Amino Acid Derivative Fails to Eliminate TB Infection in Mid-Stage Trial

N-acetylcysteine (NAC) failed to eradicate Mycobacterium tuberculosis infection, but it did appear to improve lung function in patients with moderate or far-advanced disease, according to a phase II randomized, controlled trial.

In the modified intention-to-treat population, twice-daily oral NAC (1,200 mg) for 112 days plus standard treatment for tuberculosis (TB) did not significantly increase stable culture conversion when compared with standard treatment alone (HR 0.84, 95% CI 0.59-1.20, P=0.33), reported Robert Wallis, MD, of the Aurum Institute in Johannesburg, and colleagues in NEJM Evidence.

Nor did NAC prevent TB recurrence. Five of the 65 NAC participants and two of 67 controls in the per-protocol population experienced culture-confirmed recurrent TB (OR 2.58, 95% CI 0.51-14.49). One participant in the NAC group and one in the standard therapy group met criteria for treatment failure, with growth of M. tuberculosis on sputum specimens on days 140 and 168.

Despite these negative findings, NAC was associated with some improved recovery of lung function relative to that of patients not receiving NAC, researchers found in a post-hoc analysis.

“We were pleased to see the effects of NAC on lung function,” Wallis told MedPage Today. “We had hoped to also see evidence of direct anti-TB activity, but this was not the case. Indeed, the trends for both culture conversion and TB recurrence were pointing in the wrong direction.”

In a linear mixed effects modeling analysis, the treatment was associated with improvements in forced expiratory volume in the first second and forced vital capacity, as percentages of predicted values (FEV₁% and FVC%):

• FEV₁%: NAC × month, HR 0.42 (95% CI -0.06 to 0.91)
• FVC%: NAC × month, HR 0.49 (95% CI 0.02-0.95)

“Although intriguing, these results should be interpreted within the context of two key limitations,” Akshay Gupte, PhD, MBBS, of the Boston University School of Public Health, and Edward Nardell, MD, of Brigham & Women’s Hospital in Boston, wrote in an accompanying editorial.

First, the trial was not adequately powered to detect a meaningful difference in lung function. Secondly, whether the improvements in lung function are clinically meaningful is unclear, they commented.

NAC is a derivative of the amino acid cysteine that protects against cellular damage from oxidative stress. Some evidence supports the use of NAC as a mucolytic and expectorant, and to protect against hepatic necrosis from acetaminophen toxicity. However, evidence is sparse for any positive effects in TB, but NAC may increase the antimicrobial activity of some anti-TB drugs.

“As far as we know, this is the first clinical trial of NAC to examine its effects on lung function in TB,” Wallis said. “The study is small, and the findings must be confirmed” in a larger trial.

Wallis said that his group hopes to begin such a trial soon. “If confirmed, it would mean that a relatively short course of adjunctive treatment with an inexpensive, well-tolerated dietary supplement might provide a long-term benefit to patients recovering from tuberculosis,” he emphasized.

“The global health burden due to post-TB disease is at least equal to that of active TB, yet until very recently the problem has been largely ignored,” Wallis explained. “Many TB patients have progressive loss of lung function despite TB ‘cure,'” possibly due to damage to airways and lung parenchyma and impairment of host defenses against new non-TB infections, he said.

“Adjunctive treatments such as NAC may be disease-modifying, preserving lung function post-TB, much as [disease-modifying anti-rheumatic drugs] preserve joint function in [rheumatoid arthritis]. It would be remarkable if we could accomplish this with NAC,” he posited.

The open-label trial was conducted as a single-site trial nested within the TB SEQUEL project, a study that is examining long-term consequences of TB and factors that contribute to poor outcomes. The trial enrolled adults at the Mbeya Medical Research Center of the National Institute for Medical Research in Tanzania with rifampin-susceptible pulmonary TB and chest x-rays showing moderate to far-advanced disease. People with HIV-1 were permitted to participate in the study if they were receiving or willing to receive antiretroviral therapy (ART) and had a CD4+ cell count over 100/µL. Pregnant or breastfeeding individuals and critically ill patients were excluded.

Of enrollees, 47% had far-advanced disease on chest radiography and 84% had a maximally positive acid-fast bacilli smear.

The modified intention-to-treat population consisted of 69 participants randomized to the NAC group and 70 to the control group. The per-protocol population included 65 patients in the NAC group and 67 in the control group.

Scheduled follow-up clinical evaluations, sputum culture, and spirometry were performed through day 168.

There were no differences in rates of serious or grade 3/4 non-serious adverse events between the NAC and control groups. There were three unexpected events during the study. One NAC recipient with far-advanced TB died after worsening dyspnea. A control participant with moderately advanced TB and newly diagnosed HIV infection died suddenly on day 3. At month 4, a participant in the control group had a stroke. Also, drug-induced liver injury in one NAC recipient after ART initiation required temporary treatment interruption.

In addition to the small sample size and single-site design, the authors acknowledged that another limitation of the study was its unblinded design, which may have increased risk of bias.

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