased odds of death.
Interpretation: Use of ART and more effective anti-tuberculosis drugs is associated with lower odds of death among HIV-positive patients with multidrug-resistant tuberculosis. Access to these therapies should be urgently pursued.
Funding: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Authors
Gregory P Bisson, Mayara Bastos, Jonathon R Campbell, Didi Bang, James C Brust, Petros Isaakadis, Christoph Lange, Dick Menzies, Giovanni B Migliori, Jean W Pape, Domingo Palmero, Parvaneh Baghei, Payam Tabarsi, Piret Viiklepp, Stalz Vilbrun, Jonathan Walsh, Suzanne M Marks

 

[link url="https://www.infectiousdiseaseadvisor.com/home/topics/hiv-aids/tuberculosis-drugs-and-antiretroviral-therapy-decrease-mortality-in-hiv/"]Infectious Diseases Advisor material[/link]

 

[link url="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31316-7/fulltext"]The Lancet abstract[/link]

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