AFP-L3 and DCP strongly predict early hepatocellular carcinoma recurrence after liver transplantation.

BACKGROUND & AIMS: Alpha-fetoprotein (AFP) predicts hepatocellular carcinoma (HCC) recurrence after liver transplant (LT) but remains an imperfect biomarker. The role of DCP (des-gamma-carboxyprothrombin) and AFP-L3 (AFP bound to Lens culinaris agglutinin) in predicting HCC recurrence remains incompletely characterized. AFP-L3 and DCP could identify patients at high risk of post-transplant HCC recurrence and serve as liver transplant exclusion criteria to defer transplant until patients receive additional risk-reducing pre-transplant locoregional therapy. METHODS: This prospective cohort study included consecutive patients with HCC who underwent LT (within or down-staged to Milan criteria) between 2017 and 2022. Pre-transplant AFP, AFP-L3, and DCP measurements were obtained. The primary endpoint was the ability of biomarkers to predict HCC recurrence-free survival. RESULTS: This cohort included 285 patients with a median age of 67 (IQR 63-71). At LT, median biomarker values were AFP 5.0 ng/ml (IQR 3.0-12.1), AFP-L3 6.7% (0.5-13.2), and DCP 1.0 ng/ml (0.3-2.8). Most (94.7%) patients received pre-LT locoregional therapy. After a median post-LT follow-up of 3.1 years, HCC recurrence was observed in 18 (6.3%) patients. AFP-L3 and DCP outperformed AFP with C-statistics of 0.81 and 0.86 respectively, compared with 0.74 for AFP. A dual-biomarker combination of AFP-L3 ≥15% and DCP ≥7.5 predicted 61.1% of HCC recurrences, whereas HCC only recurred in 7 of 265 (2.6%) patients not meeting this threshold. The Kaplan-Meier recurrence-free survival rate at 3 years post-LT was 43.7% for patients with dual-positive biomarkers compared to 97.0% for all others (p <0.001). CONCLUSIONS: Dual-positivity for AFP-L3 ≥15% and DCP ≥7.5 strongly predicted post-LT HCC recurrence. This model could refine LT selection criteria and identify high-risk patients who require additional locoregional therapy prior to LT. IMPACT AND IMPLICATIONS: Alpha-fetoprotein (AFP) is used to predict hepatocellular carcinoma (HCC) recurrence after liver transplant, but it remains an imperfect biomarker. In this prospective study, the biomarkers DCP (des-gamma-carboxyprothrombin) and AFP-L3 (AFP bound to Lens culinaris agglutinin) strongly predicted early HCC recurrence and outperformed AFP. A dual-biomarker combination of AFP-L3 ≥15% and DCP ≥7.5 predicted the majority of recurrences and could be used to further refine liver transplant eligibility criteria.

AFP-L3 and DCP are superior to AFP in predicting waitlist dropout in HCC patients: Results of a prospective study.

In patients with HCC awaiting liver transplantation (LT), there is a need to identify biomarkers that are superior to AFP in predicting prognosis. AFP-L3 and des-gamma-carboxyprothrombin (DCP) play a role in HCC detection, but their ability to predict waitlist dropout is unknown. In this prospective single-center study commenced in July 2017, 267 HCC patients had all 3 biomarkers obtained at LT listing. Among them, 96.2% received local-regional therapy, and 18.8% had an initial tumor stage beyond Milan criteria requiring tumor downstaging. At listing, median AFP was 7.0 ng/mL (IQR 3.4-21.5), median AFP-L3 was 7.1% (IQR 0.5-12.5), and median DCP was 1.0 ng/mL (IQR 0.2-3.8). After a median follow-up of 19.3 months, 63 (23.6%) experienced waitlist dropout, while 145 (54.3%) received LT, and 59 (22.1%) were still awaiting LT. Using Cox proportional hazards analysis, AFP-L3≥35% and DCP≥7.5 ng/mL were associated with increased waitlist dropout, whereas AFP at all tested cutoffs, including ≥20,≥ 100, and≥250 ng/mL was not. In a multivariable model, AFP-L3≥35% (HR 2.25, p =0.04) and DCP≥7.5 ng/mL (HR 2.20, p =0.02) remained associated with waitlist dropout as did time from HCC diagnosis to listing ≥ 1 year and increasing MELD-Na score. Kaplan-Meier probability of waitlist dropout within 2 years was 21.8% in those with AFP-L3<35% and DCP<7.5 ng/mL, 59.9% with either AFP-L3 or DCP elevated, and 100% for those with both elevated ( p <0.001). In this prospective study, listing AFP-L3% and DCP were superior to AFP in predicting waitlist dropout with the combination of AFP-L3≥35% and DCP≥7.5 ng/mL associated with a 100% risk of waitlist dropout, thus clearly adding prognostic value to AFP alone.

DCP and AFP-L3 Are Complementary to AFP in Predicting High-Risk Explant Features: Results of a Prospective Study.

Among patients with hepatocellular carcinoma (HCC), elevated α-fetoprotein (AFP) has been shown to predict waitlist dropout, high-risk histopathologic features, and inferior post-liver transplant (LT) outcome.1,2 Nevertheless, many patients with HCC have a normal AFP and yet still experience waitlist dropout or post-LT recurrence.2 Because of the degree of imprecision associated with AFP, there is a quest for other biomarkers that may be complementary to or better than AFP in predicting prognosis in LT. Lectin-reactive AFP (AFP-L3) and des-gamma-carboxyprothrombin (DCP) are biomarkers that have been used in conjunction with AFP as HCC surveillance or diagnostic tools.3,4 However, the utility of these biomarkers in LT for HCC is not established.

Tofacitinib for Rescue Therapy in Acute Severe Ulcerative Colitis: A Real-world Experience.

BACKGROUND: Acute severe ulcerative colitis is a high stakes event with significant numbers still requiring emergent colectomy, representing a need to establish alternative medical management options. We report a case series of tofacitinib as rescue therapy in biologic-experienced patients with acute severe ulcerative colitis. METHODS: Four patients were identified over a 1-year period at our institution who initiated tofacitinib for acute severe ulcerative colitis. All four had previously failed at least two biologics, including infliximab, and were failing high-dose oral prednisone therapy before admission. All patients had Mayo disease activity index of at least 10 at admission. After no significant improvement despite receiving a minimum of 3 days of intravenous methylprednisolone and based on elevated Ho and Travis indices at Day 3, patients were offered rescue tofacitinib for induction of remission, or colectomy. Standard induction of tofacitinib was used [10 mg twice daily], and one patient was escalated to 15 mg twice daily after inadequate response. RESULTS: All patients experienced improvement in objective symptoms and laboratory markers, and were discharged without colectomy on tofacitinib as maintenance therapy and prednisone taper; 30-day and 90-day colectomy rates on tofacitinib maintenance therapy were zero and 90-day readmission rate was also zero. Two of four patients achieved steroid-free remission on maintenance tofacitinib monotherapy based on clinical symptoms and follow-up endoscopy. No major adverse reaction was reported during induction or maintenance therapy. CONCLUSIONS: Tofacitinib may be an acceptable rescue agent in biologic-experienced patients with acute severe ulcerative colitis. Tofacitinib may also be safely continued as maintenance therapy once remission has been achieved.

Hypertension testing and treatment in Uganda and Kenya through the SEARCH study: An implementation fidelity and outcome evaluation.

BACKGROUND: Hypertension (HTN) is the single leading risk factor for human mortality worldwide, and more prevalent in sub-Saharan Africa than any other region [1]-although resources for HTN screening, treatment, and control are few. Most regional pilot studies to leverage HIV programs for HTN control have achieved blood pressure control in half of participants or fewer [2,3,4]. But this control gap may be due to inconsistent delivery of services, rather than ineffective underlying interventions. METHODS: We sought to evaluate the consistency of HTN program delivery within the SEARCH study (NCT01864603) among 95,000 adults in 32 rural communities in Uganda and Kenya from 2013-2016. To achieve this objective, we designed and performed a fidelity evaluation of the step-by-step process (cascade) of HTN care within SEARCH, calculating rates of HTN screening, linkage to care, and follow-up care. We evaluated SEARCH's assessment of each participant's HTN status against measured blood pressure and HTN history. FINDINGS: SEARCH completed blood pressure screens on 91% of participants. SEARCH HTN screening was 91% sensitive and over 99% specific for HTN relative to measured blood pressure and patient history. 92% of participants screened HTN+ received clinic appointments, and 42% of persons with HTN linked to subsequent care. At follow-up, 82% of SEARCH clinic participants received blood pressure checks; 75% received medication appropriate for their blood pressure; 66% remained in care; and 46% had normal blood pressure at their most recent visit. CONCLUSION: The SEARCH study's consistency in delivering screening and treatment services for HTN was generally high, but SEARCH could improve effectiveness in linking patients to care and achieving HTN control. Its model for implementing population-scale HTN testing and care through an existing HIV test-and-treat program-and protocol for evaluating the intervention's stepwise fidelity and care outcomes-may be adapted, strengthened, and scaled up for use across multiple resource-limited settings.

History of Marijuana Use Does Not Affect Outcomes on the Liver Transplant Waitlist.

BACKGROUND: Data are limited on marijuana use and its impact on liver transplant (LT) waitlist outcomes. We aimed to assess the risk of waitlist mortality/delisting and likelihood of LT among prior marijuana users and to determine the prevalence and factors associated with marijuana use. METHODS: Retrospective cohort of adults evaluated for LT over 2 years at a large LT center. Marijuana use was defined by self-report in psychosocial assessment and/or positive urine toxicology. Ongoing marijuana use was not permitted for LT listing during study period. RESULTS: Eight hundred eighty-four adults were evaluated, and 585 (66%) were listed for LT (median follow-up, 1.4 years; interquartile range, 0.5-2.0). Prevalence of marijuana use was 48%, with 7% being recent users and 41% prior users. Marijuana use had statistically significant association with alcoholic cirrhosis (incidence rate ratio [IRR], 1.9) and hepatitis C (IRR, 2.1) versus hepatitis B, tobacco use (prior IRR, 1.4; recent IRR, 1.3 vs never), alcohol use (never IRR 0.1; heavy use/abuse IRR 1.2 vs social), and illicit drug use (prior IRR, 2.3; recent, 1.9 vs never). In adjusted competing risk regression, marijuana use was not associated with the probability of LT (prior hazard ratio [HR], 0.9; recent HR, 0.9 vs never) or waitlist mortality/delisting (prior HR, 1.0; recent HR, 1.0 vs never). However, recent illicit drug use was associated with higher risk of death or delisting (HR, 1.8; P = 0.004 vs never). CONCLUSIONS: Unlike illicit drug use, marijuana use was not associated with worse outcomes on the LT waitlist. Prospective studies are needed to assess ongoing marijuana use on the LT waitlist and post-LT outcomes.

Population-Based Assessment of Hypertension Epidemiology and Risk Factors among HIV-Positive and General Populations in Rural Uganda.

BACKGROUND: Antiretroviral therapy scale-up in Sub-Saharan Africa has created a growing, aging HIV-positive population at risk for non-communicable diseases such as hypertension. However, the prevalence and risk factors for hypertension in this population remain incompletely understood. METHODS: We measured blood pressure and collected demographic data on over 65,000 adults attending multi-disease community health campaigns in 20 rural Ugandan communities (SEARCH Study: NCT01864603). Our objectives were to determine (i) whether HIV is an independent risk factor for hypertension, and (ii) awareness and control of hypertension in HIV-positive adults and the overall population. RESULTS: Hypertension prevalence was 14% overall, and 11% among HIV-positive individuals. 79% of patients were previously undiagnosed, 85% were not taking medication, and 50% of patients on medication had uncontrolled blood pressure. Multivariate predictors of hypertension included older age, male gender, higher BMI, lack of education, alcohol use, and residence in Eastern Uganda. HIV-negative status was independently associated with higher odds of hypertension (OR 1.2, 95% CI: 1.1-1.4). Viral suppression of HIV did not significantly predict hypertension among HIV-positives. SIGNIFICANCE: The burden of hypertension is substantial and inadequately controlled, both in HIV-positive persons and overall. Universal HIV screening programs could provide counseling, testing, and treatment for hypertension in Sub-Saharan Africa.

Evaluating linkage to care for hypertension after community-based screening in rural Uganda.

OBJECTIVES: To determine the frequency and predictors of hypertension linkage to care after implementation of a linkage intervention in rural Uganda. METHODS: During a multidisease screening campaign for HIV, diabetes and hypertension in rural Uganda, hypertensive adults received education, appointment to a local health facility and travel voucher. We measured frequency and predictors of linkage to care, defined as visiting any health facility for hypertension management within 6 months. Predictors of linkage to care were calculated using collaborative-targeted maximum likelihood estimation (C-TMLE). Participants not linking were interviewed using a standardised instrument to determine barriers to care. RESULTS: Over 5 days, 2252 adults were screened for hypertension and 214 hypertensive adults received a linkage intervention for further management. Of these, 178 (83%) linked to care within 6 months (median = 22 days). Independent predictors of successful linkage included older age, female gender, higher education, manual employment, tobacco use, alcohol consumption, hypertension family history and referral to local vs. regional health centre. Barriers for patients who did not see care included expensive transport (59%) and feeling well (59%). CONCLUSIONS: A community health campaign that offered hypertension screening, education, referral appointment and travel voucher achieved excellent linkage to care (83%). Young adults, men and persons with low levels of formal education were among those least likely to seek care.

Epidemiology and awareness of hypertension in a rural Ugandan community: a cross-sectional study.

BACKGROUND: Hypertension is one of the largest causes of preventable morbidity and mortality worldwide. There are few population-based studies on hypertension epidemiology to guide public health strategies in sub-Saharan Africa. Using a community-based strategy that integrated screening for HIV and non-communicable diseases, we determined the prevalence, awareness, treatment rates, and sociodemographic factors associated with hypertension in rural Uganda. METHODS: A household census was performed to enumerate the population in Kakyerere parish in Mbarara district, Uganda. A multi-disease community-based screening campaign for hypertension, diabetes, and HIV was then conducted. During the campaign, all adults received a blood pressure (BP) measurement and completed a survey examining sociodemographic factors. Hypertension was defined as elevated BP (≥ 140/≥ 90 mmHg) on the lowest of three BP measurements or current use of antihypertensives. Prevalence was calculated and standardized to age distribution. Sociodemographic factors associated with hypertension were evaluated using a log-link Poisson regression model with robust standard errors. RESULTS: Community participation in the screening campaign was 65%, including 1245 women and 1007 men. The prevalence of hypertension was 14.6%; awareness of diagnosis (38.1%) and current receipt of treatment (20.6%) were both low. Age-standardized to the WHO world standard population, hypertension prevalence was 19.8%, which is comparable to 21.6% in the US and 18.4% in the UK. Sociodemographic factors associated with hypertension included increasing age, male gender, overweight, obesity, diabetes, alcohol consumption, and family history. Prevalence of modifiable factors was high: 28.3% women were overweight/obese and 24.1% men consumed ≥ 10 alcoholic drinks per month. CONCLUSIONS: We found a substantial burden of hypertension in rural Uganda. Awareness and treatment of hypertension is low in this region. Enhanced community-based education and prevention efforts tailored to addressing modifiable factors are needed.