Short treatment regimen for Multidrug Resistant Tuberculosis

Clinical treatment protocol for Uzbekistan

Joint MSF - Operational Centre Amsterdam / MOH Uzbekistan Research Protocol

April 2014

1.Introduction

2.Diagnosis and DST

3.Eligibility and inclusion criteria for short MDR TB Treatment regimen

4.Treatment delivery model

5.Treatment Regimen and doses

6.Baseline examination

7.Monitoring

8.Regional Consilium

9.Management of DST related issues

10.Considerations for HIV positive patients

11.Psychosocial components and adherence support

12.Contact tracing

13.Discontinuation of treatment

14.Adverse Events and management

15.Data Handling and Record keeping

16.Treatment Outcome Definitions

Annex 1. Algorithm for Xpert MTB+/RIF+ (xxx district)

Annex 2: Management of Main Side Effects of Treatment

Annex 3. MDR TB paediatric drug dosage table

Annex 4. Short course MDR-TB treatment - clinical examples……………………………………………………………27

  1. Introduction

This protocol is to be used in conjunction with the Clinical guidelines on comprehensive TB treatment for drug sensitive and drug resistant TB for Karakalpakstan. This protocol presents the details for managing patients enrolled in the pilot study of short course MDR TB treatment in Uzbekistan, however not all patients will be eligible for enrolment in this regimen and these patients will require treatment with the standard protocols approved for Karakalpakstan.

  1. Diagnosis and DST

Criteria for molecular testing (for Xpert® MTB/RIF) and Baseline smear testing

All patients suspected of pulmonary tuberculosis in the short course pilot districts will submit minimum 2 sputum samplesin Falcon tubes, if each of 2 samples contains at least 5ml of sputum (lower volume mark on the tube): 1 sample for microscopy and for molecular testing (Xpert® MTB/RIF assay) and 1 sample for sputum culture and drug susceptibility testing (DST). The sputum samples should be submitted on the same day – 1 early morning at patient home and 1 spot sample under direct observation. Alternatively, the spot sputum samples can be taken under direct observation on the same day with at least 1 hour between samples. In case if the total volume of samples in both tubes less than 10ml, a third sample should be requested from the patient right away, either collected on the spot one hour afterwards or on the next morning.

Xpert® MTB/RIF and Hain MTBDR plus test results indicate the presence of M. tuberculosis complex DNA, as well as mutations conferring Rifampicin-resistance. Sputum-smear microscopy serves only as baseline for follow up.

All Xpert MTB+/RIF+ or Hain MTBDR+/RIF+ patients will be included as soon as possible into the study (see annex 1)with the study treatment regimen. Two remaining sputum specimens will have MGIT-culture and first and second line DST, performed at the Nukus Laboratory. In case of contamination of the culture the patient will be asked to provide an additional sputum sample for repetition of culture and FL-DST & SL-DST.

All suspected TB patients with Xpert MTB-/RIF- or Hain MTBDR-/RIF- will have culture +/- DST performed at Nukus Laboratory. If the culture is positive then Hain MTBDR plus will be repeated and if the Hain MTBDR plus demonstrates rifampicin resistance the patient will be eligible for inclusion in the study.

All patients with Xpert MTB+/RIF+ or Hain MTBDR+/RIF+ (or with Hain MTBDR plus showing rifampicin resistance on culture after negative Xpert MTB/RIF) will have a sample tested by Genotype MTBDR sl for rapid diagnosis of presumptive ofloxacin resistance (results for injectable, ethambutoland pyrazinamide resistance will not be used).

All patients with Xpert MTB-/RIF- or Hain MTBDR-/RIF- who subsequently have a culture and DST demonstrating MDR TB according to the eligibility criteria below will be eligible for short course MDR TB treatment.

Patients with presumptive extra-pulmonary MDR TB only are excluded from the study and should be offered conventional MDR TB treatment according to the Comprehensive TB Protocol for Karakalpakstan.

In children suspect of TB presumptive diagnosis by Xpert® MTB/RIF and mycobacteriological proof by MGIT culture and FL-DST is not always possible. However: all clinically feasible methods of gaining samples, including induced sputum should be employed. Children who are clinically suspect of TB andare unable to deliver an adequate sample for analysis and are close contact of a proven MDR-TB patient are offered to be included in the study regimen without mycobacteriological proof and followed up clinically.

Criteria for Xpert MTB/RIF, Hain MTBDR plus, microscopy, culture and DST (first and second line):

  • All new and previously treated cases with suspected pulmonary TB will have sputum samples tested with molecular DST, microscopy and culture and all positive cultures will be tested to confirm MTB complex and tested with FL-DST and SL-DST simultaneously.
  1. Eligibility and inclusion criteria for short MDR TB Treatment regimen

The following patients will be offered inclusion in the study (as described in the research protocol):

  • New presumptively diagnosed MDR TB patients (adults and children) with Xpert® MTB/RIF, Hain MTBDR plus or confirmed with Hain MTBDR plus on positive cultures if initial molecular tests negative or confirmed from MGIT culture/DST if initial molecular tests negative;
  • Children (<14 yo) suspected of MDR TB without bacteriological confirmation but documented as a close contact of a confirmed MDR TB patient;

AND

  • Informed consent to participate in the study signed by the patient or the responsible caretaker for patients <16 years old (as per national legislation).

Only patients with a history of prior treatment with second line anti-TB drugs for less than one month will be eligible for inclusion.

Patients will be included regardless of HIV status.

Exclusion criteria at baseline:

  • Baseline contraindications to any medications of the study regimen medications, where benefits of the regimen do not outweigh the risks as judged by treating physician;
  • Severe renal insufficiency with estimated creatinine clearance of <30 ml/min at baseline (calculated with Cockcroft-Gault formula);
  • Patients with extrapulmonary TB only (without involvement of lung parenchyma)
  • Patients with documented ofloxacin resistance
  • Patients with XDR TB (additional resistance to SLD kanamycin (or capreomycin) AND ofloxacin);
  • Patients with resistance to both Km and Cm.
  • Critically ill and in the judgement of the treating physician unlikely to survive more than 1 week (these patients may still be commenced on standard MDR TB treatment according to the Karakalpakstan comprehensive TB treatment guidelines)
  • Patients with meningeal or osteoarticular involvement
  • Has one or more of the following risk factors for QTc prolongation:
  • A confirmed prolongation of QTc interval (Fridericia formula), e.g., repeated demonstration of QTcF (Fridericia correction) interval > 500 ms in the screening ECG (i.e., retesting to reassess eligibility will be allowed once using an unscheduled visit during the screening phase);

Of note, pregnancy and breastfeeding are not exclusion criteria. Consideration to treatment initiation after the first trimester (12 weeks of pregnancy) as it is done with the standard 20+ month regimen and comprehensive information and counseling of risks and benefits will be offered to pregnant women. We decide to include pregnant women because the alternative is a longer regimen with similar toxicity risks and similar safety class drugs and with limited evidence of safety as well. All cases of pregnancy /breastfeeding and pediatric cases will be discussed with the TB / HIV adviser and a mini-consilium consisting of the medical team leader, the Head pediatric TB doctor for Karakalpakstan and the chief physician for TB2 inpatient facility.

Preconditions before initiation of treatment with the study regimen:

  1. Live or be willing to spend the entire treatment course in short course pilot districts (Shumanay, Kegeily or Nukus City)
  2. No exclusion criteria;
  3. Completion of the baseline tests;
  4. Completion of one preliminary adherence counseling session
  1. Treatment delivery model

At all sites, the model of care will be ambulatory treatment with daily direct observation of treatment (DOT) 7 days a week. Depending on which option is most appropriate for the individual patient, DOT may take place at the health facility or at the patient’s home. Essential medications for other medical conditions, including ART, will be given together with the MDR-TB drugs as far as medically possible and practically feasible.

When a patient necessitates inpatient care, s/he will be hospitalized in Nukus TB 2 DR TB Unit if smear positive and in TB1 or TB3 DR TB unit if smear negative. Once a patient is discharged, s/he will resume ambulatory treatment as described above.

  1. Treatment Regimen and doses

Patients will be started on shortened MDR TB treatment regimen based on presumptive diagnosis after being diagnosed with molecular test (Xpert MTB+/RIF+ or Hain MTBDR plus). Upon receipt of results from culture and first and second line DST results the regimen choice will be confirmed as short course MDR TB treatment or changed to the appropriate standard MDR TB if exclusion criteria (resistance to ofloxacin or injectables) are met or changed to appropriate TB regimen according to the standard Karakalpakstan comprehensive TB care protocol.

The standardised short regimen for MDR TB and duration

Intensive Phase / Continuation Phase
Duration / Pyrazinamide + Ethambutol + Isoniazid + Moxifloxacin + Capreomycin (Kanamycin) + Prothionamide + Clofazimine for at least 4 months and smear negative. If smear positive at 4 months continue until first sputum culture is negative, maximum 6 months (time when 5-month-culture result becomes available.) / Pyrazinamide + Ethambutol + Moxifloxacin + Prothionamide + Clofazimine for 5 months, starting after 4 months or first negative culture, whichever is later.
Description / Seven drugs;
Includes injectable & high dose Isoniazid / Five drugs;
Only oral drugs in standard dosage.

Dosing of standardized MDR TB Drugs for adults and adolescents > 25 kg, including pregnant women

Drug / Formulation / Frequency / Weight range in Kg
<25 / 25-32 / 33-50 / >50*
Isoniazid (H) / 300mg tab / od / 15-20 mg/kg / 1 / 1
and / >55kg 2
100 mg tab / od / 1
Pyrazinamide (Z) / 400mg tab / od / 30-40 mg/kg / 2.5 / 4 / 5
Ethambutol (E) / 400mg tab / od / 15-25 mg/kg / 1.5 / 2 / 3
Moxifloxacin (Mfx) / 400mg tab / od / 7.5-10 mg/kg / 1 / 1 / 1
Prothionamide (Pto) / 250mg tab / od# / 15/25 mg/kg / 1 / 2 / >55kg 3
Clofazimine (Cfz) / 100mg cap / od / 2-3 mg/kg / 1 / 1 / 1
Capreomycin (Cm)$ / od / 15mg/kg

*For Pto and H highest doses are given above 55kg

# Pto can be given twice a day in the intensive phase if maximum doses are used and the patient has major GI side effects not responding to anti-emetics.

$ If sensitive to Kanamycin and not taken Kanamycin previously then change to Kanamycin at the same dose.

Medications are started at full dose on day 1. However if nausea occurs that is not controlled by anti-emetics, then doses of prothionamide may be started at half dose and increased to full dose over 7 days

Treatment will be given 7 days a week with all doses given under DOT. Supervision of drug intake will be done by either the health care worker or by the treatment supporter according to the model described in chapter 4. Any missed doses will be added at the end of each phase.

Patients will be commenced on capreomycin. When DST results are available patients with no past history of kanamycin treatment for more than 1 month and a sensitive DST to kanamycin will be changed from capreomycin to kanamycin. (This adjustment of the regimen will not be considered “withdrawal” from the original study protocol. However, resistance in SL-DST to Km andOfl (=XDR-TB) will lead to exclusion from the study and offer of an appropriate XDR-TB treatment.)

General remarks:

  • Pyridoxine at a dose of 25 mg/day will be added to the regimen as prophylaxis of peripheral neuropathy with the use of high dose Isoniazid (increased risk in HIV co-infected patients, malnourished, diabetic, alcoholic and pregnant women). If neuropathy appears it should be treated with higher dose of pyridoxine from 100-200 mg/day.
  • Mfx must be administered separately from antacids, iron, magnesium, and vitamins by 4 hours.
  • In cases of renal or hepatic failure, dosing of some medications need adjustment (see table 9.2 WHO Guidelines for the programmatic management of MDR TB emergency update 2008) and discuss with HIV/TB advisor.

Women in childbearing age, pregnancy and breast-feeding:

  • Women in child bearing age who are not pregnant will be offered hormonal contraception and barrier methods. The intended method should be recorded.
  • Women who get pregnant while on treatment are not automatically withdrawn from the regimen; however adjustment of the regimen is done according to the risk-benefit analysis of the treating medical doctor in collaboration with the HIV/TB advisor and medical consilium.
  • Women who are pregnant in the first 12 weeks of pregnancy at time of MDR-TB diagnosis should not be included in the regimen before the end of 12th weeks of pregnancy.
  • Women who are breastfeeding or pregnant beyond the 12th week of gestation can be enrolled into the regimen and they will be adequately informed and counselled of risks and benefits.
  • Mfx, Cfz and Km are safety class C drugs[1] and Cfz is excreted in breast milk. Pregnant or breastfeeding women will be informed about potential risk and benefits in a separate informed consent.

Children < 14 years of age:

  • See in annex 3 MDR TB drug dosage and prescription for paediatric cases <25 kg
  1. Baseline examination

All examinations and follow up are summarized in table 3. All patients will have a clinical examination prior to starting MDR TB treatment. The baseline examination includes the following:

1)Thorough history and clinical examination including:

  • Signs, symptoms, diagnosis, and documentation of co-morbidities including treatment;
  • Signs and symptoms of mental disorder (psychiatric assessment if indicated by either physician or counsellor) including treatment;
  • Psychosocial assessment with a focus on factors that may affect adherence (e.g. living situation, substance use/abuse, psychosocial support);
  • Hearing assessment (clinical and/or audiometry)
  • Weight/height, BMI, weight-for-height z-score for children, blood pressure;

2)Molecular DST (Xpert® MTB/Rif test), culture and DST, sputum smear microscopy. A culture should be taken 30 days prior to treatment or within 7 days of commencement ;

3)Provider initiated counseling and testing for HIV (this includes the “opt out” for HIV-testing)

4)Blood tests: See Table 3below for required tests including pregnancy test for women;

5)Chest X-ray

6)Electrocardiogram (ECG)

  1. Monitoring

Exact follow-up needs will be individualized according to patient’s clinical response and tolerance of medications. However there is a standard minimum of clinical and mycobacteriological monitoring including biochemistry. All those routine, minimum examinations are listed in table 3.

Clinical Monitoring:

First two months of treatment:

1)Doctor: week 2, then monthly for Clinical follow-up and if develops side effects (referred by nurse)

1)Nurse: Daily DOT provision according to chapter 4

2)Specialist referral if clinically indicated

Months 3 and following months of intensive phase and continuation phase

1)Doctor: Monthly for Clinical follow-up, and if develops side effects (referred by nurse)

2)Nurse: Daily DOT provision according to chapter 4

3)Specialist referral if clinically indicated

Mycobacteriological monitoring during treatment

1)Sputum smear microscopy monthly on 2 specimens (spot and morning samples).

2)Sputum culture at baseline and monthly to the end of treatment.

  1. Regional Consilium
  • All cases will be discussed at the regional consilium at the following points:
  • All patients meeting inclusion criteria – for decision about starting on short course regimen
  • When first and second line DST results are available
  • Occurrence of severe side effects / intolerance to 1 or more of the medications in the short course regimen that is not managed by the side effect management protocol in Annex 2 and may require a change of dose or stopping one of the medications (note that for severe reactions the medication may be withheld while awaiting discussion in the consilium or patient may require hospitalisation with decisions on treatment made in discussion with the TB/HIV adviser).
  • End of intensive phase
  • Patient remaining culture positive at 5 months
  • During the intensive phase a patient who has been culture negative and develops further positive cultures
  • Patient with adherence difficulties for more than 2 weeks despite interventions of counsellor, nurse and TB doctor
  • All patients requiring final outcome
  1. Management of DST related issues
  • Discordant results between rapid molecular tests and first line DST will be discussed in the consilium. In general repeat testing of sputum for microscopy, culture and DST will be undertaken and results from culture will be considered the gold standard, however past treatment history needs to be taken into account in this decision.
  • Pyrazinamide testing: All patients will continue on pyrazinamide regardless of the resistance test result due to lower reliability of lab testing for pyrazinamide DST and the limited data currently available for the short course regimen.
  • Ethambutol resistance testing: All patients will continue on ethambutol regardless of the resistance testing result, due to the limited data around impact of drug resistance on the efficacy of the short course MDR TB regimen.
  • Km resistance but Cm sensitivity: Continue Cm for duration of the intensive phase
  • Cm resistance but Km (and Ofl) sensitivity: Switch Cm to Km and continue the short course regimen with the extension of the intensive phase to a minimum 4 months of Km
  • Km and Cm resistance: Patient withdrawn from the short course regimen (outcome withdrawal from study and final analysis), repeat sputum culture and DST taken (to check for amplification of resistance) and commenced on appropriate DR TB regimen according to the Comprehensive TB Treatment Protocol
  • Ofloxacin resistance on Hain SL: patient will be commenced on the standard MDR TB regimen as per the comprehensive TB guidelines and not start the short course regimen. If the phenotypic DST shows ofloxacin sensitive then may be commenced on the short course regimen in discussion with the TB/HIV adviser.
  • Ofloxacin resistance on phenotypic DST: patient will be commenced on the appropriate DR TB regimen according to the Comprehensive TB Treatment Protocol and not start/discontinue the short course regimen.

Electrocardiogram

Both moxifloxacin and clofazimine may potentially prolong the QT interval as measured on an electrocardiogram. Prolonged QT interval in the presence of some drugs has been associated with torsade de pointes, which is a life threatening arrhythmia. However, a direct link between QT prolongation and torsade de pointe arrhythmia has not been established, and prolonged QT can occur without increased risk of arrhythmia (Giorgi 2010).