Outcome measures analysis following total knee arthroplasty in patients with severe haemophilic arthropathy of the knee.

Total knee arthroplasty (TKA) has been the gold standard for treating severe haemophilic arthropathy of the knee when all conservative measures fail. However, performing a TKA in patients with haemophilic arthropathy is difficult due to severe joint deformity and destruction, and poor bone quality. The aim of the present study was to evaluate the short-term results of TKA in the treatment of knee haemophilic arthropathy in a tertiary referral centre, with an emphasis on health-related quality of life and knee function. A prospective study was conducted that included 19 male patients with end-stage haemophilic knee arthropathy who underwent TKA in a tertiary referral centre. Clinical outcome and health-related quality of life were assessed by the Western Ontario and McMaster Universities Arthritis (WOMAC) index and the Short Form-36 (SF-36) both pre-operatively and at 1-year post-operatively. The mean age of the patients was 50.37±7.63 years (range, 40-65 years). Pre-operative health-related quality of life was impaired in all patients in all SF-36 domains but was markedly improved after TKA. Knee function in all dimensions (pain, stiffness and physical function), as measured by the WOMAC questionnaire, significantly improved after TKA. Pre-operative pain, stiffness and function, along with total WOMAC score, were strongly and negatively correlated with pre-operative SF-36. Overall, the present study indicated a significant improvement in quality of life and clinical outcome after TKA in patients with advanced haemophilic arthropathy. More studies with longer follow-up periods in a larger population are needed to fully elucidate the mid- and long-term values of TKA in haemophilic patients.

Low pre-ART CD4 count is associated with increased risk of clinical progression or death even after reaching 500 CD4 cells/µL on ART.

INTRODUCTION: Clinical disadvantages of initiating ART at low CD4 counts have been clearly demonstrated but whether any excess risk remains even after reaching relatively high/safe CD4 levels remains unclear. We explore whether individuals starting ART with <500 CD4 cells/µL who increased their CD4 count above this level, have, from this point onwards, similar risk of clinical progression to serious AIDS/non-AIDS events or death with individuals starting ART with ≥500 CD4 cells/µL. METHODS: Data were derived from a multicenter cohort (AMACS). Adults, starting PI, NNRTI or INSTI based ART, in or after 2000 were eligible, provided they started ART with ≥500 ("High CD4") or started with CD4 <500 cells/µL but surpassed this threshold while on ART ("Low CD4"). Baseline was the date of ART initiation ("High CD4") or of first reaching 500 CD4 cells/µL ("Low CD4"). Survival analysis, allowing for competing risks, was used to explore the risk of progression to study's endpoints. RESULTS: The study included 694 persons in the "High CD4" and 3,306 in the "Low CD4" group. Median (IQR) follow-up was 66 (36, 106) months. In total, 257 events (40 AIDS related, 217 SNAEs) were observed. Rates of progression did not differ significantly between the two groups but the subgroup of those initiating ART with <200 CD4 cells/µL had significantly higher risk of progression after baseline, compared to those in the "High CD4" group. CONCLUSIONS: Individuals starting ART with <200 cells/µL remain on increased risk even after reaching 500 CD4 cells/µL. These patients should be closely followed.

Clinical, economic, and health-related quality of life burden associated with von Willebrand disease in adults and children: Systematic and targeted literature reviews.

INTRODUCTION: Debilitating clinical complications in von Willebrand disease (VWD) can affect health-related quality of life (HRQoL), increase healthcare costs and cause long-lasting consequences. However, the magnitude of these burdens needs to be more fully explored. AIM: To estimate the prevalence and burden of clinical complications, the impact on HRQoL and the economic burden associated with VWD. METHODS: Embase® , MEDLINE® , the Cochrane Library and conference proceedings were searched for studies on VWD evaluating clinical complications, HRQoL and cost and resource use. RESULTS: Among 16 studies assessing clinical complications in VWD, the most prevalent bleeding symptoms were menorrhagia (2%-95% [n = 7 studies]), epistaxis (12%-80% [n = 6]) and easy bruising (46%-65% [n = 2]). Among 17 studies evaluating HRQoL, the most common assessment scales were the generic SF-36 (n = 8 studies) and the EQ-5D (n = 2). Bleeding symptoms were associated with reduced QoL in six of seven studies, and of six studies evaluating treatment impact, four reported improvements in one or more HRQoL components. Among 25 studies on cost and resource use, key observations included higher post-surgery healthcare costs in VWD versus non-VWD patients (n = 1 study) and higher costs and resource use in VWD patients with bleeding complications versus those without (n = 1). CONCLUSION: Although limited, available evidence suggests that VWD patients experience a high burden of clinical complications, reduced QoL and high healthcare costs. Haemarthrosis is more common in severe VWD than is often assumed, and bleeds (including haemarthrosis) can reduce QoL. Research efforts to improve QoL and other outcomes should be prioritized.

New Inhibitors in the Ageing Population: A Retrospective, Observational, Cohort Study of New Inhibitors in Older People with Hemophilia.

INTRODUCTION: A second peak of inhibitors has been reported in patients with severe hemophilia A (HA) aged >50 years in the United Kingdom. The reason for this suggested breakdown of tolerance in the aging population is unclear, as is the potential impact of regular exposure to the deficient factor by prophylaxis at higher age. No data on hemophilia B (HB) have ever been reported. AIM: The ADVANCE Working Group investigated the incidence of late-onset inhibitors and the use of prophylaxis in patients with HA and HB aged ≥40 years. METHODS: A retrospective, observational, cohort, survey-based study of all patients aged ≥40 years with HA or HB treated at an ADVANCE hemophilia treatment center. RESULTS: Information on 3,095 people aged ≥40 years with HA or HB was collected. Of the 2,562 patients with severe HA, the majority (73% across all age groups) received prophylaxis. In patients with severe HA, the inhibitor incidence per 1,000 treatment years was 2.37 (age 40-49), 1.25 (age 50-59), and 1.45 (age 60 + ). Overall, the inhibitor incidence was greatest in those with moderate HA (5.77 [age 40-49], 6.59 [age 50-59], and 4.69 [age 60 + ]) and the majority of inhibitor cases were preceded by a potential immune system challenge. No inhibitors in patients with HB were reported. CONCLUSION: Our data do not identify a second peak of inhibitor development in older patients with hemophilia. Prophylaxis may be beneficial in older patients with severe, and possibly moderate HA, to retain a tolerant state at a higher age.

Zero incidence of factor VIII inhibitors and successful haemostatic response in previously factor VIII-treated patients with haemophilia A switching to turoctocog alfa in a noninterventional study.

INTRODUCTION: Turoctocog alfa (NovoEight® ) is a B-domain-truncated recombinant factor VIII (FVIII) approved for patients with haemophilia A. AIM: To investigate the long-term safety and efficacy of turoctocog alfa in routine clinical practice. METHODS: Guardian 5 was a prospective, multinational, non-interventional, post-authorisation safety study. Male previously treated patients (> 150 exposure days [EDs]) of any age with severe/moderately severe haemophilia A (FVIII ≤ 2%) and a negative inhibitor test prior to first dosing (independent of FVIII-inhibitor history) were included to receive prophylaxis or on-demand treatment. The primary endpoint was the proportion of patients developing FVIII inhibitors (≥.6 Bethesda Units [BU]) after baseline visit, measured as per routine practice of each study site during clinic visits. Secondary endpoints included haemostatic effect, annualised bleeding rate (ABR), and adverse reactions assessment. The study concluded when 50 patients reached 100 EDs/patient minimum. RESULTS: Seventy patients were screened and 68 exposed to turoctocog alfa; 63 (92.6%) were on prophylaxis and five received on-demand treatment. Six (8.8%) patients reported a history of positive inhibitors. During the study, patients were exposed to turoctocog alfa for a mean (standard deviation) of 131.9 (99.0) days/patient. Fifty-five of 58 patients who completed the study were tested for FVIII inhibitors; no positive tests were reported. Overall success rate of turoctocog alfa for treatment of bleeds was 87.3%. Among patients receiving prophylaxis, median (range) ABR was 1.97 (.0-25.5) bleeds/year; estimated ABR (negative binomial model) was 3.65 (95% confidence interval: 2.53-5.25). CONCLUSION: Turoctocog alfa was safe and efficacious for haemophilia A treatment in routine clinical practice.

Long-term evolution of CD4+ cell count in patients under combined antiretroviral therapy.

OBJECTIVE: Combined antiretroviral treatment (cART) results in profound immunologic improvement, but it is unclear whether CD4 cell counts return to levels similar to those of HIV-negative individuals. We explore long-term CD4 cell count evolution post-cART and its association with baseline levels, virologic suppression, pre-cART cumulative viremia and other factors. DESIGN: Data were derived from the AMACS. Included individuals were adults who started cART, at least 2003, while previously ART-naive. METHODS: Changes in CD4 cell counts were modeled through piecewise linear mixed models. RESULTS: A total of 3405 individuals were included. The majority was male (86.0%), homosexual (58.8%) with median (IQR) age at cART initiation 36 (31-44) years and a median (IQR) follow-up of 3.9 (2.0-6.9) years. Most persons (57%) starting cART with less than 200 cells/µl did not reach 600 cells/µl after 7 years of treatment. Those starting cART with 200-349 CD4 cells/µl could reach 600 cells/µl within less than 2 years of fully suppressive treatment. Probability of CD4 normalization (i.e. >800 cells/µl) after 7 years of suppressive treatment was 24 and 46% for those starting treatment with less than 200 or 200-349 CD4 cells/µl, respectively. Lower pre-cART cumulative viremia was associated with faster CD4 recovery. CD4 cell count increases after 4 years were either insignificant or very slow, irrespectively of baseline levels. CONCLUSION: cART initiation before CD4 cell count drops below 350 cells/µl is crucial for achieving normal CD4 levels. These findings underline the importance of timely diagnosis and cART initiation as the risk of both AIDS and non-AIDS-related morbidity/mortality remains increased in patients with incomplete CD4 recovery.

HIV cascade of care in Greece: Useful insights from additional stages.

BACKGROUND: Aiming to eliminate HIV infection, UNAIDS has set a global "90-90-90" target by 2020. We sought to construct a 6-stages HIV Cascade of Care (CoC) in Greece, overall and by risk group, to assess risk-group and stage-specific progress in achieving the UNAIDS target. PATIENTS AND METHODS: Combining data from the HIV/AIDS surveillance system and a population-based HIV cohort study, the CoC included: i) number of people living with HIV (PLHIV) by end of 2013; ii) proportion of PLHIV ever diagnosed; iii) proportion of diagnosed linked-to-care iv) proportion of linked-to-care ever initiating antiretroviral therapy (ART); v) proportion of treated who retained-in-care vi) proportion of those retained-in-care who were virally suppressed (≤200 copies/mL) at their last visit (01/07/2012-31/12/2013). RESULTS: In 2013, 14147 PLHIV were in Greece. Overall, proportions of each stage in the cascade were: 78.4% diagnosed; 86% linked-to-care; 78.5% initiated ART; 86.4% retained-in-care, and 87.1% virally suppressed. Totally, 42.6% of all PLHIV were virally suppressed. The percentage diagnosed was lower among heterosexual men and women (heterosexuals) than in MSM (men who have sex with men) or PWID (people who inject drugs). Most MSM were linked to care (97.2% of diagnosed) while a substantial proportion of PWID were not (80.8% of diagnosed). Once treated, PWID remained in care in similar proportions to MSM. Unlike PWID, a high proportion of the retained in care MSM and heterosexuals achieved viral suppression. CONCLUSIONS: At the end of 2013, we identified gaps in the HIV CoC in Greece, which differed across risk groups. Targeted interventions are critical in optimizing early diagnosis and timely linkage. A 6-stage CoC, stratified by risk group, can inform strategic public health planning in improving HIV treatment outcomes.

The HIV patient profile in 2013 and 2003: Results from the Greek AMACS cohort.

Combined Antiretroviral therapy (cART) has improved life-expectancy of people living with HIV (PLHIV) but as they age, prevalence of chronic non-AIDS related comorbidities may increase. We study the evolution of HIV-disease markers and comorbidities' prevalence in PLHIV in Greece. Two cross-sectional analyses (2003 and 2013) on data from the AMACS cohort were performed. Comparisons were based on population average models and were repeated for subjects under follow-up at both 2003 and 2013. 2,403 PLHIV were identified in 2003 and 4,910 in 2013 (1,730 contributing for both cross-sections). Individuals in 2013 were on average older, diagnosed/treated for HIV for longer, more likely to be on cART, virologically suppressed, and with higher CD4 counts. Chronic kidney disease, dyslipidemia and hypertension prevalence increased over time. There was an increase in prescription of lipid-lowering treatment (3.5% in 2003 vs. 7.7% 2013, p<0.001). Among 220 and 879 individuals eligible for Framingham 10-year Event Risk calculation, the proportion of patients in the high-risk group (>20%) increased from 18.2% to 22.2% (p = 0.002). Increase in the prevalence of comorbidities was more pronounced in the subset of patients who were followed in both 2003 and 2013. The increased availability and uptake of cART led to significant improvements in the immuno-virological status of PLHIV in Greece, but they aged alongside an increase in prevalence of non-AIDS related comorbidities. These results highlight the need for appropriate monitoring, optimal cART selection and long-term management and prevention strategies for such comorbidities.

Effect of steviol, steviol glycosides and stevia extract on glucocorticoid receptor signaling in normal and cancer blood cells.

The use of steviol glycosides as non-caloric sweeteners has proven to be beneficial for patients with type 2 diabetes mellitus (T2D), obesity, and metabolic syndrome. However, recent data demonstrate that steviol and stevioside might act as glucocorticoid receptor (GR) agonists and thus correlate with adverse effects on metabolism. Herein, we evaluated the impact of steviol, steviol glycosides, and a Greek-derived stevia extract on a number of key steps of GR signaling cascade in peripheral blood mononuclear cells (PBMCs) and in Jurkat leukemia cells. Our results revealed that none of the tested compounds altered the expression of primary GR-target genes (GILZ, FKPB5), GR protein levels or GR subcellular localization in PBMCs; those compounds increased GILZ and FKPB5 mRNA levels as well as GRE-mediated luciferase activity, inducing in parallel GR nuclear translocation in Jurkat cells. The GR-modulatory activity demonstrated by stevia-compounds in Jurkat cells but not in PBMCs may be due to a cell-type specific effect.

Health-Related Quality of Life and Association With Arthropathy in Greek Patients with Hemophilia.

Health-related quality of life (HRQoL) is increasingly implicated in contemporary hemophilia management. This study focuses on the assessment of HRQoL in Greek patients with hemophilia and the comparison with normative data from the general population, as well as on the extent arthropathy may affect the patients' HRQoL. One hundred and nine adult patients completed the Greek social functioning (SF-36) and Haem-A-QoL questionnaires. Arthropathy was assessed by both the World Federation of Hemophilia clinical score and Pettersson radiological score. The most impaired domains of Haem-A-QoL were sports/leisure (SL) and physical health (PH; mean scores 61.2 and 42.2, respectively). The patients experienced statistically significant lower mean scores in all SF-36 domains than the normative sample, especially in role physical (RPH), bodily pain (BP), and general health (GH) subscales. Among Haem-A-QoL subscales, SL and PH were found strongly associated with severity of arthropathy using both orthopedic scores ( P < .001), and maintained the statistical significance after adjustment for age ( P < .05). A poor orthopedic status was also negatively associated with certain SF-36 subscales. However, none of these correlations remained after adjustment with age. Compared to normative data from Greece, patients with hemophilia showed deterioration in all HRQoL subscales, with a more pronounced effect in RPH, BP, and GH subscales. Health-related quality of life was strongly influenced by arthropathy, mainly in the physical aspects of HRQoL. The use of the disease-specific Haem-A-QoL tool can capture additional associations between HRQoL and hemophilic arthropathy.

Occult hepatitis B virus infection in Greek patients with congenital bleeding disorders.

Occult Hepatitis B Infection (OBI) is a form of chronic HBV infection characterized by low level HBV DNA, without detectable HBV surface antigen (HBsAg). OBI is frequently associated with the presence of anti-HBc and in some cases also with anti-HBs. Patients, who formerly received non-inactivated factor concentrates, can potentially be considered at high risk for OBI, especially since these patients usually are HIV or HCV co-infected. This study aimed to assess the prevalence of occult HBV infection in Greek patients with hereditary bleeding disorders. The study sample comprised of 114 patients from a single haemophilia center. All patients were screened for HBV serum markers and individually tested for HBV DNA using a qualitative PCR. Presence of HBV DNA was further confirmed by quantification of viral load with an ultrasensitive in-house real time PCR. 88 and 21 patients with haemophilia A and B, respectively, 4 patients with von Willebrand Disease and 1 patient with severe factor VII deficiency were screened for the presence of OBI. Anti-HBc were detected in 53 (46.5%) subjects; 18 of them were anti-HBs(-) and 35 anti-HBs(+). Anti-HBe were present in 26 subjects. Two out of 114 patients were HBsAg(+). Of the remaining 112 HBsAg(-) patients tested, two (1.8%) were found HBsAg(-), HBV DNA(+), anti-HBc(+) and anti-HBs(-) and were identified as potential OBI cases. Both cases exhibited very low DNA levels; 38.2IU/mL in patient A and 14.2IU/mL in patient B. Both patients were HBeAg(-), but patient A had HBe antibodies. Patient B was also HIV/HCV co-infected. In conclusion, two cases of OBI with low HBV viraemia were identified among patients with congenital bleeding disorders. Although the incidence in our sample is moderately low (1.8%), close monitoring of these infections is of great clinical significance, especially in patients with co-infections and concomitant immunosuppression.

Role of coagulation factors in urological malignancy: A prospective, controlled study on prostate, renal and bladder cancer.

OBJECTIVES: To study the behavior of specific coagulation factors in different types of non-metastatic urological cancers, and to identify their possible role as diagnostic and prognostic markers. METHODS: This was a prospective controlled study, which included three cancer patient groups and a control group of healthy individuals. The cancer subgroups consisted of renal (n = 44), prostate (n = 56) and bladder cancer (n = 47). We excluded patients receiving anticoagulant therapy, or with significant comorbidity. In all patients, certain coagulation parameters were measured (prothrombin time, international normalized ratio, partial thromboplastin time, D-dimers, fibrinogen, F1 + 2, thrombin-antithrombin complex). Statistical analysis was carried out to explore the association of hemostasis markers with tumor-nodes-metastasis stage, Gleason score, transitional cell carcinoma grade, Fuhrman grade and prostate-specific antigen. RESULTS: Our final sample consisted in 58 control patients and 147 patients with urological cancer. We found specific patterns of increased coagulation factors in the different cancers that were statistically significant. Renal cancer showed increased levels of D-dimers, partial thromboplastin time and fibrinogen. D-dimers and fibrinogen were increased in prostate cancer; whereas in bladder cancer, only fibrinogen was elevated. Correlations were found between certain factors and tumor stage and grading, with D-dimers being independently associated with higher tumor grade. Thrombin-antithrombin complex was associated with Gleason score. Furthermore, D-dimers, fibrinogen and F1 + 2 were associated with higher tumor stages (II-IV). CONCLUSIONS: The coagulation pathway seems to be activated in urological malignancies. Specific panels of coagulation factors might play a role as screening or prognostic tools in earlier stages of renal, prostate and bladder cancer. Further research should also focus on their role in the association of cancer with thromboembolic events.

Associations of ABO, D, and Lewis blood groups and HLA Class I and Class II alleles with West Nile virus Lineage 2 disease outcome in Greece, 2010 to 2013.

BACKGROUND: West Nile virus (WNV) infection, commonly asymptomatic, may cause mild West Nile fever (WNF) or potentially fatal neuroinvasive disease (WNND). An outbreak of 262 cases of the new Lineage 2 strain in Greece in 2010 continued with high mortality (17%) in WNND. The objective was to investigate ABO, D, and Lewis blood groups, as well as HLA Class I and Class II alleles, in relation to WNV Lineage 2 disease morbidity. STUDY DESIGN AND METHODS: A cohort of 132 Greek WNV cases in 2010 to 2013 (65% male; mean age 64 years; 41% WNF, 59% WNND) was compared to 51,339 healthy WNV-negative blood donors and 246 healthy subjects. RESULTS: Blood group A was more common in WNV cases (51%) than blood donors (39%) and group O less common (32% vs. 42%). D negativity within group A was higher in WNV than in blood donors (18% vs. 10%, p = 0.044). The frequency of secretors (Lewis(a-b+)) was 60% in WNV and 68% in donors (p = 0.16). HLA alleles C*08, DRB1*O4:O5, and DQB1*O2 occurred significantly less frequently in WNV than controls (p < 0.05 unadjusted for multiple testing) and DRB1*10:O1 more frequently (p = 0.039). CONCLUSION: This first study of symptomatic WNV Lineage 2 suggests A/D negativity as a new risk factor associated with WNV infection and level of morbidity. Further studies are required of the possibility that HLA C*08, DRB1*O4:O5, and DQB1*O2 are protective alleles and DRB1*10:O1 a "susceptible" allele to WNV infection and the role of secretor status in relation to WNV infection.

Treatment Modifications and Treatment-Limiting Toxicities or Side Effects: Risk Factors and Temporal Trends.

Combined antiretroviral treatment (cART) modifications are often required due to treatment failure or side effects. We investigate cART regimens' durability, frequency of treatment-limiting adverse events, and potential risk factors and temporal trends. Data were derived from the Athens Multicenter AIDS Cohort Study (AMACS). Statistical analyses were based on survival techniques, allowing for multiple contributions per individual. Overall, 2,756 individuals, aged >15 years, initiated cART. cART regimens were grouped by their initiation date into four calendar periods (1995-1998, 1999-2002, 2003-2006, and 2007+). Median [95% confidence interval (CI)] time to first treatment modification was 2.11 (1.95-2.33) years; cumulative probabilities at 1 year were 31.6%, 29.0%, 33.1%, and 29.6% for the four periods, respectively. cART modifications were less frequent in more recent years (adjusted HR=0.96 per year; p<0.001). Longer treatment duration was associated with lower HIV-RNA, higher CD4 counts, and being previously ART naive. cART modifications due to treatment failure became less frequent in recent years (adjusted HR=0.91 per year; p<0.001). Estimated (95% CI) 1 year cumulative probabilities of treatment-limiting side effects were 16.4% (12.0-21.3%), 19.3% (15.6-23.3%), 24.9% (20.3-29.7%), and 21.1% (13.4-29.9%) for the four periods, respectively, with no significant temporal trends. Risk of side effects was lower in nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens or triple nucleoside reverse transcriptase inhibitor (NRTI)-based cART regimens. Treatment modifications have become less frequent in more recent years. This could be partly attributed to the lower risk for side effects of NNRTI-based cART regimens and mainly to the improved efficacy of newer drugs. However, the rate of drugs substitutions due to adverse events remains substantially high.

Psychometric properties of the Greek Haem-A-QoL for measuring quality of life in Greek haemophilia patients.

BACKGROUND AND OBJECTIVES: Health Related Quality of Life (HRQoL) is an important health outcome measure in haemophilia. The aim of this study was to assess the psychometric properties of the Greek version of Haem-A-QoL, a disease-specific questionnaire for haemophiliacs. METHODS: Haem-A-QoL and SF-36 were administered to 118 adult haemophilia patients. Hypothesized scale structure, internal consistency (Cronbach's α ), and test-retest reliability, as well as various types of construct validity were evaluated. RESULTS: Scale structure of Haem-A-QoL was confirmed, with good item convergence (87%) and discrimination (80.6%) rates. Cronbach's α was >0.70 for all but one dimension (dealing) and test-retest reliability was significantly high. The strength of Spearman's correlations between Haem-A-QoL and SF-36 scales ranged from 0.25 to 0.75 (P < 0.01). Multiple stepwise linear regression analysis revealed that all but one Haem-A-QoL dimensions were important predictors of SF-36 scales. Known-groups comparisons yielded consistent support of the instruments' construct validity and significant relationships were identified for age, educational level, haemophilia type, disease severity, and viral infections. CONCLUSION: Overall, the psychometric properties of the Greek version of Haem-A-QoL, resulting from this first time administration of the instrument to Greek adult haemophiliacs, confirmed it as a reliable and valid questionnaire for assessing haemophilia-specific HRQoL in Greece.

Long-term mortality in HIV-positive individuals virally suppressed for >3 years with incomplete CD4 recovery.

BACKGROUND: Some human immunodeficiency virus (HIV)-infected individuals initiating combination antiretroviral therapy (cART) with low CD4 counts achieve viral suppression but not CD4 cell recovery. We aimed to identify (1) risk factors for failure to achieve CD4 count >200 cells/µL after 3 years of sustained viral suppression and (2) the association of the achieved CD4 count with subsequent mortality. METHODS: We included treated HIV-infected adults from 2 large international HIV cohorts, who had viral suppression (≤500 HIV type 1 RNA copies/mL) for >3 years with CD4 count ≤200 cells/µL at start of the suppressed period. Logistic regression was used to identify risk factors for incomplete CD4 recovery (≤200 cells/µL) and Cox regression to identify associations with mortality. RESULTS: Of 5550 eligible individuals, 835 (15%) did not reach a CD4 count >200 cells/µL after 3 years of suppression. Increasing age, lower initial CD4 count, male heterosexual and injection drug use transmission, cART initiation after 1998, and longer time from initiation of cART to start of the virally suppressed period were risk factors for not achieving a CD4 count >200 cells/µL. Individuals with CD4 ≤200 cells/µL after 3 years of viral suppression had substantially increased mortality (adjusted hazard ratio, 2.60; 95% confidence interval, 1.86-3.61) compared with those who achieved CD4 count >200 cells/µL. The increased mortality was seen across different patient groups and for all causes of death. CONCLUSIONS: Virally suppressed HIV-positive individuals on cART who do not achieve a CD4 count >200 cells/µL have substantially increased long-term mortality.

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A.

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population.

Effect of HIV type 1 subtype on virological and immunological response to combination antiretroviral therapy: evidence for a more rapid viral suppression for subtype A than subtype B-infected Greek individuals.

Whether response to combination antiretroviral therapy (cART) differs between those infected with HIV-1 subtype A or B remains unclear. We compared virological and immunological response to cART in individuals infected with subtype A or B in an ethnically homogeneous population. Data derived from the Athens Multicenter AIDS Cohort Study (AMACS) and analysis were restricted to those of Greek origin. Time to virological response (confirmed HIV-RNA <500 copies/ml) and time to failure (>500 copies/ml at any time or no response by month 6) were analyzed using survival models and CD4 changes after cART initiation using piecewise linear mixed effects models. Of the 571 subjects included in the analysis, 412 (72.2%) were infected with subtype B and 159 (27.8%) with subtype A. After adjusting for various prognostic factors, the rate of virological response was higher for those infected with subtype A versus B (adjusted HR: 1.35; 95% CI: 1.08-1.68; p=0.009). Subtype A was also marginally associated with a lower hazard of virological failure compared to subtype B (HR=0.73; 95% CI: 0.53-1.02; p=0.062). Further adjustment for treatment adherence did not substantially changed the main results. No significant differences were observed in the rates of CD4 increases by subtype. The overall median (95% CI) CD4 increase at 2 years of cART was 193 (175, 212) cells/µl. Our study, based on one of the largest homogeneous groups of subtype A and B infections in Europe, showed that individuals infected with subtype A had an improved virological but similar immunological response to cART compared to those infected with subtype B.