|THE EVOLUTION - HITTING IT HARD
|Year : 2017 | Volume
| Issue : 1 | Page : 63-66
High-Dose rifampicin: Time to dose it right!
Arvind Kate1, Amita Nene2
1 Department of Respiratory Medicine, Zen Multispeciality Hospital, Mumbai, Maharashtra, India
2 Department of Respiratory Medicine, Bombay Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||6-Nov-2017|
Head, Department of Respiratory Medicine, Bombay Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Tuberculosis (TB) remains a major cause of mortality worldwide. Effective control of TB is being hampered by the prolonged duration of therapy which leads to poor patient compliance. This can lead to increased relapse rates and emergence of drug-resistant organisms, thus further compounding the problem. An exciting new avenue to reduce the duration of therapy is the use of high-dose rifampicin. High-dose rifampicin is being extensively studied and the data is exciting. It has shown to result in better sterilization and earlier culture conversion with no increase in adverse reactions. These effects of high-dose rifampicin can possibly help reduce the duration of TB treatment. Whether this “high-dose-reduced-duration-rifampicin-regimen” will lead to increased relapse rates is yet to be studied. If not, then this gives physicians a well proven and inexpensive option to cure TB and hence may be the future of TB treatment.
Keywords: High-dose rifampicin, rifampicin, TB relapse
|How to cite this article:|
Kate A, Nene A. High-Dose rifampicin: Time to dose it right!. Astrocyte 2017;4:63-6
| Introduction|| |
Tuberculosis (TB) is the leading infectious disease killer worldwide. Effective TB control is hindered by bacterial persistence, which requires giving multiple anti-TB drugs for a prolonged period. This prolonged multidrug combination regimen leads to poor patient compliance, which subsequently results in high relapse rates and acquired drug resistance., Thus, shortening the duration of treatment will help improve patient compliance, reduce relapse rates, and drug resistance and will be of great clinical benefit.
Development of new drugs, though exciting, is expensive and time consuming., Strategies involving new applications of existing drugs are urgently needed to reduce the time required to cure patients with TB. Use of high-dose of rifampicin (RMP) is one such approach.
In 1970, the British Medical Research Council was responsible for the first large randomized clinical trial of short-course anti-TB therapy that included RMP. This trial was conducted in east Africa, and led to the shortening of chemotherapy to 6 months.,, At that time, RMP was a costly medicine and studies were designed to use the smallest dose of RMP considered effective (and not the optimal dose). This facilitated the use of RMP at the dose of 10 mg/kg/day.
RMP is no longer expensive, and given that the standard dose of 10 mg/kg or a maximum of 600 mg of RMP currently used was developed as the minimum effective dose and optimal dosing for rifampicin was overlooked in these trials due to cost constrains, there has been a renewed interest in the efficacy and safety of using higher doses of RMP in combination therapy for active TB. Of prime interest is whether higher-than-standard doses of RMP might enable duration of therapy to be reduced to less than 6 months without increasing drug side effects or relapse rates.,,,,,
| Rifampicin|| |
Rifampicin is a semisynthetic derivative of rifamycin B which is produced by Amycolatopsis (formerly Streptomyces) rifamycinica. The unique role of RMP is believed to be due to its ability to kill two populations of Mycobacterium tuberculosis, those undergoing rapid metabolism and those in a dormant state but undergoing metabolism for limited periods of time. These bactericidal as well as sterilizing activity against tubercle bacilli in both cellular and extracellular locations makes RMP a key drug for the short course TB regimen.
Rifampicin and its role in short-course chemotherapy
Combination chemotherapy has been considered as the gold standard care for TB since the 1950s, when it was demonstrated that combining streptomycin with para-aminosalicylic acid and, later, with isoniazid prevented the emergence of drug resistance and ensured good results of cures following 18–24 months of treatment (1972). In the 1980s, the sequential incorporation of rifampicin and pyrazinamide accelerated the eradication of bacterial “persisters” and reduced the treatment duration needed to prevent relapse. Combining the synergistic antimicrobial properties of RMP and pyrazinamide with the potent bactericidal activity of isoniazid formed the basis of the current 6-month “short-course” regimen, which showed the least frequency of relapse.
Yet, despite the high efficacy of this regime, TB remains a global threat, in part because even this 6-month regimen poses considerable and significant challenges for the resource-limited healthcare infrastructures of many TB-endemic countries.
To reduce treatment duration for TB, currently available drugs are being revisited, with newer dosage regimens and newer protocols. The most promising among these is the use of high-dosage RMP. Results from studies with mice  and studies on early bactericidal activity of high dose RMP in humans  indicate that a single dosage of 600 mg of RMP in TB treatment is at the lower end of the concentration-response curve. Rosenthal's study on murine TB models suggested that, by increasing the dose of RMP, the sterilizing activity of the regimen proportionately increased. Another study by Steenwinkel et al., again on murine models, showed that an eightfold increase in the 10 mg/kg RMP dose which is currently used could reduce duration of treatment from 6 to 2 months and was well tolerated. An important study by Hu et al. using high-dosage RMP (50 mg/kg) in mice showed that lung culture-conversion and relapse-free cure were obtained much earlier, thereby allowing for a shorter treatment course without disease relapse.
However, it has been clearly accepted by TB experts that the conclusions made in mice studies do not necessarily reflect outcomes in human clinical trials, and that early sterilization is not predictive of relapse rates and therefore cure in humans.
In patients with osteoarticular TB, there is recent evidence indicating that increasing the RMP concentration at the infection site can improve its anti-TB action, even against some RMP-resistant strains. Steingart et al. reviewed literature in 2011 and concluded that high-dose RMP results in improved culture conversion rates. Currently, several clinical trials are examining the efficacy and safety of higher dosages of rifampicin in humans than the currently used dosage of 10 mg/kg against drug-susceptible TB. Many investigators have performed studies in patients with TB to establish the maximum tolerated dose, assess the incidence and severity of adverse events, describe the pharmacokinetics, and measure the bactericidal effect of higher doses of rifampin.
| Recent Trials on High-Dose Rifampicin|| |
The PanACEA HIGHRIF1 trial
This trial assessed safety, pharmacokinetics, and anti-mycobacterial activity of rifampicin at doses up to 40 mg/kg. Eighty-three pulmonary tuberculosis patients received 10, 20, 25, 30, 35, or 40 mg/kg RMP daily over 2 weeks, supplemented with standard doses of isoniazid, pyrazinamide, and ethambutol in the second week.
It was found that administering up to 40 mg/kg of RMP for 2 weeks is safe and well tolerated, resulting in a nonlinear increase in exposure to RMP without an apparent ceiling effect, and increased early bactericidal activity at 14 days.
The PanACEA HIGHRIF2 trial
This trial examined the efficacy of RMP given at 10, 15, and 20 mg/kg daily. This study found no serious adverse events for 2 months of RMP at 15 and 20 mg/kg.
The NIAID HIRIF trial
This trial started in September 2013, and is a randomized trial of high-dosage RMP in patients with new, smear-positive TB. It is comparing RMP doses of 20 and 15 mg/kg/day to the standard 10 mg/kg/day for the first 2 months of TB treatment.
PanACEA HIGHRIF3 trial
This is a dosage-ranging, multi-arm, multi-stage study designed to identify the optimal RMP dosage for evaluation of efficacy. It compared one group with 35 mg/kg of RMP (isoniazid/rifampin35/pyrazinamide/ethambutol), a second group with 20 mg/kg of RMP combined with moxifloxacin (isoniazid/rifampicin20/pyrazinamide/moxifloxacin), and a third with 20 mg/kg of RMP combined with the novel ethylenediamine, SQ109 with the standard regime (isoniazid/rifampin10/pyrazinamide/ethambutol).
This study showed that 35 mg/kg RMP given over 12 weeks was safe and shortened the time to stable culture conversion in liquid media from 62 to 48 days, showing the potential for an enhanced regimen. The other experimental arms, including various combinations of 10 mg/kg or 20 mg/kg of rifampicin, moxifloxacin, and SQ109, did not achieve significant improvements over the control arm.
Clinical outcome was assessed at 12 months post randomization (6 months after completion of treatment). However, unfortunately, relapse rates were similar between regimens.
This was a toxicity study of higher doses of RMP 600 mg vs. RMP 900 and 1200 mg. This study indicated that RMP at 900 and 1200 mg daily for the first 4 months of the standard 6-month regimen was safe, with no increase in serious adverse events. However, these higher dosages of RMP did not significantly improve culture conversion rates at 2 months.
This is a phase III study based on the results of RIFATOX study and has been initiated to assess the treatment-shortening potential of high-dosage (1200/1800 mg) rifampicin given for 4 months (2 months of isoniazid/rifampicin/pyrazinamide/ethumbutol + 2 months of isoniazid/rifampicin).
In this trial, the investigators are assessing whether giving an increased dose of RMP to patients receiving the standard treatment for TB is safe, and when given for 4 months only, will also result in greater and faster killing of the tubercle bacillus in the lungs and result in relapse rates similar to those found in the standard 6-month regimen.
Above trials have shown that RMP at the dose of 40 mg/kg for 2 weeks and at the dose of 35 mg/kg for 12 weeks is safe and well tolerated and is not associated with increased adverse effects. Further, in many of the trials, it resulted in increased bactericidal activity and earlier culture conversion. However, the end-points of all the trials mentioned above (except RIFASHORT) were to see either pharmacokinetics or tolerability of high dose RMP or time to culture conversion. Assessment of relapse, which is the definitive endpoint of a pivotal trial, is only being studied in RIFASHORT study. The newly developed phase 2c STEP trial design by Boeree et al. will address this issue in their future trials.
| Conclusions|| |
TB remains a global health emergency, in part, because even a 6-month regimen poses formidable challenges for the resource-limited healthcare infrastructures of many TB-endemic countries. A long duration of therapy is also fraught with the risk of nonadherence, which in turn increases the likelihood of acquiring drug resistance and continuing transmission of disease within the community.
Rifampicin is a pivotal drug for the treatment of TB. In combination with pyrazinamide, it became possible to shorten the duration of TB treatment to 6 months. Virtually all the studies that support these recommendations used a 10 mg/kg dose of RMP, but a dose-finding study with an assessment of the maximum tolerated dose was never performed. The recommended dose was chosen on the basis that it was effective at the lowest cost and limited by fear of adverse effects. Given that the standard dose of 10 mg/kg or a maximum of 600 mg of RMP currently used was developed as the minimum effective dose, there has been a resurgence of interest in the efficacy and safety of using higher doses of RMP in combination therapy for active TB.
Use of high-dosage RMP against M. tuberculosis is promising as it may not only result in enhanced killing of mycobacteria and shorter therapy duration but may also result in the prevention of drug resistance, which are highly desirable properties in an anti-TB regimen. While these preclinical studies are subject to questions regarding their predictive accuracy for assessing the efficacy of anti-TB regimens, the results of various ongoing studies mentioned above promise to provide further guidance on the optimal dosage of rifampicin.
Though above studies have shown that high-dose RMP results in faster culture conversion and that high-dose rifampicin is well tolerated and is safe, whether high-dosage RMP results in reduced relapse rates remains to be explored in clinical studies. Additional studies with relapse rates as the endpoint are required before decision on high dose RMP can be taken. For joint HIV–TB treatment, it is important to determine if high-dosage RMP can shorten the time required to cure TB without increasing adverse events and drug interactions with other anti-TB drugs and antiretroviral agents.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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