Duration and Intermittency of rifampin on TB treatment outcomes
Why is duration and intermittency of rifampin treatment important for tuberculosis patients?
Tuberculosis (TB) is a global health concern which kills nearly two million people per year. Rifampin (also known as rifampicin) is an antibiotic usually provided as a part of the treatment plan. It is taken either daily or 3 times weekly for the first two months of treatment and can be taken continuously for up to 6 to 8 months. Increasing the duration of rifampin treatment to 6 months can reduce the risk of developing drug resistance and may improve treatment outcomes compared to shorter regimens. In addition, intermittent regimens in which rifampin is taken twice or thrice weekly may allow for less intensive treatment plans with similar benefits.
Does increased duration and intermittency of rifampin improve treatment outcomes?
- Regimens that used rifampicin during only the first 1–2 months of treatment had higher rates of failure (antibiotics did not eliminate the infection), relapse, and acquired drug resistance than regimens that used rifampicin for 6 months or more
- Relapse rates decreased with the duration of rifampicin treatment up to 8 months of treatment
- Treatment outcomes were similar with all intermittent schedules evaluated, but there is insufficient evidence to support administration of treatment twice weekly throughout therapy compared to treatments administered both daily and 3 times weekly.
Equity - Does longer duration and/or increased intermittency of rifampin work for the disadvantaged?
- The trials included in the review were conducted in high-income (UK, USA, Hong Kong, Singapore, Poland, Ireland, Denmark), middle-income (South Africa, Iran) and low-income countries (Democratic Republic of Congo)
- Increased rifampin duration may increase cost of treatment which will have a significant impact on low and middle income countries
Intervention Delivery
- The intervention was varying durations and intermittencies of rifampin treatment (450 mg/d in three trials and 600 mg/d in all other trials)
- Comparison 1: 2 months versus 3-4 months (450 mg/d and 600 mg/d)
- Comparison 2: 2 months versus 6 months (600mg/d)
- Comparison 3: 4 months versus 6 months (600mg/d)
- Comparison 4: 6 months versus 9+ months (600mg/d)
Population and Setting
- Patients were adults (18+), from low to high income countries, and were previously untreated for TB
Summary of Findings [SOF] Table:
Patient or population: All trials involved adults (18+), previously untreated for TB
Settings: Countries with low to high TB prevalence
Intervention: Rifampin treatment duration of more than 2 months and increased intermittency of treatment
Comparison: Rifampin treatment for two months or less and daily treatment regimens
Table 1: Stratified estimates of treatment failures, relapses, and ADRs in RCT in new cases.
Outcomes | Pooled Event Rate (95% CI) | No of Events/Participants | What does this mean? | ||
Anticipated Absolute Event per 1000 Participants | |||||
| Failure | |||||
| Duration of Rifampin | 1 to 2 months | 23 per 1000 | 1.8 (0.2 to 3.3) | 94/4,133 (72) | There is a trend towards decreased failure amongst treatments lasting longer than 2 months. 8+ months of treatment had the lowest pooled event rate for failure whereas treatments of 2 months or less had the highest. |
| 3 to 5 months | 6 per 1000 | 0.3 (0 to 0.6) | 16/2,508 (42) | ||
| 6 to 7 months | 15 per 1000 | 0.4 (0.1 to 0.7) | 150/10,060 (178) | ||
| 8+ months | 7 per 1000 | 0.2 (0 to 0.6) | 10/1,384 (18) | ||
| Intermittency of Rifampin | Daily throughout | 16 per 1000 | 0.4 (0.2 to 0.7) | 179/11,510 (159) | There was no significant difference in failure rates amongst the varying intermittencies studied. |
| Daily then thrice weekly | 4 per 1000 | 0.3 (0 to 1.0) | 4/961 (35) | ||
| Daily then twice weekly | 18 per 1000 | 1.2 (0.1 to 2.4) | 49/2,749 (46) | ||
| Thrice weekly throughouta | 13 per 1000 | 0.5 (0 to 1.0) | 38/2,865 (70) | ||
| Relapse | |||||
| Duration of Rifampin | 1 to 2 months | 110 per 1000 | 16.0 (11.1 to 20.9) | 367/3,349 (70) | Treatments lasting 2 months or less were found to have a significantly higher relapse rate compared to treatments lasting longer than 2 months. The longer the duration of treatment, the less the likelihood of relapse. |
| 3 to 5 months | 77 per 1000 | 7.1 (4.5 to 9.7) | 185/2,389 (42) | ||
| 6 to 7 months | 42 per 1000 | 3.8 (2.9 to 4.7) | 364/8,639 (171) | ||
| 8+ months | 12 per 1000 | 1.0 (0.2 to 1.7) | 14/1,181 (18) | ||
| Intermittency of Rifampin | Daily throughout | 58 per 1000 | 4.8 (3.6 to 6.0) | 566/9,829 (153) | There was no significant different in relapse rates amongst the varying intermittencies studied. |
| Daily then thrice weekly | 36 per 1000 | 2.9 (0.7 to 5.2) | 33/907 (34) | ||
| Daily then twice weekly | 76 per 1000 | 7.3 (4.0 to 10.7) | 181/2,367 (44) | ||
| Thrice weekly throughouta | 61 per 1000 | 5.7 (3.1 to 8.3) | 150/2,455 (70) | ||
| Acquired Drug Resistance | |||||
| Duration of Rifampina | 1 to 2 months | 14 per 1000 | 0.8 (0 to 1.6) | 41/2,847 (61) | There is a trend towards decreased rate of acquired drug resistance with longer duration of treatment. Treatmetns lasting 2 months or less were found to have the highest rate of acquired drug resistance. |
| 3 to 5 months | 5 per 1000 | 0.3 (0 to 0.6) | 10/1,932 (33) | ||
| 6 to 7 months | 8 per 1000 | 0.4 (0.1 to 0.7) | 60/7,180 (146) | ||
| 8+ months | 5 per 1000 | 0.2 (0 to 0.5) | 61/1,249 (17) | ||
| Intermittency of Rifampina | Daily throughout | 8 per 1000 | 0.3 (0.1 to 0.6) | 67/8,541 (125) | There was no significant difference in rates of acquired drug resistance amongst the varying intermittencies. |
| Daily then thrice weekly | 5 per 1000 | 0.6 (0 to 1.8) | 3/636 (28) | ||
| Daily then twice weekly | 7 per 1000 | 0.4 (0 to 1.0) | 12/1,748 (36) | ||
| Thrice weekly throughout | 15 per 1000 | 0.9 (0 to 2.0) | 35/2,283 (68) | ||
Event rate and 95% CI are in bold if confidence intervals for two or more strata do not overlap a In all but one trial, if therapy was intermittent initially, the same schedule was continued throughout therapy. | |||||
Relevance of the review for disadvantaged communities
Findings | Interpretation |
Equity – Which of the PROGRESS groups examined |
|
The trials included in the review were conducted in high (UK, USA, Hong Kong, Singapore, Poland, Ireland, Denmark), middle (South Africa, Iran) and low-income countries (Democratic Republic of Congo). There is a greater prevalence of tuberculosis in middle and lower income countries relative to those of high income.
| This review evaluates the effectiveness of rifampin across varying durations of ttreatment. The duration of treatment is of particular importance in countries where resistant forms of the disease are common. |
An analysis of the efficacy of treatment across PROGRESS subgroups was not performed in this review. | This review did not analyze the effect of rifampin duration across additional PROGRESS groups. Future research would be required to explore variations in outcome. |
Equity Applicability |
|
The review summarized trials only treating adult populations and there was a lack of trials addressing treatment of HIV+ populations. | Children and individuals diagnosed HIV+ are particularly vulnerable to TB as a result of their lowered levels of adaptive immunity. There is an urgent need for more trials testing treatment regimens in these populations as they represent a significant portion of new TB cases globally. |
Cost-equity |
|
No studies contributed economic data. | The cost and availability of rifampin may vary across countries and their differing health systems. As rifampin treatment duration increases, it can be expected that the cost of the regimen will increase as well. Further economic analyses are needed to develop an understanding of the most cost-effective and efficient treatment. |
Community/Stakeholder Preferences |
|
Increased duration of rifampin treatment iimproved treatment outcomes.
| With increased duration of treatment there may come an increased cost, this may impact the opinion of certain stakeholders. Patient preference for shorter regimens and/or different intermittent regimens was not discussed.
|
Comments on this summary? Please contact Jennifer Petkovic.
This summary was prepared by Nicholas Lebel