Tuberculosis

Clinical Description

General principles

The goals of TB treatment are to cure the patient and restore their quality of life, to prevent death from TB, to reduce transmission of TB in the community and to prevent the development and spread of drug-resistance.

Directly observed treatment (DOT)

The treatment supervisor watches the patient swallow the tablets throughout the whole course to treatment. DOT ensures that the TB patient takes the right drugs, in the right doses at the right times. Supervisors or “treatment supporters,” can be health workers, volunteers, trained members of the community or guardians. A patient-centered approach with proper communication between the patient and treatment supporter promotes patient education, good adherence and early identification of challenges with treatment (including side-effects and clinical worsening). All treatment supporters should be chosen together with and should be acceptable to the patient. The need for good adherence and follow-up should always be reinforced. Patients should be reminded about the duration of treatment and common side effects.

TREATMENT OF SUSCEPTIBLE TB

• Susceptible TB is treated with first-line drugs: Rifampicin (R), Isoniazid (H), Ethambutol (E), Pyrazinamide (Z). The four oral drugs (RHZE) come as an FDC tablet.
• Patients should not be admitted in the ward or hospital for administration of TB drugs except where they are very sick or unable to walk.
• TB drugs should be provided on ambulatory basis in all facilities.

Dosages of FDC formulations of first line anti-TB drugs for adults

Body weight Initiation phase (2 months)

Continuation phase (4 months)

RHZE] [R150/H75/Z400/E275]

Number of tablets [RH] [R150/H75]

Number of tablets 30-37 2 2 38-54 3 3 55-74 4 4 75 and over 5 5

Dosages of FDC formulations of first line anti-TB drugs for children

Body weight Intensive phase (2 months) Continuation phase

RHZ 75/50/150 number of tablets

Ethambutol 100mg number of tablets

RH 75/50 number of tablets 4-7kg 1 1 1 8-11kg 2 2 2 12-15kg 3 3 3 16-24kg 4 4 4 25 +kg Takes Adult

Formulation

TB PREVENTIVE THERAPY (TPT)

TB preventive Therapy (TPT) remains one of the main stay of TB prevention. The following group of patients are targeted for latent TB treatment using isoniazid or Rifapentine in combination with Isoniazid

Household contact

• Under-five children who are household contact of pulmonary TB cases and who are found not to have active TB on an appropriate clinical evaluation
• HIV negative adult contacts of pulmonary TB cases

PLHIV

• Children living with HIV who are >12 months of age who screen negative for TB using the ICF tool.
• Children living with HIV who are <12 months of age, who have contact with a PTB and screen negative for TB using the ICF tool.
• All adult PLHIV above who screen negative for TB using the ICF tool.

Overview of the TPT Regimens

Regimen Description Target population

Frequency Duration of

Treatment

Precautions/

Recommendations

Isoniazid preventive

Therapy

A single dose formulation of Isoniazid (INH)

Children of all ages

Once daily 6 Months 180 doses

Preferred Regimen for HIV-infected children taking lopinavir-ritonavir, nevirapine, or dolutegravir, 3HP A short- course TPT regimen that combines

Isoniazid and Rifapentine

Adults and

Children ≥2

years old

Once weekly 12 weeks 12 doses

Safe to give with dolutegravir-based

ART in Adults

Reduces lopinavir- ritonavir and nevirapine levels.

Do not use or use with dose adjustment for HIV-infected children taking lopinavir-ritonavir, nevirapine, or dolutegravir 3RH A short- course TPT regimen that combines

Children of all ages

Once daily 12 Weeks 90 doses

Reduces lopinavir- ritonavir and nevirapine levels.

Do not use or use with dose

Isoniazid (INH )and Rifampicin (R) adjustment for HIV-infected children taking lopinavir-ritonavir, nevirapine, or dolutegravir

It is important to note that RIF and RPT are potent inducers of the cytochrome P450 oxidase system. Their administration may affect the pharmacokinetics of other drugs including some antiretrovirals (ARVs). For people living with HIV/AIDS, both 3HP and 3RH are safe to give with efavirenz-based ART without any dosing adjustments. In adults, 3HP is safe to give with dolutegravir-based ART without any dosing adjustment. Both 3HP and 3RH reduce lopinavir- ritonavir and nevirapine levels. Thus, dosing adjustments are needed. So, neither can be used together with lopinavir-ritonavir or nevirapine. As a consequence, for HIV-infected children taking lopinavir-ritonavir, nevirapine, or dolutegravir, the preferred TPT regimen is represented by 6H (preferably with the dispersible formulation), which does not require dose adjustment.

TB PREVENTIVE THERAPY AMONGST ADULTS 3HP Regimen

• The table below summarizes the weight banded dosing for 3HP amongst individuals above 14 years (classified as adults).

3HP dosage by weight band for Adults (>14 years)

Age >14 years

Medicine formulation 30- 35kg 45kg 55kg 70kg >70kg

FDC Rifapentine /Isoniazid (300/300mg) 3 3 3 3 3

TB PREVENTIVE THERAPY AMONGST CHILDREN

• The section below summarizes weight banded dosing for TB Preventive Therapy regimens amongst children.

Isoniazid preventive Therapy dosage for children under 5

• For all under 5 children who are contacts of pulmonary TB patients, the recommended dosing of Isoniazid Preventive Therapy (IPT) is 10 mg/kg once daily for 6 months 3HP dosage by weight band for children (2-14 years)

Age 2-14years

Medicine formulation 10- 15kg 16-23kg 24- 30kg 34kg >34kg

Isoniazid 100mg 3 5 6 7 7

Rifapentine 150mg 2 3 4 5 5 *3HP is an option for TPT amongst children but not a preferred regimen because there are no child friendly formulations yet on the market. The use of 3HP amongst children will be considered as optimized formulations become available on the market.

3RH dosage by weight band for children (same with the dosages for treatment)

Body weight RH 75/50 number of tablets 4-7kg 1 8-11kg 2 12-15kg 3 16-24kg 4 25 +kg

DRUG RESISTANT TUBERCULOSIS

In 2018 WHO regrouped medicines into three categories (A, B and C) and ranked based on the latest evidence about the balance of effectiveness to safety. Injectables are no longer recommended for DR-TB treatment and have been phased out in Malawi

Group A: levofloxacin/moxifloxacin, bedaquiline and linezolid. These are medicines that must be prioritized for the standardized DR-TB regimen

Group B: clofazimine, cycloserine/terizidone. These are the medicines to be added next for the standardized DR-TB regimen

Group C: ethambutol, delamanid, pyrazinamide, imipenem-cilastatin, meropenem, amikacin (streptomycin), ethionamide/prothionamide, p-aminosalicylic acid. These are the medicines to be included to complete the regimens and when agents from Groups A and B cannot be used.

Imipenem-cilastatin and meropenem not recommended in Malawi due to cost and complexities of administration. p-aminosalicylic acid and amikacin (streptomycin) not recommended in Malawi due to relative ineffectiveness and risk of toxicity. Ethambutol, delamanid and pyrazinamide can be used under specified conditions (see below)

For DR-TB patients without Fluoroquinolone (FQ) resistance for both adults and children

• All oral, longer treatment regimen (LTR) for 18-20 months, containing at least 4 active medications from Group A, B, and C
• The regimen for Malawi comprises six months of Bedaquiline (Bdq), Levofloxacin (Lfx), Linezolid (Lzd), Clofazimine (Cfz) and Cycloserine (Cs) followed by 12-14 months of Levofloxacin, Linezolid, Clofazimine and Cycloserine
• Standardized regimen for DR-TB patients without Fluoroquinolone (FQ) resistance for both adults and children: 6 Bdq-Lfx-Lzd-Cfz-Cs/12-14 Lfx-Lzd-Cfz-Cs. Delamanid to be used in place of Bedaquiline in children under six years.

For MDR/RR-TB patients with FQ resistance (Pre-XDR-TB) or resistance to second-line medications, the following regimen could be applied for both adults and children.

• This is an individualized regimen that must be designed based on the resistance pattern of the TB strain, tolerance to the available medicines and treatment history
• Examples of medicines that can be considered include Bedaquiline (Bdq), Delamanid (Dlm), Ethionamide (Eto), Moxifloxacin (Mfx) and Prazinamide (Z)
• The regimen must be for a total duration of 18-20 months long. If Bedaquiline is considered, it must be restricted to the first 6 months .

DOSING GUIDELINES FOR ADULTS

DOSING GUIDELINES FOR CHILDREN

Medicine Recommended dosing

Levofloxacin 100mg scored, dispersible tablets 15-20mg/kg/day

Cycloserine 125mg capsules 15-20mg/kg/day

Clofazimine 50mg tablet 2-5mg/kg/day

Linezolid 150mg, scored, dispersible tablets 10-12mg/kg once daily for children < 12 years who weigh 16kg or more; 15mg/kg once daily in children < 12 years who weigh less than 16kg; 10mg/kg once daily in children 12 years and above *Bedaquiline 20mg tablet (Children ages six and above)

For children who weigh more than 30kg, the standard adult dose of 400mg daily for 14 days followed by 200mg three times a week for an additional 22 weeks is given. For children who weigh 16-30kg, the recommended dosing is 200mg daily for 14 days followed by 100mg three times a week for an additional 22 weeks.

**Delamanid 25mg dispersible tablet (Children ages three years and above)

For children who weigh more than 35kg, the standard adult dose of 100mg twice daily is given (for a total daily dose of 200mg). For children who weigh 24-34kg, the recommended dosing is 50mg twice daily (for a total daily dose of 100mg). A practical dosing table for children based on weight is below.

*Bedaquiline is a drug that is recommended for children ages six years and above. Currently, there are not weight-based dosing recommendations for children being treated with bedaquiline. Rather, children who weigh more than 30kg, the standard adult dose of 400mg daily for 14 days followed by 200mg three times a week for an additional 22 weeks is given.

For children who weigh 16-30kg, the recommended dosing is 200mg daily for 14 days followed by 100mg three times a week for an additional 22 weeks ** Delamanid is a drug that is recommended by the World Health Organization for individuals with rifampicin-resistant tuberculosis (RR-TB), and for children ages three years and above.

Currently, there are not weight-based dosing recommendations for children being treated with Delamanid. Rather, children who weigh more than 35kg, the standard adult dose of 100mg twice daily is given (for a total daily dose of 200mg). For children who weigh 24-34kg, the recommended dosing is 50mg twice daily (for a total daily dose of 100mg).

Notes on DR-TB treatment regimens

• Scientific and programmatic evidence on the composition, effectiveness, safety, dosages and duration of treatment for DR-TB regimens is evolving. Please refer to the latest guidelines from the National TB and Leprosy Control Program during the course of implementation of these STGs
• For DR-TB patients without Fluoroquinolone (FQ) resistance, an all oral, shorter treatment regimen for 9-12 months, containing at least 4 active medications from

Group A, B, and C

• can be used for both adults and children at programmatic level under Operational

Research (OR) ground. Under this regimen, Linezolid is only used for the first two months.

• The Standardized shorter regimen for DR-TB patients without Fluoroquinolone (FQ) resistance for both adults and children: 2 Bdq-Lfx-Lzd-Cfz-Cs/4 Bdq -Lfx-Cfz-Cs /3- 6 Lfx-Cfz-Cs. Delamanid to be used in place of Bedaquiline in children under six years.