Residual Human Immunodeficiency Virus (HIV) Type 1 RNA and DNA in Lymph Nodes and HIV RNA in Genital Secretions and in Cerebrospinal Fluid after Suppression of Viremia for 2 Years

Residual viral replication persists in a significant proportion of human immunodeficiency virus (HIV)-infected patients receiving potent antiretroviral therapy. To determine the source of this virus, levels of HIV RNA and DNA from lymphoid tissues and levels of viral RNA in serum, cerebrospinal fluid (CSF), and genital secretions in 28 patients treated for ⩽2.5 years with indinavir, zidovudine, and lamivudine were examined. Both HIV RNA and DNA remained detectable in all lymph nodes. In contrast, HIV RNA was not detected in 20 of 23 genital secretions or in any of 13 CSF samples after 2 years of treatment. HIV envelope sequence data from plasma and lymph nodes from 4 patients demonstrated sequence divergence, which suggests varying degrees of residual viral replication in 3 and absence in 1 patient. In patients receiving potent antiretroviral therapy, the greatest virus burden may continue to be in lymphoid tissues rather than in central nervous system or genitourinary compartment

Residual Human Immunodeficiency Virus (HIV) Type 1 RNA and DNA in Lymph Nodes and HIV RNA in Genital Secretions and in Cerebrospinal Fluid after Suppression of Viremia for 2 Years

Residual viral replication persists in a significant proportion of human immunodeficiency virus (HIV)-infected patients receiving potent antiretroviral therapy. To determine the source of this virus, levels of HIV RNA and DNA from lymphoid tissues and levels of viral RNA in serum, cerebrospinal fluid (CSF), and genital secretions in 28 patients treated for ⩽2.5 years with indinavir, zidovudine, and lamivudine were examined. Both HIV RNA and DNA remained detectable in all lymph nodes. In contrast, HIV RNA was not detected in 20 of 23 genital secretions or in any of 13 CSF samples after 2 years of treatment. HIV envelope sequence data from plasma and lymph nodes from 4 patients demonstrated sequence divergence, which suggests varying degrees of residual viral replication in 3 and absence in 1 patient. In patients receiving potent antiretroviral therapy, the greatest virus burden may continue to be in lymphoid tissues rather than in central nervous system or genitourinary compartment

Neonatal Brain Injury and Neuroanatomy of Memory Processing following Very Preterm Birth in Adulthood: An fMRI Study

Altered functional neuroanatomy of high-order cognitive processing has been described in very preterm individuals (born before 33 weeks of gestation; VPT) compared to controls in childhood and adolescence. However, VPT birth may be accompanied by different types of adverse neonatal events and associated brain injury, the severity of which may have differential effects on brain development and subsequent neurodevelopmental outcome. We conducted a functional magnetic resonance imaging (fMRI) study to investigate how differing degrees of neonatal brain injury, detected by neonatal ultrasounds, affect the functional neuroanatomy of memory processing in VPT young adults. We used a verbal paired associates learning task, consisting of four encoding, four cued-recall and four baseline condition blocks. To further investigate whether differences in neural activation between the groups were modulated by structural brain changes, structural MRI data were also collected. We studied 12 VPT young adults with a history of periventricular haemorrhage with associated ventricular dilatation, 17 VPT individuals with a history of uncomplicated periventricular haemorrhage, 12 individuals with normal ultrasonographic findings, and 17 controls. Results of a linear trend analysis demonstrated that during completion of the paired associates learning task right frontal and right parietal brain activation decreased as the severity of neonatal brain injury increased. There were no statistically significant between-group differences in on-line task performance and participants' intelligence quotient (IQ) at assessment. This pattern of differential activation across the groups was observed particularly in the right middle frontal gyrus during encoding and in the right posterior cingulate gyrus during recall. Structural MRI data analysis revealed that grey matter volume in the right superior temporal gyrus, right cerebellum, left middle temporal gyrus, right globus pallidus and right medial frontal gyrus decreased with increasing severity of neonatal brain injury. However, the significant between-group functional neuroanatomical differences were not directly attributable to the detected structural regional differences

The PASTIS trial: testing tadalafil for possible use in vascular cognitive impairment

Introduction: There are few randomized clinical trials in vascular cognitive impairment (VCI). This trial tested the hypothesis that the PDE5 inhibitor tadalafil, a widely used vasodilator, increases cerebral blood flow (CBF) in older people with symptomatic small vessel disease, the main cause of VCI. Methods: In a double‐blind, placebo‐controlled, cross‐over trial, participants received tadalafil (20 mg) and placebo on two visits ≥7 days apart (randomized to order of treatment). The primary endpoint, change in subcortical CBF, was measured by arterial spin labelling. Results: Tadalafil increased CBF non‐significantly in all subcortical areas (N = 55, age: 66.8 (8.6) years) with greatest treatment effect within white matter hyperintensities (+9.8%, P = .0960). There were incidental treatment effects on systolic and diastolic blood pressure (–7.8, –4.9 mmHg; P < .001). No serious adverse events were observed. Discussion: This trial did not identify a significant treatment effect of single‐administration tadalafil on subcortical CBF. To detect treatment effects may require different dosing regimens

Testing the cognitive effects of tadalafil. Neuropsychological secondary outcomes from the PASTIS trial

Cerebral small vessel disease (SVD) is a major cause of cognitive impairment in older people. As secondary endpoints in a phase-2 randomised clinical trial, we tested the effects of single administration of a widely-used PDE5 inhibitor, tadalafil, on cognitive performance in older people with SVD. In a double-blinded, placebo-controlled, cross-over trial, participants received tadalafil (20 mg) and placebo on two visits ≥ 7 days apart (randomised to order of treatment). The Montreal Cognitive Assessment (MOCA) was administered at baseline, alongside a measure to estimate optimal intellectual ability (Test of Premorbid Function). Then, before and after treatment, a battery of neuropsychological tests was administered, assessing aspects of attention, information processing speed, working memory and executive function. Sixty-five participants were recruited and 55 completed the protocol (N = 55, age: 66.8 (8.6) years, range 52–87; 15/40 female/male). Median MOCA score was 26 (IQR: 23, 27], range 15–30). No significant treatment effects were seen in any of the neuropsychological tests. There was a trend towards improved performance on Digit Span Forward (treatment effect 0.37, C.I. 0.01, 0.72; P = 0.0521). We did not identify significant treatment effects of single-administration tadalafil on neuropsychological performance in older people with SVD. The trend observed on Digit Span Forward may help to inform future studies

Raltegravir with Optimized Background Therapy for Resistant HIV-1 Infection

Background: Raltegravir (MK-0518) is an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase active against HIV-1 susceptible or resistant to older antiretroviral drugs. Methods: We conducted two identical trials in different geographic regions to evaluate the safety and efficacy of raltegravir, as compared with placebo, in combination with optimized background therapy, in patients infected with HIV-1 that has triple-class drug resistance in whom antiretroviral therapy had failed. Patients were randomly assigned to raltegravir or placebo in a 2:1 ratio. Results: In the combined studies, 699 of 703 randomized patients (462 and 237 in the raltegravir and placebo groups, respectively) received the study drug. Seventeen of the 699 patients (2.4%) discontinued the study before week 16. Discontinuation was related to the study treatment in 13 of these 17 patients: 7 of the 462 raltegravir recipients (1.5%) and 6 of the 237 placebo recipients (2.5%). The results of the two studies were consistent. At week 16, counting noncompletion as treatment failure, 355 of 458 raltegravir recipients (77.5%) had HIV-1 RNA levels below 400 copies per milliliter, as compared with 99 of 236 placebo recipients (41.9%, P<0.001). Suppression of HIV-1 RNA to a level below 50 copies per milliliter was achieved at week 16 in 61.8% of the raltegravir recipients, as compared with 34.7% of placebo recipients, and at week 48 in 62.1% as compared with 32.9% (P<0.001 for both comparisons). Without adjustment for the length of follow-up, cancers were detected in 3.5% of raltegravir recipients and in 1.7% of placebo recipients. The overall frequencies of drug-related adverse events were similar in the raltegravir and placebo groups. Conclusions: In HIV-infected patients with limited treatment options, raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.

Rheumatoid arthritis - clinical aspects: 134. Predictors of Joint Damage in South Africans with Rheumatoid Arthritis

Background: Rheumatoid arthritis (RA) causes progressive joint damage and functional disability. Studies on factors affecting joint damage as clinical outcome are lacking in Africa. The aim of the present study was to identify predictors of joint damage in adult South Africans with established RA. Methods: A cross-sectional study of 100 black patients with RA of >5 years were assessed for joint damage using a validated clinical method, the RA articular damage (RAAD) score. Potential predictors of joint damage that were documented included socio-demographics, smoking, body mass index (BMI), disease duration, delay in disease modifying antirheumatic drug (DMARD) initiation, global disease activity as measured by the disease activity score (DAS28), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and autoantibody status. The predictive value of variables was assessed by univariate and stepwise multivariate regression analyses. A p value <0.05 was considered significant. Results: The mean (SD) age was 56 (9.8) years, disease duration 17.5 (8.5) years, educational level 7.5 (3.5) years and DMARD lag was 9 (8.8) years. Female to male ratio was 10:1. The mean (SD) DAS28 was 4.9 (1.5) and total RAAD score was 28.3 (12.8). The mean (SD) BMI was 27.2 kg/m2 (6.2) and 93% of patients were rheumatoid factor (RF) positive. More than 90% of patients received between 2 to 3 DMARDs. Significant univariate predictors of a poor RAAD score were increasing age (p = 0.001), lower education level (p = 0.019), longer disease duration (p < 0.001), longer DMARD lag (p = 0.014), lower BMI (p = 0.025), high RF titre (p < 0.001) and high ESR (p = 0.008). The multivariate regression analysis showed that the only independent significant predictors of a higher mean RAAD score were older age at disease onset (p = 0.04), disease duration (p < 0.001) and RF titre (p < 0.001). There was also a negative association between BMI and the mean total RAAD score (p = 0.049). Conclusions: Patients with longstanding established RA have more severe irreversible joint damage as measured by the clinical RAAD score, contrary to other studies in Africa. This is largely reflected by a delay in the initiation of early effective treatment. Independent of disease duration, older age at disease onset and a higher RF titre are strongly associated with more joint damage. The inverse association between BMI and articular damage in RA has been observed in several studies using radiographic damage scores. The mechanisms underlying this paradoxical association are still widely unknown but adipokines have recently been suggested to play a role. Disclosure statement: C.I. has received a research grant from the Connective Tissue Diseases Research Fund, University of the Witwatersrand. All other authors have declared no conflicts of interes

Subgroup and Resistance Analyses of Raltegravir for Resistant HIV-1 Infection

Background: We evaluated the efficacy of raltegravir and the development of viral resistance in two identical trials involving patients who were infected with human immunodeficiency virus type 1 (HIV-1) with triple-class drug resistance and in whom antiretroviral therapy had failed. Methods: We conducted subgroup analyses of the data from week 48 in both studies according to baseline prognostic factors. Genotyping of the integrase gene was performed in raltegravir recipients who had virologic failure. Results: Virologic responses to raltegravir were consistently superior to responses to placebo, regardless of the baseline values of HIV-1 RNA level; CD4 cell count; genotypic or phenotypic sensitivity score; use or nonuse of darunavir, enfuvirtide, or both in optimized background therapy; or demographic characteristics. Among patients in the two studies combined who were using both enfuvirtide and darunavir for the first time, HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 89% of raltegravir recipients and 68% of placebo recipients. HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 69% and 80% of the raltegravir recipients and in 47% and 57% of the placebo recipients using either darunavir or enfuvirtide for the first time, respectively. At 48 weeks, 105 of the 462 raltegravir recipients (23%) had virologic failure. Genotyping was performed in 94 raltegravir recipients with virologic failure. Integrase mutations known to be associated with phenotypic resistance to raltegravir arose during treatment in 64 patients (68%). Forty-eight of these 64 patients (75%) had two or more resistance-associated mutations. Conclusions: When combined with an optimized background regimen in both studies, a consistently favorable treatment effect of raltegravir over placebo was shown in clinically relevant subgroups of patients, including those with baseline characteristics that typically predict a poor response to antiretroviral therapy: a high HIV-1 RNA level, low CD4 cell count, and low genotypic or phenotypic sensitivity score. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

The risk of germline copy number variants (CNVs) in BRCA1 and BRCA2 pathogenic variant carriers in breast cancer is assessed, with CNVs overlapping SULT1A1 decreasing breast cancer risk in BRCA1 carriers.The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.Peer reviewe

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction