Treatment of Tuberculosis. Dr Sarabjit Chadha The Union

Transcription

1 Treatment of Tuberculosis Dr Sarabjit Chadha The Union

2 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

3 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

4 History of treatment of TB. In 1854 Hermann Brehmer build the first sanatorium

5 History of treatment of TB. Sanatorium Rest Good food Milk (Calcium) Sunlight High altitude

6 History of treatment of TB.. Surgical treatment Pneumothorax Carlo Forlanini Thoracoplasty Rib resection (Quincke) Total (Sauerbruch) Plombage

7 The advent of chemotherapy Dr. Selman A. Waksman - Discovered STREPTOMYCIN in Together with his laboratory assistant A. Schatz

8 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

9 Sm resistance 5-year assessment showed that Sm did not improve outcomes due to emergence of Sm resistance Days since Start of Treatment

10 Other anti-tb drugs In 1949 PAS was introduced BMRC trial using Sm+PAS showed reduced incidence of resistance to SM S SP 60 % resistant cultures Months of treatment

11 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 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

12 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

13 Fundamentals of TB treatment Drug combinations Long term treatment Single dose administration

14 Drug Combinations Used mainly to prevent drug resistance as it prevents selection of resistant mutants The fall and rise mechanism

15 An unselected population of Mycobacterium tuberculosis S H E R S E E H

16 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

17 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

18 Single dose administration Achieve peak blood levels Facilitate supervision Fixed dose combinations

19 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

20 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

21 Anti-TB Drugs. Early Bactericidal Activity (EBA, 2 Days), measured for the reduction in the CFU in Sputum Edited: HL Rieder

22 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

23 Chemotherapy in TB

24 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

25 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

26 Which is a better regimen? 2RHZE/4RH or 2RHZE/6HE

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28 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:

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

30 How long to give rifampicin? 2 Months or 6 Months

31 - 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

32 Ideal treatment regimen 2 HRZE / 4 HR

33 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?

34 Toman s, 2004 Lag phase

35 Bacteriopausal Effects during re-growth Number of viable bacilli Susceptible to Drug A Mutants resistant to A Lag due to drug A Lag due to drug B Regrowth starting Killing phase Regrowth Mitchison DA. In J Tuberc Lung Dis 1998;2:10-15

36 Toman s, 2004

37 Toman s, 2004

38 Is intermittent regimen recommended now?

39 - 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

40 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, ]; HR for adquired rifampin resistance ARR-, 6.4 [95% CI, ]). 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.

41 citations (6 randomized trials and 21 cohort studies) - Relapse was more common with regimens using 2 months rifamycin (ARR, 3.6; 95% CI, ) 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, ) and relapse [ARR, 4.8; 95% CI, ). - 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.

42 - Thrice-weekly treatment increased the risk of relapse in comparison with daily treatment (OR 3.92, 95% CI ), whereas prolonging both intensive phase and overall treatment by 50% or more protected against relapse (OR 0.24, 95% CI ) - When pretreatment culture was positive and cavitation was absent, the 30-month relapse rate for standard thrice-weekly regimen was 1.1% (95% CI %) - The corresponding rates in the presence of cavitation were 7.8% (95% CI %) for standard thrice-weekly regimen; 3.3% (95% CI %) for standard daily regimen; 0.5% (95% CI %) for extended thrice-weekly regimen; and 0.4% (95% CI %) for extended daily regimen

43 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 monoresistance 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

44 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

45 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?

46 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??

47 Lancet Infect Dis 2010, 10:

48 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:

49 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:

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51 Of patients evaluated, were smear-negative at 2 months (2M ); 1871 and 1870 (2M+) were randomised to no extension or extension (1M). Respectively 0.3% (95%CI ), 1.2% (95%CI ) and 2.0% (95%CI ) smear- and culture-positive failures, and 1.2% (95%CI ), 2.6% (95%CI ) and 0.9% (95%CI ) relapses were detected. Extension significantly reversed the relative risk (RR) of relapse of 2M+ vs. 2M patients from 2.2 (95%CI ) to 0.7 (95%CI ). The RR for failure remained high, at 7.3 (95%CI ) with and 4.2 (95% CI ) without extension.

52 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

53 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

54 Shorter regimens 4 months OFLOTUB trial- completed REMOX trial- completed 3 months PaMZ- ongoing

55 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

56 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

57 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????

58 Amplification of resistance in case of initial INH 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)

59 Amplification Amplification of of resistance resistance of resistance in in case case of in of initial case initial INH of INH resistance resistance initial MDR TB 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

60 WHO guidelines 2017

61 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

62 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.

63 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

64 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

65 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

66 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

67 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

68 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

69 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.

70 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

71 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 HIVpositive 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

72 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

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75 Thank You