Intermittent tuberculosis treatment regimens have been developed to facilitate treatment supervision. Their efficacy has been substantiated by clinical trials and tuberculosis control programmes, notwithstanding the lack of head-to-head comparison between daily and intermittent regimens. Recently, there has been opposing evidence from observational studies, pharmacokinetic-pharmacodynamic studies and animal models that intermittent treatment increases the risk of relapse, treatment failure or acquired rifamycin resistance, especially among HIV-infected patients. Systematic reviews have been conflicting. PubMed, Ovid MEDLINE and EMBASE were systematically searched for publications in English to evaluate the evidence about dosing schedules and treatment efficacy. Levels of evidence and grades of recommendation were assigned largely according to clinical evidence with reference to the Scottish Intercollegiate Guidelines Network guideline development handbook. A total of 32 articles were included after excluding 331 ineligible articles, 42 non-analytical studies, 22 narrative reviews or expert opinions and 44 articles embedded in systematic reviews. These included 9 systematic reviews, 8 controlled studies, 9 pharmacokinetic-pharmacodynamic studies, 5 mouse studies and 1 article about guinea pig experiments. Findings suggest high levels of evidence for using daily dosing schedules, especially during the initial phase in the presence of cavitation, isoniazid resistance and advanced HIV co-infection, to reduce the risk of treatment failure, recurrence and acquired drug resistance including acquired rifamycin resistance. This review justifies the use of daily schedules in standard tuberculosis treatment regimens (particularly in the initial phase), corroborates prevailing understanding of pharmacokinetics-pharmacodynamics and mycobacterial persisters, and supports exploration of rifapentine-containing regimens in higher dosages and frequency.
- Acquired rifamycin resistance
- treatment failure
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- Acquired rifamycin resistance
- treatment failure
Tuberculosis (TB) is an old infectious disease. Despite the availability of chemotherapy against the tubercle bacillus, our battle with this old human enemy is still far from over. With the rather unusual biological characteristics of this pathogen,1 the disease shows a distinctive natural history2 3 and a very slow response to existing chemotherapeutic agents.1 4 5 Poor treatment adherence, acquired drug resistance, treatment failure and relapse have been encountered since the early days of chemotherapy.6 A series of landmark trials in Madras (now Chennai),7 8 Africa, Hong Kong and Singapore helped to establish the currently adopted 6-month standard regimens given under supervision.9 These studies laid the foundation for the global comprehensive strategy for TB control known as directly observed treatment, short-course (DOTS), which was promulgated in 1993 by the World Health Organization (WHO) alongside a declaration of TB as a global emergency.10 Despite some recent controversies over the exact role of the act of directly observed treatment (DOT),11–13 no alternative method of drug administration has been conclusively shown to offer a similarly high rate of treatment success as that demonstrated by DOTS under functional programme settings.14–16
Intermittent drug delivery either throughout the entire 6-month course or only during the continuation phase in the last 4 months has been widely adopted to facilitate treatment supervision on an outpatient basis ever since the introduction of DOTS.17 The lower number of treatment visits helps to reduce both operational and patient-related costs, especially if long travelling distances are involved. As intermittent treatment poses lesser interference on usual lifestyles, patients can carry on their regular daily activities and work. This helps to promote access to care and treatment adherence by patients, especially in resource-limited areas or for underprivileged segments of populations.
In vitro demonstration of the post-antibiotic effect (PAE) has provided the scientific basis for intermittent TB treatment in clinical settings by showing that exposure to drugs, especially isoniazid, for a few hours resulted in suppression of mycobacterial growth for several days.18–21 For rifampicin and possibly other TB drugs, free peak drug concentration to minimum inhibitory concentration (MIC) ratio best correlates with the PAE and suppression of resistance.21 The PAE has also been suggested by animal studies. A series of guinea pig experiments have shown that, when the same total drug amount is given as a single dose or fractionated into multiple doses of different sizes, better efficacy is observed with high doses given at long intervals, especially for rifampicin and ethambutol.22 This suggests concentration-dependent activity in the tested drug. Higher doses in murine models also demonstrated longer PAEs with the exception of rifampicin.23 PAEs of TB drugs in humans were first demonstrated in non-rifampicin regimens in a randomised controlled clinical trial that compared twice-weekly isoniazid plus streptomycin and daily isoniazid plus para-aminosalicylic acid in the treatment of pulmonary TB,24 and later in clinical trials of 6-month rifampicin- and isoniazid-containing regimens in the 1970s and 1980s. Standard 6-month intermittent regimens have been widely used in TB control programmes with good results.25 26 Although the exact mechanisms are not fully understood, the PAE is thought to be commonly mediated via suppression of bacterial RNA or protein synthesis.27
However, a number of recent studies have challenged the orthodoxy of intermittent treatment. In order to facilitate the development of new TB drugs and regimens for successful implementation in TB control programmes based on DOTS, we conducted a systematic review to examine the seemingly controversial evidence about dosing intermittency and treatment efficacy across different subpopulations of patients. Measures of treatment efficacy included relapse or recurrence, treatment failure, cure, drug resistance and acquired rifamycin resistance.
PubMed, Ovid MEDLINE and EMBASE were systematically searched through 2 June 2010 for publications in English using a search algorithm that combined the following keywords in Medical Subject Headings, titles, abstracts, or journal titles, as appropriate, with the help of Boolean operators (‘and’, ‘or’) and wildcards (*): (i) tuberculosis; (ii) relapse or recurrence; (iii) treatment and failure; (iv) resistance, and rifamycin, rifampin, rifampicin, rifabutin or rifapentine; (v) intermittent, interruption, once-weekly, twice-weekly, biweekly, three-times-weekly, thrice-weekly, once a week, twice a week, thrice a week, dosing schedule, or dosing frequency; (vi) systematic review or meta-analysis; (vii) Cochrane Database Systematic Review or Clinical Evidence; (viii) therapy, chemotherapy, treatment, rifamycin, rifampin, rifampicin, rifabutin, or rifapentine; and (ix) pharmacokinetics and pharmacodynamics. The search algorithm in PubMed is shown in appendix 1 in the online supplement. The above literature search was supplemented by a WHO reference.28
The literature search included clinical studies, in vitro studies, animal experiments, narrative reviews or expert opinion, with focus on systematic reviews and controlled clinical studies. Only analytical clinical studies that evaluated the relationship between dosing schedules and treatment efficacy of rifamycin-based regimens or non-analytical clinical studies involving rifamycin-based regimens given for at least 6 months were included. Non-analytical studies, expert opinions and narrative reviews were subsequently excluded when a clinical question could be sufficiently addressed by systematic reviews or controlled clinical studies. Levels of evidence and grades of recommendation were assigned largely according to clinical evidence with reference to the Scottish Intercollegiate Guidelines Network guideline development handbook29 (see appendix 2 in the online supplement). Studies rated as having high risk of bias were not used for making recommendations. The risk of bias was judged as high when major potential confounders were not adjusted, low in the absence of quality assessment in systematic reviews or blind assessment when outcome was assessed by objective data, and not applicable for non-conclusive findings.
Studies of non-rifampicin regimens, irrelevant articles and those with no specific information about the impact of dosing schedules on treatment efficacy were excluded. Articles already embedded in systematic reviews were also excluded to reduce materials to a manageable size without losing essential information. Data were extracted by the first author (KCC) and checked by the co-authors for accuracy and interpretation. Disagreement was resolved by consensus.
The search algorithm initially identified 469 articles. A total of 331 articles were excluded for the following reasons: irrelevance (n=295), effect of dosing schedule on treatment efficacy not evaluated (n=23), rifampicin given for less than 6 months (n=12) and update within the same year (n=1). After further excluding 42 non-analytical studies, 22 narrative reviews or expert opinions and 44 articles already included in systematic reviews, and adding two articles22 30 from a WHO reference,28 a total of 32 articles were included in the current review (figure 1). These publications included nine systematic reviews with or without meta-analysis, eight controlled studies, nine pharmacokinetic-pharmacodynamic (PK-PD) studies, five studies of TB mouse models and one publication about guinea pig experiments. Studies included in the current review can be grouped under five categories: HIV-related TB, HIV-negative TB, TB with isoniazid resistance, childhood TB, and in vitro studies and animal experiments.
Table 1 shows three studies regarding the impact of dosing intermittency on treatment efficacy in HIV-related TB: one systematic review with meta-analysis and two retrospective cohort analyses. All suggest that intermittent treatment, especially in the initial phase, reduces treatment efficacy as shown by a higher risk of treatment failure, relapse or acquired rifamycin resistance. The level of evidence is 1+ and the grade of recommendation for avoiding dosing intermittency, especially in the initial phase in HIV-related TB, is A.
Table 2 shows 11 studies regarding the impact of dosing intermittency on treatment efficacy in HIV-negative tuberculosis: six systematic reviews with or without meta-analysis, two controlled clinical trials, one retrospective cohort analysis and two case–control studies. The risk of bias was low for four, high for three and not applicable for four. Studies with a low risk of bias suggest that intermittent treatment reduces TB treatment efficacy as shown by a higher risk of relapse or treatment failure. The negative impact appears to be most prominent in the presence of initial cavitation.34 35 A systematic review of standard 6-month regimens suggests no significant difference between daily treatment throughout and daily treatment in the initial phase.35 Among studies with a high risk of bias, all except one suggest that dosing intermittency does not reduce treatment efficacy.
The level of evidence for a negative impact of dosing intermittency on TB treatment efficacy in HIV-negative TB is 1+ and the grade of recommendation for avoiding dosing intermittency, especially in the initial phase in the presence of cavitation, is A.
TB with isoniazid resistance
Table 3 shows two studies regarding the impact of dosing intermittency on treatment efficacy in TB with isoniazid resistance. Both suggest that dosing intermittency reduces TB treatment efficacy as shown by a higher risk of treatment failure, relapse or acquired drug resistance. The level of evidence is 1+ and the grade of recommendation for avoiding dosing intermittency, especially in the initial phase in the presence of isoniazid resistance, is A.
Table 4 shows one study regarding the impact of dosing intermittency on treatment efficacy in childhood TB. It suggests that twice-weekly TB treatment may be less efficacious than daily treatment in achieving cure. The level of evidence is 1+ and the grade of recommendation for avoiding dosing intermittency in childhood TB is A.
In vitro studies and animal experiments
Table 5 shows 15 in vitro studies and animal experiments. All except two suggest that dosing intermittency may reduce treatment efficacy with internal consistency. PK-PD studies have substantiated the association between dosing intermittency and treatment efficacy by reaffirming that the classical pharmacodynamic parameter, which is the area under the concentration-time curve (AUC) to MIC ratio, best correlates with the bactericidal or sterilising effect of rifampicin21 49 and pyrazinamide.50 Such findings corroborate the significant association between AUC of rifabutin and failure or relapse in a clinical trial,51 the treatment-shortening effect of rifapentine-based regimens in TB mouse models52–54 and an increase in the risk of relapse55 or treatment failure with acquired resistance to rifampicin or isoniazid following reduction in dosing frequency in TB mouse models.
The current review suggests high levels of evidence for using daily dosing schedules, especially in the initial phase, to reduce the risk of treatment failure, recurrence and acquired drug resistance (including acquired rifamycin resistance, particularly in patients with advanced HIV infection). Compared with intermittent treatment throughout, daily treatment throughout significantly reduces the risk of relapse in the presence of initial cavitation34 35 or HIV infection,32 while daily treatment in the initial phase significantly reduces failure, relapse and acquired drug resistance rates among patients with HIV infection31 33 or isoniazid-resistant strains.46 47 Treatment with a daily initial phase followed by a thrice-weekly continuation phase is probably comparable to daily treatment throughout.35 Inconclusive findings from systematic reviews37–40 are largely due to insufficient head-to-head comparison of different schedules in controlled clinical trials, which has been provided by only one randomised controlled trial.62 63 Negative findings from a systematic review and meta-analysis41 may be partly attributable to lack of controlling for major confounders of relapse such as initial cavitation and 2-month sputum culture status,34 64 65 and partly due to the inclusion of daily regimens containing no rifampicin in the continuation phase, such as isoniazid and ethambutol66 or isoniazid and pyrazinamide.67–69
The available evidence suggests that the effect of dosing schedules on treatment efficacy is best harnessed in the initial phase rather than in the continuation phase. In fact, there has been in vitro evidence for a few decades that the more rapid the antibacterial effect, the less likely is the emergence of persisters and the lower is the risk of relapse.70 It has been hypothesised that there are four subpopulations of tubercle bacilli: actively dividing bacteria, bacteria that divide slowly in an acidic microenvironment, semi-dormant persisters that are metabolically active in spurts, and dormant bacilli.22 While rifampicin and pyrazinamide have appreciable sterilising activity,71 72 rifampicin is the only first-line TB drug with putative activity against persisters, which are also characterised by phenotypic resistance to isoniazid. This hypothesis of mycobacterial subpopulations has been supplemented by a Yin-Yang model of reverters and persisters, which suggests a dynamic change between bacillary persisters and the other subpopulations during treatment of both TB disease and latent TB infection.5 Thus, optimising bactericidal and sterilising effects of TB drugs in the initial phase can minimise the overall bacterial load from which persisters emerged. A smaller population of persisters, which are phenotypically resistant to isoniazid and virtually eradicated only by rifampicin, leads to a lower probability of selecting out rifampicin-resistant mutants (and hence acquired rifamycin resistance) that are inadequately contained by poor host immunity in advanced HIV infection.73
Several biological factors may explain why using daily dosing schedules of standard rifampicin regimens improves treatment efficacy. First, while it may be sufficient for drugs with prolonged PAEs to kill rapidly or slowly dividing bacteria that replicate periodically, intermittent treatment may be less efficacious against persisters with intermittent metabolic activity when dosing is asynchronous with the metabolic bursts. Increasing the frequency of dosing reduces the chance of asynchrony. Second, food–drug interaction with rifampicin may cause erratic absorption of rifampicin.74 Lastly, protein binding may also reduce penetration of rifampicin into cavities, especially during the continuation phase when there is less inflammation and more fibrosis.75 The maximum serum concentration of rifampicin is reduced to approximately 2 mg/l after food.74 It has been shown that broth-determined MIC for rifampicin ranged from 0.06 to 0.25 mg/l.76 Assuming that 80% of rifampicin in blood is bound to protein,74 total plasma rifampicin levels of 0.3–1.25 mg/l can achieve broth-determined MIC. However, based on a peak serum rifampicin level of approximately 12 mg/l in patients treated with rifampicin 600 mg daily74 77and a peak sputum rifampicin level of approximately 6 mg/l at the same rifampicin dosage,74 78 rifampicin levels in TB cavities may be about half of serum levels. More frequent dosing may compensate for less sterilising activity and shorter PAEs due to lower rifampicin levels in TB cavities.
It is perhaps important not to forget PAEs in the pursuit of optimal dosing schedules. Twice-weekly high-dose isoniazid is at least as efficacious as daily isoniazid.24 Pyrazinamide 3 g thrice weekly, which is higher than the average dosage used in intermittent regimens, is more effective than 1.5 g once daily.79 In a relatively small clinical trial involving thrice-weekly treatment of patients with predominantly isoniazid-resistant TB with rifampicin, ethambutol and pyrazinamide, the 2-year relapse rate was non-significantly lower among subjects given pyrazinamide 2.5–3 g thrice weekly than those given pyrazinamide 1.5–2 g thrice weekly (11.3% vs 16.3%).80 If not for the higher risk of immune-mediated adverse events due to intermittent high-dose rifampicin81–83 and unwarranted fear of hepatotoxicity due to intermittent high-dose pyrazinamide,79 84 85 the observed difference between daily and intermittent treatment regimens might be reduced by increasing dosages of rifampicin and pyrazinamide in intermittent regimens. The much longer elimination half-life of rifapentine may allow intermittent treatment without compromising treatment efficacy,52–54 and make it possible to harness PAEs to facilitate DOT and better suppress drug resistance.21
Optimising dosing schedules should not be the only approach for improving TB treatment. Lessons from the study of pyrazinamide, which has completely different mechanisms of sterilising activity from rifampicin, have suggested that shortening TB treatment necessitates development of new drugs that are able to eradicate persisters with different modes of action.86 Unfortunately, the development of new drugs with good sterilising activity is difficult and in part hampered by the lack of good surrogate markers of relapse. Further studies for identifying better surrogates of relapse seem warranted.87 88 In addition, timely initiation of effective antiretroviral treatment in HIV-related TB can restore CD4 counts and reduce the risk of recurrence89 and possibly acquired rifamycin resistance.
In conclusion, the current review suggests high levels of evidence for using daily schedules in standard TB treatment regimens, especially during the initial phase in the presence of cavitation, isoniazid resistance and advanced HIV co-infection. It corroborates prevailing understanding of pharmacokinetics-pharmacodynamics and mycobacterial persisters and supports exploration of rifapentine-containing regimens in higher dosages and frequency.34–45
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.