Implementation and subgroup considerations The GDG agreed that the benefits of all the treatment options being recommended outweigh their potential harm. Programmes and clinicians should also consider the characteristics of each individual concerned to maximize the likelihood that treatment is completed as expected. The decision on which treatment to offer should not be confined to the manner in which it was studied in a trial (e.g. 1HP to replace 9H) but by considerations such as age, risk of toxicity or interaction, co-morbidity, drug susceptibility of the strain of the most likely source case, availability – including child-friendly formulations – and the individual’s preferences. All recommended treatment options are possible in people with HIV. On the basis of existing practice, albeit in the absence of a direct comparison, the GDG judged that 9H is an equivalent option to 6H in countries with a strong health infrastructure. It noted, however, that 6H is preferable to 9H from the point of view of feasibility, resource requirements and acceptability to people who need TPT. Nonetheless, both 6H and 9H have become less preferable for TPT as shorter rifamycin-containing regimens become more widely available, as they facilitate administration for both the person taking them and health-care services. The conditional recommendation to give at least 36 months of daily isoniazid monotherapy to people with HIV in high TB transmission settings is now considered obsolete and has been withdrawn in this second edition of the consolidated guidelines on TPT (see above). The GDG agreed unanimously that, in individuals aged < 15 years, the benefits of 3HR outweigh the harm, given the safety profile of this regimen, the higher rate of completion as compared with isoniazid monotherapy and the availability of child-friendly, fixed-dose combinations of rifampicin and isoniazid. The GDG therefore made a strong recommendation despite the low certainty of the evidence. Data on the safety and pharmacology of rifapentine in children < 2 years have recently become available, which make it possible to administer the 3HP regimen even to children in this age group (12,98). The data from the 1HP trial reviewed for the 2020 update of the guidelines relate only to individuals with HIV aged ≥ 13 years. The GDG considered that extrapolation of the effects to children aged 2–12 years is reasonable, although the daily dosage of rifapentine in this age group has yet to be established. In the absence of further data, the 1HP regimen thus continues to be recommended only for individuals aged ≥ 13 years. The GDG that prepared the 2020 update of the guidelines considered that there was moderate certainty that 4R is not inferior to 9H. When considering the good safety profile of the 4R regimen and its reduced length, it also recommended that this regimen could also be used in high TB-burden settings. When deciding to make a conditional recommendation, the GDG considered that most people would prefer a shorter regimen but raised concern about the variable acceptability; uncertainty in resource requirements, given its higher cost; the feasibility of delivering appropriate dosages in lower weight bands with the current formulation of single-dose rifampicin capsules; and a potential reduction in equity if it deflects resources and decreases the treatment coverage of more vulnerable individuals. The GDG agreed that introduction of 4R should be preceded by mobilization of appropriate resources to avoid shortages in other programmatic needs. The GDG also observed that the impact on equity could change if the price and policy of use of 4R changed. (See Annex 4 for more details of the GDG decisions.) With respect to 1HP, the GDG that prepared the 2020 update of the guidelines concluded that there was low certainty that its effectiveness would be non-inferior to 9H when used in programmatic settings for different populations at risk. When also taking into account the good safety profile of 1HP and the much shorter regimen than other approved TBI regimens, the GDG recommended that this regimen could also be used in high TB-burden settings and in people without HIV infection. The GDG considered that most people would prefer its much shorter duration over other options and that its implementation would be feasible but raised concern about uncertain resource requirements and potentially reduced equity. These considerations led to a conditional recommendation. (See Annex 4 for more details of the GDG decisions). In the update to the 2020 guidelines, the GDG considered that all regimens could be used in any setting, regardless of TB burden, provided that the health infrastructure could ensure that treatment is given correctly without creating inequity and that TB disease could be excluded reliably before initiation of treatment. The GDG noted that all the TPT regimens can be self-administered. A number of recent trials and other studies attest to the feasibility of self-administered treatment of 3HP as compared with directly observed treatment (28,99–101). The GDG noted that a requirement for direct observation could be a significant barrier to implementation. People receiving TPT should be supported with advice on treatment and management of adverse events during encounters with health services. The GDG further noted that individuals receiving treatment, clinicians providing treatment and programme managers would prefer shorter to longer regimens. Drug–drug interactions Rifamycins induce certain cytochrome P-450 enzymes and may therefore interfere with medicines that depend on this metabolic pathway by accelerating their elimination. These medicines include ART and many other medicines, such as anticonvulsants, antiarrhythmics, quinine, oral anticoagulants, antifungals, oral and injectable contraceptives, corticosteroids, cyclosporine, fluoroquinolones and other antimicrobials, oral hypoglycaemic agents, methadone and tricyclic antidepressants. These medicines might therefore have to be avoided when taking rifampicin- or rifapentine-containing regimens or their dosages should be adjusted. TPT regimens containing rifampicin or rifapentine should be prescribed with caution to people with HIV who are on certain ART because of potential drug–drug interactions. TPT regimens can significantly decrease the concentrations of boosted protease inhibitors or nevirapine and should not be co-administered, including to HIV-exposed infants on TPT. The results of a phase 1/2 clinical trial of 3HP and dolutegravir in adults with HIV indicate good tolerance and viral load suppression, no adverse events higher than grade 3 related to 3HP, and do not indicate that rifapentine reduced dolutegravir levels sufficiently to require dose adjustment (102). Recent work continues to support this position (103–105). Preliminary evidence from the phase 1/2 trial also supports an immediate start of TPT among ART-naive people starting a dolutegravir-based regimen. When 3HP was administered to 50 people with HIV who were ART-naive and who were started on dolutegravir-containing ART, high rates of viral suppression, comparable to those with 6H, were achieved, and no difference in grade 3 or 4 adverse events was observed (105). Administration of rifapentine with raltegravir was also found to be safe and well tolerated (106). The 3HP regimen can be administered to patients receiving efavirenz-based antiretroviral regimens without dose adjustment, according to a study of pharmacokinetics (107). No dose adjustment is required when rifampicin is co-administered with efavirenz, and the two drugs can be used together safely. When given with rifampicin, however, the dose of dolutegravir has to be increased to 50 mg twice daily (108), a dose that is usually well tolerated and shows equivalent efficacy as efavirenz in viral suppression and recovery of CD4 cell count. Concurrent use of alcohol should be avoided with all TPT regimens. Pregnancy In preparation for the 2020 update of the guidelines, a systematic review was conducted in 2019 to assess evidence in support of or against the results of one RCT that showed adverse pregnancy outcomes associated with use of IPT (109,110). Further, three non-randomized, comparative observational studies provided data on at least one of the pregnancy outcomes in women with HIV (111–113) (see PICO 9 in Annex 3). While the RCT showed a higher risk of adverse pregnancy outcomes in women who initiated IPT during pregnancy (Mantel-Haenszel OR stratified by gestational age, 1.51 95% CI 1.09 ; 2.10), all three of the other studies reported an overall OR < 1, suggesting the opposite (I2=80%, P=0.002). A meta-analysis of two observational studies that reported adjusted estimates and the data of which could be pooled suggested a lower risk for composite adverse pregnancy outcomes (OR 0.40, 95% CI 0.20 ; 0.74) (111,112). The observational studies did not reproduce the associations with IPT reported in the RCT for individual adverse outcomes, such as fetal or neonatal death, prematurity, low birth weight and congenital anomaly. No statistically significant risks for maternal hepatotoxicity, grade 3 or 4 events or death were reported in any of the four studies. The GDG therefore concluded that there were insufficient grounds to change previous guidance or to develop a separate recommendation for use of IPT in pregnant women with HIV, and no evidence-todecision table was developed for this PICO in Annex 4. The GDG considered that systematic deferral of IPT to the post-partum period would deprive women of its protective effect at a time when they are more vulnerable to TB. Moreover, a study published in 2023 showed no difference in acquisition of TB in the infants of mothers with HIV who received IPT during pregnancy and those who received it post partum (114). Appropriate care during the antenatal and postnatal periods and during delivery may reduce the risk of adverse pregnancy outcomes. While baseline testing for liver function is strongly encouraged when IPT is given during pregnancy, it is not required, and routine liver function testing when IPT is given in pregnancy is not indicated unless other risk factors for liver toxicity are present. Routine vitamin B6 supplementation should nevertheless be considered. The GDG agreed that the area requires more research, such as on the pharmacokinetics of IPT, pharmacovigilance and other preventive treatment regimens. Rifampicin is generally considered safe in pregnancy. There are few data on the pharmacokinetics and safety of rifapentine in pregnancy, precluding use of 3HP and 1HP in pregnancy until more information on the appropriate dosing and safety of these regimens becomes available. In a study of 3HP in 112 pregnant women, the rates of spontaneous abortion and birth defects were similar to those in the general US population (97). Moreover, the results of a recent trial in Africa showed that the frequency of spontaneous abortion and adverse pregnancy outcomes (when analysed as a composite outcome) were similar in 63 women exposed to 3HP and in 142 women who were not exposed to 3HP (115). Other subgroups and settings In candidates for transplantation or anti-TNF treatment, it may be particularly important to complete TPT rapidly; therefore, shorter regimens such as 1HP and 3HP could be advantageous. Likewise, shorter treatment could be more suitable than longer regimens for homeless people and people being released from prison, for whom there is limited opportunity for repeated encounters for treatment. Other populations, in addition to people with HIV on ART, who may be more commonly at risk of drug–drug interactions with rifampicin, include women of childbearing age on contraceptive medicines (who should be counselled about potential interactions and consider nonhormonal birth control while receiving rifampicin) and opiate users on substitution therapy with methadone. Other considerations With the widespread use of rifampicin-containing fixed-dose combinations to treat drug-susceptible TB, the demand by TB programmes for single-dose rifampicin has decreased. Quality-assured supplies of rifampicin should be used. Provision of 4R outside TB programme centres (e.g. primary care facilities, HIV programmes) should be accompanied by stepwise guidance on maximizing the effect of rifampicin and on avoiding its diversion for improper use as a broad-spectrum antibiotic in the community. Fixed-dose combinations of rifampicin plus isoniazid – including dispersible formulations for children – should be used when possible to reduce the number of pills to be taken. Combinations of 300 mg isoniazid with 300 mg rifapentine are now also available, which will facilitate administration of 3HP to adults (12). For children, dispersible formulations of both isoniazid and rifapentine can facilitate administration of 3HP. Shorter regimens are also more likely to be completed. Concern about adherence should not be a barrier to starting TPT, and support should be provided to ensure better person-centred care. There are no data-supported recommendations on handling interruptions of TPT, such as on how many missed doses can be made up for by prolonging treatment without compromising efficacy. Individuals at risk of peripheral neuropathy, such as those with malnutrition, chronic alcohol dependence, HIV infection, renal failure or diabetes or who are pregnant or breastfeeding, should receive pyridoxine (vitamin B6) when taking isoniazid-containing regimens. A different dose of isoniazid from that proposed might be required to avoid toxicity if there is a high population prevalence of “slow acetylators”. Combination tablets of co-trimoxazole, isoniazid and pyridoxine could be given to people with HIV. Lack of availability of pyridoxine should not be a reason for withholding TPT. Interventions to enhance adherence and completion of treatment should be tailored to each risk group and local context. A systematic review conducted for the WHO 2015 TPT guidelines provided heterogeneous results for interventions to improve treatment adherence and completion, and the evidence was considered inconclusive (39). WHO guidance for TB care and support includes several interventions to support adherence, which could also be applied to TPT (116,117). In areas with high background resistance to rifampicin, such as countries in eastern Europe, it is particularly important to test the strain from the presumed source for drug susceptibility so that TPT is more likely to work. Contacts of patients with laboratory-confirmed isoniazid-resistant, rifampicin-susceptible TB may be offered a 4-month regimen of daily rifampicin. If there is rifampicin monoresistance or other contraindications to rifampicin, an isoniazid regimen of ≥ 6 months may be the most appropriate option. Unfortunately, in many settings, rifampicin resistance is often accompanied by isoniazid resistance – MDR-TB – so that other drugs are required (see below).