Clinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis: The results up to 30 months

doi:10.1016/0041-3879(81)90016-7

Tubercle

Volume 62, Issue 2, June 1981, Pages 95-102

Tubercle

https://doi.org/10.1016/0041-3879(81)90016-7 Get rights and content

Abstract

In a study in Singapore, Chinese, Malay and Indian patients with pulmonary tuberculosis received 2 months of daily treatment with streptomycin, isoniazid, rifampicin, and pyrazinamide followed by daily isoniazid, and rifampicin either with pyrazinamide (SHRZ/HRZ) or without it (SHRZ/HR), allocated at random. Both regimens were given for either 6 or 4 months by random allocation.

All 330 patients with drug-sensitive tubercle bacilli pretreatment had a favourable bacteriological response during chemotherapy. After chemotherapy none of 78 SHRZ/HRZ patients and only 2 of 80 SHRZ/HR patients treated for 6 months relapsed bacteriologically, but 9 (11 %) of 79 SHRZ/HRZ and 6 (8 %) of 77 SHRZ/HR patients treated for 4 months relapsed. Of 33 patients with bacilli resistant to isoniazid, streptomycin, or both drugs pretreatment, only 1 had an unfavourable response during chemotherapy; none of 9 patients treated for 6 months and 2 of 22 treated for 4 months relapsed bacteriologically after stopping chemotherapy.

Résumé

Dans une étude réalisée à Singapour, des malades chinois, malais et indiens atteints de tuberculose pulmonaire ont reçu 2 mois de traitement quotidien par la streptomycine, I'isoniazide, la rifampicine et le pyrazinamide, suivi de l'administration quotidienne d'isoniazide et de rifampicine, avec pyrazinamide (SHRZ/HRZ) ou sans pyrazinamide (SHRZ/HR), selon une répartition au hasard. Les deux régimes étaient donnés soit pendant 6 mois, soit pendant 4 mois, selon un choix aléatorie.

Les 330 malades porteurs de bacilles tuberculeux sensibles aux médicaments avant traitement ont eu une réponse bactériologique favorable au cours du traitement. Après l'arrêt de la chimiothérapie, aucun des 78 malades du groupe SHRZ/HRZ et 2 seulement des 80 malades du groupe SHRZ/HR traites 6 mois ont eu une rechute bactériologique, mais 9 (11 %) des 79 malades SHRZ/HRZ et 6 (8 %) des 77 malades SHRZ/HR traités 4 mois ont fait une rechute. Sur les 33 malades porteurs de bacilles résistants, avant traitement, à l'isoniazide, à la streptomycine ou aux deux, un seulement a eu une réponse défavorable au cours de la chimiothérapie; aucun des 9 malades traités 6 mois et 2 des 22 malades traités 4 mois ont eu une rechute bactériologique après arrêt de la chimiothérapie.

Resumen

En un estudio realizado en Singapur, enfermos chinos, malayos e hindúes con tuberculosis pulmonar recibieron durante 2 meses un tratamiento cotidiano con estreptomicina, isoniacida, rifampicina y pirazinamida, seguido de tratamiento cotidiano con isoniacida y rifampicina, ya sea con pirazinamida (SHRZ/HRZ) o sin ella (SHRZ/HR) según una distribución aleatoria. Ambos esquemas fueron administrados durante 6 ó 4 meses, también según una distribución al azar.

El total de los 330 pacientes con bacilos de la tuberculosis sensibles a las drogas antes del tratamiento, tuvieron una respuesta bacteriológica favorable durante el tratamiento. Después de la suspension del tratamiento, ningún paciente de los 78 de la serie SHRZ/HRZ tuvo recaída bacteriológica y la tuvieron sólo 2 de los 80 SHRZ/HR tratados durante 6 meses; sin embargo, en la serie de enfermos tratados durante 4 meses tuvieron recaidas 9 (11 %) de los 79 SHRZ/HRZ y 6 (8 %) de los 77 SH RZ/HR.

De los 33 pacientes con bacilos resistentes a la isoniacida, a la estreptomicina o a ambas drogas antes del tratamiento, sólo uno tuvo una respuesta defavorable durante la quimioterapia; ninguno de los 9 pacientes tratados durante 6 meses y 2 de los 22 tratados durante 4 meses, tuvieron recaidas bacteriológicas después de suspender la quimioterapia.

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Mind the gap – Managing tuberculosis across the disease spectrum
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Citation Excerpt :
These studies were initially conducted in those with smear positive (i.e. extensive/cavitary) pulmonary disease, establishing the 6-month short course regimen; isoniazid and rifampicin supplemented by pyrazinamide and streptomycin (S) for the first 2 months (2SHRZ/4HR) in the first instance (subsequently is was established that streptomycin was not needed as part of this regimen).12 Two year relapse rates were 1–3% with this 6-month regimen and reducing this to 4-months (2SHRZ/2HR) in the smear positive population increased relapse to 8–16%.12–14 Later trials in the 1980’s, conducted by the MRC and Hong Kong Chest Service (HKCS), in smear-negative pulmonary TB demonstrated that in those with lower burden of disease could be effectively treated with the shorter 4-month regimen (Table 1).12,15,16
We currently have a binomial approach to managing tuberculosis. Those with active disease, ideally confirmed microbiologically, are treated with a standard 6-month, multi-drug regimen and those with latent infection and no evidence of disease with shorter, one or two drug regimens. Clinicians frequently encounter patients that fall between these two management pathways with some but not all features of disease and this will occur more often with the increasing emphasis on chest X-ray-based systematic screening. The view of tuberculosis as a spectrum of disease states is being increasingly recognised and is leading to new diagnostic approaches for early disease. However, the 6-month regimen for treating disease was driven by the duration required to treat the most extensive forms of pulmonary TB and shorter durations appear sufficient for less extensive disease. It is time undertake clinical trials to better define the optimal treatment for tuberculosis across the disease spectrum.
Modelling the effects of bacterial cell state and spatial location on tuberculosis treatment: Insights from a hybrid multiscale cellular automaton model
2018, Journal of Theoretical Biology
Citation Excerpt :
Although a minimum of six months of therapy is recommended, it has long been recognised that many patients require less and are culture negative in two months or less (Fox, 1981). Shortening treatment to four months or less results in unacceptably high relapse rates (Gillespie et al., 2014) and studies (Singapore, 1981; Study, 1981) described in (Fox et al., 1999). It has recently been shown that, for some patients who become culture negative in only a week, there is still a non-zero risk of relapse (Phillips et al., 2016).
If improvements are to be made in tuberculosis (TB) treatment, an increased understanding of disease in the lung is needed. Studies have shown that bacteria in a less metabolically active state, associated with the presence of lipid bodies, are less susceptible to antibiotics, and recent results have highlighted the disparity in concentration of different compounds into lesions. Treatment success therefore depends critically on the responses of the individual bacteria that constitute the infection.
We propose a hybrid, individual-based approach that analyses spatio-temporal dynamics at the cellular level, linking the behaviour of individual bacteria and host cells with the macroscopic behaviour of the microenvironment. The individual elements (bacteria, macrophages and T cells) are modelled using cellular automaton (CA) rules, and the evolution of oxygen, drugs and chemokine dynamics are incorporated in order to study the effects of the microenvironment in the pathological lesion. We allow bacteria to switch states depending on oxygen concentration, which affects how they respond to treatment. This is the first multiscale model of its type to consider both oxygen-driven phenotypic switching of the Mycobacterium tuberculosis and antibiotic treatment. Using this model, we investigate the role of bacterial cell state and of initial bacterial location on treatment outcome. We demonstrate that when bacteria are located further away from blood vessels, less favourable outcomes are more likely, i.e. longer time before infection is contained/cleared, treatment failure or later relapse. We also show that in cases where bacteria remain at the end of simulations, the organisms tend to be slower-growing and are often located within granulomas, surrounded by caseous material.
pncA mutations are associated with slower sputum conversion during standard treatment of multidrug-resistant tuberculosis
2017, International Journal of Antimicrobial Agents
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In 2011, the Chinese health authorities reported an incidence rate of 39.5 per 100,000 individuals nationwide, with 2.3% of primary TB cases being multidrug-resistant (MDR); however, very few MDR-TB cases had drug susceptibility testing (DST) before treatment, in particular testing for pyrazinamide (PZA) susceptibility [2]. The key components of treatment regimens for MDR-TB are second-line drugs (SLDs) and PZA [3,4], which have potent sterilising effects [5,6] thereby enabling a shorter treatment duration [7,8]. Therefore, treatment of MDR-TB may be impaired by resistance to these drugs [9].
Despite the strong association between drug resistance and genetic mutations, the value of molecular diagnosis of drug resistance to guide the treatment of multidrug-resistant tuberculosis (MDR-TB) remains unclear. This is particularly relevant in resource-limited areas where it is difficult to perform drug susceptibility testing (DST). Here we investigated the association between drug susceptibility phenotypes and genotypes and treatment outcomes in patients with MDR-TB. This study enrolled 74 consecutive patients with confirmed MDR-TB between 2010 and 2011, and outcomes were followed-up over the 24-month treatment course. All of the isolates were tested for phenotypic susceptibility to second-line drugs using the Mycobacteria Growth Indicator Tube (MGIT)-based system, and genotypic mutations were assessed by DNA sequencing. Among the 74 MDR-TB isolates, 29 (39.2%) were resistant to fluoroquinolones and/or second-line injectable drugs, of which 21 (72.4%) harboured a mutation in drug resistance-related genes (gyrA, rrs or eis). In addition, 32 individuals (43.2%) also had pyrazinamide (PZA)-resistant isolates, with 28 (87.5%) containing the pncA mutation. By backward selection in the multivariate logistic regression and Cox proportional hazard models, PZA resistance and its related pncA gene mutation demonstrated a correlation with a lower likelihood of culture conversion at 8 weeks and treatment success. Meanwhile, the fluoroquinolone resistance-related gyrA gene mutation was negatively correlated with treatment success. DST for PZA and fluoroquinolones together with genetic information appears to provide a clinically useful indicator of the treatment outcome of MDR-TB in China.
Short course treatment regimens for tuberculosis: A review
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La tuberculose est un problème de santé publique mondial. De nouveaux régimes thérapeutiques efficaces sur des durées plus courtes que les traitements actuels pourraient permettre d’améliorer les issues de traitement et de diminuer l’incidence globale de la tuberculose, sensible ou résistante.
Revue de la littérature sur le raccourcissement du traitement antituberculeux, des formes sensibles et résistantes.
Bien que les études de phase 2 avec des associations antituberculeuses contenant des fluoroquinolones ou de la rifapentine aient été prometteuses pour le traitement des formes sensibles, les récents essais cliniques de phase 3 n’ont pas permis de démontrer la non-infériorité de ces nouveaux régimes, principalement en raison d’un taux de rechute plus élevé. Pour les formes multirésistantes, des régimes thérapeutiques d’une durée raccourcie à 9–12 mois et contenant de la clofazimine ont obtenu de bons résultats mais il est nécessaire de mener des études de phase 3 à grande échelle pour confirmer leur efficacité. Le développement de nouvelles molécules (bédaquiline, délamanide, oxazolidinones…) laisse espérer une possibilité de raccourcissement futur des durées de traitement des formes sensibles ou résistantes, par de nouvelles associations.
Les traitements courts associant une fluoroquinolone ou de la rifapentine à des molécules de première ligne ont un taux de rechute plus élevé que le traitement standard d’une durée de 6 mois. Dans l’état actuel des connaissances, le traitement de 6 mois utilisant les molécules de première ligne reste donc le traitement de référence à proposer en première intention aux patients. De nouvelles études de phase 3 testant des durées raccourcies de traitement avec des combinaisons thérapeutiques innovantes utilisant les molécules en développement sont nécessaires.
Tuberculosis is a major and worldwide public health challenge. The built of new and efficient short course regimens could improve patient outcomes and reduce the global incidence of tuberculosis.
Literature review on short course treatment regimens for drug-sensitive and multidrug-resistant tuberculosis.
The results of phase 2 studies on fluoroquinolone- or rifapentine-based regimens for drug-sensitive tuberculosis were encouraging. However, non-inferiority was not shown in three recent multicentric and randomized trials comparing short course (4 months) of these new combinations to the reference 6 months-treatment containing first line drugs, mainly because of higher relapse rates in experimental arms. For multidrug-resistant tuberculosis, new regimens during 9 to 12 months and containing clofazimine in addition to other second line drugs showed promising results in pilot studies. However, randomized trials are now required to confirm long-term efficacy and outcomes. The development of new antituberculosis drugs (like bedaquiline, delamanide, or oxazolidinone) enables innovative associations and the hope of shortening the duration of drug-sensitive and multidrug-resistant tuberculosis treatment in the future.
Moxifloxacin or rifapentine-based short course regimens in association with first line drugs for drug–sensitive tuberculosis results in high relapse rates and should nowadays not be preferred to the standard 6 months regimen. Further trials that explore short course of new antituberculosis drugs associations are needed for either drug-sensitive or resistant tuberculosis.
Pyrazinamide susceptibility testing of Mycobacterium tuberculosis by high resolution melt analysis
2014, Tuberculosis
Citation Excerpt :
Pyrazinamide (PZA) is a first-line drug for the treatment of tuberculosis. Its use allows shortening of the treatment period from 9 to 6 months and it is also widely included in regimens for MDR-Tb [1–4]. The importance of PZA susceptibility testing has increased due to the recognition of PZA monoresistant strains of Mycobacterium tuberculosis and the need for improved MDR-TB regimens, since some new TB drugs such as bedaquiline appear to benefit from PZA [5,6].
Pyrazinamide (PZA) plays the important role in shortening the tuberculosis treatment period and in treating MDR-TB. Phenotypic PZA susceptibility methods are limited because they require specialized acidified media, which increases costs and complexity. In this study we developed a genotypic high resolution melt (HRM) analysis technique to detect pncA mutations associated with PZA resistant Mycobacterium tuberculosis. Seven overlapping primer pairs were designed to cover the entire pncA gene and upstream regions. Each gene segment was individually amplified by real-time PCR followed by HRM analysis. The assay was evaluated on 98 clinical M. tuberculosis isolates (41 PZA susceptible by MGIT method, 55 PZA resistant, 2 undetermined). HRM was 94% concordant to full-length sequencing results, with most discrepancies attributable to mixed populations per HRM or transversions. Sequencing and HRM yielded 82% and 84% concordance, respectively, to phenotypic PZA susceptibilities by MGIT, with most discrepancies attributable to isolates with wild-type pncA but phenotypic PZA resistance. This HRM technique is a simple and high-throughput method for screening clinical M. tuberculosis samples for PZA resistance.
Four-month Moxifloxacin-based regimens for drug-sensitive tuberculosis
2014, New England Journal of Medicine
Citation Excerpt :
The similarity in outcome among women in the isoniazid group and the control group may represent a chance finding but merits further investigation. It has been previously suggested that Asian patients often have a more chronic form of tuberculosis with a different clinical course than that in African patients,18,19 but we did not see any evidence of variation in clinical-disease outcome in the different racial groups. Our approach in the conduct of this trial, including standardized laboratory methods and clinical management, has resulted in consistent results across more than 20 sensitivity analyses, with minimal variation among study centers on different continents.
Early-phase and preclinical studies suggest that moxifloxacin-containing regimens could allow for effective 4-month treatment of uncomplicated, smear-positive pulmonary tuberculosis.
We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to test the noninferiority of two moxifloxacin-containing regimens as compared with a control regimen. One group of patients received isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid and rifampin (control group). In the second group, we replaced ethambutol with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (isoniazid group), and in the third group, we replaced isoniazid with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (ethambutol group). The primary end point was treatment failure or relapse within 18 months after randomization.
Of the 1931 patients who underwent randomization, in the per-protocol analysis, a favorable outcome was reported in fewer patients in the isoniazid group (85%) and the ethambutol group (80%) than in the control group (92%), for a difference favoring the control group of 6.1 percentage points (97.5% confidence interval [CI], 1.7 to 10.5) versus the isoniazid group and 11.4 percentage points (97.5% CI, 6.7 to 16.1) versus the ethambutol group. Results were consistent in the modified intention-to-treat analysis and all sensitivity analyses. The hazard ratios for the time to culture negativity in both solid and liquid mediums for the isoniazid and ethambutol groups, as compared with the control group, ranged from 1.17 to 1.25, indicating a shorter duration, with the lower bounds of the 95% confidence intervals exceeding 1.00 in all cases. There was no significant difference in the incidence of grade 3 or 4 adverse events, with events reported in 127 patients (19%) in the isoniazid group, 111 (17%) in the ethambutol group, and 123 (19%) in the control group.
The two moxifloxacin-containing regimens produced a more rapid initial decline in bacterial load, as compared with the control group. However, noninferiority for these regimens was not shown, which indicates that shortening treatment to 4 months was not effective in this setting. (Funded by the Global Alliance for TB Drug Development and others; REMoxTB ClinicalTrials.gov number, NCT00864383.)
One approach to improving tuberculosis therapy is to shorten the duration from 6 months to 4 months. In this trial in over 1900 patients with smear-positive tuberculosis, two 4-month moxifloxacin-based regimens did not perform as well as the standard 6-month regimen.
A short-term tuberculosis treatment regimen could improve rates of adherence, reduce rates of adverse events, and lower costs. Fluoroquinolones have shown promising activity against mycobacteria¹ and are established as a critical component of the treatment of multidrug-resistant tuberculosis,²,³ with later fluoroquinolones recognized as having a more potent effect. It has been proposed that these drugs may have a role in reducing the duration of tuberculosis treatment.⁴
Moxifloxacin has been approved for a range of indications globally.⁵ It has favorable pharmacokinetics, a large volume of distribution, and penetration into epithelial-lining fluid and macrophages.6, 7, 8 The activity of moxifloxacin in vitro . . .

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Original articleClinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis: The results up to 30 months

Abstract

Résumé

Resumen

Lancet

Chest

Lancet

Chest

Tubercle

Controlled clinical trial of four 6-month regimens of chemotherapy for pulmonary tuberculosis. Second report

American Review of Respiratory Disease

Controlled trial of 6-month and 8-month regimens in the treatment of pulmonary tuberculosis. First report

American Review of Respiratory Disease

Two three-month treatment regimens for pulmonary tuberculosis

Bulletin of the International Union Against Tuberculosis

Clinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis

American Review of Respiratory Disease

Original article
Clinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis: The results up to 30 months