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 populatio

Long-term Mortality in HIV-Positive Individuals Virally Suppressed for >3 Years With Incomplete CD4 Recovery

Virally suppressed HIV-positive individuals on combination antiretroviral therapy who do not achieve a CD4 count >200 cells/µL have substantially increased long-term mortality. The increased mortality was seen across different patient groups and for all causes of deat

A Phylogenetic Analysis of Human Immunodeficiency Virus Type 1 Sequences in Kiev: Findings Among Key Populations

Background: The human immunodeficiency virus (HIV) epidemic in Ukraine has been driven by a rapid rise among people who inject drugs, but recent studies have shown an increase through sexual transmission. Methods: Protease and reverse transcriptase sequences from 876 new HIV diagnoses (April 2013–March 2015) in Kiev were linked to demographic data. We constructed phylogenetic trees for 794 subtype A1 and 64 subtype B sequences and identified factors associated with transmission clustering. Clusters were defined as ≥2 sequences, ≥80% local branch support, and maximum genetic distance of all sequence pairs in the cluster ≤2.5%. Recent infection was determined through the limiting antigen avidity enzyme immunoassay. Sequences were analyzed for transmitted drug resistance mutations. Results Thirty percent of subtype A1 and 66% of subtype B sequences clustered. Large clusters (maximum 11 sequences) contained mixed risk groups. In univariate analysis, clustering was significantly associated with subtype B compared to A1 (odds ratio [OR], 4.38 [95% confidence interval {CI}, 2.56–7.50]); risk group (OR, 5.65 [95% CI, 3.27–9.75]) for men who have sex with men compared to heterosexual males; recent, compared to long-standing, infection (OR, 2.72 [95% CI, 1.64–4.52]); reported sex work contact (OR, 1.93 [95% CI, 1.07–3.47]); and younger age groups compared with age ≥36 years (OR, 1.83 [95% CI, 1.10–3.05] for age ≤25 years). Females were associated with lower odds of clustering than heterosexual males (OR, 0.49 [95% CI, .31–.77]). In multivariate analysis, risk group, subtype, and age group were independently associated with clustering (P < .001, P = .007, and P = .033, respectively). Eighteen sequences (2.1%) indicated evidence of transmitted drug resistance. Conclusions Our findings suggest high levels of transmission and bridging between risk groups

The natural history of hepatitis C in a cohort of haemophilia patients

Chronic hepatitis C (CHC) is a common cause of morbidity and mortality among haemophiliacs. Coinfection with HIV, almost at the same time point, aggravates the course of HCV infection to ESLD and HCC. Aim of this study was to evaluate the natural history of HCV infection in a cohort of Greek haemophilia patients and investigate the impact of HIV infection in HCV progression. A total of 324 haemophilia patients with CHC and known seroconversion dates were followed up prospectively, among them 160 (49,4%) coinfected with HIV. The cumulative incidence of ESLD and death without ESLD was estimated using competing risks methodology. In coinfected patients, the relative importance of several virological and epidemiological factors in the histologically determined severity of CHC was investigated. The Cox proportional hazards model was used to investigate factors’ effects on the cause-specific hazards of both endpoints. Finally the response to different anti-HCV regimen was evaluated in both groups. The estimated cumulative incidence (95% CI) of ESLD at 30 years was 12%. (4,2%, 15,8%) In total, 34 (10.5%) patients progressed to ESLD, 22 of them among the coinfected. HIV infection was a strong determinant of negative outcome. Cumulative incidence of ESLD was higher in HCV/HIC coinfected than in HCV monoinfected patients irrespectively of the years passed from HCV seroconversion. HCC was diagnosed in 1,9% of the patients, exclusively in the ΖIV negative group. In liver histology a significant positive association of hepatitis grade with CD4 level was observed, suggesting that coinfection may aggravate the course of hepatitis, most probably through an immune mediated process. The impact of HAART in coinfected patients had beneficial effect in HCV infection course. While a mild transient hepatotoxicity was observed during the first months after HAART initiation, immune recovery resulted in significant reduction (81,9%) of cause specific hazard for ESLD (p=0.001). In fact, there was no statistically significant difference in CSH of ESLD between monoinfected individuals and HCV/HIV coinfected patients with stable HAART (p-value=0.413). Treatment for HCV infection was found to be safe and effective in HIV negative patients, with response rates similar to other HCV positive groups, in contrast to coinfected patients, where, very low response rate and high incidence of adverse events was found. Conclusions: Greek Haemophilia patients present a high incidence of HCV infection and CHC. The cumulative incidence of ESLD 30 years after HCV infection is relatively low, but higher among coinfected patients. An early and potent anti-HIV therapy in this group or patients, before the occurrence of immunosuppression, may reduce the rate of HCV morbidity and mortality. Anti-HCV therapy has similar safety and response rate to other risk groups only in monoinfected patients.Η χρόνια ηπατίτιδα C (CHC) καθώς και η συλλοίμωξη με HIV αποτελούν συχνές αιτίες νοσηρότητας και θνησιμότητας στην ομάδα των αιμορροφιλικών ασθενών. Σκοπός της μελέτης αυτής ήταν να μελετηθεί η φυσική ιστορία της ηπατίτιδας C, σε κοόρτη HCV θετικών Ελλήνων αιμορροφιλικών και να διερευνηθεί η επίδραση της HIV λοίμωξης στην εξέλιξή της. Μελετήθηκαν προοπτικά 324 ασθενείς με χρόνια HCV λοίμωξη από τους οποίους 160 (49,4%) με HIV συλλοίμωξη. Εκτιμήθηκε η αθροιστική πιθανότητα της εμφάνισης σοβαρής ηπατικής νοσηρότητας (ESLD) και του μη σχετιζόμενου με το ήπαρ θανάτου, συγκριτικά στις δύο ομάδες με τη μεθοδολογία ανταγωνιστικών κινδύνων. Στους ασθενείς με συλλοίμωξη διερευνήθηκαν η σημασία ιολογικών και επιδημιολογικών παραγόντων στη βαρύτητα της ιστολογικής βλάβης και η επίδραση της HAART στην εξέλιξη της HCV λοίμωξης. Εφαρμόστηκε ημιπαραμετρικό μοντέλο αναλογικών ανά-αιτία κινδύνων, για την εκτίμηση της επίδρασης διαφόρων παραγόντων στην εξέλιξη της CHC. Τέλος εκτιμήθηκε η ανταπόκριση των δύο ομάδων στην αντι-HCV θεραπεία. Ο αθροιστικός κίνδυνος (95% CI) ανάπτυξης ESLD 30 χρόνια από την HCV λοίμωξη ήταν καθοριστικός παράγοντας κακής εξέλιξης. Οι ασθενείς με συλλοίμωξη παρουσίασαν μεγαλύτερο ποσοστό συμβάντων ESLD από τους ασθενείς με μόνο HCV λοίμωξη, [22 (13,8%) vs. 12 (7,3%)] και στατιστικά υψηλότερο κίνδυνο για ESLD σε 20 (1,29% vs. 8,12%, 25 (3.92% vs. 12.37%) και 30 (7.64% vs. 14.61%) χρόνια από την HCV ορομετατροπή. ΗΚΚ διαπιστώθηκε σε ποσοστό 1,9% των ασθενών αποκλειστικά στην ομάδα των HIV αρνητικών. Η θετική συσχέτιση του βαθμού ηπατίτιδας με τα επίπεδα των CD4 στην ιστολογική μελέτη των HIV θετικών, αποτελεί ένδειξη ότι η ηπατική βλάβη προκαλείται στο ήπαρ μέσω ανοσολογικού μηχανισμού στη φάση της ανοσοεπάρκειας. Η επίδραση της HAART στους ασθενείς με συλλοίμωξη ήταν ευεργετική στην εξέλιξη της HCV λοίμωξης. Παρά την ήπια παροδική ηπατοτοξικότητα στους πρώτους μήνες χορήγησης, η αποκατάσταση του ανοσολογικού συστήματος οδήγησε σε σημαντική ελάττωση του κινδύνου (81,9%) για ESLD (p=0.001), ώστε να πλησιάζει αυτόν των HIV αρνητικών. Η ασφάλεια και αποτελεσματικότητα της HCV θεραπείας στους ασθενείς με μονολοίμωξη ήταν παρόμοια με τις άλλες ομάδες HCV θετικών ασθενών. Αντίθετα στην ομάδα των HIV θετικών, η απάντηση ήταν πτωχή με μεγάλα ποσοστά τοξικότητας. Συμπεράσματα: Οι Έλληνες αιμορροφιλικοί παρουσιάζουν υψηλή συχνότητα HCV λοίμωξης και χρόνιας ηπατίτιδας C. Η συνολική πιθανότητα εμφάνισης ESLD 30 χρόνια μετά τη λοίμωξη είναι σχετικά χαμηλή (12%), σαφώς μεγαλύτερη όμως στους ασθενείς με συλλοίμωξη. Η συνεργική δράση των δύο ιών στην ομάδα αυτή επιταχύνει την ηπατική βλάβη νωρίς στη φάση της ανοσοεπάρκειας, επομένως έγκαιρη και αποτελεσματική αντι-HIV θεραπεία, μπορεί να ελαττώσει τον κίνδυνο της HCV σχετιζόμενης νοσηρότητας και θανάτου. Η αντι-HCV θεραπεία έχει παρόμοια ασφάλεια και αποτελεσματικότητα με τις άλλες ομάδες κινδύνου, μόνο στην ομάδα των ασθενών με μονολοίμωξη

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

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

Practical aspects of DDAVP use in patients with von Willebrand Disease undergoing invasive procedures: a European survey.

INTRODUCTION: Desamino D-arginine vasopressin (DDAVP or desmopressin) is a useful and effective haemostatic treatment for patients with von Willebrand Disease (VWD). However, there are still issues regarding in which subtypes of VWD DDAVP is appropriate and little consensus on its use in different surgical settings. We also lack information concerning the appropriate laboratory parameters that should be monitored. AIM: The European Haemophilia Therapy Strategy Board (EHTSB) wished to investigate published information and clinical use of DDAVP in VWD patients. METHODS: We conducted a literature survey on management of VWD during surgical interventions and undertook a survey of specialist haematologist centres across Europe to assess current management of VWD patients. RESULTS: DDAVP is ineffective in type 3 VWD and its use in type 2B remains controversial due to the possibility of thrombocytopenia. It can, however, be used effectively to cover minor surgery and dental procedures in most other VWD patients. For major surgery there is wider use of factor concentrate in preference to DDAVP depending on the subtype of VWD. We give consensus recommendations on the use of DDAVP for surgical interventions in VWD including laboratory parameters that denote an adequate response and contraindications to its use. CONCLUSIONS: DDAVP can be recommended to cover invasive procedure in selected patients with VWD, however, we need more information and systematic recording of adverse events associated with DDAVP use in VWD. A companion paper will be published covering the use of factor concentrates in VWD patients

Differences in HIV RNA levels before the initiation of antiretroviral therapy among 1864 individuals with known HIV-1 seroconversion dates

To assess the effects of sex, risk group, age at and year of seroconversion (SC), and presentation during acute infection on HIV RNA trends before antiretroviral therapy (ART) initiation. Multiple HIV RNA measurements from 1864 individuals with reliably estimated dates of SC, aged >/= 15 years at SC were studied using random effects models. Models were adjusted for selective HIV RNA data truncation due to ART initiation or AIDS development and for HIV RNA quantification assay. HIV RNA levels declined precipitously during the first 10 months after SC followed by a slow increase. Women infected heterosexually and through injecting drug use, had an average 34% [95% confidence interval (CI), 2.3-56%] and 46% (95% CI, 17-66%) lower HIV RNA load respectively, compared to men in the same risk group. Among men, those infected heterosexually and by injecting drug use had on average 56% (95% CI, 36-69%) lower HIV RNA levels than homosexual men. Older subjects tended to have higher viral levels. There was no evidence that differences by sex, risk or age group diminished over time, but follow-up was mostly before CD4 cell count had fallen below 200 x 10 cells/l. HIV RNA levels at the same stage of HIV-1 infection differ significantly by sex, risk group and age at SC. Given the lack of evidence of a survival difference by sex or risk group prior to initiation of effective therapy, further research on differential effects of virus load on treatment-free disease progression is needed, before a conclusion about considering these factors for ART initiation is draw

Denosumab versus zoledronate for the treatment of low bone mineral density in male HIV-infected patients

Introduction: We aimed to compare annual changes in the bone mineral density (BMD) at the lumbar spine (LS) and the femoral neck (FN) in males with HIV-associated osteoporosis treated with either zoledronate (ZOL) or denosumab (Dmab). Methods: In this open label, 12-month, prospective, multicenter, cohort study, 23 male people living with HIV (PLWH) under antiretroviral therapy (ART) with low BMD were administered either a single iv infusion of ZOL 5 mg (n = 10) or Dmab 60 mg sc injections biannually (n = 13). Fourteen age-matched male PLWH with normal BMD served as controls. BMD was measured at baseline and at 12 months. Results: LS-BMD increased within both treatment groups at 12 months (ZOL 5.43% +/- 3.60%, p = 0.001; Dmab 5.76% +/- 3.44%, p &lt; 0.005) and decreased in controls ( 2.58% +/- 4.12, p = 0.04). FN-BMD increased in both treatment groups at 12 months (ZOL 7.23% +/- 5.46%, p = 0.003; Dmab 3.01% +/- 2.46%, p &lt; 0.005), and remained unchanged in controls (1.22% +/- 2.09, p = 0.06). LS-BMD changes did not differ between the two treatment groups, but FN-BMD changes were more prominent in the ZOL group (p &lt; 0.05). None of our study cohort sustained new fragility fractures during the 12-month study period, and no case of acute phase response was recorded in the ZOL group. Conclusions: In male PLWH under ART requiring osteoporosis treatment both ZOL and Dmab are efficient and well tolerated therapeutic options achieving BMD increases at least for the first year of treatment