Khaled Mohammed

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)

Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity malignant diseases: a systematic review and meta-analysis

BACKGROUND Malignant tumours arising within the nasal cavity and paranasal sinuses are rare and composed of several histological types, rendering controlled clinical trials to establish the best treatment impractical. We undertook a systematic review and meta-analysis to compare the clinical outcomes of patients treated with charged particle therapy with those of individuals receiving photon therapy. METHODS We identified studies of nasal cavity and paranasal sinus tumours through searches of databases including Embase, Medline, Scopus, and the Cochrane Collaboration. We included treatment-naive cohorts (both primary and adjuvant radiation therapy) and those with recurrent disease. Primary outcomes of interest were overall survival, disease-free survival, and locoregional control, at 5 years and at longest follow-up. We used random-effect models to pool outcomes across studies and compared event rates of combined outcomes for charged particle therapy and photon therapy using an interaction test. FINDINGS 43 cohorts from 41 non-comparative observational studies were included. Median follow-up for the charged particle therapy group was 38 months (range 5-73) and for the photon therapy group was 40 months (14-97). Pooled overall survival was significantly higher at 5 years for charged particle therapy than for photon therapy (relative risk 1·51, 95% CI 1·14-1·99; p=0·0038) and at longest follow-up (1·27, 1·01-1·59; p=0·037). At 5 years, disease-free survival was significantly higher for charged particle therapy than for photon therapy (1·93, 1·36-2·75, p=0·0003) but, at longest follow-up, this event rate did not differ between groups (1·51, 1·00-2·30; p=0·052). Locoregional control did not differ between treatment groups at 5 years (1·06, 0·68-1·67; p=0·79) but it was higher for charged particle therapy than for photon therapy at longest follow-up (1·18, 1·01-1·37; p=0·031). A subgroup analysis comparing proton beam therapy with intensity-modulated radiation therapy showed significantly higher disease-free survival at 5 years (relative risk 1·44, 95% CI 1·01-2·05; p=0·045) and locoregional control at longest follow-up (1·26, 1·05-1·51; p=0·011). INTERPRETATION Compared with photon therapy, charged particle therapy could be associated with better outcomes for patients with malignant diseases of the nasal cavity and paranasal sinuses. Prospective studies emphasising collection of patient-reported and functional outcomes are strongly encouraged. FUNDING Mayo Foundation for Medical Education and Research.

Oral vs Transdermal Estrogen Therapy and Vascular Events: A Systematic Review and Meta-Analysis

BACKGROUND Menopausal hormone therapy is widely used to alleviate climacteric symptoms but may increase the risk of venous and arterial vascular events. OBJECTIVE The objective was to synthesize the evidence about the risk of vascular events in postmenopausal women who use oral estrogen therapy (ET) and transdermal ET. METHODS We searched bibliographical databases through August 2013 for longitudinal comparative studies that enrolled postmenopausal women using either oral or transdermal ET and reported the outcomes of interest: venous thromboembolism (VTE), pulmonary embolism, deep venous thrombosis (DVT), myocardial infarction (MI), and stroke. Two reviewers independently selected and appraised studies. Outcomes were pooled using random effects meta-analysis and were reported as risk ratio (RR) and 95% confidence interval (CI). RESULTS We included 15 observational studies at moderate risk of bias with follow-up of 3 to 20.25 years. When compared to transdermal ET, oral ET was associated with increased risk of a first episode of VTE (RR, 1.63; 95% CI, 1.40-1.90; I(2) = 53%), DVT (RR, 2.09; 95% CI, 1.35-3.23; I(2) = 0 %), and possibly stroke (RR, 1.24; 95% CI, 1.03-1.48; a single case-controlled study), but not MI (RR, 1.17; 95% CI, 0.80-1.71; I(2) = 74%). CONCLUSION Observational evidence warranting low confidence suggests that compared to transdermal ET, oral ET may be associated with increased risk of VTE and DVT, but not MI.

Creating a Patient-Centered Health Care Delivery System A Systematic Review of Health Care Quality From the Patient Perspective

Patient experience is one of key domains of value-based purchasing that can serve as a measure of quality and be used to improve the delivery of health services. The aims of this study are to explore patient perceptions of quality of health care and to understand how perceptions may differ by settings and condition. A systematic review of multiple databases was conducted for studies targeting patient perceptions of quality of care. Two reviewers screened and extracted data independently. Data synthesis was performed following a meta-narrative approach. A total of 36 studies were included that identified 10 quality dimensions perceived by patients: communication, access, shared decision making, provider knowledge and skills, physical environment, patient education, electronic medical record, pain control, discharge process, and preventive services. These dimensions can be used in planning and evaluating health care delivery. Future research should evaluate the effect of interventions targeting patient experience on patient outcomes.

Surgical Interventions and Medical Treatments in Treatment-Naïve Patients With Acromegaly: Systematic Review and Meta-Analysis

CONTEXT Acromegaly is usually treated with surgery as a first-line treatment, although medical therapy has also been used as an alternative primary treatment. OBJECTIVE We conducted a systematic review and meta-analysis to synthesize the existing evidence comparing these two approaches in treatment-naïve patients with acromegaly. DATA SOURCES This study performed a comprehensive search in multiple databases, including Medline, EMBASE, and Scopus from early inception through April 2014. STUDY SELECTION The study used original controlled and uncontrolled studies that enrolled patients with acromegaly to receive either surgical treatment or medical treatment as their first-line treatment. DATA EXTRACTION Reviewers extracted data independently and in duplicates. Because of the noncomparative nature of the available studies, we modified the Newcastle-Ottawa Scale to assess the quality of included studies. Outcomes evaluated were biochemical remission and change in IGF-1 or GH levels. We pooled outcomes using the random-effects model. DATA SYNTHESIS The final search yielded 35 studies enrolling 2629 patients. Studies were noncomparative series with a follow-up range of 6-360 months. Compared with medical therapy, surgery was associated with a higher remission rate (67% vs 45%; P = .02). Surgery had higher remission rates at longer follow-up periods (≥ 24 mo) (66% vs 44%; P = .04) but not the shorter follow-up periods (≤ 6 mo) (37% vs 26%; P = .22) [Corrected].Surgery had higher remission rates in the follow-up levels of GH (65% vs 46%; P = .05). In one study, the IGF-1 level was reduced more with surgery compared with medical treatment (-731 μg/L vs -251 μg/L; P = .04). Studies in which surgery was performed by a single operator reported a higher remission rate than those with multiple operators (71% vs 47%; P = .002). CONCLUSIONS Surgery may be associated with higher remission rate; however, the confidence in such evidence is very low due to the noncomparative nature of the studies, high heterogeneity, and imprecision.

Efficacy of intervertebral disc regeneration with stem cells - A systematic review and meta-analysis of animal controlled trials

Management of intervertebral disc (IVD) degenerative disease is challenging, as it is accompanied by irreversible loss of IVD cells. Stem cell transplantation to the disc has shown promise in decelerating or arresting the degenerative process. Multiple pre-clinical animal trials have been conducted, but with conflicting outcomes. To assess the effect of stem cell transplantation, a systematic review and meta-analysis was performed. A comprehensive literature search was conducted through Week 3, 2015. Inclusion criteria consisted of controlled animal trials. Two reviewers screened abstracts and full texts. Disagreements were resolved by a third reviewer. Random effects models were constructed to pool standardized mean difference (SMD). Twenty two studies were included; nine of which were randomized. Statistically significant differences were found with the stem cell group exhibiting increased disc height index (SMD=3.64, 95% confidence interval (CI): 2.49, 4.78; p<0.001), increased MRI T2 signal intensity (SMD=2.28, 95% CI: 1.48, 3.08; p<0.001), increased Type II collagen mRNA expression (SMD=3.68, 95% CI: 1.66, 5.70; p<0.001), and decreased histologic disc degeneration grade (SMD=-2.97, 95% CI: -3.97, -1.97; p<0.001). There was statistical heterogeneity between studies that could not be explained with pre-planned subgroup analyses based on animal species, study designs, and transplanted cell types. Stem cells transplanted to the IVD in quadruped animals decelerate or arrest the IVD degenerative process. Further studies in human clinical trials will be needed to understand if such benefit can be translated to bipedal humans.

Menopausal Hormone Therapy and Mortality: A Systematic Review and Meta-Analysis

OBJECTIVES The objective was to assess the effect of menopausal hormonal therapy (MHT) on all-cause and cause-specific mortality. METHODS We conducted a comprehensive search of several databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, and Scopus) from inception until August 2013. We included randomized controlled trials (RCTs) of more than 6 months of duration comparing MHT with no treatment. Pairs of independent reviewers selected trials, assessed risk of bias and extracted data. We estimated risk ratios (RRs) and 95% confidence intervals (CIs) using the random-effects model. RESULTS We included 43 RCTs at moderate risk of bias. Meta-analysis showed no effect on mortality (RR 0.99 [95% CI, 0.94-1.05]), regardless of MHT type or history of preexisting heart disease. No association was found between MHT and cardiac death (RR 1.04 [95% CI 0.87-1.23]) or stroke (RR 1.49 [95% CI 0.95-2.31]). Estrogen plus progesterone use was associated with a likely increase in breast cancer mortality (RR 1.96 [95% CI 0.98-3.94]), whereas estrogen use was not. MHT use was not associated with mortality of other types of cancer. In 5 trials, MHT was likely started at a younger age: 2 RCTs with mean age less than 60 and 3 RCTs with MHT started less than 10 years after menopause. Meta-analysis of these 5 RCTs showed a reduction of mortality with MHT (RR 0.70 [95% CI 0.52-0.95]). CONCLUSION The current evidence suggests that MHT does not affect the risk of death from all causes, cardiac death and death from stroke or cancer. These data may be used to support clinical and policy deliberations about the role of MHT in the care of symptomatic postmenopausal women.

Antiviral therapy in management of chronic hepatitis B viral infection in children: A systematic review and meta‐analysis

Most individuals with chronic hepatitis B viral (HBV) infection acquired the infection around the time of birth or during early childhood. We aimed to synthesize evidence regarding the effectiveness of antiviral therapy in the management of chronic HBV infection in children. We conducted a comprehensive search of multiple databases from 1988 to December 2, 2014, for studies that enrolled children (<18 years) with chronic HBV infection treated with antiviral therapy. We included observational studies and randomized controlled trials (RCTs). Two independent reviewers selected studies and extracted data. In the 14 included studies, two cohort studies showed no significant reduction in the already low risk of hepatocellular carcinoma or cirrhosis and 12 RCTs reported intermediate outcomes. In RCTs with posttreatment follow‐up <12 months, antiviral therapy compared to placebo improved alanine aminotransferase normalization (risk ratio [RR] = 2.3, 95% confidence interval [CI] 1.7‐3.2), hepatitis B e antigen (HBeAg) clearance/loss (RR = 2.1, 95% CI 1.5‐3.1), HBV DNA suppression (RR = 2.9, 95% CI 1.8‐4.6), HBeAg seroconversion (RR = 2.1, 95% CI 1.4‐3.3), and hepatitis B surface antigen clearance (RR = 5.8, 95% CI 1.1‐31.5). In RCTs with posttreatment follow‐up ≥12 months, antiviral therapy improved cumulative HBeAg clearance/loss (RR = 1.9, 95% CI 1.7‐3.1), HBeAg seroconversion (RR = 2.1, 95% CI 1.3‐3.5), alanine aminotransferase normalization (RR = 1.4, 95% CI 1.1‐1.7), and HBV DNA suppression (RR = 1.4, 95% CI 1.1‐1.8) but not hepatitis B surface antigen clearance or seroconversion. Conclusion: In children with chronic HBV infection, antivirals compared to no antiviral therapy improve HBV DNA suppression and frequency of alanine aminotransferase normalization and HBeAg seroconversion. (Hepatology 2016;63:307–318)

Imaging for the diagnosis of hepatocellular carcinoma: A systematic review and meta-analysis

Multiphasic computed tomography (CT) and magnetic resonance imaging (MRI) are both used for noninvasive diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis. To determine if there is a relative diagnostic benefit of one over the other, we synthesized evidence regarding the relative performance of CT, extracellular contrast–enhanced MRI, and gadoxetate‐enhanced MRI for diagnosis of HCC in patients with cirrhosis. We also assessed whether liver biopsy versus follow‐up with the same versus alternative imaging is best for CT‐indeterminate or MRI‐indeterminate liver nodules in patients with cirrhosis. We searched multiple databases from inception to April 27, 2016, for studies comparing CT with extracellular contrast–enhanced MRI or gadoxetate‐enhanced MRI in adults with cirrhosis and suspected HCC. Two reviewers independently selected studies and extracted data. Of 33 included studies, 19 were comprehensive, while 14 reported sensitivity only. For all tumor sizes, the 19 comprehensive comparisons showed significantly higher sensitivity (0.82 versus 0.66) and lower negative likelihood ratio (0.20 versus 0.37) for MRI over CT. The specificities of MRI versus CT (0.91 versus 0.92) and the positive likelihood ratios (8.8 versus 8.1) were not different. All three modalities performed better for HCCs ≥2 cm. Performance was poor for HCCs <1 cm. No studies examined whether adults with cirrhosis and an indeterminate nodule are best evaluated using biopsy, repeated imaging, or alternative imaging. Concerns about publication bias, inconsistent study results, increased risk of bias, and clinical factors precluded support for exclusive use of either gadoxetate‐enhanced or extracellular contrast–enhanced MRI over CT. Conclusion: CT, extracellular contrast–enhanced MRI, or gadoxetate‐enhanced MRI could not be definitively preferred for HCC diagnosis in patients with cirrhosis; in patients with cirrhosis and an indeterminate mass, there were insufficient data comparing biopsy to repeat cross‐sectional imaging or alternative imaging. (Hepatology 2018;67:401‐421).

Therapies for Advanced Stage Hepatocellular Carcinoma with Macrovascular invasion or Metastatic Disease: a Systematic Review and Meta‐analysis

Hepatocellular carcinoma (HCC) is a complex disease most commonly arising in the background of chronic liver disease. In the past two decades, there has been a significant increase in our understanding of both the clinical and molecular heterogeneity of HCC. There has been a robust increase in clinical trial activity in patients with poor prognostic factors, such as macrovascular invasion and extrahepatic spread (EHS). We aimed to synthesize the evidence for the treatment of patients with advanced HCC based on these baseline characteristics, including patients with both Child‐Pugh (CP) scores of A and B. A comprehensive search of several databases from each database inception to February 15, 2016 any language was conducted. We included 14 studies (three randomized controlled studies [RCTs] and 11 observational studies). We included studies that compared sorafenib, transarterial bland embolization/transarterial chemoembolization, yttrium‐90/radiation therapy, ablation (or combination), and no therapy. Two RCTs comparing sorafenib to best supportive care demonstrated a consistent improvement in overall survival (OS) for patients with advanced HCC and metastatic vascular invasion (MVI) and/or EHS and CP A liver disease (hazard ratio, 0.66 [95% confidence interval, 0.51‐0.87]; I2 = 0%). Several observational studies evaluated locoregional therapies alone or in combination with other treatments and were limited by very‐low‐quality of evidence. This was true for both patients with EHS and MVI. Conclusion: In patients with advanced HCC and CP A liver function, sorafenib is the only treatment that has been shown to improve OS in randomized studies. High‐quality data supporting the use of other treatment modalities in this setting, or in the setting of patients with less compensated (CP B) liver disease, are lacking. (Hepatology 2018;67:422‐435)