Khalid Benkhadra

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)

The association between sleep disturbances and suicidal behaviors in patients with psychiatric diagnoses: a systematic review and meta-analysis

BackgroundIdentifying patients with increased risk of suicidal behaviors is a constant challenge and concern for clinicians caring for patients with psychiatric conditions. We conducted a systematic review to assess the association between suicidal behaviors and sleep disturbances in psychiatric patients.MethodsA systematic literature search of Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid PsycInfo, Ovid Cochrane Database of Systematic Reviews, Ovid Cochrane Central Register of Controlled Trials, and Scopus was conducted using earliest inclusive dates to 28 June 2013. Eligible studies were comparative observational studies that reported sleep disturbances in psychiatric patients and the outcome of interest (any type of suicidal behaviors). Pairs of reviewers extracted descriptive data, study quality, and outcomes. Odds ratios (OR) and 95% confidence intervals (CI) were pooled across studies using the random-effects model. Newcastle-Ottawa scale was used to critically appraise study quality.ResultsNineteen studies met the inclusion criteria. Compared to those without sleep disturbances, patients with psychiatric diagnoses and co-morbid sleep disturbances were significantly more likely to report suicidal behaviors (OR = 1.99, 95% CI 1.72, 2.30, P <0.001). The association was also demonstrated across several psychiatric conditions including depression (OR = 3.05, 95% CI 2.07, 4.48, P <0.001), post-traumatic stress disorder (PTSD) (OR = 2.56, 95% CI 1.91, 3.43, P <0.001), panic disorder (OR = 3.22, 95% CI 1.09, 9.45, P = 0.03), and schizophrenia (OR = 12.66, 95% CI 1.40, 114.44, P = 0.02). In subgroup analysis based on the type of sleep disorder, we also found suicidal behavior to be significantly associated with the presence of insomnia, parasomnias, and sleep-related breathing disorders, but not hypersomnias.ConclusionsThis systematic review and meta-analysis suggests that in patients with psychiatric diagnoses, sleep disturbances are associated with the increased risk of suicidal behaviors.

ACTH Stimulation Tests for the Diagnosis of Adrenal Insufficiency: Systematic Review and Meta-Analysis

CONTEXT The diagnosis of adrenal insufficiency is clinically challenging and often requires ACTH stimulation tests. OBJECTIVE To determine the diagnostic accuracy of the high- (250 mcg) and low- (1 mcg) dose ACTH stimulation tests in the diagnosis of adrenal insufficiency. METHODS We searched six databases through February 2014. Pairs of independent reviewers selected studies and appraised the risk of bias. Diagnostic association measures were pooled across studies using a bivariate model. DATA SYNTHESIS For secondary adrenal insufficiency, we included 30 studies enrolling 1209 adults and 228 children. High- and low-dose ACTH stimulation tests had similar diagnostic accuracy in adults and children using different peak serum cortisol cutoffs. In general, both tests had low sensitivity and high specificity resulting in reasonable likelihood ratios for a positive test (adults: high dose, 9.1; low dose, 5.9; children: high dose, 43.5; low dose, 7.7), but a fairly suboptimal likelihood ratio for a negative test (adults: high dose, 0.39; low dose, 0.19; children: high dose, 0.65; low dose, 0.34). For primary adrenal insufficiency, we included five studies enrolling 100 patients. Data were only available to estimate the sensitivity of high dose ACTH stimulation test (92%; 95% confidence interval, 81-97%). CONCLUSION Both high- and low-dose ACTH stimulation tests had similar diagnostic accuracy. Both tests are adequate to rule in, but not rule out, secondary adrenal insufficiency. Our confidence in these estimates is low to moderate because of the likely risk of bias, heterogeneity, and imprecision.

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.

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.

Bone turnover markers in Paget’s disease of the bone: A Systematic review and meta-analysis

SummaryThe aim of this systematic review and meta-analysis is to study the utility of the commonly used bone turnover markers in evaluating disease activity in patients with Paget’s disease of bone before and after treatment with bisphosphonates. We found good correlation between the bone turnover marker concentrations and disease activity assessed by bone scintigraphy.IntroductionPaget’s disease of bone is a common skeletal disorder of the elderly. Bone turnover marker concentrations are used for diagnosis and follow-up. We aimed to compare the available bone turnover markers and determine their utility in assessing disease activity when compared to quantitative bone scintigraphy.MethodsWe conducted a systematic review and meta-analysis searching MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus. We evaluated total alkaline phosphatase (total ALP), bone-specific alkaline phosphatase (bone ALP), procollagen type 1 amino-terminal propeptide (P1NP), serum, and urine C-terminal telopeptide (uCTx and sCTx, respectively), and urine N-terminal telopeptide (uNTx). The main outcome of interest was the correlation of disease activity with concentrations of bone turnover markers in Paget’s disease patients before and after treatment with bisphosphonates. Correlation coefficients were pooled across studies using the random effects model.ResultsWe included 17 observational studies and one trial reporting on 953 patients. Prior to treatment, all studied bone turnover markers had moderate to strong correlation with scintigraphic indices (correlation coefficients ranging from 0.58 to 0.80) with no statistically significant difference between the bone turnover markers overall (p = 0.08). P1NP, uNTx, and bone ALP tend to have higher correlation with scintigraphy. After starting treatment with bisphosphonate, there was moderate to strong correlation with disease activity with all markers except bone ALP (correlation coefficients ranging from 0.43 to 0.70).ConclusionThe findings of this meta-analysis suggest the Paget’s disease activity is best monitored by following P1NP levels. However, total ALP, bone ALP, and uNTx are good alternatives as markers of disease activity in untreated patients. Total ALP and uNTx can be useful in following patients with Paget’s disease after treatment if P1NP is not available. Clinicians, however, should take availability, cost, and the presence of liver disease into consideration when deciding which bone turnover marker is most appropriate when evaluating patients with Paget’s disease.

Continuous subcutaneous insulin infusion versus multiple daily injections in individuals with type 1 diabetes: a systematic review and meta-analysis

The relative efficacy of continuous subcutaneous insulin infusion and multiple daily injections in individuals with type 1 diabetes is unclear. We sought to synthesize the existing evidence about the effect of continuous subcutaneous insulin infusion on glycosylated hemoglobin, hypoglycemic events, and time spent in hypoglycemia compared to multiple daily injections. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, and Scopus from January 2008 through November 2015 for randomized controlled trials that enrolled children or adults with type 1 diabetes. Trials identified in a previous systematic review and published prior to 2008 were also included. We included 25 randomized controlled trials at moderate risk of bias. Meta-analysis showed a significant reduction in glycosylated hemoglobin in patients treated with continuous subcutaneous insulin infusion compared to multiple daily injections (mean difference 0.37; 95 % confidence interval, 0.24–0.51). This effect was demonstrated in both children and adults. There was no significant difference in minor or severe hypoglycemic events. Continuous subcutaneous insulin infusion was associated with lower incidence of nocturnal hypoglycemia. There was no significant difference in the time spent in hypoglycemia. In children and adults with type 1 diabetes and compared to multiple daily injections, continuous subcutaneous insulin infusion is associated with a modest reduction in glycosylated hemoglobin. There was no difference in severe or minor hypoglycemia, but likely a lower incidence of nocturnal hypoglycemia with continuous subcutaneous insulin infusion.

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.

Oncologic surveillance in bladder cancer following radical cystectomy: A systematic review and meta-analysis.

PURPOSE The existing guidance on bladder cancer surveillance following radical cystectomy is limited and variable. Additionally, the effect of surveillance on mortality is debatable. Herein, we perform a systematic review to evaluate the characteristics of alternative oncologic surveillance protocols and determine the association of detection of asymptomatic vs. symptomatic recurrences on mortality. METHODS An electronic search of PubMed, MEDLINE, EMBASE, and Cochrane Library databases was performed from 1970 to 2015. In all, 3 reviewers independently assessed the 1,729 candidate studies for eligibility and abstracted data based on an a priori established protocol. Outcomes were pooled using random effects meta-analysis. RESULTS We identified 7 studies for inclusion that were uncontrolled and thereby represented a body of evidence at high risk of bias; 5 studies developed surveillance protocols using a methodology similar to that of established guidelines. The majority proposed a pathologic stage-stratified approach, but ended surveillance for all patients at 5 years. Detection of asymptomatic recurrences was associated with a nonsignificant reduction in mortality (relative risk = 0.78; 95% CI: 0.58-1.04). This effect became statistically significant when upper and lower urinary tract recurrences were included in the analyses (relative risk = 0.69; 95% CI: 0.59-0.79). CONCLUSIONS Only sparse evidence supports alternative oncologic surveillance protocols for bladder cancer following radical cystectomy. The majority of existing protocols proposed similar strategies to those recommended by published guidelines. Detecting asymptomatic recurrences may lead to a reduction in overall mortality, which could provide a rationale for surveillance.