Disclaimer: most part of this article is taken from the Central Tuberculosis Division, govt of India. some aspects are added from the practice followed at the field level in Himachal (state and district tb units). A few important points from some studies are also included.

Key facts:

• Treatment of tuberculosis is NOT the same for all patients.
• Treatment is provided FREE of cost to all patients in India.
• Mere crossing the weight band is NOT sufficient to change the number of pills during the treatment of Drug-Sensitive Tuberculosis.
• Two follow-up samples, one at the End of an Intensive Phase and the other before the last dose (4 doses Before the Last Dose) of the continuation phase are taken during the treatment of microbiologically confirmed DS-TB patients.
• For the follow-up, only One sputum sample (preferably morning) is sent for examination.
• Although treatment is provided as Directly observed treatment (DOT), unsupervised drug intake may be allowed in certain circumstances.
• Tablet vitamin B6 (pyridoxine) is not necessarily given to all adults but to those at risk of developing neuropathy whereas in the case of children, it is given to all.
• During the screening of close contacts with Pulmonary Tb patients, Active TB is always ruled out first before initiation of TPT (TB Preventive Treatment) or chemoprophylaxis.
• Streptomycin is administered only in certain situations, like TB meningitis or if any first-line drug needs to be replaced due to ADR as per the weight of the patient
• If any ADR (adverse drug reaction) develops the 5-step rule of Humb is followed.
• Orange discolouration of urine during ATT intake is NOT an adverse drug reaction.
• DAIDS grading of Adverse events may be quite helpful in the assessment of adverse events and the timely intervention.

You may be surprised to know that the treatment of tuberculosis is NOT the same for all. It depends upon the status of the sensitivity of antibiotics against the mycobacterium of the patient. The Mycobacterium of some patients may be sensitive to some antibiotics and resistant to others and so the treatment regimen varies.

When first-line drugs of TB (Isoniazid, Rifampicin, Pyrazinamide, Ethambutol) are effective (sensitive) to the Mycobacterium, then it is called Drug-Sensitive Tuberculosis (DS-TB).

Treatment of Drug Sensitive Tuberculosis (DS-TB)

Treatment starts once the diagnosis of tuberculosis is established.

Drugs Used in the Treatment of Drug-sensitive Tuberculosis

• In India Drugs are offered as a fixed drug combination:
  • 4 FDC (Four drugs- H R Z E are combined in a single pill) 
  • 3 FDC (Three drugs- H R E are combined in a single pill)

• Treatment is given in two phases:- Intensive Phase and the Continuation Phase
  • 4 FDC is given in the Intensive Phase for 8 weeks (56 doses) and 3 FDC is given in Continuation Phase for 16 weeks (112 doses) as given below:

*streptomycin has been withdrawn from the first-line drug list owing to the high prevalence of streptomycin resistance in Mycobacterium¹. Also, streptomycin is an injectable drug and may be subject to compliance issues.

*Streptomycin is administered only in certain situations, like TB meningitis or if any first-line drug need to be replaced due to ADR as per the weight of the patient⁴.

*H= isonizide, R= Rifampicin, Z=pyrazinamide, E- Ethambutol

*tablet Pyridoxine (vitamin B6) is not necessarily to be given to all but to those at risk of developing Isoniazid related Neuropathy:

1. alcoholics
2. malnourished person
3. pregnant and lactating women
4. HIV infection
5. Persons with conditions like- chronic renal failure, and diabetes.

• Treatment duration may be increased in some cases depending upon clinical decision.

Number of Pills Given per Day

The Number of Pills per Day depends upon the weight band of the patient as given below:

*Mg= milligram, Kg= kilogram

If a patient gains or loses more than 5 kg of weight AND crosses the weight band, the number of pills is changed to the new weight band.

• Pills are given to patients by the Treatment supporter under his/her supervision daily at a place decided by both the patient and treatment supporter ( following the principle of DOT- Directly Observed Treatment, used in India)
  • Unsupervised drug intake can be allowed in exceptional circumstances like:
    • During the transfer of patients to nearby health institutions on discharge from the hospital. Drugs for one week are given to the patient.
    • Person unsuitable for DOT due to his/her job profile like Truck driver, sailor etc (keep moving and don’t stay in one place)

Screening of Eligible Contacts and Chemoprophylaxis

This part is very important for the Prevention of Tuberculosis in other family members, especially children below the age of 6 years.

• Once the patient is diagnosed with Pulmonary Tuberculosis:
  1. The patient is Initiated on treatment.
  2. All Adults of family or close contacts:
     • if symptomatic are screened for the active TB
     • if non-symptomatic are screened for Latent infection (by IGRA or TST)
  3. All Children in close contact:
     • Under the age of 5 years, are screened for active TB. If active TB is not found in them, they are given Isoniazid prophylaxis in a dose of 10mg/kg/day for at least 6 months.
     • Isoniazid Chemoprophylaxis is also given to a child born to a mother having TB in her pregnancy, after ruling out congenital TB

Follow-up and Support

• Every TB patient is to be clinically evaluated by a Medical Officer at least once a month.
• Treatment for TB patients is provided free of cost including the diagnostic tests. Even the travel charges of the patient and accompanying attendant are also addressed.
• In addition to that, every TB patient is provided Rs 500 per month for nutritional support by direct beneficiary transfer. Treatment supporter is also given an incentive of Rs 1000 on completion of treatment of the concerned patient.
• For microbiologically confirmed DS-TB patient follow-up sputum samples are taken as given below:
  • At the end of the Intensive phase
  • 4 doses Before the last dose of the continuation phase (to decide if to extend the treatment or assign the outcome of the patient)
  • At 6, 12, 18, and 24th months after the outcome (successful treatment) of the patient.
  • Only a Morning sample of sputum is taken for follow-up (contrary to two samples required for diagnosis)

Special Consideration in Some Cases⁴

Adverse Drug Reactions (ADRs) of Anti-TB Drugs

First-line anti-TB drugs (given to DSTB patients) are usually well tolerated by most patients. 

At Risk of Developing ADR

Some patients remain at higher risk of developing ADRs compared to others:

1. Those consuming alcohol or other addictive substances during the treatment
2. Not taking treatment regularly as advised
3. Elderly
4. Anemic or malnourished
5. The person living with HIV infection
6. The person with co-morbidities such as -diabetes, high blood pressure, thyroid disorders, liver or renal diseases, etc.
7. Those taking medicine simultaneously from alternate systems of medicines like- homoeopathy, ayurveda, unani, etc.

ADRs of First-Line Anti-TB Drugs

• Of those developing ADRs, Gastrointestinal side effects are the most common.

• ADRs of first-line anti-TB drugs are given as below:

• Rifampicin causes orange discolouration of body fluids especially urine is not considered ADR of anti-tubercular drugs.
• Ethambutol is considered as least toxic drug among first-line drugs. Retrobulbar neuritis is an uncommon side effect, sometimes seen with higher doses and in renal patients. There is no specific treatment but on reversal of diseases (improvement ) over months is seen on stopping the drugs².
• Pyrazinamide contributes to higher liver toxicity among all first-line anti-TB. A baseline liver function test should be done at the initiation of treatment to compare the reports on suspicion of hepatitis.

Baseline Investigation to be Done at the Initiation of Treatment 

The baseline investigations are the investigations done at the initiation of the treatment. They are advised to be done, so as to compare the test reports following any ADRs or to ensure the well-being of the patient on anti-TB drugs.

These comprehensive investigations may be required in the case of DR-TB patients. 

While in the case of DS-TB patients on first-line anti-TB drugs, few investigations may be sufficient (practically done in the field).

• CBC
• Blood sugar
• HIV testing
• Liver function tests
• Renal function tests
• Chest X-ray

Drugs Recommended for Managing ADRs Due to Anti-TB Drugs

As we discussed earlier first-line drugs are usually well tolerated. Only limited ADRs like- GI symptoms, heartburn, nausea, vomiting, mild rash or itching, etc are found with First-line drugs prescribed to DS-TB patients. 

Other serious ADRs discussed in the table above are usually seen with drugs prescribed to DR-TB patients (second-line drugs and others).

Assessment of Hepatitis and its management shall be discussed in the treatment part of DR-TB patients.

DAIDS Grading for Adverse Events

DAIDS is the Division of AIDS established under the National Institute of Allergy and Infectious Diseases, USA has published the severity grading of adverse events in patients using pharmacological products. it ranges from 1 to 5 and includes both clinical and laboratory parameters.

it helps treatment providers in timely identifying, managing and referring patients to higher centres.

DAIDS grading of Adverse events for laboratory tests can be used to assess the severity of adverse events and timely intervention. lab values are given in the pdf below:

Association of Adverse Drug Reaction with Suspected Drug

For any ADR developing from anti-TB drugs, we follow the 5-step Rule of Thumb as given below:

Whether the ADRs are due to anti-TB drugs or due to some other reasons. We follow some steps to reach the conclusion, as given below:

1. Time relationship- The time between drug administration and adverse event
2. Pharmacological characteristics- Previous knowledge of side effects. Whether the suspected medicine is capable of producing such side effects.
3. Medical plausibility- supported by sign symptoms, lab tests, pathological findings
4. De-challenge- withholding the suspected drug and recording the outcome
5. RE-challenge- Re-administration of drug and recording the outcome

Taking the above-mentioned things into consideration the association is established as:

1. Certain– (clear association with drug) (all 5 parameters met)
   1. Time relationship is there
   2. Definite pharmacological characteristics 
   3. Medical plausibility present
   4. Positive de-challenge (patient improved on withdrawal of suspected drug)
   5. Positive Re-challenge
2. Probable– (likely related to the drug) (only first 4 parameters met)
   1. Time relationship is there
   2. Definite pharmacological characteristics 
   3. Medical plausibility present
   4. Positive de-challenge 
3. Possible – (may be related to the suspected drug) (only first 3 parameters met)
   1. Time relationship is there
   2. Definite pharmacological characteristics 
   3. Medical plausibility present
4. Unlikely (only first 2 parameters met)
   1. Time relationship is there
   2. Definite pharmacological characteristics 

Adverse event (AE) vs. Adverse drug reaction (ADR)

I shall discuss the treatment outcome of DS-TB patients and the treatment of DR-TB (drug-resistant TB)  patients in the upcoming articles.