REPUBLIC OF BOTSWANA

MINISTRY OF HEALTH

TUBERCULOSIS
PREVENTIVE
THERAPY

Handbook
List of abbreviations
3HP:
3 months of weekly Rifapentin and Isoniazid
BoMRA:
Botswana Medicines Regulatory Authority
HIV:
Human Immuno Deficiency Virus
IDCC:
Infectious Diseases Care Clinic
INH:
Isoniazid
PLHIV:
People Living With HIV
RPT:
Rifapentine
TPT:
Tuberculosis Preventive Therapy
TB:
Tuberculosis
UNHLM:
United Nations High Level Meeting

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Introduction

Botswana is one of the pioneers of implementation of TB preventive

Therapy among People Living with HIV. The first implementation of TPT
was in the form of Isoniazid given once daily in combination with
pyridoxine for a period of 6 months. This was halted in 2008 following
challenges in implementation and changes in WHO guidelines, which
required the use of a positive tuberculin test as an eligibility criteria for
TPT.

TPT for PLHIV was re-instituted in 2019 following the commitments made
at the UNHLM on TB in New York in 2018 in which countries including
Botswana committed to ambitious and powerful political declaration
to accelerate progress towards End TB targets. This guideline is meant
to assist primary health clinicians to provide quality TB prevention
package. This guideline does not replace but augments the existing TB
and HIV guidelines.

The country has made a decision to switch from Isoniazid Preventive

Therapy to 3 months of once weekly Isoniazid combined with
Rifapentine (3HP) with the intention to improve completion rates and
reduce the morbidity associated with side effects of prolonged use of
Isoniazid.

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Tuberculosis Overview

Botswana is one of the pioneers of implementation of TB Preventive

Therapy (TPT) among People Living with HIV (PLHIV). The first
implementation of TPT was in the form of isoniazid given once daily in
combination with pyridoxine for a period of 6 months. This was halted
in 2008 following challenges in implementation and changes in WHO
guidelines, which required the use of a positive tuberculin test as an
eligibility criterion for TPT.

TPT for PLHIV was re-instituted in 2019 following the commitments made
at the UNHLM on TB in New York in 2018 in which countries including
Botswana committed to the ambitious and powerful political
declaration to accelerate progress towards End TB targets. This
guideline is meant to assist primary health clinicians in providing a
quality TB prevention package. This guideline does not replace but
augments the existing TB and HIV guidelines.

Botswana has made a decision to switch from Isoniazid Preventive

Therapy to 3 months of once weekly isoniazid combined with
rifapentine (3HP) with the intention to improve completion rates and
reduce the morbidity associated with side effects of prolonged use of
isoniazid.

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Rationale for TB preventive therapy

Rationale for TB preventive therapy

Tuberculosis has been established as the leading cause of illness and
death among people living with HIV (PLHIV). Provision of TB Preventive
Therapy (TPT) will reduce the number of PLHIV and children infected
with TB progressing to TB disease.

Ultimate goal of TPT is to interrupt transmission of active TB. While

treatment of active TB disease directly interrupts transmission, treating
latent TB indirectly interrupts transmission. TB is therefore not only
treatable and curable but preventable. The implementation of this
guideline is intended to decrease the burden of disease in some
selected high risk groups: adults living with HIV, asymptomatic
pediatric contacts of confirmed TB cases (irrespective of HIV status if <5
years) and HIV positive if 6 years to 12 years.

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TB Preventive Therapy (TPT) overview

There are different regimen options for treatment of latent TB. The
choice of treatment for adults will be 3HP and 6H for children who are
contacts of bacteriologically confirmed TB cases.
Groups of patients that will receive TPT include:

•Adults and adolescents living with HIV who have a negative TB

screen irrespective of the degree of immunosuppression, ART status
and previous TB.
•Asymptomatic contacts of bacteriologically confirmed TB cases <5
years irrespective of HIV status and 6-12 years if HIV positive

TB preventive therapy will be given to this group of patients as part of

a comprehensive package of HIV care.

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Does TB preventive treatment (TPT) promote resistant TB?

The myth that TPT may promote resistance has prevented programs
and individuals from accessing lifesaving TB preventive treatment.
There are a few reasons why the development of resistance is
extremely unlikely:

• TPT is used for patients who do not currently have active TB

• Active TB can be quickly and easily excluded using TB screening
questionnaire
• Individuals with latent TB infection have a small number of slowly
replicating bacteria. These bacteria are at low risk of selecting for
drug resistance
• Most resistance arises from suboptimal treatment of active TB
disease, hence preventing active disease may be decrease
development resistance
• Multiple trials have failed to find scientific evidence of a significant
association between TB drug-resistance and the use of isoniazid or
rifamycins for TPT

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Adherence Counselling for TPT

Before starting Tuberculosis Preventive Therapy counsel your

patients on;

TPT TB

•Risk and benefits of TPT •Difference between LTBI

and Active TB

•Importance of Adherence •What is TB , how it spreads

and follow-up and signs /symptoms of TB?

•Side effects to 3HP and what •Relationship between TB

to do if they occur & HIV

•How ART can reduce the

•Duration of Treatment
risk of TB

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TB Screening & TPT Algorithm

Screen for TB with anyone of the following:

Current cough, Fever, Weight loss and Night sweats
VL >200, CD4<200

Figure 1: TB screening and TPT algorithm

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Diagnosis of TB infection

TB preventive therapy is for treatment of latent TB infection. Patients

with active TB require a full course of TB treatment.
Identifying clients who are eligible for TPT will be done through a TB
screening algorithm. Those who do not report any of the symptoms of
current cough, fever, weight loss or night sweats are unlikely to have
active TB and should be offered TB preventive treatment. The use of
chest Xray and blood tests will not be required prior to initiating TPT.

Table 1: Difference between Latent TB infection and Active TB Disease

Latent TB infection Active TB disease

Have one or more of the following:
No symptoms suggestive
fever, cough, weight loss, night sweats,
of TB disease

TB blood test or TST result TB blood test or TST result may be

usually positive positive or negative

Chest radiograph is Chest radiograph is usually abnormal,

typically normal but may be normal in people with
advanced HIV

Sputum AFB smear, Gene Usually smear, Gene Xpert and/or

Xpert and culture negative culture positive, but may be negative

Cannot spread TB bacteria Can spread TB bacteria to others and

to others need treatment for TB disease

Should be given treatment for active TB

Should be given TPT if eligible disease according to TB treatment
guidelines

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Patients eligible for TPT will be identified through intensified case finding
at IDCC and active case finding through contact investigation. (See
algorithm at annexures)

TPT Regimens
Three Months of Once-weekly Isoniazid (INH) plus Rifapentine (RPT)
Regimen: 3HP

The 3-month regimen of 12 once-a-week doses of INH and RPT is also

known as the 3HP regimen. The regimen will be self-administered.
The 3HP regimen is recommended for PLHIV older than 12 years of age.
There is no need for dose adjustment of dolutegravir (DTG).

Patients who are virologically detectable while on any ART regimen

should not be given 3HP.

The 3HP regimen will not be given to the following individuals:

.Children younger than 12 years of age
.Pregnant women
.Patients on any PI based regimen

Six Months of Daily Isoniazid (INH) Regimens: 6H

The WHO-recommended regimen for pediatric population is 3HR,
however given the need for dose adjustments with concurrent use of
Lopinavir/ritonavir and nevirapine: 6H will be the preferred regimen for
this group. This regimen is a daily six-month administration of INH. It is
recommended for:

Children under 5 who are contacts of bacteriologically confirmed

cases and have been found to be asymptomatic after TB screening
irrespective of HIV status

HIV positive children between 6-12 years who are contacts of

bacteriologically confirmed cases and have been found to be
asymptomatic after TB screening.

TABLE 2: Dosing Guidelines for TPT Regimens

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Regimen Duration Dosage Frequency
Isoniazid INH: 15 mg/kg rounded up to the Once
(INH) and nearest 100 mg; 900 mg maximum weekly
Rifapentin RPT: 10.0–14.0 kg, 300 mg
e (RPT) 14.1–25.0 kg, 450 mg
25.1–32.0 kg, 600 mg
32.1–49.9 kg, 750 mg
≥50.0 kg, 900 mg maximum
Isoniazid 6 months 10 mg/kg Daily
(INH)

3HP Dosage Image 1:

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Table 3 : Eligibility for and Contraindications to TPT (3HP/6H)

ELIGIBLE FOR TPT NOT ELIGIBLE FOR TPT

PLHIV > 12 years of age Clinical or laboratory evidence of

irrespective of ART status hepatitis

Former TB patients
Acute or chronic liver disease
(completed treatment >2
years ago)

Breastfeeding women Previous severe adverse event to drugs

used for TPT

Children <5 years old with Previous TPT (<2 years)

recent exposure to TB cases
regardless of HIV status

Children with HIV who are

Active TB disease
>5 but less than 12 years
with recent exposure to TB
cases VL>200 and CD4<200

Pregnant women

Special Considerations for TPT

Pregnancy
• There is potential for an increased risk of hepatotoxicity during
pregnancy and the first 2–3 months of the post-partum period.
• The 3HP regimen is not recommended for pregnant women or
women expecting to become pregnant during the treatment
period
• For pregnant women, 3HP should be delayed until 2–3 months
post-partum

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Breastfeeding Women
• 3HP is not contraindicated in women who are breastfeeding
• The amount of INH or RPT in breast milk is inadequate for treatment of
infants with LTBI

Infants and Children

Because of their young age, infants and young children who have
been in contact with confirmed TB cases are at high risk for progressing
to TB disease if infected.
• Infants and young children are also more likely than adults to
develop severe forms of TB disease
• Children under 5 years of age who are contacts of an adult with
bacteriologically confirmed TB should receive 6H irrespective of HIV
status if they are found to be asymptomatic.
HIV positive children between 6 and 12 years who are contacts of
bacteriologically confirmed TB cases should receive 6H if found to be
asymptomatic.
TB disease should be excluded by chest Xray and symptom screening.
• Risk of INH-related hepatitis in infants, children, and adolescents is
minimal.
• Routine monitoring of serum liver enzymes is not necessary unless the
child has risk factors for hepatotoxicity.

Adverse Effects of drugs used for TPT

3HP is generally effective, safe, and has higher completion rates and
lower rates of hepatotoxicity than the longer 6 months regimen with
INH monotherapy.
To ensure safe and efficacious treatment, patients should have
monthly assessment for adherence and adverse events.

Adverse Effects of INH

• Elevated AST/ALT: Asymptomatic elevation of serum liver enzyme
concentrations occurs in 10%–20% of people taking INH.
• INH should be withheld if a patient’s transaminase level exceeds 3
times the upper limit of normal if associated with symptoms, or 5 times
the upper limit of normal if the patient is asymptomatic.

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Adverse Effects of INH

• Elevated AST/ALT: Asymptomatic elevation of serum liver enzyme

concentrations occurs in 10%–20% of people taking INH.
• INH should be withheld if a patient’s transaminase level exceeds 3
times the upper limit of normal if associated with symptoms, or 5 times
the upper limit of normal if the patient is asymptomatic

Drug induced hepatitis: Drug induced hepatitis occurs in less than 1% of

people taking INH and is more common when INH is combined with
other hepatotoxic agents. Factors that may increase the rates or the
severity of hepatitis include daily alcohol consumption, underlying liver
disease or risks for liver disease, and the concurrent use of other
medications that are metabolized in the liver. Patients with underlying
risk factors for liver disease should be monitored with monthly liver
enzymes.

Figure 2: Algorithm for the management of TPT induced liver elevated

enzymes.

Hold ARVs

Hold ARVs Hold ARVs

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Peripheral neuropathy: Peripheral neuropathy occurs in less than 1% of
people taking INH at normal doses. It is more likely in the presence of
other conditions associated with neuropathy. Persons with risk factors
for neuropathy (e.g., pregnant women; breastfeeding infants; persons
infected with HIV; those with diabetes, alcoholism, malnutrition, or
chronic renal failure; or those who are of advanced age) are given
pyridoxine (vitamin B6) at a dose of 50 mg/week.

Figure 3: Clinical Management of Peripheral Neuropathy caused

by INH

It is important to ruleout other causes of Peripheral Neuropathy

eg: diabetes, B-12 deficiency and excessive alcohol intake

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Adverse Effects of Rifapentine (RPT)

Hepatotoxicity: 3HP treatment regimen generally has a lower risk of

hepatotoxicity than longer 6 month regimen of INH monotherapy.

Flu-like syndrome: Rifapentine, and other rifamycins, may cause a

flu-like syndrome characterized by fever, muscle aches, and weakness.
3HP must be discontinues if this syndrome occurs.

Hypersensitivity reactions: Rarely, rifamycins can be associated with

hypersensitivity reactions, including hypotension, anaphylaxis, nephritis
or thrombocytopenia, and manifested by symptoms such as fever,
headache, dizziness/lightheadedness, musculoskeletal pain,
petechiae, and pruritus.

Gastrointestinal symptoms: Symptoms such as nausea, anorexia, and

abdominal pain are rarely severe enough to discontinue treatment.

Discoloration of body fluids: Orange-red discoloration of body fluids,

such as urine and breast milk, is expected and harmless. This
phenomenon is reversible after cessation of treatment.

ADHERENCE MONITORING IN PATIENTS ON TPT

The model of implementation of TPT for PLHIV is integrated with ART

care. The following should occur when patients present for scheduled
visits.
Patients on 3HP should be monitored baseline,1 month and 3 months.
3HP visits should be aligned with ART visits. At every visit:
Screen for symptoms of active TB
Monitor for signs and symptoms of adverse events
Monitor adherence at pharmacy and during consultation
Conduct pill counts at every visit
Conduct follow-up home visits for patients who don’t come for refills

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How to handle missed doses of 3HP
Encourage a weekly routine of taking medications i.e. Sunday. If a
patient misses a day of treatment, they can take 3HP within 3 days of
the missed day and then revert to their normal weekly routine

• If they miss a dose for more than 3 days there are two options:
- They may skip this dose and go back to their original chosen weekly
day and continue until all 12 doses have been taken OR
- Start the new schedule on the new day in which they remembered
to take the missed dose
• The 12-dose course should be finished by 16 weeks which provides
some leeway for missed doses

Classification of Outcomes for TPT

TPT Outcome Definitions

ompleted Completed 12 weeks’ worth of
medication in 16 weeks

Stopped
Treatment stopped by clinician for
adverse event or any other reason

Active TB Developed TB disease whilst on TPT

Lost to follow-up Did not complete the 12 doses in 16

weeks

Died
Dies whilst of TPT treatment

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