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Description : CPG Treatment on DRTB, Treatment of Drug-Resistant Tuberculosis

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Treatment of DrugResistant Tuberculosis
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POLICIES
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1. MDR-TB and RR-TB treatment shall be started within seven days from diagnosis. 2. Standard treatment regimens for MDR-TB and RR-TB shall be given based on patient eligibility and exclusion criteria. Individualized treatment shall be given to patients who are not eligible for any of the standard regimens. 3. First- and second-line LPA test shall be done prior to MDR-TB and RR-TB, pre-XDR-TB and XDR-TB treatments. Results should be available within 14 days from submission and prompt adaptation of treatment shall be done if with resistance to fluoroquinolones (FQ), or both high-dose isoniazid and prothionamide.
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4. Regular adherence counselling shall begin before treatment and continue two weeks after treatment, as well as monthly throughout treatment. All health facilities with TB services shall establish a responsive treatment adherence mechanism that allows for prompt followup of patients who interrupt treatment. 5. Patients shall be provided with support to enhance treatment adherence. This includes, but is not limited to, community-based care, transportation allowance and conditional cash transfers.
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6. Each patient shall be assigned a treatment supporter – either a health worker, a trained lay volunteer or a family member – who shall ensure daily intake at home, designated community area, workplace or health facility. Use of digital adherence technologies (e.g. video-based treatment, 99 DOTS or artificial intelligence (AI) to aide self-administered treatment but reinforced with proper and regular adherence counselling and support may be applied, if feasible. 7. Treatment monitoring shall be undertaken by clinical, microbiological (SM and culture) and laboratory investigation according to recommended schedules and as needed. 8. Prompt management of adverse events shall be undertaken. Modification of treatment shall be done in case of intolerance to drugs (e.g. persistent nausea and vomiting). Prompt referral shall be made for patients who need hospital care for severe adverse events or other co-morbidities.
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9. All severe adverse events and adverse events of special interest shall be recorded and reported through the Pharmacovigilance Information Management System (PViMS) or through the paper form using FDA standard report form for ADRs. 10. Treatment education, including infection prevention education, shall be given to patients and family members prior to and during treatment. 11. Prompt discussion of the cases with TB Medical Advisory Committee shall be done for patients whenever indicated.
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PROCEDURES
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A. Education, counselling and support to patients and family members prior totreatment
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Inform the patient that they have MDR-TB or RR-TB disease. 2. Educate about TB and MDR-TB or RR-TB disease and the nature of treatment and motivate them to undergo treatment. For patients less than 18 years old, talk to the parent/guardian regarding the need for treatment. Provide, as necessary, the following key messages for TB patients and their families: • basic information about TB disease covering cause, mode of transmission, clinical signs and symptoms suggestive of TB, how TB disease is diagnosed and how to prevent TB; • duration of treatment: nine to 20 months for MDR-TB and RR-TB cases; • the schedule of regular clinical and laboratory follow-up for treatment monitoring;
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• potential adverse events during treatment and how to address them; • the relevance of contact investigation; • tracing mechanism in case of treatment interruption (missed dose); and • availability of free of charge services for TB and DR-TB diagnosis and treatment, and LTBI treatment for contacts. 3. Discuss with patients their social and financial needs and offer possible sources of support to enable adherence to treatment, for example SSS, GSIS, ECC, DSWD, LGUs, etc.
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B. Pre-treatment evaluation
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1. Determine other co-morbidities (HIV, Diabetes, renal disease) and other health issues (tobacco, alcohol, illicit drug use and abuse) and manage them accordingly. Referral to specialist, if needed. (Annex 3D. Special Situations in DR-TB Treatment) 2. Do pretreatment evaluation including the following baseline tests: • clinical examination including body weight and height; • smear microscopy (SM); • TB culture (and DST); • first- and second-line LPA test ; • chest X-ray; • electrocardiogram (ECG); • visual acuity and color vision test; • potassium, Blood Urea Nitrogen (BUN), creatinine, aspartate transaminase (AST),alanine (ALT), fasting blood sugar (FBS);
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• complete blood count (CBC); • HIV rapid antibody test (with written consent); • pregnancy test; • thyroid stimulating hormone (TSH); • mental health screening; • brief peripheral neuropathy screen (BPNS); and • baseline tests required for specific regimens: albumin, if regimen contains delamanid (Standard Long All Oral Regimen [SLOR] Fluoroquinolone Resistance [FQ-R]) Audiometry, if regimen will contain amikacin or streptomycin (individualized treatment regimen [ITR]).
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For Baseline Mental Health Screening, a simple questionnaire may be used (Annex 3E. PHQ9 Questionnaire) or routinely ask five simple questions: 1. Any mood changes? (easy irritation, agitation, challenge to concentration) 2. Any change in sleeping pattern? (insomnia, oversleep) 3. Any feeling of sadness? 4. Any feeling of hopelessness? 5. Any thought of hurting themselves? (suicidal ideation) Refer to a psychologist or psychiatrist if any of the above is present.
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C. Assigning the appropriate DR-TB treatment regimen
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Assignment of the appropriate DR-TB regimen will depend on standard eligibility criteria set by the program and results of DST (Xpert, first- and second-line LPA and phenotypic DST). See Table 18 and Fig. 8 for different DR-TB regimens.
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Children (< 15 years old) diagnosed with MDR-TB and RR-TB shall be evaluated for eligibility to standard all oral regimens recommended for children (page 54, Section E.) 2. The standard treatment regimens shall only be offered to patients if all of the drugs in the regimen are available and accessible. Patients who are pregnant and contacts of patients who failed on MDR-TB treatment shall be referred to the TB Medical Advisory Committee (TB MAC) for design of an individualized treatment regimen (ITR). 3. Patients who are adults (15 years old or above), not pregnant and not a contact of a patient who failed MDR-TB treatment are eligible to receive standard short all oral regimen (SSOR) if they do not have any of the following exclusion criteria:
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4. If all the exclusion criteria are absent, start treatment with SSOR 4–6 months: Lfx-Bdq(6months)-Cfz-Pto-E-Z-HdH 5 months: Lfx-Cfz-Z-E
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5. If not eligible to SSOR, check eligibility to SLOR FQ-S 6. If all of the exclusion criteria are absent, start treatment with SLOR FQ-S 6 Months: Lfx-Bdq-Lzd-Cfz 12–14 months: Lfx-Lzd-Cfz
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7. If not eligible to SLOR FQ-S, check eligibility to SLOR FQ-R 8. If all of the exclusion criteria are absent, start treatment with SLOR FQ-R 6 Months: Lzd-Bdq-Dlm-Cfz-Cs 12–14 months: Lzd-Cfz-Cs
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9. If not eligible to SLOR FQ-R, refer to TB MAC for composition of individualized treatment regimen (ITR) 9.1 Usually the cases that are not eligible to both SSOR and SLOR are MDR-TB and RR- TB patients with previous exposure to second-line drugs for more than one month (i.e., second-line retreatment cases – relapse, failure, LTFU from previous DRTB regimens) or who are contacts of an index case who failed MDR-TB treatment 9.2 In patients for whom design of an effective regimen based on existing recommendations is not possible, bedaquiline-pretomanid-linezolid regimen may be considered as a last resort under prevailing ethical standards, with strict implementation of active drug safety monitoring and management (aDSM) and after consultation with TB MAC
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10. Follow recommended regimen from the TB MAC
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11. Perform the following for off-label use of anti-TB drugs: 11.1 Any situation that requires the off-label use of an anti-TB drug should be presented to TB MAC. These situations include the following:20 Use of bedaquiline and delamanid in combination Extended use of bedaquiline and/or delamanid for more than 24 weeks (six months) Use of bedaquiline and delamanid in EPTB Use of bedaquiline in children less than 6 years old and pregnant patients Use of delamanid in children less than 3 years old and pregnant patients In general, informed consent form is required for patients who will be enrolled under Regimen 5
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11. Perform the following for off-label use of anti-TB drugs: 11.2 (SLOR FQ-R) and patients who need extension of Bdq and Dlm 11.3 Once approved by the TB MAC, explain to the patient and/or significant others the benefits and risks involved with off-label use 11.4 Once a patient agrees to the use of anti-TB drugs off-label, ask the patient to sign the informed consent form. For patients who cannot be fully informed (e.g. less than 18 years old, mentally incapacitated), seek consent from the parent(s) or legal guardian
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12. After determining treatment regimen, follow the dosing in Table 20 (adults) and Table 21 (children). 12.1 For regimens containing prothionamide (Pto), start Pto in two divided dosage (morning and evening) for the first two weeks of treatment if total daily dose is > 250 mg 12.2 Advise patients to only take Pto after light meals 12.3 Once tolerance has improved, change Pto dosing to once daily after two weeks
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13. Upon receipt of first- and second-line DST results of LPA and phenotypic DST test, revise the regimen accordingly
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13. Upon receipt of first- and second-line DST results of LPA and phenotypic DST test, revise the regimen accordingly 13.1 Check the result of LPA for the presence of fluoroquinolone (FQ) resistance, high-dose isoniazid (H) resistance and Prothionamide (Pto) resistance (which also refers to low-dose H resistance). Results of the LPA will be reported for each drug/drug group as follows:
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13. Upon receipt of first- and second-line DST results of LPA and phenotypic DST test, revise the regimen accordingly 13.2 Take appropriate action based on LPA results
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13. Upon receipt of first- and second-line DST results of LPA and phenotypic DST test, revise the regimen accordingly 13.3 If LPA result is MTB not detected, invalid for MTB detection, or indeterminate resistance for any drug, and result is received before treatment or within two weeks from start of treatment, recollect sputum specimen for repeat LPA testing and continue initial regimen. If treatment is already more than two weeks, just continue initial regimen and wait for the phenotypic DST result
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13. Upon receipt of first- and second-line DST results of LPA and phenotypic DST test, revise the regimen accordingly 13.4 If LPA results (whether initial or repeat) are received within two months of treatment, adjust the regimen according to guidelines above 13.5 If LPA result is delayed for more than two months or not available, correlate results with patient’s clinical condition, sputum smear and culture results: If there is sputum culture conversion and clinical improvement, continue the initial regimen If there is no culture conversion at the fourth month of treatment, or no clinical improvement, or with recurrence of TB signs and symptoms, repeat DST (both LPA and phenotypic) and consult the case with TB MAC
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13. Upon receipt of first- and second-line DST results of LPA and phenotypic DST test, revise the regimen accordingly 13.6 Follow the same procedures above upon receipt of phenotypic DST results. Incase of discordant result between LPA and phenotypic DST, follow the worse result (i.e. that with more drug resistance) and consult the case with TB MAC for regimen revision, if needed. Moreover, if phenotypic DST or other molecular DST from a quality-assured reference laboratory showed resistance to pyrazinamide (Z) and/ or ethambutol (E), discuss the case with TB MAC
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D. MDR-TB and RR-TB treatment in HIV co-infected
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D. MDR-TB and RR-TB treatment in HIV co-infected 1. Antiretroviral treatment (ART) all MDR-TB patients living with HIV, regardless of CD4 cell count TB treatment should be initiated first, followed by ART as soon as possible within the first 8 weeks of treatment Profound immunosuppression (e.g. CD4 counts less than 50 cells/mm3), HIV-positive MDR-TB should receive ART within the first 2 weeks of initiating treatment, except for those who are suspected to have TB meningitis for whom ART initiation should be deferred due to the risk of developing potentially fatal immune reconstitution inflammatory syndrome (IRIS).
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D. MDR-TB and RR-TB treatment in HIV co-infected 2. For co-administration of bedaquiline and antiretroviral drugs (ARVs) EFAVIRENZ (EFV) –> NEVIRAPINE (NVP) if still susceptible EFV decreases Bdq blood concentration level by 52% 5 days for washout (i.e. substitute NVP then start MDR-TB treatment five days later) if patient is critically ill, no need to wait for a washout period just start MDR-TB treatment immediately
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D. MDR-TB and RR-TB treatment in HIV co-infected 2. For co-administration of bedaquiline and antiretroviral drugs (ARVs) Use Bdq with iopinavir/ritonavir (LPV/r) only when other options are not available LPV/r increases Bdq concentration threefold Better option: substitute with and integrase inhibitor such as raltegravir or dolutegravir together with dual nucleoside reverse-transcriptase use with extreme caution and closely monitor ECG every 2 weeks if really needed
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D. MDR-TB and RR-TB treatment in HIV co-infected 2. For co-administration of bedaquiline and antiretroviral drugs (ARVs) CAUTION ! When using with LINEZOLID- containing treatment regimen HIV-related neuropathy: STAVUDINE Bone marrow dysfunction (Anemia): ZIDOVUDINE DOLUTEGRAVIR widely used globally in first-line ART no significant interactions with Bdq, Dlm or Lzd
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Source: NTP MOP 6th Edition
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Source: NTP MOP 6th Edition
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Source: NTP MOP 6th Edition
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E. MDR-TB and RR-TB treatment in children
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E. MDR-TB and RR-TB treatment in children Design a regimen consisting of 4-5 drugs for the entire treatment duration (Table 22) Consult with TB MAC. Initiation of treatment should be in accordance with the regimen and dosage advised by TB MAC. Avoid injectable drugs as much as possible to avoid hearing loss, which will affect child’s language development and social skills. The following regimens should be considered, especially those who have disseminated TB and bacteriologically confirmed, FQ-resistant MDR-TB and RR-TB
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E. MDR-TB and RR-TB treatment in children Source: NTP MOP 6th Edition
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E. MDR-TB and RR-TB treatment in children 2. Determine the severity of the disease. Severity of TB in children is usually defined by presence of: • positive TB bacteriology (smear, Xpert MTB/RIF, culture); • cavities or bilateral disease on chest radiography or smear-positivity; • extrapulmonary forms of disease other than lymphadenopathy (peripheral nodes or isolated mediastinal mass without compression); and • presence of co-morbid condition or disease such as severe malnutrition or advanced immunosuppression
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E. MDR-TB and RR-TB treatment in children 3. Give treatment accordingly: • 9 to 12 months for non-severe disease depending on the clinical progress as assessed by physician • 15–18 months for severe or extensive disease
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E. MDR-TB and RR-TB treatment in children 4. Monitoring of treatment For children with no bacteriologic confirmation at baseline (e.g. children who cannot expectorate), monitor clinically: • resolution of TB signs and symptoms; • monthly weight gain and growth (weight and height chart for children < 5 years old); • baseline chest X-ray and follow-up chest X-ray at six months to check resolution of lesions in case of thoracic TB; • follow-up CT scan/MRI scan at six months for intrathoracic or EPTB diagnosed with this imaging tests; and • healing of other EPTB lesions (e.g. cold abscess).
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E. MDR-TB and RR-TB treatment in children 4. Monitoring of treatment For children who have bacteriologic confirmation: • monitor clinically as above; and • follow the bacteriological monitoring schedule for sputum and culture tests
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Source: NTP MOP 6th Edition
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Source: NTP MOP 6th Edition
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F. INITIATION OF TREATMENT
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INITIATION OF TREATMENT Accomplish Form 4c. DR-TB Treatment Card and Form 5. TB and TPT Patient Card and assign case number.
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INITIATION OF TREATMENT Record patient details in Form 6b. DR-TB Register (ITIS)
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INITIATION OF TREATMENT Discuss and finalize the appropriate treatment adherence mechanism with patient. Consider the most suitable location of drug intake and treatment supporter based on the patient’s condition. Options include: location: can be at home, community, workplace or health facility; and treatment supporter: can be family member, trained lay volunteer and health worker.
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INITIATION OF TREATMENT If daily intake is not in the health facility, the health worker can provide initially a one week supply to the treatment supporter and adjust later to a maximum of monthly dispensing depending on the situation. Ensure that health workers or trained volunteers regularly communicate with patient at least every two weeks as part of psychosocial support. Other modes of treatment supervision such as self-administered treatment assisted by technology (e.g. video DOT, call- or SMS-based DOT, AI-based therapy) may also be done.
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INITIATION OF TREATMENT Other modes of treatment supervision: 99 DOTS pairs customized medication packaging with basic phone call/SMS technology to provide accurate, real-time data on patient treatment adherence existing fixed-dose combination (FDC) antibiotic medication blister packs are repackaged in a custom cardstock sleeve with a series of unpredictable hidden toll-free phone numbers or SMS codes that are revealed each time a patient removes their pills for the day Patient sends an SMS of the code which registers as drug intake for the day
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INITIATION OF TREATMENT Smart pillboxes digital medication monitor that combines the functionality of a low-cost medication box with a small-scale, battery-powered sensor and mobile data connection Patients store and organize their TB medications in the box, and when they open the box for daily medication intake, the sensor is activated and sends dosing- event information in real-time to the adherence platform using the mobile data connection
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INITIATION OF TREATMENT Video-supported treatment (VOT) An Android application (app) that utilizes video recording and mobile communication to remotely monitor and support TB medication intake patients are guided to record videos of themselves ingesting their daily medication These videos are automatically synced via secure mobile connection with the adherence platform, where they are then reviewed by the patient’s health-care provider and marked as complete
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G. MONITORING TREATMENT
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MONITORING TREATMENT Record successful intake of daily dose in Form 4c. DR-TB Treatment Card and Form 5. TB and TPT Patient Card by affixing the initials of the health staff or treatment supporter Conduct treatment monitoring clinically, microbiologically and by laboratory investigation as per schedule. Check the following and manage accordingly: general well-being, weight and height in children, resolution of symptoms and mental health screening; identify any occurrence of adverse events and provide prompt and appropriate management; and remind patient to submit sputum specimen and have other laboratory examinations done according to schedule
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MONITORING TREATMENT Weigh the patient monthly and adjust dosage accordingly based on weight Give positive feedback on the patient’s treatment (e.g. weight gain and/or resolution of other symptoms as good signs of clinical response). Record the interaction in the individual treatment record or patient’s chart Manage any adverse events appropriately.
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MONITORING TREATMENT (ADVERSE EVENTS) PERIPHERAL NEUROPATHY Possible anti-TB drug causes: Lzd, Cs, H, Am, S, FQ, Pto/Eto, E. common side effect of MDR-TB treatment caused by drug toxicity to the nerves of the peripheral nervous system. Signs and symptoms of peripheral neuropathy are: numbness, tingling, burning, pain in the feet or hands. If a patent complaint of the above signs and symptoms, grading by using Brief Peripheral Neuropathy Screen (BPNS) system should be done.
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MONITORING TREATMENT (ADVERSE EVENTS) Ask the subject to rate the severity of each symptom on a scale from 01 (mild) to 10 (most severe) for right and left feet and legs. Enter the score for each symptom in the columns marked R (right lower limb) and L (left lower limb).
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MONITORING TREATMENT (ADVERSE EVENTS) Clinical management of peripheral neuropathy according to severity grading
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MONITORING TREATMENT (ADVERSE EVENTS) Many patients experience improvement when the offending drugs are suspended, especially if the symptoms are mild. If linezolid should be immediately stopped and not reintroduced when symptomatic neuropathy develops (grade 2 or above), consider additional anti-TB drugs to reinforce the regimen. In HIV coinfected patients, avoid use of d4T or ddI in combination with cycloserine or linezolid because of an increased risk of peripheral neuropathy. All patients taking linezolid should receive at least 50 mg of pyridoxine daily. This is largely to prevent myelosuppression, but may also prevent peripheral neuropathy
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MONITORING TREATMENT (ADVERSE EVENTS) Symptomatic relief: Non-steroidal anti-inflammatory drugs or acetaminophen may help alleviate symptoms. Tricyclic antidepressants have also been used successfully. Start amitriptyline 25 mg at bedtime. The dose may be increased to a maximum of 150 mg daily for refractory symptoms. Carbamazepine may also be effective in relieving pain and other symptoms of peripheral neuropathy. Carbamazepine is a strong inducer of CYP3A4 and should not be used with bedaquiline or delamanid.
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MONITORING TREATMENT (ADVERSE EVENTS) MYELOSUPPRESSION (anemia, thrombocytopenia, or neutropenia) Possible anti-TB drug causes: Lzd. Other drug: AZT Exclude other cause of anemia (e.g. TB itself, iron deficiency, occult blood loss, etc.). AZT induced anemia is more likely to be macrocytic anemia which can be determined by mean corpuscular volume (MCV). If the patient has thrombocytopenia or neutropenia, this is more likely to be due to linezolid.
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MONITORING TREATMENT (ADVERSE EVENTS) All patients taking linezolid should also be receiving at least 50 mg of pyridoxine daily. This is largely to prevent myelosuppression, but may also prevent peripheral neuropathy. Acute blood loss (e.g. occult GI bleeding from a peptic ulcer) can cause anemia. Other causes of anemia (TB, iron-deficiency, etc.) are possible, but less likely to occur in the middle of treatment, especially if the patient is clinically improving.
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MONITORING TREATMENT (ADVERSE EVENTS) Clinical management of myelosuppression according to severity grading
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MONITORING TREATMENT (ADVERSE EVENTS) Suggested management strategy: Stop the causative drug immediately. Monitor full blood counts regularly. Hospitalize the patient and consider transfusion or erythropoietin if the myelosuppression is severe Consider additional anti-TB drugs to reinforce the regimen
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MONITORING TREATMENT (ADVERSE EVENTS)
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MONITORING TREATMENT (ADVERSE EVENTS) PROLONGED QT INTERVAL Possible anti-TB drug causes: Cfz, Bdq, Mfx, Dlm, and Lfx (a mild QT prolonging drug) Possible other causes: Many other drugs can cause QT prolongation (e.g. erythromycin, clarithromycin, quinidine, ketoconazole, fluconazole, antipsychotics (all have some risk including haloperidol, chlorpromazine and risperidone), many anti-nausea drugs (ondansetron/granisetron, domperidone), methadone, and some antiretrovirals); genetic causes such as long QT syndrome; hypothyroidism. Check an ECG if the patient has clinical symptoms (tachycardia, syncope, palpitations, or weakness or dizziness) of cardiotoxicity. Check the QT interval and rule out an arrhythmia.
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MONITORING TREATMENT (ADVERSE EVENTS)
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MONITORING TREATMENT (ADVERSE EVENTS) Checking and replacing serum electrolytes Serum potassium (K + ), ionized calcium (ionized Ca ++ ), and magnesium (Mg ++ ) should be obtained in the event a prolonged QT interval is detected. Abnormal electrolytes are most commonly due to the injectable and should be corrected. Whenever a low potassium is detected it should trigger urgent management with replacement and frequent repeat potassium testing (often daily or multiple times a day) to document the potassium is moving in the correct direction. If potassium is found low, always check magnesium and ionized calcium and compensate as needed. (If unable to check, consider oral empiric replacement doses of magnesium and calcium).
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MONITORING TREATMENT (ADVERSE EVENTS) Suggested management strategy: Stop all QT prolonging drugs immediately. Hospitalize and consider continuous electrocardiac monitoring for Grade 3. Hospitalization should occur in a facility capable in the management of Torsades de Pointes arrhythmia. Check electrolytes and manage as described above. Check a TSH and treat if any hypothyroidism found.
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MONITORING TREATMENT (ADVERSE EVENTS) Once stable (QTCF interval below 450 or baseline value and normal electrolytes), critical QT prolonging anti-TB drugs can be added back: If the patient was on moxifloxacin consider using levofloxacin instead. If the patient was on clofazimine consider suspending it permanently if not critical to the regimen. If the patient is on bedaquiline and it is considered critical to the regimen, consider adding the drug back to the patient’s regimen while suspending all other QT prolonging drugs (with the exception of stopping ART, which should not normally be suspended in the management of QT prolongation). If the patient is on delamanid and it is considered critical to the regimen, consider adding the drug back to the patient’s regimen while suspending all other QT prolonging drugs (with the exception of stopping ART, which should not normally be suspended in the management of QT prolongation).
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MONITORING TREATMENT (ADVERSE EVENTS) OPTIC NERVE DISORDER (OPTIC NEURITIS) Possible anti-TB drug causes: Lzd, E, Eto/Pto, Cfz, rifabutin, H, S. Other drug: ddl Optic neuritis is inflammation of the optic nerve eventually resulting in permanent vision loss. The first sign of optic neuritis is usually the loss of red-green color distinction. This is best tested using the Ishihara test. Other symptoms include central scotomas. Linezolid is by far the most common cause of optic neuritis among all of the TB drugs. Mostly after four months of treatment. Patients with diabetes are at increased risk for optic neuritis. They should be managed with tight glucose control as a means of prevention. Patients with advanced kidney disease are also at increased risk for optic neuritis.
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MONITORING TREATMENT (ADVERSE EVENTS)
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MONITORING TREATMENT (ADVERSE EVENTS) Suggested management strategy: Do not restart the suspected causative drug (linezolid or ethambutol). Refer patient to an ophthalmologist for immediate evaluation and management. Optic neuritis generally improves following cessation of offending drug, if it can be stopped early enough. Consider additional anti-TB drugs to reinforce the regimen.
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MONITORING TREATMENT (ADVERSE EVENTS) HEPATITIS Possible anti-TB drug causes: Z, Lzd, Cfz, Bdq. Hepatitis is characterized by nausea, vomiting, jaundice, scleral icterus, tea-colored urine, pale stool and diminished appetite in the setting of elevated liver function tests. Mild elevation of liver enzymes, especially at baseline, may be related to TB rather than an adverse effect of treatment. Generally, hepatitis due to medications resolves upon discontinuation of suspected drug. In HIV co-infection, nevirapine and cotrimoxazole can be a cause of hepatotoxicity.
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MONITORING TREATMENT (ADVERSE EVENTS)
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MONITORING TREATMENT (ADVERSE EVENTS) Reintroduce anti-TB drugs once liver enzymes return to baseline. Anti-TB drugs should be reintroduced in serial fashion by adding a new medicine every three to four days. The least hepatotoxic drugs should be added first, while monitoring liver function tests after each new exposure. Consider suspending the most likely offending drug permanently if it is not essential to the regimen. This is often the case for pyrazinamide if it is less likely to be effective by clinical history. Consider additional anti-TB drugs to reinforce the regimen.
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MONITORING TREATMENT Report serious adverse events (SAE) or adverse events of special interest (AESI) using FDA Suspected Adverse Reaction Form* For patients who cannot tolerate any of the drugs in the regimen (e.g. hearing loss, intolerable pain to amikacin, persistent vomiting) consider modification of treatment. Discuss the case with TB MAC for possible shift of SSOR to other regimens if it is necessary to replace more than one drug* Revise the regimens based on first- and second-line LPA and phenotypic DST test results*
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MONITORING TREATMENT Adjust the SSOR regimen based on results of follow-up SM. If the is smear negative at the fourth month, shift to continuation phase (i.e. discontinue HdH and Pto). If smear positive, extend intensive phase for one month. If intensive phase extended to five months and SM is still positive, extend intensive phase for another month. If negative, shift to continuation phase (i.e. discontinue HdH and Pto). If the intensive phase is extended to six months and SM is still positive, refer to the TB MAC. If negative, shift to continuation phase (i.e. discontinue HdH and Pto). Discontinue Bdq at month six.
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MONITORING TREATMENT If there is no culture conversion (for all regimens) at month four of treatment or if there is culture reversion, collect one sputum sample from patients and request for repeat LPA, DST and culture/phenotypic second-line DST. If there is any drug resistance amplification detected from the repeat DST tests, declare the case as failure. When failure is declared or in any other situation when failure is suspected, consult with TB MAC for the possible causes, patient management strategy and registration of outcome.
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H. ACTIVE DRUG SAFETY MONITORING AND MANAGEMENT (aDSM)
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H. ACTIVE DRUG SAFETY MONITORING AND MANAGEMENT (aDSM) ACTIVE DRUG SAFETY MONITORING AND MANAGEMENT (ADSM) IS AN ESSENTIAL COMPONENT IN TREATING DR-TB. ONE OF THE KEY ACTIVITIES IN ADSM IS THE REPORTING OF ALL SERIOUS ADVERSE EVENTS (SAE) AND ADVERSE EVENTS OF SPECIAL INTERESTS (AESI).
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1. REPORT ALL SAES OR AESIS THROUGH THE PRESCRIBED REPORTING FORM OR SYSTEM.
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SAE REFERS TO ANY UNTOWARD MEDICAL OCCURRENCE THAT AT ANY DOSE: RESULTS IN DEATH; IS LIFE THREATENING; REQUIRES INPATIENT HOSPITALIZATION OR RESULTS IN PROLONGATION OF EXISTING HOSPITALIZATION; RESULTS IN PERSISTENT DISABILITY/INCAPACITY; IS A CONGENITAL ANOMALY/BIRTH DEFECT; OR DOES NOT IMMEDIATELY RESULT IN ONE OF THE ABOVE OUTCOMES, BUT WHICH REQUIRE AN INTERVENTION TO PREVENT A SERIOUS OUTCOME.
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ADVERSE EVENTS OF SPECIAL INTERESTS REFERS TO AN ADVERSE EVENT DOCUMENTED TO HAVE OCCURRED DURING CLINICAL TRIALS AND FOR WHICH THE MONITORING PROGRAM IS SPECIFICALLY SENSITIZED TO REPORT REGARDLESS OF ITS SERIOUSNESS, SEVERITY OR CAUSAL RELATIONSHIP TO THE TB TREATMENT. THESE ARE THE FOLLOWING: ACUTE KIDNEY INJURY (ACUTE RENAL FAILURE); HEPATITIS, DEFINED AS INCREASES IN ALANINE AMINOTRANSFERASE (ALT) OR ASPARTATE AMINOTRANSFERASE (AST) ≥ 5X THE UPPER LIMIT OF NORMAL (ULN), OR INCREASES IN ALT OR AST ≥ 3X ULN WITH CLINICAL MANIFESTATIONS, OR INCREASES IN ALT OR AST ≥ 3X ULN WITH CONCOMITANT INCREASE IN BILIRUBIN ≥1.5X ULN;
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HYPOKALEMIA; MYELOSUPPRESSION (MANIFESTED AS ANEMIA, THROMBOCYTOPENIA, NEUTROPENIA OR LEUCOPENIA); OPTIC NERVE DISORDER (OPTIC NEURITIS) OR RETINOPATHY; OTOTOXICITY (HEARING IMPAIRMENT, HEARING LOSS OF ANY DEGREE); PANCREATITIS; PERIPHERAL NEUROPATHY (PARESTHESIA); PROLONGED QT INTERVAL (FRIDERICIA CORRECTION) OF > 500 MS OR > 60 MS INCREASED FROM BASELINE; AND PSYCHIATRIC DISORDERS AND CENTRAL NERVOUS SYSTEM TOXICITY (E.G. DEPRESSION, PSYCHOSIS, SUICIDAL INTENTION, SEIZURES).
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REPORT ALL SAES OR AESIS THROUGH THE PRESCRIBED REPORTING FORM OR SYSTEM. 2. COMPLETE THE REPORT THROUGH THE PHARMACOVIGILANCE MONITORING SYSTEM (PVIMS). 3. IN CASE PVIMS IS NOT ACCESSIBLE, COMPLETE THE FDA SUSPECTED ADVERSE REACTION FORM (ADSM REPORTING FORM). THE PAPER REPORT SHALL BE SUBMITTED TO CENTER FOR HEALTH DEVELOPMENT (CHD) NTP COORDINATOR AND NATIONAL DRUG POLICY COMPLIANCE OFFICER (NDPCO). THIS SHALL BE LATER ENTERED INTO PVIMS BY NDPCO.
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4. THROUGH PVIMS OR PAPER FORMAT, SUBMIT THE REPORT WITHIN TWO WORKING DAYS FROM OCCURRENCE OF EVENT OR IMMEDIATELY UPON RECEIPT OF INFORMATION. 5. MANAGE ALL ADVERSE EVENTS ACCORDINGLY
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I. MODIFICATION OF TREATMENT REGIMEN
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I. MODIFICATION OF TREATMENT REGIMEN MODIFICATION OF A TREATMENT REGIMEN CAN BE DONE IF AN ANTI-TB DRUG NEEDS TO BE REPLACED DUE TO INTOLERANCE OR TOXICITY THAT MAY LEAD TO THE NEGATIVE CONSEQUENCES TO PATIENTS SUCH AS PERMANENT DISABILITY, LIFE-THREATENING COMPLICATIONS, DEATH OR LOSS-TO-FOLLOW-UP.
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FOR PATIENTS STARTED ON SSOR MODIFICATION OF THE SAME REGIMEN IS ALLOWED, AS FOLLOWS IF COMPLETE CESSATION OF BEDAQUILINE OR LEVOFLOXACIN IS REQUIRED, CONSULT THE CASE WITH TB MAC (TB MEDICAL ADVISORY COMMITTEE) IN CASE OF TOXICITY OR INTOLERANCE TO PROTHIONAMIDE , QUICKLY SHIFT PRIOTHIONAMIDE TO CYCLOSERINE (OR LINEZOLID IF THERE IS CONTRAINDICATION TO USE CYCLOSERINE) IF SPLITTING THE DOSE FOR THE FIRST TWO WEEKS DID NOT PREVENT VOMITING, OR TOLERANCE TO PTO DID NOT IMPROVE.
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FOR CLOFAZIMINE INTOLERANCE, REPLACE WITH CYCLOSERINE (OR LINEZOLID IF THERE IS CONTRAINDICATION TO USE CYCLOSERINE) AND GIVE FOR THE ENTIRE TREATMENT DURATION. IF PATIENT HAS UNDERLYING SEIZURE OR MENTAL HEALTH CONDITION (E.G. DEPRESSION, PSYCHOSIS), LINEZOLID IS PREFERRED OVER CYCLOSERINE. IF IT HAPPENS AFTER INTENSIVE PHASE, BEDAQUILINE MAY BE CONTINUED FOR ENTIRE DURATION WITHOUT REPLACEMENT OF CLOFAZIMINE WITH CYCLOSERINE OR LINEZULID
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FOR ETHAMBUTOL, PYRAZINAMIDE AND ISONIAZID, DISCONTINUE THE SUSPECTED CULPRIT DRUG RELATED TO AN ADVERSE DRUG EVENT WITHOUT REPLACEMENT. TREATMENT DURATION IS NINE TO 11 MONTHS BASED ON SMEAR CONVERSION. IF MODIFICATION REQUIRES REPLACEMENT OR PREMATURE DISCONTINUATION OF TWO OR MORE DRUGS, OR COMPLETE DISCONTINUATION OF SSOR, SHIFT TO ITR IN CONSULTATION WITH TB MAC.
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FOR PATIENTS ON SLOR, MODIFICATION OF REGIMEN IS ALLOWED IN CASE AN ANTI-TB DRUG NEEDS TO BE REPLACED DUE TO SEVERE INTOLERANCE OR TOXICITY. THE FOLLOWING MAY BE CONSIDERED: DELAMANID IS THE FIRST CHOICE TO REPLACE BEDAQUILINE, LEVOFLOXACIN OR LINEZOLID. CYCLOSERINE (IF NEVER USED BEFORE) MAY BE USED TO REPLACE CLOFAZIMINE. P AMINO SACICYLIC ACID, PROTHIONAMIDE AND ETHAMBUTHOL (IF NEVER USED BEFORE) ARE THE LAST OPTION TO CHOOSE FOR REPLACEMENT.
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IF PATIENT NEEDS TO STOP LINEZOLID AFTER SIX MONTHS OF TREATMENT – WHEN BEDAQUILINE HAS BEEN STOPPED – REPLACE LINEZOLID WITH CYCLOSERINE AS LONG AS THE REASON FOR STOPPING LINEZOLID IS NOT DUE TO PERIPHERAL NEUROPATHY
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OTHER ALTERNATIVE IF CYCLOSERINE CANNOT BE USED ARE: ETHIONAMIDE/PROTHIONAMIDE OR P-AMINOSALICYLIC ACID; ETHAMBUTOL OR PYRAZINAMIDE MAY BE CONSIDERED TO REPLACE CLOFAZIMINE OR CYCLOSERINE IF THERE IS DRUG-SUSCEPTIBILITY TESTING CONFIRMING SUSCEPTIBILITY TO ETHAMBUTOL AND PYRAZINAMIDE IF THE ORAL ANTI-TB DRUGS CANNOT BE USED DUE TO PREVIOUS USE IN A FAILING REGIMEN, CONFIRMED RESISTANCE OR INTOLERANCE, CONSIDER IMIPENEM-CILASTATIN OR AMIKACIN (OR STREPTOMYCIN) IF SUSCEPTIBLE TO AMIKACIN/STREPTOMYCIN.
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J. ASSIGNING TREATMENT OUTCOME
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J. ASSIGNING TREATMENT OUTCOME AFTER COMPLETION OF TREATMENT OR IF PATIENT IS DISCHARGED FROM THE PROGRAM, ASSIGN THE APPROPRIATE TREATMENT OUTCOMES FOR DR-TB PATIENTS FOR SSOR AND FOR SLOR.
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LOST TO FOLLOW UP : IF A PATIENT HAS RECEIVED THE SSOR FOR MORE THAN A MONTH, AND RETURNS FOR TREATMENT AFTER AN INTERRUPTION OF TWO CONSECUTIVE MONTHS OR MORE, HE IS NOT RESTARTED ON THE SSOR BUT ON A LONGER MDR-TB REGIMEN WHICH IS INDIVIDUALIZED BASED ON THE MEDICINES MOST LIKELY TO BE EFFECTIVE. IF THE INTERRUPTION IS LESS THAN TWO MONTHS, E.G. MEDICAL INDICATION IN CASE OF ADVERSE EVENTS), OR PATIENT’S DECISION, THEN THE SSOR CAN BE CONTINUED AND THE MISSED DOSES ADDED TO THE REST OF THE TREATMENT.
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Culture Conversion and Reversion CULTURE CONVERSION (TO NEGATIVE) - TWO CONSECUTIVE CULTURES TAKEN AT LEAST 30 DAYS APART, ARE FOUND TO BE NEGATIVE, THE SPECIMEN COLLECTION DATE OF THE FIRST CULTURE IS TAKEN AS CULTURE CONVERSION DATE. CULTURE REVERSION (TO POSITIVE) - AFTER AN INITIAL CONVERSION; TWO CONSECUTIVE CULTURES TAKEN AT LEAST 30 DAYS APART, ARE FOUND TO BE POSITIVE, FOR THE PURPOSE OF DEFINING “TREATMENT FAILED,” CULTURE REVERSION IS CONSIDERED ONLY WHEN IT OCCURS AFTER EIGHT MONTHS OF TREATMENT.
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2. RECORD THE TREATMENT OUTCOME IN THE FORM 4C. DR-TB TREATMENT CARD AND UPDATE FORM 6C. TB REGISTER FOR DR-TB TREATMENT (ITS).
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3. ISSUE THE CERTIFICATE OF COMPLETION OF TREATMENT FOUND IN FORM 5B. DRTB PATIENT CARD AND ADVISE PATIENT ON POST-TREATMENT FOLLOW-UP.
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K. POST TREATMENT FOLLOW-UP
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K. POST TREATMENT FOLLOW-UP DO POST-TREATMENT FOLLOW-UP AT MONTH SIX AND 12 AFTER SUCCESSFUL COMPLETION OF TREATMENT (CURE OR COMPLETED) FOLLOW-UP PROCEDURES INCLUDE: CLINICAL EVALUATION OF TB SIGNS AND SYMPTOMS CHEST X-RAY SM AND CULTURE.
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2. DEFINE THE OUTCOMES OF POST-TREATMENT FOLLOW-UP: NON-RELAPSING CURE: A SUCCESSFULLY TREATED INDIVIDUAL WHO REMAINS CULTURE-NEGATIVE WITHIN SIX TO 12 MONTHS POST-TREATMENT. RELAPSE: RECURRENT TB DISEASE IN A SUCCESSFULLY TREATED INDIVIDUAL WHO BECOMES CULTURE-POSITIVE WITHIN SIX TO 12 MONTHS AFTER CURE OR TREATMENT COMPLETION. DIED: A PATIENT WHO DIES FOR ANY REASON DURING THE 12 MONTHS FOLLOWING TREATMENT. LOST TO FOLLOW-UP AFTER TREATMENT COMPLETION: INDIVIDUALS WHO HAD AN OUTCOME RECORDED BUT CANNOT BE TRACED IN THE 12 MONTHS FOLLOWING TREATMENT OUTCOME
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3. RECORD THE OUTCOME OF POST-TREATMENT FOLLOW-UP IN FORM 4C. DR-TB TREATMENT CARD
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