Latent tuberculosis infection in liver transplant patients: a review

INTRODUCTION

Tuberculosis (TB) in solid organ transplant (SOT) recipients is associated with greater morbidity and mortality. Understanding the dynamics of this complex infection becomes more relevant as the number of liver transplant recipients steadily increases.¹ Frequency of active TB is up to 74 times higher in SOT recipients, which can be associated with a mortality of up to 40%.² More than 80% of active TB cases arise from previously untreated latent tuberculosis infection (LTBI),³ hence preventive strategies are paramount. In light of the significant burden that TB may inflict in this population, routine screening for LTBI in liver transplant candidates (LTCs) is recommended.⁴

The management of LTBI represents a therapeutic dilemma in LTCs. First, standard immunodiagnostic methods, including the tuberculin skin test (TST) and interferon gamma release assays (IGRAs)—although commonly used—have higher false negativity rates in this population. In addition, current treatment regimens are associated with variable degrees of hepatotoxicity [isoniazid (INH) and rifamycins] and drug-drug interactions (DDIs) with immunosuppressants that hamper graft function and may precipitate organ rejection (rifamycins).² Herein, we describe current recommendations and controversies in management of LTBI in liver transplant patients.

DISCUSSION

Controversies in testing

TST positivity rate is greatly affected by the immune competence of the host. In addition to traditional immunosuppressive conditions (eg, HIV, transplantation, etc.), patients with chronic liver disease also exhibit lower positivity rates with the TST.²

IGRAs (QuantiFERON-TB Gold Plus or T-SPOT.TB) are often preferred by practitioners because of its cost-effectiveness, since it can be taken in a single visit and it is not affected by previous Bacille Calmette-Guérin (BCG) vaccination status. Nonetheless, IGRAs have frequent negative and uninterpretable results in LTCs and its predictive value over the TST to predict progression to active TB is comparable.^5,6 Immunodiagnostic challenges⁷ are summarized in Table 1. In the absence of a gold standard, diagnosis of LTBI in LTCs must be individualized based on clinicoepidemiological history and chest radiographic findings.

TABLE 1.

Immunodiagnostic challenges in latent TB infection

	False positives	False negatives
TST	BCG vaccination status Nontuberculous mycobacteria infection Improper administration or interpretation	Immune suppression/anergy Recent live virus vaccination or infection Recent (<8 wk) exposure to TB Improper administration or interpretation
IGRAs	Nontuberculous mycobacteria infection Improper performance of the assay	Immune suppression Recent (<8 wk) exposure to TB Improper performance of the assay

Abbreviations: BCG, Bacille Calmette-Guérin; IGRA, interferon gamma release assay; TB, tuberculosis; TST, tuberculin skin test

Initiation of treatment

Despite its diagnostic difficulties, treatment for LTBI has been shown to be highly effective in preventing progression to active TB in SOT recipients. To overcome these testing challenges, patients must be risk-stratified to determine the likelihood of infection and progression to active TB based on TST/IGRAs positivity, history and imaging findings.⁸ An algorithm describing eligibility criteria to initiate treatment is displayed in Figure 1. Of note, a singular uninterpretable IGRA (eg, indeterminate QuantiFERON-TB Gold Plus) requires a repeat test.⁹ In the case of consecutive indeterminate results, the decision to initiate treatment shall be based on clinical assessment similar to the approach to that of a negative result.⁴

FIGURE 1.

Initiation of treatment. Abbreviations: AFB, acid-fast bacilli; IGRA, interferon release gamma assays; LTBI, latent tuberculosis infection; LTC, liver transplant candidate; MELD, Model for End-Stage Liver Disease; TB, tuberculosis; TST, tuberculin skin test.

Pretransplant versus posttransplant treatment

In the setting of compensated liver disease, starting LTBI treatment before liver transplant protects the graft from unnecessary exposure to potentially hepatotoxic medication, avoids potential DDI with immunosuppressants, and prevents TB reactivation while waiting for transplant. However, it may precipitate acute-on-chronic liver injury and prompt discontinuation of therapy. Therefore, strict liver function tests (LFTs) monitoring is critical. If patients were still on treatment at the time of transplant then the treatment should be discontinued at the time of surgery and restarted as soon as LFTs get normalized. Please note that nonrifamycin regimens are preferred posttransplant given DDI between rifamycin and calcineurin and mammalian target of rapamycin inhibitors.⁴

Treatment should be deferred posttransplant in the context of decompensated cirrhosis, as the first-line drugs (rifamycins and INH) are potentially hepatotoxic. Practitioners should wait for normalization of LFTs to initiate therapy. Early initiation of treatment is recommended as the majority of cases occur within 12 months posttransplant.⁴ A summary of treatment strategies relative to timing to transplantation is shown in Figure 2.

FIGURE 2.

Treatment strategies relative to timing of transplantation. Abbreviations: ETM, ethambutol; INH, isoniazid; LFT, liver function test; LT, liver transplant; LVX, levofloxacin; RPT, rifapentin; VB6, vitamin B6.

Treatment regimens and complications

Selecting a treatment regimen for LTBI in liver transplant patients is complex and must be based on an array of factors including timing relative to the transplant, efficacy and potential complications that may arise from such therapy.

The first-line regimens recommended by the SOT TB 2019 guidelines are INH daily for 9 months, rifampin daily for 4 months and rifapentine (RPT)/INH weekly for 3 months,⁴ and the first-line regimens by the CDC 2020 guidelines are the 4-month rifampin, the 3-month RPT/INH and 3-month course of daily INH/rifampin.¹⁰ The latter regimen was not included in our review paper, as its use has not been reported in LTCs. The 9-month INH regimen was not included as a first-line regimen as it is associated with higher toxicity rates and lower completion rates.¹⁰

The use of rifamycins should be limited, if possible, to the pretransplant setting to avoid DDI with immunosuppressive drugs.⁴ Rifampin daily for 4 months has lower rates of hepatotoxicity compared with INH.¹¹ However, it might not be a good choice in patients taking direct-acting antivirals for hepatitis C due to DDI.¹² Combination of RPT/INH weekly for 3 months is also appealing given its short duration and lower rates of toxicity, yet the data in this population is limited, and like rifampin is associated with DDI,¹³ limiting its use with concurrent immunosuppressive medication.

INH/vitamin B6 (VB6) daily for 9 months is effective in the pretransplant and posttransplant period. Despite its high efficacy, there is apprehension to INH/VB6 due to the risk for hepatotoxicity, which has been variably reported in the literature; although most patients do not warrant discontinuation of the drug.⁴

Alternatively, levofloxacin (LVX) has been compared with INH/VB6 in LTCs. Although both had comparable efficacy, the LVX group had much higher rates of tenosynovitis; therefore, quinolones are not recommended as first-line treatment.¹⁴ Ethambutol (ETM) is occasionally added to the LVX regimen.⁴

Available treatment regimens for pretransplant and posttransplant periods are summarized in Tables 2 and 3, respectively.

TABLE 2.

Therapeutic regimens—pretransplant

Therapy	Dosis	Duration (mo)	Adverse effects
INH/VB6/RPT (first line)	Maximum: 900 mg once weekly for INH and RPT	3	INH: See below RPT: Similar to rifampin
Rifampin (first line)	10 mg/kg (maximum: 600 mg daily)	4	DDI, drug-induced hepatitis, flu-like syndrome, red-orange discoloration of body fluids
INH/VB6 (first or second line)a	5 mg/kg daily (maximum: 300 mg/d)/25–50 mg	9	Hepatotoxicity, peripheral neuropathy, polyserositis
LVX ± ETM (second line)	500 mg daily	9	LVX: Tenosynovitis, QTc prolongation, risk of aortic aneurysm and dissection ETM: Optic neuritis

^a First line by the SOT Tuberculosis 2019 guidelines⁴ and second line by the CDC Tuberculosis 2020 guidelines.¹⁰

Abbreviations: DDI, drug-drug interaction; ETM, ethambutol; INH, isoniazid; LVX, levofloxacin; RPT, rifapentin; VB6, vitamin B6.

TABLE 3.

Therapeutic regimens—posttransplant

Therapy	Dosis	Duration (mo)	Adverse effects
INH/VB6a (first line)	5 mg/kg daily (maximum: 300 mg/d)/25–50 mg	9	Same as listed in Table 2
LVX±ETMa (second line)	500 mg daily	9	Same as listed in Table 2

^a Treatment should be continued after liver transplant to complete a total of 9 months if it was started before transplant and has not been completed.

Abbreviations: ETM, ethambutol; INH, isoniazid; LVX, levofloxacin; VB6, vitamin B6.

CONCLUSIONS

LTBI in LTCs is a challenging therapeutic scenario because of imperfect testing strategies, the adverse reactions from available regimens and the need to determine proper time of treatment initiation. After risk stratification and determination of eligibility for therapy, patients should be ideally treated pretransplant to avoid exposing the graft to potentially hepatotoxic medications, except in the setting of decompensated liver disease. INH and rifamycins are highly effective, yet have variable rates of hepatotoxicity. Rifamycins are avoided in the posttransplant setting due to DDI with immunosuppressants. LVX±ETM is a nonhepatotoxic regimen but not recommended as first-line treatment. Individualized management is recommended.