Essa A. Mohamed

Antiviral therapy for chronic hepatitis B viral infection in adults: A systematic review and meta‐analysis

Chronic hepatitis B viral (HBV) infection remains a significant global health problem. Evidence‐based guidelines are needed to help providers determine when treatment should be initiated, which medication is most appropriate, and when treatment can safely be stopped. The American Association for the Study of Liver Diseases HBV guideline methodology and writing committees developed a protocol a priori for this systematic review. We searched multiple databases for randomized controlled trials and controlled observational studies that enrolled adults ≥18 years old diagnosed with chronic HBV infection who received antiviral therapy. Data extraction was done by pairs of independent reviewers. We included 73 studies, of which 59 (15 randomized controlled trials and 44 observational studies) reported clinical outcomes. Moderate‐quality evidence supported the effectiveness of antiviral therapy in patients with immune active chronic HBV infection in reducing the risk of cirrhosis, decompensated liver disease, and hepatocellular carcinoma. In immune tolerant patients, moderate‐quality evidence supports improved intermediate outcomes with antiviral therapy. Only very low‐quality evidence informed the questions about discontinuing versus continuing antiviral therapy in hepatitis B e antigen‐positive patients who seroconverted from hepatitis B e antigen to hepatitis B e antibody and about the safety of entecavir versus tenofovir. Noncomparative and indirect evidence was available for questions about stopping versus continuing antiviral therapy in hepatitis B e antigen‐negative patients, monotherapy versus adding a second agent in patients with persistent viremia during treatment, and the effectiveness of antivirals in compensated cirrhosis with low‐level viremia. Conclusion: Most of the current literature focuses on the immune active phases of chronic HBV infection; decision‐making in other commonly encountered and challenging clinical settings depends on indirect evidence. (Hepatology 2016;63:284–306)

Combinations of biomarkers and Milan criteria for predicting hepatocellular carcinoma recurrence after liver transplantation.

Growing evidence suggests that pretransplant alpha‐fetoprotein (AFP) predicts outcomes of hepatocellular carcinoma (HCC) patients treated with liver transplantation. We aimed to determine whether pretransplant AFP, Lens culinaris agglutinin‐reactive alpha‐fetoprotein (AFP‐L3), and des‐gamma‐carboxyprothrombin (DCP) predicted HCC recurrence after transplantation. A retrospective cohort study of 313 HCC patients undergoing transplantation between 2000 and 2008 was conducted, and 48 (15.3%) developed recurrence during a median follow‐up of 90.8 months. The 127 patients with available serum drawn before transplantation were included; they included 86 without recurrence and 41 with recurrence. Serum was tested for AFP, AFP‐L3%, and DCP in a blinded fashion with the μTASWako i30 immunoanalyzer. All biomarkers were significantly associated with HCC recurrence. The hazard ratios (HRs) were 3.5 [95% confidence interval (CI), 1.9‐6.7; P < 0.0001] for DCP ≥ 7.5 ng/mL and 2.8 (95% CI, 1.4‐5.4; P = 0.002) for AFP ≥ 250 ng/mL. The HR increased to 5.2 (95% CI, 2.3‐12.0; P < 0.0001) when AFP ≥ 250 ng/mL and DCP ≥7.5 ng/mL were considered together. When they were combined with the Milan criteria, the HR increased from 2.6 (95% CI, 1.4‐4.7; P = 0.003) for outside the Milan criteria to 8.6 (95% CI, 3.0‐24.6; P < 0.0001) for outside the Milan criteria and AFP ≥ 250 ng/mL and to 7.2 (95% CI, 2.8‐18.1; P < 0.0001) for outside the Milan criteria and DCP ≥7.5 ng/mL. Our findings suggest that biomarkers are useful for predicting the risk of HCC recurrence after transplantation. Using both biomarkers and the Milan criteria may be better than using the Milan criteria alone in optimizing the decision of liver transplantation eligibility. Liver Transpl 21:599–606, 2015.

Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein

Cholangiocarcinoma is a highly lethal cancer with limited therapeutic options. Recent genomic analysis of cholangiocarcinoma has revealed the presence of fibroblast growth factor receptor 2 (FGFR2) fusion proteins in up to 13% of intrahepatic cholangiocarcinoma (iCCA). FGFR fusions have been identified as a novel oncogenic and druggable target in a number of cancers. In this study, we established a novel cholangiocarcinoma patient derived xenograft (PDX) mouse model bearing an FGFR2-CCDC6 fusion protein from a metastatic lung nodule of an iCCA patient. Using this PDX model, we confirmed the ability of the FGFR inhibitors, ponatinib, dovitinib and BGJ398, to modulate FGFR signaling, inhibit cell proliferation and induce cell apoptosis in cholangiocarcinoma tumors harboring FGFR2 fusions. In addition, BGJ398 appeared to be superior in potency to ponatinib and dovitinib in this model. Our findings provide a strong rationale for the investigation of FGFR inhibitors, particularly BGJ398, as a therapeutic option for cholangiocarcinoma patients harboring FGFR2 fusions.

Characteristics, management, and outcomes of patients with hepatocellular carcinoma in Africa: a multicountry observational study from the Africa Liver Cancer Consortium

BACKGROUND Hepatocellular carcinoma is a leading cause of cancer-related death in Africa, but there is still no comprehensive description of the current status of its epidemiology in Africa. We therefore initiated an African hepatocellular carcinoma consortium aiming to describe the clinical presentation, management, and outcomes of patients with hepatocellular carcinoma in Africa. METHODS We did a multicentre, multicountry, retrospective observational cohort study, inviting investigators from the African Network for Gastrointestinal and Liver Diseases to participate in the consortium to develop hepatocellular carcinoma research databases and biospecimen repositories. Participating institutions were from Cameroon, Egypt, Ethiopia, Ghana, Ivory Coast, Nigeria, Sudan, Tanzania, and Uganda. Clinical information-demographic characteristics, cause of disease, liver-related blood tests, tumour characteristics, treatments, last follow-up date, and survival status-for patients diagnosed with hepatocellular carcinoma between Aug 1, 2006, and April 1, 2016, were extracted from medical records by participating investigators. Because patients from Egypt showed differences in characteristics compared with patients from the other countries, we divided patients into two groups for analysis; Egypt versus other African countries. We undertook a multifactorial analysis using the Cox proportional hazards model to identify factors affecting survival (assessed from the time of diagnosis to last known follow-up or death). FINDINGS We obtained information for 2566 patients at 21 tertiary referral centres (two in Egypt, nine in Nigeria, four in Ghana, and one each in the Ivory Coast, Cameroon, Sudan, Ethiopia, Tanzania, and Uganda). 1251 patients were from Egypt and 1315 were from the other African countries (491 from Ghana, 363 from Nigeria, 277 from Ivory Coast, 59 from Cameroon, 51 from Sudan, 33 from Ethiopia, 21 from Tanzania, and 20 from Uganda). The median age at which hepatocellular carcinoma was diagnosed significantly later in Egypt than the other African countries (58 years [IQR 53-63] vs 46 years [36-58]; p<0·0001). Hepatitis C virus was the leading cause of hepatocellular carcinoma in Egypt (1054 [84%] of 1251 patients), and hepatitis B virus was the leading cause in the other African countries (597 [55%] of 1082 patients). Substantially fewer patients received treatment specifically for hepatocellular carcinoma in the other African countries than in Egypt (43 [3%] of 1315 vs 956 [76%] of 1251; p<0·0001). Among patients with survival information (605 [48%] of 1251 in Egypt and 583 [44%] of 1315 in other African countries), median survival was shorter in the other African countries than in Egypt (2·5 months [95% CI 2·0-3·1] vs 10·9 months [9·6-12·0]; p<0·0001). Factors independently associated with poor survival were: being from an African countries other than Egypt (hazard ratio [HR] 1·59 [95% CI 1·13-2·20]; p=0·01), hepatic encephalopathy (2·81 [1·72-4·42]; p=0·0004), diameter of the largest tumour (1·07 per cm increase [1·04-1·11]; p<0·0001), log α-fetoprotein (1·10 per unit increase [1·02-1·20]; p=0·0188), Eastern Cooperative Oncology Group performance status 3-4 (2·92 [2·13-3·93]; p<0·0001) and no treatment (1·79 [1·44-2·22]; p<0·0001). INTERPRETATION Characteristics of hepatocellular carcinoma differ between Egypt and other African countries. The proportion of patients receiving specific treatment in other African countries was low and their outcomes were extremely poor. Urgent efforts are needed to develop health policy strategies to decrease the burden of hepatocellular carcinoma in Africa. FUNDING None.

Biliary tract cancers: epidemiology, molecular pathogenesis and genetic risk associations

Biliary tract cancers (BTC) are malignancies that arise from the epithelium of the biliary system and comprise the second most common type of hepatobiliary cancer worldwide. BTC are sub-classified as intrahepatic cholangiocarcinoma (iCCA), perhilar/hilar cholangiocarcinoma (pCCA), distal cholangiocarcinoma (dCCA), and gallbladder carcinoma. Due to the differences in their etiologic risk factors, pathogenesis, and molecular and genetic characteristics, each of these subtypes is considered a separate biological entity. The geographic diversity of risk factors for the subtypes of biliary cancers results in profound differences in the worldwide incidence of each. In this article we provide a review of the current epidemiology of BTC and their associated risk factors. Further, we discuss the available evidence for genetic predisposition to BTC and anticipate the results of planned large-scale, genome-wide association studies (GWAS) exploring the inherited sequence variants conferring risk of BTC. These studies may also potentially of reveal important pathogenic mechanisms of the biliary tract cancer subtypes.

Non-pharmacological treatment of depression: a systematic review and evidence map

Background The comparative effectiveness of non-pharmacological treatments of depression remains unclear. Methods We conducted an overview of systematic reviews to identify randomised controlled trials (RCTs) that compared the efficacy and adverse effects of non-pharmacological treatments of depression. We searched multiple electronic databases through February 2016 without language restrictions. Pairs of reviewers determined eligibility, extracted data and assessed risk of bias. Meta-analyses were conducted when appropriate. Result We included 367 RCTs enrolling ∼20 000 patients treated with 11 treatments leading to 17 unique head-to-head comparisons. Cognitive behavioural therapy, naturopathic therapy, biological interventions and physical activity interventions reduced depression severity as measured using standardised scales. However, the relative efficacy among these non-pharmacological interventions was lacking. The effect of these interventions on clinical response and remission was unclear. Adverse events were lower than antidepressants. Limitation The quality of evidence was low to moderate due to inconsistency and unclear or high risk of bias, limiting our confidence in findings. Conclusions Non-pharmacological therapies of depression reduce depression symptoms and should be considered along with antidepressant therapy for the treatment of mild-to-severe depression. A shared decision-making approach is needed to choose between non-pharmacological therapies based on values, preferences, clinical and social context.

Sex hormone therapy and progression of cardiovascular disease in menopausal women.

One of the most controversial health decisions facing women is deciding upon the use of hormonal treatments for symptoms of menopause. This brief review focuses on the historical context of use of menopausal hormone treatments (MHT), summarizes results of major observational, primary and secondary prevention studies of MHT and cardiovascular (CV) outcomes, provides evidence for how sex steroids modulate CV function and identifies challenges for future research. As medicine enters an era of personalization of treatment options, additional research into sex differences in the aetiology of CV diseases will lead to better risk identification for CV disease in women and identify whether a woman might receive CV benefit from specific formulations and doses of MHT.

Are there sex differences following treatment of left ventricular outflow tract obstruction in adults with hypertrophic cardiomyopathy

Hypertrophic obstructive cardiomyopathy (HOCM) is the most common inherited cardiomyopathy, affecting approximately 1 in 500 individuals. The male predominance of the condition varies from 51% to 91%, suggesting other factors (i.e. environment, sex hormones, and epigenetics) affect the phenotype. Women with HOCM tend to be more symptomatic, present later in life, are more likely to have left ventricular outflow tract obstruction, and have greater mortality when< 50 years of age. Because the selection of treatment is based on symptom presentation, it is unclear if there is a sex bias in applying the criteria and/or outcomes independent of selection bias, and whether females’ benefit more from a particular therapy. Thus, an a priori protocol to determine if there were sex differences in selection of treatment and outcomes for HOCM was created for a systematic review to predefine population criteria, description of interventions, and comparisons of the outcomes of interest of three treatments for HOCM: surgical myectomy (SM), alcohol septal ablation (ASA), and dual chamber pacing (DDD) according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Electronic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus) were searched for studies of a minimum of 5 adults who underwent SM, ASA, or DDD as a primary procedure from inception in 1946 to 30 December 2015. The detailed search strategy, list of studies included and discussion are reported in the Supplementary material online. Sixty-three studies were included (Figure 1) reporting on 4586 patients: 1852 (40.4%) were male, 1780 (38.8%) were female, 954 (20.4%) were unidentifiable by sex. Of the total number of patients, 2212 (48.2%) underwent ASA, 1920 (41.9%) underwent SM and 454 (9.8%) underwent DDD. Of the 63 studies, 11 articles did not report sex in basic demographics, or grouped all treatments together, such that numbers of each sex by treatment could not be determined. Where sex was reported, females made up 847 (49.6%) of patients in ASA studies, 770 (48.5%) of patients in SM, and 163 (48.0%) of patients in DDD studies. Only 1 case series of 18 patients (9 males) treated by DDD reported outcomes by sex. In that study, there was no difference in mean gradient reduction following DDD pacing: males -58.5 (25.5) mmHg vs. females -55.7 (19.3) mmHg (P= 0.82). Similarly, reduction in New York Heart Association functional class did not differ by sex. None of the other studies stratified any of the baseline characteristics of patients by sex and there were minimal outcome data stratified by other confounders such as age and disease severity. Therefore, subgroup analyses based on sex and other patient characteristics that are prognostic effect modifiers were not possible. A patient’s sex, age, stage of disease, and other comorbidities will influence choice of treatment and outcomes. Therefore, critical to evaluations of outcomes in treatment modalities is the accurate reporting of these characteristics. Sex is a basic biological variable that should be included in reporting of clinical outcomes even if the study is not powered to show a sex difference. In the USA, the 1993 Revitalization Act required inclusion of women in clinical studies but not in the reporting of data by sex. As medicine embraces a precision, personalized approach, reporting and analysis of data by sex and other important patient characteristics will inform the practice so that treatment approaches maximize patient outcomes. Requiring such reporting in future studies would accelerate the knowledge base to better inform patient selection and treatment strategies.

Model combining pre-transplant tumor biomarkers and tumor size shows more utility in predicting hepatocellular carcinoma recurrence and survival than the BALAD models

AIM To assess the performance of BALAD, BALAD-2 and their component biomarkers in predicting outcome of hepatocellular carcinoma (HCC) patients after liver transplant. METHODS BALAD score and BALAD-2 class are derived from bilirubin, albumin, alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP (AFP-L3), and des-gamma-carboxyprothrombin (DCP). Pre-transplant AFP, AFP-L3 and DCP were measured in 113 patients transplanted for HCC from 2000 to 2008. Hazard ratios (HR) for recurrence and death were calculated. Univariate and multivariate regression analyses were conducted. C-statistics were used to compare biomarker-based to predictive models. RESULTS During a median follow-up of 12.2 years, 38 patients recurred and 87 died. The HRs for recurrence in patients with elevated AFP, AFP-L3, and DCP defined by BALAD cut-off values were 2.42 (1.18-5.00), 1.86 (0.98-3.52), and 2.83 (1.42-5.61), respectively. For BALAD, the HRs for recurrence and death per unit increased score were 1.48 (1.15-1.91) and 1.59 (1.28-1.97). For BALAD-2, the HRs for recurrence and death per unit increased class were 1.45 (1.06-1.98) and 1.38 (1.09-1.76). For recurrence prediction, the combination of three biomarkers had the highest c-statistic of 0.66 vs. 0.64, 0.61, 0.53, and 0.53 for BALAD, BALAD-2, Milan, and UCSF, respectively. Similarly, for death prediction, the combination of three biomarkers had the highest c-statistic of 0.66 vs 0.65, 0.61, 0.52, and 0.50 for BALAD, BALAD-2, Milan, and UCSF. A new model combining biomarkers with tumor size at the time of transplant (S-LAD) demonstrated the highest predictive capability with c-statistics of 0.71 and 0.69 for recurrence and death. CONCLUSION BALAD and BALAD-2 are valid in transplant HCC patients, but less predictive than the three biomarkers in combination or the three biomarkers in combination with maximal tumor diameter (S-LAD).

Barriers in Hepatitis C Treatment in Somali Patients in the Direct Acting Antiviral Therapy Era

BACKGROUND AND AIMS Hepatitis C virus (HCV) treatment has changed dramatically in the last few years. Our observations suggest that a minority of HCV infected Somalis are treated. In this study, we aimed to evaluate for treatment and health outcome disparities between Somali and non-Somali patients during the direct acting antiviral (DAA) era. METHODS Patients with HCV seen in the gastroenterology clinic in 2015 were included in the study. Patients were identified using ICD9 and 10 codes. Electronic medical records were analyzed to evaluate for treatment candidacy, acceptance and reasons for refusal of treatment. RESULTS Genotype 4 followed by 3 were the most common genotypes in the Somalis while genotype 1 was the most common in the non-Somalis. Majority of patients were offered treatment, active alcohol and substance abuse was a common reason for not offering treatment in non-Somalis while the presence of hepatocellular carcinoma was the most common reason in Somalis. Somalis had higher rates of declining treatment given the asymptomatic nature of their disease and the feeling that treatment is not needed. Sustained virologic response rates were comparable in both groups. CONCLUSIONS Disparities in acceptance of HCV treatment persist in the DAA era. The asymptomatic nature of the infection and potential cultural mistrust makes patients hesitant to undergo treatment. Healthcare providers must find interventions aimed at reducing barriers to treatment and increasing acceptance of HCV treatment.