5.2.1. HIV infection
An IPD meta-analysis that included 11,920 patients with MDR-TB found that HIV-positive patients not on antiretroviral therapy have 4-fold higher odds of death when compared to HIV-negative patients.105 The same study reported that among HIV-positive people with MDR-TB, odds of death were significantly lower with use of at least 1 Group A medication and with antiretrovirals. Hence, the aforementioned recommendations and best practice statements should be followed regardless of HIV status and antiretroviral therapy should be used for all HIV-positive patients with MDR-TB (or other circumstances requiring second-line anti-TB drugs), irrespective of CD4 cell count, and following the same timeline with respect to initiation as for drug-susceptible TB93 (see Chapter 10: Treatment of Active Tuberculosis in Special Populations). It is important to carefully consider how to manage drug-drug interactions between antiretrovirals and anti-TB medications to ensure that both HIV and MDR-TB are optimally treated. Such strategies could include measuring therapeutic drug levels or increasing the frequency of monitoring for adverse events. In addition to drug-drug interactions, other challenging issues that arise with the treatment of HIV and MDR-TB co-infection include: overlapping adverse effects (eg, neuropathy);56 paradoxical reactions related to immune reconstitutions; a high pill burden;56 malabsorption of medications;56 and heightened negative psychosocial factors (eg, stigmatization, isolation).106
Good practice statement
For the treatment of MDR-TB in HIV-positive people, TB treatment providers should consult with patients’ HIV providers and with pharmacists with expertise in HIV and TB in order to identify, and determine how to manage, potential drug-drug interactions that could compromise the effectiveness or increase the toxicity of HIV and/or MDR-TB treatment. Given the strong evidence supporting the effectiveness of bedaquiline, moxifloxacin or levofloxacin, and linezolid, treating teams should strive to identify strategies to ensure the safe and effective use of Group A anti-TB drugs even in the presence of drug-drug interactions with antiretrovirals.
MDR-TB management is very complex in pregnancy, and these patients should be co-managed by clinicians with expertise in both drug-resistant TB and high-risk pregnancy. The ATS/CDC/ERS/IDSA writing group conducted a systematic literature review on pregnant women with MDR-TB.94 They found several observational case reviews that included a total of 65 women. Among them, 69% had a successful treatment outcome. Regarding pregnancy outcomes:
78.5% of women had healthy births;
12% of women had premature or low birthweight babies;
12% of women had medical abortions;
3% of women had spontaneous abortions;
1.5% of women had a stillbirth;
3% of babies were born with HIV; and
1.5% of babies were born with HIV/TB coinfection.
A more recent review of 108 pregnant women treated for MDR-TB in South Africa found similar MDR-TB treatment outcomes (including 67% success).107 In that study, 91% of the babies were born alive, but 28% were pre-term and 35% low birthweight; this high proportion of unfavorable pregnancy outcomes was felt likely to be due to the high prevalence of HIV infection (81%). Fetal exposure to bedaquiline in utero was associated with low birthweight in that study; otherwise, there were no other significant differences in infant outcomes, pregnancy outcomes or maternal treatment outcomes, including weight gain in the infants until 1 year of age. MDR-TB should be treated promptly in pregnant women and should not be deferred, as the benefits of treatment outweigh the harms. The regimen may need modification and the woman will need concurrent care by a TB expert and an obstetrician with expertise in high-risk pregnancies. There are no data to support a particular regimen, however aminoglycosides and ethionamide are generally avoided because of potential teratogenicity.
5.2.3. Central nervous system MDR-TB
Treatment of central nervous system (CNS) MDR-TB should be guided by DST results and by whether the medications cross the blood-brain barrier. Immediate consultation with an expert in MDR-TB management is strongly advised. Levofloxacin/moxifloxacin, ethionamide, cycloserine, linezolid, imipenem-cilastatin, high-dose INH and PZA penetrate the CNS well,93 while p-aminosalicylic acid and EMB do not. Amikacin and streptomycin penetrate the CNS only in the presence of meningeal inflammation. There are sparse data on the CNS penetration of clofazimine, bedaquiline and delamanid.108–110
Any child being considered for treatment of drug-resistant TB should be managed by a clinician with experience with such cases. The signs, symptoms and radiographic findings of TB disease in children are outlined in Chapter 9: Pediatric Tuberculosis, and are the same in both drug-susceptible and drug-resistant TB. Drug-resistant TB in children is confirmed using the same microbiologic criteria as those outlined for adults. High-quality sputum specimens, and other specimens appropriate to the site of disease, should always be collected with considerations about optimal collection method guided by age (Chapter 9: Pediatric Tuberculosis).
The challenges of confirming the microbiologic diagnosis in infants and young children are the same for both drug-resistant and drug-susceptible TB. The bacillary burden is much lower in infants and young children with primary TB disease, than in teens and adults, and the majority of these children will not have a positive nucleic acid amplification test or culture. The choice to initiate therapy for drug-resistant TB must thus be guided by other considerations. A child who has clinical and radiographic diagnosis of TB disease and who has been exposed to an infectious drug-resistant TB source case is considered to have probable drug-resistant TB.99 A child who has clinical and radiographic diagnosis of TB disease and who has not responded to first-line TB treatment after 2 to 3 months, or who has been exposed to an infectious source case who has died, failed treatment or is a retreatment case is also considered to have possible drug-resistant TB disease.99
The regimen design for children should ideally be based on the child’s own isolate, but if none is available, then the infectious source case’s isolate serves as a surrogate. Generally, the same regimen designs that are outlined for adult drug-resistant TB treatment can be used in children, with the exceptions of bedaquiline and delamanid, which have lower recommended age limits (Table 5). Aminoglycosides should be avoided as much as possible, to avoid the risk of permanent hearing loss, which has a profound impact on child development.93
Prescribing second-line agents in age- and weight-appropriate doses is challenging. Many of the dosing recommendations for children are extrapolated from adult strategies.93 This is further complicated by the lack of child-friendly formulations, which means some drugs cannot be given at a precise amount of drug per kilogram. General guidance is given on dosing of second-line agents in Table 5; please review the weight-banded dosing strategies from the primary references cited for more specific guidance. Several pharmacokinetic and safety studies are underway for fluoroquinolones, linezolid, bedaquiline and delamanid.101
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