تعليقTPTs for an infection with M. tuberculosis strains presumed to be drug-susceptible can be broadly categorized into two types: monotherapy with isoniazid for at least 6 months (IPT) and treatment with regimens containing a rifamycin (rifampicin or rifapentine). IPT has been the most widely used form of TPT, but the shorter duration of rifamycin regimens presents a clear advantage, making these regimens increasingly preferred. TPT for MDR/RR-TB requires a different approach, primarily with levofloxacin. The recommendations for these treatment options and the conditions under which they apply are discussed below.
- The following TB preventive treatment options are recommended regardless of HIV status: 6 or 9 months of daily isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or a 3-month regimen of daily isoniazid plus rifampicin. (Strong recommendation, moderate-to-high certainty of the estimates of effect).
- The following alternative TB preventive treatment options may be used regardless of HIV status: a 1-month regimen of daily rifapentine plus isoniazid or 4 months of daily rifampicin. (Conditional recommendation, low to moderate certainty of the estimates of effect).
TPT with isoniazid or rifamycins
A strong recommendation for TPT alternatives to 6 months of daily isoniazid monotherapy (6H), based on evidence of moderate to high certainty, has featured in previous WHO guidance (17,37,77). These consist of 3 months of weekly isoniazid plus rifapentine (3HP) and 3 months of daily isoniazid plus rifampicin (3HR). In the 2020 guidelines, the GDG made conditional recommendations for two regimens: daily rifapentine plus isoniazid for 1 month (1HP) and daily rifampicin monotherapy for 4 months (4R) in all settings, based on low to moderate certainty of the estimates of effect. In the current second edition, the recommendation from 2020 has been divided: recommendation 19 for regimens that are strongly recommended and recommendation 20 for alternative regimen options. Recommended TPT options are applicable in all settings, regardless of TB burden.
Justification and evidence
Daily isoniazid monotherapy
The efficacy of 6H or more has been shown in different populations and settings in a number of systematic reviews (21,78,79). A systematic review of RCTs in people with HIV showed that isoniazid monotherapy reduces the overall risk for TB by 33% (RR 0.67; 95% CI 0.51 ; 0.87) and that preventive efficacy reached 64% for people with a positive TST (RR 0.36; 95% CI 0.22 ; 0.61) (21). Furthermore, the efficacy of the 6-month regimen was not significantly different from that of 12 months of daily isoniazid monotherapy (RR 0.58; 95% CI 0.3 ; 1.12). A systematic review of RCTs also showed a significantly greater reduction in TB incidence among participants given the 6-month regimen than in those given a placebo (odds ratio [OR] 0.65; 95% CI 0.50 ; 0.83) (80). No controlled clinical trials were found of daily isoniazid monotherapy for 9 months (9H) versus 6H. Re-analysis and modelling of the US Public Health Service trials of isoniazid conducted in the 1950s and 1960s, however, showed that the benefit of isoniazid increases progressively when it is given for up to 9–10 months and stabilizes thereafter (81). For this reason, 9H is retained as an alternative regimen to 6H in the recommended TPT options.
Until the 2020 updated guidelines, daily IPT for 36 months was conditionally recommended for adults and adolescents with HIV, regardless of whether they were receiving ART, in settings with a high risk of TB transmission (82). This recommendation was based on low-certainty evidence from a systematic review and meta-analysis of three RCTs (78). In two of the studies reviewed, ART was not used, and, in the third, ART coverage was low at baseline but increased during the period of observation. The GDG for this second edition of the TPT guidelines decided to withdraw this recommendation given its poor uptake by countries since its release in 2011. In the past decade, access to ART has increased substantially worldwide, and shorter TPT options are preferred to isoniazid monotherapy.
Weekly rifapentine plus isoniazid for 3 months (3HP)
A systematic review was conducted for the 2018 update of the guidelines to compare the effectiveness of 3HP with that of isoniazid monotherapy. The review was of four RCTs (84–87), which were analysed for three subgroups: adults with HIV infection, adults without HIV infection and children and adolescents (2–17 years) who could not be stratified according to HIV status because the relevant studies were lacking. The evidence base for this revised recommendation is summarized in the GRADE tables for PICO 8 in annexes 3 and 4.
Two of the RCTs involved adults with HIV in Peru, South Africa and a number of countries with a TB incidence < 100/100 000 population. No significant difference in the incidence of TB disease was found between participants given 3HP and 6H or 9H (RR 0.73, 95% CI 0.23 ; 2.30). Furthermore, the risk for hepatotoxicity was significantly lower with 3HP in both adults with HIV (RR 0.26, 95% CI 0.12 ; 0.55) and those without HIV (RR 0.16, 95% CI 0.10 ; 0.27). The 3HP regimen was also associated with a higher completion rate in all subgroups (adults with HIV: RR 1.25, 95% CI 1.01 ; 1.55; adults without HIV: RR 1.19, 95% CI 1.16 ; 1.22; children and adolescents: RR 1.09, 95% CI 1.03 ; 1.15). One RCT included a comparison between 3HP and continuous isoniazid monotherapy in adults with HIV (84). No significant difference in TB incidence was found in an intention-to-treat analysis; however, a per protocol analysis showed a lower rate of TBI or death among participants given continuous isoniazid. In all the studies, 3HP was given under direct observation.
Daily rifampicin plus isoniazid for 3 months (3HR)
A systematic review updated in 2017 showed that the efficacy and the safety profile of 3–4 months of daily rifampicin plus isoniazid were similar to those of 6 months of isoniazid (80,88). A previous GDG therefore strongly recommended that daily rifampicin plus isoniazid be used as an alternative to isoniazid in settings with a TB incidence < 100/100 000 population (37). A review of studies in which the effectiveness of rifampicin plus isoniazid daily for 3 months was compared with that of isoniazid for 6 or 9 months in children comprised one RCT and two observational studies (89–91). (See also GRADE evidence summaries for PICO 5 in annexes 3 and 4.) The RCT found no clinical disease in either group when new radiographic findings suggestive of TB disease were used as a proxy for clinical disease (90). Fewer participants given daily rifampicin plus isoniazid than those given 9 months of isoniazid developed radiographic changes (RR 0.49, 95% CI 0.32 ; 0.76). The authors also reported a lower risk for adverse events (RR 0.33, 95% CI 0.20 ; 0.56) and a higher adherence rate (RR 1.07, 95% CI 1.01 ; 1.14) among children given daily rifampicin plus isoniazid. Similar findings were reported in the observational studies (89,91).
Daily rifapentine plus isoniazid for 1 month (1HP)
Before updating the 2020 guidelines, the GDG considered data from the only known published study of the 1HP regimen: a randomized, open-label, phase 3 non-inferiority trial of the efficacy and safety of 1HP as compared with 9 months of isoniazid alone (9H) in people with HIV aged ≥ 13 years in areas of high TB prevalence or who had evidence of TBI (92). Enrolment was restricted to individuals who were not pregnant or breastfeeding. Noninferiority would be shown if the upper limit of the 95% confidence interval for the between-group difference in the number of events per 100 person-years was < 1.25. For all study participants, the difference in the incidence rate of TB (including deaths from any cause) between 1HP and 9H (i.e. 1HP arm minus 9H arm) was −0.02 per 100 person-years (95% CI −0.35 ; +0.30); the RR for treatment completion of 1HP as compared with 9H was 1.04 (95% CI, 0.99 ; 1.10); the RR for grade 3–5 adverse events was 0.86 (95% CI, 0.58 ; 1.27); the hazard ratio for death from any cause was 0.75 in favour of 1HP (95% CI, 0.42 ; 1.31); and the RRs for emergence of resistance to isoniazid and rifampicin were, respectively, 1.63 (95% CI, 0.17 ; 15.99) and 0.81 (95% CI, 0.06 ; 11.77). Overall non-inferiority as defined by the study protocol was shown in the modified intention-to-treat population. Non-inferiority was also shown for the sub-group with confirmed TBI (incidence rate difference per 100 person-years = 0.069 [–0.830 to 0.690]) in males and females and among people on or not on ART at the start of the study. Few patients had a CD4+ < 250 cells/mm3, and neither inferiority or noninferiority of 1HP was shown in this stratum. The evidence for this recommendation is summarized in the GRADE tables for PICO 7 in annexes 3 and 4.
Daily rifampicin monotherapy for 4 months (4R)
A systematic review conducted for the 2015 TPT guidelines and updated in 2017 found similar efficacy for 3–4 months’ daily rifampicin and 6H (odds ratio, 0.78; 95% CI, 0.41 ; 1.46) (80,88). The review also showed that individuals given rifampicin daily for 3–4 months had a lower risk for hepatotoxicity than those treated with isoniazid monotherapy (OR 0.03; 95% CI 0.00 ; 0.48).
Before the 2020 guidelines were updated, the GDG discussed the implications of using 4R in high TB burden settings based on findings from RCTs of 4R vs 9H that included adults and children in such countries (93–96). In study participants aged > 17 years, the difference in rate of confirmed TB between 4R and 9H (4R arm minus 9H arm) was < 0.01 cases per 100 person-years (95% CI, −0.14 ; 0.16); the difference in treatment completion was 15.1% (95% CI, 12.7 ; 17.4); and the difference in grade 3–5 adverse events was −1.1% (95% CI −1.9 ; –0.4). In individuals < 18 years, the difference in the rate of TB disease between 4R and 9H was –0.37 cases per 100 person-years (95% CI, −0.88 ; 0.14); the difference in treatment completion was 13.4% (95% CI, 7.5 ; 19.3); and the difference in risk for adverse events attributed to the medicine used and resulting in discontinuation was −0.0 (95% CI, −0.1 ; 0.1). The evidence for this revised recommendation is summarized in the GRADE tables for PICO 6 in annexes 3 and 4.
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-to-decision 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).
TB preventive treatment with levofloxacin
- In contacts exposed to multidrug- or rifampicin-resistant tuberculosis, 6 months of daily levofloxacin should be used as TB preventive treatment. (Strong recommendation, moderate certainty of the estimates of effect).
Drug-resistant TB is one of the most prominent causes of morbidity and mortality from an antimicrobial resistant organism. It is thus important to take all measures possible to lower the risk of secondary cases of MDR/RR-TB. This includes use of appropriate TPT with regimens of proven effectiveness. Recommendation 21 was first issued in this edition of the consolidated guidelines and is based on moderately certain evidence, as summarized in the GRADE tables (see PICO 10 in annexes 3 and 4). The current recommendation replaces the previous conditional recommendation for TPT in selected household contacts of MDR/RR-TB that was issued in 2018 that was based on very low certainty of the estimates of effect (39).
Justification and evidence
Before this second edition of the guidelines, the GDG considered evidence from two randomized controlled trials, TB CHAMP and V-QUIN (15,16), and a systematic review commissioned by WHO on TPT for MDR/RR-TB (Annex 5). In addition, studies on the programmatic feasibility and acceptability of 6Lfx were conducted. In contrast, the previous WHO recommendation in the 2018 guidelines was based on a review of 10 studies, none of which was an RCT. Overall, 6Lfx reduced the risk of TB by 62% over 1 year among household contacts of people with MDR/RR-TB (RR 0.38; 95% CI 0.17 ; 0.86), with similar effects in the two trials: hazard ratio, 0.44; 95% CI 0.15 ; 1.25 for TB CHAMP and 0.34; 95% CI 0.09 ; 1.25 for V-QUIN. A Bayesian analysis of data from the two clinical trials gave similar findings, with credible intervals showing a statistically significant difference from 1 (hazard ratio, 0.38; 95% credible interval, 0.15 ; 0.94 in TB CHAMP and 0.41; 95% credible interval, 0.18 ; 0.95 in V-QUIN).
A systematic review of relevant studies published between June 2016 and September 2023 comprised three observational studies of TB prevention with fluoroquinolones (alone or in combination with other TB drugs), and one assessed prevention of TB with isoniazid. All four were observational studies with substantial risk of bias, notably selection bias. Data from these studies could not be pooled for a joint analysis. An analysis of unpublished data on 496 527 individual contacts identified 8952 contacts of patients with MDR/RR-TB of whom 722 received isoniazid and 4223 received no TPT. The reasons for initiating or not initiating isoniazid and the duration of isoniazid were not given, and data on completion of TPT, concomitant exposure and drug sensitivity patterns in the untreated group that developed disease were not available. The GDG noted that the findings on effectiveness, survival and completion were inconclusive and considered that the analysis – and also a published study of IPT in contacts of cases of MDR-TB (118) – did not fully address the PICO question (effects of levofloxacin vs other or no TPT). (For more details, see annexes 3 and 4.)
The treatment completion rate in the levofloxacin arm was 86% in TB CHAMP (placebo arm: 86%) and 70% in V-QUIN (placebo arm: 85%), with RRs of 1.00 [95% CI 0.95 ; 1.06] and 0.83 [0.79 ; 0.87], respectively. There was an important difference in the risk of adverse events between children and adults, with very good tolerance in children, which decreased with age. This probably contributed to poorer adherence to TPT by the participants in the V-QUIN. The prevalence of adverse events of grade 3 or more was not significantly higher in the TB CHAMP trial among people < 18 years receiving 6Lfx (RR 0.53, 95% CI 0.16 ; 1.70), but significantly higher rates were found in the V-QUIN trial, in which 97% of participants were > 14 years (RR 5.26, 95% CI 1.16 ; 23.95). Overall, the likelihood of treatment discontinuation among individuals on 6LFx with adverse events of any grade was high (RR 6.32, 95% CI 3.43 ; 11.63), occurring in 43 more patients out of 1000 (range, 20–89). Microbiological studies within both trials did not provide conclusive evidence of the emergence of additional fluoroquinolone resistance in TB strains or in microbiota other than M. tuberculosis (e.g. gut flora) at the time of analysis.
A systematic review of studies published between June 2016 and September 2023 identified five observational studies of adverse events with fluoroquinolone (alone or in combination with other TB drugs). All were observational studies with substantial risk of bias, notably selection and ascertainment bias. Fluoroquinolone monotherapy with levofloxacin, ofloxacin or moxifloxacin was found to be generally safe in three studies, with some mild or moderate drug-related adverse events in children but no grade 3 or 4 or serious adverse events reported. (For more details, see annexes 4 and 5.) No evidence was found to support shortening of levofloxacin TPT to < 6 months or its prolongation beyond 6 months.
Subgroup considerations
Children and adolescents: Levofloxacin can be used in children and adolescents, in whom completion and tolerability in the TB CHAMP trial (which included only individuals aged < 18 years) were much better than in the V-QUIN trial (in which 97% of participants were aged ≥ 15 years). There is no requirement to test for TBI before starting levofloxacin in children who are contacts of people with MDR/RR-TB. Although there has been concern about use of fluoroquinolones in children because of retardation of cartilage development shown in juvenile animals exposed to these agents (119), similar effects have not been found in humans (120,121).
Pregnancy and breastfeeding: TPT with levofloxacin in pregnancy requires a risk–benefit assessment and an informed choice by pregnant woman on whether to take TPT or to defer TPT to the end of pregnancy. The advice should depend on the circumstances (e.g. first trimester versus later). Pregnancy increases the risk of progression from infection to disease and the risk of poor maternal and fetal outcomes should TB disease occur. MDR/RR-TB in pregnancy is a serious condition, and some of the drugs used to treat MDR-TB may be toxic to the fetus. Observations from studies in animals exposed to levofloxacin have limited its use in pregnancy; however, one meta-analysis of observational studies with 2800 pregnant women given fluoroquinolones for any indication (e.g. urinary tract infection) found no difference in the incidence of birth defects, spontaneous abortion or prematurity from that in unexposed pregnant women (122). The concentrations of levofloxacin in breastmilk appeared to be far lower than the dose for infants and would not be expected to cause adverse effects in breastfed infants (123). Its use should therefore not be suspended during breastfeeding. While effects of fluoroquinolones on bone and cartilage observed in animals have not been seen in humans, the data and follow-up times of infants are limited. Recent alerts have, however, highlighted safety concerns associated with prolonged use of fluoroquinolones in humans (124–126).
HIV infection: Levofloxacin can be used in people with HIV. No specific drug–drug interaction with ART has been observed in people with HIV exposed to MDR/RR-TB, and there is no need to test for infection before starting levofloxacin.
Contraindication: Levofloxacin should not be given to people who are allergic to fluoroquinolone, who have another contraindication to the same class of drugs or when there is potential drug–drug interaction. Levofloxacin should be discontinued if the person develops a serious or severe adverse drug reaction. (See below for other TPT regimen options in such a case.)
Implementation considerations
The strong recommendation reflects the GDG opinion that the benefits of levofloxacin outweigh the potential harm in most people who are eligible to receive it. Health programmes and clinicians should strictly ensure eligibility for its use, maximize the likelihood of treatment completion as expected and ensure that contacts are followed up regardless of whether TPT was completed. Contacts of people with RR-TB are usually treated as for MDR-TB, unless susceptibility to isoniazid is reliably confirmed in the index person, in which case isoniazid may be considered an effective TPT option.
The GDG considered that levofloxacin could be used in any setting, regardless of TB burden, provided that the health infrastructure can ensure that treatment is given correctly without creating inequity, and that TB disease can be excluded reliably before initiation of treatment. Levofloxacin is widely available as a generic drug, in both adult and paediatric formulations. As for other TPT, the GDG noted that treatment can be self-administered and that a requirement for direct observation could be a significant barrier to implementation. Digital adherence technologies (e.g. electronic medication monitors) may be used, but few studies have been conducted on their use for TPT. The GDG noted that the 6-month duration of levofloxacin treatment may appear long to patients and caregivers when compared with the shorter, 4- or 12-week TPT regimens that are now available for prevention of drug-susceptible TB. People receiving TPT should also be provided with advice on treatment and management of adverse events.
Levofloxacin is the preferred fluoroquinolone for use in TPT, and it was used in both trials. Instructions on dosage are provided in the WHO operational handbook on TPT (12). While there are no comparable data on alternatives, moxifloxacin can be used if levofloxacin is not available. Drug-susceptibility testing of the source case strain would provide important additional information, especially in situations where fluoroquinolone resistance is known to be high. If the strain in the source patient is resistant to these medicines, other TB drugs (e.g. ethionamide, ethambutol) can be used as TPT according to the best available information on the drug susceptibility profile of the presumed strain. In this case, the certainty of the effectiveness of TPT is much lower than with levofloxacin (see also below). A positive test for TBI before starting TPT for MDR/RR-TB is not required for child contacts or people with immunocompromising conditions. In other populations, this would be desirable but not mandatory. Lack of availability of testing should not be a barrier to providing TPT to individuals who are at risk. Screening of all household and other close contacts for co-prevalent TB disease will be important. The approach to screening and ruling out TB in contacts is otherwise no different from that described earlier (see section 1.2). Provision of TPT with levofloxacin should include consideration of factors such as age, risk of toxicity or interaction, co-morbidity, the susceptibility to drugs of the strain of the most likely source case, background resistance to fluoroquinolones in MDR/RR-TB strains, availability and the individual’s preferences.
The capacity of a programme to provide TPT for MDR/RR-TB should be carefully planned to ensure that all the necessary resources are in place, including programme capacity to rule out TB disease, perform quality-assured testing for drug susceptibility in the presumed source case, deliver the necessary medications and closely monitor adverse events and emergence of TB disease. Engagement of stakeholders in the community is important, as for other means to address constraints to implementation.
A paediatric formulation of levofloxacin can be used. Instructions on dosage are provided in the WHO operational handbook on TPT (12). If fluoroquinolones cannot be used because of intolerance or resistance in the strain from the presumed source case, treatment with the other TB drugs used in some studies may be considered (e.g. ethambutol, ethionamide), although the evidence for their efficacy is much less certain (127,128). While ethambutol is considered safe in pregnancy, ethionamide has been associated with teratogenic potential at high doses in experimental animals, although there are minimal data on human pregnancy. There is limited evidence for the optimal duration of MDR-TB preventive treatment, which should be based on clinical judgement. In the studies conducted so far, levofloxacin was given for 6, 9 or 12 months. None of studies included studies of pharmacokinetics or safety in pregnancy or a comparison of risks for adverse events, although one reported no serious adverse events attributable to fluoroquinolone-based preventive treatment (104).