Hospitalizations for opportunistic infections following transplantation and associated risk factors: A national cohort study of Medicare beneficiaries.

BACKGROUND: Opportunistic infections (OIs) are a significant cause of morbidity and mortality after organ transplantation, though data in the liver transplant (LT) population are limited. METHODS: We performed a retrospective cohort study of LT recipients between January 1, 2007 and Deceber 31, 2016 using Medicare claims data linked to the Organ Procurement and Transplantation Network database. Multivariable Cox regression models evaluated factors independently associated with hospitalizations for early (≤1 year post transplant) and late (>1 year) OIs, with a particular focus on immunosuppression. RESULTS: There were 11 320 LT recipients included in the study, of which 13.2% had at least one OI hospitalization during follow-up. Of the 2638 OI hospitalizations, 61.9% were early post-LT. Cytomegalovirus was the most common OI (45.4% overall), although relative frequency decreased after the first year (25.3%). Neither induction or maintenance immunosuppression were associated with early OI hospitalization (all p > .05). The highest risk of early OI was seen with primary sclerosing cholangitis (aHR 1.74; p = .003 overall). Steroid-based and mechanistic target of rapamycin inhibitor-based immunosuppression at 1 year post LT were independently associated with increased late OI (p < .001 overall). CONCLUSION: This study found OI hospitalizations to be relatively common among LT recipients and frequently occur later than previously reported. Immunosuppression regimen may be an important modifiable risk factor for late OIs.

Severe Acute Liver Injury After Hepatotoxic Medication Initiation in Real-World Data.

Importance: Current approaches to classify the hepatotoxic potential of medications are based on cumulative case reports of acute liver injury (ALI), which do not consider the size of the exposed population. There is little evidence from real-world data (data relating to patient health status and/or the delivery of health care routinely collected from sources outside of a research setting) on incidence rates of severe ALI after initiation of medications, accounting for duration of exposure. Objective: To identify the most potentially hepatotoxic medications based on real-world incidence rates of severe ALI and to examine how these rates compare with categorization based on case reports. Design, Setting, and Participants: This series of cohort studies obtained data from the US Department of Veterans Affairs on persons without preexisting liver or biliary disease who initiated a suspected hepatotoxic medication in the outpatient setting between October 1, 2000, and September 30, 2021. Data were analyzed from June 2020 to November 2023. Exposures: Outpatient initiation of any one of 194 medications with 4 or more published reports of hepatotoxicity. Main Outcomes and Measures: Hospitalization for severe ALI, defined by either inpatient: (1) alanine aminotransferase level greater than 120 U/L plus total bilirubin level greater than 2.0 mg/dL or (2) international normalized ratio of 1.5 or higher plus total bilirubin level greater than 2.0 mg/dL recorded within the first 2 days of admission. Acute or chronic liver or biliary disease diagnosis recorded during follow-up or as a discharge diagnosis of a hospitalization for severe ALI resulted in censoring. This study calculated age- and sex-adjusted incidence rates of severe ALI and compared observed rates with hepatotoxicity categories based on cumulative published case reports. Results: The study included 7 899 888 patients across 194 medication cohorts (mean [SD] age, 64.4 [16.4] years, 7 305 558 males [92.5%], 4 354 136 individuals [55.1%] had polypharmacy). Incidence rates of severe ALI ranged from 0 events per 10 000 person-years (candesartan, minocycline) to 86.4 events per 10 000 person-years (stavudine). Seven medications (stavudine, erlotinib, lenalidomide or thalidomide, chlorpromazine, metronidazole, prochlorperazine, and isoniazid) exhibited rates of 10.0 or more events per 10 000 person-years, and 10 (moxifloxacin, azathioprine, levofloxacin, clarithromycin, ketoconazole, fluconazole, captopril, amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and ciprofloxacin) had rates between 5.0 and 9.9 events per 10 000 person-years. Of these 17 medications with the highest observed rates of severe ALI, 11 (64%) were not included in the highest hepatotoxicity category when based on case reports. Conclusions and Relevance: In this study, incidence rates of severe ALI using real-world data identified the most potentially hepatotoxic medications and can serve as a tool to investigate hepatotoxicity safety signals obtained from case reports. Case report counts did not accurately reflect the observed rates of severe ALI after medication initiation.

COVID-19 in organ donors: An organ procurement organization perspective.

BACKGROUND: The COVID-19 pandemic presented a significant challenge for Organ Procurement Organizations (OPOs) with the use of SARS-CoV-2 positive donors varying widely. This study used detailed single OPO data to determine the success of using SARS-CoV-2 positive donors. METHODS: We performed a retrospective cohort study including all SARS-CoV-2 positive donors referred to the Gift of Life OPO from January 1, 2021, to June 30, 2023. Descriptive analyses were performed to characterize referral and organ utilization. RESULTS: There were 861 organ referrals with 1 positive SARS-Cov-2 test: 282 were ruled out with telephone evaluation, 431 referrals were ruled out with onsite evaluation ("evaluated nondonors") and 148 became donors. For donors who had both nasopharyngeal and lower respiratory testing completed, there was notable result discordance observed. Median cycle threshold (Ct) values were similar between donors and evaluated nondonors with no change in median donor Ct values over the study period. Transplanted organs from COVID-positive donors included 27 hearts, 88 livers, 5 pancreata, and 107 kidneys; no lung donation occurred. The proportion of COVID-positive donors significantly increased over the study period. CONCLUSION: This large volume donor referral study demonstrates increasing COVID-19 referrals progressing to donation over time, supporting the increased use of these donors for nonlung transplantation.

Protease inhibitor-based direct-acting antivirals are associated with increased risk of aminotransferase elevations but not hepatic dysfunction or decompensation.

BACKGROUND & AIMS: Cases of acute liver injury (ALI) have been reported among chronic HCV-infected patients receiving protease inhibitor (PI)-based direct-acting antiviral (DAA) regimens, but no analyses have compared the risk of ALI in patients receiving PI- vs. non-PI-based DAAs. Thus, we compared the risk of 3 ALI outcomes between patients (by baseline Fibrosis-4 [FIB-4] group) receiving PI-based or non-PI-based DAAs. METHODS: We conducted a cohort study of 18,498 patients receiving PI-based DAA therapy (paritaprevir/ritonavir/ombitasvir±dasabuvir, elbasvir/grazoprevir, glecaprevir/pibrentasvir) matched 1:1 on propensity score to those receiving non-PI-based DAAs (sofosbuvir/ledipasvir, sofosbuvir/velpatasvir) in the 1945-1965 Veterans Birth Cohort (2014-2019). During exposure to DAA therapy, we determined development of: i) alanine aminotransferase (ALT) >200 U/L, ii) severe hepatic dysfunction (coagulopathy with hyperbilirubinemia), and iii) hepatic decompensation. We used Cox regression to determine hazard ratios (HRs) with 95% CIs for each ALI outcome within groups defined by baseline FIB-4 (≤3.25; >3.25). RESULTS: Among patients with baseline FIB-4 ≤3.25, those receiving PIs had a higher risk of ALT >200 U/L (HR 3.98; 95% CI 2.37-6.68), but not severe hepatic dysfunction (HR 0.67; 95% CI 0.19-2.39) or hepatic decompensation (HR 1.01; 95% CI 0.29-3.49), compared to those receiving non-PI-based regimens. For those with baseline FIB-4 >3.25, those receiving PIs had a higher risk of ALT >200 U/L (HR, 2.15; 95% CI 1.09-4.26), but not severe hepatic dysfunction (HR, 1.23 [0.64-2.38]) or hepatic decompensation (HR, 0.87; 95% CI 0.41-1.87), compared to those receiving non-PI-based regimens CONCLUSION: While risk of incident ALT elevations was increased in those receiving PI-based DAAs in both FIB-4 groups, the risk of severe hepatic dysfunction and hepatic decompensation did not differ between patients receiving PI- or non-PI-based DAAs in either FIB-4 group. LAY SUMMARY: Cases of liver injury have been reported among patients treated with protease inhibitor-based direct-acting antivirals for hepatitis C infection, but it is not clear if the risk of liver injury among people starting these drugs is increased compared to those starting non-protease inhibitor-based therapy. In this study, patients receiving protease inhibitor-based treatment had a higher risk of liver inflammation than those receiving a non-protease inhibitor-based treatment, regardless of the presence of pre-treatment advanced liver fibrosis/cirrhosis. However, the risk of severe liver dysfunction and decompensation were not higher for patients treated with protease inhibitor-based regimens.

Differences in Early Immunosuppressive Therapy Among Liver Retransplantation Recipients in a National Cohort.

BACKGROUND: There is no unified consensus as to the preferred immunosuppression (IS) strategy following liver retransplantation (reLT). METHODS: This was a retrospective cohort study using the United Network for Organ Sharing database. Recipient, donor, and center characteristics associated with induction use and early maintenance IS regimen were described. Multivariable Cox proportional hazards analysis evaluated induction receipt as a predictor of post-reLT survival. RESULTS: There were 3483 adult reLT recipients from 2002 to 2018 at 116 centers with 95.6% being performed at the same center as the initial liver transplant. Timing of reLT was associated with induction IS use and the discharge regimen (P < 0.001 for both) but not with regimens at 6- and 12-month post-reLT (P = 0.1 for both). Among late reLTs (>365 d), initial liver disease cause was a more important determinant of maintenance regimen than graft failure cause. Low-reLT volume centers used induction more often for late reLTs (41.1% versus 22.6% high volume; P = 0.002) yet were less likely to wean to calcineurin inhibitors alone in the first year (19.1% versus 38.7% high volume; P = 0.002). Accounting for recipient and donor factors, depleting induction marginally improved post-reLT mortality (adjusted hazard ratio, 0.77; 95% CI, 0.61-0.99; P = 0.08), whereas nondepleting induction had no significant effect. CONCLUSIONS: Although several recipient attributes inform early IS decision-making, this does not occur in a uniform manner and center factors also play a role. Further studies are needed to assess the effect of early IS on post-reLT outcomes.

Attainment of target rifampicin concentrations in cerebrospinal fluid during treatment of tuberculous meningitis.

OBJECTIVE: There is considerable uncertainty regarding the optimal use of rifampicin for the treatment of tuberculous (TB) meningitis. A pharmacokinetic modeling and simulation study of rifampicin concentrations in cerebrospinal fluid (CSF) during TB meningitis treatment was performed in this study. METHODS: Parameters for rifampicin pharmacokinetics in CSF were estimated using individual-level rifampicin pharmacokinetic data, and the model was externally validated in three separate patient cohorts. Monte Carlo simulations of rifampicin serum and CSF concentrations were performed. The area under the rifampicin CSF concentration-versus-time curve during 24 h (AUC0-24) relative to the minimum inhibitory concentration (MIC) served as the pharmacodynamic target. RESULTS: Across all simulated patients on the first treatment day, 85% attained the target AUC0-24/MIC ratio of 30 under a weight-based dosing scheme approximating 10 mg/kg. At the rifampicin MIC of 0.5 mg/l, the probability of AUC0-24/MIC target attainment was 26%. With an intensified dosing strategy corresponding to 20 mg/kg, target attainment increased to 99%, including 93% with a MIC of 0.5 mg/l. CONCLUSIONS: Under standard dosing guidelines, few TB meningitis patients would be expected to attain therapeutic rifampicin exposures in CSF when the MIC is ≥0.5 mg/l. Either downward adjustment of the rifampicin MIC breakpoint in the context of TB meningitis, or intensified rifampicin dosing upwards of 20 mg/kg/day, would reflect the likelihood of pharmacodynamic target attainment in CSF.

Assessing Response to Therapy for Nontuberculous Mycobacterial Lung Disease: Quo Vadis?

Assessing progression of disease or response to treatment remains a major challenge in the clinical management of nontuberculous mycobacterial (NTM) infections of the lungs. Serial assessments of validated measures of treatment response address whether the current therapeutic approach is on track toward clinical cure, which remains a fundamental question for clinicians and patients during the course of NTM disease treatment. The 2015 NTM Research Consortium Workshop, which included a patient advisory panel, identified treatment response biomarkers as a priority area for investigation. Limited progress in addressing this challenge also hampers drug development efforts. The Biomarker Qualification Program at the FDA supports the use of a validated treatment response biomarker across multiple drug development programs. Current approaches in clinical practice include microbiologic and radiographic monitoring, along with symptomatic and quality-of-life assessments. Blood-based monitoring, including assessments of humoral and cell-mediated NTM-driven immune responses, remain under investigation. Alignment of data collection schemes in prospective multicenter studies, including the support of biosample repositories, will support identification of treatment response biomarkers under standard-of-care and investigational therapeutic strategies. In this review, we outline the role of treatment monitoring biomarkers in both clinical practice and drug development frameworks.

Tuberculous Meningitis in Children and Adults: New Insights for an Ancient Foe.

PURPOSE OF REVIEW: Tuberculous meningitis is the most devastating manifestation of infection with Mycobacterium tuberculosis and represents a medical emergency. Approximately one half of tuberculous meningitis patients die or suffer severe neurologic disability. The goal of this review will be to review the pathogenic, clinical, and radiologic features of tuberculous meningitis and to highlight recent advancements in translational and clinical science. RECENT FINDINGS: Pharmacologic therapy includes combination anti-tuberculosis drug regimens and adjunctive corticosteroids. It is becoming clear that a successful treatment outcome depends on an immune response that is neither too weak nor overly robust, and genetic determinants of this immune response may identify which patients will benefit from adjunctive corticosteroids. Recent clinical trials of intensified anti-tuberculosis treatment regimens conducted in Indonesia and Vietnam, motivated by the pharmacologic challenges of treating M. tuberculosis infections of the central nervous system, have yielded conflicting results regarding the survival benefit of intensified treatment regimens. More consistent findings have been observed regarding the relationship between initial anti-tuberculosis drug resistance and mortality among tuberculous meningitis patients. Prompt initiation of anti-tuberculosis treatment for all suspected cases remains a key aspect of management. Priorities for research include the improvement of diagnostic testing strategies and the optimization of host-directed and anti-tuberculosis therapies.

Deaths Related to Nontuberculous Mycobacterial Infections in the United States, 1999-2014.

RATIONALE: Unlike tuberculosis, nontuberculous mycobacterial disease is not reportable to public health authorities in the United States, and the total burden of disease is uncertain. OBJECTIVES: To estimate the mortality of nontuberculous mycobacterial disease in the United States over a 15-year period and to identify temporal trends. METHODS: The U.S. Multiple Cause of Death Files from 1999 through 2014 were searched for a listing of nontuberculous mycobacterial disease by International Classification of Diseases, Tenth Revision code as either the underlying or a contributing cause of death. Characteristics of individuals with nontuberculous mycobacteria-related deaths in the United States were summarized according to demographic characteristics. Age-adjusted mortality rates and rate ratios were calculated using bridged-race population estimates of U.S. census population data. Time trends were evaluated with negative binomial regression. MEASUREMENTS AND MAIN RESULTS: There was a significant increase in nontuberculous mycobacteria-related deaths among individuals without a diagnosis of HIV infection (P = 0.004). Mortality rates increased with advancing age. Age-adjusted mortality rate ratios were lower for men (risk ratio [RR], 0.84; 95% confidence interval [CI], 0.80-0.87) compared with women, and were lower for Hispanic individuals (RR, 0.53; 95% CI, 0.49-0.56) and black, non-Hispanic persons (RR, 0.83; 95% CI, 0.77-0.88) compared with white, non-Hispanic individuals. CONCLUSIONS: The mortality rate of nontuberculous mycobacterial disease among HIV-uninfected individuals has increased in the United States between 1999 and 2014. These deaths occurred disproportionately in older white women. Considering the concurrent decline in tuberculosis-related deaths, these findings demonstrate a shift in the epidemiology of fatal mycobacterial infections in the United States.

Viral load monitoring as a tool to reinforce adherence: a systematic review.

OBJECTIVE: Viral load monitoring has been proposed as a tool to reinforce adherence, but outcomes have never been systematically assessed. DESIGN: A meta-analysis was conducted to systematically analyze the research on viral load monitoring as a tool to reinforce adherence. Viremic resuppression is defined here as a decrease in viral load beneath a particular threshold following viral load levels that have been elevated despite antiretroviral treatment. METHODS: Six databases were searched for studies published up to November 2012, which reported the use of viral load monitoring as a tool to identify patients in need of adherence support. Three conference abstract sites were reviewed for studies reported in the last 2 years. Randomized and quasi-randomized trials and observational studies, were eligible. No language or geographical restrictions were applied. RESULTS: Six retrospective and 2 prospective observational studies reported data from 8 countries: South Africa, the United States, Thailand, Mali, Burkina Faso, Swaziland, India, and France. Five studies reported on viremic resuppression, with a pooled estimate of 70.5% (95% confidence interval: 56.6% to 84.4%) resuppressed. The remaining 3 studies all reported declines in mean viral load. Delayed onset of routine viral load monitoring was associated with the emergence of drug resistance. CONCLUSIONS: The clear trend of resuppression, following viral load testing and adherence support, demonstrates the utility of viral load as a tool to identify patients in need of enhanced adherence support.