Treatment of Tuberculosis

Dr Sarabjit Chadha

The Union

History of treatment of TB…….

• Believed to be as old as mankind

• Spinal TB has been diagnosed in Egyptian mummies dating 2400 BC

• Egyptian medical treatise (1500 BC) describes pulmonary consumption with cervical lymphnodes – surgical lancing of the cyst

– application of mixture of acacia, peas, fruits, animal blood, insect blood, honey and salt

• In India Yakshma (resembles TB) finds a mention in scriptures dated 1500 BC to be treated with – Breast milk, meat, alcohol and rest

– Move to higher altitudes

History of treatment of TB…

• Hippocrates (460 BC)- gave the name ‘Pthisis’

– Nurse the patient in temple, good food and asses milk

• Galen (200 AD)

– Opium, blood letting; barley water, fish and fruit

• In 1600s Henry IV started the practice of ‘Royal touch’

– Unfortunately Henry IV himself died of TB

History of treatment of TB….

• In 1854 Hermann Brehmer build the first sanatorium

History of treatment of TB….

• Sanatorium

– Rest

– Good food

– Milk (Calcium)

– Sunlight

– High altitude

History of treatment of TB…..

• Surgical treatment

– Pneumothorax – Carlo Forlanini

– Thoracoplasty – Rib resection (Quincke)

Total (Sauerbruch)

– Plombage

The advent of chemotherapy

Dr. Selman A. Waksman

- Discovered STREPTOMYCIN in 1943

- Together with his laboratory assistant A. Schatz

Streptomycin….the wonder drug

• Treatment of TB started in 1946, with streptomycin

• First clinical trial by BMRC

– Dramatic reduction in immediate mortality

• Bed rest and Sm (27% vs 7%)

– Striking improvement in chest radiology and bacteriology

Sm resistance

• 5-year assessment showed that Sm did not improve outcomes due to emergence of Sm resistance

Days since Start of Treatment

Other anti-TB drugs

• In 1949 PAS was introduced

• BMRC trial using Sm+PAS showed reduced incidence of resistance to SM

0

10

20

30

40

50

60

70

80

90

1 2 3 4 5 6

S SP

Months of treatment

% resistant cultures

Other anti TB drugs – INH, R and Z

• INH introduced in 1952; • Several studies with INH +Sm/PAS • Sir John Crofton –

– 3 SPH/9PH with no failures – 1 year of hospitalisation/Sanatorium - Very expensive

• 1960- Famous trial at TRC in India – Domiciliary treatment as effective as sanatorium

treatment

• Z in 1954 and Rif in 1963 – addition of R and Z reduce the relapse rate when added to

INH+Sm – Short course therapy

Other anti TB drugs

• Clinical trials in various countries

– bactericidal synergism between R and Z

– R an effective sterilising drug throughout treatment, Z only in IP

– Initial intensive phase should last 2 months

• Treatment regimens – 2RHZE/4RH were extensively trialled in Singapore

– 2 RHZE/6 TH (trialled in East Africa)

• HIV infection made Thioacetazone unusable – Replaced with Ethambutol

• 6-month regimen - 2HRZE/4RH

• 8-month regimen 2 HRZE/6HE

Fundamentals of TB treatment

• Drug combinations

• Long term treatment

• Single dose administration

Drug Combinations

• Used mainly to prevent drug resistance as it prevents selection of resistant mutants

The fall and rise mechanism

An unselected population of Mycobacterium tuberculosis

E

R S

E

S H

H

E

Selecting resistance by INH monotherapy

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H H

H

H

H

H

H H

Long term treatment

• Allows action on different bacterial populations – Rapidly multiplying bacteria

• Extracellular with maximum oxygenation

– Slowly multiplying bacteria • Intramacrophagic location; acidic pH

– Intermittently growing bacteria • Solid caseum

– Bacteria in latent/dormant stage • Relapses and reactivation

INH

PZA

RIF

No drugs

Single dose administration

• Achieve peak blood levels

• Facilitate supervision

• Fixed dose combinations

Objectives of treatment

• To make the patient non-infectious as early as possible – Early bactericidal activity of drugs

• To prevent relapse – Sterilising action

• To prevent selection of resistance – Combination of drugs

• Minimal side effects

Early bactericidal activity (EBA)

• Fall in viable CFU of M. TB /ml sputum per day

• During first few days of treatment with a drug

• EBA does not tell us anything about sterilization

• An agent with a good EBA may be a poor sterilizing agent

• INH has the maximum EBA

• Therapeutic margin –

– Therapeutic dose/Minimal effective dose

– INH – 20; Rif - 4; Sm-1.5

– High therapeutic margin indicates that the drug can penetrate large

necrotic lesions

Anti-TB Drugs. Early Bactericidal Activity (EBA, 2 Days),

measured for the reduction in the CFU in Sputum

Edited: HL Rieder

Sterilisation

• The ability to kill the persisting, dormant or

intermittently active bacilli, responsible for

relapses

• Rapid sterilization will lead to the shortening of

treatment

• R and Z are responsible for most of the killing of

persisting bacilli

• Z may have a better sterilising action as

compared to other drugs

Chemotherapy in TB

Principles for designing TB regimen

• At least 3 new or probably effective drugs

• At least 1 bactericidal and 1 sterilising drug to be continued through out the treatment

– H – bactericidal

– R and Z are the sterilising drugs

– H and R continued throughout the treatment

– Z is stopped after Intensive Phase

• Regimen could be RHZ/RH

Why do we need a fourth drug?

• The fourth drug is given to protect against

possible initial resistance to INH, not to kill

bacilli

• Streptomycin is probably a better drug

– higher bactericidal activity

– In most countries more than the 50% of the

strains with initial resistance to INH have also

resistance to SM

Which is a better regimen?

2RHZE/4RH

or

2RHZE/6HE

The Union Study A Outcome at 12 and 30 months after stopping treatment

Regimen Unfavourable outcome at 12 mths 30 mths

Failure Relapse Total Total

2EHRZ/6EH 5.5% 4.9% 10.4% 11.7%

2(EHRZ)3/6EH 6.3% 7.4% 13.7% 15.3%

2EHRZ/4HR 3.5% 1.4% 4.9% 6%

Lancet 2004;364: 1244-1251

Regimen INH susc INH -resist

2EHRZ/6EH 9.3% 38.5%

2(EHRZ)3/6EH 10.2% 27.3%

2EHRZ/4HR 3.7% 4.3%

Lancet 2004;364: 1244-1251

The Union study A Unfavourable outcomes at 12 mths (H res)

How long to give rifampicin?

2 Months

or

6 Months

- 57 trials with 312 arms and 21,472 participants were included

- Regimens utilizing rifampin only for the first 1–2 m had

significantly higher rates of failure, relapse, and acquired

drug resistance, as compared to regimens that used rifampin

for 6 m.

- This was particularly evident when there was initial drug

resistance to isoniazid, streptomycin, or both.

- On the other hand, there was little evidence of difference in

failure or relapse with daily or intermittent schedules of

treatment administration

Ideal treatment regimen

2 HRZE / 4 HR

Intermittent regimen

• Rationale behind intermittent regimen

– Lag phase

– Easy to supervise

– Cost effective

• How does intermittent regimen work?

• Is it as effective as daily regimen?

Lag phase

Toman’s, 2004

Mitchison DA. In J Tuberc Lung Dis 1998;2:10-15

Regrowth Killing phase

Susceptible to Drug A

Mutants resistant to A

Regrowth starting

Lag due to drug A

Lag due to drug B

Num

ber o

f via

ble

bacilli

Bacteriopausal Effects during re-growth

Toman’s, 2004

Toman’s, 2004

Is intermittent regimen recommended now?

- 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

• HIV-infected patients treated with rifampin-based regimens alone had a

higher risk for relapse and development of rifampin resistance if

intermittent dosing of rifampin was started during the intensive phase of

treatment, compared with patients who did not receive intermittent

dosing (hazard ratio [HR] for relapse, 6.7 [95% CI, 1.1–40.1]; HR for

adquired rifampin resistance –ARR-, 6.4 [95% CI, 1.1–38.4]).

• This association remained when confined to patients with a CD4+ T

lymphocyte count of < 100 lymphocytes/mm3.

• Intermittent dosing started only after the intensive phase of treatment

did not increase the risks of relapse and ARR among HIV-infected

patients with TB.

- 5158 citations (6 randomized trials and 21 cohort studies)

- Relapse was more common with regimens using 2 months rifamycin (ARR,

3.6; 95% CI, 1.1–11.7) than with regimens using rifamycin for at least 8

months.

- Compared with daily therapy in the initial phase (3352 patients from 35

study arms), thrice-weekly therapy (211 patients from 5 study arms) was

associated with higher rates of failure (ARR, 4.0; 95% CI, 1.5–10.4) and

relapse [ARR, 4.8; 95% CI, 1.8–12.8).

- There were trends toward higher relapse rates if rifamycins were used for

only 6 months, compared with 8 months, or if antiretroviral therapy was not

used.

- Thrice-weekly treatment increased the risk of relapse in comparison

with daily treatment (OR 3.92, 95% CI 1.78–8.63), whereas prolonging

both intensive phase and overall treatment by 50% or more protected

against relapse (OR 0.24, 95% CI 0.08–0.70)

- When pretreatment culture was positive and cavitation was absent, the

30-month relapse rate for standard thrice-weekly regimen was 1.1%

(95% CI 0.6–2.0%)

- The corresponding rates in the presence of cavitation were 7.8% (95%

CI 4.0–14.6%) for standard thrice-weekly regimen; 3.3% (95% CI 1.9–

5.5%) for standard daily regimen; 0.5% (95% CI 0.1–2.6%) for extended

thrice-weekly regimen; and 0.4% (95% CI 0.1–0.9%) for extended daily

regimen

• Only six cohort studies were identified, in which failure rates were

18%–44% in those with isoniazid resistance.

• In nine trials, using very different regimens in previously treated

patients with mono-resistance to isoniazid, the combined failure and

relapse rates ranged from 0% to over 75%.

• From pooled analysis of 33 trials in 1,907 patients with mono-

resistance to isoniazid, lower failure, relapse, and acquired drug

resistance rates were associated with longer duration of rifampin, use

of streptomycin, daily therapy initially, and treatment with a greater

number of effective drugs

Intermittent regimen - Conclusions

- Inspite of the limited evidence, it seems

the daily treatment (at least in the

Intensive phase) can reduce the rate of

relapses, specially in patients HIV+, with

Cavitary TB and with INH Resistance

- As these patients are very frequent,

perhaps the NTP should evaluate to

introduce daily regimens

Important questions

• Follow up of patients on treatment

– How frequently?

– Does sputum monitoring predict outcome ?

• Does extending IP improve outcomes?

• Can we reduce the duration of treatment?

• Is the current retreatment regimen rational?

Response to treatment

• Sputum examination is done – End of intensive phase

– Mid of the continuation phase

– End of the treatment

• Assess response to treatment

• Identify those at risk of failure

• Identify those who are at risk of relapse??

Lancet Infect Dis 2010, 10: 387-94

PREDICTING RELAPSES

- The pooled SENSITIVITY for both 2-month SMEAR (24% [95% CI 12–42%],

6 Studies) and CULTURE (40% [95% CI 25–56%], 4 studies) were low.

-Corresponding SPECIFICITY (85% [95% CI 72–90%] and 85% [95% CI 77–

91%])were higher, but modest.

Lancet Infect Dis 2010, 10: 387-94

PREDICTING FAILURES

- 2-month smear (seven studies) had low SENSITIVITY (57% [95% CI

41–73%]) and higher, although modest, SPECIFICITY (81% [95% CI

72–87%]).

- Sensitivity is the proportion of patients who experienced treatment failure and had a positive sputum

examination.

- Specificity is the proportion of patients who did not experience treatment failure and had a negative

sputum examination

Lancet Infect Dis 2010, 10: 387-94

• Of 16 708 patients evaluated, 12 967 were smear-negative at 2 months

(2M−);

• 1871 and 1870 (2M+) were randomised to no extension or extension

(1M).

• Respectively 0.3% (95%CI 0.2–0.4), 1.2% (95%CI 0.7–1.8) and 2.0%

(95%CI 1.4–2.8) smear- and culture-positive failures, and 1.2% (95%CI

1.0–1.4), 2.6% (95%CI 1.9–3.4) and 0.9% (95%CI 0.5–1.4) relapses

were detected.

• Extension significantly reversed the relative risk (RR) of relapse of 2M+

vs. 2M− patients from 2.2 (95%CI 1.6–3.0) to 0.7 (95%CI 0.4–1.2).

• The RR for failure remained high, at 7.3 (95%CI 4.7–11.5) with and 4.2

(95% CI 2.5–7.2) without extension.

Conclusions:

• Treatment failure and acquired RMP resistance cannot be prevented by a 1-month extension of the intensive phase

• It is possible that the reduced relapse rate could also have been obtained by extending the continuation phase.

• This would reduce costs, adverse events and the risk of amplifying resistance by continued use of EMB and PZA if MDR-TB is present

Conclusion

• Historically extension was recommended when Rif was used only for 2 months (4RHZE/6HE)

• Based on only 1 study

• In 1000 TB patients with a 7% risk of relapse, extending the treatment of 183 patients would avert 16 of the 70 expected relapses

• To achieve this 23% reduction in relapses, 158 patients per 1000 would be incorrectly predicted to relapse; their treatment would be extended unnecessarily

Shorter regimens

• 4 months

– OFLOTUB trial- completed

– REMOX trial- completed

• 3 months

– PaMZ- ongoing

• Non-inferiority, randomised trial

– New, Smear+, Rif sensitive cases

– Control arm- 2HRZE/4HR

– Experimental arm- 2HRZG/2HRG

• The standard regimen compared with the 4-month regimen

– Higher dropout rate during treatment (5.0% vs. 2.7%)

– more treatment failures (2.4% vs. 1.7%)

– fewer recurrences (7.1% vs. 14.6%).

– No evidence of increased risks of prolongation of the QT interval or dysglycemia with the 4-month regimen

• Non-inferiority of the 4-month regimen to the standard regimen not shown

• Randomised, double blinded, placebo controlled trials • Compare 2 Moxifloxacin containing regimens with a

control regimen – Group 1 (Control): HRZE (8 weeks)/HR (18 weeks) – Group 2: Ethambutol replaced by Moxifloxacin (17 weeks) – Group 3: INH replaced by Moxifloxacin (17 weeks)

• The Moxi regimens showed more rapid initial decline in bacterial load (culture conversion)

• Favourable outcome in control group (92%) was better than the INH group (85%) and Emb group (80%)

• Non-inferiority for Moxi regimens was not demonstrated • Shortening of treatment to 4 months was not effective

Re-treatment regimen

• 2RHZES/1RHZE/5RHE • Indications-

– Relapses – Treatment after LFU (TAD) – Failures

• In case of relapse and TAD most of the patients are susceptible so Cat I should work as well

• In case of failures where the prevalence of MDR TB is higher retreatment regimen will only amplify resistance

• It may be beneficial in INH resistant cases protecting rifampicin resistance ????

2 HRZE/4 H R FAILURE

Initial Resistance to H

2 HRZE/4 H R MDR, but suscpt. Z+E

2HRZES/1HRZE/5H R E Risk of Amplifying Resistance E

(Avoidable if DST before 3rd Month)

Amplification of resistance in case of initial INH resistance

2 HRZE/4 H R FAILURE

Initial M.D.R.

2 HRZE/4 H R Resistance to HR+E+Z

2HRZES/1HRZE/5H R E Risk of Amplifying

Resistance to S

Amplification of resistance in case of initial INH resistance

Amplification of resistance in case of initial INH resistance

Amplification of resistance in case of initial MDR TB

WHO guidelines 2017

• Regimens included

– 4MfxHRZ, 4MfxRZE, 2MfxRZE/2(Mfx+RFP)2, 2MfxRZE/4(Mfx+RFP)1, 2(MfxHRZ)3/2(MfxHR)3

– 2GfxHRZ/2GfxHR, 2(GfxHRZ)3/2(GfxHR)3,

• Shorter FQ containing regimens of 4 months are associated with significantly higher rates of relapse at 18 months

• No reduction of adverse events with the fluoroquinolone containing regimen

• May lead to a rise in FQ resistance

• Test non-inferiority of 4 month FQ containing regimens in – Body mass index (BMI) greater than 18

– nonsevere non-cavitary disease

– Extra-pulmonary disease

• The optimal dosing of fluoroquinolone needs to be determined

• To determine why certain groups are more likely to do worse with a 4-month FQ containing regimen.

• FDCs are non-inferior and as effective as separate drug formulations in terms of treatment failure, death, treatment adherence and adverse events

• Patient satisfaction was higher with FDCs

• Slightly higher rate of relapse and acquired drug resistance with FDCs

• Bioavailability of the drugs in the FDCs were not evaluated

• Additional research on the reasons why FDC formulations did not show a clear benefit over separate drug formulations

• Pharmacokinetic studies of the bioavailability of FDCs versus separate drug formulations

• Thrice-weekly dosing had a higher risk of treatment failure, disease relapse and acquired drug resistance in DS-TB and unknown susceptibility

• More vulnerable populations are at risk of missing medication doses or not absorbing the doses (HIV) well with intermittent regimen – increased risk of unfavourable outcomes.

• Requirements for different drug manufacturing and packaging and a reduced drug supply buffer and risk of stock-outs

• Adherence to treatment was not addressed adequately enough in the reviewed studies to be included as an outcome

• The data used in this review examined only patients with DS pulm TB and had no adverse reactions requiring modification of the dosing schedule

• The utility and efficacy of 5 days per week versus 7 days of treatment per week in the intensive phase of therapy

• The optimal duration of the intensive phase of therapy.

• Additional research on the benefit of thrice-weekly dosing in the continuation phase

• The review focused on the relative benefits of ART within 2 weeks ("earlier initiation”) or 8 weeks (“early initiation”) compared to ART after 8 weeks (“delayed initiation”)

• High-quality evidence (8 trials) showed that across CD4 strata, earlier and early ART is associated with a reduction in overall mortality compared to delayed ART

• Similar grade 3/4 non-IRIS events in early and delayed ART

• Higher incidence of IRIS in early ART – Higher mortality but absolute number of deaths was small

• PLHIV responding to ART need not expect a more unfavourable outcome to TB treatment than HIV neg

• Rates of failure and death did not differ between persons treated with 6 months rifampicin vs those treated for 8 months or later with or without ART

• Relapse rate was higher in 6 months regimen if patient was not on ART

• Ensuring the early start of ART should be prioritized

• What are the factors that may cause PLHIV to not respond well to TB treatment

– starting ART late, low CD4 cell counts, drug resistance, cumulative drug toxicity, drug-drug interaction

• Explore and describe etiological factors leading to higher death rates and rates of adverse events in HIV-positive TB patients.

• RCTs showed lower mortality, death, severe disability and relapse when patients treated with steroids in addition to anti-TB treatment

• Steroids should be given regardless of the severity of meningitis

• In TB pericarditis, benefit of steroid treatment with regard to death and constrictive pericarditis and treatment adherence

• Steroids may increase risk of HIV related cancers (non-Hodgkins’ lymphoma and Kaposi sarcoma)

• Individually, the largest study (n=1400) and IMPI study showed no benefit of steroids

• The optimal steroid dose and duration for TB meningitis (including different drug formulations and for different severities)

• • The different effects of steroids on people who are HIV-positive or HIV-negative, or who are being treated with ART or not

• The relationship between steroid treatment and cancer risk – with reference to the Mayosi et al. study on pericarditis

• Standard of care is to do DST in all retreatment cases and treat accordingly

• Failures, interrupted treatment, relapse have higher risk of drug resistance

– Cat II adds single drug (Sm) to an unsuccessful regimen??

– Streptomycin causes a high rate of adverse events, including ototoxicity and nephrotoxicity

• INH resistant patients are at higher risk of amplifying drug resistance

– Xpert® does not detect H resistance

• The systematic review found had only indirect evidence from observational studies and no RCTs

• What to give in place of Cat II??? – Mono or poly non MDR drug resistance

– RHZE through out

Thank You