The CCR5 gene encodes a cell surface chemokine receptor molecule that serves as the principal coreceptor, with CD4, for macrophage-tropic (R5) strains of human immunodeficiency virus-type 1 (HIV-1). ...Genetic association analysis of five cohorts of people with acquired immunodeficiency syndrome (AIDS) revealed that infected individuals homozygous for a multisite haplotype of the CCR5 regulatory region containing the promoter allele, CCR5P1, progress to AIDS more rapidly than those with other CCR5 promoter genotypes, particularly in the early years after infection. Composite genetic epidemiologic analyses of genotypes bearing CCR5P1, CCR5-Δ32, CCR2-641, and SDF1-3′A affirmed distinct regulatory influences for each gene on AIDS progression. An estimated 10 to 17 percent of patients who develop AIDS within 3.5 years of HIV-1 infection do so because they are homozygous for CCR5P1/P1, and 7 to 13 percent of all people carry this susceptible genotype. The cumulative and interactive influence of these AIDS restriction genes illustrates the multigenic nature of host factors limiting AIDS disease progression.
A broad, vigorous CD4 T cell response, mediated by class II human leukocyte antigens (HLAs), favors hepatitis C virus (HCV) clearance. HLA-DQB1*0301 has been associated with viral clearance in an ...ethnically homogeneous cohort. To validate this association and to identify other class II associations in an ethnically varied cohort, molecular class II HLA typing was performed on 200 HCV clearance and 374 matched persistently infected subjects. HLA-DQB1*0301 was weakly associated with viral clearance in combined ethnic groups (odds ratio OR, 0.72; 95% confidence interval CI, 0.53–0.97) but was stronger in black subjects. In white subjects, viral clearance was associated with DRB1*0101 (OR, 0.32; 95% CI, 0.17–0.60) and its DQB1*0501 haplotype, whereas viral persistence was associated with DRB1*0301 (OR, 2.36; 95% CI, 1.23–4.52) and its DQB1*0201 haplotype. These results support a role for class II alleles in the immune response to HCV and underscore the importance of studying genetic associations in an ethnically diverse cohort
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 ∼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.
The critical role of chemokine receptors (CCR5 and CXCR4) in human immunodeficiency virus-type 1 (HIV-1) infection and pathogenesis prompted a search for polymorphisms in other chemokine receptor ...genes that mediate HIV-1 disease progression. A mutation (CCR2-64I) within the first transmembrane region of the CCR2 chemokine and HIV-1 receptor gene is described that occurred at an allele frequency of 10 to 15 percent among Caucasians and African Americans. Genetic association analysis of five acquired immunodeficiency syndrome (AIDS) cohorts (3003 patients) revealed that although CCR2-64I exerts no influence on the incidence of HIV-1 infection, HIV-1-infected individuals carrying the CCR2-64I allele progressed to AIDS 2 to 4 years later than individuals homozygous for the common allele. Because CCR2-64I occurs invariably on a CCR5-+-bearing chromosomal haplotype, the independent effects of CCR5-Δ32 (which also delays AIDS onset) and CCR2-64I were determined. An estimated 38 to 45 percent of AIDS patients whose disease progresses rapidly (less than 3 years until onset of AIDS symptoms after HIV-1 exposure) can be attributed to their CCR2-+/+ or CCR5-+/+ genotype, whereas the survival of 28 to 29 percent of long-term survivors, who avoid AIDS for 16 years or more, can be explained by a mutant genotype for CCR2 or CCR5.
Hemophilic arthropathy occurs in all patients with severe and moderate hemophilia A and B in early adolescence after repeated bleeding in a major joint unless treated with replacement of the missing ...factor. Regular infusions of recombinant factor or treated plasma derived factor given prophylactically to prevent spontaneous bleeding are recommended for all children to maintain a plasma factor level of >1%. Recombinant factor product or treated plasma derived product should be used. Prophylaxis should begin when bleeding occurs repeatedly and is superior to on-demand therapy. Hypertrophied synovium should be removed surgically or with a sclerosing agent, either radioactive or chemical material, to impede further cartilaginous and bony deterioration. Arthroplasty of the knee and hip have been successful in reducing pain and loss of motion when other efforts to control synovial hypertrophy fail.
Many persons with hemophilia were infected with hepatitis C and B viruses (HCV, HBV) and HIV, but the consequences of these transfusion-acquired infections are poorly defined. We estimated the risk ...of HCV-related end-stage liver disease (ESLD) and the associations of age, HBV, and HIV with that risk. All 1816 HCV-seropositive hemophilic patients at 16 centers were followed for up to 16 years. Of these, 624 were HIV− and 1192 were HIV-coinfected; 135 had persistent HBV surface antigenemia, 1374 had resolved HBV infection, and 287 were HBV-uninfected. ESLD was defined as bleeding esophageal varices, hepatic encephalopathy, persistent ascites, or death excluding nonhepatic causes of these conditions. Competing risk models were used to estimate the annual hazard rate and cumulative incidence of ESLD. Proportional hazards models were used to estimate relative hazards of ESLD with covariates. ESLD developed in 127 of the HCV/HIV-coinfected participants, with an estimated 16-year cumulative incidence of 14.0% (95% confidence interval CI, 11.6%-16.4%). Without HIV, 10 HCV-infected participants developed ESLD, for a significantly lower cumulative incidence of 2.6% (95% CI, 1.0%-4.3%,P < .0001). ESLD risk increased steeply with age in both groups. With HIV, ESLD risk was increased 8.1-fold (95% CI, 1.9-35.2) with HBV surface antigenemia, 2.1-fold (95% CI, 1.3-3.3) with fewer than 0.2 × 109/L (200/μL) CD4+lymphocytes, and 1.04-fold (95% CI, 1.03-1.06) per year of age. Thus, HIV is associated with a markedly increased risk of HCV-related ESLD for persons with hemophilia, particularly with HBV infection, low CD4+ lymphocytes, or older age.
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 Development Study. Participants were observed during prospective follow-up for approximately 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% confidence 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.
Activated prothrombin complex concentrates have been used to treat bleeding episodes for patients who have developed an inhibitor to factor VIII (FVIII). FEIBA‐Vh® (FVIII bypassing activity, FEIBA) ...has been used since 1970 for this purpose and with FVIII for immune tolerance programmes. Studies have not been presented to show the safety and efficacy of FEIBA when given over a long period of time to prevent haemophilic arthropathy with bleeding into the joints of these patients. This study was undertaken to ascertain the outcome of haemophilic arthropathy with FEIBA prophylaxis. Data were collected on seven patients with known long‐standing high‐titre FVIII inhibitors given FEIBA prophylaxis for 3–6½ years. Patients were given 50–100 units of FEIBA three to four times weekly. A functional joint evaluation revealed some degree of arthropathy already present in all patients at time of prophylaxis initiation. Safety was measured by medical status, evidence of thrombosis, life‐threatening bleeding and inhibitor titre. Efficacy was measured for joint outcome by a functional physical therapeutic scale. At the conclusion of the study, efficacy was mixed as all of the joints for which the patients were placed on prophylaxis had progressed and developed synovitis. Two patients had a functional improvement in their arthropathy, and all were functional enough to attend regular school. The product was deemed safe for long‐term use, as there were no complications of therapy with no thrombosis, no life‐threatening bleeding episodes and no anamnesis caused by FEIBA alone. Inhibitor titres fell in all patients over the course of the study. Total product usage ranged from approximately 9373–15 571 U kg−1 year−1. FEIBA is safe for long‐term prophylaxis when given in the recommended dosage for an extended period of time. Efficacy to prevent arthropathy could not be seen as all patients had some degree of arthropathy at time of prophylaxis initiation. An additional study needs to be performed using FEIBA before arthropathy has developed.
We evaluated a multicenter cohort of 1219 subjects with hemophilia or related disorders prospectively, focusing on 319 subjects with documented dates of seroconversion to human immunodeficiency virus ...type 1 (HIV-1). The incidence rate of the acquired immunodeficiency syndrome (AIDS) after seroconversion was 2.67 per 100 person-years and was directly related to age (from 0.83 in persons 1 to 11 years old up to 5.66 in persons 35 to 70 years old; Ptrend = 0.00003). The annual incidence of AIDS ranged from zero during the first year after seroconversion to 7 percent during the eighth year, with eight-year cumulative rates (+/- SE) of 13.3 +/- 5.3 percent for ages 1 to 17, 26.8 +/- 6.4 percent for ages 18 to 34, and 43.7 +/- 16.4 percent for ages 35 to 70. Serial immunologic and virologic markers (total numbers of CD4 lymphocytes, presence of serum interferon or HIV-1 p24 antigen, and low or absent serum levels of anti-p24 or anti-gp120) predicted a high risk for the subsequent development of AIDS. Adults 35 to 70 years old had a higher incidence of low CD4 counts than younger subjects (P less than or equal to 0.005), whereas adolescents had a low rate of anti-p24 loss (P = 0.0007) and subjects 1 to 17 years old had a lower incidence of AIDS after loss of anti-p24 (P = 0.03). These findings not only demonstrate that the risk of AIDS is related directly to age but also suggest that older adults are disproportionately affected during the earlier phases of HIV disease, that adolescents may have a low replication rate of HIV, and that children and adolescents may tolerate severe immunodeficiency better because they have fewer other infections or because of some unmeasured, age-dependent cofactor or immune alteration in the later phase of HIV disease.
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