Chapter 4. Treatment of Tuberculosis

4A. Rifampicin Sensitive Tuberculosis

4A.1. Basis of Pharmacotherapy

The choice of anti-TB drugs is based on several determinants such as bacillary and metabolic subpopulation, bacillary load, drug-resistant strains, pharmacokinetic profile, pathological factors, etc. There are different types of bacillary metabolic populations in every case of tuberculosis. Hence, drugs are selected in a combination to attack the entire (extracellular and intracellular, slow and rapidly growing) bacillary population for successful chemotherapy. Isoniazid (INH) and rifampicin (RMP) kill the fast-growing bacilli, pyrazinamide (Z) acts against intracellular organisms in an acidic medium, while RMP best kills extracellular slow-growing bacilli. Thus, every case of tuberculosis must be treated at least with these four drugs. Ethambutol (E) is recommended as the fourth drug in the intensive phase and as a third drug in the continuation phase due to high INH resistance (around 13% in new cases) in our country.

TB treatment is biphasic. The chances of naturally occurring mutants are higher if the bacillary load is more, and therefore, such cases need more drugs like in the initial stage of the disease. The Intensive Phase (IP) results in early and rapid killing of M. tb, prevent deterioration and death, reduces infectivity. Sputum conversion is achieved in 80-90%. In addition to PZA to RMP, INH minimises the duration of therapy to 6 months due to its sterilising effect. The addition of E is valuable if initial drug resistance to INH is high. The Continuation Phase (CP) eliminates most residual bacilli and thus reduces failures and relapses. As fewer bacilli are left after eight weeks of therapy, the continuation phase needs fewer drugs (usually RMP and INH). However, if there is a high prevalence of background resistance to INH, another medication may be necessary to prevent amplification of drug resistance during CP. In our country, the continuation phase has thus ethambutol added as the third drug for all new cases.

Standardised therapy with presumed drug sensitivity had been the way TB was treated until recent times, as testing for drug resistance was challenging and not pragmatic due to the long lead time. We currently understand that treating rifampicin-resistant strain with a standardised first-line regimen can lead to therapy failure and increase the risk of amplifying resistance to other drugs. Therefore, now first-line standardised regimen is only used after ruling out resistance to rifampicin upfront in all cases (U-DST). Molecular testing for rifampicin using a rapid test (e,g, Xpert Rif, Truenat, LPA) is now possible and available throughout the country. Molecular tests and liquid culture (MGIT™) are used to detect resistance to other drugs. The standard retreatment regimen (erstwhile category II) has been withdrawn due to the risk of poor outcomes and amplification of drug resistance. Furthermore, no routine extension of IP is done at the end of 2 months for a patient with slower or non-response; instead, investigations for DR-TB are carried out again.

As the dividing time of TB bacilli is about 21 hours, all the drugs are administered to achieve peak concentration at once to inundate the bacilli. Intermittent therapy has been replaced by daily treatment with continued treatment support.

Fixed Drug Combination tablets have replaced erstwhile combipacks and patient-wise boxes.  Furthermore, studies have also shown that most non-rifampicin resistance has poor outcomes due to INH mono/poly resistance. A new regimen for INH mono-poly resistance is advised (detailed in DR-TB section). Tests for INH resistance are carried out using first-line drug line probe assay (FL LPA) either directly on a clinical sample if it is smear-positive or on the isolate obtained through liquid culture. All Rifampicin-Sensitive TB (RS-TB) cases are given the standard therapy even if they have been treated in the past. Adjunctive surgical therapy may be needed in certain situations like spinal compression. As the anti-TB drug concentration achieved in a caseum and sequestrated tissue is poor, surgical removal should be done wherever feasible.

To summarise, now the patients are no more classified as New and Previously treated (see Box 2. for definitions) to allocate them standard four-drug (erstwhile category I) and five drug regimens (former category II). The primary aim is to segregate the patients upfront as rifampicin resistance detected (RR-TB) or rifampicin resistance not detected (RS-TB). All RS-TB cases are given the standard therapy even if they have been treated in the past. All patients undergo testing for other drugs, particularly for INH (mono or poly) and are treated with a different regimen if INH resistance is identified (discussed under DR-TB section).

 

Case Definitions 

 

Box 2. Case Definitions

 

4A. 2. Treatment Regimen

 

 

 

 

 

Table 3.  Treatment Regimen for Rifampicin-Sensitive TB

a. Molecular testing shall be done in all new cases in children with suspected TB at diagnosis and RSTB (Rifampicin resistance not detected) cases included in this regimen.

b. In the case of Neuro and spinal TB, the continuation phase is extended to 10 months.

c. All these categories of children shall be evaluated as DR-TB suspects and assessed as per the DR-TB Algorithm. DST based treatment shall be followed. If they are found to be Rifampin (and INH) sensitive, they shall be re-started on the regimen as for a new case. This group was earlier treated with CAT II regimen, which is now withdrawn from NTEP.

 

The drug dosages have been rationalised based on recent data on pharmacokinetics of ATT drugs and are as shown in the table below (Table 4):

 

 

 

 

 

Table 4.  Drug Dosages for Rifampicin-Sensitive TB Treatment

 

NTEP has introduced Fixed Drug Combinations (FDCs) incorporating multi-drug therapy for TB. FDCs are preferred due to safety, simplified treatment, and avoiding errors in missing one or more of the combination drugs, thus reducing the risk of emergence of drug-resistant strains. From a programmatic viewpoint, it has simplified drug supply management, shipping and distribution. FDC tablets of good quality and proven bioavailability of rifampicin are being used in combination in treating TB. 

 

There are two types of Paediatric FDCs available under NTEP-Formulation: Dispersible and Flavoured.

• For Intensive Phase (IP): 3 Drugs FDC Dispersible Tablets (DT) (H 50, R 75, Z150) (10:15:30) 
• For Continuation Phase (CP): 2 Drug FDC DT (H 50, R 75) (10:15) 

 

As Ethambutol is not available in the DT form, a non-DT 100 mg Ethambutol tablet is given for each Paediatric FDC during IP and CP.

 

There are two types of Adult FDCs available under NTEP, which are used in older children:

• For Intensive Phase: 4 FDC (H 75, R 150, Z 400, E 275)
• For Continuation Phase: 3FDC (H 75, R 150, E 275)

 

The therapy recommended as per body weight is detailed below (Table 5):

 

 

 

 

Table 5. Recommended Drug dosages and FDC Pill combination from 0-18 years of age

 

4A.3. Adjunct Therapy along with anti-Tuberculosis Drugs

I. Steroids in Tuberculosis

Definite indications for concomitant steroid therapy in TB include TB Meningitis, pericarditis, Addison’s disease, miliary TB with alveolo-capillary block and TB uveitis. The evidence in other forms of intracranial TB like tuberculomas is unclear. In addition, steroids may be used in endobronchial tuberculosis, bronchial compression, mediastinal compression syndrome, pleurisy with severe distress, laryngeal TB, TB Immune Reconstitution Inflammatory Syndrome (IRIS) and miliary disease with alveolo-capillary block.

Steroids decrease inflammation-related injury. They are shown to reduce the mortality in pericardial disease and improve outcomes in intracranial TB by reducing the development of hydrocephalus and vasculitis. Moreover, the interaction between the microbial factors and host immunological factors in the lung, lymph nodes, intracranial tuberculosis lesions may cause paradoxical worsening of symptoms due to the release of pro-inflammatory markers like IL 2 and Interferon-gamma. Most such cases recover with the continuation of therapy. However, few circumstances can have severe life-threatening manifestations and sequelae. In such cases, steroids may bring relief by suppressing inflammation. 

Steroids like prednisolone 1-2 mg/kg/day or dexamethasone 0.6 mg/kg/day or its equivalent are used for 2-4 weeks and then are tapered over the next four weeks. Any steroid in equipotent doses can be used. 

 

II. Adjunctive Pyridoxine Therapy 

Usually, no adjunctive therapy in the form of multivitamin or multi-mineral is advised as there is no evidence of these improving outcomes of TB patients. However, Isoniazid interferes competitively with pyridoxine (Pdx) metabolism by inhibiting the formation of the active form of the vitamin and can result in peripheral neuropathy.  Furthermore, earlier, the adjunctive vitamin B6 (Pyridoxine) was not recommended routinely for all children on TB treatment. Previously it was recommended only for high-risk groups like HIV, alcohol abuse, malnutrition, Diabetes Mellitus (DM), Renal failure, Liver failure, and Multi-Drug Resistant TB (M-DR TB) treatment and. Nonetheless, it is worth mentioning that earlier, every child in the continuation phase of the Intermittent Directly Observed Treatment (DOT) regimen was getting Pyridoxine on drug holidays. 

 

However, now there has been a rethink on the need for Vitamin B6 (Pyridoxine) supplementation due to: 

(a) increased dose of INH (10-15 mg/kg/d) has potential for an increase in dose-related adverse effects, 

(b) The high prevalence of malnutrition in children with TB makes them prone to peripheral neuropathy. Moreover, peripheral neuropathy in young children can go unrecognised and untreated with severe and prolonged morbidity.

Lastly, low cost, safety and lack of interference with INH action by the small prophylactic dose favour its use for likely benefit. Therefore, Pyridoxine (Vitamin B6) supplementation (10mg per day) is recommended to all patients receiving therapy with INH containing regimens.

 

 

 

4B. Monitoring and Follow-Up of Rifampicin-Sensitive Paediatric TB Cases

 

Children should be closely monitored for treatment progress and disease response. There are two components of follow up: 

1. Clinical follow up 
2. Laboratory follow up

 

Clinical follow up should be done every month during treatment. After completion of treatment, it may be done every six months for two years. Furthermore, an additional initial visit within two weeks of starting the therapy is desirable, where possible, to reassess that patient is on the correct dose and combination and is tolerating all drugs, 

 

I. Clinical Follow Up:

On each follow-up child should be assessed for the following:

a. Improvement in clinical symptoms, including cough, fever, appetite or other clinical signs. These will be assessed as no improvement, partial improvement or improved after asking parents or attendants. Most patients will show amelioration of symptoms by the end of four weeks of therapy.

b. Physical examination: This will include individualised relevant examination including respiratory rate, heart rate, temperature (if fever), blood pressure if indicated, chest examination for breath sound, crackles, evidence of pleural effusion, chest indrawing, recording of lymph node size, anaemia, abdomen for organomegaly or distension. Furthermore, examination of the relevant system, e.g. cardiovascular system in pericardial TB, the central nervous system in TBM or intracranial TB, etc., should be done. The physician will record their assessment as either no improvement, partial improvement or improvement.

Lastly, the treating physician should also record the child's weight (as precise to 0.1 Kg) by using an appropriate weighing scale (Bassinette type electronic weighing scale for infants and lever type scale for children who can stand) and check for weight gain in comparison to weight on the last visit. Causes of poor weight gain may be insufficient intake, vomiting, a side effect of medications, wrong diagnosis, comorbid conditions, concurrent infections such as diarrhoea, pneumonia or poor response to treatment. These causes will be assessed by asking history and performing the examination. If the assessment suggests no clinical deterioration, the family will be counselled for increasing food intake. Suppose a child is losing weight or is assessed to be unresponsive to treatment. In that case, they should be re-evaluated for TB, drug-resistant TB or alternative diagnosis by seeking expert advice. In a co-infected case, this may also signify Anti-Retroviral Treatment (ART) failure. With appropriate therapy, catch-up growth and the expected growth of a child as per age could remain unimpeded. This may necessitate an upward revision of drug dosage whenever a patient crosses his pre-treatment weight band.

c. Side effects of medications: Common side effects of ATT are given in table V. Most of these are minor and consist of vomiting, rashes, pain abdomen etc. Significant side effects of ATT include hepatotoxicity manifesting as nausea, vomiting, pain abdomen, poor appetite or clinically evident jaundice. The treating physician will also assess for rashes, visual acuity, colour vision for older children. The adverse effects of anti-TB drugs as well their management are outlined in subsequent chapters.

d. Treatment of Comorbid conditions like HIV, Severe Acute Malnutrition (SAM), DM etc., should be monitored during each visit. Decongestive measures and anti-convulsants are often prescribed in neurological TB and should be observed at follow-up. Refer for paediatric consultation in the case of pneumothorax or lungs collapse (manifested as respiratory difficulty on assessment). Similarly, in instances of a subacute intestinal obstruction, refer for gastroenterology and surgical opinion. 

e. Adherence to therapy should be revisited and ensured at each follow-up visit or unscheduled visit. Use Pill count, social support, family-based DOT and Treatment supervisor as needed.

 

 

 

 

Box 3. Interrupted TB Treatment

 

II. Monitoring by Laboratory Investigations will include sputum or gastric aspirate examination, imaging X-ray film of chest, Ultrasound abdomen, Echocardiography, CT scan of organ involved (Head, Chest, Abdomen) or MRI (spine). Lab investigation for side effects of medications comprises monitoring drug levels for antiepileptic drugs, Liver function test (LFT) if hepatotoxicity is considered or developed.

a. Microbiological:  The respiratory secretions, if available, are tested at the end of IP and completion of treatment (Bacterial negativity- sputum, GA etc. with smear and culture; repeat NAAT for any acquisition of Rif Resistance, if follow up smear is positive) 

Mycobacteria Growth Indicator Tube (MGIT) culture: should be performed if the child is not responding even after four weeks of therapy. However, as most of the children in their young years are unable to produce sputum or may have complete resolution of their cough and sputum. In such situations, response to treatment may need to be assessed clinically with help of radiological testing. Other relevant investigations may also be taken.

b. Liver function test: No routine or baseline LFT testing is required for patients on first-line drugs without evidence of any hepatopathy. These tests are done if any child shows symptoms or signs suggesting hepatic dysfunction.

c. Follow up Chest radiographs should be performed only at the end of therapy or earlier if assessed to be: clinically non-improvement, emerging complications or deterioration.

d. Other imaging, including Ultrasound of abdomen, echocardiography, CT/MRI scan of the affected organ system, is advised at the completion of treatment or when the patient is unresponsive to treatment or shows deterioration while on treatment. 

 

III. Clinical or Radiological non-response or Deterioration during follow up:

The causes for a clinical non-response could be: 

1. Incorrect diagnosis (particularly if a clinically diagnosed case of TB)
2. Lack of adherence to therapy 
3. Incorrect drugs or dosages
4. Inability to retain drugs- children often may vomit out medications due to the bad taste or upon forceful consumption of the medicine.
5. Secondary infection or a comorbidity
6. Drug resistance
7. Paradoxical upgrading reactions

Further pertinent investigations are decided based on clinical clues for any of the above conditions. Detailed analyses for drug resistance should be sent for MGIT DST or LPA, or CBNAAT.   Moreover, drug resistance should not be labelled without microbiological confirmation in most circumstances. Diagnosis of drug-resistant TB through bacteriological diagnosis is often untenable, with few notable exceptions where lack of access to appropriate specimen may not allow microbiological confirmation of drug resistance. History of contact with a proven case of M-DR or history of prolonged or irregular therapy in a source case within household or peer groups of the child is a good clue for suspecting DR-TB. Often such history is not available upfront but is provided later on follow-up by the family as they become more aware of the disease and may check around for such a case to whom the child may have been exposed.

Lastly, radiological deterioration alone without clinical symptoms should be reviewed with a skilled radiologist. The difference in respiration phase, rotation, and radiological factors can seriously affect the assessment of improvement (or lack of it) on follow-up images.

 

IV. Paradoxical Upgrading Reactions (PURs)

It refers to enlargement of existing lesions or unexpected appearance of new lesions during apparently adequate ATT. It usually occurs 3–12 weeks after the beginning of therapy, most frequently after treatment for 6- 7 weeks, & lasts for approximately two months. PURs are generally self-limiting and resolve without serious sequelae. It usually regresses without a change of initial drug regimen. It may occur post-treatment (as late as two years) in cases of lymph node TB as the retained caseum may track up and result in sinus formation.

Active TB can result in depression of immunity. Nevertheless, after successful ATT, the focal immune response improves. Accumulation of inflammatory exudates at previously invisible microscopic tuberculous foci elsewhere may appear as new lesions. Reversible roentgenographic progression in the initial treatment of TB may be more common than previously expected if there is frequent monitoring by chest radiograph. It is for this very reason, routine monitoring by radiographs is not recommended.

 

Types of reported Paradoxical Upgrading Reactions (PRUs)

• Increase in size of mediastinal lymph nodes or areas of pulmonary infiltration in paediatric patients with primary TB
• Appearance of new lung infiltrates in patients with extrapulmonary TB
• Development of TB pleural effusion
• Increase in size of effusion/appearance of effusion on the contra lateral side
• Appearance of new lymph nodes/ enlargement of original nodes
• Increase in size or number of tuberculoma/ infarctions / hydrocephalus on treatment of intracranial TB

 

 

 

 

Box 4. Types of reported Paradoxical Upgrading Reactions (PRUs)

 

The absence of any systemic symptoms is a helpful indicator of PUR. Moreover, a lack of systemic symptoms is usually seen in paradoxical reactions (non-HIV settings). It might be difficult to distinguish a paradoxical response from an actual drug resistance TB- and thus, PUR is never diagnosed without excluding DR-TB. 

 

V. Long-term follow up: After completion of treatment, the patients should be followed up every six months for two years to assess for early detection of any relapse of illness. Monitoring on each visit will include the same as described above.