Research Areas
Researcher: Dr Nombulelo Magula
Designation: HOD of General Medicine
Study: Metabolic Complications of Antiretroviral Therapy in a South African Black Population
Summary: The study included three groups of participants – those that were HIV infected and not starting antiretroviral therapy (ART), HIV infected starting ART, and HIV negative controls.
It investigated the prevalence of metabolic complications (dysglycaemia and dyslipidaemia) and body fat distribution patterns associated with HIV infection and compared this with HIV negative controls. Those starting antiretroviral therapy were then followed up for two years to study the incidence of dysglycaemia, dyslipidaemia and the pattern of fat distribution associated with ART.
According to Magula, there is very limited data in Africa particularly using the tools that were employed in her study – the Computerised Tomography (CT) scan and the Dual Energy Absorptiometry (DXA) scan to measure fat distribution. There is paucity of longitudinal data on dysglycaemia, dyslipidaemia and body fat distribution in Africa.
The study combined a cross-sectional and a prospective design. While there was no diabetes at baseline in the HIV-infected participants using the oral glucose tolerance test, there were incident cases during follow up on ART. Following two years of ART, there was a significant increase in body mass index (BMI) as indicated by overweight/obesity, trunk and total body fat measured by DXA scan, visceral and subcutaneous fat by CT scan. The significance of this is that these are all risk factors for cardiovascular diseases.
Researcher: Dr Nombulelo Magula
Designation: HOD of General Medicine
Study: Low dose versus high dose stavudine for treating people with HIV infection
Summary: Stavudine remains a component of combination antiretroviral therapy (ART) in resource-constrained countries due to its relatively low cost despite the WHO recommendation for its phasing out as a strategy to reduce stavudine associated toxicities. Where stavudine is still in use, it is recommended at a dose lower than the standard dose in order to reduce stavudine related toxicity.
To compare the safety and virologic efficacy of low dose versus high dose stavudine for treating HIV-1 infection.
The comprehensive search strategy developed by the Cochrane HIV/AIDS Review Group was used to identify randomised controlled trials that compared the use of low dose versus high dose stavudine. The last search was conducted in February 2014 and the searches covered the period 1996 to 2014.
Randomised controlled trials comparing the use of low dose and high dose stavudine as part of ART combination therapy for treating adults.
Two reviewers independently selected eligible trials, assessed methodological quality of the included studies and completed data extraction and analysis.
The search identified 3952 abstracts which were scanned for relevance. Three trials met the inclusion criteria (Milinkovic 2007; McComsey 2008; Sanchez-Conde 2005). All three trials were conducted in developed countries, participants were ART experienced and all had sustained virologic suppression at baseline. A total of 157 participants were recruited to the trials. Sample sizes ranged from 24 to 92 and more than 79% of participants were male.The studies were at a high risk of selection, performance/detection and selective outcome reporting biases. Some baseline characteristics differed among the groups, including triglyceride levels in two studies and body mass index in one study. In light of variation in the design and follow-up of the study results, no meta-analysis was performed and the results of single studies are presented. There was no significant difference in virologic suppression in the included studies (Milinkovic 2007; McComsey 2008; Sanchez-Conde 2005); Risk Ratio (RR) 1.09 (95% CI: 0.93 to 1.28), 0.94 (95% CI:0.59 to 1.50) and 1.03 (95% CI: 0.90 to 1.18) respectively. Symptomatic hyperlactatemia was seen in the high dose arm of the Milinkovic 2007 study; RR 0.21 (95% CI: 0.01 to 4.66), in no participants in the McComsey 2008 trial and not reported on in the Sanchez-Conde 2005 trial. McComsey 2008 and Milinkovic 2007 demonstrated a reduction in bone mineral density (BMD), reduction in limb fat and an increase in triglycerides in the high dose arms. The studies did not indicate that any participants discontinued treatment due to adverse events.
This systematic review identified only three small trials that evaluated virologic efficacy and safety of high dose versus low dose stavudine. All three trials were conducted in developed countries and none reported from developing countries yet stavudine remains a component of ART combination therapy in many developing countries. It was not possible to perform a meta-analysis on these trails. Individual results from the trials were imprecise and have not identified a clear advantage in virologic efficacy or safety between low and high dose stavudine. Furthermore, enrolled participants were treatment experienced with sustained virologic suppression and so existing data cannot be generalized to settings where stavudine is currently used in ART naive patients with high viral loads. Stavudine dose reduction trials in ART naive patients, in developing countries where stavudine is still being used are warranted as the phasing out of stavudine that is recommended by WHO may not be immediately universally feasible.
Researcher: Dr Nombulelo Magula
Designation: HOD of General Medicine
Study: Prednisolone and Mycobacterium indicus pranii in Tuberculous Pericarditis
Summary: Background: Tuberculous pericarditis is associated with high morbidity and mortality even if antituberculosis therapy is administered. We evaluated the effects of adjunctive glucocorticoid therapy and Mycobacterium indicus pranii immunotherapy in patients with tuberculous pericarditis.
Methods: Using a 2-by-2 factorial design, we randomly assigned 1400 adults with definite or probable tuberculous pericarditis to either prednisolone or placebo for 6 weeks and to either M. indicus pranii or placebo, administered in five injections over the course of 3 months. Two thirds of the participants had concomitant human immunodeficiency virus (HIV) infection. The primary efficacy outcome was a composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis.
Results: There was no significant difference in the primary outcome between patients who received prednisolone and those who received placebo (23.8% and 24.5%, respectively; hazard ratio, 0.95; 95% confidence interval [CI], 0.77 to 1.18; P=0.66) or between those who received M. indicus pranii immunotherapy and those who received placebo (25.0% and 24.3%, respectively; hazard ratio, 1.03; 95% CI, 0.82 to 1.29; P=0.81). Prednisolone therapy, as compared with placebo, was associated with significant reductions in the incidence of constrictive pericarditis (4.4% vs. 7.8%; hazard ratio, 0.56; 95% CI, 0.36 to 0.87; P=0.009) and hospitalization (20.7% vs. 25.2%; hazard ratio, 0.79; 95% CI, 0.63 to 0.99; P=0.04). Both prednisolone and M. indicus pranii, each as compared with placebo, were associated with a significant increase in the incidence of cancer (1.8% vs. 0.6%; hazard ratio, 3.27; 95% CI, 1.07 to 10.03; P=0.03, and 1.8% vs. 0.5%; hazard ratio, 3.69; 95% CI, 1.03 to 13.24; P=0.03, respectively), owing mainly to an increase in HIV-associated cancer.
Conclusions: In patients with tuberculous pericarditis, neither prednisolone nor M. indicus pranii had a significant effect on the composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis. (Funded by the Canadian Institutes of Health Research and others; IMPI ClinicalTrials.gov number, NCT00810849.).
Researcher: Dr Nombulelo Magula
Designation: HOD of General Medicine
Study: The use of readily available biomarkers to predict CD4 cell counts in HIV-infected individuals
Summary:
Researcher: Professor Bruce Biccard
Designation: Honorary Associate Professor
Study: General vs Neuraxial Anaesthesia in Decreasing Postoperative Mortality and Morbidity Following Vascular Surgery: A Meta-Analysis
Summary: Postoperative complications after vascular surgery may be used as a quality indicator of care. Patients presenting for vascular surgery have a number of co-morbidities including coronary artery disease, congestive cardiac failure, hypertension, respiratory insufficiency, chronic obstructive pulmonary disease, diabetes and a smoking history, and as such vascular surgery is considered a high risk surgical procedure. It is possible that choice of anaesthetic technique may improve outcome in vascular surgical patients.
Aim: The aim of this meta-analysis was to determine whether neuraxial anaesthesia (with or without general anaesthesia) was superior to general anaesthesia alone in decreasing mortality and postoperative cardiac, respiratory and surgical morbidity in patients undergoing vascular surgery.
Methods: An electronic search of Medline was conducted. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were adhered to. We included randomised controlled trials of vascular surgery comparing general and neuraxial anaesthesia.
Results: Seventeen trials were identified. Meta-analysis showed that acute respiratory failure (OR 0.51, CI 0.36-0.73), pneumonia (OR 0.52, 95% CI 0.33-0.83) and surgical morbidity (OR 0.58, 95% CI 0.39-0.84) were significantly decreased in patients randomised to neuraxial blockade. The other outcomes showed no statistical difference.
Conclusion: Acute respiratory failure, pneumonia and surgical morbidity were significantly decreased in patients randomised to neuraxial blockade. The current data is insufficient to assess potential survival benefit and cardiac protection associated with neuraxial blockade.
Researcher: Professor Bruce Biccard
Designation: Honorary Associate Professor
Study: The impact of acute preoperative beta-blockade on perioperative cardiac morbidity and all-cause mortality in hypertensive South African vascular surgery patients
Summary: Background. Acute ß-blockade has been associated with poor perioperative outcomes in non-cardiac surgery patients, probably as a result of ß-blocker-induced haemodynamic instability during the perioperative period, which has been shown to be more severe in hypertensive patients. Objective. To determine the impact of acute preoperative ß-blockade on the incidence of perioperative cardiovascular morbidity and allcause mortality in hypertensive South African (SA) patients who underwent vascular surgery at a tertiary hospital. Methods. We conducted two separate case-control analyses to determine the impact of acute preoperative ß-blockade on the incidence of major adverse cardiovascular events (MACEs, a composite outcome of a perioperative troponin-I leak or all-cause mortality) and perioperative troponin-I leak alone. Case and control groups were compared using ?2, Fisher’s exact, McNemar’s or Student’s t-tests, where applicable. Binary logistic regression was used to determine whether acute preoperative ß-blocker use was an independent predictor of perioperative MACEs/troponin-I leak in hypertensive SA vascular surgery patients. Results. We found acute preoperative ß-blockade to be an independent predictor of perioperative MACEs (odds ratio (OR) 3.496; 95% confidence interval (CI) 1.948 – 6.273; p<0.001) and troponin-I leak (OR 5.962; 95% CI 3.085 – 11.52; p<0.001) in hypertensive SA vascular surgery patients. Conclusions. Our findings suggest that acute preoperative ß-blockade is associated with an increased risk of perioperative cardiac morbidity and all-cause mortality in hypertensive SA vascular surgery patients.
Researcher: Professor Bruce Biccard
Designation: Honorary Associate Professor
Study: Comparison of hydroxyethyl starch colloids with crystalloids for surgical patients: A systematic review and meta-analysis
Summary: Background: Fluid therapy is one of the most ubiquitous medical therapeutic interventions. There is a debate over whether colloids or crystalloids are better for fluid resuscitation. Recent large trials and meta-analyses suggest no mortality benefit and possible harm with hydroxyethyl starch (HES) use. However, these trials were conducted in critically ill and septic patients and their applicability to perioperative patients has been challenged.
Objective: We aimed to evaluate the impact of HES use in scheduled and elective surgical patients.
Design: We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs).
Eligibility criteria: Only RCTs comparing the use of the synthetic colloid HES with any crystalloid in adults undergoing noncardiac surgery (up to 24 h postop) were considered eligible. For each eligible trial, we extracted the outcomes of all-cause mortality within 90 days, length of hospital stay, major infectious complications, acute kidney injury (AKI) and renal replacement therapy (RRT).
Results: We identified 1555 citations, selected 90 for full-text evaluation, and identified 13 eligible RCTs. Trials were small (n = 20 to 202) with low event rates. There was a trend to increased mortality with HES within 90 days [13/373 vs. 3/368; risk ratio 2.97; 95% confidence interval (95% CI) 0.96 to 9.19; I = 0%], no difference in AKI and RRT (risk ratio 1.11; 95% CI 0.26 to 4.69; I = 34%), and no difference in major infectious complications (risk ratio 1.19; 95% CI 0.59 to 2.39; I = 0%). Patients resuscitated with HES had a shorter length of hospital stay (mean difference -1.52 days; 95% CI -2.87 to -0.18), although heterogeneity was high (I = 90%).
Conclusion: This meta-analysis, based on small studies with low event rates, suggests that there are currently insufficient data to identify a difference in outcomes associated with crystalloids and HES in scheduled or elective noncardiac surgery.
Researcher: Professor Bruce Biccard
Designation: Honorary Associate Professor
Study: N-terminal pro-B-type Natriuretic Peptides’ Prognostic Utility Is Overestimated in Meta-analyses Using Study-specific Optimal Diagnostic Thresholds
Summary: N-terminal fragment B-type natriuretic peptide (NT-proBNP) prognostic utility is commonly determined post hoc by identifying a single optimal discrimination threshold tailored to the individual study population. The authors aimed to determine how using these study-specific post hoc thresholds impacts meta-analysis results.
The authors conducted a systematic review of studies reporting the ability of preoperative NT-proBNP measurements to predict the composite outcome of all-cause mortality and nonfatal myocardial infarction at 30 days after noncardiac surgery. Individual patient-level data NT-proBNP thresholds were determined using two different methodologies. First, a single combined NT-proBNP threshold was determined for the entire cohort of patients, and a meta-analysis conducted using this single threshold. Second, study-specific thresholds were determined for each individual study, with meta-analysis being conducted using these study-specific thresholds.
The authors obtained individual patient data from 14 studies (n = 2,196). Using a single NT-proBNP cohort threshold, the odds ratio (OR) associated with an increased NT-proBNP measurement was 3.43 (95% CI, 2.08 to 5.64). Using individual study-specific thresholds, the OR associated with an increased NT-proBNP measurement was 6.45 (95% CI, 3.98 to 10.46). In smaller studies (
Post hoc identification of study-specific prognostic biomarker thresholds artificially maximizes biomarker predictive power, resulting in an amplification or overestimation during meta-analysis of these results. This effect is accentuated in
