Lize van der Merwe

Low lopinavir plasma or hair concentrations explain second line protease inhibitor failures in a resource-limited setting

Background:In resource-limited settings, many patients, with no prior protease inhibitor (PI) treatment on a second-line, high genetic barrier, ritonavir-boosted PI-containing regimen have virologic failure. Methods:We conducted a cross-sectional survey to investigate the aetiology of virologic failure in 2 public health antiretroviral clinics in South Africa documenting the prevalence of virologic failure (HIV RNA load >500 copies/mL) and genotypic antiretroviral resistance; and lopinavir hair and plasma concentrations in a nested case-control study. Results:Ninety-three patients treated with a second-line regimen including lopinavir boosted with ritonavir were included, of whom 50 (25 cases, with virologic failure and 25 controls) were included in a nested case control study. Of 93 patients, 37 (40%) had virological failure, only 2 of them had had major PI mutations. The negative predictive values: probability of failure with lopinavir plasma concentration >1 μg/mL or hair concentrations >3.63 ng/mg for virologic failure were 86% and 89%, and positive predictive values of low concentrations 73% and 79%, respectively, whereas all virologic failures with HIV RNA loads above 1000 copies per milliliter, of patients without PI resistance, could be explained by either having a low lopinavir concentration in plasma or hair. Conclusions:Most patients who fail a lopinavir/ritonavir regimen, in our setting, have poor lopinavir exposure. A threshold plasma lopinavir concentration (indicating recent lopinavir/ritonavir use) and/or hair concentration (indicating longer term lopinavir exposure) are valuable in determining the aetiology of virologic failure and identifying patients in need of adherence counselling or resistance testing.

Neuropsychological status of bipolar I disorder: impact of psychosis

BACKGROUNDnThe presence of schizotypal personality traits in some people with bipolar disorder, together with reports of greater cognitive dysfunction in patients with a history of psychotic features compared with patients without such a history, raises questions about the nosological relationship between bipolar disorder with psychotic features and bipolar disorder without psychotic features.nnnAIMSnTo test the impact of a history of DSM-IV-defined psychosis on the neuropsychological status of participants with bipolar disorder while statistically controlling for confounding factors such as mood, medication, alcohol misuse/dependence and childhood abuse, and to evaluate the impact of schizotypal personality traits (and thus potential vulnerability to psychotic illness) on the cognitive performance of people with bipolar disorder and their healthy relatives.nnnMETHODnNeuropsychological data were obtained for 25 participants with type I bipolar disorder and a history of psychosis, 24 with type I bipolar disorder but no history of psychosis and 61 unaffected relatives. Schizotypal traits were measured with the Schizotypal Personality Scale (STA). Childhood trauma was measured with the Childhood Trauma Questionnaire.nnnRESULTSnThe group with a history of psychosis performed significantly worse than the healthy relatives on measures of verbal working memory, cognitive flexibility and declarative memory. Nevertheless, the two bipolar disorder groups did not differ significantly from each other on any cognitive measure. Scores on the STA were negatively associated with verbal working and declarative memory, but positively associated with visual recall memory.nnnCONCLUSIONSnPsychotic and non-psychotic subtypes of bipolar disorder may lie on a nosological continuum that is most clearly defined by verbal memory impairment.

Investigating SAPAP3 variants in the etiology of obsessive-compulsive disorder and trichotillomania in the South African white population

BACKGROUNDnObsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder characterized by repeated obsessions and compulsions. Trichotillomania (TTM), a psychiatric disorder characterized by repetitive hairpulling, is presently classified as an impulse control disorder, but has also been viewed as an obsessive-compulsive spectrum disorder. Both conditions are complex disorders, with evidence from family and twin studies indicating that their etiology includes a genetic component. Results from a recent knockout animal model suggest that SAP90/PSD95-associated protein 3 (SAPAP3) may be involved in the pathophysiology of both disorders.nnnMETHODSnSeven polymorphic variants distributed across the gene encoding SAPAP3 were genotyped in South African white OCD (n = 172), TTM (n = 45), and control (n = 153) subjects. Single-locus and haplotype analyses were conducted to determine association between genetic variants and subjects with OCD, TTM, and controls.nnnRESULTSnAlthough single-locus analysis revealed a significant association between rs11583978 in SAPAP3 and TTM, this association was nonsignificant after correction for multiple testing. In the OCD group, a significant association was observed between earlier age at onset and the A-T-A-T (rs11583978-rs7541937-rs6662980-rs4652867) haplotype compared with the C-G-G-G haplotype.nnnCONCLUSIONSnThis study generated preliminary evidence to link SAPAP3 variants to the development of earlier onset OCD. Future studies should concentrate on locating the susceptibility variant(s) by focusing on functional polymorphisms within SAPAP3.

β-Lactams against Tuberculosis — New Trick for an Old Dog?

To the Editor: New treatments are needed to combat the worldwide increase in resistance to antituberculosis drugs.1 The outlook for patients with tuberculosis who do not show a response to the key agents used in treatment — isoniazid, rifampin, fluoroquinolones, and aminoglycosides — is grim and reminiscent of the plight of patients with cancer in the era before chemotherapy.2 New agents are emerging, but the obligatory evaluation of their safety and efficacy in combination with other antituberculosis and antiretroviral agents slows the pace of progress. Repurposing or combining commercially available products may offer a faster track to new antituberculosis regimens. .xa0.xa0.

The apoptosis pathway and the genetic predisposition to Achilles tendinopathy

Achilles tendinopathy (AT) is a degenerative condition for which several risk factors have been implicated including components of the inflammatory pathway. The aim was to assess functional variants within genes encoding components of the apoptosis signaling cascade and the effectiveness of a polygenic apoptosis profile to capture tendinopathy (TEN) risk. A total of 358 unaffected control (CON) participants [159 South Africa (SA CON) and 199 Australia (AUS CON)] and 166 affected AT (TEN) participants (87 SA TEN and 79 AUS TEN) were genotyped for four variants [CASP8 (rs384129), CASP8 (rs1045485), NOS3 (rs1799983), and NOS2 (rs2779249)]. Logistic regression was used to derive risk models for AT. A receiver operator characteristic (ROC) curve was plotted to determine the effectiveness of a model to capture AT risk. This study indicates the independent association of CASP8_rs1045485 and CASP8_rs3834129 as well as their haplotype with AT risk and the identification of an optimal model which included genetic loci CASP8_rs384129 and CASP8_rs1045485 together with sex to capture AT risk in both SA and AUS. Collectively, these results further implicate the apoptosis signaling cascade as one of the biological pathways involved in the development of AT.

Protease inhibitor resistance in South African children with virologic failure

Background: In South Africa, first-line antiretroviral therapy for children younger than 3 years of age combines a protease inhibitor (PI) with 2 nucleoside reverse transcription inhibitors. In our study, some pediatric patients received ritonavir (RTV) as single PI (RTV-sPI) and others ritonavir-boosted lopinavir (LPV/r), which has a higher resistance barrier. We explored antiretroviral resistance mutations in pediatric patients failing PI-based antiretroviral therapy and the predictors of major PI resistance mutations (MPIRM) in these patients. Materials and Methods: We studied pediatric HIV patients at Tygerberg Academic Hospital experiencing virologic failure on a PI regimen. Mixed-effects linear- and mixed-effect logistic regression modeling, were used to explore predictors of MPIRM. Results: MPIRM were found in 12 of 17 patients exposed to RTV-sPI compared with 1 of 13 patients treated with LPV/r. Exposure to RTV-sPI was significantly associated with MPIRM, with both exposure time and estimated failing time on RTV-sPI being significant positive predictors of MPIRM. Neither CD4 count, viral load, age at first visit nor receiving rifampin predicted MPIRM. Conclusions: RTV-sPI in infants and children poses a significant risk of MPIRM which is dependent on the exposure time and time failing while receiving the regimen.

The association of interleukin-18 genotype and serum levels with metabolic risk factors for cardiovascular disease.

OBJECTIVEnCirculating levels of interleukin (IL)-18 are associated with the metabolic syndrome and risk for the development of cardiovascular disease (CVD). This study investigated the association between the circulating IL-18 levels and the -137 G/C polymorphism within the IL-18 gene with metabolic risk factors for CVD in normal-weight and obese black South African women.nnnMETHODSnBlood pressure (BP), body composition (dual-energy X-ray absorptiometer), visceral adiposity (computerized tomography), as well as fasting glucose, insulin, lipid profile, IL-18 levels, and IL-18 genotype were measured in 104 normal-weight (body mass index (BMI) < or = 25 kg/m2) and 124 obese (BMI > or = 30 kg/m2) black South African women.nnnRESULTSnSubjects with a GC genotype (23%) had a greater mean arterial pressure (MAP, 90.6+/-11.1 vs 85.5+/-10.3 mmHg, P<0.001) than the subjects with the GG genotype. Serum IL-18 levels were not associated with IL-18 genotype (P=0.985); however, they significantly correlated with percentage of body fat (r=0.25, P<0.001), visceral adiposity (r=0.32, P<0.001), MAP (r=0.22, P=0.001), HOMA-IR (r=0.33, P<0.001), fasting insulin (r=0.25, P<0.001), triglyceride (r=0.16, P<0.05), and high-density lipoprotein-cholesterol (r=-0.14, P<0.05) levels, after adjusting for age and body fatness.nnnCONCLUSIONSnWe show for the first time that the GC genotype of the IL-18 -137 G/C polymorphism and the circulating IL-18 levels are independently associated with raised BP. Moreover, fasting IL-18 levels are associated with the other metabolic risk factors for CVD in normal-weight and obese black South African women.

Antiretroviral resistance patterns and factors associated with resistance in adult patients failing NNRTI‐based regimens in the western cape, South Africa

Antiretroviral drug resistance in patients failing non‐nucleoside reverse transcriptase inhibitor (NNRTI)‐based first‐line combination antiretroviral treatment (ART) is influenced by: regimen choice, HIV‐1 subtype, detection of and response to therapy failure. In order to describe resistance patterns by genotypic testing, at the time of first‐line ART failure and to describe associations with having M184I/V, K65R, three or more thymidine analog mutations (TAMs) and etravirine (ETV) resistance, the prevalence of antiretroviral drug resistance associated mutations in a cross‐sectional study, at two South African public health clinic settings, at the time of virologic failure (HIV‐1 RNA load >400u2009copies/ml) are described. Also reported are associations of therapy choice, prolonged virologic failure, and concurrent HIV viral load and CD4 count with the presence of M184I/V, TAMs, K65R, and resistance to ETV. Of 167 adult patients with virologic failure on first‐line ART, 28 (17%) had no resistance, 137 (82%) had NNRTI resistance, 101 (60%) M184I/V, 20 (12%) TAMs, of which 4 had 3 or more TAMs, and 7 (4%) had K65R, of which 6 were on D4T and one on AZT. A prolonged estimated period of failure was associated with having ≥3 TAMs. Patients treated with nevirapine (NVP) were more likely to have ETV resistance than those treated with efavirenz (EFV). Major protease inhibitor mutations were not detected. A delayed response to ART failure may risk accumulation of TAMs in patients on an NNRTI‐based regimen. The use of NVP rather than EFV was associated with ETV resistance. J. Med. Virol. 83:1764–1769, 2011.

Associations Between Human Leukocyte Antigen Class I Variants and the Mycobacterium tuberculosis Subtypes Causing Disease

BACKGROUNDnu2003The development of active tuberculosis disease has been shown to be multifactorial. Interactions between host and bacterial genotype may influence disease outcome, with some studies indicating the adaptation of M. tuberculosis strains to specific human populations. Here we investigate the role of the human leukocyte antigen (HLA) class I genes in this biological process.nnnMETHODSnu2003Three hundred patients with tuberculosis from South Africa were typed for their HLA class I alleles by direct sequencing. Mycobacterium tuberculosis genotype classification was done by IS6110 restriction fragment length polymorphism genotyping and spoligotyping.nnnRESULTSnu2003We showed that Beijing strain occurred more frequently in individuals with multiple disease episodes (P < .001) with the HLA-B27 allele lowering the odds of having an additional episode (odds ratio, 0.21; P = .006). Associations were also identified for specific HLA types and disease caused by the Beijing, LAM, LCC, and Quebec strains. HLA types were also associated with disease caused by strains from the Euro-American or East Asian lineages, and the frequencies of these alleles in their sympatric human populations identified potential coevolutionary events between host and pathogen.nnnCONCLUSIONSnu2003This is the first report of the association of human HLA types and M. tuberculosis strain genotype, highlighting that both host and pathogen genetics need to be taken into consideration when studying tuberculosis disease development.

A pathway-based approach investigating the genes encoding interleukin-1β, interleukin-6 and the interleukin-1 receptor antagonist provides new insight into the genetic susceptibility of Achilles tendinopathy

Objectives Achilles tendinopathy (AT) is a multifactorial condition for which genetic risk factors have been identified. A pathway-based approach was used to investigate genes within the inflammatory pathway. Methods Functional polymorphisms within IL-1β (−31T→C and −511C→T), IL-1RN (variable number tandem repeat) and IL-6 (−172G→C) were investigated for associations with AT in a South African (SA) and Australian (AUS) case–control studies. A total of 369 (161 SA and 208 AUS) asymptomatic control participants (CON) and 175 (90 SA and 85 AUS) participants with AT (TEN) were genotyped. Allele combinations were constructed using the above polymorphisms in combination with the COL5A1 BstUI RFLP. Results Independently, no associations were observed between any of the polymorphisms tested and risk of TEN. The allele combinations of five polymorphisms were, however, found to have a highly significant relationship with AT (p=0.005), after adjusting for gender and country (SA or AUS). Conclusions Variations within the interleukin genes and the COL5A1 BstUI CC genotype are collectively significantly associated with risk of AT. This research emphasises that a pathway-based genetic association study may be a more effective approach to capture and understand the genetic risk factors underlying the multifactorial conditions, such as AT.