TB or not TB: A Journey Through Chemotherapy

This is quite a corny and overtold joke. I have discussed some new drugs for multidrug resistant tuberculosis (MDR-TB), which is defined as resistance to both rifampin and isoniazid, however I felt like going back to the basics of TB therapy. Indeed, we all learn in STEP 1 and med school about “RIPE-ing it up” which is a mnemonic for “Rifampin, INH, PZA, and Ethambutol” however, besides the rationale of preventing drug resistance, I do not think anybody really knows how we ended up with this regimen. Indeed, tuberculosis has long been a dreaded disease with several decades of research being done to find adequate and safe therapy. 

I highly recommend you listen to the “Bedside Rounds” podcast, episode 39 (http://bedside-rounds.org/episode-39-the-white-plague/). It gives a bit of a perspective on the way tuberculosis was treated i.e how it was not treated. In short, prior to the mid 1940s, these folks were put in a sanitoria and recommended for bedrest. After the introduction of streptomycin, immediate mortality was reduced in tuberculosis patients, with improvement in bacteriology and chest radiography, however despite this, the 5 year mortality rate was equivalent in those who received the drug vs those who did not (1). The organization who performed what is considered the first clinical trial, the British Medical Research Council (BMRC), combined streptomycin with PAS, reducing the incidence of streptomycin resistance. Following this, INH was introduced in the 1950s, with the standard of care camping combination therapy with the three available drugs to avoid resistance, followed by consolidation therapy with PAS and INH (2). One of the most comprehensive reviews on the topic came from the BMRC themselves, highlighting the major steps towards the modern therapy we know of today:

• 1946: initial evaluation of streptomycin
• 1948: combination therapy with streptomycin and PAS decreases incidence of resistance 
• 1958-1967: search for cheaper options other than PAS
• 1970: Rifampin or PZA, added to streptomycin/INH reduced relapse rate
• 1976: demonstration that PZA use is limited to the first 2 months (i.e. its goot at sterilizing during the first 2 months), while rifampin/INH has sterilizing activity throughout the continuation phase

Prior to looking at the data, I think it may be helpful to look at the main drugs and their role in tuberculosis therapy. In general, INH, rifampin, and ethambutol have activity against large populations of tubercle bacilli in cavities (3). Furthermore, INH and rifampin have bactericidal activity against tubercle bacilli in either caviatry, intracellular, or necrotic foci which is the rationale behind their use throughout therapy. A study of 15 patients who underwent lung resection, it was found that PZA and INH diffused rapidly into necrotic cores and cellular layers (4). It was also found to have a homogeneous distribution across the cavity wall and caseum in patients with cavitary disease. This is in contrast with moxifloxacin, which does not distribute in acellular caseum. Similarly, rifampicin also accumulated in caseum and remained detectable in necrotic lesions despite decrease in plasma concentration. Streptomycin penetrates cells poorly and is inactive at acidic pH. PZA, which is inactive at neutral or slightly alkaline pH, is active only in acidic environments such as macrophages. A few special things to note about each drug:

1. INH – it is highly bactericidal against dividing bacteria with an MIC of 0.05 ug/mL. It does have a slower action against non-multiplying cells. One thing to note about INH is that when therapy contains this medication, and the content  of MTB in sputum is measured, there is a rapid fall that occurs in the first 7 days, followed by a level off:

This seems to be due to INH’s activity against the multiplying part of the bacterial population. 

2. Rifampin – another bactericidal drug against MTB, with an MIC of 0.5ug/mL, responsible for a major part of the bactericidal activity of the regimen. It has activity against intracellular, slowly replicating bacilli and somewhat against nearly dormant organisms in necrotic foci. 

3. PZA – the activity of this drug is highly pH dependent, usually working best in acidic environments. It is believed the pH level of acute tuberculous inflammation to be in the order of a pH of 5.8, which would explain why its benefit does not extend beyond the first 2 months of therapy. Animal studies found that while PZA has little activity during the first 2 days and may even have antagonistic activity with INH, it persistently kills so that its addition leads to significant decrease in colonies of tubercle (5):

One of the concepts that comes up in the therapeutics of tuberculosis is that of sterilizing activity of a drug (4). The sterilizing activity is the ability of a drug to kill all or virtually all of the bacilli in the lesions as rapidly as possible, however as the speed of killing gets progressively slower during chemotherapy, sterilization really means can it kill bacteria even when the organism is not actively replicating. One early theoretical model on the action of all drugs during therapy proposes that the majority of tubercle bacilli at the start of therapy are rapidly growing (4). This population is targeted by INH and rifampicin. The dormant population are killed slowly by INH, while a subset of organisms are semi-dormant in an acidic environment. Here, PZA works best. Other semi-dormant organisms tend to have spurts of metabolic activity, with rifampicin working best as it acts much faster before INH. 

Another proposed model posits that most bacilli in the lesions at the start of therapy exist in extracellular sites, including areas of caseation where they are not surrounded by inflammatory cells. As a result, these are killed by both INH and rifampicin. Some bacilli lead to inflammation, and lower pH which leads to higher efficacy for PZA:

A Short Overview:

I’ll fast forward through most of the early data and go to the mid-1960s. Here, an early study compared PAS/INH/streptomycin with ethambutol/INH/streptomycin and rifampicin/INH/streptomycin in the intensive phase, with different continuation phases as highlighted below for a total of 12 months of therapy (6):

412 patients were compared, and by month 2 the patients in the rifampin group had achieved culture conversion at a higher rate when compared to the other regimens (PAS 38% vs ethambutol 37% vs rifampicin 60% vs 36% in the intermittent dosing group). Indeed, several studies after this would suggest that rifampicin had much better activity than PAS or thiacetazone, and it was one of the drugs that heralded the era of short-course therapy. One of the early trials on short-course therapy was conducted in the 1970s (7). Here, four different 6 month regimens were compared to the standard of streptomycin/thiacetazone/INH 18 month regimen (with streptomycin being given for the first 8 weeks). The regimens were as follows:

• Streptomycin/INH/Rifampin
• Streptomycin/INH/PZA
• Streptomycin/INH/Thiazetazone
• Streptomycin/INH

610 patients were evaluated, and it was found that culture negativity was achieved faster in the streptomycin/INH/rifampin and streptomycin/INH/PZA regimens (94% in the first regimen, 90% in the second regimen by 3 months, compared to 79% in the INH/thiacetazone regimen and 85% in the streptomycin/INH regimen). By 6 months, there was no significant difference in the proportion of patients who had a favorable outcome in all regimens, suggesting that regimens containing rifampin and PZA were just as efficacious but more importantly, that therapy could be shortened significantly:

Notably, most relapses occurred in the streptomycin/INH group, at 18%, perhaps suggesting the lack of significant activity of streptomycin and the benefits of adding a drug such as rifampicin or PZA. Two trials further highlighted that thiacetazone was not as potent as INH or rifampicin (8, 9). Here, the following 6-month regimens were evaluated in 953 patients:

• streptomycin/INH/rifampin 
• INH/rifampin
• Streptomycin/INH/rifampin/PZA for 2 months followed by thiacetazone/INH for 4 months
•  streptomycin/INH/rifampin/PZA for 2 months followed by streptomycin/INH/PZA twice per week for 4 months

The third report of the previous study (9) found that relapses in the streptomycin/INH/thiacetazone and the streptomycin/INH were significantly higher than the INH/rifampin or INH/PZA, though numerically, the lowest relapse rates were found on the triple therapy group of streptomycin/INH/rifampicin:

These data suggest that both rifampicin and INH in combination with streptomycin not only had rapidly bactericidal activity but also sustained culture conversion post-therapy, again highlighting their sterilizing activity. This was seen in a pair of trials. In one, four 6-month regimens were compared (10):

• streptomycin/INH/rifampin
• INH/rifampin
• streptomycin/INH/rifampin/PZA for 2 months followed by thiacetazone/INH for 4 months
• streptomycin/INH/rifampin/PZA for 2 months followed by streptomycin/INH/PZA twice per week for 4 months

734 patients were evaluated, with the regimens that included the four-drugs during the first 2 months achieving the fastest rate of culture negativity, although the rates of culture negativity by 6 months were fairly equal:

Relapse at 12 months was similar amongst all cohorts:

In a similar study (11), a 6 month therapy of streptomycin/INH in combination with either rifampin, PZA, or thiacetazone was compared with a 6 month regimen of streptomycin/INH and streptomycin/INH/thiacetazone followed by thiacetazone/INH. The highest rate of culture negativity by month 2 was achieved by the regimen that had rifampin:

By month 6, there was a similar proportion of favorable outcomes between all groups. Relapse rates, however, was the highest amongst the INH/PZA, INH/thiacetazone, and the 6 month INH/streptomycin regimen when compared to the streptomycin/thiacetazone/INH and the rifampicin-containing regimen:

A trial of 740 patients compared the following regimens (12):

• Two months of streptomycin/INH/rifampicin/PZA followed by thiacetazone/INH
• One month of four-drug regimen followed by thiacetazone/INH
• One month of four-drug regimen followed by streptomycin/INH/PZA twice per week
• 2 months of streptomycin/INH/rifampicin followed by thiacetazone/INH

The two-month 4-drug regimen group had the fastest rate of culture conversion by month 2, and the regimen that omitted PZA also had a slower rate of culture conversion:

Relapse rates were also lower in the 2-month intensive therapy group followed by thiacetazone/INH (7%) compared to the one month group followed by thiacetazone/INH (10%) or the three drug group (12%). The other regimen of four-drugs for one month followed by streptomycin/INH/PZA twice per week had a similar rate of relapse to the first group (5%). 

Into Shorter Therapy

While 6-month therapy was being evaluated in the above studies, several attempts at even shorter courses were undertaken with the advent of rifampicin and PZA. Four regimens, comparing 6 months and 8 months of therapy, were compared in a trial involving over 740 patients (13). The following regimens were compared:

• streptomycin/INH/rifampicin/PZA for 2 months followed by thiacetazone/INH daily for 6 or 8 months(control)
• streptomycin/INH/rifampicin/PZA for one month followed by thiacetazone/INH daily for 6 or 8 months
• streptomycin/INH/rifampicin/PZA for one month, followed by streptomycin/INH/PZA twice weekly for 6 months (and if being given for 8 months, the first 6 months was followed by daily thiacetazone/INH for 2 months)
• streptomycin/INH/rifampin for 2 months followed by thiacetazone/INH

The relapse rate was  overall higher in the 6 month regimen compared to the 8 month regimen. When combining all regimens, streptomycin/INH/rifampicin/PZA followed by streptomycin/INH/PZA had lower relapse rates than the thiacetazone/INH regimen (either the four drug intensive phase or 3 drug invasive phase, p =0.05):

Multiple regression analysis found that increasing the length of treatment from 6 to 8 months, and the duration of PZA administration was associated with lower rates of relapse. In other words, 6 month regimen that consisted of a four-drug phase for the first 2 month had higher relapse rates than the same regimen when given for 8 months, and when omitting the PZA during the first 2 months, the relapse rates were higher in both 6-month and 8-month regimens. A similar study compared the following 4 continuation regimen after an initial 2-month phase of streptomycin/INH/rifampicin/PZA (14):

• Four months of INH/rifampicin
• Four months of INH/PZA
• Four months of INH alone 
• 6 months of INH alone

Relapse rate at 30-months post therapy was significantly higher in the 4-month INH as well as the 4 month INH/PZA, suggesting superiority of the 4 month rifampin/INH as continuation medications:

The first few iterations of the well-known four drug regimen was evaluated in a study of 530 patients (15, 16):

• rifampin/streptomycin/INH/PZA for 2 months -> streptomycin/INH/PZA twice per week for 3 months
• rifampin/streptomycin/INH/PZA for 2 months -> streptomycin/INH/PZA twice per week for 5 months
• streptomycin/INH/PZA for 2 months followed by the same regimen twice per week for 5 months. 

The rate of culture conversion was faster and higher in the rifampin-containing regimens  (15):

Relapse was highest in the 5 month, four-drug followed by 2 drug regimen when compared to the rest (16):

Taken together, a few conclusions could be drawn. First, rifampicin-containing regimens tended to clear cultures faster, with higher rates of culture conversion by month 2 when compared to other regimens. Second, the addition of PZA seems to lead to faster rates of culture conversion, and finally, continuation therapy containing either INH or rifampicin, as opposed to PZA or thiacetazone, seemed to lead to lower rates of relapse. Despite the possibility of a 6-month regimen, attempts at shortening this even further were undertaken. One of the earlier trials evaluated four-month regimens, with all receiving streptomycin/INH/rifampin/PZA for the first 8 weeks followed by the following (17):

–  INH/Rifampin/PZA for 9 weeks

– INH/rifampin for 9 weeks

– INH/PZA for 9 weeks

– INH for 9 weeks

– INH/rifampin/PZA for 8 weeks followed by INH for 9 weeks

555 patients were analyzed, with all achieving a high rate of culture negativity by month 4, however there was a numerical difference when comparing the four drug regimens to the three drug regimen:

Moreover, the rate of relapse was significantly higher in the regimens that did not include rifampicin during the continuation phase (the table below should say “HR” for the second series):

A trial comparing continuation INH/rifampin/PZA vs INH/rifampin for either 4 or 6 months found that relapse was significantly higher in both 4 month regimens (18):

Another study evaluated five 4-month regimens (19):

• streptomycin/INH/rifampin/PZA for 8 weeks followed by INH/rifampin/PZA for 9 weeks
• streptomycin/INH/rifampin/PZA for 8 weeks followed by INH/rifampin for 9 weeks
• streptomycin/INH/rifampin/PZA for 8 weeks followed by INH/PZA for 9 weeks
• streptomycin/INH/rifampin/PZA for 8 weeks followed by INH for 9 weeks
• INH/rifampin/PZA for 8 weeks followed by INH for 9 weeks. 

555 patients were enrolled, with fairly high culture  conversion at the end of therapy among all groups, ranging from 96-99% in most regimens, with the exception of the INH/rifampin/PZA cohort, which had a 93% culture conversion rate. Relapse at 2 years was significantly lower in the first 2 regimens which included a 4-drug intensive phase followed by INH/rifampin:

This suggests that PZA beyond the initial intensive phase does not provide any long-term benefit in terms of relapse or culture conversion. This was confirmed in a 6-month regimen trial that evaluated the thrice weekly dosing of medications, with regimens including INH and rifampin throughout the 6 months (20). Three regimens contained streptomycin for the first 4 months, with PZA being given for either 2 months, 4 months, or 6 months. 420 patients were evaluated, with the patients receiving streptomycin achieving culture clearance much faster when compared to the no streptomycin regimens:

Furthermore, there were no statistical differences in the rate of relapses across regimens at 30 months:

Moreover, the rates of culture conversion at month 2 was the same regardless of how long PZA was given for, suggesting once again, the benefits are usually greatest during the first 2 months of therapy even when therapy is given intermittently. Similarly, a trial of 411 patients from Poland evaluated the following regimens (21):

After the first month of therapy, all regimens  had similar rates of culture conversion with all patients having negative cultures by month 5:

The rates of relapse at 18-months was significantly higher in regimen B (twice per week rifampin and INH) when compared to regimen D (twice weekly triple-drug therapy), however there was no statistical difference between the rest, however numerically, the lowest relapse rate was seen in the triple-drug therapy administered twice per week:

This suggests that a minimum of twice per week dual-therapy in the continuation phase is necessary for sustained culture conversion, and one can get a bit more benefit from triple-drug therapy dosed as such.  At 30 months post therapy, however, relapse rate was fairly high amongst all groups, suggesting that perhaps intermittent therapy is not ideal (22):

More modern studies have attempted to shorten the time course even more. For instance, the 6 month regimen of RIPE (with ethambutol being taken off once susceptibilities were known and PZA being given only during the first 8 weeks) was compared with a 9-month regimen of rifampin and INH (23). A total of 1451 patients were randomized, with patients in the 6-month regimen having a higher conversion rate than the 9-month regimen group at week 6 of therapy, and from week 8 to week 16 of therapy:

At 16 weeks, the rate of culture conversion was 94.6% in the 6-month regimen  compared to 89.9% in the 9-month regimen. Notably, the rate of adverse events was higher in the 6-month regimen, from week 4 through week 13, however at the end of therapy the rates of adverse events were not statistically different. Further, a higher proportion of patients were able to complete the 6-month regimen (61.4%) compared to the 9-month regimen (50.6%). A multicenter, phase 3, randomized open label trial evaluated the possibility of shortening therapy from 6-months to 4 months in HIV-negative patients with non-cavitary tuberculosis who had converted their sputum cultures after 2 months of therapy (24). All subjects received RIPE for the first 2 months and then rifampin and INH thereafter. Patients were then randomized to either stop therapy at 4 months or keep for an additional 2 months. Primary endpoint was bacteriological or clinical relapse at 30 months. 394 patients were randomized, and found a higher rate of relapse in the 4-month regimen:

Indeed, due to this the study stopped recruiting patients at the recommendation of the Data and Safety Monitoring board. 

A Word on Ethambutol:

As one can see, however, streptomycin tends to be part of the initial intensive phase of regimen with the caveat to this being its IV formulation. As a result, many of these folks are admitted for the initial phase of therapy, which makes compliance very difficult. A trial of 248 patients compared a regimen of ethambutol-INH at 2 different doses with PAS and INH and found no difference in terms of culture conversion at the end of therapy (25):

A proof of concept trial (26) found that the rate of defauling of therapy was similar in therapies that contained streptomycin and those that contained ethambutol. A trial comparing similar therapies in advanced tuberculosis (27) found that culture conversion was similar amongst all 3 regimens (regimen 1: ethambutol/INH, regimen 2: streptomycin/INH/PAS, regimen 3: ethambutol/INH/PAS):  

With the advent of HIV and drug-interactions, thiacetazone was ultimately replaced with ethambutol and in the attempts of making therapy more convenient, it was ultimately used in lieu of streptomycin. This was compared in a large trial of nearly 1000 patients, which compared both bacteriological results and compliance between a regimen that contained streptomycin and one that continued INH (28). The rate of compliance was not statistically different between the groups, and the outcome at the end of the intensive phase was also not significantly different:

This leads us to the standard RIPE therapy, which was tested in a multicenter trial, comparing the standard INH/rifampin/PZA/ethambutol given for 2 months followed by 4 months of INH/rifampin (29). The control regimen was compared to the same 4-drug intensive phase followed by either 6 months of INH/ethambutol, or by an intermittent 4-drug regimen where the medications were given three times per week, followed by INH/ethambutol. In 1355 patients, culture negativity at 2 months was significantly lower in the intermittent drug group (aOR 1.8, 95% CI 1.32 to 2.46). 

Moreover, a higher proportion of patients in the standard therapy group had favorable outcomes when compared to the other regimens:

And amongst the groups, the standard therapy had more favorable outcomes when compared to the regimens containing ethambutol following the 2 months of intensive therapy, with no statistical difference between the ethambutol-containing regimens:

One of the interesting is that the number of unfavorable outcomes continued to accumulate after cessation of therapy in those who got the 8-month regimen, while those in the 6-month regimen had their unfavorable outcomes within the first 18-months:

Alternative to RIPE

Fluoroquinolones have been used as a second line agent for drug-resistant tuberculosis. Several trials have attempted to replace ethambutol for moxifloxacin, and rifampin with rifapentine in an effort to shorten therapy even further. One of the first studies evaluating the relative sterilizing activities of several quinolones, including moxifloxacin, was carried out Rustomjee et al (30). This open label, 8-week phase IIB randomized patients to either a control arm, a moxi arm, a gati arm, or a oflo arm with the quinolones substituting ethambutol in the regimen. 209 patients were included in the serial sputum colony counting analysis, and found that moxifloxacin was superior in the early phase of a bi-exponetnial fall in colony counts, while both gatifloxacin and moxifloxacin were equal in their bacilly elimination in the late phase:

Cox regression estimates found that moxifloxacin was significantly associated with the speed of culture conversion:

A phase 2 trial evaluated the combination of rifapentine, moxifloxacin, PZA, and INH with RIPE, and found no statistical difference in the mITT analysis in terms of culture negativity in both liquid and solid media at the end of 8 weeks (31):

Notably, the per protocol analysis found that the investigational therapy had a higher number of culture negativity in the liquid culture, but not the solid culture. A randomized, double-blind study evaluated moxifloxacin vs ethambutol in HIV-negative patients with smear-positive sputum (32). Primary endpoint was the proportion of patients with negative sputum cultures after 8 weeks of treatment. 177 patients were randomized, and in the mITT analysis, 80% of patients in the moxifloxacin group achieved negative cultures compared to 63% for ethambutol (p = 0.03):

Multivariate analysis found that treatment with moxifloxacin was associated with a 1.88-fold increase in the odds of being culture negative at week 8. The landmark phase 3 trial evaluated rifapentine with or without moxifloxacin in drug-susceptible pulmonary TB and compared this 4-month regimen with the standard RIPE 6-month regimen (33). Patients were randomized in a 1:1:1 fashion to 8 weeks of RIPE followed by 18 weeks of rifampin and INH, rifapentine +IPE for 8 weeks followed by 9 weeks of rifapentine + INH, and rifapentine + moxifloxacin + INH/PZA for 8 weeks followed by 9 weeks of rifapentine + INH + moxifloxacin. Primary endpoint was survival free of TB at 12 months. 2516 patients were randomized, of which the evaluable population consisted of 2343 patients. Overall, there was no difference in the primary outcome in the ITT, microbiologically eligible, or accessible population when comparing the rifapentine-moxifloxacin group and control, using a non-inferiority margin of 6.6:

The rifapentine group was not shown to be non-inferior in the secondary analysis:

Notably, the rifapentine-moxifloxacin group had a faster time to stable conversion of sputum cultures to negative when compared to control (HR 1.4, 95% CI 1.2 to 1.5 in liquid media, 1.3 95% CI 1.2 to 1.5 on solid media) as well as rifapentine (HR 1.3, 95% CI 1.2 to 1.4 in liquid media and 1.3, 95% CI 1.2 to 1.4 in solid media). Indeed, as a result of these data, the CDC has published guidance with regards to how to use this quinoline-containing in a select number of patients (34). While outside of the scope of this blog, this uses the rifamycin rifapentine, which tends to have a longer half-life than rifampin, which allows the shortening of therapy to 4-months only. 

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