Panel’s Recommendations
Detection of Latent TB Infection Diagnostic methods for latent tuberculosis (TB) infection (LTBI) include the tuberculin skin test (TST), administered by the Mantoux method with an Food and Drug Administration (FDA)-approved purified protein derivative, or FDA-approved interferon gamma release assays (IGRA) (QuantiFERON®-TB Gold In-Tube, and T SPOT®.TB); TST is preferred over IGRA in children aged <5 years (Bll). TST and IGRA should NOT be used to rule out disease and cannot replace regular screening for TB exposure (AII). In high-TB-burden settings, screening for TB exposure and for signs or symptoms suggestive of TB disease is universally applicable and should occur at every health care visit (AII).
Treatment for LTBI HIV-infected children should receive preventive therapy if they have a positive TST or IGRA result or if they are exposed to an individual with infectious TB (regardless of previous treatment for TB or the TST or IGRA result), after TB disease has been excluded (AII). The preferred preventive therapy regimen is isoniazid daily for 9 months (AII). If adherence with daily isoniazid cannot be ensured, then consider twice-weekly isoniazid by directly observed therapy (DOT) by a trained worker, not a family member (BII). With exposure to an isoniazid mono-resistant source case, preventive therapy consisting of daily rifampin for 6 months is recommended, with adjustment of combination antiretroviral therapy (cART) as required (BII). A 12-dose combination regimen of once-weekly isoniazid and rifapentine by DOT is as safe and effective as other regimens in preventing TB disease, and the completion rate is greater than for longer regimens. However, pediatric experience with this regimen is limited, and drug-drug interactions between rifapentine and other antiretroviral drugs have not been determined. This regimen is not recommended for children aged <2 years, nor for HIV-infected adults or children who are receiving cART or individuals who have LTBI with presumed isoniazid or rifampin resistance; the preferred regimen for children aged 2 to 11 years remains daily isoniazid for 9 months.
Treatment of TB Disease In children diagnosed with TB, DOT must be started immediately (AII) and all cases of suspected and confirmed TB disease must be reported to the relevant health authorities. All children diagnosed with TB should be tested for HIV infection (AIII). In HIV-infected children, the recommended treatment for fully-drug-susceptible TB is a 4-drug regimen consisting of isoniazid, rifampin, pyrazinamide, and ethambutol given daily during the 2-month intensive phase, followed by a 7-month continuation phase using only isoniazid and rifampin (AII), with adjustment of cART as required. With good adherence and treatment response, thrice- weekly treatment under DOT during the continuation phase can be considered (CII). For children with extrapulmonary disease caused by drug susceptible TB involving the bones or joints, central nervous system (CNS), or disseminated/miliary disease, the recommended duration of treatment is 12 months (AIII). For TB meningitis (TBM), pending drug-susceptibility testing results, ethionamide can replace ethambutol (or an injectable aminoglycoside) as the fourth drug because of its superior cerebrospinal fluid penetration (CII). Children with suspected and confirmed multidrug resistant (MDR) TB (i.e., resistance to both isoniazid and rifampin) should be managed in consultation with an expert. In the United States, treatment of MDR-TB should be individualized based on drug susceptibility test (DST) results (in cases where DST results for the child are not available, then DST results for the source case should be used to guide initial choice of regimen) (AII). Treatment for TB must commence as soon as the diagnosis is established in HIV-infected children, both those who are already on cART and those not yet receiving cART; those not yet on cART should be evaluated for early cART initiation, preferably within 2 to 8 weeks of starting TB therapy (AII). Depending on age and previous cART exposure, an efavirenz-based regimen usually is preferable because such regimens are associated with better treatment outcomes (AII). Nevirapine with potential dose adjustment with concomitant rifampin administration can also be considered (CIII). If a protease inhibitor-based regimen is used, superboosting with ritonavir (using a ritonavir dose equal to the lopinavir dose) for the full duration of rifampin treatment (and 2 weeks after termination) is required (AII). Pyridoxine supplementation (1–2 mg/kg body weight/day, max 50 mg/day) is recommended for all HIV-infected children who are taking isoniazid (AII) or cycloserine (AIII). Adjunctive corticosteroids treatment (with ongoing treatment for TB) is indicated for children with TBM or pericardial effusion (AII). It can also be considered with severe immune reconstitution inflammatory syndrome, airway compression, or pleural effusion (BII). Liver chemistry tests should be performed before initiation and after 2, 4, and 8 weeks of treatment for TB (the same for cART initiation while receiving treatment for TB) (BIII). Beyond 2 months, routine testing every 2 to 3 months is advisable for all children receiving cART, or more frequently if clinically indicated (BIII).

Rating of Recommendations: A = Strong; B = Moderate; C = Optional

Rating of Evidence: I = One or more randomized trials in children^† with clinical outcomes and/or validated endpoints; I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying data in children^† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children^† with long-term outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical outcomes with accompanying data in children^† from one or more similar nonrandomized trials or cohort studies with clinical outcome data; III = Expert opinion

^†Studies that include children or children/adolescents, but not studies limited to post-pubertal adolescents