Re-evaluating the role of isoniazid in treatment of pulmonary tuberculosis

For more than half a century, isoniazid has served as a principal component of combination drug regimens to treat tuberculosis. Selective in spectrum to mycobacteria, isoniazid primarily inhibits mycolic acid synthesis thereby disrupting cell wall construction, and has shown the greatest bactericidal effect against populations of Mycobacterium tuberculosis in the logarithmic growth phase.1Timmins GS Deretic V Mechanisms of action of isoniazid.Mol Microbiol. 2006; 62: 1220-1227Crossref PubMed Scopus (245) Google Scholar The early bactericidal activity (EBA) of isoniazid was first examined in humans with tuberculosis by Jindani and colleagues,2Jindani A Aber VR Edwards EA Mitchison DA The early bactericidal activity of drugs in patients with pulmonary tuberculosis.Am Rev Respir Dis. 1980; 121: 939-949PubMed Google Scholar and their work has since informed tuberculosis therapeutics by defining the crucial role of isoniazid during the initial days of tuberculosis treatment and its contribution to long-term treatment success. Recent evidence has begun to challenge this dogma. Clinical trials and observational studies of people with isoniazid-monoresistant tuberculosis treated with rifampicin, pyrazinamide, and ethambutol for 6 months have shown either similar treatment success or no increase in mortality compared with people with isoniazid-susceptible tuberculosis treated with the traditional first-line drug regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol for 2 months, followed by a continuation phase of isoniazid and rifampicin for 4 months.3Fregonese F Ahuja SD Akkerman OW et al.Comparison of different treatments for isoniazid-resistant tuberculosis: an individual patient data meta-analysis.Lancet Respir Med. 2018; 6: 265-275Summary Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 4Stagg HR Bothamley GH Davidson JA et al.Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance.Eur Respir J. 2019; 541900982Crossref PubMed Scopus (7) Google Scholar Furthermore, rates of isoniazid monoresistance are on the rise in many settings, and both in vitro models5Gumbo T Louie A Liu W et al.Isoniazid's bactericidal activity ceases because of the emergence of resistance, not depletion of Mycobacterium tuberculosis in the log phase of growth.J Infect Dis. 2007; 195: 194-201Crossref PubMed Scopus (79) Google Scholar and molecular epidemiology from genomic sequencing6Manson AL Cohen KA Abeel T et al.Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into the emergence and spread of multidrug resistance.Nat Genet. 2017; 49: 395-402Crossref PubMed Scopus (120) Google Scholar suggest that isoniazid resistance precedes rifampicin resistance, thus providing the conditions for multidrug-resistant tuberculosis and associated clinical implications of increased morbidity and mortality. In The Lancet Microbe, Andreas Diacon and colleagues7Diacon A Miyahara S Dawson R et al.Assessing whether isoniazid is essential during the first 14 days of tuberculosis therapy: a phase 2a, open-label, randomised controlled trial.Lancet Microbe. 2020; 1: e84-e92Summary Full Text Full Text PDF Scopus (2) Google Scholar cast further doubt on whether isoniazid is essential as part of the first-line regimen for pulmonary tuberculosis.7Diacon A Miyahara S Dawson R et al.Assessing whether isoniazid is essential during the first 14 days of tuberculosis therapy: a phase 2a, open-label, randomised controlled trial.Lancet Microbe. 2020; 1: e84-e92Summary Full Text Full Text PDF Scopus (2) Google Scholar 69 adults from the Western Cape region of South Africa with sputum-smear positive tuberculosis were recruited before treatment initiation for an open-label, randomised controlled trial in which patients were randomly assigned to four regimens. All interventions occurred as variations of tuberculosis chemotherapy consisting of rifampicin (R), isoniazid (H), pyrazinamide (Z), ethambutol (E), and moxifloxacin (M) administered during study days 1–14 while participants were followed as inpatients. The HRZE1–2-RZE3–14 arm received isoniazid only on days 1 and 2; the HRZE1–2-MRZE3–14 arm received isoniazid on days 1 and 2 followed by the substitution of isoniazid for moxifloxacin on days 3–14; the RZE1–14 arm received no isoniazid; and the HRZE1–14 arm was the control group that received standard therapy of isoniazid for all 14 days. The primary endpoint was the daily decrease in log10-transformed colony-forming unit (CFU) counts per mL of sputum between baseline (day 0) and day 14. Of the 69 participants, 57 (83%) were men, and only four (6%) were living with HIV, reflective of exclusion criteria of people on antiretroviral therapy and people with or CD4 counts of up to 200 cells per μL. Although the three isoniazid-containing arms had a more rapid bactericidal activity as evidenced by a faster drop in CFU counts in the first 2 days, quite surprisingly the mean EBA of all regimens over the first 14 days were markedly similar with overlapping 95% CIs, and without clear difference from the standard-of-care regimen. These results were replicated when CFU was replaced by time-to-positivity of sputum culture in liquid media. Interestingly, the classic biphasic response of early CFU decline in the first few days followed by a levelling over the remainder of the 2 weeks in the isoniazid-containing regimens was not as pronounced in the current study compared with historical EBA studies of isoniazid. Diacon and colleagues7Diacon A Miyahara S Dawson R et al.Assessing whether isoniazid is essential during the first 14 days of tuberculosis therapy: a phase 2a, open-label, randomised controlled trial.Lancet Microbe. 2020; 1: e84-e92Summary Full Text Full Text PDF Scopus (2) Google Scholar did find in post-hoc subgroup analyses that those with greatest EBA in the first 2 days of treatment (so-called sharp-drop responders) also had significantly higher pre-treatment CFU counts, which were on par with CFU counts observed in patients in the historical EBA studies. The authors rightly note the limitations of EBA studies, including the difficulty in generalising the results of this particular study population, and rather suggest that the findings of an absence of bactericidal cost when isoniazid is excluded in the first 14 days of therapy warrants trials where other novel or recently introduced anti-mycobacterial agents replace isoniazid in the first-line regimen. To date, replacement of isoniazid has been easier conceived than accomplished, for example moxifloxacin in replacement of isoniazid in a 4-month regimen to shorten tuberculosis treatment did not show non-inferiority in treatment failure or relapse compared with the isoniazid-containing 6-month standard of care.8Gillespie SH Crook AM McHugh TD et al.Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis.N Engl J Med. 2014; 371: 1577-1587Crossref PubMed Scopus (386) Google Scholar Yet, such trials are of even greater importance given that commonly used tests to diagnose M tuberculosis, such as the Xpert platforms, do not interrogate isoniazid resistance, and thus undetected isoniazid-monoresistant M tuberculosis would effectively receive rifampicin monotherapy for months in the continuation phase and further pressure the development of multidrug-resistant tuberculosis. For the clinician who is treating tuberculosis, isoniazid is indeed the enemy one knows. Born of much studied and socially critiqued trials such as the initial Many Farms experiments among the Navajo people of Arizona in the USA throughout the 1950s,9Jones DS The health care experiments at Many Farms: the Navajo, tuberculosis, and the limits of modern medicine, 1952-1962.Bull Hist Med. 2002; 76: 749-790Crossref PubMed Scopus (24) Google Scholar isoniazid's numerous and relatively frequent toxic effects were tempered at the time by the dire need for a novel tuberculocidal medicine. Rates of peripheral neuropathy and severe and fatal hepatitis observed in older people,10Pande JN Singh SP Khilnani GC Khilnani S Tandon RK Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study.Thorax. 1996; 51: 132-136Crossref PubMed Scopus (225) Google Scholar coupled with less common haematological and neurological complications, call into question whether isoniazid would even be approved in the contemporary regulatory environment. Nevertheless, even if a less toxic and novel regimen excluding isoniazid proves of equal or greater activity while preventing acquired resistance, important scenarios where isoniazid continues to be essential will likely remain, such as with CNS penetration in tuberculosis meningitis, or in cases of sepsis from tuberculosis with higher circulating mycobacterial burden. Thus, while the door on isoniazid use in modern tuberculosis treatment is not shut, it has certainly inched further closed. We declare no competing interests. Assessing whether isoniazid is essential during the first 14 days of tuberculosis therapy: a phase 2a, open-label, randomised controlled trialThe EBA over 14 days for RZE was not significantly changed by the addition of isoniazid for the first 2 days or for the first 14 days of treatment. In a post-hoc analysis, significantly higher day 2 EBAs were observed for all groups among participants with higher baseline sputum CFU counts. Our finding that isoniazid does not contribute to EBA suggests that isoniazid could be replaced with another drug during standard treatment to improve efficacy and decrease rates of resistance to first-line drugs. Full-Text PDF Open Access

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