Could a common over-the-counter anti-inflammatory drug become a new weapon against drug-resistant TB? Early findings suggest immune benefits, but larger trials are needed to determine whether these translate into improved patient outcomes.
Study: Adjuvant ibuprofen in extensively drug-resistant and extensively drug-resistant tuberculosis: an open-label phase IIA pilot clinical trial. Image credit: george martin studio/Shutterstock.com
Adding ibuprofen to standard treatment for highly drug-resistant tuberculosis did not improve clinical outcomes in a pilot trial, although the anti-inflammatory drug showed signs of reducing inflammation, according to a study published in Nature communications.
Can ibuprofen improve outcomes in drug-resistant tuberculosis?
Tuberculosis (TB) is an airborne bacterial infection that mainly affects the lungs and can be spread from person to person. It is among the top ten causes of death worldwide. Drug-resistant tuberculosis remains a major global public health challenge, as drug-resistant bacteria do not respond to the antibiotics used to treat the infection.
The most effective antibiotics against tuberculosis include rifampicin, isoniazid, pyrazinamide, and ethambutol. However, overuse or inappropriate use of these antibiotics can lead to the emergence of drug-resistant or multi-resistant bacteria.
Given the increasing prevalence, greater disease severity, limited therapeutic options, and poorer disease outcomes in multidrug-resistant or extensively drug-resistant TB, it has become necessary to develop new therapies that suppress pathogen survival and pathogenesis by affecting host immune responses and cellular processes.
Host-directed therapies have emerged as a promising alternative to improve treatment outcomes by targeting the host immune system and controlling tissue damage and hyperinflammation. However, most of the drugs that have been proposed as host-directed therapeutics, including thalidomide and etanercept, have shown serious side effects in clinical trials.
Ibuprofen is a nonsteroidal anti-inflammatory drug that has been used for decades to treat pain, fever, and inflammation. In animal models of TB, this drug has shown promise in reducing lung damage, suppressing the burden of infection, and increasing survival.
Given these preclinical benefits, the current The phase IIA open-label pilot trial was designed to evaluate the feasibility, safety, and biological activity of adjunctive ibuprofen in adults with extensively drug-resistant or extensively drug-resistant tuberculosis in Georgia.
A total of 28 patients participated in the trial, all of whom received personalized anti-tuberculosis treatment. Half of the participants received an additional 400 milligrams of ibuprofen daily for two months as adjunctive therapy, while the remaining participants received individualized TB treatment alone and served as controls. Patients were followed for six months.
Clinical outcomes were unchanged with adjunctive ibuprofen
Analysis of bacterial cultures showed that two-month treatment with ibuprofen did not increase the proportion of patients with negative sputum cultures at two months, and both groups achieved negative sputum cultures at six-month follow-up.
Similarly, both the control and ibuprofen groups showed similar improvements in radiological signs over time, including primary and secondary parenchymal abnormalities, nodular lesions, and pleural abnormalities.
Although ibuprofen did not improve final treatment outcomes, with approximately 71% of participants in both groups classified as cured at the end of follow-up, it was associated with numerically greater reductions in blood-based inflammatory mediators and transcriptional signature scores associated with poor TB outcomes than the control group.
Because reducing inflammation didn’t improve outcomes
Preliminary findings from this phase IIA pilot trial indicate that the addition of a 2-month course of ibuprofen to individualized antituberculosis therapy did not improve microbiological, radiologic, or clinical outcomes compared with individualized antituberculosis therapy alone. Both treatment approaches also showed similar safety and tolerability, suggesting that low-dose adjunctive ibuprofen was feasible but did not provide measurable clinical benefit during the study period.
Although these clinical outcomes were comparable, the researchers observed exploratory evidence of immunomodulatory activity in the ibuprofen group. Compared with the standard care group, participants who received ibuprofen had numerically greater decreases in the monocyte-to-lymphocyte ratio, a marker previously associated with greater severity of TB. This finding suggests that ibuprofen may affect inflammatory pathways involved in disease progression and supports further investigation of the drug as a host-directed therapy.
This pattern extended to circulating immune mediators, with participants receiving ibuprofen showing numerically greater reductions in both pro- and anti-inflammatory cytokines than those receiving standard therapy alone. The researchers suggest that this may reflect ibuprofen’s action as a non-selective cyclooxygenase inhibitor, which can alter the prostaglandin-mediated feedback loops that regulate cytokine production.
However, they emphasize that these immune patterns are exploratory and cannot be attributed specifically to ibuprofen due to the trial’s small sample size, baseline differences between groups, and variation in individualized TB regimens.
A similar trend was observed in the transcriptional analyses. Ibuprofen-treated participants showed greater reductions in blood RNA signature scores previously associated with TB treatment failure. These signatures are enriched for neutrophil-related genes, which are expressed at higher levels in patients who eventually experience treatment failure, suggesting that excessive inflammation before treatment may contribute to worse outcomes.
Despite these encouraging biological signals, they did not translate into improved microbiological or clinical outcomes. The researchers suggest several possible explanations, including the study’s small sample size, imbalances at baseline between treatment groups, the open design, the absence of a placebo control, and differences in individualized anti-TB regimens.
They also suggest that the relatively low dose of ibuprofen may not have reduced inflammation enough to change the TB disease course. Together, these findings support further evaluation of higher doses or alternative host-directed therapies in larger, adequately powered, placebo-controlled trials.
Pilot findings support larger TB trials of ibuprofen
Overall, this pilot trial highlights the feasibility of using ibuprofen 400 milligrams once daily as adjunctive therapy during the intensive phase of treatment in adults with extensively drug-resistant or extensively drug-resistant tuberculosis.
While the findings support further investigation of NSAIDs as host-directed therapies, the authors conclude that larger, adequately powered, placebo-controlled trials are needed to determine whether these immune effects translate into significant clinical benefits.
