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25 páginas, 6 figuras, 2 tablas, Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele., This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the Supplementary Not

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele. © 2022. The Author(s).

Background: The identification of modifiable risk factors for Alzheimer’s disease (AD) is paramount for early prevention and the targeting of new interventions. We aimed to assess the associations between health conditions diagnosed in primary care and the risk of incident AD over time, up to 15 years before a first AD diagnosis. Methods: Data for 20,214 AD patients from the United Kingdom and 19,458 AD patients from France were extracted from The Health Improvement Network (THIN) database. For each AD case, a control was randomly assigned after matching for sex and age at dementia diagnosis. We agnostically tested the associations between 123 different ICD10 diagnoses extracted from health records and AD dementia, by conditional logistic regression. We focused on two time periods: 2 to 10 years vs. 0 to 2 years before the diagnosis of AD, to separate risk factors from early symptoms/comorbidities. Findings: We report odds ratios (ORs) for the association of AD with the various health conditions were calculated after Bonferroni correction for multiple comparisons. Ten health conditions were significantly associated with high odds ratios for AD when diagnosed 2 to 10 years before AD, in the British and French samples: major depressive disorder (OR 95% confidence interval (UK):1.23-1.46)), anxiety (1.25-1.47), reaction to severe stress (1.24-1.59), hearing loss (1.11-1.28), constipation (1.22-1.41), spondylosis (1.14-1.39), abnormal weight loss (1.33-1.63), malaise and fatigue (1.14-1.32), memory loss (6.65-8.76) and syncope and collapse (1.1-1.37). Depression was the first comorbid condition associated with AD, appearing at least nine years before the first clinical diagnosis of AD, followed by, anxiety, constipation and abnormal weight loss. Interpretation: These results from two independent primary care databases provide new evidence on the temporality of risk factors and early signs of Alzheimer’s disease. These results could guide new dementia prevention strategies. Funding: Grants ANR-10-IAIHU-06 and ANR-19-P3IA-0001. Declaration of Interest: SE reports personal fees from Biogen, Eisai, Roche, and GE Healthcare, for presentations or participation to advisory boards. FM, LG and BE are full time employees of Cegedim. Other authors declare no competing interests. Ethical Approval: The French database obtained approval for data collection from the French National Data Protection Authority (CNIL) in 2002. For the UK database, ethical approval was granted by the NHS South-East Multicentre Research Ethics Committee in 2003 (ref: 03/01/073) for establishment of the THIN database, and it was updated in 2011. The study was a retrospective analysis of secondary anonymised patient data only.

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-α and/or IFN-ω are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or IFN-ω (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients >80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or IFN-ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases. © 2021 The Authors, some rights reserved.

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P

IntroductionLate-onset Alzheimer’s disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly1, and risk is partially driven by genetics2. Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS)3–8. To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 × 10−7) indicating that additional rare variants remain to be identified.

Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 x 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

The gene encoding apolipoprotein E (APOE) on chromosome 19 is the only confirmed susceptibility locus for late-onset Alzheimer's disease. To identify other risk loci, we conducted a large genome-wide association study of 2,032 individuals from France with Alzheimer's disease (cases) and 5,328 controls. Markers outside APOE with suggestive evidence of association (P 10 5) were examined in collections from Belgium, Finland, Italy and Spain totaling 3,978 Alzheimer's disease cases and 3,297 controls. Two loci gave replicated evidence of association: one within CLU (also called APOJ), encoding clusterin or apolipoprotein J, on chromosome 8 (rs11136000, OR = 0.86, 95% CI 0.81-0.90, P = 7.5 × 10 9 for combined data) and the other within CR1, encoding the complement component (3b/4b) receptor 1, on chromosome 1 (rs6656401, OR = 1.21, 95% CI 1.14-1.29, P = 3.7 × 10 9 for combined data). Previous biological studies support roles of CLU and CR1 in the clearance of Β amyloid (AΒ) peptide, the principal constituent of amyloid plaques, which are one of the major brain lesions of individuals with Alzheimer's disease. © 2009 Nature America, Inc. All rights reserved.

Background and purposeWhite matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.MethodsHeritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies.ResultsA total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P

ObjectiveThe Multidomain Alzheimer Preventive Trial (MAPT study) was designed to assess the efficacy of isolated supplementation with omega-3 fatty acid, an isolated multidomain intervention (consisting of nutritional counseling, physical exercise, cognitive stimulation) or a combination of the two interventions on the change of cognitive functions in frail subjects aged 70 years and older for a period of 3 years. Ancillary neuroimaging studies were additionally implemented to evaluate the impact of interventions on cerebral metabolism (FDG PET scans) and atrophy rate (MRIs), as well as brain amyloïd deposit (AV45 PET scans).Design patients1680 subjects (mean age: 75.3 years; female: 64.8 %), enrolled by 13 memory clinics, were randomized into one of the following four groups: omega-3 supplementation alone, multidomain intervention alone, omega-3 plus multidomain intervention, or placebo. Participants underwent cognitive, functional and biological assessments at M6, M12, M24 and M36 visits. The primary endpoint is a change of memory function at 3 years, as assessed by the Free and Cued Selective Reminding test. All participants will be followed for 2 additional years after the 3-years intervention (MAPT PLUS extension study).Interventions1/Omega-3 supplementation: two soft capsules daily as a single dose, containing a total of 400 mg docosahexaenoic acid (DHA), i.e., 800 mg docosahexaenoic acid per day, for 3 years. 2/ Multidomain intervention: collective training sessions conducted in small groups (6-8 participants) in twelve 120-minute sessions over the first 2 months (two sessions a week for the first month, and one session a week the second month) then a 60-minute session per month in the following three areas: nutrition, physical activity, and cognition until the end of the 3 years. In addition to the collective sessions, individualized preventive outpatient visits exploring possible risk factors for cognitive decline are performed at baseline, M12 and M24.Baseline populationFor cognition, the mean MMSE at baseline was 28.1 (± 1.6). About 58% and 42% of participants had a CDR score equal to 0 and 0.5, respectively. Regarding mobility status, 200 (11.9%) had a 4-m gait speed lower or equal to 0.8 m/s. According to the Fried criteria, 673 (42.1%) participants were considered pre frail, and 51 (3.2%) frail. The red blood cell DHA content was 26.1 ± 8.1 µg/g. Five hundred and three participants underwent baseline MRI. AV45 PET scans were performed in 271 individuals and preliminary results showed that 38.0% had a cortical SUVR > 1.17, which gave an indication of significant brain amyloïd deposit. DISCUSSION: The MAPT trial is presently the first largest and longest multidomain preventive trial relevant to cognitive decline in older adults with subjective memory complaints. The multidomain intervention designed for the MAPT trial is likely to be easily implemented within the general population.

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10−9, MIR2113; rs17522122, P=2.55 × 10−8, AKAP6; rs10119, P=5.67 × 10−9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10−6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10−17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer’s disease: TOMM40, APOE, ABCG1 and MEF2C.

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10−9, MIR2113; rs17522122, P=2.55 × 10−8, AKAP6; rs10119, P=5.67 × 10−9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10−6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10−17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer’s disease: TOMM40, APOE, ABCG1 and MEF2C. publishedVersion

© 2015 American Heart Association, Inc. Background-The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies. Methods and Results-We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10-19) and identified novel loci on chr10q24 (P=1.6×10-9) and chr2p21 (P=4.4×10-8). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10-8) and chr2p16 (P=1.5×10-8). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16). Conclusions-We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

PubMed ID: 25112663, Aims: Estimated central systolic blood pressure (cSBP) and amplification (Brachial SBP-cSBP) are non-invasive measures potentially prognostic of cardiovascular (CV) disease. No worldwide, multiple-device reference values are available. We aimed to establish reference values for a worldwide general population standardizing between the different available methods of measurement. How these values were significantly altered by cardiovascular risk factors (CVRFs) was then investigated. Methods and results: Existing data from population surveys and clinical trials were combined, whether published or not. Reference values of cSBP and amplification were calculatedas percentiles for 'Normal' (no CVRFs) and 'Reference' (any CVRFs) populations. We included 45 436 subjects out of 82 930 that were gathered from 77 studies of 53 centres. Included subjects were apparently healthy, not treated for hypertension or dyslipidaemia, and free from overt CV disease and diabetes. Values of cSBP and amplification were stratified by brachial blood pressure categories and age decade in turn, both being stratifiedbysex. Amplification decreased with age and more so in males than in females. Sex was the most powerful factor associated with amplification with 6.6 mmHg (5.8-7.4) higher amplification in males than in females. Amplification was marginally but significantly influenced by CVRFs, with smoking and dyslipidaemia decreasing amplification, but increased with increasing levels of blood glucose. Conclusion: Typical values of cSBP and amplification in a healthy population and a population free of traditional CVRFs are now available according to age, sex, and brachial BP, providing values included from different devices with a wide geographical representation. Amplification is significantly influenced by CVRFs, but differently in men and women. © 2014 Published on behalf of the European Society of Cardiology.

Background: We sought to identify optimal approaches by calibrating longitudinal cognitive performance across studies with different neuropsychological batteries. Methods: We examined four approaches to calibrate cognitive performance in nine longitudinal studies of Alzheimer's disease (AD) (n = 10,875): (1) common test, (2) standardize and average available tests, (3) confirmatory factor analysis (CFA) with continuous indicators, and (4) CFA with categorical indicators. To compare precision, we determined the minimum sample sizes needed to detect 25% cognitive decline with 80% power. To compare criterion validity, we correlated cognitive change from each approach with 6-year changes in average cortical thickness and hippocampal volume using available MRI data from the AD Neuroimaging Initiative. Results: CFA with categorical indicators required the smallest sample size to detect 25% cognitive decline with 80% power (n = 232) compared to common test (n = 277), standardize-and-average (n = 291), and CFA with continuous indicators (n = 315) approaches. Associations with changes in biomarkers changes were the strongest for CFA with categorical indicators. Conclusions: CFA with categorical indicators demonstrated greater power to detect change and superior criterion validity compared to other approaches. It has wide applicability to directly compare cognitive performance across studies, making it a good way to obtain operational phenotypes for genetic analyses of cognitive decline among people with AD. i 2014 S. Karger AG, Basel

Background Toll-like receptors (TLRs) are transmembrane receptors that activate cells of the innate immune systems upon recognition of pathogen-associated molecular patterns. The TLR4 is an essential component of the innate immune response to various microorganisms. We investigated the impact of TLR4 polymorphism on development of opportunistic diseases in HIV-infected patients. Methods The presence of TLR4 Asp299Gly single nucleotide polymorphisms (SNPs) was determined in a cohort of 180 antiretroviral treatment-naive HIV-1 infected patients and evaluated in relation to the occurrence of opportunistic infections. TLR4 genotyping was performed by real-time PCR. Results One hundred sixty-five patients were homozygous for the wild-type genotype (AA); 15 patients (8,3%) were heterozygous for the Asp299Gly SNP (AG). TLR4 polymorphism was associated with more frequent development of the opportunistic infections, such as active tuberculosis (OR=3.27; 95% CI [1.21–10.29]), herpes zoster (OR=4.15; 95% CI [1.24–7.29]) and toxoplasmosis (OR=6.23; 95% CI [1.19–18.67]) compared with genotype AA. In addition, TLR4 SNP was associated with development of opportunistic diseases among individuals with CD4 cell count of>100 cells/mm3, compared with homozygous HIV-infected patients (OR, 5.25; 95%, CI [2.28–10.47]). Conclusion This study suggests a greater risk of developing of active tuberculosis and other opportunistic infections in patients with the Asp299Gly TLR4 polymorphism., Background Diagnosis of acute HIV infection (AHI) is uncommon in resource limited settings. This abstract describes acute HIV infection in women in three East African countries. Methods Women at high risk of infection were recruited from ‘hot spots’ in Kericho (rural Kenya), Kampala (urban Uganda) and Mbeya (rural Tanzania). HIV negative eligible women were prospectively screened twice a week using HIV nucleic acid testing. A positive test led to entry into an intensive one-month diagnostic verification phase to definitively establish HIV infection status. Clinical and laboratory assessments were performed semiweekly. Supportive care and symptomatic treatment was provided. Results Overall, 1197 high-risk volunteers have enrolled to date with 37 cases of AHI identified (31 prior to detectable antibodies). Mean age at HIV acquisition was 24.4 years (range 18–34). Only six reported unprotected sex with a known HIV positive partner. Crude incidence was 2.77/100 PY (95% CI:±0.87). Of the 37 AHI cases; 14 presented with malaria-like symptoms (all smear negative), 7 flu-like symptoms while 16 had 1–2 mild complaints (8) or no symptoms (8). Overall, AHI cases were evaluated at 302 visits and at least one symptom was reported in only 75 visits (24.8%). Pregnancy did not increase the frequency of symptoms but dehydration due to vomiting resulted in 2 of the 3 hospitalizations observed. Conclusion Identification of AHI is feasible in East Africa. Young, rural, females are most vulnerable. Individuals with clinical syndromes suggestive of malaria, but excluded by microscopy, should raise index of suspicion for AHI. The majority of cases had few or no symptoms or brief non-specific symptoms not requiring medical intervention. Screening protocols based on malaria syndromic presentation would not identify the majority of AHI cases., Background The use of combination antiretroviral therapy (cART) has resulted in dramatic reductions in HIV-related mortality and morbidity. Nevertheless, despite sustained suppression of viral replication there remains evidence of increased levels of immune activation, particularly in patients initiating treatment during late-stage infection. We asked whether early initiation of therapy could potentially ameliorate this apparent limitation of cART. Methods 40 subjects identified as acutely or early HIV-1 infected were treated with either 3-drug cART (N=14) which included TDF/FTC, a ritonavir-boosted protease inhibitor (atazanavir or darunavir) or 5-drugs (N=26) cART as above with raltegravir and maraviroc. CD38 and HLA-DR expression on CD8+ T cells were determined by flow cytometry at baseline and weeks 48 and 96. Levels of sCD14 by ELISA were measured at weeks 48 and 96. These results were compared to values in 13 healthy, HIV-1 uninfected volunteers. Results A total of 29 subjects, 11 on 3-drugs and 18 on 5-drugs remained on therapy, suppressed and were available for analysis at 48 weeks. After 96-weeks 25 subjects, 9 on 3-drugs and 16 on 5-drugs were similarly analyzed. There are no statistically significant differences (Mann-Whitney, p, Background HIV controllers, maintaining low plasma HIV RNA levels (, Background HIV+ individuals in care with access to ART may experience a wider range of non-AIDS-related complications than previously. It is important to accurately classify causes of death, and monitor trends over time. Ratio ratio (95% CI) for underlying cause of death over calender time (reference=1999/2000)2001/20022003/20042005/20062007/20082009–2011 Total deaths Unadjusted0.98 (0.85–1.12)0.91 (0.79–1.04)0.69 (0.60–0.80)0.58 (0.50–0.67)0.48 (0.41–0.55)Adjusteda 1.06 (0.92–1.23)1.03 (0.89–1.18)0.80 (0.69–0.93)0.71 (0.61–0.83)0.66 (0.56–0.77) AIDS Unadjusted0.91 (0.71–1.16)0.88 (0.69–1.12)0.56 (0.43–0.72)0.44 (0.34–0.57)0.31 (0.24–0.42)Adjusteda 1.11 (0.87–1.43)1.20 (0.94–1.54)0.86 (0.66–1.11)0.82 (0.62–1.07)0.85 (0.64–1.13) Liver-related Unadjusted0.96 (0.67–1.37)0.71 (0.50–1.03)0.63 (0.43–0.90)0.46 (0.32–0.68)0.28 (0.18–0.42)Adjusteda 1.02 (0.70–1.47)0.80 (0.55–1.17)0.73 (0.49–1.07)0.59 (0.39–0.88)0.39 (0.25–0.61) Non-AIDS malignancyb Unadjusted1.18 (0.74–1.89)1.34 (0.84–2.11)1.16 (0.73–1.84)1.16 (0.73–1.83)1.09 (0.69–1.72)Adjusted1.10 (0.68–1.78)1.19 (0.75–1.90)0.95 (0.59–1.52)0.91 (0.57–1.46)0.83 (0.52–1.35) CVD-related Unadjusted1.07 (0.69–1.66)0.97 (0.63–1.51)0.77 (0.50–1.20)0.69 (0.44–1.07)0.46 (0.29–0.74)Adjusteda 0.99 (0.64–1.55)0.84 (0.54–1.32)0.62 (0.39–0.98)0.51 (0.32–0.82)0.31 (0.19–0.51) Other/Unknownc Unadjusted0.97 (0.76–1.25)0.90 (0.70–1.15)0.71 (0.55–0.92)0.59 (0.45–0.76)0.59 (0.45–0.76)Adjusteda 1.05 (0.82–1.36)1.00 (0.77–1.29)0.82 (0.63–1.07)0.71 (0.55–0.93)0.75 (0.57–0.99)Results from Poisson Regression Model.aAdjusted for (fixed) gender, age, ethnicity, riskgroup, HBV status, HCV status, smoking, diabetes, hypertension, (time-updated) viral load, BMI and CD4 count.bIncludes lung, prostate, anal, primary liver, GI, breast, uterus, testicular and bladder cancers, leukemias and Hodgkin's lymphomas.cAlt deaths that do not meet criteria for other categories. Methods Individuals from a large prospective cohort collaboration (D:A:D) were followed starting from 1999 until death, loss-to-follow-up or February 2011, whichever came first. Underlying causes of death were attributed based on the Coding of causes of Death (CoDe) system. Results 3,802 deaths occurred in 49,734 individuals followed for 304,695 person-years (rate=12.5/1000 person-years [95% CI 12.1–12.9]). Leading underlying causes were: AIDS-related (29%), non-AIDS-defining malignancies (NADM; 14%), liver disease (LD; 13%), cardiovascular disease (CVD; 11%), invasive bacterial infection (7%), drug overdose (3%), accidents (2%), renal disease (1%) and unknown (7%). Decreases over time occurred in rates of all-cause (17.4/1000 person-years in 1999–2000 to 8.3 in 2009–2011), AIDS-related (5.9−1.9), LD (2.7−0.8) and CVD-related (1.8−0.8) mortality. However, the rate of NADM deaths remained stable (1.5−1.6). After accounting for factors including current CD4 count (Table), there was still evidence of decreases over time in LD and CVD deaths, but not AIDS-related. The proportion of all deaths attributed to AIDS (34% in 1999–2000 to 22% in 2009–2011), NADM (9%–20%) and LD (16%–9%) changed over time. Conclusion Underlying causes of death have changed markedly over the last 12 years. AIDS remains the leading cause. Although there have been marked reductions over time in AIDS-related deaths, this effect is removed when accounting for current CD4 and other factors. NADMs are now the leading non-AIDS cause. Rates of LD and CVD-related deaths have decreased substantially, even after accounting for the factors listed below, suggesting other improvements in patient management during the study period. No trends in emerging causes of unexpected deaths were observed. Collection of specific causes of deaths is important to allow earlier interventions in HIV case management., Background US CDC guidelines recommend at least annual HIV testing for those at high risk. Nonadherence to testing guidelines and late diagnosis of infection may contribute to HIV transmission. Methods HPTN 061 is a feasibility study of a multi-component HIV prevention intervention for at-risk black MSM in 6 US cities. At enrollment, participants were offered HIV testing. Participants reporting past HIV-uninfected or unknown status at enrollment and no HIV testing within the prior 12 months were considered nonadherent to HIV testing guidelines. Participants with newly diagnosed HIV and CD4, Background Recent data showing a high incidence of HIV infection among men who have sex with men (MSM) who had been tested during the past year suggest that MSM might benefit from more frequent HIV screening (e.g., every 3 to 6 months). We assessed the cost-effectiveness of HIV screening at 3 and 6 month intervals compared with annual screening. Methods We used a published mathematical model of HIV transmission to evaluate screening intervals for a cohort of 10,000 MSM ages 14–64. We incorporated HIV transmissions averted due to serostatus awareness for each screening interval (e.g. 3, 6, 12 months), as well as HIV testing costs and treatment costs for averted transmissions. We assumed an HIV incidence of 1.27% for MSM and conducted threshold analyses on incidence. We assumed conventional testing with a 3rd generation antibody test and 75% receipt of results. In sensitivity analyses, we investigated the impact of all rapid testing and 100% receipt of results. We valued each HIV transmission averted using lifetime treatment costs of $367,134. Results Compared to annual screening, conventional HIV testing every 3 months and 6 months averted 2.04 and 1.36 HIV transmissions, respectively, and both were cost-saving. The incremental cost-effectiveness of 3-month versus 6-month screening also was cost-saving. Threshold values for HIV incidence at which screening was cost-saving were 0.3% and 0.5% at the 3-month and 6-month screening intervals, respectively. Screening with a rapid test was cost-saving at both 3- and 6-month intervals compared to annual screening. The incremental cost-effectiveness of 3-month versus 6-month screening was $813 per QALY saved. Every 6 months compared to annually Every 3 months compared to annually Every 3 months compared to every 6 months HIV Screening Costs$97,340$284,574$187,233HIV Transmissions Averted1.362.040.68QALYs Saved8.7613.144.38HIV Treatment Costs Saved$500,149$750,223$250,074Incremental Cost-effectiveness RatioCost-savingCost-savingCost-savingCost-effectiveness of HIV Screening for MSM. Conclusion HIV screening with either conventional or rapid testing as frequently as every 3 months is cost-saving or very cost-effective. Reexamination of HIV screening intervals for MSM should be considered on the basis of the economic evidence., Background Pooling techniques have been advanced to improve the cost effectiveness of nucleic acid testing for diagnosis of serologically undetectable acute HIV infections in resource limited settings. Previously reported methods have relied on serum samples. The goal of this study is to develop and apply a novel dried blood spot (DBS) based RT-PCR pooling technique to facilitate household sample collection, efficient diagnosis, and treatment-as-prevention strategies in Mochudi, Botswana. Methods Laboratory-prepared DBS samples with plasma viral load >50,000 copies/mL are diluted with HIV negative DBS samples to generate estimates of sensitivity for pool sizes of 5, 10, 25, 50, and 100 samples. RT-PCR is performed using the Abbott RealTime HIV-1 assay. This analysis will inform the development of an acute HIV case detection pooling algorithm to be applied to all seronegative samples collected as part of a large prevention study cohort.Table 1Sensitivities of DBS pooled RT-PCR Mean copies per mL (95% CI) Pool size % Sensitivity 38680.96 (28170.00, 49191.91)510019965.30 (15020.37, 24910.23)1094.18735.91 (6800.21, 10671.61)2571.44992.78 (3579.63, 6405.93)5070.63121.21 (1676, 4566.20)10027.8 Results Preliminary findings based on 9 HIV positive samples used to create 90 pools, reflected sensitivities ranging from 27.8% for pools at 1/100 dilution to 100% for 1/5. We were able to detect the presence of an HIV positive sample in pools of 10 with a sensitivity of 94.1%. The difference in sensitivity between pool sizes of 25 and 50 was minimal. Conclusion We have demonstrated the feasibility of using DBS pooling for acute HIV diagnosis. Because acute HIV infection involves high viral loads, we can reasonably expect to detect acute cases >50,000 copies/mL in pools of 10 with 94.1% sensitivity. Although increasing pool size decreases sensitivities, the false negative rate during the acute window period could be significantly reduced even with the use of larger pools. Because secondary HIV transmission in acute and recent HIV infection may contribute significantly to the epidemic in Botswana, the potential for a treatment-as-prevention strategy would be facilitated by screening methods to detect acute HIV cases., Background In Kenya, HIV-1 viral load (VL) monitoring is commonly performed with the COBAS Amplicor using plasma specimens, but interest is growing in transitioning to real-time PCR (RT-PCR), including the COBAS Ampliprep/COBAS Taqman (CAP/CTM), using dried blood spots (DBS). RT-PCR has several advantages including full automation, lower detection limit, and broader measuring range. Benefits with DBS include sample collection via finger or heel stick, low biohazard risk, and specimen transportation under ambient conditions. Prior to implementation, a direct evaluation of the two assays using DBS field specimens is required. Methods This analysis compares sensitivity, specificity, negative (NPV) and positive (PPV) predictive values, concordance correlation, and agreement, as evaluated with Bland Altman analyses, between HIV-1 VL measurements using paired plasma and DBS specimens obtained from 512 HIV-1 infected treatment-naive pregnant women enrolled in the Kisumu Breastfeeding Study, and tested with the COBAS Amplicor and CAP/CTM assays. Results The sensitivity and NPV of VL detection in DBS specimens were higher with CAP/CTM (sensitivity: 100%, 95% CI: 99.1–100.0; NPV: 100%, 95% CI: 59.0–100.0) than COBAS Amplicor (sensitivity: 96.6%, 95% CI: 94.3–98.1; NPV: 58.8%, 95% CI: 40.7–75.4), with comparable PPV; 99.5%, 95% CI: 98.3–99.9 and 99.6%, 95% CI: 98.6–100.0 for the respective assays. The specificity of VL detection in DBS specimens was lower with CAP/CTM (77.8%, 95% CI: 40.0–97.2) than COBAS Amplicor (95.2%, 95% CI: 76.2–99.9). Good concordance and agreement were observed when testing paired plasma and DBS specimens (Figures 1 and 2).Figure 1 Concordance correlation analyses of HIV-1 viral load quantification among plasma and DBS specimens collected from patients enrolled in Kisumu Breastfeeding Study and tested with COBAS Amplicor and CAP/CTM. COBAS Amplicor plasma viral loads were used as reference group for comparison: a)vs. COBAS Amplicor DBS viral loads; b) vs. CAP/CTM plasma viral loads; c) vs. CAP/CTM DBS viral loads [Correlation plots]. Figure 2 Bland-Altman analyses to evaluate agreement in HIV-1 viral load quantification among plasma and DBS specimens collected from patients enrolled in Kisumu Breastfeeding Study and tested with COBAS Amplicor and CAP/CTM. COBAS Amplicor plasma viral loads were used as reference group for comparison. The difference between the reference and the comparision assay/specimen type were plotted against the average of the reference group and the comparision assay/specimen type o; a)COBAS Amplicor DBS viral loads; b) CAP/CTM plasma viral loads; c) CAP/CTM DBS viral loads [Bland-Altman plots]. Conclusion There was good correlation between DBS and plasma viral loads as well as between COBAS Amplicor and CAP/CTM. However, CAP/CTM had a better sensitivity compared to COBAS Amplicor. Our findings show that DBS may be an alternative sample type to plasma for viral load measurement, which could increase access to viral load monitoring in resource limited settings. Disclaimer The content and views in this abstract are solely the responsibility of the authors and do not necessarily represent the official views of the affiliated organizations, United States Government, or Government of Kenya., Background Routine viral load (VL) testing is not available or recommended for patients on HAART in India. The implications of not having routine VL testing are not known in this setting. Methods As part of a longitudinal adherence study, participants on first-line HAART in Bangalore, India were monitored every six months, for 24 months, with CD4 cell count, HIV VL, and genotype, if VL>1000copies/ml. Participants with virologic failure (VF) often continued on first line therapy due to local resource constraints. We compared the incidence of WHO-defined criteria for immunologic failure (IF) to VF, defined as two consecutive VL >1000 copies/ml or VL>10,000 copies/ml for those who had only one VL available. Results Five hundred nine participants were included in the study (63% male, median age 36, median duration on HAART at start of study 14 months). Forty (7.8%) experienced VF, 25 (6.1%) IF and 10 (2.0%) both VF and IF. The sensitivity of immunologic criteria to detect VF was 20%, specificity 95% and positive-predictive value 29%. Of the 40 participants with VF only, 18 developed new thymidine analogue mutations over the follow-up period during which they continued on first line therapy; 11 of 18 developed high- level NRTI resistance, which would preclude subsequent tenofovir use. In addition, six participants developed NNRTI mutations, which confer genotypic resistance to etravirine and rilpivirine. Conclusion WHO IF criteria have low sensitivity for detecting VF and presence of IF poorly predicts VF. Relying on CD4 count data alone would lead a substantial number of unnecessary switches to second-line therapy. A notable proportion of patients would be continued on first line therapy that they are already failing, jeopardizing future HAART options. Universal access to VL monitoring would avoid costly switches to second line therapy and preserve future therapeutic options., Background Rapid scale-up of antiretroviral therapy (ART) in Southern Africa has put enormous strain on health systems. Information about acquired drug resistance in treated individuals is important to monitor quality of programmes and to ensure that ART policies remain appropriate. The majority of resistance data so far have come from urban, hospital-based programmes; limited data have been reported from rural treatment programmes. Methods Adult (≥16 years) HIV-infected individuals with virological failure (2×VL>1000 copies/ml) on first-line NNRTI-based ART were enrolled from all 17 primary health care clinics of the Hlabisa ART Programme. Genotypic resistance testing was performed using the in-house SATuRN/Life Technologies system. Sequences were analysed and genotypic susceptibility scores (GSS) were calculated using RegaDB and Stanford HIVDB 6.0.5 algorithms. Results 187 adults enrolled between Dec 2010 and Dec 2011; median age 37 years (IQR 31–45); 70% female. Median time on ART 41 months (IQR 31–53); median time on failing regimen 30 months (IQR 20–42). 120 (64%) had never achieved full virological suppression (VL≤50 copies/ml). 160 (86%) individuals had ≥1 drug resistance mutation; 149 (80%) and 153 (82%) respectively had NRTI and NNRTI mutations. 72 (38%) had at least one thymidine analogue mutation (TAM) and 32 (17%) had ≥3 TAMs. 14 (7%) had other NRTI mutations that might impact on second-line therapy (K65R-12 (6%); Q151M-3 (2%)). The standard second-line regimen was substantially compromised (defined as GSS≤1.5) in 33 (18%) individuals. Conclusion There are high levels of acquired drug resistance associated with prolonged virological failure in this rural primary health care programme. Standard second-line regimens would be significantly compromised in almost one in five adults. This suggests a role for genotypic resistance testing in routine care but, more importantly, it highlights the need for increased attention to quality of care and adherence to virological monitoring guidelines., Background In assessing the cost-effectiveness of CD4 versus viral load (VL) monitoring strategies, the “resistance cost” associated with delays in identifying non-suppression must be considered, and would likely favor a VL strategy. Here we examined the extent of protease (PR) mutation accumulation according to duration of 2nd-line (2L) failure. Methods Since 2004, the Harvard PEPFAR/APIN Program has provided ART to over 85,000 people in Nigeria. Approximately 8% of patients have received protease inhibitor (PI)-based 2L therapy (mostly LPV/r). A subset of patients with VL failure, defined as 2 consecutive VLs >1000cpm after ≥6 months on 2L, underwent genotypic resistance testing. Accumulation of PR mutations according to time on failing regimen was determined. Results Of 6714 patients who received PI-based ART, 661 (9.8%) met virologic failure criteria. Genotypes were performed on 53 samples (median CD4 183; VL 30150 at 2L failure). Time on Failing 2nd-line Regimen Characteristic 0–12 months (n=15) 13–24 months (n=27) >24 months (n=11) Total (n=53) Age (years), median (IQR)43 (34–47)40 (34–43)42 (32–51)42 (33–46)% Female33%48%55%45%# ARVs previously used, median (range)6 (4–7)6 (4–8)6 (5–9)6 (4–9)Duration on 1L (months), median (IQR)23 (19–37)28 (16–37)16 (14–23)24 (15–35)Duration on 2L (months)12 (8–20)20 (18–22)36 (34–50)20 (16–34)Time Failing 2L Regimen (months)8 (6–11)18 (16–20)34 (32–40)17 (12–22)2L Adherence (%), median (IQR)89 (79–98)96 (87–100)91 (78–100)92 (84–100)Characteristics of Patients Failing 2L ART. Patients on non-suppressive 2L therapy for ≤12 months prior to genotype testing had a median of 3 (IQR, 1–5) International AIDS Society (IAS) PR mutations, compared with 6 (IQR, 0–6.5) among patients failing for >24 months. Patients developed a median of 1.1 (IQR, 0–2.3) IAS PR mutations per 6 months on failing 2L therapy. In 30% of failing patients no PR mutations were present, suggesting non-adherence; when these patients were excluded, the median number of IAS PR mutations/6 months increased to 1.8 (IQR, 1.1–2.8). For patients failing >24 months, high- or intermediate-level resistance to LPV/r and ATV/r was present in 64%, with 9% to DRV/r. Time on Failing 2L Regimen Protease Resistance 0–12 months (n=15) 13–24 months (n=27) >24 months (n=11) Total (n=53) Total # PR mutations, median (IQR)3 (1–5)2 (0–5)6 (0–6.5)3 (0–5)Major PR mutations0 (0–1.5)0 (0–3)3 (0–4)1 (0–3)Minor PR mutations2 (0.5–3.5)2 (0–2)2 (0–3)2 (0–2)High- or Intermediate-level PI Resistance, # (%)Lopinavir (LPV/r) and Atazanavir (ATV/r)4 (27%)12 (44%)7 (64%)23 (43%)Darunavir (DRV/r)0 (0%)4 (15%)1 (9%)5 (9%)# PR mutations/6 mo. on Failing 2L, median (IQR)2.7 (0.5–3.7)0.9 (0–1.8)0.8 (0–1.1)1.1 (0–2.3)# PR mutations/6 mo. on Failing 2L (No PR mutations excluded)3.4 (2.6–4)1.4 (0.8–2.3)1.1 (0.9–1.2)1.8 (1.1–2.8)Protease Mutation Accumulation by Time Failing. Conclusion This is the first report assessing the impact of duration of non-suppressive 2L therapy on the accumulation of PR resistance in a resource-limited setting. This information provides insight into the “resistance cost” associated with failing to switch non-suppressive 2L regimens, and highlights the issue of 3rd-line access., Background In the USA, CD4 cell counts and HIV-1 viral load (VL) have been tested concomitantly 2–4 times/year for persons receiving antiretroviral therapy (ART). With the advancement of effective HIV care, many individuals now have viral suppression and higher CD4 cell counts. After therapy is initiated, the CD4 cell count is used to monitor the need for prophylaxis against opportunistic infections and immunologic response to ART. We assessed whether CD4 cell counts may be performed less frequently after viral suppression of, Background Cryptococcal meningitis (CM) is a leading cause of death in AIDS patients in sub-Saharan Africa. Cryptococcal antigen (CRAG) can be detected weeks before symptom onset, and those who are asymptomatic but CRAG+ have a high risk of subsequent CM and mortality. A new CRAG point-of-care immunochromatographic lateral flow assay (LFA) is available that is remarkably easy to administer without laboratory infrastructure or expertise and has excellent sensitivity and specificity. Methods We assessed the cost-benefit of targeted CRAG screening for patients with CD4, Background Penicillium marneffei is an emerging dimorphic mycosis endemic in South and Southeast Asia, and a leading cause of mortality among HIV-infected people in the region. Factors governing the seasonal incidence of P. marneffei infection have yet to be identified, and may yield critical insights into possible reservoirs or modes of transmission. We used P. marneffei incidence data from Ho Chi Minh City (HCMC), Vietnam from 2004–2010, as well as high-resolution weather data, to identify climactic factors that could account for the observed seasonality of P. marneffei infection. Methods This study included all P. marneffei, Cryptococcus neoformans, and HIV-related admissions to the Hospital for Tropical Disease (HTD) in HCMC from 2004–2010, as well as temperature, humidity, wind, and precipitation data for the corresponding period. We used logistic regression modeling to identify factors significantly associated with P. marneffei and C. neoformans admissions. We also estimated the P. marneffei incubation period by incorporating different exposure-to-admission delays in our models. Results This analysis included 719 HIV-infected patients presenting with penicilliosis. P. marneffei admissions were closely associated with humidity (P, Background RIF upregulates CYP 450 isoenzymes and can lower EFV exposure, particularly if weight ≥50 kg, However, clinical data have not shown reduced HIV virologic suppression with 600 mg EFV+RIF. We conducted a nested PK study to evaluate EFV concentrations and virologic suppression in A5221 patients on EFV(600 mg) and RIF-based TB treatment. Table 1 Weight (kg) 4) compared to Whites(22.9% vs 3.9%;p=0.002). Conclusion Overall, RIFcoadministration was not associated with lower EFV trough concentrations; patients weighing ≥50 or ≥60 kg had lower EFV Cmin, but there was no association with subtherapeutic Cmin nor virologic suppression. These data from a multinational, predominantly non-White population do not support guidelines for weight-based dosing of EFV with RIF., Background HIV is the strongest risk factor for progressing from latent M. tuberculosis infection to tuberculosis (TB). 9 months of daily self-administered INH (9H) is efficacious but has low completion rates and may cause hepatotoxicity. PREVENT TB demonstrated that 3 months of once-weekly rifapentine 900 mg+INH 900 mg under direct observation (3HP) was at least as effective as 9H, but only 3% of the participants were HIV+, so enrollment of HIV+ persons was extended to adequately assess tolerability. Methods HIV+ persons ≥2 years old who were either tuberculin skin test positive or close contacts of TB cases were randomized to 3HP or 9H. Persons could not receive antiretroviral therapy (ART) for 90 days after enrollment. Participants were enrolled from the U.S., Brazil, Spain, Peru, and Canada between June 2001 and December 2010. Follow-up for TB continues through 2013. Results Of 4,128 participants enrolled with known HIV status and who received ≥1 dose of study therapy, 393 were HIV +: 207 in the 3HP and 186 in the 9H arm. In the MITT analysis (enrolled participants who were eligible), 178/201 (89%) HIV+ persons completed 3HP vs. 125/193 (65%) on 9H (P< 0.001). The proportion of participants with a serious adverse event (SAE), ≥1 AE, or hepatotoxicity was lower in 3HP than 9H (4 vs. 11%; P=0.006; 22 vs. 40%; P=0.004; 2 vs. 6%; P=0.03). Compared to 1,888 HIV-negative participants treated with 3HP, HIV+ persons were less likely to permanently discontinue treatment for any reason (11 vs. 20%; P, Background HIV and TB are threats to pregnant women and infants. Treatment with rifampin can reduce ART concentrations and increase risk of treatment failure and vertical transmission. We describe the pharmacokinetics (PK) and pharmacodynamics of EFV among pregnant HIV-infected women. Methods Prospective cohort of HIV-infected pregnant women with and without TB in Soweto. Women taking ART with EFV 600 mg had PK sampling at 37 weeks’ gestation or at delivery and then six weeks post-partum. EFV concentrations were measured in cord blood at delivery and in infants at 7 days. Post-hoc Bayesian estimates of PK parameters from nonlinear mixed-effects modeling with allometric scaling are reported. Results Among 41 HIV-infected pregnant women taking EFV ART, 19 received rifampin (TB/HIV) and 22 ART alone. Median age and weight were 29 years and 70 kg. For 35 women with pre-/peripartum EFV PK, median (IQR) estimated EFV trough (Cmin) was 1.31 (0.84, 1.86)mg/L, apparent oral clearance (CL/F) 13.62 (10.67, 18.44)L/h, and volume of distribution (Vd/F) 516 (440, 591)L. 31% had Cmin20 copies/mL (one had TB/HIV). Median cord blood EFV concentration was 1.09 (0.46, 2.38)mg/L. EFV concentrations were BLQ in 6/24 cord blood and 25/30 infant 7-day samples; both correlated with maternal concentrations. 0/35 infants were HIV-infected at 6 weeks. In mothers 6 weeks postpartum, median EFV Cmin was 1.75mg/L, CL/F 10.79L/h, and Vd/F 433L; 30% had Cmin, Background TMC207 (bedaquiline) (B) is a diarylquinoline in Phase 2 development to treat drug-sensitive and drug-resistant tuberculosis. It is being evaluated in novel combination regimens with an aim to minimize adverse interactions with antiretroviral therapy (ART). This study investigated the effect of enzyme inducers rifapentine (P) or rifampicin (R) on TMC207 pharmacokinetics.Geometric LS Means of Bedaquiline Confidence IntervalsTreatment GroupParameterWith InducerAloneMean Ratio90% ConfidenceRifapentine Group 1Cmax 2077333962.2(53.4, 72.5)AUC(0–1) 276126453142.3(37.8, 48.5)Rifampicin Group 2Cmax 2240371860.2(52.0, 69.8)AUC(0–1) 253146120941.4(37.7, 45.4)Results Table. Methods This was a 2-period, single-sequence drug interaction study performed in 2 groups of healthy subjects. Period 1 examined the PK of B and its M2 metabolite after a single 400 mg dose of B. Period 2 examined the effects of repeated doses of either P or R on the PK of B and M2. Subjects took P 600 mg (Group 1) or R 600 mg (Group 2) q.d. for 22 days. A single 400 mg dose of B was administered on Study Day 10 of period 2 followed by PK sampling for 14 days. Results 32 subjects were enrolled and 29 completed; B, alone, and in combination with P or R, was generally well tolerated. P and R both reduced the Cmax and AUC of B greater than M2. Conclusion Both P and R reduce the Cmax and AUC of single doses of B by approximately 58%. Future regimens with B to treat TB should avoid the inclusion of P or R. The development of B with R sparing regimens is ongoing., Background PA-824 (Pa) and bedaquiline (B) (TMC) are novel compounds in phase 2 development with established Early Bactericidal Activity (EBA) over 14 days. The study presented is an EBA study that evaluated these drugs alone or in combination with each other and with moxifloxacin (M) and pyrazinamide (Z) to identify a regimen with the potential to shorten treatment of TB in patients without the use of rifamycins or other drugs that interact adversely with antiretroviral Therapy (ART). Methods 83 participants enrolled (26% F, 74% M, including 6 HIV+) as five cohorts of 15 TB patients, each who received daily dosages of B alone, B with Z, B with Pa, Pa with Z and Pa with M and Z. A cohort of 8 patients received daily standard TB treatment (isoniazid, rifampin, Z and ethambutol: HRZE) as a control for the EBA quantitative mycobacteriology. The primary efficacy endpoint was the rate of change in number of colony forming units (CFU) of Mycobacterium tuberculosis per ml of sputum incubated on agar plates from serial sputum collections over the period Day 0 to Day 14. Results All cohorts had decreases in logCFU counts/ml of sputum from Days 0 to 14 that ranged from 1.2–2.7 over 14 days. While Z potentiated the activity of both B and Pa and compared favorably with the HRZE standard regimen, the cohort with the combination Pa-M-Z had numerically the greatest effect on CFU reduction. Conclusion The combination regimen of Pa-M-Z has potent bactericidal activity over 14 days in patients with pulmonary TB and has the potential to treat both Drug Sensitive- and Drug Resistant-TB (contains no INH or rifampicin) without adverse clinical interactions with ART. This regimen has been taken into an 8 week trial to treat DS- and DR-TB in patients with and without HIV infection., Background The impact of HIV on MDR-TB treatment outcomes in sub-Saharan Africa remains unclear where extensive rollout of highly active antiretroviral therapy (HAART) has occurred. We therefore compared the time to initial culture conversion among patients with and without HIV infection in a setting of individualized, ambulatory MDR-TB care in Botswana. Methods We performed a prospective cohort study of MDR-TB patients receiving ambulatory care at two public clinics in Botswana. The time to culture conversion and proportion converting were compared by HIV status using Cox proportional hazard ratios (HRs). Results 40 HIV-infected and 30 HIV-uninfected patients with MDR-TB and follow up cultures were identified. The median CD4+T-lymphocyte count of those with HIV was 215 cells/mm3 (IQR 129–347), and 36 (90%) were on HAART. 85% of HIV-infected and 83% of HIV-uninfected achieved culture clearance. The median time to initial culture conversion was 78 days (IQR 42–186) for HIV-infected and 95 days (IQR 70–133)for HIV-uninfected individuals [log rank p=0.62; unadjusted HR=0.9 (95% CI: 0.5 to 1.5)]. Adjusting for age, gender, TB treatment history and number of active antitubercular drugs used did not change this result [adjusted HR=0.8 (95% CI: 0.4 to 1.4)]. Toxicity was frequent in all subjects: ototoxicity occurred in 53% and 70%, neuropathy in 40% and 10%, and nephropathy in 25% and 7% of HIV-infected and uninfected patients, respectively. Neuropathy (p=0.005) & nephropathy (p=0.044) were significantly associated with HIV infection. Conclusion We found no difference in the proportion or time to initial sputum culture conversion between an HIV-infected and non-infected cohort of MDR-TB patients in Botswana. These results suggest that microbiologic outcomes among those with HIV can be comparable to those without HIV in similar settings with access to individualized TB treatment and HAART., Background Tuberculosis, the leading cause of death among HIV patients, is difficult to diagnose with smear microscopy. Xpert MTB/RIF, a near point-of-care, fully automated, nucleic acid amplification test for TB and for the detection of rifampin resistance, has been endorsed by WHO. Xpert has increased sensitivity compared with smear microscopy; however its cost-effectiveness and affordability in resource limited settings is still controversial. Methods Between August and December 2011, Partners in Hope integrated Xpert MTB/RIF alongside fluorescence microscopy for TB evaluation.Attribute of LaboratoryMicroscope typeTechnician experience and expertiseLaboratory staff workloadQuality of AFB MicroscopyPartners in HopeFluoroscenceAdvancedUsually manageableGoodStandard Malawian AFB laboratoryConventionalUsually limitedUsually overburdenedUsually poorAttributes of study laboratory and standard lab. All HIV-TB suspects were evaluated with spot AFB smear, morning Xpert and another spot smear. Patients were classified as smear-positive, indeterminate (only one scanty smear) or smear-negative based on Malawi TB Guidelines. Smear and Xpert results were compared to determine the number of excess cases detected by Xpert. Cost per excess case detected was calculated. Results 436 clinical samples were tested using Xpert. 417 were sputum samples and 19 extrapulmonary samples. Of 64 samples which tested positive by Xpert, 61 were sputum samples and 3 extrapulmonary samples. Corresponding smear results were available for 58 sputum samples. Table 1 shows a comparsion of Xpert and smear results. AFB smear Positive AFB smear indeterminate AFB smear negative Xpert positive (Total 58 with smears available)35158% of total positive60%26%14%Comparsion of Xpert and Smear results. 14% of the Xpert positive samples were smear negative and only diagnosed by Xpert testing. Another 26% of samples were indeterminate and Xpert helped confirm the diagnosis. No sputum yielded a positive smear and negative Xpert. Xpert increased detection by 16% if scanty smears are considered positive, or 65% if scanty smears are considered negative. Cost per smear negative case detected is shown in Table 2 (note the two calculations based on how scanty smears classified). Total smear negative sputum samples Smear negative with positive Xpert NNT to detect one smear negative Cost per test cartridge Total cost to detect one smear negative case with Xpert “Scanty” smears considered positive367846$20$920“Scanty” smears considered negative3822317$20$340Cost to detect one smear negative case. Conclusion Xpert MTB/RIF increased TB detection by 16%-65% compared to fluorescence microscopy in a well-equipped laboratory. The Xpert may perform differently in a less sophisticated laboratory. However, cost per case detected was high and not affordable in Malawi., Background Xpert® MTB/RIF is a new molecular diagnostic tool, developed to increase detection and shorten time to diagnosis of sputum-smear-negative (SSN) tuberculosis (TB). In April 2011, Médecins Sans Frontières (MSF) in collaboration with the Zimbabwean Ministry of Health and Child welfare implemented two Xpert® MTB/RIF systems in a rural district in Zimbabwe serving two hospitals and 26 decentralised primary care clinics. Methods From May to October 2011, parallel testing with both smear microscopy and Xpert® MTB/RIF was performed on specimens from all TB suspects. We used information abstracted from clinical and laboratory records to compare the number of laboratory-confirmed TB cases, number of TB notifications, and the time to diagnosis among HIV/TB co-infected patients with sputum-smear-negative TB during 6 months before and after Xpert® MTB/RIF implementation. Results A total of 1672 sputum specimens were processed, of which 184 (11.0%) were smear-positive. Mycobacterium tuberculosis was detected by Xpert® MTB/RIF in 116 (7.8%) of the 1488 remaining smear-negative specimens. Comparing the period after implementing Xpert® with the period before, the proportion of TB notifications that were smear positive (33% versus 27%), smear-negative (48% versus 49%), sputum not tested (11% versus 12%), and extra-pulmonary (8% versus 12%) was unchanged. The median time to TB treatment initiation among HIV/TB co-infected patients with sputum-smear-negative TB, decreased at decentralised sites (from 18.5 days to 7 days), but remained constant at the hospital level (5.5 days before and 6 days after). Conclusion Xpert® MTB/RIF increased the number of laboratory-confirmed TB cases in rural Zimbabwe, enabling further task shifting of TB management. In settings where access to chest X-Ray and trained doctors is lacking the impact on TB notifications may be greater. Time-to-initiation of TB treatment at the decentralized clinics was reduced, which has the potential to reduce morbidity in individuals and reduce the risk of TB transmission to others., Background Recently, WHO recommended that GeneXpert MTB/RIF be used as first line diagnostic to test for TB in HIV positive individuals. Most patients initiating ART lack the classical symptoms for TB resulting in missed diagnosis. The role of symptom screen in predicting a positive GeneXpert result among pre-ART patients was studied. Methods This was a nested cohort study within a GeneXpert impact evaluation trial in pre-ART patients. TB symptomatic and asymptomatic adults (>18 yrs) at an ART initiation clinic in Harare were recruited between October 2011 and February 2012. For each patient, two spot sputum samples were collected and induction with 6% hypertonic NaCl performed in those who could not expectorate. Sputum samples were tested with GeneXpert (Cepheid) Test. Participants were followed-up for 3months. Results 150 participants were recruited and 126 produced specimens and were tested for TB using GeneXpert. Median CD4 count was 165cells/ul (IQR 79–256). Fifty-four percent of the participants had a cough (68/126). Induction was carried out in 19 participants and of these, 47% (9/19) were coughers and 53% (10/19) non-coughers. TB was diagnosed in 10% of participants (13/126; 95% CI 4–16); with an additional 2 cases diagnosed on second GeneXpert test. Significant predictors of disease were cough of any duration (p=0.019), night sweats (p=0.03) and weight loss (p=0.04). Of those induced, 16% (3/19) had a positive GeneXpert result. Notably, induced samples accounted for 23% (3/13) of the TB cases detected. Three percent (2/58) of the non-coughers were GeneXpert positive. Seven participants (5%) with negative GeneXpert results were started on TB treatment based on clinical suspicion. Conclusion TB testing using GeneXpert in pre-ART patients, with sputum induction, should be carried out routinely regardless of patient TB symptom status. A two step screening test and Xpert testing algorithm is needed for scale-up of universal TB testing in pre-ART patients., Background PNU-100480 is a linezolid analog with superior bactericidal activity against Mycobacterium tuberculosis in the hollow fiber, whole blood and mouse models that is time-dependent and unaffected by resistance mutations for standard TB drugs. PNU-100480 neither induces nor inhibits CYP3A4. This study is its first in TB patients. Methods Sputum AFB smear positive South African patients (incl. HIV+ not requiring ART) were randomly assigned to PNU-100480 600 mg BID (N=25) or 1200 mg QD (N=25), or standard 4-drug therapy (HREZ, N=9) for the first 14 days of treatment. Sputum mycobacterial burden was monitored both as log CFU/ml and time to detection (TTP) in automated liquid culture system (MGIT). Results 20% of subjects were women; 7% were HIV+. All subjects completed assigned treatments. There were no treatment-related serious adverse events nor any permanent discontinuations or dose reductions due to laboratory abnormalities. There was no effect on the QT interval. At baseline, the mean log CFU/ml and TTP were 6.95 and 116 hrs, respectively. Changes in mycobacterial burden during treatment are shown below. Lines indicate estimates by mixed-effect model repeated measures (MMRM) analysis; shading indicates 90% CI. MMRM analysis revealed that the 90% CI after the full treatment period excluded zero for all 3 treatments and for both monitoring methods. Seven PNU-treated patients (14%) had transient, asymptomatic ALT elevations on day 14 to 2–3x ULN that subsequently returned promptly to normal; none met Hy's law criteria. Conclusion Treatment with PNU-100480 600 mg BID or 1200 mg QD reduced the mycobacterial burden in sputum during 14 days of treatment. Both treatments were safe and reasonably well tolerated. Further studies of PNU-100480 in tuberculosis are warranted. EBA., Background More than 80% of patients with multidrug-resistant tuberculosis (MDR-TB) in Tugela Ferry, South Africa are co-infected with HIV. Concomitant treatment for both diseases is recommended, but concern about severe and additive toxicities of MDR-TB therapy and ART has slowed acceptance of community-based treatment. Methods Confirmed MDR-TB patients were treated at home by an injection team and returned to the clinic monthly where they were screened for common adverse events (AEs). Severity was graded using the DAIDS toxicity table. Safety labs were drawn monthly and TSH was drawn every 3 months. We reviewed clinical and laboratory AEs for all patients between November 2008 and April 2011. We examined the incidence of each AE in 6-month time blocks and the within-patient trend of each AE over time. We compared those who received concomitant MDR-TB/ART treatment to those who received MDR-TB treatment alone. Results Of 91 MDR-TB patients, 55% were female; median age was 34 (IQR 29–41); and 84% were HIV co-infected. 74 patients (97% of HIV+) were receiving ART and median baseline CD4 cell count was 207 cells/mm3 (IQR: 89–411). Ninety-nine percent of patients reported at least one AE during treatment, but most were mild and did not require therapy modification. The most common AEs were peripheral neuropathy (73%), injection site pain (66%), and arthralgia (43%). The most common severe AEs (grade=3) were psychosis (10%) and hypothyroidism (29%). Patients receiving concurrent ART did not experience AEs more frequently than those on MDR-TB therapy alone. Patients were significantly less likely to report most AEs later in their treatment course (Figure 1).Figure 1 AEs by 6-month time blocks. Conclusion Home-based treatment of MDR-TB and HIV is associated with high rates of mild AEs which are not increased by concurrent ART and can be managed symptomatically without changing MDR-TB therapy or ART. Treatment can be safely administered in a home-based care setting., Background The effect of chronic hepatitis B (HBV) on HIV outcomes is relatively unknown in sub-Saharan Africa (SSA) where a high burden of HIV-HBV co-infection exists. Methods Clinical and immunologic outcomes in response to ART were compared longitudinally between HIV mono- (HIV+) and HIV-HBV co-infected (HIV&HBV+) adults enrolled between November 2004-December 2010 at 18 Management and Development for Health (MDH)-PEPFAR supported HIV clinics in Tanzania. Inclusion criteria were: tested ≥×1 for HbsAg (DIMA), age ≥15, no prior ART. Results The prevalence of HBV was 837/13,107 (6.4%).Compared to HIV+ patients, HIV&HBV+ patients were more likely to be male, older, have lower median CD4+ cell counts, and higher ALT's (p values 120IU/L [38/813 (4.7%) vs. 303/12,136 (2.5%); HR 1.76 (1.25, 2.49), p200IU/l [20/831 (2.4%) vs. 102/12,236 (0.8%); HR 2.74, (1.66, 4.05), p, Background Few studies have examined the natural history of chronic hepatitis C virus (HCV) infection among HIV-infected persons in the era of combination antiretroviral therapy (cART). Our objectives were to: 1) compare the incidence of hepatic decompensation between cART-treated HIV/HCV-coinfected and HCV-monoinfected patients, and 2) evaluate determinants of decompensation among coinfected patients on cART. Methods We performed a cohort study among 4,286 cART-treated HIV/HCV-coinfected and 6,639 HCV-monoinfected patients in the Veterans Aging Cohort Study Virtual Cohort (1997–2010). All patients had HCV viremia and were HCV treatment-naïve. Coinfected patients received cART for at least one year and had an HIV RNA result >500 copies/mL within 180 days prior to starting cART (to identify new cART initiators). Hepatic decompensation events (defined by diagnoses of ascites, spontaneous bacterial peritonitis, variceal hemorrhage, or hepatocellular carcinoma) and death were evaluated. Cox regression was used to determine the adjusted hazard ratio (aHR) of hepatic decompensation associated with cART-treated coinfection and evaluated baseline risk factors for decompensation (alcohol abuse, non-black race, diabetes mellitus, FIB-4 >3.25, hemoglobin3.25 (aHR=7.18 [5.12−10.07]), and baseline hemoglobin, Background HIV-1/HCV coinfected patients respond poorly to pegylated interferon(PEG-IFN) and weight-based ribavirin(WBR), with sustained virologic response(SVR) of 27% in genotype 1 HCV treatment-naïve subjects (ACTG 5178 results). Nitazoxanide(NTZ) plus PEG-IFN and WBR has demonstrated improved efficacy in HCV monoinfected subjects. We hypothesized that addition of NTZ to PEG-IFN/WBR would improve HCV virologic responses in HIV-1/HCV co-infected persons. Methods HIV-1/HCV genotype 1 co-infected subjects naïve to HCV treatment received 4-week lead-in of NTZ(1000 mg/day) followed by 48 weeks of NTZ, PEG-IFN alfa-2a(180 µg/week) and WBR(1000–1200 mg/day). SVR was defined as undetectable serum HCV RNA (, Background The objective of this study was to examine the immunogenicity of the HPV-6, -11, -16, -18 vaccine in HIV-infected young women. Methods This phase II, open-label, multi-center trial was conducted through the Adolescent Trials Network for HIV/AIDS Interventions. Participants were 16-23 year-old women behaviorally infected with HIV. Two groups were enrolled: Group A (ART naÿ or had not received HAART for at least six months prior to study entry) and Group B (had received HAART for at least 6 months, with two HIV-1 RNA plasma viral loads, Background HIV-infected women are disproportionately affected by human papillomavirus (HPV)-related anogenital disease. A5240 is a clinical trial of 319 HIV-infected women at US, Brazil and South Africa sites to determine immunogenicity and safety of the quadrivalent HPV vaccine. Methods Safety and serostatus of HPV types 6, 11, 16, and 18 were examined in 222 women. The vaccine was administered at 0, 8, 24 weeks in 3 strata based on screening CD4: >350 (A), 201-350 (B), ≤200 cells/mm3 (C). HPV serotyping was performed using competitive Luminex Immuno-Assay (HPV-4 cLIA). HPV type-specific seroconversion analysis was on participants seronegative for the given type at baseline. Seroconversion was defined by: ≥20, ≥16, ≥20, ≥24 mMU/mL for types 6, 11, 16, 18 respectively. Two-sided 95% CIs are provided. Results We report preliminary safety and week 28 seroconversion results from A and B. At baseline, median age was 37 years (range 19–45), 13% were white, 57% black, and 29% Hispanic. Median nadir CD4 was 262 cells/mm3, 41% had undetectable HIV-1 viral load, 13% from non-US sites. No safety issues were identified; none of the grade ≥3 AEs was thought to be vaccine-related. Proportion of Women who Seroconverted 4 weeks After the Vaccination Series: HPV Type Baseline seronegatives 6 11 16 18 Stratum A CD4>350N=50N=79N=62N=73>Seroconversion proportion (95% CI)96% (86–99%)97% (91–100%)98% (91–100%)90% (81–96%)Geometric Mean Titers (95% CI)425 (289–627)454 (337–611)1088 (777–1524)160 (114–225)Stratum B 200200., Background Antiretroviral therapy (ART) reduces the risk of tuberculosis, but the incidence still exceeds that in HIV-uninfected people. Retrospective cohort studies suggest an additive benefit of isoniazid preventive therapy (IPT) in patients on ART, but there are no controlled data on the efficacy and safety of IPT for patients on ART. Methods Using a pragmatic randomized double-blind placebo-controlled study design, we evaluated the efficacy of IPT among HIV-infected participants established on ART or newly starting ART in Khayelitsha, South Africa. Participants were randomized to daily isoniazid or matching placebo for twelve months, and followed for up to four years. Tuberculosis was excluded at screening by sputum culture. Development of incident tuberculosis was the primary endpoint. Secondary endpoints included toxicities and deaths. Results 1,329 participants contributed 3227 person-years (PY) of follow-up in the modified intention to treat analysis; 662 on placebo and 667 on IPT, with comparable CD4+count and proportion starting ART. Overall there were 95 incident tuberculosis cases: 3.6 (95% CI 2.8–4.7) versus 2.3 (95% CI 1.6–3.1) per 100 PY in the placebo and IPT arms respectively (HR 0.63, 95% CI 0.41–0.94, p=0.026). Study drug was discontinued due to pre-specified toxicity in 2.5% in the placebo arm and 4.1% in the IPT arm (logrank p=0.13). The number of deaths was similar between arms (3.0% and 2.1 respectively, logrank p=0.29). Conclusion Under field conditions, twelve months of IPT reduced the incidence of TB without causing excess harm in HIV-infected individuals established on ART or newly starting ART. It is feasible to implement IPT in busy ART clinics in settings with high HIV/TB co-morbidity., Background With improved survival of HIV-infected children, neurocognition is an important area to address. We examined the effects of HIV infection on cognitive, neurological, and behavioral functioning on perinatally-infected children. Methods HIV-infected children (4–15yrs) were recruited from a tertiary-care center in India, along with age-gender-and-income-matched HIV-negative children. Assessment tools included (i) soft neurological signs: Physical and Neurological Examination for Soft Signs (PANESS); (ii) neurocognition: culturally-adapted Wechsler Preschool and Primary Scales of Intelligence (WPPSI), Wechsler Intelligence Scale for Children (WISC-III); (iii) adaptive behaviour: Vineland Adaptive Behaviour Scales (VABS). Results We studied 167 children, (82 HIV-infected, 85 HIV-uninfected) with 56% males and mean age 8.6 yrs. Total IQ scores were lower among HIV-infected children compared to HIV-uninfected children (74.9 12.9 versus 87.915.4, p20%, (IQ 77.112.8, p=0.03). Viral load and ART status has no effect on IQ scores. Multivariate regression revealed that HIV status, weight-for-age Z-score and hemoglobin were independent factors that affected IQ scores (adjusted r2=0.25, p=0.006). The presence of HIV infection independently decreased IQ scores by 9.22 units. PANESS scores were higher among HIV-infected children compared to uninfected children (HIV-positive: 7.5, [3, 13.3]; HIV-negative: 4, [1.5, 9.5], p=0.02) suggesting higher degree of subtle neurological abnormalities in this group. Adaptive behaviour scores were similar for both HIV-infected and uninfected children irrespective of age and sex. Conclusion HIV-infected children had lower IQ scores and higher prevalence of soft neurological signs compared to HIV-uninfected children, indicating that subtle neurocognitive impairment is an important feature of perinatally-acquired HIV infection, particularly those with poor nutritional status. We recommend routine neurocognitive assessment and suggest that early intervention with initiation of ART before the onset of severe immunosuppression may improve outcomes in these children., Background HIV infected patients receiving combination antiretroviral therapy are at higher risk of cardiovascular morbidity and have accelerated aging notably of cognitive functions. The link between cardiovascular risk factors and cognition has rarely been investigated in HIV-infected cohorts. In a large hospital-based cohort, we explored whether cardiovascular risk factors are associated with cognitive performances. Methods The ANRS-CO3 Aquitaine Cohort recruits patients through a hospital-based information system on HIV-1 infection in the Bordeaux University Hospital in the Aquitaine region, South Western France. Between 2007 and 2009, 403 patients participated in a sub-study and had a thorough assessment of several cognitive domains. Cognitive performances were analyzed using both the raw test scores and the presence of neurocognitive impairment (NCI), based on the most recent definition of HIV-associated neurocognitive disorders. Selected cardiovascular risk factors were type 2 diabetes, hypertension, hypercholesterolemia, smoking status and BMI. Covariance analyses were computed to investigate the association between cardiovascular risk factors and raw cognitive test scores, adjusting for potential confounders. Logistic regression with the same covariates was used to analyse NCI as dependent variable. Results Mean age was 47.3 years and 79% were male. The prevalence of cardiovascular risk factors ranged from 9.7% for diabetes to 49.6% for current smoking, and 37.7% of participants had NCI. Lower performances in all cognitive tests were related to older age and lower education. Among cardiovascular risk factors, diabetes was significantly associated with lower performances in all cognitive tests after adjusting for potential confounders. By contrast, no such consistent associations were noted for any other cardiovascular risk factors. Diabetes prevalence did not significantly differ by NCI status (p=0.44). Conclusion In this hospital-based cohort, diabetes, but not the other cardiovascular risk factors, is associated with lower performances in all assessed cognitive domains. The mechanisms underlying our findings remain to be clarified but could involve inflammation and microcirculation., Background Current literature indicates that infection with HIV contributes to an increased risk of acute stroke. The goal of this study is to compare clinical and epidemiological characteristics of stroke patients with and without HIV infection. Methods We performed a retrospective chart review of stroke patients who were admitted to the stroke unit between January of 2005 and June of 2011. We identified 43 patients with known HIV infection at the time of admission for acute stroke. 101 controls were randomly selected from non-HIV patients who had acute stroke within the same time period. Clinical and epidemiological characteristics of two groups were compared. Results Of 1679 admissions with acute stroke, 43 (2.6%) were in HIV-infected patients (32 males, 11 females) and 101 in non-HIV infected patients (45 males, 56 females). Mean age was 57.8 years and 72.6 years, respectively. All 144 patients had acute ischemic stroke confirmed by imaging. Significant difference was identified in age, race, blood pressure on admission, National Institute of Health Stroke Scale (NIHSS) on admission, and HDL level (Table 1). The presence of co-morbidities (HTN, DM, hyperlipidemia), body mass index (BMI), homocysteine level, LDL, and coagulation profiles were not statistically different between two groups. In the HIV+ group, 30 patients (83%) were taking HAART prior to stroke onset. CD4 count was available in 37 patients; 21 had CD4 >200 cells/mm3 and 16 had CD4< 200 cells/mm3 (mean CD4 count=329.7 cells/mm3).Table 1Results of Significant CharacteristicsCharacteristicHIV Positive Group(N = 43)HIV Negative Group (N = 101)P ValueAge-Mean (Range)57.8 (41–80)71.6 (34–99)0.001Male sex-no (%)32 (74.4%)45 (44.6%)0.007Race0.001Caucasian11 (45.8%)72 (72.7%)African American13 (54.2%)14 (14.1%)Asian0 (0%)13 (13.1%)NIHSS on admission5.399.090.03Systolic Blood Pressure on Admission142.18158.190.018HDL (mg/dl)40.7247.710.043 Conclusion HIV infection increases the risk of stroke in younger patients. They have lower blood pressure, HDL and NIH stroke scale on admission compared to HIV negative stroke patients. Prevalence of DM, HTN, hyperlipidemia and other metabolic factors were not significantly different in the two groups, although the relatively small sample size and retrospective nature of the study represent limiting factors., Background To further our understanding of anal lesions in relationship to HPV genotypes in HIV-infected men who have sex with men (MSM), we analyzed HPV genotype distribution in anal disease categories based on cytology and histology results. Knowledge of HPV genotype attribution can allow estimation of the preventable fraction of anal intraepithelial neoplasia (AIN) and may indicate disease misclassification. Methods 363 HIV-infected MSM underwent anal cytology and high-resolution anoscopy/biopsy at an anal cancer screening clinic. Anal disease categories were determined by combining histology and anal cytology results. We evaluated presence of HPV genotypes by Linear Array and estimated preventable fractions of anal lesions based on attribution to genotypes included in bivalent, quadrivalent, and nonavalent HPV vaccines. We explored classification of histology-cytology disease groups based on distribution of carcinogenic HPV genotypes using unsupervised hierarchical clustering. Results The proportion of carcinogenic HPV infections increased from 51.4% in MSM without AIN to 98.2% in those with AIN3. HPV16 was the most common HPV genotype overall (28.1%) and among MSM with AIN2/3 lesions (51.8%). The attribution fractions of AIN2/3 to genotypes included in HPV vaccines ranged from 56.4% (95% CI: 47.0–65.3) for the bivalent vaccine to 89.1% (95% CI: 81.9–93.7) for the nonavalent vaccine. (Table) In the exploratory clustering analysis, the disease group of normal histology/HSIL cytology and AIN1histology/HSIL cytology clustered with AIN2/AIN3 on histology based on the distribution of carcinogenic HPV types. (Figure).Figure 1 Unsupervised hierarchical clustering of AIN disease categories (various cytology-histology combinations) by distribution of carcinogenic HPV gentypes. Table 1Potential range of vaccine protection in a cross-sectional study of n=363 HIV-infected MSM: attribution schemes for AIN2/3* lesions to HPV genotypes in prophylactic HPV vaccines Prevalence of HPV vaccine genotypes in AIN2/3 lesions Cases with single carcinogenic HPV type1 Cases with any HPV type2 Hierarchical attribution fraction of AIN2/3 to HPV vaccine genotypes3 Genotypes in bivalent HPV vaccine: HPV16/18 36.7% (95% CI: 21.9–54.5) 61.8% (95% CI: 52.5–70.3) 56.4% (95% CI: 47.0–65.3) Genotypes in quadrivalent HPV vaccine: HPV16/18/6/11 40.0% (95% CI: 24.6–57.7) 70.0% (95% CI: 60.9–77.8) 56.4% (95% CI: 47.0–65.3) Genotypes in nonavalent HPV vaccine: HPV16/18/6/11/31/33/45/52/58 86.7% (95% CI: 70.3–94.7) 92.7% (95% CI: 86.3–96.3) 89.1% (95% CI: 81.9–93.7)*AIN2/3: refers to a diagnosis using a combined cytologic-histologic endpoint of AIN2 (AIN2 histology or HSIL-AIN2/ ASC-H cytology) or AIN3 (AIN3 histology or HSIL-AIN3 cytology); this does not refer to a histologic classification of “AIN2/3” (or moderate to severe dysplasia) which would be classified as AIN3 (based on automatic default to the more severe disease category in case of dual/intermediate disease classification).1Genotypes from cases in whom only a single carcinogenic type is detected, irrespective of additional possible/non/unknown carcinogenic types (n=30 cases of HO cases of AIN2/3).2Genotypes from cases in whom arty HPV type was detected (n=l09 cases of 110 cases of AIN2/3).3in ‘Hierarchical attribution’, HPV genotypes are attributed proportionally to the case by the most frequent type (according to hierarchical frequencies in the AIN2/3 category), This allows attribution of HPV genotypes to the disease category regardless of multiplicity of infections.. Conclusion A substantial fraction of high grade AIN can be prevented by prophylactic HPV vaccines. Both anal cytology and high resolution anoscopy followed by anal biopsy and histology have limited sensitivity for prevalent anal precancer. We demonstrate that combined histology-cytology disease categories can improve misclassification in cross-sectional studies. Our analytical framework can be useful to compare attribution of anal disease categories to HPV genotypes across various populations and to estimate the extent of disease misclassification., Background Maraviroc (MVC) is a CCR5 antagonist approved for the treatment of CCR5-tropic (R5) HIV-1. This study evaluated a once-daily (QD), dual-therapy regimen of MVC plus atazanavir/ritonavir (ATV/r) in treatment-naïve patients; 96-week outcomes are presented. Methods In this Phase 2b, randomized, open-label study, 121 R5 HIV-1-infected patients received either MVC 150 mg QD (n=60) or tenofovir/emtricitabine (TDF/FTC) 200/300 mg QD (n=61) with ATV/r 300/100 mg QD for 48 weeks, later extended to 96 weeks. The primary endpoint was the proportion of patients with HIV-1 RNA500 copies/mL at failure or study discontinuation; virologic analyses detected no resistance, change in tropism or loss of susceptibility relevant to treatment in either arm. At Week 48, there was a greater reduction in immune activation on CD4+ cells in patients receiving MVC versus TDF/FTC. Markers of bone formation were significantly different between arms at both 48 and 96 weeks. Conclusion Durable virologic activity of MVC 150 mg QD+ATV/r was demonstrated through 96 weeks, with no differences between the arms in the rates of virologic failure, no resistance or change in tropism seen, and with most of the treatment difference due to low-level transient viremia. Differences between the arms in immune activation and bone markers require further investigation., Background Cobicistat is a novel investigational pharmacoenhancer with no anti-HIV activity. Methods An international, randomized, double-blind, double-dummy, active controlled trial was conducted to evaluate the efficacy and safety of cobicistat vs ritonavir as pharmacoenhancers of atazanavir (ATV/co vs ATV/r group) in combination with tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) in treatment-naïve patients. Key eligibility criteria were HIV-1 RNA ≥5,000 copies/mL, estimated glomerular filtration rate by Cockcroft-Gault formula (eGFR) ≥70 mL/min. Primary endpoint was HIV-1 RNA 100,000 copies/mL, the response rates were similar (86 vs 86%). Two subjects in ATV/co and none in ATV/r group developed resistance mutations to study drugs; both were M184V/I. Similar percentages of subjects in both groups (ATV/co vs ATV/r) had serious adverse events (AEs) (11 vs 7%), discontinued study drug due to any AEs (7 vs 7%), or had bilirubin-related AEs (4 vs 3%). Median increases in total bilirubin at Week 48 in ATV/co and ATV/r group were 1.9 and 1.7 mg/dL. Median increases in serum creatinine were 0.13 and 0.09 mg/dL. Median increases in total cholesterol were 4 and 10 mg/dL; increases in triglycerides were 16 and 24 mg/dL. Plasma exposures of ATV (steady state mean Ctau [ng/mL]) were comparable (796.1 vs 853.4). Conclusion ATV/co was noninferior to ATV/r in combination with TDF/FTC at Week 48. Both regimens achieved high rates of virologic success. Safety and tolerability profiles of the two regimens were comparable. ATV/co (n=344) ATV/r (n=348) Age (years), median3637Male83%83%Race-White58%62%HIV-1 RNA (log10copies/mL), median4.784.84HIV-1 RNA >100,000 copies/mL38%41%CD4 count (cells/mm3), median348341CD4 count ≤200 cells/ mm3 17%16%Baseline Characteristics. ATV/co (n=344) ATV/r (n=348) Snapshot Analysis85%87%Snapshot Analysis (Per Protocol)98%98%Time to Loss of Virologic Response83%85%Missing=Failure89%90%Missing=Excluded97%96%Efficacy at Week 48 (HIV-1 RNA, Background Antiretroviral regimen simplification improves both quality of life, and long-term medication adherence while reducing the risk of HIV virologic failure (VF) and long-term drug-related toxicities. FTC/RPV/TDF is a well-tolerated, once daily STR treatment option. This is the first study to evaluate the efficacy and safety of switching from boosted Protease Inhibitor (PI) based HAART to a simplified regimen of FTC/RPV/TDF STR. Methods A randomized, open-label, multi-center, international, 48 week study to evaluate the safety and efficacy of switching from ritonavir-boosted PI regimens to FTC/RPV/TDF in virologically-suppressed (HIV RNA, Background Once-daily elvitegravir (EVG) was noninferior in efficacy and well-tolerated relative to twice-daily raltegravir (RAL) in combination with a fully active ritonavir-boosted protease inhibitor (PI/r) and another second agent in a phase 3 study of treatment-experienced patients (GS-US-183-0145) at Week 48. We present the blinded 96-week results. Methods Randomized, double-blinded, active-controlled, 96-week noninferiority trial. Key eligibility criteria were HIV-1 RNA ≥1,000 copies/mL, any CD4 cell count, and resistance to and/or 6 months’ experience with at least two classes of antiretroviral drugs. Primary endpoint was achievement and maintenance of HIV-1 RNA 5×ULN) were less common on EVG vs. RAL (2.3 vs. 5.9%; 1.7 vs. 5.3%). No other differences in graded laboratory abnormalities were seen. Conclusion At Week 96, once-daily EVG in combination with a fully active PI/r and another second agent in treatment-experienced patients continue to be noninferior to twice-daily RAL in efficacy with excellent tolerability. These data support the long-term use of EVG in treatment-experienced patients. TLOVR EVG (n=351) RAL (n=351) Virologic response47.6%45.0%Virologic failure22.8%27.4%Death0.6%2.6%Drug discontinuation26.5%20.8%Adverse events2.6%4.3%Lack of efficacy3.7%2.0%Lost to follow-up5.4%6.8%Other reasons17.4%12.0%Emerging major INSTI resistance6.6%7.4%Efficacy at Week 96 (HIV-1 RNA, Background The integrase inhibitor, Dolutegravir (DTG; S/GSK1349572), has shown rapid and durable antiviral response, with a favorable tolerability profile. Methods In this multicenter, double-dummy-blinded, Phase III, non-inferiority study, HIV-1 infected ART-naive adults with HIV-1 RNA ≥1000 c/mL and no evidence of viral resistance were randomized 1:1 to receive DTG 50 mg QD or RAL 400 mg BID, in addition to investigator-selected backbone NRTIs of either TDF/FTC or ABC/3TC. Subjects were stratified by screening HIV-1 RNA (≤ and >100,000 c/mL) and backbone NRTI selection. The primary endpoint was proportion of subjects with HIV-1 RNA100,000 c/mL, 41% ABC/3TC. Proportion of subjects meeting the primary endpoint was 88% for DTG and 85% for RAL; difference (2.5%; 95% CI: −2.2% to 7.1%) met 10% non-inferiority criteria. For subjects with HIV-1 RNA >100,000 c/mL, response rate was 82% for DTG vs 75% for RAL. Secondary analyses supported non-inferiority: HIV-1 RNA, Background AZT/3TC/NVP and TDF/3TC/NVP BID have been recommended 1st-line ART regimens in Rwanda. TDF/3TC/NVP is the least well studied of the WHO-recommended 1st-line regimens. We compared the efficacy of this regimen with AZT/3TC/NVP. Methods Between 2009 and 2011, we enrolled ART-naive patients. CD4 counts (cells/ul) and viral load (VL) were collected before ART and at 26 and 52 weeks. The primary endpoint was a VL 1000 copies/ml. Results 1,072 HIV+ ART-naive patients were enrolled: 521 (48.6%) received AZT/3TC/NVP (AZT), 551 (51.4%) received TDF/3TC/NVP (TDF). Median age was 37; 64% were women. Median baseline CD4 count was similar 260, VL was >100,000 copies/ml in 43% (AZT) vs. 32% (TDF) (p< 0.001). The AZT versus TDF, 5.4% vs. 3.8% transferred to others health facilities, 3.6% vs. 4.0% were lost to follow-up, and 1.9% vs. 2.7% died. 10%(AZT) vs 4%(TDF) of discontinued therapy due to adverse effects (p=0.001). The primary endpoint were: 80% (441/551) TDF and 78% (410/521) receiving AZT attained a VL < 200 copies/ml by week 52. The median CD4 count increase was 88 in the AZT and 50 in the TDF groups (p=0.034). However, in patients with baseline VL >100,000 copies/ml, 44% (133/351) in the TDF vs. 56% (170/351) in the AZT group attained the primary endpoint (p= 0.001). 11.8% (TDF) and 7.7% (AZT) underwent GRT. 58% had >=1 NNRTI-resistance mutation: most commonly Y181C (34%) and K103N (16%). 53% had >=1 NRTI-resistance mutation: most commonly M184V (48%) and K65R (29%). K65R emerged exclusively in the TDF group. Conclusion TDF/3TC/NVP was as effective as AZT/3TC/NVP at attaining, Background In the ECHO and THRIVE studies (HIV-1 treatment-naive patients), rilpivirine (RPV) 25mg qd and efavirenz (EFV) 600mg qd plus background N(t)RTIs resulted in a 78% response rate (viral load [VL], Background In 2009, South Africa's National AIDS Council recommended TDF access to HIV+ adults and ABC to HIV+ infants/children. We analyzed the effects of these guideline changes on NRTI-resistance mutations in ART virological failure (VF) and analyzed the effect of the cumulative second-line LPV/r use on emerging PI resistance. Methods HIV RT and PR sequences were obtained from plasma samples submitted for genotypic resistance testing to the Tygerberg National Health Service Laboratory between 2006 and 2011 from patients experiencing ART VF. Demographic and ART treatment data were obtained from the physicians submitting samples. Results Between 2006 and 2011, 1,525 plasma samples were obtained from 1,293 patients, of whom 57% were female and 42% =1 of the following major PI-resistance mutations: V32I, M46I, I47A, I50V, I54V, L76V, V82A/F, I84V, and L90M. 17 (4%) of 42 LPV/r recipients had major DRV/r resistance mutations (V32I, I50V, and L76V). Conclusion The increased use of TDF and ABC since 2009 has been associated with a markedly increased frequency of TDF-resistance (K65R) and ABC-resistance (L74V). Compared with TDF/3TC/EFV recipients, the risk of developing K65R was higher in patients with TDF/3TC/NVP VF (88% vs 31%; p=0.002) and lower in patients with TDF/3TC/LPV/r VF (7% vs 31%; p=0.008). Among 439 LPV/r recipients, 42 (10%) had LPV/r resistance and 17(4%) DRV/r cross-resistance., Background Since the availability of viral load (VL) assay with a threshold of 20 copies/mL, some patients display VL values between 20 and 50 copies/mL. The aims of our study were to: (i) identify factors associated with low level viremia (LLV) in patients receiving stable suppressive antiretroviral therapy (cART); and (ii) assess virological outcome during the year following LLV detection. Methods Retrospective study among the 4820 patients followed in our institution fulfilling the inclusion criteria: (i) stable cART for at least 6 months; (ii) all VL 50 copies/mL)/(number of VL determinations) before study inclusion. Results Among the 656 patients included, 5.8% were in group LLV+. The nature of the ongoing cART did not differ between LLV- and LLV+ groups. In the multivariate analysis, only CDC clinical stage B/C at study inclusion (OR=2.9; 95% CI=1.4–5.9; P=0.003) and a higher “Blip Ratio” before study inclusion (OR=0.9; 95% CI=0.9–1.0; P=0.001) were independently associated with LLV. During the follow-up, the proportion of patients experiencing virological failure (2 consecutive VL >50 copies/mL) was not different between LLV- and LLV+ groups (4% vs 8%, respectively; P=0.32); and 40% of patients shifted from LLV+ to LLV- status. Conclusion LLV was infrequent in our series and the one-year follow-up did not evidence a higher rate of virological failure than in patients always fully-suppressed. LLV seems to be a transient phenomenon that might be driven by residual ongoing viral replication and/or viral release and/or accuracy of VL assay in lower values., Background Alternatives to EFV for the treatment of HIV-infection in patients with TB are warranted. Rifampin decreases RAL exposure in healthy volunteers. We estimated the safety and efficacy of two doses of RAL and EFV in HIV-1-infected adults receiving rifampin for TB. Methods Multicentre, open-label, randomized, phase II trial. Antiretroviral naïve HIV-1-infected adults were randomized to receive RAL (400 or 800 mg bid) or EFV (600 mg qd), in combination with TDF and 3TC, after starting rifampin. The primary efficacy end-point was the proportion of patients with plasma HIV-RNA level50cp/ml was the main reason for failure and occurred in 6, 11 and 16 patients in RAL800, RAL400 and EFV, respectively. There was a trend towards more RAL, 3TC, and TDF resistance in the RAL400 than RAL800 arm. Safety of the three regimens was good with only 1, 1 and 3 grade 3/4 ALT elevations in RAL800, RAL400 and EFV arms, respectively. Conclusion At week 24, RAL800 mg bid provided the highest success rate in HIV-1-infected patients receiving a rifampin-based therapy for TB and should be considered for further evaluation., Background A5202 was a randomized equivalence study of four daily regimens of efavirenz (EFV) or atazanavir/ritonavir (ATV/r) with double-blinded tenofovir and emtricitabine or abacavir and lamivudine. Previous findings from A5202 reported women assigned ATV/r had higher-risk of virologic failure (VF) than women assigned EFV; also, women on ATV/r had higher risk of VF than men on ATV/r. This analysis relates ATV clearance (CL) to treatment efficacy and safety. Methods The associations between ATV CL and times to VF and safety event (first increased grade 3/4 sign, symptom, or laboratory abnormality), while on ATV/r (as-treated), were estimated with hazard ratios (HR) from Cox proportional hazards models, adjusted for screening HIV-1 RNA (105 copies/mL) and NRTIs. Additionally adjusted models included race-ethnicity (RE), age, baseline CD4 count, and body mass index. Interactions between ATV CL and sex, RE, and NRTIs were evaluated. A 1-compartment pharmacokinetic (PK) model including 815 subjects (88% of 928 randomized to ATV/r) was used to estimate subject-specific ATV CL. Atazanavir CL was categorized by overall sample tertiles (slow:¯9 L/hr). Analyses were restricted to 768 subjects of white, black, or Hispanic RE. Results Atazanavir CL association with time to VF differed significantly by sex (p=0.003, Table 1). The association between ATV CL and time to VF did not differ significantly by NRTIs (p=0.6) or RE (p=0.085); additionally adjusted model results were similar. There was no significant association between ATV CL and time to safety event (rapid vs. intermediate: HR 1.06; 95% confidence interval (0.79, 1.43); slow vs. intermediate: HR 1.28 (0.95, 1.72), p=0.22), nor a significant interaction with sex, NRTIs or RE for this outcome (p≥0.31). ATV Clearance Association with time to VF N=768: 131 females (28 VFs), 655 males (78 VFs) Comparison Hazard Ratio (95% Confidence Interval) Rapid (n=38) vs. Intermediate (n=29) among Female3.49 (1.24–9.84)Slow (n=64) vs. Intermediate among Female0.82 (0.26–2.54)Rapid (n=249) vs. Intermediate (n=210) among Male1.50 (0.82–2.71)Slow (n=196) vs. Intermediate among Male2.10 (1.16–3.77)*ATV CL by Sex Interation: p=0.003. Conclusion The differential in CL association with time to VF by sex may reflect PK/pharmacodynamic reasons for failure, and will require further investigations., Background Nevirapine (NVP) is metabolized by cytochrome P450 (CYP) 2B6. We investigated associations between single nucleotide polymorphisms (SNPs), haplotypes, and pharmacokinetics (PK) following SD NVP to prevent mother-to-child transmission (MTCT). Methods Protocol A5207 evaluated strategies to prevent NVP resistance following intrapartum SD NVP. At onset of labor, participants received SD NVP (200 mg) and were randomized to lamivudine/zidovudine, emtricitabine/tenofovir, or lopinavir/ritonavir (LPV/r), for 7 or 21 days. Plasma for NVP assay was obtained at post-partum day 1 and week 1, 3 and 5. Derived PK parameters included the NVP elimination constant estimated using linear mixed effect models based on natural logarithm of NVP measured between day 1 and week 3. We assayed 214 SNPs in ABCB1, CYP2B6, CYP2C19, CYP3A4, CYP3A5 and NR1I2. CYP2B6 metabolizer status was based on *6/*18 haplotypes. SNP and CYP2B6 haplotype associations were based on parametric regression models adjusted for body mass index and treatment arm as indicated. Results In A5207, 422 women in Haiti, India, Malawi, South Africa, Tanzania, and Uganda received SD NVP at onset of labor. This analysis includes 304 women (217 and 87 of African and Indian descent, respectively) with suitable NVP assay and genotype data. Among individuals of African descent, CYP2B6 metabolizer status was associated with slower NVP elimination (p =0.045), but not with week 5 NVP BLQ (below limit of quantification). Median elimination constants were −0.0105 (*6/*6 6/*18 or *18/*18*), −0.0108 (*6/− or *18/−), and −0.0113 (−/−) h−1. Among these individuals on LPV/r, an ABCB1 SNP (rs7787082) was associated with slower NVP elimination (p=0.0046). Among Indians, an NR1I2 SNP (rs2472682) was associated with increased likelihood of week 5 NVP BLQ (p=0.0061). Conclusion Slow metabolizer CYP2B6 genotypes were associated with slower elimination following SD NVP. This association appeared less pronounced than that described at steady state, suggesting effects on gene inducibility. Non-CYP2B6 SNP associations may be spurious., Background Prior studies investigating pharmacogenomics and efavirenz exposure use single plasma drug levels, which are limited by marked day-to-day variability. The Women's Interagency HIV Study (WIHS) performed 24 hour pharmacokinetics (PK) studies in a large number of HIV-infected women on efavirenz and calculated areas-under-the-curve (AUC) as measures of short-term exposure; concentrations in hair assessed long-term exposure. We typed 183 single nucleotide polymorphisms (SNPs) in 9 candidate genes known to influence efavirenz absorption, distribution, metabolism and elimination (ADME) and examined them in relation to AUC and hair levels in multivariate models. Methods Intensive PK studies were conducted in 111 women (74% African American; 17% Hispanic; 9% white). SNPs (n=183) with a minor allele frequency of >0.05 were analyzed in CYP2B6, CYP2C19, CYP3A4/A5, ABCB1, ABCC2, CYP2D6, SCL22A6, UDP, and UGT1A, along with other factors that could influence PK (race, age, menstrual status, diet, liver and renal function, weight). Hair efavirenz levels were measured in 84 women. Variables were examined with log-transformed EFV AUC and hair levels via linear regression; multivariable models were constructed by forward stepwise selection, including non-genetic predictors with p-values< 0.05 and genetic predictors with p-values< 0.001. Results Non-genetic factors, such as transaminase levels and orange juice consumption, were associated with EFV AUCs, but the most significant predictors associated with exposure were CYP2B6 516G>T, CYP2B6 983T>C and a p-glycoprotein transporter (ABCB1) haplotype (Table). CYP2B6 516TT (12.6% prevalence) was associated with 3.5-fold (95% CI 2.7–4.5, p=8.6x10−19) increases in AUC and 3.2-fold (2.1–4.7, p=1.3x10−11) increases in hair concentrations.Genetic and non-genetic factors associated with short-term EFV exposure (AUC, n=111) FactorEffect on AUC (±95% CI)p-valueDistribution of factorOranges or orange juice in preceding 5 days1.26 (1.05–1.50) 0.0119 76 (68.5%)For every doubling of ALT level1.23 (1.11–1.36) 0.0001 Median ALT (range) 23 (8–117) IU/LCYP2B6 983 T > C (rs28399499) 2.2×10 −10 0 doses of minor allele (TT)1.0095 (85.6%)–0 dose 1 or 2 doses of minor allele (TC/CC)1.96 (1.54–2.5)16(14.4%)–1 doseCYP2B6 516 G > T (rs3745274) 1.4×10 −18 0 or 1 dose of minor allele (GG, GT)1.0097 (87.4%)–0/1 dose 2 doses of minor allele (TT) 3.5 (2.7–4.5) 14(12.6%)–2 dosesABCB1 hdplotype (2SNPs:rs7779562 &rs4148745) 0.0004 0 doses of the haplotype1.0014 (12.6%)–0 dose 1 or 2 doses of the haplotype1.60 (1.24–2.1)97 (87.4%)–1/2 doses Factors associated with long-term exposure (hair levels, n = 84) -models include adherence Factor Effect on hair (±95% CI) p-value Distribution of factor ALT, Orange juice, ABCB1 haplotype, and adherence (below) not significantly associated with hair levelsCYP2B6 983 T > C ( rs28399499)0.021 0 doses of minor allele (TT)1.0074 (88.1%) –0 dose 1 or 2 doses of minor allele (TC/CC)1.70 (1.09–2.7)10 (11.9%)–1/2 dosesCYP2B6 516 G > T (rs3745274)1.0×10−10 0 or 1 dose of minor allele (GG, GT)1.0071 (84.5%) –0/1 dose2 doses of minor allele (TT) 3.2 (2.1–4.7) 13 (15.5%)–2 dosesSelf-reported adherence ≤74%1.004 (4.8%)75–94%0.94 (0.45–1.96)0.8813 (15.4%)≥95%1.10 (0.56–2.2)0.7767 (79.8%)Hair EFV PG table. Conclusion A comprehensive search for SNPs in genes associated with efavirenz ADME demonstrated that CYP2B6 516TT was associated with >3-fold increases in short-term (AUC) and long-term (hair) EFV exposure. The effect of this SNP on exposure over the prolonged duration represented by hair levels is reported for the first time. Genetic testing may allow optimization of EFV dosing., Background The pharmacokinetics of raltegravir in HIV-1 infected subjects is characterized by high inter/intra-patient variability. We investigated the potential contribution of the drug pharmaceutical formulation on raltegravir pharmacokinetics. Methods We firstly compared in vivo the pharmacokinetics of raltegravir from 50 patients given the drug by swallowing with those obtained from 10 HIV-infected patients that chewed raltegravir due to swallowing difficulties. Subsequently we evaluated in vitro the dissolution of raltegravir tablets under different conditions (pH 1, pH 6.8 buffer and water). Dissolution tests were performed comparing raltegravir whole tablets with tablets crushed by grinding in mortar and pestle. Results In the in vivo study we found that the raltegravir pharmacokinetic profiles in patients given the drug by swallowing were highly variable, characterized in some cases by multiple peaks and irregular/limited absorption. Conversely, patients given raltegravir by chewing presented regular pharmacokinetic profiles, characterized by single sharp drug peak and higher raltegravir absorption compared with patients given the drug by swallowing (Figure 1).Figure 1 Raltegravir time-concentration profiles in HIV-patients given the drug by swalling or chewing. The in vitro studies showed that the whole tablets presented relatively slow release profiles due to lacking disintegration. Crushed tablets tested in water and pH 6.8 buffer exhibited prompt and complete dissolution of raltegravir. For whole tablets tested in the acidic medium the raltegravir concentrations were very low, reaching less the 10% of the dose after 2h, owing to well-known poor solubility of raltegravir at low pH. However, when crushed tablets were tested in acid the profiles presented significantly higher concentrations of raltegravir (Figure 2)Figure 2 In vitro dissolution profiles of whole tabletes versus crushed tablets of raltegravir at different pH. . Conclusion HIV-infected patients given raltegravir by chewing showed higher drug absorption compared with patients given the drug by swallowing. This may be depends to problems related to the tablets disintegration leading to erratic drug release. The improvement of the raltegravir pharmaceutical formulation could reduce variability of raltegravir pharmacokinetics, eventually contributing to increase the response of HIV-infected patients., Background To inform optimal timing of ART initiation, we analyzed clinical outcomes during follow-up of HPTN 052 incorporating both AIDS and non-AIDS events related to HIV and ART. 052 WTS LB-K-M and table. Methods HIV+ adults (CD4+350 550/µL) from Africa, Asia, and South America were randomized to ART immediately or after CD4+, Background Nigeria's population of over 150 million and HIV prevalence of 3.8% ranks it among the top 5 countries with the highest HIV burden. Since 2004, HRSA has provided PEPFAR support to Harvard/APIN to develop a HIV prevention, care and treatment program at 32 hospitals in Nigeria. Methods ART eligibility in the adult program is consistent with the Nigerian and WHO ART guidelines. Enrolled patients that gave written informed consent with greater than 6 months of ART were included in this study. Patients had clinical exams and laboratory tests, at baseline, month 3, 6, and every 6 months thereafter. All patient data was collected and stored electronically. Treatment failure was defined as 2 consecutive viral loads > 1000 copies/mL following 6 months on ART. Results As of December 2010, 76,269 adult patients were enrolled on ART, 60,600 (79.5%) of which were ARV-naïve at baseline. Nine tertiary hospitals accounted for the majority of patients (53,406; 88.4%) with the remainder at 23 secondary. Female patients were more common (64.3%) and younger compared to men (median age 32 versus 39 years). Median baseline CD4 was 143 cells/mm3 and VL was 68,731 copies/mL. First-line ART for treatment-naïve patients included zidovudine (AZT) (51.6%), tenofovir (TDF) (35.3%) or stavudine (d4T) (7.5%) plus lamivudine/emtricitabine (3TC/FTC) plus an NNRTI - nevirapine (NVP) (68.4%)/efavirenz (EFV) (26%). The cumulative virologic failure rate for naïve patients was 21.4%, with the majority of failures occurring in the first year (56.9%). Applying the revised 2010 WHO recommendation defining virologic failure at > 5000 copies/mL, the cumulative failure rate was 13.6%, with 55.8% of failures in the first year. Virologic failure by time on ART. Conclusion Virologic failure rates were highest in the first year of ART and decreased with duration of ART. Particular emphasis on drug adherence and retention in care during the first year of ART may optimize patient outcomes., Background The second-line ART was rolled out in India in 2009 at 10 centers. Patients meeting immunologic/clinical failure criteria were evaluated by an expert panel and underwent viral load testing. Those found to have a confirmed virologic failure (VL> 5,000c/mL) were started on second-line ART (zidovudine/tenofovir/lamivudine/ lopinavir/ritonavir). We evaluated 18-month outcomes of patients started on second-line treatment. Methods Patients seen monthly and CD4 was performed every 6 months. VL testing was conducted 6 months after second-line ART initiation. We performed multivariable logistic regression modeling to determine factors associated with 6-month virologic suppression (, Background A large proportion of individuals enter health care very late in the course of their HIV-infection, these individuals have a poor clinical prognosis. This analysis aims to investigate trends in the percentage of individuals presenting late for care and identify factors associated with late presentation. Methods Individuals enrolled in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE), which includes 33 cohorts from across Europe, who presented for care for the first time after 1st January 2000 were included. Late presentation was defined, as a person presenting for care with a CD4 count, Background Lipoprotein Lipase (LPL) is a key enzyme in lipid metabolism, especially for plasma circulating triglycerides (TG). Genetic variants of LPL have been associated to lipid levels in healthy individuals, cardiovascular disease, obesity and diabetes. Our aim was to evaluate the influence of three polymorphisms: Hind III (intron 8), Pvu II (intron 6) and S447X (exon 9) in plasma TG levels in HIV-1 infected children under HAART. Methods 52 children (28 girls and 24 boys) diagnosed with HIV-1 between 2005 and 2009, were retrospectively selected with at least one plasma TG level assessment. Also, 86 seronegative blood donors were randomly selected to estimate allelic frequencies in Argentinean population. TG levels were examined before and after one-year of HAART. Hypertriglyceridemia was defined as TG>150 mg/dL. Hind III (H+/H−), Pvu II (P+/P−) and S447X (S/X) were determined by PCR-RFLP. Wilcoxon sum rank test was used to compare median plasma TG among groups. Results Allelic frequencies for HIV-1 infected children were: H-,0.21 P-, 0.53 and X: 0.05, with no significant difference to controls. After one year of HAART, median TG levels were significantly lower in P+/P− (144 mg/dL) and P−/P− (95 mg/dL) compared to P+/P+ (180 mg/dL) (p=0.03 and p= 0.0002, respectively). A gene dose-dependent effect was observed for P- allele, and its presence was associated with a 7-fold lower risk of hypertriglyceridemia. Additionally, when H-is accompanying P-, the risk diminished to 15-fold (p=0.008, OR=0.06, 95% CI=, Background There are limited data on the pharmacokinetics (PK) of tenofovir (TFV) administered to pregnant women during labor or to newborns. Methods HPTN 057 is a phase I trial of tenofovir disoproxil fumarate (TDF) in HIV-infected pregnant women and their neonates in Malawi and Brazil. In the current cohort, women received 600 mg TDF at labor onset or 4 hours prior to C section (C/S) and newborns received 6 mg/kg TDF suspension daily ×7 doses. Plasma samples were obtained from mothers at delivery, from cord blood and from infants before and 2, 10 and 24 hours after the 1st, 4th and 7th doses. TFV concentration (conc) was determined by HPLC/MS/MS; lower limit of quantitation was 5 ng/mL. The PK target was to keep infant TFV conc >50 ng/ml (mean trough conc in nonpregnant adults) for the first week of life. Data are presented as median (range) or geometric mean (%CV). Results 33 mother-infant pairs were studied (21 vaginal deliveries, 12 C/S). Delivery occurred median of 4.5 (0.6–11.4) hours after dosing. Mean maternal TFV conc at delivery was 108 (76.1%) ng/mL. Mean cord blood TFV conc was 61 (69.3%) ng/mL. Cord blood TFV conc was>50 ng/mL in 24/31 (77%). Mean ratio of cord blood to maternal delivery TFV conc was 0.55 (64.0%). Infant 24 hr postdose conc was>50 ng/mL in 28/31 (90.3%) after the first dose, in 27/28 (96.4%) after the 4th dose and in 22/30 (73.3%) after the 7th dose. All infant TFV conc were >30 ng/mL. All mothers and infants tolerated TDF well. Mean (CV%) infant PK parameters are presented below: Dose Cmax(ng/mL) C24h(ng/mL) AUC(ng*hr/mL) t½ (hrs) 1288 (49.9%)104 (47.9%)3939 (37.6%)13.2 (80.1%)4336 (40.5%)112 (52.1%)4413 (37.4%)14.5 (45.0%)7221 (66.1%)69.7 (45.7%)3060 (49.0%)14.6 (96.1%)Mean (CV%) infant PK parameters. Conclusion This regimen provides TFV exposure similar to adults receiving 300 mg daily doses and is appropriate for use in neonates in studies of TDF used for HIV prophylaxis or treatment., Background P1093, is an ongoing, Phase 1/2 open-label PK, safety dose finding study of DTG plus optimized background regimen (children 6 wks to, Background Pharmacokinetics, safety and antiviral activity of fosamprenavir (FPV)/ritonavir (RTV) twice daily were evaluated in protease inhibitor (PI)-naive and -experienced HIV-1-infected children aged 6 months to48 weeks. PK parameters and comparisons with historical adult data are shown in the table. Historical healthy adult 6 months to, Background Etravirine has demonstrated efficacy and safety in treatment-experienced, HIV-1-infected adults. Pediatric development is ongoing. Methods PIANO (TMC125-C213; NCT00665847) is a 48-week, Phase II, open-label trial of the safety, efficacy and pharmacokinetics of etravirine 5.2 mg/kg (maximum dose 200mg) bid in HIV-1-infected, treatment-experienced children (6–95% adherent; 70% were >80% adherent. The most common drug-related AE was rash (18%) (Table). Four percent discontinued due to rash. Serious AEs were seen in 5% of patients while 14% experienced a grade 3/4 AE. Laboratory toxicities were predominantly grade 1/2. At W48, 56% of patients achieved VL10% of patients overallzgrouped term including rash not further specified, rash macula-papular, rash generalized, rash erythematous, rash macular rash papular and rash puritic¶occurnng in >5% of patients overall; AE, adverse event NC = F, non-completer equals failure; SE standard error; TLOVR, time-to-loss of virologic response algorithm. Conclusion The efficacy, safety and resistance profiles of etravirine 5.2 mg/kg bid plus OBR in this difficult-to-treat, antiretroviral-experienced pediatric population were comparable to those observed in treatment-experienced adults (DUET trials). Responses were better in children than adolescents, most likely due to less advanced disease, better adherence and less previous NNRTI use., Background New antiretrovirals are needed for HIV+ children. IMPAACT P1066 is a Phase I/II open label multicenter trial to evaluate pharmacokinetics (PK), safety, tolerability, and efficacy of multiple RAL formulations in treatment experienced HIV+ youth. RAL was given with an optimized background regimen. Dose selection was based upon intensive PK and safety data: 400 mg BID of RAL film-coated tablet (6–18 years) and weight-based dosing (~6mg/kg BID) of RAL chewable tablet (2 to, Background In Kenya, an estimated 7,000-10,000 children are HIV infected yearly. National targets for 10% of all HIV clinic patients registered being pediatric are often difficult to reach or fall behind adult uptake. In addition, concerns exist regarding retention of children in HIV/AIDS clinics. Such challenges are often magnified in rural settings due to frequent changes in caregivers,distances away from pediatric clinics, and extremes in poverty. Methods In 2004, HIV/AIDS care and treatment programs began developing under the President's Emergency Plan for AIDS Relief (PEPFAR) program in the SRV Province of Kenya, a largely rural population. Effort has been made to decentralize care, making more clinics closer to rural populations available. In addition, initiatives such as the “Mwangalizi” (“care givers”, often HIV positive adults linked with children to assure they come to HIV clinics) project have been implemented, and pediatric HIV support groups have been established. We describe aggregate program level data for the development of/uptake in HIV pediatric clinics. Results Between 2004 and 2011, 17,572 children received HIV testing through both voluntary counseling and testing (VCT) and diagnostic testing and counseling (DTC) initiatives. 5,310 children (mean age 10.0 +/− 3.3 years, 50.6% female) were enrolled in 57 pediatric HIV clinics. Of those enrolled, 44.3% started first line ART, 2.5% switched to 2nd line ART, and 1 has advanced to 3rd line ART. In 2005, 7.0% of HIV clinic attendees were children on ART, which increased to 10.5% in 2011 (p, Background Lipid abnormality is a common long-term complication in HIV-infected children. This study aimed to compare lipid profiles in children randomized to immediate versus deferred nevirapine-based antiretroviral therapy (ART). Methods This was a substudy of PREDICT (NCT00234091), a 144-week randomized trial of immediate ART (at CD4 15–24%) versus deferred ART (at CD4200 mg/dl, Triglyceride > 130 mg/dl, LDL>130 mg/dl, HDL≤40 mg/dl. Conclusion After 3 years, children randomized to immediate nevirapine-based ART had less dyslipidemia and lower TC/HDL ratio than the deferred ART group. This supports earlier nevirapine-based initiation to achieve favorable lipid profile in children with mild to moderate HIV-associated immune deficiency., Background Metabolic abnormalities, common among perinatally HIV-infected children (HIV+), may be caused by mitochondrial dysfunction that is induced by antiretroviral therapy (ARV) or chronic viral infection. We compared mitochondrial function [oxidative phosphorylation (OXPHOS) enzyme activities and lactate levels] of HIV+ and HIV-exposed, uninfected (HEU) children and, among HIV+, determined associations with fasting glucose, insulin, and homeostatic model assessment of insulin-resistance (HOMA-IR). Methods HIV+ and HEU were enrolled from the PHACS Adolescent Master Protocol. Children with known, non-HIV-associated mitochondrial disorders were excluded. Demographic and BMI [all] and CD4, HIV viral load, ARV exposures, and fasting insulin/glucose [HIV+ only] were collected. Main outcomes included venous and point-of-care (POC) lactate, venous pyruvate, and PBMC NADH dehydrogenase (CI) and cytochrome c oxidase (CIV) enzyme activities. A Wilcoxon test was used to compare outcomes between HIV+ and HEU; Spearman correlations were determined between insulin/glucose and OXPHOS activity in HIV+. Results 112 HIV+ and 66 HEU children were enrolled as of December 2011. HIV+ were older than HEU (15.8yr vs 12.4yr) with similar gender and racial distributions. BMI-Z was lower in HIV+ (0.41SD vs 0.54SD). Among HIV+, 45% were CDC stage B/C and 74% had CD4 >500 cell/mm3 with 60% having viral load, Background Peripheral neuropathy is a well-recognised and common condition in HIV-infected adults and may be related to use of antiretroviral therapy (ART) as well as be directly caused by HIV infection. Data on the prevalence, manifestations and risk factors of neuropathy in children are limited. Only few tools are available for clinical screening for peripheral neuropathy in children. We used the neuropathy symptom score (NSS) and neuropathy disability score (NDS) to screen for peripheral neuropathy in a cohort of children on ART. Methods In this cross-sectional study we included 182 children aged 5-15 years attending to healthcare facilities for ART collection in rural Mopani District, South Africa. Subjective and objective assessment of neuropathy was done using the NSS respectively NDS. These scores are feasible for resource-poor and skills-limited settings and only require a reflex hammer, cotton butt, tooth pick, and cold water. A definite diagnosis of peripheral neuropathy was defined by NSS≥3 or NDS≥ 2. Results Neuropathy screening was completed for 174/182 (96%) of children as 8 children did not fully cooperate. Median age was 9 years old and time on ART 2.0 years (2 months-6.4 years) with 86% on a stavudine-containing regimen. Symptoms related to neuropathy were reported by 49 children (27%) while NDS was positive for 25 children (14%). Forty-one (24%) of children fulfilled the criteria of peripheral neuropathy. Co-trimoxazole use was negatively associated with neuropathy presentation (OR 0.42, 95% CI 0.20–0.88; p=0.019) while there were tendencies for peripheral neuropathy to be associated with older age (p=0.09) and longer time on ART (p=0.06). Conclusion Peripheral neuropathy is a common condition in children collecting ART at healthcare facilities in rural Mopani District. The NSS and NDS can be used to screen for this condition in resource-poor settings., Background Antiretroviral (ARV) administration to HIV positive pregnant women and neonates reduces perinatal HIV transmission to less than 2% worldwide. However, concerns have been raised about potential toxicity in some neonates following gestational ARV exposure. Precise quantification of ARV exposure by history is difficult. Quantitative meconium analysis may better reflect fetal exposure during the third and perhaps second trimesters than history alone. Therefore, we developed and validated the first liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for ARVs and metabolites in meconium. Methods Blank meconium (0.25g) was fortified with 16 ARVs and 4 metabolites, chosen based on prevalence of use by HIV-infected mothers in the SMARTT (Surveillance Monitoring of ART Toxicities) Study of PHACS. Samples were homogenized in methanol and subjected to solid phase extraction prior to quantification by LC-MS/MS. Tenofovir (TDF), lamivudine (3TC), emtricitabine (FTC), abacavir (ABC) and its carboxylate (CABC) and glucuronide (GABC) metabolites, nevirapine (NVP), raltegravir (RAL), saquinavir (SQV), amprenavir (AMP), darunavir (DRV), atazanavir (ATV), ritonavir (RTV), lopinavir (LPV), nelfinavir (NFV) and its bioactive hydroxyl (M8) metabolite were quantified with positive ionization; stavudine (d4T), efavirenz (EFV), zidovudine (AZT) and its glucuronide (GAZT) metabolite were quantified with negative ionization. Results Chromatographic separation was achieved with gradient elution; two injections were required due to the need for both positive (35 min) and negative (18 min) ionization modes. Extraction efficiencies were greater than 60% for all analytes except GABC (30%), and TDF, 3TC, GAZT and CABC (50%). Linear calibration curves employing 1/x2 weighting ranged from 10–2500ng/g (TDF, FTC, ABC, GABC, NVP, RAL, SQV, ATV, RTV, LPV, NFV, and M8), 50–2500ng/g (3TC), 75–2500ng/g (CABC), 100–25,000ng/g (AMP, DRV, AZT, EFV) and 500–25,000ng/g (d4T, and GAZT). Conclusion We developed a selective and sensitive LC-MS/MS method to detect antiretroviral medications and metabolites in meconium, which may be useful in quantifying the in utero ARV exposure for children of HIV-infected women., Background Mechanisms for increased cardiovascular risk in HIV-infected adults are incompletely understood, but heighted inflammation leading to a pro-thrombotic state has been proposed as a major contributor. In vitro platelet aggregation has been studied as a robust biological marker of coronary events and mortality. Methods We studied platelet aggregation in 25 HIV-infected subjects on ART with undetectable plasma HIV-1 RNA, median CD4 537 cells/mm3 (73.9%men) and 29 healthy HIV seronegative controls (44.4%men) in response to submaximal adenosine diphosphate (ADP, 0.4uM), arachidonic acid (AA, 0.15mM), or without agonist (spontaneous platelet aggregation [SPA]). The effects of one week of aspirin 81mg daily on activation markers, as measured by flow cytometry, and platelet aggregation were investigated. Two-tailed paired t tests and non-parametric Mann-Whitney U test tests were used for statistical analyses, with results given as medians with interquatile ranges. Results Compared to controls, HIV subjects on ART had increased platelet aggregation in response to ADP (10.8% [6.5, 42.3] vs 7.6% [3.3, 10.2], p=0.02), AA (54.9% [8.7, 89.9] vs 11% [2.5, 77.6], p, Background Limited data exist regarding the relationship between dysfunctional HDL (dys-HDL) and the osteoprotegerin (OPG)/receptor activator of the NF-kB ligand (RANKL) in HIV infection. Oxidized HDL (dys-HDL) has been shown to activate the NF-kB pathway in vitro. In view of this observation and the important role of biomarkers of activation of the NF-kB pathway (RANKL/OPG axis) in systemic inflammatory conditions, we used a novel assay that measures oxidation of HDL to explore possible associations between dys-HDL with RANKL/OPG and parameters that may predict these biomarkers. Methods We used cryopreserved serum samples from a prospective study (A5078) where subjects were enrolled as risk factor-matched triads of HIV-infected subjects (n=55) and HIV-uninfected individuals (n=36). Relationships between HIV infection, RANKL, OPG, RANKL/OPG, and dys-HDL were assessed using Wilcoxon tests and mixed effects linear regression analysis. The baseline covariates considered in the analysis are shown in Table 1 and also included fasting glucose and lipids, insulin, use of statins, anthropometric parameters of obesity, years of protease inhibitors (PI) use, and nadir CD4+ T cells. Significant (p, Background The association of inflammatory biomarkers with clinical events after ART initiation is unclear. Methods A5202 randomized 1857 treatment-naive subjects to abacavir/lamivudine or tenofovir DF/emtricitabine with efavirenz or atazanavir/ritonavir. Substudy A5224s measured inflammatory biomarkers on all substudy subjects with available plasma from baseline and weeks 24 or 96. The association of hsCRP, IL-6, sTNF-RI, sTNF-RII, TNF-a, sVCAM-1, and sICAM-1 with times to AIDS and non-AIDS defining events was analyzed with Cox proportional hazards models, with adjustment by ART assignment, and HIV-1 RNA or CD4. Time-updated analyses used the most current value. Results Analysis included 244 subjects; 85% male, 48% white non-Hispanic, with median age 39 years, HIV-1 RNA 4.6 log10 copies/mL, and CD4 240 cells/µL. A total of 13 AIDS-defining events (9 opportunistic infections; 3 AIDS-cancers, 1 recurrent bacterial pneumonia) and 18 non-AIDS defining events (6 diabetes, 4 cancers, 3 cardiovascular, 5 pneumonias) occurred. Higher baseline IL-6, sTNF-RI, sTNF-RII, and sICAM-1 were significantly associated with increased risk of AIDS-defining events. Adjustment for baseline HIV-1 RNA did not change results, while adjusting for CD4 count left sTNF-RI and sICAM-1 significantly associated with increased AIDS-defining events risk. Time-updated values of these biomarkers were also associated with increased risk of AIDS-defining events, even after adjusting for ART assignment, baseline and changes in CD4 and HIV-1 RNA. For non-AIDS events, only baseline hsCRP was significantly associated with increased risk; after adjustment for baseline CD4 count, IL-6 became significantly associated with higher risk. Analyses of time-updated biomarker value showed TNF-a to be significantly associated with increased risk of non-AIDS-defining events, even after adjustment for ART, baseline and changes in CD4 and HIV-1 RNA.Table 1Baseline and Time-Updated Biomarker Association with AIDS-Defining Events Unadjusted Baseline CD4, NRTI and NNRTI/PI Adjusted Time-Updated CD4, NRTI and NNRTI/PI Adjusted Biomarker HR (95% CI) p-value HR (95% CI) p-value HR (95% CI) p-value Baseline hsCRP (per 1 log, ug/ml higher)1.21 (0.80, 1.83)0.361.26 (0.84, 1.88)0.26Time-updated hsCRP (per 1 log, ug/ml higher)1.17 (0.78, 1.77)0.441.17 (0.78, 1.75)0.441.18 (0.78, 1.76)0.43Baseline IL-6 (per l log, pg/ml higher)1.98 (1.06, 3.69)0.0321.79 (0.96, 3.34)0.066Time-updated IL-6 (per 1 log, pg/ml higher)2.06 (1.12, 3.77)0.0201.88 (1.02, 3.47)0.0421.92 (1.04, 3.55)0.037Baseline sICAM-1 (per 1 log, ng/ml higher)8.28 (1 93, 35.59)0.0046.13 (1.51, 24.78)0.011Time-updated sICAM-1 (per 1 log, ng/ml higher)4.45 (1.18, 16.68)0.0273.66 (1.03, 13.08)0.0463.55 (0.98, 13.56)0.053Baseline sTNF-RI (per 1 log, pg/ml higher)10.24 (2.08, 50.32)0.0046.25 (1.17, 33.36)0.032Time-updated sTNF Rl (per 1 log, pg/ml higher)18.14 (2.94, 112.01)0.00211.58 (1.81, 73.92)0.01012.83 (1.99, 82.59)0.007Baseline sTNF-RII (per 1 log, pg/ml higher)3.45 (1.28, 9.33)0.0152.89 (0.99, 8.46)0.052Time-updated sTNF-RII (per 1 log, pg/ml higher)3.51 (1.27, 9.67)0.0152.98 (1.03, 8.60)0.0443.03 (1.04, 8.79)0.041Baseline sVCAM 1 (per 1 log, ng/ml higher)2.29 (0.59, 8.92)0.231.92 (0.47, 7.75)0.36Time-updated sVCAM 1 (per 1 log, ng/ml higher)1.77 (0.41, 7.64)0.4515.9 (0.36, 6.98)0.541.47 (0.34, 6.43)0.51Baseline TNF-a (per 1 log, pg/ml higher)2.28 (0.67, 7.78)0.192.17 (0.61,7.79)0.23Time-updated TNF-a (per 1 log, pg/ml higher)1.94 (0.54, 6.98)0.311.78 (0.47, 6.74)0.401.76 (0.47, 6.62)0.40Biomarker Association with AIDS-Defining Events. Conclusion Higher levels of several inflammatory biomarkers were associated independently of CD4 count with increased risk of AIDS and non-AIDS events. Larger and longer studies should investigate the use of these markers as predictors of clinical endpoints.Table 2Baseline and Time-updated Biomarker Association with Non-AIDS-Defining Events Unadjusted Baseline CD4, NRTI and NNRTI/PI Adjusted Time-Updated CD4, NRTI and NNRTI/PI Adjusted Biomarker HR (95% CI) p-value HR (95% CI) p-value HR (95% CI) p-value Baseline hsCRP (per 1 log, ug/ml higher)1.66 (1.15, 2.41)0.0071.66 (1.14, 2.43)0.008Time-updated hsCRP (per 1 log, ug/ml higher)1.15 (0.81, 1.64)0.441.16 (0.81, 1.67)0.411.16 (0.81, 1.65)0.42Baseline IL-6 (per l log, pg/ml higher)1.68 (0.96, 2.93)0.0681.81 (1.01, 3.25)0.047Time-updated IL-6 (per 1 log, pg/ml higher)0.96 (0.51, 1.83)0.911.01 (0.53, 1.93)0.970.99 (0.52, 1.87)0.97Baseline sICAM-1 (per 1 log, ng/ml higher)0.81 (0.53, 1.24)0.330.79 (0.51, 1.22)0.28Time-updated sICAM-1 (per 1 log, ng/ml higher)0.89 (0.55, 1.44)0.640.88 (0.55, 1.42)0.610.89 (0.55, 1.44)0.65Baseline sTNF-RI (per 1 log, pg/ml higher)1.31 (0.24, 7.26)0.751.69 (0.27, 10.69)0.58Time-updated sTNF Rl (per 1 log, pg/ml higher)2.58 (0.34, 19.84)0.363.06 (0.36, 25.89)0.312.55 (0.31, 20.76)0.38Baseline sTNF-RII (per 1 log, pg/ml higher)1.66 (0.69, 4.01)0.261.98 (0.81, 4.87)0.14Time-updated sTNF-RII (per 1 log, pg/ml higher)2.07 (0.76, 5.61)0.152.32 (0.84, 6.40)0.112.14 (0.77, 5.97)0.15Baseline sVCAM 1 (per 1 log, ng/ml higher)1.03 (0.32, 3.32)0.951.16 (0.35, 3.85)0.81Time-updated sVCAM 1 (per 1 log, ng/ml higher)2.14 (0.60, 7.55)0.242.22 (0.62, 7.95)0.222.14 (0.59, 7.83)0.25Baseline TNF-a (per 1 log, pg/ml higher)2.33 (0.80, 6.76)0.122.35 (0.83, 6.66∣0.11Time-updated TNF-a (per 1 log, pg/ml higher)3.75 (1.31, 10.77)0.0144.01 (1.39, 11.55)0.0103.87 (1.34, 11.18)0.012Biomarker Association with NONAIDS-Defining Events., Background HIV-positive patients may be at increased risk of premature onset of age-associated non-communicable comorbidity (AANCC). Methods Comprehensive assessment for AANCC in an ongoing prospective cohort study of HIV-1-infected patients ≥45 years from a tertiary care HIV-outpatient clinic, and concurrently recruited HIV-uninfected public sexual health clinic-attendants, comparable regarding age, gender, ethnicity and risk-behavior. Baseline data on AANCC (blood pressure ≥140/90 mmHg, FEV1/FVC, Background The report of a successful HIV cure after allogeneic bone marrow transplant for acute leukemia has generated major interest in HIV eradication. We examined the efficacy, cost, and relapse rate combinations that would make ‘cure’ cost-effective compared with antiretroviral therapy (ART). Methods We used a Monte Carlo simulation of HIV disease (CEPAC model) to assess the impact of suppressive ART either continued indefinitely, or followed by one of three hypothetical strategies for HIV eradication: gene therapy (GeneRx), chemotherapy to activate the latent viral reservoir (Chemo), and an allogeneic bone marrow transplant (BMT). Patients eligible for inclusion in the model were virologically suppressed on first-line ART for one year. Patients who relapsed after a cure strategy restarted on ART. For each strategy we examined combination rates of cure, upfront cost, and monthly relapse rates to determine benchmarks for which the eradication strategies would compare favorably to ART. Model outcomes included projected life expectancy in months (LMs), cost, and discounted (3%) cost-effectiveness (C-E) in $US/QALY using a C-E threshold of

Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI-infarct, in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.