The role of alternative regimens in the management of tuberculosis in transplant recipients: From past challenges to future opportunities

Tuberculosis is a serious infection in transplanted patients.1 Treatment can be a challenge and optimal therapy in this population remains open to debate. The general recommendation to reduce immunosuppression may put patients with mild tuberculosis disease at risk of rejection. It is an “axiom” of transplant infectious diseases that the worst thing that can happen to transplanted patients treated for a nonlife-threatening chronic infection is that we provoke rejection. This can occur when immunosuppression is reduced or due to drug interactions that reduce immunosuppressant levels in serum.2 Isoniazid and rifampicin are hepatotoxic drugs and mildly elevated liver enzymes interfere in the diagnosis of rejection in liver transplant recipients.2,3 Rifampicin has serious interactions with immunosuppressive therapy.2,3 Aminoglycosides potentiate the nephrotoxicity of calcineurin inhibitors.2 Quinolones can produce severe tendinitis,4 whereas linezolid is myelotoxic and neurotoxic, especially in patients onmultiple medications such as transplant recipients.2 As regards rifampicin, the debate has reached its peak. Although most consensus statements recommend its use, this is not a unanimous opinion. The GESITRA consensus statement indicates that rifampicin should only be used in the presence of disseminated life-threatening disease, and immunosuppressant levels can be monitored.2 This recommendation is based on studies showing that the use of rifampicin increases the risk of rejection, graft loss, and death.5 In this issue of Transplant Infectious Disease, Radisic et al.6 present the results of a series of 30 tuberculosis patients treated with a rifampicin-free regimen. Clinical cure was achieved in 28 cases (93%) and in 27 cases (97%) with normal functioning grafts. Only two patients (7%) died while receiving treatment. This is an important experience that demonstrates similar outcomes to historical studies, thus illustrating that it is possible to treat transplanted patients without rifampicin. But this studywill not definitively settle the debate. The study is not controlled, it only includes patients with renal or pancreas/kidney transplants and does not analyze patients treated with rifampicin in the same period. Consequently, it lacks an adequate control population. All the available evidence for rifampicin-free regimens, as the authors point out, comes fromuncontrolledobservational studies, similar to this experience. The highest quality evidence is supported by controlled clinical trials. We donot have these studies, nor does it seem likely thatwewill have them in the near future. We would need, at least, cohort studies with a large number of patients treated with and without rifampicin and with adequate control (survivor bias, propensity score for rifampicin use, etc.). International consortia are necessary to perform these studies. The recommendation to use rifabutin instead of rifampicin, an equivalent drug with less capacity to induce cytochrome P450 metabolism, has not resolved the debate in clinical practice either.2 In this editorial, we are tempted to recommend that these studies be carried out. However, we ask, should we go further in producing the necessaryevidencewith classical drugsor shouldwemove forwardand use the newly available drugs to treat tuberculosis? Undoubtedly, both options are valid and complementary. But we think it is necessary to explore the applicability of novel therapeutic options in transplantation andproduce thequality evidenceweneed.Wemustnot repeat themistakes of the past. In other words, we need specific clinical trials using “novel” anti-tuberculosis drugs in transplanted patients. What are these drugs and what problems can they cause in transplant recipients? What evidence do we need to expand their use to these patients? The “novel” drugs we are referring to are bedaquiline, delamanid, and pretomanid. They are authorized when an effective treatment regimen cannot otherwise be provided for reasons of resistance or tolerability. In the general population, they are mainly used for the treatment of multidrug-resistant tuberculosis. Fortunately, research is currently being conducted onmany other molecules. Bedaquilinebelongs to thediarylquinoline class of drugs and inhibits the ATP synthase subunit c of Mycobacterium spp. It has bactericidal activity independent of the bacillus replication state. The main side effects of bedaquiline are nausea, arthralgia, headache, diarrhea, skin rash, elevated transaminases, pancreatitis, hyperuricemia, and prolongation of the QTc interval. Cytochrome P450 3A4 (CYP3A4) inducers (i.e., rifamycin, carbamazepine, phenytoin, and efavirenz) decrease its serum concentration. CYP3A4 inhibitors (i.e., itraconazole, voriconazole, posaconazole, and lopinavir/ritonavir) increase exposure and the risk of adverse effects. Bedaquiline is not a substrate or inhibitor of P-glycoprotein. Interactions with immunosuppressants are not known, andexperience in the treatment of tuberculosis in transplant recipients is limited to publications of short case series.7 Delamanid belongs to the nitroimidazole class of drugs (likemetronidazole) and inhibits the biosynthesis of methoxy-mycolic and ketomycolic acids, components of the mycobacterial wall. It is active against bacilli that are not actively multiplying. The main side effects