Recommended dosages of TPT medication
The WHO task force on pharmacokinetics and pharmacodynamics analysed available evidence from clinical trials of rifapentine and suggested a simplified dose for various weight bands for 3HP and 1HP as summarized in Table 5.2 (2020 guideline update). Table 5.2 presents standard dosing for the recommended TPT regimens by age and body weight.
a A triple pill combination containing isoniazid 300 mg + pyridoxine 25 mg + sulfamethoxazole 800 mg + trimethoprim 160 mg (scored) is the preferred alternative regimen for PLHIV being considered for isoniazid monotherapy (1 pill daily for adults, half pill for children 5 years and older of age and quarter for children < 5 years of age).
b 300 mg formulation can be used to reduce the pill burden.
c Expected to become available in a near future.
d Dosage may differ among adults and children in overlapping weight-bands.
e Levofloxacin 100 mg dispersible tablets available for children.
Regimens containing isoniazid and rifampicin can be used in individuals of all ages, however there are limited pharmacokinetic data to inform appropriate dosage and safety of rifapentine among children < 2 years of age and hence the 3HP regimen is recommended only for use in children two years and older. Furthermore, data from the 1HP trial relates only to individuals 13 years of age and above. Appropriate dose of daily rifapentine in children < 13 years is therefore not yet established and hence suitability of 1HP for those under 13 years of age needs to be reviewed after data from pharmacokinetic and safety studies from children become available.
Availability of appropriate formulations
Rifampicin: Given the widespread use of rifampicin-containing FDCs to treat drug-susceptible TB, single-dose rifampicin is less commonly used, hence less procured, and therefore likely to be available only in limited quantities to national programmes. Additionally, child-friendly dispersible formulations of single-dose rifampicin are not available currently. If 4R is the regimen of choice, the demand for loose tablets of rifampicin will increase and programmes would need to identify quality-assured suppliers for rifampicin single doses. Use of rifampicin should also be regulated and limited for use as part of the TPT regimen and not diverted for use as a broad-spectrum antibiotic. The supplies of 4R to peripheral centres (primary care facilities, HIV programmes) should be accompanied by stepwise guidance on specific use of rifampicin
Isoniazid plus rifampicin FDC: Child-friendly dispersible FDCs of 3HR are available and already used in many countries for treatment of TB disease among children. The same formulations can be used for TPT. Child-friendly FDCs should be preferred over single pills to reduce the pill burden. Similarly, FDCs used for treatment of adult TB disease may be used for TPT among adults.
Isoniazid plus rifapentine (weekly/daily): The only formulation for rifapentine currently available is the 150 mg single tablet. The pill burden for both 3HP and 1HP among adults with the single formulation is very high. Development of 3HP FDCs (with a one-to-one ratio of rifapentine and isoniazid) has begun with an adult 3HP FDC likely to be available in 2020. This will reduce the pill burden for 3HP in adults from nine to three pills. There is also a single rifapentine 300 mg tablet being developed, which may also be available in 2020, to reduce the pill burden for 1HP to just three pills as well. Similarly, child-friendly 3HP FDC formulations (150 mg/150 mg) when available will reduce the pill burden for children. Further research to define the appropriate dose of rifapentine and identify drug–drug interactions (such as dolutegravir) among children under two years of age for both 3HP and 1HP will facilitate the use of 3HP/1HP in this age group.
Isoniazid + cotrimoxazole + pyridoxine combination: is available at discounted price through STBP/GDF and the Global Fund Pooled Procurement Mechanism. These combination pills may be considered as an alternative for PLHIV when: shorter rifamycin-containing regimens are not available, drug–drug interactions occur, or during gradual scale-up. These are single scored tablets. Therefore, if the required dose is one third of the adult formulation, this FDC cannot be used for children below five years of age living with HIV.
Role of pyridoxine and its availability
Pyridoxine (B6): One of the undesirable side-effects of long term treatment with high-dose isoniazid is peripheral neuropathy that develops secondary to a deficiency of vitamin B6 (pyridoxine) during therapy. Individuals at risk for peripheral neuropathy, such as those with malnutrition, chronic alcohol dependence, HIV infection, renal failure or diabetes, or who are pregnant or breastfeeding, should receive vitamin B6 supplements when taking isoniazid-containing regimen. Additionally, pregnant and postpartum women and exclusively breastfed infants should receive vitamin B6 while taking isoniazid. The standard dose of pyridoxine when used prophylactically for prevention of neuropathy among patients taking isoniazid is 10–25 mg/day. Peripheral neuropathy occurs infrequently among other patients taking standard doses of isoniazid, which is easily recognized (as symmetrical numbness and tingling of the extremities) and usually easily reversible upon withdrawal of isoniazid and institution of high-dose pyridoxine therapy (100–200 mg/day). Therefore, routine pyridoxine supplementation with isoniazid is probably not necessary and its absence should not become a barrier to TPT initiation.
In vivo, pyridoxine is converted into coenzymes which play an essential role in the metabolism of protein, carbohydrates, fatty acids and several other substances, including brain amines. Isoniazid apparently competitively inhibits the action of pyridoxine in these metabolic functions (59). The incidence of peripheral neuropathy correlates closely with the dose of isoniazid used. Studies from the 1950s (60–62) reported that while a large proportion (> 40%) of people receiving high-dose isoniazid (16–24 mg/kg/day) developed signs and symptoms of peripheral neuropathy, only 2% of those receiving 4–6 mg/kg/day developed neuropathy. While high-dose isoniazid may be relevant to the treatment of certain forms of TB disease, in TPT the standard dose of isoniazid is used. Signs of toxicity appear much later among those taking lower doses of isoniazid. The earliest symptom is usually paraesthesia, followed by pricking pain and burning sensation in the feet and later in the hands (symmetrical numbness and tingling). If untreated, the symptoms worsen and cause distress. These symptoms are easily recognized and are usually easily reversible upon withdrawal of isoniazid and institution of pyridoxine therapy.
Routine pyridoxine supplementation in otherwise healthy individuals receiving standard dose isoniazid is probably not justified and not required (62). However, even low doses of isoniazid can produce neuropathy among malnourished patients (up to 20%) (63), and among slow acetylators of isoniazid7 (reaching 20% with 4–6 mg/kg isoniazid). Other individuals known to have higher risk for peripheral neuropathy include those with chronic alcohol dependence, HIV infection, renal failure or diabetes, or women who are pregnant or breastfeeding. Concurrent administration of pyridoxine with isoniazid protects against the development of peripheral neuropathy in these individuals.
An adequate human diet containing 1–2 mg of vitamin B6 compounds daily may protect against isoniazid toxicity. Good dietary sources of vitamin B6 include carrots, spinach, peas, potatoes, milk, cheese, eggs, fish, meat and fortified flour. Otherwise, a small daily dose of 10–25 mg pyridoxine may be given alongside TPT in high risk individuals. Pyridoxine may be given as a part of vitamin B-complex supplements, especially in those who may also be deficient in other vitamins. For established isoniazidinduced peripheral neuropathy, pyridoxine should be given at a larger therapeutic dose of 50–75 mg daily and even up to 100 mg to 200 mg per day (64). It is important to maintain pyridoxine supplementation at the right dose because higher levels may interfere with the antibacterial activity of isoniazid. Moreover, excessively high doses of pyridoxine-2000 mg daily or more have been reported to cause toxicity, including peripheral neuropathy (65–67).
Currently, the pyridoxine formulation available on the Global Fund’s Pool Procurement Mechanism, and the Global Drug Facility products list are 50 mg uncoated tablets and 100 mg film coated tablets (51). Both formulations are primarily suited for therapeutic use and are difficult to fraction to the dosage recommended for prophylactic supplementation. National programmes may consider local procurement of a quality assured product of lower dose pyridoxine (10–25 mg) for use among high risk individuals, or alternatively procure vitamin B-complex. Among PLHIV, use of isoniazid-B6- cotrimoxazole combination tablet may be considered. Programmes are nonetheless also advised to stock higher dose pyridoxine (which is available through the GDF products list) for the treatment of peripheral neuropathy.
Key message: During the scale-up of TPT services, lack of pyridoxine should not become a barrier to starting TPT. Clinical evaluation of the risk for neuropathy should be undertaken before prescribing of pyridoxine supplementation
Introduce and scale-up TPT
Considerations for programmatic implementation of TPT
• Define roles and responsibilities for cadre of health care workers to prescribe TPT. Trained doctors, nurses and peripheral health care workers can evaluate and start TPT once TB disease is reliably ruled out following national protocol. Nurses and frontline health care workers in the periphery can also be trained to monitor TPT and make decisions about whether TPT should be suspended or changed (e.g. in the case of adverse events) or restarted (e.g. after an interruption by the person on treatment). In most instances there is no need to seek opinion of a medical doctor or a specialist for such decisions however, there should be a provision to solicit such support in case it becomes necessary.
• Define levels of health care system where TPT can be started and medicines refilled for continuation.
• Develop SOPs for TPT initiation and follow up to:
– maintain flow of persons considered for TPT in various health facilities and across different service points within those facilities;
– ascertain the role and responsibilities of health providers, community health workers and key stakeholders (such as malnutrition care services, prisons, correctional facilities, refugee camps, mining communities) in evaluation of eligibility and start of TPT;
– provide adherence support for TPT;
– manage TPT interruptions; and
– identify, document and manage adverse drug events.
• Establish TPT services in all relevant service delivery sites (such as TB treatment site, ART centres, maternal and child health services centre, community health centre).
• Decentralize to TB facilities providing ART or TB treatment (initiation and continuation) closest to person’s residence to minimize travel time to receive TPT.
• Leverage on existing TB, HIV and general health services to provide specialized care as needed for people receiving TPT (such as management of adverse events, drug–drug interactions, special situations (pregnancy)).
• Evaluate capacity and availability of health care workers and assess additional needs for nationwide scale-up of TPT services.
• Evaluate availability and capacity of community health workers and other networks (such as former TB patients) that can contribute to TPT service delivery and support to individuals.
• Build capacity:
– through initial training, sensitization and capacity building of staff;
– of primary care doctors, nurses and other health care workers in history taking, symptom screening and referral for investigations, assessment of eligibility for TPT and starting TPT; and
– of community health workers in the provision of TPT and follow-up.
• Undertake phase-in/phase-out planning for TPT medications (from a procurement perspective) as the national programme transitions to shorter TPT regimens. This is important during the introduction of the new regimen.
• Review and strengthen the mechanism for quantification, ordering and un-interrupted supply of commodities (such as TPT medications, pyridoxine).
• Address specific issues regarding TPT for children to:
– coordinate TPT with multiple family member households (parents/grandparents) as children may receive care at multiple service delivery sites (such as maternal and child health services, TB or HIV centres);
– build capacity on counselling and actions on post-dose emesis and indications for redosing; and
– provide information on food to mask the taste of medication.
• Strengthen systematic recording and reporting, including information from the case form or alternatively capture data on electronic platforms. Key data variables should be integrated into the HMIS for monitoring and evaluation of performance.
TPT initiation and pre-TPT baseline assessment
Once TB disease is ruled out, and decision to consider TPT is made, baseline assessment to determine the eligibility of an individual for TPT should be undertaken. The baseline assessment includes personal and medication history and investigations as per national guidelines.
• Personal history: elicit information relevant for TPT initiation and continuation, such as
– allergy or known hypersensitivity to TB drugs (isoniazid, rifampicin, rifabutin or rifapentine)
– HIV status and ART regimen
– pregnancy status or birth control method used
– comorbidity: assess presence of comorbidities (such as malnutrition, diabetes, viral hepatitis) and record medications being taken
– contacts of drug resistant TB patients (isoniazid, rifampicin only or MDR-TB)
– potential contraindications to TPT: such as active hepatitis (acute or chronic) or known elevation in transaminases (> 3x Upper Limit of Normal), regular and heavy alcohol consumption and symptoms of peripheral neuropathy. These conditions should prompt detailed investigations and application of clinical judgement to weigh harms versus the benefits of TPT, and timing to start TPT if benefits outweigh harms. History of past TB treatment or current pregnancy should not be considered as contraindications for starting TPT.
• History of medication: elicit medication history to guide the choice of TPT regimen or determine the need for modification of treatment of comorbid conditions. Certain drug classes – ARVs, opioids, antimalarials – often affect TPT.
• Liver function test (LFT): There is insufficient evidence to support mandatory or routine LFT at baseline (68), and perhaps the benefit of TPT without LFT would likely outweigh harms, particularly with less hepatotoxic regimen. However, where feasible, baseline testing is strongly encouraged for individuals having risk factors – such as history of liver disease, regular use of alcohol, chronic liver disease, HIV infection, age more than 35 years and pregnancy or immediate postpartum period (within 3 months of delivery). In individuals having abnormal baseline LFT results, sound clinical judgement is required to determine if the benefit of TPT outweighs the risk of adverse events. These individuals should be tested routinely at subsequent visits.
Key point: Routine LFT is not necessary prior to starting TPT. Available evidence suggests that close clinical monitoring of signs and symptoms of liver disease is sufficient for early detection and management of adverse events, more so with shorter rifamycin-containing TPT regimen. However, LFT is encouraged for individuals having additional risk factors.
• Social and financial situation: of the person and the family should be assessed and support required to overcome the barriers for TPT completion identified.
– Explain to the individual that (s)he is eligible for TPT and provide key messages to the individual and her/his family/treatment supporter on:
▪ rationale for TPT and benefits to the individual, the household and the wider community;
▪ TPT being available free of charge through national programmes;
▪ TPT regimen prescribed, including the duration, directions for intake of medicines and follow-up schedule;
▪ potential side-effects and adverse events involved and what to do in the event of various side-effects;
▪ the importance of completing the full course of TPT;
▪ reasons and schedule of regular clinical and laboratory follow-up for treatment monitoring; and
▪ signs and symptoms of TB and advise on steps if they develop them.
– Agree on the best approach to support treatment adherence, including the most suitable location for drug intake and treatment support based on each individual's preference. Options may include:
▪ Location: Home, community or health facility (with counselling support).
▪ Treatment supporter: Assess if a treatment supporter is needed or self-administration is possible. If a treatment supporter is needed, options may include an oriented family member/ community volunteer/workplace treatment partner or health care worker. For a weekly regimen, it is preferable that intake of each dose is directly observed by the oriented family member, community member, workplace treatment partner, or health care worker (either in person or through a digital tool).
▪ Digital tools: include video observed treatment (VOT)/phone missed call/SMS reminders.
Adherence to the TPT course and treatment completion are important determinants of clinical benefit, both at individual and population levels (Chapter 7). Irregular or inadequate treatment reduces the protective efficacy of TPT regimen. Further, poor adherence or early cessation of TPT can potentially increase the risk of the individual developing TB including drug-resistant TB (although not supported by existing evidence from research settings). It is known that the efficacy of TPT is greatest if at least 80% of the doses are taken within the duration of the regimen. The total number of doses taken is also a key determinant of the extent of TB prevention (69,70).
Trials have used varied definitions for completion of course of preventive treatment – 80% of recommended dose consumed within 120% of planned TPT duration (71), or 90% of recommended dose consumed within 133% of planned TPT duration (72). Table 5.3 below summarizes all recommended regimens and suggested criteria to assess the completion of different regimen. It is expected that shorter regimens are better adhered to and have higher rate of treatment completion..
a 90% of recommended number of doses
National programmes should tailor mechanisms to improve adherence to the specific needs of risk groups and local country context. In general, all TPT options can be effectively self-administered. TPT is unlikely to increase the risk of selection of drug-resistant mycobacteria, contrary to treatment of TB disease. The modality for treatment provision and adherence support should be determined primarily by the individual’s preference. WHO 2015 TPT guidelines reveal heterogeneous results with inconclusive evidence regarding interventions to improve treatment adherence and completion (73). However, pill counting by providers at every contact with the person on TPT is inexpensive and feasible, and has been shown in a clinical trial to have excellent predictive value for TB risk reduction (69); this should be incorporated into all TPT services. Also, procurement of blister packaged products may facilitate better adherence monitoring compared to pill bottles.
WHO guidelines for treatment of drug-susceptible TB proposes several interventions to support adherence, which could also be applied to TPT (74). These include peer support networks, coaching and educational interventions including quality counselling and VOT. National programmes should dedicate necessary financial and human resources to strengthen adherence mechanisms for TPT and not allow concerns about adherence or the lack of adherence tools to become a barrier in scale-up of TPT services.
Management of treatment interruptions: No recommendations informed by evidence exist on how to manage interruption of TPT, i.e. how many missed doses can be made up for by prolonging treatment without compromising efficacy. Chapter 7 summarizes suggested actions to manage preventive treatment interruptions based on the above indicative definition of preventive treatment completion. National programmes may choose between more or a stringent definition for treatment completion (90% of recommended doses within 120% of treatment duration or 80% of recommended doses within 133% duration or a combination of both).
In addition to monitoring treatment completion (see also Chapter 8), a number of unfavourable endpoints are proposed that could be used to trigger a review of case management and, in some instances, changes to treatment (see list below).
• Failed – development of TB disease any time while on TPT
• Died – death for any reason while on TPT
• Lost to follow-up – TPT interrupted by person for eight consecutive weeks or more for 6H, four consecutive weeks or more for 3HP, 3HR and 4R, and 10 consecutive days for 1HP
• TPT discontinuation due to toxicity – by clinician due to adverse events or drug–drug interactions, with or without restart or switching of regimen
• Not evaluated – such as records lost, transfer to another health facility with record of TPT completion
Monitoring and support during TPT
Individuals receiving TPT should be monitored at every contact with health care providers. This may be done at least monthly or more frequently as required for care of persons on TPT or as per national policy mandate. Nurses and other frontline health care workers in the periphery can be trained to monitor and decide whether TPT should be changed due to adverse events or restarted (e.g. after an interruption by the person on treatment). Medical doctors or specialists are not required routinely for such decisions, but their services should be made available when required.
Alternatively, monitoring may be aligned with mechanisms under differentiated service delivery (DSD) model for PLHIV where implemented, or schedule for collection of other medication (such as ARV). As a principle, the schedule for follow-up visit or drug collection should consider the individual’s convenience as paramount. It is important that an informed decision to not take treatment by a person offered TPT, or to stop it after having started it, be respected; people should not feel coerced to take treatment (see also ethical principles in Chapter 9). During every contact with the person receiving TPT, the provider should:
• reinforce the person’s understanding of symptoms of TB disease, reasons for TPT, and the importance of completing the course.
• check for presence of signs or symptoms of TB disease; and if diagnosed with TB disease, TPT should be stopped and curative TB treatment started.
• measure weight, if possible, and adjust dosage accordingly. This is especially important for young children as rapid weight gain can normally occur in growing infants and young children over the period of TPT, thus requiring dosage adjustment. On the other hand, documented weight loss or failure to thrive is an early clinical indicator of TB disease.
• check for adverse drug reactions, and manage any toxicity identified or refer for specialist care if needed.
• remind the person on TPT of the need to contact a health care worker/provider if they notice adverse events, such as anorexia, nausea, vomiting, abdominal discomfort, persistent fatigue or weakness, dark-coloured urine, pale stools or jaundice. These are suggestive of liver injury and require urgent evaluation. If a health care provider cannot be consulted at the onset of such symptoms, the person on TPT should be advised to stop treatment immediately.
• elicit reasons for any missed dose and extend necessary support to enable future adherence to TPT.
• continue the management of comorbid conditions and consult with the treating doctor when necessary.
• ask about pregnancy, breastfeeding and contraceptive use.
• make a record of the visit, drug intake and findings using information from individual case files or forms prescribed by the national programme.
Key point: At every opportunity TPT providers should remind the recipients about potential adverse events and re-emphasize signs and symptoms that should alert them to contact the health care worker and/or stop TPT.
Differentiated HIV service delivery and implications for TPT scale-up
High HIV burden countries, particularly in sub-Saharan Africa, are increasingly scaling up HIV DSD. DSD models for recipients of HIV care who are stable use a person-centred approach and aim to shift people who are doing well on treatment, to less-intensive models requiring fewer visits to health facilities. DSD models for delivery of TB services can be modified to accommodate the different needs of PLHIV of different ages. They can also be expanded to non-PLHIV populations at increased risk of developing TB disease, including household contacts of TB patients.
Various models of differentiated ART delivery have been tested recently including health care workermanaged group models; models driven by people taking TPT; facility-based individual models; and community-based individual models. A few examples of implemented DSD models (75,76) are listed below.
• Appointment spacing (facility-based, individual model): multimonth prescriptions and rapid circuit established at high-volume facilities to enable stable patients to have a quick check-up and proceed directly to the pharmacy to collect medication.
• Community-based points of ART distribution (community-based individual models): screening and drug distribution are provided by lay health workers.
• Adherence clubs (facility- and community-based): treatment distribution during support group meetings (every three to six months).
• Specialized child-friendly clinics providing two to eight weeks of supply of TPT and ART, depending on travel schedules of the individual recipient.
• Remote pick-ups from commercial pharmacies or pillboxes (“medication ATMs”) without any community health care worker involvement.
• DSD approaches for PLHIV who are stabilized are expected to reduce overcrowding at ART clinics, enhance the quality of care, improve adherence and viral suppression rates, and increase convenience for people. DSD is expected to enable appropriate support and education on potential adverse events, tolerability and importance of treatment completion. In principle, all recommended TB services should be incorporated within these models of service delivery and existing mechanisms to review the quality of ART services should be harnessed for monitoring the implementation of intensified TB case finding (ICF) and TPT services. The following interventions should be considered for TB care under all DSD programmes.
• All recommended TB/HIV services offered to PLHIV – including regular TB screening, referral for diagnosis when TB symptoms are noted, and TPT if TB disease is ruled out – should be done at regular intervals (at least once a quarter).
• TPT may be started during pre-ART evaluation or before starting spaced appointments under DSD, particularly for the shorter regimens (1HP) or at the time of follow-up visit to the health centre if longer regimens (6H, 4R, 3HR, 3HP) are implemented as per national guidelines.
While TPT regimens of any length can be provided under DSD, it is critical to establish a mechanism to identify and manage any adverse event considering the duration of TPT regimens and document TPT indicators systematically (see Chapter 8). Fig. 5.1 depicts the key elements to integrate TPT into DSD initiatives.
As more countries implement DSD, one key opportunity to scale up TPT services is presented by a country’s decision to transition to dolutegravir (or other new regimens) based ART. Several countries in eastern and southern Africa have decided to align transition to TLD (tenofovir, lamivudine, dolutegravir) regimen with the scale-up of shorter TPT regimens (3HP). As transition to new ART entails more frequent clinical follow-up, national programmes are also leveraging this opportunity to start TPT and generate implementation experience to guide national scale-up.
Key point: Differentiated HIV service delivery is being scaled up for ARV services. Intensified TB case finding and TPT should be integrated within these models. Establishing DSD should not become a reason for delaying or denying benefits of TPT to PLHIV. In fact, patient visits should be scheduled such that they can pick up ARV and TPT drugs at the same time.
Provision of TPT for special populations
TPT among pregnant and postpartum women
Pregnant women living with HIV are at higher risk for TB during pregnancy and postpartum, which can have severe consequences for both the mother and the infant (77,78). Pregnancy should not disqualify women living with HIV or HIV-negative pregnant women who are eligible for receiving TPT since isoniazid and rifampicin, the medicines commonly used in preventive treatment, are considered safe for use in pregnancy (classified as Pregnancy Category C by U.S. Food and Drug Administration) (79,80). WHO conducted a systematic review for the 2019 update of LTBI guidelines, to assess evidence in support or against a recent report from one RCT showing increased risk of adverse pregnancy outcomes with IPT (81). However, review of all other existing evidence did not reproduce an association of IPT with adverse pregnancy outcomes, such as foetal/neonatal death, prematurity, low birth weight, congenital anomaly. Similarly, no statistically significant risks for maternal hepatotoxicity, grade 3 or 4 events or death were reported. Therefore, deferral of TPT to the postpartum period may not be required, and preventive treatment should be started during the antenatal and postnatal periods along with due care. Routine LFT is not indicated when TPT is given during pregnancy unless there are other hazards. Vitamin B6 supplementation should be given routinely to all pregnant and breastfeeding women on TPT. Rifampicin is generally considered safe for use during pregnancy, and no dose adjustment is needed although no safety or efficacy data are available specifically for pregnant and postpartum women (82). There are limited data on the efficacy and safety of rifapentine in pregnancy and therefore 1HP and 3HP should not be used in pregnancy until more safety data are available.⁸ Until such data become available, the triple pill combination of isoniazid + cotrimoxazole + B6 may be used for TPT among pregnant and postpartum women with HIV with due supportive care and monitoring.
Preventive treatment using isoniazid and or rifampicin can be safely given to breastfeeding women (83). Supplemental pyridoxine (vitamin B6) should be given to the infant who is taking isoniazid or whose breastfeeding mother is taking isoniazid. Similar to pregnant women living with HIV, the triple pill combination of isoniazid + cotrimoxazole + B6 may be used among breastfeeding women with HIV.
Key point: The triple pill combination of isoniazid + cotrimoxazole + B6 may be the preferred option for TPT among pregnant and postpartum women with HIV until more safety data on the use of rifapentine-based shorter regimens are available.
Women receiving oral or hormonal contraceptives
Rifampicin and rifapentine interact with oral and hormonal contraceptive medications with a potential risk of decreased contraceptive efficacy. Women receiving oral contraceptives while on rifampicin or rifapentine should either:
• change the oral contraceptive pill and use an alternative (such as depot medroxyprogesterone acetate (DMPA) every eighth week (84) or higher dose oestrogen (50μ)) in consultation with a clinician;
• use another form of contraception, a barrier contraceptive or intrauterine device.
In women having hormonal contraceptive implants, the interval for replacing the implants may need to be shortened from 12 weeks to eight weeks (ACTG study A5338).
Liver disease or history of liver disease
Isoniazid and rifampicin/rifapentine are associated with hepatic damage. TPT should be initiated with caution among individuals whose baseline liver transaminase values are available and found to be more than three times the upper limit of normal. Preventive treatment should not be given to individuals with end-stage liver disease. However, it is known that IPT is well-tolerated among individuals with chronic hepatitis B or hepatitis C infections (85,86).
Acute hepatitis (and acute viral hepatitis)
Defer preventive treatment until the acute hepatitis has resolved.
Isoniazid and rifampicin/rifapentine are eliminated by biliary excretion. These drugs, therefore, can be given in standard dosages to patients with renal failure. Patients with severe renal failure should receive isoniazid with pyridoxine (vitamin B6) to prevent peripheral neuropathy.
People living with HIV
A key challenge in TPT with rifamycin-based regimen among PLHIV is drug–drug interaction. No dose adjustment is required when rifapentine or rifampicin are coadministered with efavirenz. The dose of dolutegravir needs to be increased to 50 mg twice daily when given with rifampicin (no dose adjustments are needed when rifapentine is used). Rifampicin or rifapentine TPT regimens should not be coadministered with protease inhibitors or nevirapine (for details see section on drug– drug interactions).
Management of babies born to mothers with TB disease
• Assess the newborn. If the newborn is not well, refer to a specialist/paediatrician. It is important to ensure that the mother receives effective TB treatment so that she is no longer infectious. Also, ensure that infection control measures are in place in the nursery, especially if the baby is in an inpatient facility for care when preterm or small at birth.
• If the newborn is well (absence of any signs or symptoms presumptive of TB), provide TPT and delay bacille Calmette-Guérin (BCG) vaccination until TPT is complete. Administer pyridoxine at 5–10 mg/day.
• If the infant is HIV-exposed (mother is HIV infected) and on nevirapine, IPT should be started. TPT with RH and HP cannot be given along with nevirapine prophylaxis since rifamycins decrease nevirapine levels and may result in increased mother-to-child transmission of HIV (87).
• At the end of TPT, perform TST or IGRA. If test for TB infection is negative or not available, give BCG (unless the baby is HIV-positive).
• If the mother is taking anti-TB drugs, she can safely continue to breastfeed. Mother and baby should stay together, and the baby may be breastfed while on TPT.
• Infant breastfeeding from a mother on either TB treatment or TPT should receive pyridoxine for the duration of the mother’s treatment.
Contacts of MDR-TB patients
Household contacts of patients with MDR-TB or isoniazid mono-resistance are at higher risk of TB infection than contacts exposed to drug-sensitive TB, however the risk of progression to TB disease does not differ among contacts in both groups (88). Studies have reported approximately 90% reduction in MDR-TB incidence with TPT (89). WHO recommends TPT among contacts exposed to MDR-TB patients following consideration of intensity of exposure; confirming the source patient and her/his drug resistance pattern (i.e. MDR-TB confirmed bacteriologically and susceptibility to a fluoroquinolone established); and ascertaining TB infection using IGRA or TST. This is to avoid potential adverse events with fluoroquinolone use for six months and preserve the option of using fluoroquinolone in the eventuality of MDR-TB disease among the contacts.
WHO suggests the use of levofloxacin for six months (paediatric formulation for child contacts) (see dosage in Table 5.2) along with other TB agents such as ethambutol or ethionamide if tolerated. Regardless of whether treatment is given or not, clinical follow-up should be done for two years and any emergent signs and symptoms suggestive of TB should be actively investigated and curative regimens started as needed. Contacts of individuals with rifampicin-resistant TB may be treated similarly to those for MDR-TB, but if isoniazid susceptibility is confirmed in index patients, contacts may be given 6H/9H. Among contacts exposed to individuals with known isoniazid-resistant TB, little evidence on choice of TPT regimens exists. However, data from Peru suggests that IPT is still effective (88). Also, 4R may be a TPT option in these situations.
Randomized controlled trials on MDR-TB preventive treatment are urgently needed to improve the evidence base. Results from following three RCTs of TPT among household contacts of MDR-TB patients are expected to become available in the next few years:
• TB CHAMP: testing six months of levofloxacin (Lfx) vs placebo in infants and young children less than five years of age exposed to MDR-TB (South Africa; ongoing recruitment and intending to publish by end 2021; http://www.isrctn.com/ISRCTN92634082).
• V-QUIN: testing 24 weeks of Lfx vs placebo in all ages with evidence of infection (Viet Nam; recruitment completed; date of ending data collection March 2022; https://anzctr.org.au/Trial/ Registration/TrialReview.aspx?id=369817).
• PHOENIx:testing 26 weeks of delamanid vs isoniazid in all ages (11 countries; estimated completion in mid 2025; https://clinicaltrials.gov/ct2/show/NCT03568383).
TPT and treatment for hepatitis C virus (HCV)
Rifamycins including rifapentine, are not recommended for use together with many of the directacting ARV drugs used to treat HCV, since rifamycins can decrease the concentration of HCV drugs to subtherapeutic levels (90,91). People with HCV should consult with their health care providers and start rifamycin-based TPT either before or after completing treatment for HCV.
TPT among people who use drugs
People who use drugs have a higher prevalence of TB infection and incidence of TB disease (92). Rifapentine has not been systematically studied among people who use drugs (PWUD). However, rifampicin is known to reduce exposures to opioid substitution therapies (OST) such as methadone and buprenorphine (93). In some people, this results in opiate withdrawal. For this reason, people taking 3HP, 3HR or 4R with OST should be closely monitored for signs of opiate withdrawal and other adverse events. Increasing the dose of methadone or buprenorphine when taking rifamycins can lessen the risk of withdrawal. IPT is safe to use among PWUD, although careful monitoring for liver toxicity is important (94). Drug use should never be taken as a blanket rationale for denying someone TPT. It is the responsibility of health care providers to proactively manage drug–drug interactions for PWUD safely (95).
⁴ See text and Table 5.2 for TPT options in multidrug-resistant tuberculosis (MDR-TB).
⁵ Pricing from StopTB/GDF Reference Price and Global Fund Catalogues – Stichting Iplussolutions, Global Fund Quality Assurance Suppliers, IDA Foundation, and the Partnership for Supply Chain Management http://www.stoptb.org/assets/documents/gdf/20191015%20GDF%20TB%20Medicines%20Budgeting%20Prices.pdf).
⁶ Data from clinical trial NCT02651259, Evaluating the pharmacokinetics, tolerability, and safety of once-weekly rifapentine and isoniazid in HIV-1-infected and HIV-1-uninfected pregnant and postpartum women with latent tuberculosis infection to be presented at Conference on Retroviruses and Opportunistic Infections 2020.
⁷ Isoniazid is metabolized by N-acetyltransferase 2 (NAT2), and a mutation in the NAT2 genotype leads to a persistence of isoniazid in the body and predisposing it to toxicity. The prevalence of NAT2 mutations differs geographically, with slow acetylators (known to be at risk of most drug-induced toxicity) being very common in some settings (83% in Egypt and 67% in the USA) but rare elsewhere (12% in China).
⁸ The IMPAACT 2001 study due to be presented at Conference on Retroviruses and Opportunistic Infections 2020, showing pharmacokinetic and relative safety of 3HP in pregnant women but highlighting the need for more studies.