Background and Aims: Very early onset inflammatory bowel disease [VEOIBD] is characterized by intestinal inflammation affecting infants and children less than 6 years of age. To date, over 60 monogenic aetiologies of VEOIBD have been identified, many characterized by highly penetrant recessive or dominant variants in underlying immune and/or epithelial pathways. We sought to identify the genetic cause of VEOIBD in a subset of patients with a unique clinical presentation. Methods: Whole exome sequencing was performed on five families with ten patients who presented with a similar constellation of symptoms including medically refractory infantile-onset IBD, bilateral sensorineural hearing loss and, in the majority, recurrent infections. Genetic aetiologies of VEOIBD were assessed and Sanger sequencing was performed to confirm novel genetic findings. Western analysis on peripheral blood mononuclear cells and functional studies with epithelial cell lines were employed. Results: In each of the ten patients, we identified damaging heterozygous or biallelic variants in the Syntaxin-Binding Protein 3 gene [STXBP3], a protein known to regulate intracellular vesicular trafficking in the syntaxin-binding protein family of molecules, but not associated to date with either VEOIBD or sensorineural hearing loss. These mutations interfere with either intron splicing or protein stability and lead to reduced STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity. Conclusion: Overall, we describe a novel genetic syndrome and identify a critical role for STXBP3 in VEOIBD, sensorineural hearing loss and immune dysregulation.

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Introduction There is an increasing incidence of CD in adolescents and young persons (AYP). Whilst anti-TNF use in AYP is well established, little is reported on the efficacy and safety of vedolizumab. We describe our multicentre experience. Methods Data was retrospectively collected on 14–23yr olds starting vedolizumab at University College London Hospital (UCLH) and The Royal London Hospital (RLH) from June 2015–18. Endpoints were: clinical (i) response (reduction in Harvey Bradshaw Index (HBI) of ≥3 or sustained HBI ≤4 points) (ii) remission (HBI ≤4 points), and biological (i) response (50% reduction in CRP) and (ii) remission (CRP<5 mg/L where baseline CRP>5 mg/L) at weeks 14, 30 and 54. Results Table 1 summarises the baseline characteristics of 35 AYP commenced on vedolizumab. 34 patients were included in the analysis at week 54. 28 patients who received induction treatment commenced 8 weekly maintenance infusions at week 14. Overall 28 patients had stopped treatment before week 54 (including 14 for primary non-response and 7 for loss of response). The median time to stopping vedolizumab was 7 months (IQR 4–29, 95%CI 5–10). Analysing paired data only, mean (sd) HBI showed a downward trend from baseline to week 14, and was significantly decreased from baseline (4.5(4.3)) to week 22 (2.5(2.9), n=20, p=0.03), to week 30 (2.4(2.9), n=16, p=0.02), and week 54 (2.0(3.4), n=9, p=0.02). Mean (s.d.) CRP (mg/L) showed a downward trend from baseline to weeks 14 and 22, and was significantly decreased from baseline (17.8(16.9)) to week 30 (8.3(7.2), n=16, p=0.04). This trend was sustained but did not achieve significance at week 54 (7(6.0), n=9, p=0.2). Mean (sd) weight (kg) showed an upward trend from baseline to weeks 14 and 22 and was significantly increased from baseline (61.5(11.7)) to week 30 (65.6(12.4), n=13, p=0.004), and week 54 (66.3(15.5), n=9, p=0.006). At weeks 14, 30 and 54, the rates of clinical (i) response and (ii) remission were (i) 56, 37 and 24% respectively and (ii) 47, 37, 24% respectively. At weeks, 14, 30 and 54, the rates of biological (i) response and (ii) remission were (i) 29, 25, and 11% respectively and (ii) 10, 15 and 9% respectively.Abstract ATH-10 Table 1 Conclusions We report on the use of vedolizumab in AYP at 2 tertiary IBD centres. Our experience suggests that whilst medium term (6 month) effectiveness in an anti-TNF experienced cohort is comparable with outcomes from adult and trial data, this is not sustained to a year. This may be reflective of a cohort of patients with early onset CD with a more aggressive phenotype and coexisting perianal disease. Further studies may help identify which adolescents would most benefit from vedolizumab. This is of growing importance in the face of an expanding therapeutic armamentarium in CD.

Age-of-diagnosis associated variation in disease location and antimicrobial sero-reactivity has suggested fundamental differences in pediatric Crohn Disease (CD) pathogenesis. This variation may be related to pubertal peak incidence of ileal involvement and Peyer’s patches maturation, represented by IFNγ-expressing Th1 cells. However, direct mucosal evidence is lacking. We characterize the global pattern of ileal gene expression and microbial communities in 525 treatment-naive pediatric CD patients and controls (Ctl), stratifying samples by their age-of-diagnosis. We show a robust ileal gene signature notable for higher expression of specific immune genes including GM-CSF and INFγ, and reduced expression of antimicrobial Paneth cell α-defensins, in older compared to younger patients. Reduced α-defensin expression in older patients was associated with higher IFNγ expression. By comparison, the CD-associated ileal dysbiosis, characterized by expansion of Enterobacteriaceae and contraction of Lachnospiraceae and Ruminococcaceae, was already established within the younger group and did not vary systematically with increasing age-of-diagnosis. Multivariate analysis considering individual taxa, however did demonstrate negative associations between Lachnospiraceae and IFNγ, and positive associations between Bacteroides and α-defensin expression. These data provide evidence for maturation of mucosal Th1 immune responses and loss of epithelial antimicrobial α-defensins which are associated with specific taxa with increasing age-of-diagnosis in pediatric CD.

BACKGROUND:Variation in care is common in medical practice. Reducing variation in care is shown to improve quality and increase favorable outcomes in chronic diseases. We sought to identify factors associated with variation in care in children with newly diagnosed Crohn's disease (CD). METHODS:Prospectively collected data from a 28-site multicenter inception CD cohort were analyzed for variations in diagnostic modalities, treatment, and follow-up monitoring practices, along with complicated disease outcomes over 3 years in 1046 children. Generalized linear mixed effects models were used to investigate the intercenter variations in each outcome variable. RESULTS:The mean age at diagnosis was 12 years, and 25.9% were nonwhite. The number of participants ranged from 5 to 112 per site. No variation existed in the initial diagnostic approach. When medication exposure was analyzed, steroid exposure varied from 28.6% to 96.9% (P < 0.01) within 90 days, but variation was not significant over a 3-year period (P = 0.13). Early anti-tumor necrosis factor (anti-TNF) exposure (within 90 days) varied from 2.1% to 65.7% (P < 0.01), but variation was not significant over a 3-year period (P > 0.99). Use of immunomodulators (IMs) varied among centers both within 90 days (P < 0.01) and during 3 years of follow-up (P < 0.01). A significant variation was seen at the geographic level with follow-up small bowel imaging and colonoscopy surveillance after initial therapy. CONCLUSIONS:Intercenter variation in care was seen with the initial use of steroids and anti-TNF, but there was no difference in total 3-year exposure to these drugs. Variation in the initiation and long-term use of IMs was significant among sites, but further research with objective measures is needed to explain this variation of care. Small bowel imaging or repeat colonoscopy in CD patients was not uniformly performed across sites. As our data show the widespread existence of variation in care and disease monitoring at geographic levels among pediatric CD patients, future implementation of various practice strategies may help reduce the variation in care.

Background Lack of evidence-based outcomes data leads to uncertainty in developing treatment regimens in children who are newly diagnosed with ulcerative colitis. We hypothesised that pretreatment clinical, transcriptomic, and microbial factors predict disease course. Methods In this inception cohort study, we recruited paediatric patients aged 4-17 years with newly diagnosed ulcerative colitis from 29 centres in the USA and Canada. Patients initially received standardised mesalazine or corticosteroids, with pre-established criteria for escalation to immunomodulators (ie, thiopurines) or anti-tumor necrosis factor-alpha (TNF alpha) therapy. We used RNA sequencing to define rectal gene expression before treatment, and 16S sequencing to characterise rectal and faecal microbiota. The primary outcome was week 52 corticosteroid-free remission with no therapy beyond mesalazine. We assessed factors associated with the primary outcome using logistic regression models of the per-protocol population. This study is registered with ClinicalTrials. gov, number NCT01536535. Findings Between July 10, 2012, and April 21, 2015, of 467 patients recruited, 428 started medical therapy, of whom 400 (93%) were evaluable at 52 weeks and 386 (90%) completed the study period with no protocol violations. 150 (38%) of 400 participants achieved week 52 corticosteroid-free remission, of whom 147 (98%) were taking mesalazine and three (2%) were taking no medication. 74 (19%) of 400 were escalated to immunomodulators alone, 123 (31%) anti-TNF alpha therapy, and 25 (6%) colectomy. Low baseline clinical severity, high baseline haemoglobin, and week 4 clinical remission were associated with achieving week 52 corticosteroid-free remission (n=386, logistic model area under the curve [AUC] 0.70, 95% CI 0.65-0.75; specificity 77%, 95% CI 71-82). Baseline severity and remission by week 4 were validated in an independent cohort of 274 paediatric patients with newly diagnosed ulcerative colitis. After adjusting for clinical predictors, an antimicrobial peptide gene signature (odds ratio [OR] 0.57, 95% CI 0.39-0.81; p=0.002) and abundance of Ruminococcaceae (OR 1.43, 1.02-2.00; p=0.04), and Sutterella (OR 0.81, 0.65-1.00; p=0.05) were independently associated with week 52 corticosteroid-free remission. Interpretation Our findings support the utility of initial clinical activity and treatment response by 4 weeks to predict week 52 corticosteroid-free remission with mesalazine alone in children who are newly diagnosed with ulcerative colitis. The development of personalised clinical and biological signatures holds the promise of informing ulcerative colitis therapeutic decisions.

Congenital heart defects (CHD) are structural malformations found at birth with a prevalence of 1%. The clinical trajectory of CHD is highly variable and thus in need of robust diagnostics and therapeutics. Major surgical interventions are often required for most CHDs. In Africa, despite advances in life sciences infrastructure and improving education of medical scholars, the limited clinical data suggest that CHD detection and correction are still not at par with the rest of the world. But the toll and genetics of CHDs in Africa has seldom been systematically investigated. We present an expert review on CHD with lessons learned on Africa. We found variable CHD phenotype prevalence in Africa across countries and populations. There are important gaps and paucity in genomic studies of CHD in African populations. Among the available genomic studies, the key findings in Africa were variants in GATA4 (P193H), MTHFR 677TT, and MTHFR 1298CC that were associated with atrial septal defect, ventricular septal defect (VSD), Tetralogy of Fallot (TOF), and patent ductus arteriosus phenotypes and 22q.11 deletion, which is associated with TOF. There were no data on epigenomic association of CHD in Africa, however, other studies have shown an altered expression of miR-421 and miR-1233-3p to be associated with TOF and hypermethylation of CpG islands in the promoter of SCO2 gene also been associated with TOF and VSD in children with non-syndromic CHD. These findings signal the urgent need to develop and implement genetic and genomic research on CHD to identify the hereditary and genome-environment interactions contributing to CHD. These projected studies would also offer comparisons on CHD pathophysiology between African and other populations worldwide. Genomic research on CHD in Africa should be developed in parallel with next generation technology policy research and responsible innovation frameworks that examine the social and political factors that shape the emergence and societal embedding of new technologies.

Very early-onset inflammatory bowel disease (VEO-IBD), defined by the onset of IBD before 6 years of age, is often associated with more severe and extensive disease than IBD in older patients. Some VEO-IBD cases have been linked to mutations in primary immunodeficiency genes, which regulate immunity and hyperinflammatory pathways, however the underlying pathophysiological mechanisms are still poorly understood. Here we describe eight patients from four unrelated families manifesting with VEO-IBD, immunodeficiency and severe bilateral sensorineural hearing loss - each carrying either heterozygous or compound heterozygous deleterious mutations in Syntaxin-Binding Protein 3 gene (STXBP3). These mutations interfere with either intron splicing or protein stability, lead to reduced STXBP3 protein expression, which in turn, affect cytotoxic T-Lymphocyte (CTL) and epithelial cell function. STXBP3 knock-down in control CTLs significantly reduces cytotoxic activity, mimicking the patients’ CTL defects. Strikingly, forced expression of STXBP3 rescues patient CTL function. Live-cell microscopy analyses show that STXBP3 is required for recycling of RAB11A-containing endosomes to the plasma membrane. Defects in this process prevent the delivery of key effector proteins that are required for granule secretion and epithelial cell polarity. Our results identify STXBP3 as a causal gene for the development of VEO-IBD with associated immunodeficiency and hearing loss.

The efficacy of proton pump inhibitor (PPI) medications is highly dependent on plasma concentrations, which varies considerably due to cytochrome P450 (CYP2C19) genetic variation. We conducted a pragmatic, pilot study of CYP2C19 genotype‐guided pediatric dosing of PPI medications. Children aged 5–17 years old with gastric‐acid‐related conditions were randomized to receive either conventional dosing of a PPI or genotype‐guided dosing for a total of 12 weeks. Sixty children (30 in each arm) were enrolled and had comparable baseline characteristics. The mean daily omeprazole equivalent dose prescribed to participants across metabolizer phenotype groups was significantly different in the genotype‐guided dosing arm (P < 0.001), but not in the conventional dosing arm. Prescribers waited for the genotype result before prescribing the PPI medication for 90% of the participants in the genotype‐guided dosing arm. The number of participants who reported an infection was marginally lower in genotype‐guided dosing vs. conventional dosing (20% vs. 44%; P = 0.07). Sinonasal symptoms were higher in the conventional dosing arm as compared with genotype‐guided dosing arm: (2.6 (2.0, 3.4) vs. 1.8 (1.0, 2.3), P = 0.031). CYP2C19 genotype‐guided PPI therapy is feasible in a clinical pediatric setting, well accepted by providers, resulted in differential PPI dosing, and may reduce PPI‐associated infections. A future large scale randomized clinical trial of CYP2C19 genotype‐guided pediatric dosing of PPI medications in children is warranted.

OBJECTIVES: Environmental factors play an important role in the pathogenesis of Crohn's Disease (CD). In particular, by virtue of the instability of the microbiome and development of immunologic tolerance, early life factors may exert the strongest influence on disease risk and phenotype. METHODS: We used data from 1119 CD subjects recruited from RISK inception cohort to examine the impact of early life environment on disease progression. Our primary exposures of interest were breastfeeding in infancy and exposure to maternal, active, or passive smoke. Our primary outcomes were development of complicated (stricturing or penetrating) disease, and need for CD-related hospitalization, and surgery. Multivariable logistic regression models were used to define independent associations, adjusting for relevant covariates. RESULTS: Our study cohort included 1119 patients with CD among whom 15% had stricturing (B2) or penetrating disease (B3) by 3 years. 331 patients (35%) and 95 patients (10.6%) required CD-related hospitalizations and surgery respectively. 74.5% were breastfed in infancy and 31% were exposed to smoking among whom 7% were exposed to maternal smoke. On multivariable analysis, a history of breastfeeding was inversely associated with complicated (B2/B3 disease) 0.65, CI 95% 0.44-96; P = 0.03) in pediatric CD. Maternal smoking during pregnancy was associated with increased risk of hospitalization during the 3-year follow-up period (OR 1.75, CI 95% 1.05-2.89; P = 0.03). CONCLUSIONS: Early life environmental factors influence the eventual phenotypes and disease course in CD.

BACKGROUND & AIMS: Helicobacter pylori eradication and endoscopic surveillance of gastric precancerous lesions are strategies to reduce gastric cancer (GC) risk.To our knowledge, this study is the longest prospective cohort of an H pylori eradication trial in a Hispanic population.METHODS: A total of 800 adults with precancerous lesions were randomized to anti-H pylori treatment or placebo.Gastric biopsy samples taken at baseline and 3, 6, 12, 16, and 20 years were assessed by our Correa histopathology score.A generalized linear mixed model with a participant-level random intercept was used to estimate the effect of H pylori status on the score over time.Logistic regression models were used to estimate progression by baseline diagnosis and to estimate GC risk by intestinal metaplasia (IM) subtype and anatomic location.RESULTS: Overall, 356 individuals completed 20 years of follow-up.Anti-H pylori therapy (intention-to-treat) reduced progression of the Correa score (odds ratio [OR], 0.59; 95% confidence interval [CI], 0.38-0.93).H pylori-negative status had a beneficial effect on the score over time (P ¼ .036).Among individuals with IM (including indefinite for dysplasia) at baseline, incidence rates per 100 person-years were 1.09 (95% CI, 0.85-1.33)for lowgrade/high-grade dysplasia and 0.14 (95% CI, 0.06-0.22)for GC.Incomplete-type (vs complete-type) IM at baseline presented higher GC risk (OR, 13.4; 95% CI, 1.8-103.8).Individuals with corpus (vs antrum-restricted) IM showed an OR of 2.1 (95% CI, 0.7-6.6)for GC.CONCLUSIONS: In a high-GC-risk Hispanic population, anti-H pylori therapy had a long-term beneficial effect against histologic progression.Incomplete IM is a strong predictor of GC risk.

Background: Several genes influence the development and phenotype of ulcerative colitis (UC).GWAS have shown 200 loci are associated with IBD susceptibility (32 exclusively UC).Most loci had a modest effect size (OR 0.84 to 1.25) with the major histocompatibility complex (MHC) demonstrating the strongest evidence (OR 3.59) of association.Aim: Use the high-density UK Biobank Axiom Array to compare the allele architecture of pediatric and adult UC.Methods: 768 children with UC (401 from the PROTECT Study (DK 095745-01) and 367 others) (mean age 12.7 yrs) were matched in PCA with 3,900 controls.After rigorous QC and selecting only Caucasians 466 cases, 2,099 controls (genomic inflation 1.07), and 746,272 SNPs remained.Imputation resulted in 3,996,700 SNPs.Association was performed (p<5*10 -8 as genome-wide significant) and compared to established adultonset UC and IBD SNPs (Nat Genet 47(9): 976-86).SNP2HLA against T1DGC reference panel [with 8,961 MHC SNPs from 5225 unrelated European ancestry individuals] was used to impute classical HLA variants and their corresponding amino acids.Results: The frequency of established common risk SNPs in adult-and pediatric-onset UC was similar in magnitude and direction.None of the SNPs in pediatric dataset reached genome-wide significance except 191 SNPs (5*10 -8 to 5*10 -10 ) in the HLA region.SNP2HLA imputation across the MHC using T1DGC reference panel determined that HLA-DRβ1*0103 [OR= 6.941, ] had the most significant association for pediatric-onset UC.HLA-DRβ1*0103 was previously reported (Nat Genet 47(2): 172-9) as the most significant SNP for adult-onset UC [OR=3.59,]. Coitional analysis determined the effect of other HLA signals.Conditioning on HLA-DRβ1*0103 showed that HLA-DRβ1*1301 (OR= 2.25, p = 7.92*10 -9) has an independent effect.Further conditioning on HLA-DRβ1*0103

Background Previous retrospective studies of paediatric ulcerative colitis have had limited ability to describe disease progression and identify predictors of treatment response. In this study, we aimed to identify characteristics associated with outcomes following standardised therapy after initial diagnosis. Methods The PROTECT multicentre inception cohort study was based at 29 centres in the USA and Canada and included paediatric patients aged 4-17 years who were newly diagnosed with ulcerative colitis. Guided by the Pediatric Ulcerative Colitis Activity Index (PUCAI), patients received initial standardised treatment with mesalazine (PUCAI 10-30) oral corticosteroids (PUCAI 35-60), or intravenous corticosteroids (PUCAI >= 65). The key outcomes for this analysis were week 12 corticosteroid-free remission, defined as PUCAI less than 10 and taking only mesalazine, and treatment escalation during the 12 study weeks to anti-tumour necrosis factor a (TNF alpha) agents, immunomodulators, or colectomy among those initially treated with intravenous corticosteroids. We identified independent predictors of outcome through multivariable logistic regression using a per-protocol approach. This study is registered with ClinicalTrials. gov, number NCT01536535. Findings Patients were recruited between July 10, 2012, and April 21, 2015. 428 children initiated mesalazine (n=136), oral corticosteroids (n=144), or intravenous corticosteroids (n=148). Initial mean PUCAI was 31.1 (SD 13.3) in children initiating with mesalazine, 50.4 (13.8) in those initiating oral corticosteroids, and 66.9 (13.7) in those initiating intravenous corticosteroids (p<0.0001 for between-group comparison). Week 12 outcome data were available for 132 patients who initiated with mesalazine, 141 with oral corticosteroids, and 143 with intravenous corticosteroids. Corticosteroid-free remission with the patient receiving mesalazine treatment only at 12 weeks was achieved by 64 (48%) patients in the mesalazine group, 47 (33%) in the oral corticosteroid group, and 30 (21%) in the intravenous corticosteroid group (p<0.0001). Treatment escalation was required by nine (7%) patients in the mesalazine group, 21 (15%) in the oral corticosteroid group, and 52 (36%) in the intravenous corticosteroid group (p<0.0001). Eight patients, all of whom were initially treated with intravenous corticosteroids, underwent colectomy. Predictors of week 12 corticosteroid-free remission were baseline PUCAI less than 35 (odds ratio 2.44, 95% CI 1.41-4.22; p=0.0015), higher baseline albumin by 1 g/dL increments among children younger than 12 years (4.05, 1.90-8.64; p=0.00030), and week 4 remission (6.26, 3.79-10.35; p<0.0001). Predictors of treatment escalation by week 12 in patients initially treated with intravenous corticosteroids included baseline total Mayo score of 11 or higher (2.59, 0.93-7.21; p=0.068 [ retained in model due to clinical relevance]), rectal biopsy eosinophil count less than or equal to 32 cells per high power field (4.55, 1.62-12.78; p=0.0040), rectal biopsy surface villiform changes (3.05, 1.09-8.56; p=0.034), and not achieving week 4 remission (30.28, 6.36-144.20; p<0.0001). Interpretation Our findings provide guidelines to assess the response of children newly diagnosed with ulcerative colitis to standardised initial therapy and identify predictors of treatment response and failure. These data suggest that additional therapeutic interventions might be warranted to improve early outcomes, especially in patients presenting with severe disease and requiring intravenous corticosteroids.

Background Stricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohn's disease. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown.Methods We did a prospective inception cohort study of paediatric patients with newly diagnosed Crohn's disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor alpha (TNF alpha) therapy exposure within 90 days of diagnosis on complication risk.Findings Between Nov 1, 2008, and June 30, 2012, we enrolled 913 patients, 78 (9%) of whom experienced Crohn's disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51-82) and specificity of 63% (55-71), with a negative predictive value of 95% (94-97). Patients who received early anti-TNF alpha therapy were less likely to have penetrating complications (hazard ratio [HR] 0.30, 95% CI 0.10-0.89; p=0.0296) but not stricturing complication (1.13, 0.51-2.51; 0.76) than were those who did not receive early anti-TNF alpha therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications. Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 1.70, 95% CI 1.12-2.57; p=0.0120). When this gene signature was included, the model's specificity improved to 71%.Interpretation Our findings support the usefulness of risk stratification of paediatric patients with Crohn's disease at diagnosis, and selection of anti-TNF alpha therapy.

Introduction: Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor prescribed as part of first-line highly active antiretroviral therapy in South Africa. Despite administration of fixed doses of EFV, inter-individual variability in EFV plasma concentrations has been reported. Poor treatment outcomes such as the development of adverse drug reactions or treatment failure have been linked to EFV concentrations outside the therapeutic range (1 - 4 µg/mL). The drug metabolising enzyme (DME), CYP2B6, is primarily responsible for EFV metabolism with minor contributions by CYP2A6, CYP3A4, CYP3A5, UGT2B7 and CYP1A2. Genes coding for DMEs have been shown to be regulated by microRNAs through targeting the 3'-untranslated region. Genetic variation in the 3'-UTR, in addition to genetic variation in the coding regions, could potentially be used to explain a larger proportion of the inter-individual variability observed in drug response. Methods: SNPs in CYP1A2, CYP2B6, UGT2B7 and NR1I2 (PXR) were selected for genotyping among 222 Bantu-speaking South African HIV-infected patients receiving EFV-containing HAART. This study is a continuation of earlier pharmacogenetics studies emphasizing specifically the role of genetic variation in the 3'-UTR of genes which products are either pharmacokinetic or pharmacodynamic targets of EFV.Results: In addition to CYP2B6 c.516G>T and c.983T>C SNPs, the CYP2B6 c.1355A>G SNP was identified as pharmacogenetics determinant of EFV concentration among CYP2B6 intermediate and extensive metabolisers (carriers of either c.516G/G+c.983T/T or c.516G/G+c.983T/C or c.516G/T+c.983T/T genotypes). NR1I2 c.522C>T and NR1I3 c.239-1089T>C SNPs were predictors of EFV concentration among CYP2B6 poor metabolisers (carriers of either c.516T/T or c.983C/C or both c.516G/T and c.983T/C genotypes).Conclusion: Genotyping results provide support for comprehensive studies of genetic variation in the 3'-UTR of genes coding for DMEs and their inclusion in predictive pharmacogenomics models to get a clearer picture on correlates of drug response.