Download Annex 1 Clinical Pro

Short treatment regimen for Multidrug Resistant
Tuberculosis
Clinical treatment protocol for Uzbekistan
Joint MSF - Operational Centre Amsterdam / MOH Uzbekistan Research
Protocol
April 2014
1
1.
Introduction ...................................................................................................................................... 3
2.
Diagnosis and DST ............................................................................................................................. 3
3.
Eligibility and inclusion criteria for short MDR TB Treatment regimen ............................................ 4
4.
Treatment delivery model ................................................................................................................ 5
5.
Treatment Regimen and doses ......................................................................................................... 6
6.
Baseline examination ........................................................................................................................ 8
7.
Monitoring ........................................................................................................................................ 8
8.
Regional Consilium ............................................................................................................................ 9
9.
Management of DST related issues .................................................................................................. 9
10. Considerations for HIV positive patients ........................................................................................ 14
11. Psychosocial components and adherence support ........................................................................ 14
12. Contact tracing ................................................................................................................................ 15
13. Discontinuation of treatment ......................................................................................................... 15
14. Adverse Events and management .................................................................................................. 15
15. Data Handling and Record keeping................................................................................................. 16
16. Treatment Outcome Definitions ..................................................................................................... 17
Annex 1. Algorithm for Xpert MTB+/RIF+ (xxx district) .......................................................................... 20
Annex 2: Management of Main Side Effects of Treatment .................................................................... 21
Annex 3. MDR TB paediatric drug dosage table ..................................................................................... 26
Annex 4. Short course MDR-TB treatment - clinical examples……………………………………………………………27
2
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.
2. 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 samples in 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 MGITculture 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, ethambutol and
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.
3
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 and
are 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.
3. 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)
4






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:
o
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
4. 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.
5
5. 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
Pyrazinamide + Ethambutol + Moxifloxacin +
+ Moxifloxacin + Capreomycin
Prothionamide + Clofazimine for 5 months,
(Kanamycin) + Prothionamide +
starting after 4 months or first negative culture,
Clofazimine for at least 4 months and
whichever is later.
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.)
Description Seven drugs;
Five drugs;
Includes injectable & high dose
Only oral drugs in standard dosage.
Isoniazid
Dosing of standardized MDR TB Drugs for adults and adolescents > 25 kg, including pregnant women
Drug
Formulation
300mg tab
Isoniazid (H)
Pyrazinamide (Z)
Ethambutol (E)
Moxifloxacin (Mfx)
Prothionamide (Pto)
Clofazimine (Cfz)
Capreomycin (Cm)$
100 mg tab
400mg tab
400mg tab
400mg tab
250mg tab
100mg cap
Frequency
Weight range in Kg
<25
od
15-20 mg/kg
od
od
od
od
od#
od
od
30-40 mg/kg
15-25 mg/kg
7.5-10 mg/kg
15/25 mg/kg
2-3 mg/kg
15mg/kg
25-32
1
2.5
1.5
1
1
1
33-50
1
and
1
4
2
1
2
1
>50*
>55kg 2
5
3
1
>55kg 3
1
*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.
6
Medications are started at full dose on day 1. However if nausea occurs that is not controlled by antiemetics, 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 and Ofl (=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 drugs1 and Cfz is excreted in breast milk. Pregnant or
breastfeeding women will be informed about potential risk and benefits in a separate informed
consent.
1
Class C in pregnancy means that animal reproduction studies have shown an adverse effect on the fetus and
there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug
in pregnant women despite potential risks.
7
Children < 14 years of age:
 See in annex 3 MDR TB drug dosage and prescription for paediatric cases <25 kg
6. 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 3 below for required tests including pregnancy test for women;
5) Chest X-ray
6) Electrocardiogram (ECG)
7. 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).
8
2) Sputum culture at baseline and monthly to the end of treatment.
8. Regional Consilium

All cases will be discussed at the regional consilium at the following points:
o All patients meeting inclusion criteria – for decision about starting on short course
regimen
o When first and second line DST results are available
o 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).
o End of intensive phase
o Patient remaining culture positive at 5 months
o During the intensive phase a patient who has been culture negative and develops
further positive cultures
o Patient with adherence difficulties for more than 2 weeks despite interventions of
counsellor, nurse and TB doctor
o All patients requiring final outcome
9. 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
9


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).
While the death rates in the cohort studies of the short course regimen that have been reported are
low, it is not known whether this will be the case in other populations. In Uzbekistan, the combination of
clofazimine and moxifloxacin has been used in drug regimens for several years for the treatment of XDR
TB and some patients failing MDR TB treatment. Anecdotally there have not been cases of sudden death
that could be due to arrhythmia, however there has not been specific monitoring with ECG and it is
possible that if cases did occur they would have been missed. As there is no universal threshold for
identifying drug-induced QTc prolongation, and given the experience of combining these 2 drugs
together already (with a higher dose of clofazimine), the thresholds chosen for QTc will be when the QTc
exceeds >60ms compared with the baseline ECG QTc or when the QTc prolongs beyond 500 ms, as these
are thresholds that have been associated with the highest risk (Fenichel 2004). The QTc will be
calculated using the Fridericia’s formula which corrects for the heart rate and has been shown to be
more accurate at slower or faster heart rates than other correction formulae:
QTc =
QTc = the corrected QT interval
QT = the time between the start of the QRS
complex and the end of the T wave
10
RR = the time between the start of one QRS complex and the start of the next QRS complex
The ECG machine should be calibrated to ensure that the following voltage and speeds apply:
As one of the secondary objectives is to describe the rate of adverse events, a baseline ECG, an ECG at
two weeks and at 1 month will be performed. The ECG machine will be portable allowing to perform
ECG in patients’ homes or DOT corners. Patients with an extension of the QT interval from baseline of
greater than 60 ms or a QTc of greater than 500 ms will have treatment withheld and will be discussed
with the study coordinator and TB/HIV adviser. Reversible causes such as low potassium and magnesium
should be checked for and corrected and a decision about stopping treatment or continuing with weekly
ECG monitoring will be made based on whether the QTc persists above the thresholds despite
correction of reversible factors.
11
12
Table 3: Monitoring Investigations for MDR TB
Baseline
visit
1st visit
Follow-up during treatment
2weeks
Clinical assessment
History &
Physical examination
(including weight)
Evaluation side effects
Outcome assessment
Laboratory
Xpert® MTB/Rif
x
1M
2M
x
3M
At every clinical consultation
At end of treatment
x
x
Smear
Culture
x
x
DST (1st and 2nd line)
x
ECG
Full Blood Count
X
X
Creatinine*
Potassium
x
x
x
x
x
x
x
x
ALT
x
x
x
x
Glucose
x
Hearing test clinical
Hearing audiometry
Visual (Ishihara chart)
CP
monthly
Genotype MTBDR sl
TSH
HepBs Antigen
Hep C Antibodies
HIV
Pregnancy test
If HIV+, CD4
If HIV+, RNA VL**
Other complementary
exams
Chest X-ray
4M-end IP
After finalizing MDR TB treatment
Follow-up/outcome visits
6 months after
12 months after
treatment
treatment
completion
completion
x
x
x
x
x
x
x
x
x
x
In case of positive culture after culture conversion
x
x
X
x
x
x
x
x
Monthly
Monthly
Monthly
Monthly
If +ve
If positive culture
Culture
after conversion
If develops syncope or dizziness
If indicated clinically
End IP
Monthly
until end
IP
Monthly
until end
IP
x
End CP
X
x
X
x
x
In case of
relapse
In case of
relapse
X
In case of
relapse
In case of
relapse
In case of
relapse
In case of
relapse
x
In case of
relapse
In case of
relapse
In case of
In case of
relapse
relapse
If clinically indicated
Monthly
x
3if
monthly
elevated
at
baseline
Perform once at 6 months and if patient has symptoms/signs suggestive of hypothyroidism
Repeat only if indicated
If negative, offer to repeat if indicated
At 6M at 12M
At 6M at 12M
Repeat only if clinically
End CP
In case of
indicated
relapse
Monthly clinical assessment during IP – refer for audiometry if indicated
For patients with suspected hearing loss
Monthly
x
x
In case of
relapse
*for patients with higher risk of renal insufficiency the monitoring of creatinine may need to be more frequent. This includes diabetes, elderly
and baseline renal dysfunction and in case of co-treatment with tenofovir.
**if on ART for at least 6 months at MDR TB treatment initiation.
13
10. Considerations for HIV positive patients
Every MDR TB patient will be offered HIV counseling and testing, regardless of self-reported status or
current anti-retroviral therapy (ART). All HIV positive patients diagnosed with TB will be initiated on ART
regardless of CD4 cell count within 2-8 weeks after MDR TB treatment initiation when tolerating MDR TB
medications.
CD4 count will be measured at baseline, at 12 months after ART initiation and every six months
thereafter, unless clinically necessary throughout treatment.
HIV RNA VL will be measured at baseline for patients already on ART and for all co-infected patients HIV
RNA VL will be measured at the end of the MDR TB treatment and at the end of the follow up period
after treatment completion.
Additional considerations for HIV positive patients include:
 All HIV positive patients will start or continue cotrimoxazole prophylaxis.
 For patients who are already on 1st line ART, stavudine will be replaced with zidovudine unless
there are other contraindications.
 All ARVs can have overlapping toxicities with second line TB drugs; therefore all HIV positive
patients will be discussed by the TB/HIV advisor prior to new ART-initiation.
 Efavirenz will be the preferred NNRTI except in patients with psychiatric co-morbidity.
 Tenofovir will be avoided during the intensive phase due to increased risk of renal failure when coadministered with injectable agents.
 Patients taking ddI will use enteric-coated capsules as the other buffered forms interfere with Mfx
absorption.
 In general the preferred first line regimen will be zidovudine + lamivudine + efavirenz in patients
without anemia, but each case will be assessed by their Medical Doctor.
11. Psychosocial components and adherence support
Comprehensive psychosocial support
Psychosocial and adherence support will be integral components of MDR TB treatment for all patients.
To ensure adherence among all patients, the study will provide treatment support, patient support and
have patient-centred treatment services. All patients will undergo DOT for the duration of treatment.
Patient support will include disease education sessions to empower patients to make informed health
care choices and psychosocial support, including motivational communication and emotional support.
Patients will get nutritional support, and nurses will be provided with taxis for home based care if
required. All services will be patient-centered involving a teamwork approach in an effort to build
provider-patient relationships. Individual patient obstacles to receiving medications regularly and other
issues impacting adherence will be addressed.
14
At initiation, all patients will be presented comprehensive information about MDR TB and the treatment
regimen. Throughout treatment, adherence counselors and nurses will continue to reinforce this
information and follow-up any questions a patient or family member might have.
As a necessary component of MDR-TB treatment, patients will participate in routine adherence
counseling during both phases of treatment. In addition to adherence support, available psychosocial
components at both clinical sites include mental health assessment, assessment of psychiatric side
effects, and general support of mental well-being.
Missed appointment tracing strategy
Missed appointment tracing will be conducted as soon as a patient misses one appointment (i.e. if a
patient does not turn up to have DOT). Counselors/adherence support nurses will trace patients via
telephone and home visitation. Adherence counseling will address specific reasons for defaulting in an
effort to find solutions to prevent future missed DOT or appointments. Every effort will be made to
convince the patient to continue treatment, and patients will be addressed in a sympathetic, friendly,
and non-judgmental manner. Every effort will be made to address the patient’s concerns and reasoning
for treatment interruption to prevent it from recurring. Patients missing appointments, after ensuring
that any side effects if present have been appropriately managed, will be managed according to the
missed appointment strategy in the comprehensive TB care protocol in Karakalpakstan.
12. Contact tracing
All close contacts of MDR TB patients will be systematically clinically screened every 6 months and will
be screened and tested with sputum for microscopy and molecular tests and culture if symptomatic.
Close contacts are those living in the same household as the patient or who spend a significant amount
of time with the patient. Contacts of MDR TB patients will be instructed to report any symptoms of
possible TB, at which point a careful assessment will be made.
13. Discontinuation of treatment
The decision to postpone, modify or to interrupt/discontinue the regimen will be left at the discretion of
the clinical team following the patient in discussion with HIV/TB advisor. Consideration to MDR TB
treatment interruption will be made in the following situations:
 Life threatening adverse effects of medications.
 Adherence problems including confirmed selling of medication, persistent failure to appear for DOT
refractory to adherence support interventions.
14. Adverse Events and management
All possible adverse events will be documented by a systematic and standardized screening of clinical
and/or laboratory data at each visit. We will utilize the DAIDS grading score to assess the type, severity
and possible relationship of side effects.
The following definitions will be used for adverse events and reactions:
Adverse event (AE): any medical occurrence in a subject to whom a medical product has been
administered including occurrences which are not necessarily cause by or related to that product.
15
Adverse reaction (AR): any unintended response to a medical product which is related to any dose
administered to the subject.
Serious Adverse Event (SAE) and Serious Adverse Reaction (SAR): any event or reaction that results in
death, is life-threatening, requires hospitalization or prolongation of existing hospitalization or results in
persistent or significant disability or incapacity. All SAE will be discussed by the CRT and reported.
Subjects will be followed-up by phone or by visitation at least once per week for the first month
following an adverse event. Following this, follow-up for adverse events will occur at a patient’s
monthly clinical visit, or more frequently, depending on clinical need.
Management of side effects will be done by the district TB doctors and general practitioners (SVP and
policlinic doctors) utilizing algorithms adapted from the 2008 WHO MDR TB management guidelines and
current algorithms in the Karakalpakstan comprehensive TB protocol. All side effects will be
systematically documented, including what influence they may have on a patient’s treatment. Side
effects will be identified early and treated immediately. Patients will be informed about certain side
effects, including that Cfz may cause discolouration of the conjunctiva, lacrimal fluid, sweat, sputum,
urine, faeces, nasal secretions, semen, breast milk and reddish to brownish-black discoloration of the
skin (in light skinned individuals). This is however reversible after stopping treatment. Permanent dose
reduction or definitive stopping of a drug is used as a last resort only when other possible solutions have
failed and it is to be made in the regional consilium. Appendix 1 summarizes minor and major side
effects and their management.
15. Data Handling and Record keeping
All data will be collected in a password protected Koch’6 database. This database is an electronic patient
monitoring system including follow up during and post treatment.
The simplified protocol will be implemented with a minimum number of forms which are kept as paper
based versions in the patient’s file. These forms are:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Form 1: Admission Form
Form 2: Current TB Episode – Initial Treatment
Form 3: Interim form change in microbiological status
Form 4: Change in treatment location
Form 5: Outcome
Form 6: Side effect form
Form 7: Changes in Treatment form
Treatment monitoring form
Patient consent to Treatment (filled once at start of treatment)
Pretreatment psychosocial assessment form
Laboratory forms
16
The clinical team will complete forms on paper. The MDR TB Treatment Card and the Monthly
Treatment Monitoring Form are sent to the data clerk after being filled out by the clinical team. The
data clerk will then return the forms to the patient’s file after data encoding.
The database will be backed up to a secondary external hard drive on a weekly basis, and backups will
be sent quarterly to headquarters epidemiologist.
16. Treatment Outcome Definitions
We will use adjusted international WHO definitions to classify the type of response to TB treatment (see
below). An assessment will be performed at the end of the treatment period, and a final assessment will
take place at the end of the follow-up (12 months after completion of the treatment).
Interim
Sputum conversion will be defined as two consecutive sets of negative smears and cultures, from
samples collected at least 30 days apart. The date of the collection of the first set of negative cultures
and smears will be used as the date of conversion. Both bacteriological techniques (microscopy and
culture) will be monitored and documented throughout the treatment. The smear will be the primary
means of determining the duration of the intensive phase as described above. For patients who remain
smear positive, then culture results will also be taken into account. However, both smear and culture
conversion will be analyzed for the study secondary end point analysis on a quarterly basis, and
correlation of both measures with primary outcomes will be done at the conclusion of the study.
End of Treatment
The TB treatment outcome at the end of the treatment period is defined as follows (adjusted outcomes
definition for MDR TB programs WHO 2008, emergency update of guidelines for the programmatic
management of drug resistant tuberculosis):
Cure: An MDR TB patient who has completed the treatment according to programme protocol and has
at least four negative cultures from samples collected at least 30 days apart within the final 5 months of
treatment and if there is a positive culture it is followed by a minimum of three consecutive negative
cultures taken at least 30 days apart in the final 3 months of treatment.
Treatment complete: An MDR TB patient who has completed treatment according to programme
protocol but does not meet the definition for cure because of lack of bacteriological results (i.e. fewer
than five cultures were performed in the final months of treatment) or otherwise, completion of
treatment with documented bacteriological conversion persisting through the end of treatment, but
fewer than five negative cultures. Treatment completion will only be an outcome for patients that are
17
not able to produce sputum; in case of patients where the lack of bacteriological results is due to other
reasons the outcome will be registered as “other” in order to avoid misclassification.
Treatment outcome “other”: An MDR TB patient who has completed treatment according to
programme protocol but does not meet the definition for cure because of lack of bacteriological results
due to programmatic reasons (reasons other than the lack of patient’s ability to produce sputum) such
as culture contamination or no timely referral of sample by the clinician, the outcome will be registered
as “other” in order to avoid misclassification. In case of contamination of the culture tube, new sputum
samples for culture will be collected and culture tubes de-contaminated and re-inoculated following
standard laboratory procedures.
Death: An MDR TB patient who dies for any reason during the course of MDR TB treatment and is not
already classified as a treatment failure prior to death. Assumed causes of death will be recorded.
Failure: Treatment will be considered failed when there is absence of bacteriological response that will
be defined as follows:


Patient fails to show culture negative by the end of month 5 of a prolonged intensive phase.
Culture positive during the continuation phase: two cultures positive during the continuation phase
or one culture positive during the last 3 months of treatment.
 Treatment will also be considered to have failed if a clinical decision has been made to terminate
treatment early because of poor clinical or radiological response or adverse events (including due to
prolonged QTc on ECG according to criteria defined in ECG section below) where the team decides
the regimen is failing and treatment is changed. These latter failures can be indicated separately in
order to do sub-analysis.
All failures with a documented positive culture will have DST and investigation of resistance to
document the rate of resistance amplification. Patients with a sputum sample collected after the
commencement of treatment that shows a positive culture and a DST demonstrating amplification of
resistance with either ofloxacin resistance or with capreomycin/kanamycin resistance will be declared
failures.
Default: An MDR TB patient whose treatment was interrupted for two or more consecutive months for
any reason without medical approval and not meeting the criteria for failure.
Transfer out: An MDR TB patient who has been transferred to another reporting and recording unit and
for whom the treatment outcome is unknown. Patients that require a transfer out will be informed that
it is very unlikely that they can continue the same regimen and they will have to change to standard
MDR TB regimen. In case that the treatment can be provided in the receiving center and the outcome
documented, this will be recorded.
18
Outcome will be considered as favorable in case of cure or treatment completion. All other outcomes at
the end of treatment (default, death, failure) will be considered as unfavorable.
End of the study follow up period - the final outcome:
All patients defined as treatment cure, complete, treatment outcome other or transfer out will be
assessed for:
Relapse-free: An MDR TB patient who meets the criteria of cured or completed short course of
treatment and remains asymptomatic at the end of the follow up period (one year after treatment
completion).
Relapse: An MDR TB patient who meets the criteria of cured or completed short course of treatment
and at any time during the follow up period (first year after treatment completion) is subsequently
diagnosed with at least one sample of bacteriologically positive MDR TB by culture and DST.
Loss to follow up during post treatment follow up: An MDR TB patient with an outcome at the end of
treatment of treatment cure, complete, treatment outcome other or transfer out who is loss to follow
up during the 12 month post treatment period (as assessed at the end of 12 months).
Death during post treatment follow up: An MDR TB patient with an outcome at the end of treatment of
treatment cure, complete, treatment outcome other or transfer out who dies of any cause during the 1
year post treatment follow up period.
Note that if patients miss the 6 month post treatment follow up appointment but are assessed at the 12
month follow up review they are still able to be assessed for an end of study period final outcome.
19
Annex 1. Algorithm for Xpert MTB+/RIF+
Clinically suspect of TB
Sputum - smear microscopy
Smear +ve
Smear -ve
Genotype MTBDR
(first line) RiF +
Xpert MTB+/RIF+
Xpert MTB-/RIF-
Xpert MTB+/RIFGenotype
MTBDR sl
Ofl
sensitive
Inclusion
in study
Standard
Study-Tx
SLDST
Ofl
resistant
Standard
MDR TB
treatment
SLDST
DST finds MDR-TB
Inclusion in study
Standard Study-Tx
SLDST
DST confirms nonMDR-TB
Tx acc. to
Karakalpakstan
Comprehensive TB
guidelines
Continue
Karakalpakstan
comprehensive TB
guidelines
diagnostic algorithm
FL and SL-DST
MGIT culture
and
FLDST/SLDST:
MDR-TB
confirmed Ofl
and Km
sensitive
Continue study
short regimen
Change Cm to
Km
MGIT culture
and
FLDST/SLDST:
Rifampicin
sensitive
MGIT cuture
and
FLDST/SLDST:
MDR + Km
resistant
Withdraw from
study, treat
according to
comprehensive
TB Guidelines
Continue study
With Cm
MGIT culture
and
FLDST/SLDST:
MDR + Oflresistant
MDR + Km
+Ofl- resistant
MGIT culture
and
FLDST/SLDST:
MDR + Cmresistant and
Km and Ofl
sensitive
Withdraw from
study, treat as
per
comprehensive
TB guidelines
(pre XDR or
XDR)
Switch Cm to
Km, continue
Km for at least
4 months
20
Annex 2: Management of Main Side Effects of Treatment
Side effect
Side effect management
Extra considerations for patients
on ARVs
Nausea,
vomiting
Possible TB and
ART responsible
drugs
Most likely Pto, H,
E, Z, Cfz, ARVs
1.Treat dehydration, check electrolytes/for hepatitis if
needed,
2.Split Pto/ in 2 doses (DOT) if possible
3.Give metoclopramide 10 mg ½ hr before doses
4.Treat reflux/gastritis if present with omeprazole 20 mg
daily
5.Supportive management of anxiety and consider low dose
benzodiazepine at night (beware of CO2 retention in severe
lung disease)
6.If fails to resolve after 2 days, give ondansetron 8 mg ½ hr
before doses for 7 days, if helpful – continue ondansetron
7.Consult TB/HIV advisor and regional consilium if still a
problem
Common and usu. self-limiting if
early but also consider NNRTI
induced hepatitis, possible sign of
lactic acidosis if occurs after several
months.
Consider pancreatitis in patients on
ddI or D4T with severe abdominal
pain
Gastritis/reflux
Pto
Diarrhea
PI especially LPV,
buffered ddI
Arthralgia
Z, fluoroquinolones
Electrolyte
disturbances
(↓ K+ or Mg2+,
↑ K+ in renal
impairment)
Km, (and other
injectable
aminoglycosides),
Cm, TDF (rare)
1. Avoid anti-acids (Note: must be at least 2 hrs before or 3
Exclude possible causes esophagitis
hrs after anti-TB drugs due to interactions)
including candida
2. Omeprazole 20 mg for 2 weeks (If effective consider
longer duration)
3. If severe/not resolving discuss with TB adviser
1. Give hydration and electrolytes as needed (ORS),
Consider opportunistic infections
2. Anti-diarrheal medication (loperamide) unless patient has /other causes of diarrhea (C.difficile)
fever or blood in stools
1. Ibuprofen 400mg twice to three times per day with meal
None
as needed (If ibuprofen cannot be tolerated because of
stomach upset, paracetamol 1000mg twice to three times
daily can be used)
2. Will often settle with time
3. If severe/not settling discuss with consilium reducing
pyrazinamide dose
1. Monitor the level of potassium in the blood
2. Give potassium supplements
3. Assess for diarrhea of vomiting
4. Risk of additive renal toxicity with TDF and injectables
5. HIV-infected have increased risk renal toxicity and electrolyte abnormalities to injectables
Note 1 potassium tablet = 8 meqK + (600 mg).
21
If the prescribed dose more than 20 mEq K  divided into two or more daily dosing, single dose
should not exceed 20 mEq.
Tablets should be taken as a whole (not chewed) with meals and drink plenty of water.
Potassium-drug intake may be needed throughout the course of aminoglycosides (Cm, Km)
- Always check renal function. If there are deviations from the norm, it is necessary to reduce the
dose of potassium drugs in mind the risk of hyperkalemia.
- For moderate hypokalemia (3.0 and above, and no symptoms), prescribe the K-1 tablet two times
a day and increase the dose to 2 tablets 2 times a day, if K is still low.
- In severe hypokalemia (symptoms and the patient cannot swallow), you must inject KCl
intravenously. As soon as the patient can swallow, go to the tablet form and stop the intravenous
administration.
- Quick intravenous administration of KCl can cause death. Must be injected i/v only in the hospital
under medical supervision.
Indicators of K and doses of K drugs
----------------------------------------------------------------------------------------------------------------------------- ----К + Normal 3,5-5,0 mEq/l
----------------------------------------------------------------------------------------------------------------------------- ----K+ 3,5 or higher  no need to prescribe KCl and continue monthly K+ tests if on injectable
----------------------------------------------------------------------------K+ 3,0 - 3,4  КCl 2 tablets 3 times per day
and repeat tests after 2 weeks, if K+ is normal then reduce the dose to 1-2 tablets 2 times daily and
to monitor creatinine on monthly basis
----------------------------------------------------------------------------------------------------------------------------- ----K+ 2,5 – 3,0  KCl 2 tablets 4 times a day
Also, prescribe the magnesium tablets (1 tablet of Alumag a day in the evening. 1 tablet of Alumag
contains 400 mg of magnesium).
To repeat the test after 3 days. If the level does not increase, prescribe magnesium and KCl 2
tablets 4 times a day and consider hospitalization for intravenous injection of KCl.
K+ Lower 2,5  Hospitalization. Intravenous injection of potassium and magnesium. Next, KCl and
magnesium tablets. If the value of K greater than 2.5, stop the intravenous injection of KCl and go
to the tablet form. Analyses repeated daily until the value of K is not more than 2.5, and the
symptoms of hypokalemia disappear. If there are improvements with K + tablets, follow the
instructions above according to K+ level
-------------------------------------------------------------------------------------------------------------------- -------------Potassium tablets can cause nausea
• For patients with low potassium in the blood, to prescribe Alumag 1 pill a day, evening, during
dinner / before bedtime. There are 400 mg in 1 tablet Magnesium.
22
Side effect
Possible
responsible drugs
Z,H,R, /Pto, E, Mfx,
NVP, EFV, all PI, all
NRTIs, CTX
Side effect management
1. Temporarily withhold all therapy if ALT > 5x normal level
or severe nausea/vomiting until improved,
2.Consider other causes of hepatitis (meds, viral
hepatitis,alcohol) and manage fluids/electrolytes
3. Discuss with TB/HIV adviser about re-introduction plan.
Extra considerations for patients
on ARVs
Timing of commencement of drugs
and hepatitis may help identify most
likely agent. Stop ARVs. Consider
switch NVP to EFV. Also consider
CTX
Skin rash
All TB agents, EFV,
NVP, ABC, CTX
1. Maculopapular rash and pruritus are common early side
effects and may resolve after few weeks spontaneously.
2. Antihistamine, topical hydrocortisone.
3. If severe with generalized erythema, blistering, fever or
mucosal involvement, cease all medications immediately
and consult TB/HIV advisor.
Usu. In first 3 months of ART.
Antihistamine only for grades 1 & 2,
stop ARVs, TB drugs + CTX and
consult TB+HIV advisor for grades 3
&4
Do not re-challenge with abacavir
Renal toxicity
Km,, Cm, TDF (rare)
1. Temporarily Stop injectable agent, and manage fluid
status. Assess electrolytes.
2. Calculate estimated creatinine clearance (Cockcroft gault
equation)
3. Consider 3 times a week dosing or lower dose of
injectable or change to Cm if on Km
4. Readjust other drug doses to renal function
Seizures*
H, Mfx
Peripheral
neuropathy
H, Km, Cm, Pto, Mfx,
d4T, ddI
1. Hospitalize the patient
2. Stop TB medications temporarily until seizures are
controlled
3. Increase pyridoxine to 200 mg/day
4. Prescribe carbamazepine. Begin with 200 mg 2 times a
day, and then increase by 200 mg every week if
required (if recurrent seizures). Maximum dose is 1600
mg (8 tabs) per day
Discuss in consilium regarding management and gradual
reintroduction of TB medications. Consider recommence
treatment with reduced dose isoniazid.
1. Increase pyridoxine to 200 mg/day
2. Withhold isoniazid for 2 weeks
3. Amitriptyline 25-50mg daily if severe symptoms
Discuss in Consilium if not resolving as medications may
need to be adjusted consider permanent cessation isoniazid
Risk of additive renal toxicity with
TDF (if on both TDF + injectable
consider switch from TDF to AZT or
ABC)
Many antiretrovirals need dose
adjusting in renal insufficiency. HIVinfected have increased risk renal
toxicity and electrolyte abnormalities
to injectables
Risk potentiated by alcohol
containing syrups (pediatric LPV/r)
Hepatitis
Generally avoid d4T or ddI with Cs
or H. If must give D4T or ddI monitor
closely, and change to
TDF/ABC/AZT if develops peripheral
neuropathy
23
Or change to Cm if Km or possible dose reduction to 3 x /
week. Check for other causes (HIV, diabetes)
Side effect
Hearing loss
Possible
responsible drugs
Km, Cm
Side effect management
Optic neuritis
E, ddI
Psychosis
H, Mfx Pto, EFV
This is low risk in 9
month regimen
1. Consult with a psychiatrist and consider hospitalization
2. Start haloperidol (0.5 – 5mg PO or IM in two divided
doses) at the earliest signs of psychosis.
3. Consider other causes (e.g. alcohol, depression)
4. Discuss in consilium regarding management and gradual
reintroduction of TB medications – may require temporary
stopping medications or reduction of dose of Pto or H
Depression*
Socio-economic
circumstances,
chronic disease,
Mfx H, Pto, Cfz
related to skin
changes, EFV
Hypothyroidism
Pto
1. Counseling
2. Screen for alcohol abuse, hypothyroidism, and
symptoms of psychosis
3. If depression is significant start mirtazapine 30mg daily
(given in the evening) and consult psychiatrist
4. If there is suicidal ideation, hospitalize patient and
temporarily discontinue medications
5. Discuss in consilium regarding TB medications and
management plans. Doses of Pto may need to be
decreased, doses of isoniazid may need to be reduced.
Treat if TSH >6 IU/mL and symptomatic
Start with Levothyroxine 0.5 mg daily. Every month increase
the dose with 0.5 mg. TSH should be repeated monthly until
normal TSH between 0.5 – 5. Continue treatment with
levothyroxine daily until 1 month after complete TB Rx
1. Document hearing loss (clinical or audiometry if
possible). Note that hearing loss is not reversible.
2. Discuss with TB/HIV adviser possibility of changing to
Cm 3x week dosing or potential early stopping of injectable
Decreased red-green colour distinction seen early,
Stop E, monitor with clinical eye examination
Extra considerations for patients
on ARVs
None
Opportunistic infections affecting eye
(examine for OI vs optic neuritis)
EFV has high rate of mild CNS
effects during first 2-3 weeks
treatment which usually resolve by
themselves (confusion, impaired
concentration, abnormal dreams,
dizziness)
Stop EFV if severe or not
responding to withholding Cs.
Discuss with TB/HIV adviser
Substitute EFV if severe or not
responding to treatment
Mixed evidence. Some studies show
ART (?D4T) associated with
subclinical hypothyroidism
24
Side effect
Possible
responsible drugs
R, H, AZT, CTX
Side effect management
Lactic acidosis
D4T, ddI, AZT, 3TC
None
Lipodystrophy/
lipoatrophy
Pancreatitis
D4T, ddI, AZT, PIs
None
D4T, ddI
Consider acute abdomen due to clofazimine – withhold
medications and admit hospital for further investigations
Abdominal pain
Cfz, Pto, All ARVs
Skin, cornea,
retina, sputum
and urine
discolouration
Icthyosis
Cfz
Often benign
Cfz has been associated with severe acute abdomen; in
those cases it should be suspended and discussed with
HIV/TB adviser and in consilium
Adequate counseling with advice to maintain regimen
If very severe, discuss with TB advisor and consilium to
explore drug change
Bone marrow
suppression
1. Mild anemia of chronic disease common – treat TB and
monitor clinically
2. Consider other co-morbidities (gastritis/nutritional
deficiency, etc)
Extra considerations for patients
on ARVs
Usu. occurs during the first 3 months
of AZT treatment. If HB<8 or
decreasing or poor respiratory
reserve switch AZT for d4T,TDF or
ABC
Consider opportunistic infections
(LIP, MAC, etc)
CTX more likely if high dose
(treating toxo or PCP)
Stop all ARVs until recovery.
Replace d4T with TDF or ABC when
restarting.
Switch NRTI to TDF/ABC.
Avoid use together, if already
present stop agent and do not use
again.
Follow up patient as it may be an
early sign of pancreatitis, hepatitis or
lactic acidosis.
Cfz
Topical hydration
If very severe, discuss with TB advisor to explore drug
change
Decreased visual Cfz
Regular hydration of dry eyes with normal saline or water
acuity, dry eyes
for injection
or eye irritation
If very severe, discuss with TB advisor to explore dose
reduction
Drugs in bold type are more strongly associated with the side effect than drugs not in bold.
Drug dosages should not be reduced without consultation with TB/HIV advisor. If a medication has to be ceased, please consult the TB/HIV
advisor regarding a suitable substitute medication to prevent resistance developing.
Cm=capreomycin, Km=kanamycin, Pto=Prothionamide, , Cfz=Clofazimine, R=Rifampicin, H=Isoniazid, E=Ethambutol, d4T=stavudine,
TDF=Tenofovir, 3TC=Lamivudine, AZT=Zidovudine, PI=protease inhibitors, Lpv=Lopinavir, ddI=didanosine, CTX=cotrimoxazole.
25
Annex 3. MDR TB paediatric drug dosage table
weight in kg
Capreomycin
/Kanamycin
Amikacin
Isoniazid
high dose
Moxifloxacin
Prothionamide
Clofazimine
Pyrazinam
dose
15-30mg/kg
1530mg/kg
15-20 mg/kg
7.5-10mg/kg
15-20mg/kg
2-3 mg/kg
30-40mg
1g in 4ml
dilution
2ml vial
formulation
250mg/ml
250mg/ml
unit
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
ml
0.5
0.5
0.75
0.75
1
1
1
1
1
1.5
1.5
1.5
2
2
2
2
2
2
2
2
2.5
ml
0.5
0.5
0.75
0.75
1
1
1
1
1
1.5
1.5
1.5
2
2
2
2
2
2
2
2
2.5
tablet
tablet
100mg 300mg
Either of the
dosages! Not
additional!
tbl
tbl
1
1
1
1.5
0.5
1.5
0.5
1.5
0.5
2
0.5
2
0.5
2
0.5
2
0.5
3
1
3
1
3
1
3
1
3
1
3
1
3
1
3
1
3
1
3
1
3
1
tablet
250mg
Pharmacolo
gical
preparation
mg
400m
tbl
0.5
0.5
0.5
0.5
0.5
0.5
1
1
1
1
1
1
1
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
mg
10-15 mg
15 mg
15-20 mg
20 mg
20-25 mg
25 mg
25-30 mg
30 mg
30-35 mg
35 mg
35-40 mg
40 mg
40-45 mg
45 mg
45-50 mg
50 mg
50-75 mg
50-75 mg
50-75 mg
50-75 mg
50-75 mg
tbl
0.5
0.5
0.5
0.75
0.75
1
1
1
1
1
1.5
1.5
1.5
1.5
1.5
1.5
2
2
2
2
2
Susp ml
tablet
400mg 20mg/ml
Either of the
dosages! Not
additional!
tbl
tbl
2
3
3
3
4
0.25
4
0.25
5
0.25
5
0.25
6
0.5
6
0.5
6
0.5
7
0.5
7
0.5
7
0.5
8
0.5
8
0.5
8
0.5
9
0.5
9
0.5
10
0.5
10
26
table
Annex 4. Short course MDR-TB treatment - clinical examples
Below are few examples of cure and failure
Outcome- cure:
Example 1:
Month
Smear
Culture
0
+
+
1
+
+
2
+
+
3
-
4
-
5
-
6
-
7
+
-
8
-
9
-
Example 2: Intensive phase extended due to positive smear at M4 to 6 months (when the first negative
culture result was available at M6)
Month
Smear
Culture
0
+
+
1
+
+
2
+
+
3
+
+
4
+
+
5
-
6
-
7
-
8
-
9
-
10
-
Example 3: Intensive phase extended due to positive smear at M4 to 5 months (when the first negative
culture result was available at M5)
Month
Smear
Culture
0
+
+
1
+
+
2
+
+
3
+
4
+
-
5
-
6
-
7
-
8
-
9
-
10
-
Example 4: Intensive phase stopped after 4 months as smear negative at M4
Month
Smear
Culture
0
+
+
1
+
+
2
+
+
3
+
4
+
5
-
Outcome- failure:
Example 5: Two negative cultures in the continuation phase
Month
0
1
2
3
4
5
Smear
+
+
+
+
Culture
+
+
+
+
-
6
-
7
-
8
-
9
-
6
-
7
+
+
8
+
9
-
Example 6: Remaining smear positive after M5 (intensive phase prolonged at M4 due to positive smear)
Month
Smear
Culture
0
+
+
1
+
+
2
+
+
3
+
+
4
+
+
5
+
6
-
27
Example 7: Positive culture in continuation phase- failure
Month
Smear
Culture
0
+
+
1
+
+
2
+
+
3
+
4
-
5
-
6
-
7
+
+
8
-
9
-
28