In patients with a history of tuberculosis (TB), the odds of residual pulmonary impairments are 2- to 3-fold higher compared with individuals with no TB history, with especially high rates in patients with multidrug-resistant TB.1 HIV has been identified as an independent risk factor for predominantly obstructive impairment in lung function. However, there is a dearth of research regarding lung function in HIV-associated TB because patients with HIV are frequently excluded from relevant studies, despite the fact that an estimated 40% of deaths in people with HIV have been attributed to TB.1,2 

Active TB in HIV-Coinfection

“TB-related lung damage may be less common in those co-infected with HIV; however, current data are conflicting,” according to a study by Stek et al.1 “Conversely, paradoxical TB immune reconstitution inflammatory syndrome (TB-IRIS) after the start of antiretroviral therapy (ART) causes inflammation and high levels of inflammatory mediators” in patients with HIV co-infected with TB, which has been linked to worse lung function in the limited research conducted on the topic to date.

To further explore these associations, the researchers assessed the prevalence of pulmonary impairments in 153 individuals with HIV-associated TB and CD4 counts ≤100 cells·μL. Participants were enrolled from a randomized, placebo-controlled trial (PredART; ClinicalTrials.gov Identifier: NCT01924286) investigating prednisone use in the prevention of TB-IRIS in HIV-infected patients commencing antiretroviral therapy.3 Additionally, they examined the effects of prophylactic prednisone use and paradoxical TB-IRIS on pulmonary dysfunction.1


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The results demonstrated abnormal spirometry measurements in 66% of patients at baseline and 50% at week 28, with low forced vital capacity representing the most frequently observed abnormality. Most patients showed little or no abnormalities on chest radiographs.

Although the use of prednisone was associated with increases in 6-minute walk distance (42 m) and forced expiratory volume in 1 second percent predicted (4.9%) at week 4, these changes were not significant at week 12 and beyond. The results further demonstrate that TB-IRIS did not lead to significant impairment in lung function.

“Post-tuberculosis lung disease is common in patients with HIV-associated TB at high risk of TB-IRIS…,” the researchers concluded.1 “Neither TB-IRIS itself, nor prednisone treatment, affected long-term pulmonary outcomes” in this patient sample.  

Latent TB Updates

According to the results of an open-label phase 3 trial published in 2019 in the New England Journal of Medicine, daily treatment with a combination of rifampicin and isoniazid for 4 weeks was noninferior to a 9-month course of isoniazid in adults and adolescents with latent TB and HIV co-infection, with higher rates of treatment completion (97% vs 90%; P <.001).4

In a general population of patients with latent TB infection (including patients with and without HIV), results of other recent studies confirmed the superior safety profile of treatment with rifampicin vs isoniazid. A retrospective cohort study of 10,559 patients showed lower risks of severe hepatotoxicity and direct costs, and higher completion rates, in patients treated with 4 months of rifampin therapy vs 9 months of isoniazid, after adjustment for age and comorbidities.5

In a post-hoc safety analysis of data from 2 open-label randomized controlled trials, Jonathon Campbell, PhD, a postdoctoral fellow in the Department of Epidemiology, Biostatistics, and Occupational Health at McGill University in Montréal, Canada, and colleagues concluded that rifampicin was a safer treatment option for latent TB infection compared to isoniazid.6 Adverse events that did occur with rifampicin were not associated with older age as they were with isoniazid. “Therefore, rifampicin should become a primary treatment option for latent tuberculosis infection based on its safety,” they wrote.

In a recent interview, Dr Campbell and the following experts offered additional details about TB treatment challenges and updates: Alvaro Ordonez, MD, a research associate at the Center for Infection and Inflammation Imaging at Johns Hopkins University School of Medicine in Baltimore, Maryland, and lead author of a new study7 on the use of positron emission tomography (PET) and computed tomography (CT) to shorten TB treatment; and Sanjay K. Jain, MD, professor of pediatrics, radiology, and radiological science at Johns Hopkins; professor of international health at the Johns Hopkins Bloomberg School of Public Health; director of the Center for Infection and Inflammation Imaging Research; and senior author of the aforementioned study.

What are some of the main challenges in treating latent TB infection? 

Dr Campbell: I think one of the biggest challenges in latent TB infection treatment has been the safety of available regimens. Only about 5% to 10% of people with latent TB will develop active TB disease, so treatment safety is paramount.8 To a lesser extent, treatment duration is a challenge — patients used to have to endure 9 months of daily isoniazid. However, regimen safety trumps duration for me, and I think that is true for many patients as well.

What are some of the main challenges in treating active TB infection?

Drs Ordonez and Jain: There are several challenges in TB treatment. Key among them are that the treatment is still too long. Patients must take many pills every day for months to years, which leads to high rates of treatment failure and relapse. Currently, we rely on sputum samples for diagnosis and to monitor treatment. These methods are highly unreliable in children, where the diagnosis is often presumptive, based on clinical findings alone. There is also the challenge of multi-drug resistant infections making treatments more complicated and expensive.

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What are differences in the approach to treatment for TB alone and TB with co-infection?

Drs Ordonez and Jain: The empiric treatment of drug-susceptible pulmonary TB consists of 2 phases: an intensive phase of 4 drugs (isoniazid, rifampin, pyrazinamide, and ethambutol) administered over 2 months, followed by a continuation phase with 2 drugs (isoniazid and rifampin) administered for 4 to 7 months. Specific treatment regimens are based on the mycobacterial susceptibility of each patient and other comorbidities.  

The treatment of TB in HIV-infected adults has similar components, but we need to pay close attention to potential drug interactions with antiretroviral agents. Specific treatment regimens are based on the mycobacterial susceptibility of each patient.  

What is the significance of your study results, and what are the relevant treatment implications?

Dr Campbell: The most significant finding is that 4 months of daily rifampicin appears to be a very safe regimen for latent TB. While not being the first regimen to be significantly shorter than 9 months of isoniazid (others include 3 months of once-weekly rifapentine and isoniazid or 3 months of daily rifampicin and isoniazid), it is the first and only regimen that has been shown to be significantly safer. There are concerns of increased adverse event risk with age with other treatments, but importantly, we found that adverse events with rifampicin were not associated with age. 

For clinicians, 4 months of daily rifampicin offers a significantly safer and shorter treatment option for latent TB that is available in all countries. For patients where rifampicin is not contraindicated due to concomitant medications or allergies, it should be a primary treatment option considered by clinicians and healthcare providers who prescribe latent TB treatment.

What are some of the most notable recent findings in TB treatment, including those of your group? 

Drs Ordonez and Jain: A recent trial showed that using a combination of pretomanid, bedaquiline, and linezolid could shorten the 18- to 24-month treatment of multidrug-resistant TB to 6 months.9 Other new drugs are also being developed with promising results. We can also optimize the drugs we already have. In our research group, we used a novel technique of carbon-11 radiolabeled rifampin (11C-rifampin) PET imaging, to identify how much rifampin was reaching the sites of infection in [patients with] TB.9

What are some of the top remaining research needs in this area?

Dr Campbell: We always want to go shorter with treatment while ensuring that it remains effective and safe. There is a ton of exciting research into shorter regimens of 4-8 weeks. For example, there is currently a clinical trial investigating 6 weeks of daily rifapentine, and we are also working on a trial evaluating 8 weeks of daily rifampicin given at double or triple the current dose.10,11 It will be interesting to see what comes of this research and if we can maintain treatment effectiveness and safety while reducing the patient burden of lengthy treatment.

References

1. Stek C, Allwood B, Du Bruyn E, et al. The effect of HIV-associated tuberculosis, tuberculosis-IRIS andprednisone on lung function. Eur Respir J. 2020;55(3):1901692.

2. NIH–National Institutes of Allergy and Infectious Diseases. One-month tuberculosis prophylaxis as effective as nine-month regimen for people living with HIV. Published March 5, 2018. AccessedMarch 25, 2020.

3. Meintjes G, Stek C, Blumenthal L, et al; for the PredART Trial Team. Prednisone for the prevention of paradoxical tuberculosis-associated IRIS. N Engl J Med. 2018;379(20):1915-1925.

4. Swindells S, Ramchandani R, Gupta A, et al; for the BRIEF TB/A5279 Study Team. One month of rifapentine plus isoniazid to prevent HIV-related tuberculosis. N Engl J Med. 2019;380(11):1001-1011.

5. Ronald LA, FitzGerald JM, Bartlett-Esquilant G, et al. Treatment with isoniazid or rifampin for latent tuberculosis infection: population-based study of hepatotoxicity, completion and costs. Eur Respir J. 2020;55(3).

6. Campbell JR, Trajman A, Cook VJ, et al. Adverse events in adults with latent tuberculosis infection receiving daily rifampicin or isoniazid: post-hoc safety analysis of two randomised controlled trials. Lancet Infect Dis. 2020;20(3):318-329.

7. Centers for Disease Control and Prevention. Tuberculosis (TB). https://www.cdc.gov/tb/publications/factsheets/general/ltbiandactivetb.htm Page last reviewed October 20, 2014. Accessed March 25, 2020.

8. Conradie F, Diacon AH, Ngubane N, et al; for the Nix-TB Trial Team. Treatment of highly drug-resistant pulmonary tuberculosis. N Engl J Med. 2020;382(10):893-902.

9. Ordonez AA, Wang H, Magombedze G, et al. Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions [published online February 17, 2020]. Nat Med. doi:10.1038/s41591-020-0770-2

10. US National Library of Congress —ClinicalTrials.gov. Assessment of the safety, tolerability, and effectiveness of rifapentine given daily for LTBI (ASTERoiD). https://clinicaltrials.gov/ct2/show/NCT03474029 Accessed on March 25, 2020.

11. US National Library of Congress —ClinicalTrials.gov. 2R2: Higher dose rifampin for 2 months vs standard dose rifampin for latent TB. (2R2). https://clinicaltrials.gov/ct2/show/NCT03988933 Accessed on March 25, 2020.