TUBERCULOSIS REGIMEN:

DOTS/WHO AND INDIAN

GUIDELINES

DR PRATYUSH KUMAR

MODERATOR :- Dr. UJJWAL

PAREKH

Epidemilogy

Definition

• New A TB patient who has never had treatment for TB or has taken anti-TB drugs for less than one month

• Relapse A TB patient who was declared cured or treatment completed by a physician and who reports back to the health facility and is now found to be sputum smear-positive

• Treatment after default: A patient, who has received treatment for TB for a month or more from any source and returns for treatment after having defaulted i.e., not taken anti-TB drugs consecutively for two months or more and found to be smear-positive

• Treatment failure Any TB patient who is

smear-positive at 5 months or more after

initiation of treatment

• Defaulted A Patient after treatment

initiation has interrupted treatment

consecutively for >2 months

Case definitions - WHO

• Tuberculous intrathoraciclymphadenopathy (mediastinal and/or hilar) or tuberculous pleural effusion, without radiographic abnormalities in the lungs, constitutes a case of extrapulmonary TB

• A patient with both pulmonary and extrapulmonary TB should be classified as a case of pulmonary TB.

• The case definition of an EPTB case with several sites affected depends on the site representing the most severe form of

AFB on ZN stain

New patients

• Presumed to have drug-susceptible TB with two exceptions: – Where there is a high prevalence of isoniazid

resistance in new patients or

– If they have developed active TB after known contact with a patient documented to have drug-resistant TB; they are likely to have a similar drug resistance pattern to the source case and DST should be carried out at the start of treatment.

• While DST results of the patient are awaited, a regimen based on the DST of the presumed source case should be started.

DOTS TB regimen

• For all “new” pulmonary (smear positive and negative), extra-pulmonary and other TB patients regimen is: 2 H3R3Z3E3 / 4H3R3.

• All “relapses, treatment after default, failures and others” are treated with the regimen for previously-treated cases: 2S3H3R3Z3E3 /1 H3R3Z3E3 / H3R3E3.

• The PWB has a color code indicating the two regimens—red for “new”, blue for “previously treated”

Regimens for previously treated patients

Non-DOTS Treatment Regimen

under RNTCP

• Treatment regimen of 12-month duration

comprising 2 months of she and 10

months of he (2 SHE/10 HE).

• Adverse reactions to rifampicin and/or

pyrazinamide

• Revised National Tuberculosis Control

Program uses short course chemotherapy

given intermittently—thrice weekly under

direct observation (DOTS) for both

pulmonary and extra-pulmonary

tuberculosis patients.

INTRODUCTION

WHO guidelines

• Wherever feasible, the optimal dosing frequency for new patients with pulmonary TB is daily throughout the course of therapy

• New patients with pulmonary TB may receive a daily intensive phase followed by three times weekly continuation phase [2HRZE/4(HR)3 ] provided that each dose is directly observed

• In populations with known or suspected high levels of isoniazid resistance, new TB patients may receive HRE as therapy in the continuation phase as an acceptable alternative to HR

Follow up

• If the sputum smear is positive after 2 months of treatment, the IP of four drugs (H, R, Z and E) is continued for another 1 month

• sputum examined after the completion of the extension of IP. Irrespective of the sputum results after this extension of the IP, 4 months of the CP is started.

• If the sputum smear is positive after 5 or more months of treatment, the patient is declared as a “Failure” and is placed on the “Previously Treated” treatment regimen afresh

Co-existent TB and diabetes

• Hospitalization in patients with poor

diabetic control

• Ideally insulin should be used

• Maintain fasting blood sugar<100 mg %

and glycosylated HB <6%

• Use of potentially neuropathic agents in

patients with peripheral neuropathy

demands special consideration and

administration of pyridoxine

Definitions

• MDR-TB is defined as tuberculosis disease where the bacilli is resistant to isoniazid (H) and rifampicin (R), with or without resistance to other drugs

• Extensively Drug Resistant TB (XDR–TB) is a subset of MDR-TB where the bacilli, in addition to being resistant to R and H, are also resistant to fluoroquinolones and any one of the second-line injectable drugs (namely Kanamycin, Capreomycin or Amikacin)

• Totally Drug–Resistant Tuberculosis (TDR-TB) TB strains that showed in-vitro resistance to all first and second line drugs tested (isoniazid, rifampicin, streptomycin, ethambutol, pyrazinamide, ethionamide, para-aminosalicylic acid, cycloserine, ofloxacin, amikacin, ciprofloxacin, capreomycin, kanamycin)

Who - data

• At the global level, 15% of previously

treated patients have MDR

• MDR to be 32% in patients returning after

defaulting or relapsing and significantly

higher (49%) in patients whose prior

treatment has failed

Multidrug Resistant TB and DOTS-

Plus• Prevention of MDR-TB is given priority under

RNTCP rather than its treatment

• The following are the criteria to label a patient as MDR-TB suspect.

• A new smear-positive patient remaining smear-positive at the end of fifth month.

• A new smear-negative patient becoming smear-positive at the end of fifth month.

• A patient treated with regimen for previously treated remaining positive at fourth month

• Smear-positive contacts of an established/confirmed MDR-TB case

RNTCP MDR-TB Treatment

Regimen

The• Diagnosis of MDR-TB should be done

through culture and drug susceptibility

testing

• 6 drugs(kanamycin [km], levofloxacin(lvx),

ethionamide [eto], pyrazinamide [Z],

ethambutol [E] and cycloserine [cs]) during

6-9 months of an intensive phase

• 4 drugs (lvx, eto, E and cs) during the 18

months of the continuation phase

Dosages of drugs are based upon

three weight bands

Treatment regime

• All drugs should be given in a single daily dosage under DOT by a DOT Provider

• On the 7th day (Sunday), the oral drugs will be administered unsupervised and kanamycin will be omitted

• If intolerance occurs to the drugs, ethionamide, cycloserine and PAS may be split into two dosages

• Intensive Phase (IP) should be given at least 6 months. It is extended up to seven/eight/nine months in patients who have a positive culture result taken in fourth/fifth/sixth month of treatment correspondingly. Continuation Phase (CP) is given for 18 months following the IP.

Follow-up Schedule (RNTCP)

• Smear examination should be conducted

monthly during the IP

• at least quarterly during the CP

• Culture examination should be done at

least at 4, 6, 12, 18 and 24 months

Monitoring the MDR-TB patient

(who)

• sputum smears and cultures should be

performed monthly until smear and culture

conversion

• Conversion is defined as two consecutive

negative smears and cultures taken 30

days apart

• After conversion, the minimum frequency

recommended for bacteriological

monitoring is monthly for smears and

quarterly for cultures.

• Each patient’s weight should be monitored

Symptom-based approach to side

effects of anti-TB drugsSymptom Drug Management

Gastrointestinal

(vomiting or

epigastric

discomfort)

Any oral

medication

Maintain hydration

Consider treatment with antiemetics

(e.g. domperidone)

and proton pump inhibitors (eg.

Omeprazole)

Itching/Rashes Isoniazid (and

other drugs

also)

Itching without rash or a mild rash

Continue treatment antihistamines

Itching with moderate to severe rash

Stop all drugs till symptoms subside

Treat with antihistamines

Patients with mucosal involvement, fever and

hypotension will requiretreatment with corticosteroids

When the reaction subsides reintroduce drugs one-

by-one in this order

1. INH. 2. Rifa. 3. Pyra. 4. Etham

Re-introduce each drug in a small dose and gradually

increase over 3 days before introducing the next

drug.

Tingling/

burning/

numbness in

the

hands and feet

Isoniazid Give pyridoxine 100 mg/day orally

or parenterally until symptoms subside.

Patients not responding to pyridoxine will

require treatment with amitryptiline

Joint pains Pyrazinamid

e

Give NSAIDs like paracetamol, Aspirin or

Ibuprofen and in severe cases Indomethacin for a

week to 10 days

In severe cases, estimate serum uric acid levels

If uric acid levels are significantly raised, treat

with NSAIDs and colchicine. Allopurinol is not

effective.

In severe cases with normal or slightly elevated

uric acid, consider reduction of the dose of

Pyrazinamide.

Impaired vision Ethambutol Impaired vision usually returns to normal within a

few weeks of stopping ethambutol.

Ringing in the

ears, Loss

of hearing,

dizziness and

loss of balance

Streptomycin As hearing loss is usually not reversible, do not

restart Streptomycin

Hepatitis:

Anorexia

nausea

/Vomiting/

Jaundice

Isoniazid,

Rifampicin

or

Pyrazinamid

e

Rule out other causes of hepatitis

Do not restart treatment till symptoms

resolve and liver enzymes return to

baseline levels

If liver enzymes cannot be performed, wait

for 2 weeks after jaundice has disappeared

to

restart treatment

Restart treatment with one drug at a time

starting with 1. INH 2. Pyra 3. Rifa

In patients with severe disease in whom

treatment cannot be stopped, use a non

hepatotoxic regimen consisting of

Streptomycin and Ethambutol

Management of drug-induced

hepatitis

• The management of hepatitis induced by

TB treatment depends on:

— whether the patient is in the intensive or

continuation phase of TB treatment;

— the severity of the liver disease;

— the severity of the TB; and

— the capacity of the health unit to manage

the side-effects of TB treatment

• If it is thought that the liver disease is

caused by the anti-TB drugs, all drugs

should be stopped.

• If the patient is severely ill with TB and it is

considered unsafe to stop TB treatment, a

non-hepatotoxic regimen consisting of

streptomycin, ethambutol and a

fluoroquinolone should be started.

• wait for liver function tests to revert to

normal and clinical symptoms (nausea,

abdominal pain) to resolve before

reintroducing the anti-TB drugs

• drugs are reintroduced one at a time

• If symptoms recur or liver function tests

become abnormal, the last drug added

should be stopped

• starting with rifampicin because it is less

likely than isoniazid or pyrazinamide to

cause hepatotoxicity and is the most

effective agent

• After 3–7 days, isoniazid may be

reintroduced

• patients who have experienced jaundice

but tolerate the reintroduction of rifampicin

and isoniazid, it is advisable to avoid

pyrazinamide

• If rifampicin is implicated, a suggested regimen without rifampicin is 2 months of isoniazid, ethambutol and streptomycin followed by 10 months of isoniazid and ethambutol.

• If isoniazid cannot be used, 6–9 months of rifampicin, pyrazinamide and ethambutol can be considered.

• If pyrazinamide is discontinued before the patient has completed the intensive phase, the total duration of isoniazid and rifampicintherapy may be extended to 9 months

• If neither isoniazid nor rifampicin can be used, the non-hepatotoxic regimen consisting of streptomycin, ethambutol and a fluoroquinolone should be continued for a

Co-management of HIV and active

TB disease

• Three I’s for reducing the burden of TB in

persons living with HIV: Intensified case-

finding (ICF), Isoniazid preventive

therapy (IPT) and TB Infection control

(IC) for people living with HIV

• WHO recommends HIV testing for patients

of all ages who present with signs or

symptoms that suggest tuberculosis

Recommendation

• receive daily TB treatment at least during the intensive phase

• For the continuation phase, the optimal dosing frequency is also daily

• three times weekly dosing during the continuation phase is an acceptable alternative

• TB patients who are living with HIV should receive at least the same duration of TB treatment as HIV-negative TB patients

• Co-trimoxazole preventive therapy

Antiretroviral therapy

• ART should be initiated for all people living

with HIV with active TB disease

irrespective of CD4 cell count

• TB treatment should be started first,

followed by ART as soon as possible and

within the first 8 weeks of starting TB

treatment

Art regimen

• two nucleoside reverse transcriptase inhibitors (NRTIs) plus one non-nucleoside reverse transcriptase inhibitor (NNRTI)

• NRTI backbone is zidovudine (AZT) or tenofovir disoproxil fumarate (TDF), combined with either lamivudine (3TC) or emtricitabine (FTC). For the NNRTI, WHO recommends either efavirenz (EFV) or nevirapine (NVP)

• recommended first-line ART regimens for TB patients are those that contain efavirenz(EFV)

• ART regimen containing a boosted protease inhibitor (PI), it is recommended to give a rifabutin-based TB treatment.

• If rifabutin is not available, the use of rifampicin and a boosted antiretroviral regimen containing lopinavir or saquinavirwith additional ritonavir dosing is recommended

• dosage of Rifabutin during the administration of second line ART regimen containing LPV/r shall be 150 mg Rifabutin, dosed thrice-weekly for all patients>30 kg weight.

Complications

• Mild to moderate IRIS is relatively common

• reported in up to one-third of patients

• present as fever, enlarging lymph nodes, worsening pulmonary infiltrates, or exacerbation of inflammatory changes at other sites

• presents within 3 months of the start of ART

• more common when CD4 cell count is low (<50 cells/mm3)

• Most cases resolve without intervention and ART can be safely continued

• IRIS is a diagnosis of exclusion.

Monitoring drug treatment

• smear microscopy may be performed at completion of the intensive phase .

• Smear status at the end of the intensive phase is a poor predictor of which new patients will relapse– therapy was poorly supervised and poor patient adherence

– poor quality of anti-TB drugs

– Doses below the recommended range;

– resolution is slow because the patient had extensive cavitation and a heavy initial bacillary load;

– co-morbid conditions interfering with adherence or with response

– drug-resistant M. tuberculosis that is not responding to first-line treatment;

– non-viable bacteria remain visible by microscopy

• It is unnecessary, unreliable and wasteful of resources to monitor the patient by chest radiography

• specimen obtained at the end of the intensive phase (month 2) is smear-positive, sputum smear microscopy should be obtained at the end of the third month

• at the end of month 3 is smear-positive, sputum culture and drug susceptibility testing (DST) should be performed

• pulmonary smear-negative disease and extrapulmonary TB the weight of the patient is a useful indicator.

Definitions of treatment

outcomes

Treatment of extra pulmonary

TB • Pulmonary and extrapulmonary disease

should be treated with the same regimens

• some experts recommend 9–12 months of treatment for TB meningitis

• 9 months of treatment for TB of bones or joints

• adjuvant corticosteroid treatment is recommended for TB meningitis and pericarditis

• In tuberculous meningitis, ethambutol should be replaced by streptomycin

Treatment regimens in special

situations • Pregnancy :-

– streptomycin is ototoxic to the fetus and should not be used during pregnancy

• Lactation:-– Mother and baby should stay together and the

baby should continue to breastfeed.

– After active TB in the baby is ruled out, the baby should be given 6 months of isoniazid preventive therapy, followed by BCG vaccination

• Women on OCPs :-– increase OCP dose, or choose alternative

contraception

Liver disorders

• If the serum alanine aminotransferase level is more than 3 times normal

• Possible regimens include:

Two hepatotoxic drugs (rather than the three in the standard regimen):

— 9 months of isoniazid and rifampicin, plus ethambutol (until or unless isoniazid susceptibility is documented);

— 2 months of isoniazid, rifampicin, streptomycin and ethambutol, followed by 6 months of isoniazid and rifampicin;

— 6–9 months of rifampicin, pyrazinamide and ethambutol.

One hepatotoxic drug:

— 2 months of isoniazid, ethambutol and streptomycin, followed by 10 months of isoniazid and ethambutol.

No hepatotoxic drugs:

— 18–24 months of streptomycin, ethambutol and a fluoroquinolone.

Renal failure

• Isoniazid and rifampicin are eliminated by

biliary excretion

• significant renal excretion of ethambutol

and metabolites of pyrazinamide

• Three times per week administration:

pyrazinamide (25 mg/kg), and ethambutol

(15 mg/kg)

• if streptomycin must be used, the dosage

is 15 mg/kg, two or three times per week