Early Outcomes of SARS-CoV-2 Infection in a Multisite Prospective Cohort of Inpatient Veterans.

Background: Over 870 000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have occurred among Veterans Health Administration users, and 24 000 have resulted in death. We examined early outcomes of SARS-CoV-2 infection in hospitalized veterans. Methods: In an ongoing, prospective cohort study, we enrolled veterans age ≥18 tested for SARS-CoV-2 and hospitalized at 15 Department of Veterans Affairs medical centers between February 2021 and June 2022. We estimated adjusted odds ratios (aORs), adjusted incidence rate ratios (aIRRs), and adjusted hazard ratios (aHRs) for maximum illness severity within 30 days of study entry (defined using the 4-category VA Severity Index for coronavirus disease 2019 [COVID-19]), as well as length of hospitalization and rehospitalization within 60 days, in relationship with demographic characteristics, Charlson comorbidity index (CCI), COVID-19 vaccination, and calendar period of enrollment. Results: The 542 participants included 329 (61%) who completed a primary vaccine series (with or without booster; "vaccinated"), 292 (54%) enrolled as SARS-CoV-2-positive, and 503 (93%) men, with a mean age of 64.4 years. High CCI scores (≥5) occurred in 61 (44%) vaccinated and 29 (19%) unvaccinated SARS-CoV-2-positive participants. Severe illness or death occurred in 29 (21%; 6% died) vaccinated and 31 (20%; 2% died) unvaccinated SARS-CoV-2-positive participants. SARS-CoV-2-positive inpatients per unit increase in CCI had greater multivariable-adjusted odds of severe illness (aOR, 1.21; 95% CI, 1.01-1.45), more hospitalization days (aIRR, 1.06; 95% CI, 1.03-1.10), and rehospitalization (aHR, 1.07; 95% CI, 1.01-1.12). Conclusions: In a cohort of hospitalized US veterans with SARS-CoV-2 infection, those with a higher CCI had more severe COVID-19 illness, more hospital days, and rehospitalization, after adjusting for vaccination status, age, sex, and calendar period.

Assessment of the Frequency, Phenotypes, and Outcomes of Acute Liver Injury Associated with Amoxicillin/Clavulanate in 1.4 Million Patients in the Veterans Health Administration.

INTRODUCTION: Drug-induced liver injury is a significant health issue, yet the exposure-based incidence remains to be characterized. OBJECTIVE: We aimed to assess the frequency, phenotypes, and outcomes of acute liver injury associated with amoxicillin/clavulanate using a large electronic health record system. METHODS: Using the Veterans Health Administration electronic health record system, we developed the framework to identify unexplained acute liver injury, defined by alanine aminotransferase and/or alkaline phosphatase elevation temporally linked to prescription records of amoxicillin/clavulanate, a major culprit of clinically significant drug-induced liver injury, excluding other competing causes. The population was subcategorized by pre-existing liver conditions and inpatient status at the time of exposure for the analysis. RESULTS: Among 1,445,171 amoxicillin/clavulanate first exposures in unique individuals [92% men; mean age (standard deviation): 59 (15) years], 6476 (incidence: 0.448%) acute liver injuries were identified. Of these, 4427 (65%) had alternative causes, yielding 2249 (incidence: 0.156%) with unexplained acute liver injuries. The incidence of unexplained acute liver injury was lowest in outpatients without underlying liver disease (0.067%) and highest in inpatients with pre-existing liver conditions (0.719%). Older age, male sex, and American Indian or Alaska Native (vs White) were associated with a higher incidence of unexplained acute liver injury. Cholestatic injury affected 74%, exhibiting a higher frequency with advanced age, inpatient exposure, and pre-existing liver conditions. Hepatocellular injury with bilirubin elevation affected 0.003%, with a higher risk at age >45 years. During a 12-month follow-up, patients with unexplained acute liver injury had a higher adjusted overall mortality risk than those without evident acute liver injury. CONCLUSIONS: This framework identifies unexplained acute liver injury following drug exposure in large electronic health record datasets. After validating in other systems, this framework can aid in deducing drug-induced liver injury in the general patient population and regulatory decision making to promote drug safety and public health.

Clinical Pattern of Tolvaptan-Associated Liver Injury in Trial Participants With Autosomal Dominant Polycystic Kidney Disease (ADPKD): An Analysis of Pivotal Clinical Trials.

RATIONALE & OBJECTIVE: Tolvaptan is associated with risk of drug-induced liver injury when used to treat autosomal dominant polycystic kidney disease (ADPKD). After this risk was described based on the clinical trials TEMPO 3:4 and TEMPO 4:4, additional data from the REPRISE trial and a long-term extension of TEMPO 4:4, REPRISE, and other tolvaptan trials in ADPKD have become available. To further characterize the hepatic safety profile of tolvaptan, an analysis of the expanded dataset was conducted. STUDY DESIGN: Analysis of safety data from prospective clinical trials of tolvaptan. SETTING & PARTICIPANTS: Multicenter clinical trials including more than 2,900 tolvaptan-treated participants, more than 2,300 with at least 18 months of drug exposure. INTERVENTION: Tolvaptan administered twice daily in split-dose regimens. OUTCOMES: Frequency of liver enzyme level increases detected by regular laboratory monitoring. RESULTS: In the placebo-controlled REPRISE trial, more tolvaptan- than placebo-treated participants (38 of 681 [5.6%] vs 8 of 685 [1.2%]) experienced alanine aminotransferase level increases to >3× the upper limit of normal (ULN), similar to TEMPO 3:4 (40 of 957 [4.4%] vs 5 of 484 [1.0%]). No participant in REPRISE or the long-term extension experienced concurrent alanine aminotransferase level increases to >3× ULN and total bilirubin increases to >2× ULN ("Hy's Law" laboratory criteria). Based on the expanded dataset, liver enzyme increases most often occurred within 18 months after tolvaptan initiation and were less frequent thereafter. Increased levels returned to normal or near normal after treatment interruption or discontinuation. Thirty-eight patients were rechallenged with tolvaptan after the initial drug-induced liver injury episode, with return of liver enzyme level increases in 30; 1 additional participant showed a clinical "adaptation" after the initial episode, with resolution of the enzyme level increases despite continuation of tolvaptan. LIMITATIONS: Retrospective analysis. CONCLUSIONS: The absence of Hy's Law cases in REPRISE and the long-term extension trial support monthly liver enzyme monitoring during the first 18 months of tolvaptan exposure and every 3 months thereafter to detect and manage enzyme level increases, as is recommended on the drug label. FUNDING: Otsuka Pharmaceutical Development & Commercialization, Inc. TRIAL REGISTRATION: Trials included in the dataset were registered at ClinicalTrials.gov with study numbers NCT00428948 (TEMPO 3:4), NCT01214421 (TEMPO 4:4), NCT02160145 (REPRISE), and NCT02251275 (long-term extension).

Medications Associated with Lower Mortality in a SARS-CoV-2 Positive Cohort of 26,508 Veterans.

BACKGROUND: Many severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) positive patients take commonly prescribed medications with properties which may affect mortality. OBJECTIVE: Assess if common medications postulated to affect clinical outcomes are associated with mortality in SARS-CoV-2 positive patients in the Veterans Health Administration (VHA). DESIGN: Observational national cohort analysis. PARTICIPANTS: Consecutive 26,508 SARS-CoV-2 positive Veterans (7% of 399,290 tested from March 1 to September 10, 2020) constitute the study cohort. MAIN MEASURES: The primary outcome was 30-day mortality from the first positive SARS-CoV-2 test date. In patients receiving medications or drug pairs within 2 weeks post-SARS-CoV-2 positive test, 30-day mortality was estimated as relative risk (RR) on the log-binomial scale or using multinomial models with and without adjusting for covariates. KEY RESULTS: The 26,508 SARS-CoV-2 positive patients were predominantly male (89%) and White (59%), and 82% were overweight/obese. Medications associated with decreased 30-day mortality risk included the following: metformin (aRR, 0.33; 95% CI, 0.25-0.43), colchicine, angiotensin-converting-enzyme inhibitors (ACEi), angiotensin II receptor blockers, statins, vitamin D, antihistamines, alpha-blockers, anti-androgens, and nonsteroidal anti-inflammatory drugs (aRR, 0.69; 95% CI, 0.61-0.78). The effect of co-prescribed medications on 30-day mortality risk revealed the lowest risk for combined statins and metformin (aRR, 0.21; 95% CI, 0.15-0.31), followed by ACEi and statins (aRR, 0.25; 95% CI, 0.18-0.35), ACEi and metformin (aRR, 0.26; 95% CI, 0.17-0.40), antihistamines and NSAIDs (aRR, 0.41; 95% CI, 0.32-0.52), and in men, combined alpha-blockers and anti-androgens (aRR, 0.51; 95% CI, 0.42-0.64). CONCLUSIONS: In this large national cohort, treatment of SARS-CoV-2 positive patients with individual or co-prescribed metformin and statins, ACEi and statins (or metformin) and other medications was associated with a markedly decreased 30-day mortality and can likely be continued safely. Clinical trials may assess their therapeutic benefit.

Pharmacogenetic variants and risk of remdesivir-associated liver enzyme elevations in Million Veteran Program participants hospitalized with COVID-19.

Remdesivir is the first US Food and Drug Administration (FDA)-approved drug for the treatment of coronavirus disease 2019 (COVID-19). We conducted a retrospective pharmacogenetic study to examine remdesivir-associated liver enzyme elevation among Million Veteran Program participants hospitalized with COVID-19 between March 15, 2020, and June 30, 2021. Pharmacogene phenotypes were assigned using Stargazer. Linear regression was performed on peak log-transformed enzyme values, stratified by population, adjusted for age, sex, baseline liver enzymes, comorbidities, and 10 population-specific principal components. Patients on remdesivir had higher peak alanine aminotransferase (ALT) values following treatment initiation compared with patients not receiving remdesivir. Remdesivir administration was associated with a 33% and 24% higher peak ALT in non-Hispanic White (NHW) and non-Hispanic Black (NHB) participants (p < 0.001), respectively. In a multivariable model, NHW CYP2C19 intermediate/poor metabolizers had a 9% increased peak ALT compared with NHW normal/rapid/ultrarapid metabolizers (p = 0.015); this association was not observed in NHB participants. In summary, remdesivir-associated ALT elevations appear to be multifactorial, and further studies are needed.

Hepatitis B Virus-related Care Quality in Patients With Hepatitis B/Human Immunodeficiency Virus Coinfection Versus Hepatitis B Monoinfection: A National Cohort Study.

BACKGROUND: Guideline-adherent hepatitis B virus (HBV) care is critical for patients with HBV, particularly patients with HBV-human immunodeficiency virus (HIV) given increased risks of liver-related complications. However, a comprehensive assessment of HBV-related care in patients with HBV-HIV is lacking. METHODS: We retrospectively assessed adherence to HBV-related care guidelines in all patients with HBV-HIV and HBV monoinfection (HBV-M) in the national Veterans Health Administration healthcare system in 2019. RESULTS: We identified 1021 patients with HBV-HIV among 8323 veterans with chronic HBV. Adherence to HBV guidelines was similar or better in HBV-HIV versus HBV-M, including HBV treatment (97% vs 71%), biannual hepatocellular carcinoma (HCC) surveillance (55% vs 55%) for patients with cirrhosis, hepatitis A virus screening (69% vs 56%), hepatitis C virus screening (100% vs 99%), and on-therapy alanine aminotransferase monitoring (95% vs 96%). Compared with those seeing gastroenterology (GI) or infectious diseases (ID) providers, patients without specialty care were less likely to receive antiviral treatment (none, 39%; GI, 80%; ID, 84%) or HCC surveillance (none, 16%; GI, 66%; ID, 47%). These findings persisted in multivariable analysis. Compared with ID care alone, a higher proportion of patients with HBV-HIV seen dually by GI and ID received HCC surveillance (GI + ID 73% vs ID 31%) and on-therapy HBV-DNA monitoring (GI + ID, 82%; ID, 68%). CONCLUSIONS: Patients with HBV-HIV received similar or higher rates of guideline-adherent HBV-related care than patients with HBV-M. Patients with HBV-HIV under dual GI and ID care achieved higher quality care compared with ID care alone. Specialty care was independently associated with higher quality HBV care in patients with HBV-HIV and HBV-M.

APOL1 Risk Variants, Acute Kidney Injury, and Death in Participants With African Ancestry Hospitalized With COVID-19 From the Million Veteran Program.

IMPORTANCE: Coronavirus disease 2019 (COVID-19) confers significant risk of acute kidney injury (AKI). Patients with COVID-19 with AKI have high mortality rates. OBJECTIVE: Individuals with African ancestry with 2 copies of apolipoprotein L1 (APOL1) variants G1 or G2 (high-risk group) have significantly increased rates of kidney disease. We tested the hypothesis that the APOL1 high-risk group is associated with a higher-risk of COVID-19-associated AKI and death. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included 990 participants with African ancestry enrolled in the Million Veteran Program who were hospitalized with COVID-19 between March 2020 and January 2021 with available genetic information. EXPOSURES: The primary exposure was having 2 APOL1 risk variants (RV) (APOL1 high-risk group), compared with having 1 or 0 risk variants (APOL1 low-risk group). MAIN OUTCOMES AND MEASURES: The primary outcome was AKI. The secondary outcomes were stages of AKI severity and death. Multivariable logistic regression analyses adjusted for preexisting comorbidities, medications, and inpatient AKI risk factors; 10 principal components of ancestry were performed to study these associations. We performed a subgroup analysis in individuals with normal kidney function prior to hospitalization (estimated glomerular filtration rate ≥60 mL/min/1.73 m2). RESULTS: Of the 990 participants with African ancestry, 905 (91.4%) were male with a median (IQR) age of 68 (60-73) years. Overall, 392 (39.6%) patients developed AKI, 141 (14%) developed stages 2 or 3 AKI, 28 (3%) required dialysis, and 122 (12.3%) died. One hundred twenty-five (12.6%) of the participants were in the APOL1 high-risk group. Patients categorized as APOL1 high-risk group had significantly higher odds of AKI (adjusted odds ratio [OR], 1.95; 95% CI, 1.27-3.02; P = .002), higher AKI severity stages (OR, 2.03; 95% CI, 1.37-2.99; P < .001), and death (OR, 2.15; 95% CI, 1.22-3.72; P = .007). The association with AKI persisted in the subgroup with normal kidney function (OR, 1.93; 95% CI, 1.15-3.26; P = .01). Data analysis was conducted between February 2021 and April 2021. CONCLUSIONS AND RELEVANCE: In this cohort study of veterans with African ancestry hospitalized with COVID-19 infection, APOL1 kidney risk variants were associated with higher odds of AKI, AKI severity, and death, even among individuals with prior normal kidney function.

COVID-19-Associated Mortality in US Veterans with and without SARS-CoV-2 Infection.

BACKGROUND: We performed an observational Veterans Health Administration cohort analysis to assess how risk factors affect 30-day mortality in SARS-CoV-2-infected subjects relative to those uninfected. While the risk factors for coronavirus disease 2019 (COVID-19) have been extensively studied, these have been seldom compared with uninfected referents. METHODS: We analyzed 341,166 White/Black male veterans tested for SARS-CoV-2 from March 1 to September 10, 2020. The relative risk of 30-day mortality was computed for age, race, ethnicity, BMI, smoking status, and alcohol use disorder in infected and uninfected subjects separately. The difference in relative risk was then evaluated between infected and uninfected subjects. All the analyses were performed considering clinical confounders. RESULTS: In this cohort, 7% were SARS-CoV-2-positive. Age >60 and overweight/obesity were associated with a dose-related increased mortality risk among infected patients relative to those uninfected. In contrast, relative to never smoking, current smoking was associated with a decreased mortality among infected and an increased mortality in uninfected, yielding a reduced mortality risk among infected relative to uninfected. Alcohol use disorder was also associated with decreased mortality risk in infected relative to the uninfected. CONCLUSIONS: Age, BMI, smoking, and alcohol use disorder affect 30-day mortality in SARS-CoV-2-infected subjects differently from uninfected referents. Advanced age and overweight/obesity were associated with increased mortality risk among infected men, while current smoking and alcohol use disorder were associated with lower mortality risk among infected men, when compared with those uninfected.

Alanine Aminotransferase Results Differ by Analyzer Manufacturer in a National Integrated Health Setting, 2012-2017.

CONTEXT.­: Disease guidelines specify universal alanine aminotransferase (ALT) thresholds for clinical decision-making, yet the effect of variability among ALT analyzers remains unclear. OBJECTIVE.­: To compare ALT results from different analyzers from 2012-2017. DESIGN.­: Veterans Health Administration (VHA) laboratories perform external ALT proficiency testing using standardized College of American Pathologists (CAP) samples in analyzers by 5 manufacturers. In this operational analysis, we evaluated 22 950 ALT values from 80 independent CAP samples tested at 223 laboratories. Using mixed effects modeling, we estimated the association between analyzer manufacturer and CAP outcome, adjusting for manufacturer, facility, and calendar year. We performed subgroup analyses on CAP samples with overall means near clinical guideline-specified thresholds, including less than 50 U/L (n = 10) and less than 35 U/L (n = 5). RESULTS.­: The VHA used Abbott Laboratories (n = 3175; 14%), Beckman Coulter Diagnostics (n = 8723; 38%), Roche Diagnostics (n = 2595; 11%), Siemens Healthineers USA (n = 5713; 25%), and Vitros/Ortho Clinical Diagnostics (n = 2744; 12%) analyzers. The CAP samples (n = 80 samples, n = 22 950 tests) covered a wide range of mean ALT values (21-268 U/L). The average difference in mean ALT value per sample between the highest-reading and lowest-reading manufacturers was 15.4 U/L (SD = 1.8) for the 10 samples with mean ALT less than 50 U/L, and it was 10.4 U/L (SD = 3.6) overall (n = 80). In linear mixed effects modeling, we found statistically significant differences in ALT values between the different manufacturers in each year. CONCLUSIONS.­: We found statistically and clinically meaningful differences between analyzers across the ALT spectrum in each year, including at ALT levels lower than 50 U/L and lower than 35 U/L. Universal ALT thresholds should be avoided as a trigger for clinical action until differences between analyzers can be resolved.

Comorbidities and Nonalcoholic Fatty Liver Disease: The Chicken, the Egg, or Both?

Improvement in NAFLD may lead to improvement of metabolic syndrome, cardiovascular disease, and malignancy and vice versa.

Identifying and Treating Nonalcoholic Fatty Liver Disease.

NAFLD improves with 7% or greater weight loss.

Preventing Hepatitis B Reactivation During Anti-CD20 Antibody Treatment in the Veterans Health Administration.

Hepatitis B virus (HBV) reactivation may occur with high risk immunosuppression, such as anti-cluster of differentiation (CD)20 antibodies (Abs). Appropriate HBV prophylaxis during anti-CD20 Ab therapy averts hepatitis, chemotherapy disruption, and death. Serologic evidence of prior HBV exposure is present in one in nine veterans in the Veterans Health Administration (VHA). In 2014, most (61%-73%) patients in the VHA who were receiving anti-CD20 Ab treatment underwent HBV testing, yet <20% of eligible patients received HBV antiviral prophylaxis. We aimed to prevent HBV reactivation by increasing HBV testing and antiviral treatment rates among anti-CD20 Ab recipients through prospective interventions. A multidisciplinary team of clinicians, pharmacists, and public health professionals developed comprehensive prevention systems, including national seminars/newsletters/websites; pharmacy criteria for HBV screening/treatment prior to anti-CD20 Ab use; changes to national formulary restrictions to expand HBV prophylaxis prescribing authority; Medication Use Evaluation Tracker to identify omissions; national e-mail alert to all VHA oncology providers detailing specific testing and HBV antiviral treatment needs; and a voluntary electronic medical record "order check" used at interested facilities (n = 11) to automatically assess pretreatment HBV testing and antiviral treatment and only generate a reminder to address deficiencies. Analysis of monthly data from June 2016 through September 2017 among anti-CD20 Ab recipients revealed pre-anti-CD20 Ab treatment HBV testing increased to 91%-96% and appropriate HBV antiviral prophylaxis to 76%-85% nationally following implementation of the intervention. Medical centers using the voluntary electronic medical record order check increased HBV testing rates to 93%-98% and HBV antiviral prophylaxis rates to 99%. Conclusion: Multimodal intervention systems to prevent HBV reactivation among VHA patients receiving anti-CD20 Ab therapies increased national rates of HBV testing to >90% and antiviral prophylaxis to >80%.

Correction to: Identifying Nonalcoholic Fatty Liver Disease Advanced Fibrosis in the Veterans Health Administration.

The original version of the article unfortunately contained errors in Table 3, Risk Factor column headings "Age > 50 (n = 115)," "Age > 50-64 (n = 154)," and "Age > 65 + (n = 60)."

Identifying Nonalcoholic Fatty Liver Disease Advanced Fibrosis in the Veterans Health Administration.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Severe NAFLD with advanced fibrosis results in substantial morbidity and mortality. Associated with metabolic syndrome, NAFLD is often initially clinically silent, yet intensive lifestyle intervention with 7% or greater weight loss can improve or resolve NAFLD. Using a Veterans Health Administration (VHA) liver biopsy cohort, we evaluated simple noninvasive fibrosis scoring systems to identify NAFLD with advanced fibrosis (or severe disease) to assist providers. METHODS: In our retrospective study of a national VHA sample of patients with biopsy-proven NAFLD or normal liver (2005-2015), we segregated patients by fibrosis stage (0-4). Non-NAFLD liver disease was excluded. We evaluated the diagnostic accuracy of the NAFLD fibrosis score (NFS), fibrosis-4 calculator (FIB-4), aspartate aminotransferase-to-alanine aminotransferase ratio (AST/ALT ratio), AST-to-platelet ratio index (APRI), and body mass index, AST/ALT ratio, and diabetes (BARD) score by age groups. RESULTS: We included 329 patients with well-defined liver histology (296 NAFLD and 33 normal controls without fibrosis), in which 92 (28%) had advanced (stage 3-4) fibrosis. Across all age groups, NFS and FIB-4 best predicted advanced fibrosis (NFS with 0.676 threshold: AUROC 0.71-0.76, LR + 2.30-22.05, OR 6.00-39.58; FIB-4 with 2.67 threshold: AUROC of 0.62-0.80, LR + 4.70-27.45, OR 16.34-59.65). CONCLUSIONS: While NFS and FIB-4 scores exhibit good diagnostic accuracy, FIB-4 is optimal in identifying NAFLD advanced fibrosis in the VHA. Easily implemented as a point-of-care clinical test, FIB-4 can be useful in directing patients that are most likely to have advanced fibrosis to GI/hepatology consultation and follow-up.

Interplay of gender, age and drug properties on reporting frequency of drug-induced liver injury.

We examined the effect of gender, age, and drug properties on liver events reporting frequency (RF) to assess patient- and drug-related risks for drug-induced liver injury (DILI). We performed a data-mining analysis of the WHO VigiBase™ to 1) identify drugs with gender- and age-biased RF and 2) characterize drug properties using the Liver Toxicity Knowledge Base. Age-, gender-specific Empirical Bayes Geometric Mean of relative reporting ratio of liver events with 90% confidence interval (CI) was calculated for 375 drugs with DILI potential. Forty-one drugs showed an increased RF in women, which had a higher prevalence of reactive metabolite formation and mitochondrial dysfunction and transporter inhibition. Fifty-nine drugs showed an increased RF in younger women (<50 yrs), many of which had a signature pattern of hepatocellular injury. In contrast, half of 17 drugs that showed an increased RF in men had a cholestatic pattern. In the older group (≥50 yrs), 17 drugs showed an increased RF and had higher transporter inhibition, Cmax, and plasma protein binding, yet shorter plasma elimination. Specific drug properties were associated with gender- and age-biased liver events RF, suggesting possible interactions of drug properties, gender, and age in DILI development.

Drug rechallenge following drug-induced liver injury.

Drug-induced hepatocellular injury is identified internationally by alanine aminotransferase (ALT) levels equal to or exceeding 5× the upper limit of normal (ULN) appearing within 3 months of drug initiation, after alternative causes are excluded. Upon withdrawing the suspect drug, ALT generally decrease by 50% or more. With drug readministration, a positive rechallenge has recently been defined by an ALT level of 3-5× ULN or greater. Nearly 50 drugs are associated with positive rechallenge after drug-induced liver injury (DILI): antimicrobials; and central nervous system, cardiovascular and oncology therapeutics. Drugs associated with high rates of positive rechallenge exhibit multiple risk factors: daily dose >50 mg, an increased incidence of ALT elevations in clinical trials, immunoallergic clinical injury, and mitochondrial impairment in vitro. These drug factors interact with personal genetic, immune, and metabolic factors to influence positive rechallenge rates and outcomes. Drug rechallenge following drug-induced liver injury is associated with up to 13% mortality in prospective series of all prescribed drugs. In recent oncology trials, standardized systems have enabled safer drug rechallenge with weekly liver chemistry monitoring during the high-risk period and exclusion of patients with hypersensitivity. However, high positive rechallenge rates with other innovative therapeutics suggest that caution should be taken with rechallenge of high-risk drugs. CONCLUSION: For critical medicines, drug rechallenge may be appropriate when 1) no safer alternatives are available, 2) the objective benefit exceeds the risk, and 3) patients are fully informed and consent, can adhere to follow-up, and alert providers to hepatitis symptoms. To better understand rechallenge outcomes and identify key risk factors for positive rechallenge, additional data are needed from controlled clinical trials, prospective registries, and large health care databases. (Hepatology 2017;66:646-654).