T. Ahmed

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)

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)

Treatment of pediatric obesity: An umbrella systematic review

Objective Multiple interventions are available to reduce excess body weight in children. We appraised the quality of evidence supporting each intervention and assessed the effectiveness on different obesity-related outcomes. Methods We conducted a systematic search for systematic reviews of randomized controlled trials evaluating pediatric obesity interventions applied for ≥6 months. We assessed the quality of evidence for each intervention using GRADE (Grading of Recommendation, Assessment, Development, and Evaluation) approach. Results From 16 systematic reviews, we identified 133 eligible randomized controlled trials. Physical activity interventions reduced systolic blood pressure and fasting glucose (low to moderate quality of evidence). Dietary interventions with low-carbohydrate diets had a similar effect to low-fat diets in terms of body mass index (BMI) reduction (moderate quality of evidence). Educational interventions reduced waist circumference, BMI, and diastolic blood pressure (low quality of evidence). Pharmacological interventions reduced BMI (metformin, sibutramine, orlistat) and waist circumference (sibutramine, orlistat) and increased high-density lipoprotein cholesterol (sibutramine) but also raised systolic and diastolic blood pressure (sibutramine). Surgical interventions (laparoscopic adjustable gastric banding, Roux-en-Y gastric bypass, sleeve gastrectomy) resulted in the largest BMI reduction (moderate quality of evidence). Combined interventions consisting of dietary modification, physical activity, behavioral therapy, and education significantly reduced systolic and diastolic blood pressure, BMI, and triglycerides. Combined parent-child interventions and parent-only interventions had similar effects on BMI (low quality of evidence). Conclusions Several childhood obesity interventions are effective in improving metabolic and anthropometric measures. A comprehensive multicomponent intervention, however, appears to have the best overall outcomes.

PREDICTORS OF BIOCHEMICAL REMISSION AND RECURRENCE AFTER SURGICAL AND RADIATION TREATMENTS OF CUSHING DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS.

OBJECTIVE We conducted a systematic review and meta-analysis to synthesize the evidence about predictors that may affect biochemical remission and recurrence after transsphenoidal surgery (TSS), radiosurgery (RS), and radiotherapy (RT) in Cushing disease. METHODS We searched multiple databases through December 2014 including original controlled and uncontrolled studies that enrolled patients with Cushing disease who received TSS (first-line), RS, or RT. We extracted data independently, in duplicates. Outcomes of interest were biochemical remission and recurrence. A meta-analysis was conducted using the random-effects model to estimate event rates with 95% confidence intervals (CIs). RESULTS First-line TSS was associated with high remission (76% [95% CI, 72 to 79%]) and low recurrence rates (10% [95% CI, 6 to 16%]). Remission after TSS was higher in patients with microadenomas or positive-adrenocorticotropic hormone tumor histology. RT was associated with a high remission rate (RS, 68% [95% CI, 61 to 77%]; RT, 66% [95% CI, 58 to 75%]) but also with a high recurrence rate (RS, 32% [95% CI, 16 to 60%]; RT, 26% [95% CI, 14 to 48%]). Remission after RS was higher at short-term follow-up (≤2 years) and with high-dose radiation, while recurrence was higher in women and with lower-dose radiation. Remission was after RT in adults who received TSS prior to RT, and with lower radiation doses. There was heterogeneity (nonstandardization) in the criteria and cutoff points used to define biochemical remission and recurrence. CONCLUSION First-line TSS is associated with high remission and low recurrence, while RS and RT are associated with reasonable remission rates but important recurrence rates. The current evidence warrants low confidence due to the noncomparative nature of the studies, high heterogeneity, and imprecision.

Mortality in adults with hypopituitarism: a systematic review and meta-analysis

PurposeHypopituitarism is a rare disorder with significant morbidity. To study the evidence on the association of premature mortality and hypopituitarism.MethodsA comprehensive search of multiple databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus was conducted through August, 2015. Eligible studies that evaluated patients with hypopituitarism and reported mortality estimates were selected following a predefined protocol. Reviewers, independently and in duplicate, extracted data and assessed the risk of bias.ResultsWe included 12 studies (published 1996–2015) that reported on 23,515 patients. Compared to the general population, hypopituitarism was associated with an overall excess mortality (weighted SMR of 1.55; 95 % CI 1.14−2.11), I2 = 97.8 %, P = 0.000. Risk factors for increased mortality included younger age at diagnosis, female gender, diagnosis of craniopharyngioma, radiation therapy, transcranial surgery, diabetes insipidus and hypogonadism.ConclusionHypopituitarism may be associated with premature mortality in adults. Risk is particularly higher in women and those diagnosed at a younger age.

The Association of Weight Loss and Cardiometabolic Outcomes in Obese Children: Systematic Review and Meta-regression

Background Excess body weight in children is associated with multiple immediate and long-term medical comorbidities. We aimed to identify the degree of reduction in excess body weight associated with cardiometabolic changes (lipid panel, liver function tests, systolic blood pressure (SBP), diastolic blood pressure, glycosylated hemoglobin, and fasting blood glucose) in overweight and obese children. Methods We conducted a comprehensive search of MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Scopus through February 12, 2015. We included randomized controlled trials and cohort studies that evaluated interventions to treat pediatric obesity (medication, surgery, lifestyle, and community-based interventions) with ≥ a 6-month follow-up. We used a random effects meta-regression approach to assess the association between body mass index (BMI)/weight and cardiometabolic changes. Results We included 42 studies (37 randomized controlled trials and five cohorts) enrolling 3807 children (mean age, 12.2 years; weight, 74.7 kg; and BMI, 31.7 kg/m2). Studies had overall moderate to low risk of bias. A 1-mm Hg decrease in SBP was significantly associated with a decrease of 0.16 kg/m2 (P = .04) in BMI. A 1-mg/dL increase in HDL was significantly associated with a 0.74-kg decrease in weight (P = .02). A 1-mg/dL decrease in triglycerides was significantly associated with a 0.1-kg decrease in weight (P = .03). The remaining associations were not statistically significant. Conclusions Weight reduction in children is associated with significant changes in several cardiometabolic outcomes, particularly HDL, SBP, and triglycerides. The magnitude of improvement may help in setting expectations and may inform shared decision-making and counseling.

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.

Treatment Effect in Earlier Trials of Patients With Chronic Medical Conditions: A Meta-Epidemiologic Study

Objective: To determine whether the early trials in chronic medical conditions demonstrate an effect size that is larger than that in subsequent trials. Methods: We identified randomized controlled trials (RCTs) evaluating a drug or device in patients with chronic medical conditions through meta‐analyses (MAs) published between January 1, 2007, and June 23, 2015, in the 10 general medical journals with highest impact factor. We estimated the prevalence of having the largest effect size or heterogeneity in the first 2 published trials. We evaluated the association of the exaggerated early effect with several a priori hypothesized explanatory variables. Results: We included 70 MAs that had included a total of 930 trials (average of 13 [range, 5‐48] RCTs per MA) with average follow‐up of 24 (range, 1‐168) months. The prevalence of the exaggerated early effect (ie, proportion of MAs with largest effect or heterogeneity in the first 2 trials) was 37%. These early trials had an effect size that was on average 2.67 times larger than the overall pooled effect size (ratio of relative effects, 2.67; 95% CI, 2.12‐3.37). The presence of exaggerated effect was not significantly associated with trial size; number of events; length of follow‐up; intervention duration; number of study sites; inpatient versus outpatient setting; funding source; stopping a trial early; adequacy of random sequence generation, allocation concealment, or blinding; loss to follow‐up or the test for publication bias. Conclusion: Trials evaluating treatments of chronic medical conditions published early in the chain of evidence commonly demonstrate an exaggerated treatment effect compared with subsequent trials. At the present time, this phenomenon remains unpredictable. Considering the increasing morbidity and mortality of chronic medical conditions, decision makers should act on early evidence with caution.

The effect of growth hormone replacement in patients with hypopituitarism on pituitary tumor recurrence, secondary cancer, and stroke

Growth hormone replacement therapy has benefits for patients with hypopituitarism. The safety profile in regard to tumor recurrence or progression, development of secondary malignancies, or cerebrovascular stroke is still an area of debate. A comprehensive search of multiple databases—MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus was conducted through August 2015. Eligible studies that evaluated long-term adverse events in adult patients with hypopituitarism treated with growth hormone replacement therapy and reported development of pituitary tumor recurrence or progression, secondary malignancies, or cerebrovascular stroke were selected following a predefined protocol. Reviewers, independently and in duplicate, extracted data and assessed the risk of bias. Random-effects meta-analysis was used to pool relative risks and 95 % confidence intervals. We included 15 studies (published 1995–2015) that reported on 46,148 patients. Compared to non-replacement, growth hormone replacement therapy in adults with hypopituitarism was not associated with statistically significant change in pituitary tumor progression or recurrence (relative risk, 0.77; 95 % confidence interval, 0.53–1.13) or development of secondary malignancy (relative risk, 0.99; 95 % confidence interval, 0.70–1.39). In two retrospective studies, there was higher risk of stroke in patients who did not receive replacement (relative risk, 2.07; 95 % confidence interval, 1.51–2.83). The quality of evidence is low due to study limitations and imprecision. This systematic review and meta-analysis supports the overall safety of growth hormone therapeutic use in adults with hypopituitarism with no clear evidence of increased risk of pituitary tumor recurrence, malignancy, or stroke.