W. Keith Hoots

Hepatitis C Virus Load Is Associated with Human Immunodeficiency Virus Type 1 Disease Progression in Hemophiliacs

Hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) coinfection is common in hemophiliacs and injection drug users. To assess the interaction between HCV load and HIV-1 disease progression, we examined 207 HIV-1/HCV-coinfected patients. Patients were followed prospectively for approximately 7 years, and annual measurements of CD4(+) cell counts and HCV and HIV-1 loads were obtained. Survival analysis was used to define the independent effects of HCV load on HIV-1 progression. After controlling for CD4(+) cell count and HIV-1 RNA level, every 10-fold increase in baseline HCV RNA was associated with a relative risk (RR) for clinical progression to acquired immunodeficiency syndrome (AIDS) of 1.66 (95% confidence interval [CI], 1.10-2.51; P=.016) and an RR for AIDS-related mortality of 1.54 (95% CI, 1.03-2.30; P=.036). These findings emphasize the need for further research regarding the use of HIV-1- and HCV-specific therapy in coinfected individuals.

Relation between HIV-1 and hepatitis C viral load in patients with Hemophilia

Summary: Coinfection with hepatitis C virus (HCV) and HIV‐1 is common in patients with hemophilia and in intravenous drug users. Little, however, is known about the relation between HIV‐1 and HCV coinfection and the effects on HCV clearance and pathogenesis. We examined data from 207 HIV‐1‐infected and 126 HIV‐1‐uninfected patients with hemophilia enrolled in the multicenter Hemophilia Growth and Devel opment Study. Participants were observed during prospective follow‐up for approxi mately 7 years with annual measurements of alanine aminotransferase (ALT), CD4+ cells, and HCV and HIV‐1 RNA levels. Clearance of HCV was more likely to occur in those uninfected with HIV‐1 (14.3 versus 2.5%; odds ratio [OR] 4.79; 95% confi dence interval [CI], 1.63‐14.08, p = .005) and was more common with decreasing age (OR, 1.23; 95% CI, 1.04‐1.47; p = .017). HCV RNA levels were higher throughout the 7 years of follow‐up in those HIV‐1‐infected (p < .001). In the HIV‐1‐infected participants, baseline CD4+ cells were inversely related to HCV RNA with every 100‐cell increase associated with a 0.19 log10 copy/ml decrease in HCV RNA (p = .002), and HIV‐1 and HCV RNA levels were directly related (p = .008). Increasing HCV RNA levels were also associated with significantly higher ALT levels regardless of HIV‐1 infection status. These results demonstrate that HIV‐1/HCV co infection is associated with a reduced likelihood of HCV clearance and that higher levels of HCV RNA are associated with increased hepatic inflammation.

IL28B polymorphism does not determine outcomes of hepatitis B virus or HIV infection

An IL28B haplotype strongly determines the outcome of natural and interferon-α treated hepatitis C virus (HCV) infection. To assess whether the polymorphism marking the haplotype (rs12979860) also affects other interferon-α responsive chronic viral illnesses, namely hepatitis B virus (HBV) and human immunodeficiency virus (HIV) type 1 infections, we genotyped 226 individuals with HBV persistence, 384 with HBV recovery, and 2548 with or at high risk for HIV infection. The C/C genotype of rs12979860 was not associated with HBV recovery (odds ratio, 0.99), resistance to HIV infection (odds ratio, 0.97), or HIV disease progression (P > .05). This IL28B single-nucleotide polymorphism affects the immune response to HCV but not to HBV or HIV.

Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia

Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs.

A novel variant marking HLA-DP expression levels predicts recovery from hepatitis B virus infection

ABSTRACT Variants near the HLA-DP gene show the strongest genome-wide association with chronic hepatitis B virus (HBV) infection and HBV recovery/persistence in Asians. To test the effect of the HLA-DP region on outcomes to HBV infection, we sequenced the polymorphic HLA-DPB1 and DPA1 coding exons and the corresponding 3′ untranslated regions (3′UTRs) in 662 individuals of European-American and African-American ancestry. The genome-wide association study (GWAS) variant (rs9277535; 550A/G) in the 3′UTR of the HLA-DPB1 gene that associated most significantly with chronic hepatitis B and outcomes to HBV infection in Asians had a marginal effect on HBV recovery in our European- and African-American samples (odds ratio [OR] = 0.39, P = 0.01, combined ethnic groups). However, we identified a novel variant in the HLA-DPB1 3′UTR region, 496A/G (rs9277534), which associated very significantly with HBV recovery in both European and African-American populations (OR = 0.37, P = 0.0001, combined ethnic groups). The 496A/G variant distinguishes the most protective HLA-DPB1 allele (DPB1*04:01) from the most susceptible (DPB1*01:01), whereas 550A/G does not. 496A/G has a stronger effect than any individual HLA-DPB1 or DPA1 allele and any other HLA alleles that showed an association with HBV recovery in our European-American cohort. The 496GG genotype, which confers recessive susceptibility to HBV persistence, also associates in a recessive manner with significantly higher levels of HLA-DP surface protein and transcript level expression in healthy donors, suggesting that differences in expression of HLA-DP may increase the risk of persistent HBV infection.

Tranexamic Acid and Trauma: Current Status and Knowledge Gaps with Recommended Research Priorities

ABSTRACT A recent large civilian randomized controlled trial on the use of tranexamic acid (TXA) for trauma reported important survival benefits. Subsequently, successful use of TXA for combat casualties in Afghanistan was also reported. As a result of these promising studies, there has been growing interest in the use of TXA for trauma. Potential adverse effects of TXA have also been reported. A US Department of Defense committee conducted a review and assessment of knowledge gaps and research requirements regarding the use of TXA for the treatment of casualties that have experienced traumatic hemorrhage. We present identified knowledge gaps and associated research priorities. We believe that important knowledge gaps exist and that a targeted, prioritized research effort will contribute to the refinement of practice guidelines over time.

Large-Scale Candidate Gene Analysis of Spontaneous Clearance of Hepatitis C Virus

Human genetic variation is a determinant of recovery from acute hepatitis C virus (HCV) infection; however, to date, single-nucleotide polymorphisms (SNPs) in only a limited number of genes have been studied with respect to HCV clearance. We determined whether SNPs in 112 selected immune response genes are important for HCV clearance, by genotyping 1536 SNPs in a cohort of 343 persons with natural HCV clearance and 547 persons with HCV persistence. PLINK (version 1.05) and Haploview (version 4.1) software packages were used to perform association, permutation, and haplotype analyses stratified by African American and European American race. Of the 1536 SNPs tested, 1426 (92.8%) were successfully genotyped. In African Americans, we identified 18 SNPs located in 11 gene regions that were associated with HCV infection outcome (empirical P value, < .01). In European Americans, there were 20 SNPs located in 8 gene regions associated with HCV infection outcome. Four of the gene regions studied (TNFSF18, TANK, HAVCR1, and IL18BP) contained SNPs for which the empirical P value was <.01 in both of the race groups. In this large-scale analysis of 1426 genotyped SNPs in 112 candidate genes, we identified 4 gene regions that are likely candidates for a role in HCV clearance or persistence in both African Americans and European Americans.

VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population

Diagnosis and classification of VWD is aided by molecular analysis of the VWF gene. Because VWF polymorphisms have not been fully characterized, we performed VWF laboratory testing and gene sequencing of 184 healthy controls with a negative bleeding history. The controls included 66 (35.9%) African Americans (AAs). We identified 21 new sequence variations, 13 (62%) of which occurred exclusively in AAs and 2 (G967D, T2666M) that were found in 10%-15% of the AA samples, suggesting they are polymorphisms. We identified 14 sequence variations reported previously as VWF mutations, the majority of which were type 1 mutations. These controls had VWF Ag levels within the normal range, suggesting that these sequence variations might not always reduce plasma VWF levels. Eleven mutations were found in AAs, and the frequency of M740I, H817Q, and R2185Q was 15%-18%. Ten AA controls had the 2N mutation H817Q; 1 was homozygous. The average factor VIII level in this group was 99 IU/dL, suggesting that this variation may confer little or no clinical symptoms. This study emphasizes the importance of sequencing healthy controls to understand ethnic-specific sequence variations so that asymptomatic sequence variations are not misidentified as mutations in other ethnic or racial groups.

Evidence for the benefits of prophylaxis in the management of hemophilia A.

The optimal treatment of hemophilia has been evolving since the advent of factor VIII concentrates, continues to vary geographically, and remains a source of debate. There now exists an extensive clinical literature that demonstrates clear benefits of prophylaxis for patients with hemophiliaA compared to on-demand treatment, including a reduction in the number of bleeding episodes, improved joint function, and greater patient well-being. However, the value of these benefits must be weighed against the heavier economic burden of increased factor use. This paper reviews the literature that compares the benefits of prophylaxis with that of on-demand treatment, compares varying prophylaxis dose and administration frequency protocols, and considers the long-term cost-benefit of prophylactic therapy.

Counteracting the effects of anticoagulants and antiplatelet agents during neurosurgical emergencies.

OBJECTIVE:Emergent neurosurgery may be precipitated or complicated by previous or concomitant administration of anticoagulants, thrombolytic medications, or antiplatelet agents. Recommendations are presented to reverse or counteract the effects of those drugs before or during neurosurgical interventions. METHODS:Directed literature review. RESULTS:Evidence-based data specific to neurosurgery are limited. CONCLUSION:Other clinical experience based on mechanisms of drug action within the coagulation process confirm that single or combined administration of platelet transfusions, fresh frozen plasma, cryoprecipitate, vitamin K, protamine, desmopressin, and recombinant activated factor VII can treat coagulopathies caused by warfarin, heparin, aspirin, adenosine diphosphate-receptor antagonist, glycoprotein IIb/IIIa receptor blocking agents, and thrombolysis. Specific interventions and recommended dosages are reviewed.