Multicenter Hemophilia Cohort Study Research Articles

359. TLR7 Gene Polymorphisms Influence Development of Hepatic Fibrosis in HCV/HIV Coinfection

BackgroundHepatic fibrosis in individuals with HCV/HIV coinfection or HCV mono-infection may be modulated by a variety of host factors. In this study, we investigated the role of gene polymorphisms of putative genes that might influence fibrosis progression including MICA (rs2596542), interferon-stimulated gene OAS2 (rs1293762) and the pathogen recognition receptors TLR7 (rs179009) and TLR9 (rs187084). Effect on a cytokine panel was evaluated.MethodsLongitudinal samples were obtained from subjects enrolled in the NCI Multicenter Hemophilia Cohort Study. Within the cohort, a subset of subjects were included based upon presence or absence of the CCR5 delta-32 mutation which was previously shown to influence the rate of fibrosis progression. Hepatic fibrosis change was determined using the serum-derived Enhanced Liver Fibrosis (ELF) Index. Four putative genes with polymorphisms that have been previously associated with the development or progression of hepatic fibrosis were evaluated using Taqman SNP genotyping assays. Cytokine assays were performed using Luminex chipsets. Samples were analyzed using Statistix 10.0 using ANOVA and least square regression models.Results58 unique subjects were evaluated. The mean age was 38 years, and all were male. 74% were HIV infected and 97% were HCV infected (76.8% coinfection). Controlling for the effect of CCR5, only the TLR7 A -> G polymorphism was predictive of change in the ELF Index. There was no statistically significant predictive difference between genotypes in the other three polymorphisms. Subjects with the TLR7 A allele (n = 47) had an average increase in ELF of 0.79 units, while the G allele (n = 11) had an increase in ELF of 2.1 units (P = 0.008). A regression model identified TLR7 as a key factor in ELF change, as well as HCV/HIV coinfection. Interferon alfa-2 levels were highly associated (increased, P = 0.0007) with the TLR7 A -> G polymorphism, while RANTES levels were inversely associated (decreased, P = 0.0443) with it.ConclusionOf the gene polymorphisms investigated, only TLR7 (rs179009) is an independent predictor of development of hepatic fibrosis in HCV/HIV coinfected subjects. The mechanism may involve modulation of inflammatory response pathways.Disclosures All authors: No reported disclosures.

Abstract W P392: Incidence Of Ischemic Or Hemorrhagic Non-fatal Strokes In Hemophiliac Adults And Teenage Children

Background: Persons with hemophilia are at high risk for spontaneous or prolonged bleeding, including intracranial hemorrhage. However, the incidence of ischemic or hemorrhagic stroke has not been studied in hemophiliac adults and teenage children. Methods: We analyzed data from the Second Multicenter Hemophilia Cohort Study (MHCS-II) that enrolled patients ≥13 years who had a congenital coagulation disorder [hemophilia A or B (congenital factor VIII or IX deficiency), von Willebrand's disease, or other], and who had serological or molecular evidence of HCV or HIV-1 infection. Participant’s medical history (including factor concentrate use), a targeted physical examination, and blood tests were performed at baseline and annually for three to four years. Person-years were estimated from the date of follow-up (the first blood sample) to the date of an event of interest (stroke), death, or censoring. We use Kaplan Meier analysis to estimate the probability of stroke or death in the study cohort. Results: A total of 2569 hemophiliac persons (age range = 13-88 years, men n=2431 (94.8%)) were recruited at 52 collaborating hemophilia centers in North and South America and Europe. The severity of hemophilia was classified as mild (>5%) (n=511, 19.9%), moderate (1-5%) (n=490, 19.1%) and severe (<1%) (n=1561, 60.9%) based on von Willebrand Type (type 1,2,3 respectively). A total of 1996 (77.8%) and 584 (22.8%) had received transfusions with factor VII and factor IX, respectively. A total of 4 participants developed stroke (including 1 intracerebral hemorrhage) over 4.5 year’s follow-up period with an estimated incidence of 0.034 per person 100 years. Conclusions: The rate of stroke appears to be low in adults and teenage children in a cohort of hemophiliacs with predominantly moderate and severe disease.

Free Light Chains and the Risk of AIDS-Defining Opportunistic Infections in HIV-Infected Individuals

The relevance of B-cell dysfunction for progression to AIDS among human immunodeficiency virus (HIV)-infected individuals has not been clearly defined. We evaluated the association between circulating κ and λ free light chains (FLCs), which are markers of B-cell dysfunction, and risk of developing an AIDS-defining opportunistic infection in HIV-infected men. The study included 252 case patients with clinical AIDS and 252 HIV-infected controls from the Multicenter Hemophilia Cohort Study I. Case patients were matched to controls on birth date, specimen type, blood sample collection date, and CD4 cell count. Levels of κ and λ FLCs were measured in serum or plasma collected 0-2.5 years before selection. Elevated FLC levels (κ or λ, above the upper limit of normal) were classified as polyclonal (normal κ-λ ratio) or monoclonal (abnormally skewed κ-λ ratio). We used conditional logistic regression to estimate odds ratios (ORs) for AIDS. FLC levels were higher in case patients than in controls, for κ (median, 4.03 vs 2.98 mg/dL) and λ (3.77 vs 2.42 mg/dL) FLCs. Compared with normal levels, above-normal FLC levels were associated with AIDS (OR, 3.13 [95% confidence interval (CI), 1.78-5.49] for κ and 3.47 [2.31-5.20] for λ FLCs), and the association with AIDS was strengthened with increasing κ and λ FLC levels (P trends < .0001). Polyclonal FLC elevation was associated with a 4-fold increase in the risk of AIDS (OR, 3.85; 95% CI, 1.97-7.54), but monoclonal FLC elevation was not associated with AIDS. Circulating FLCs are associated with elevated risk of AIDS in HIV-infected individuals. Polyclonal B-cell dysfunction may contribute to HIV-related immune suppression and predispose to clinical AIDS events.

Acute pyelonephritis and renal scarring are caused by dysfunctional innate immunity in mCxcr2 heterozygous mice

The CXCR1 receptor and chemokine CXCL8 (IL-8) support neutrophil-dependent clearance of uropathogenic Escherichia coli from the urinary tract. CXCR1 is reduced in children prone to pyelonephritis, and heterozygous hCXCR1 polymorphisms are more common in this patient group than in healthy individuals, strongly suggesting a disease association. Since murine CXCR2 (mCXCR2) is functionally similar to human CXCR1, we determined effects of gene heterozygosity on the susceptibility to urinary tract infection by infecting heterozygous (mCxcr2+/−) mice with uropathogenic Escherichia coli. Clearance of infection and tissue damage were assessed as a function of innate immunity in comparison to that in knockout (mCxcr2−/−) and wild-type (mCxcr2+/+) mice. Acute sepsis-associated mortality was increased and bacterial clearance drastically impaired in heterozygous compared to wild-type mice. Chemokine and neutrophil responses were delayed along with evidence of neutrophil retention and unresolved kidney inflammation 1 month after infection. This was accompanied by epithelial proliferation and subepithelial fibrosis. The heterozygous phenotype was intermediate, between knockout and wild-type mice, but specific immune cell infiltrates that accompany chronic infection in knockout mice were not found. Hence, the known heterozygous CXCR1 polymorphisms may predispose patients to acute pyelonephritis and urosepsis.

HLA-B alleles associate consistently with HIV heterosexual transmission, viral load, and progression to AIDS, but not susceptibility to infection.

HLA class I polymorphism is known to affect the rate of progression to AIDS after infection with HIV-1. Here we test the consistency of HLA-B allelic effects on progression to AIDS, heterosexual HIV transmission, and 'set point' viral levels. We used adjusted Cox proportional hazard models in previously published relative hazard values for the effect of HLA-B alleles on progression to AIDS (n = 1089). The transmission study included 303 HIV-1-infected men with hemophilia and their 323 female sex partners (Multicenter Hemophilia Cohort Study cohort). Among 259 HIV-1 seroconverters (Multicenter AIDS Cohort Study cohort), HIV RNA levels at 'set point' were determined in stored plasma samples by a reverse-transcription polymerase chain reaction assay. HLA-B genotyping was performed by sequence-specific oligonucleotide hybridization and DNA sequencing. Several HLA-B alleles showed consistent associations for AIDS risk, infectivity, and 'set point' HIV RNA. HLA-B*35 was associated with more rapid progression to AIDS (relative hazard 1.39; P = 0.008), greater infectivity (odds ratio 3.14; P = 0.002), and higher HIV RNA (P = 0.01), whereas the presence of either B*27 or B*57 associated with slower progression to AIDS (B*27: relative hazard 0.49, P < 0.001; B*57: relative hazard 0.40, P < 0.0001), less infectivity (odds ratio 0.22 and 0.31, respectively, though not significant), and lower viral levels (P < 0.0001). Importantly, HLA-B polymorphism in female partners was not associated with susceptibility to HIV-1 infection. HLA-B polymorphisms that affect the risk of AIDS may also alter HIV-1 infectivity, probably through the common mechanism of viral control, but they do not appear to protect against infection in our cohort.

Host Genetic Influences on Highly Active Antiretroviral Therapy Efficacy and AIDS-Free Survival

We studied the influence of AIDS restriction genes (ARGs) CCR5-Delta32, CCR2-64I, SDF1-3'A, IL10-5'A, CX3CR1-V249I, CX3CR1-T280M, and MDR1-C3435T and haplotypes of the CCR5 P1 promoter and RANTES variants -403A, In1.1C, 3'222C, and -28G among HIV-1 infected patients on highly active antiretroviral therapy (HAART) in the Multicenter AIDS Cohort Study (MACS) and the Multicenter Hemophilia Cohort Study (MHCS). Our results indicate that several ARGs also influence therapy efficacy (ie, the success in viral suppression) and subsequent progression to AIDS while on HAART. CCR5-Delta32 decreased time to viral suppression (<200 HIV RNA copies/mL, relative hazard [RH]=1.40; P=0.008) and was protective against AIDS (RH=0.11; P=or<0.0001), whereas the CCR5 P1 haplotype was associated with delayed viral suppression (RNA<50 copies/mL, odds ratio [OR]=0.65; P=0.03) and accelerated time to AIDS (RH=2.68; P=0.02). SDF1-3'A reduced viral suppression (OR=0.61; P=0.02) and accelerated AIDS (RH=3.18; P=0.009). Accelerated AIDS progression was also observed with the RANTES haplotype carrying RANTES-IN1.1C and RANTES-3'222C (P=0.005 to 0.007). In contrast, the RANTES haplotype H1, which lacks suspected deleterious single-nucleotide polymorphisms, was protective against AIDS. CX3CR1-V249I seemed to accelerate viral suppression (RNA<50 copies/mL, OR=1.27; P=0.01). ARG influence after HAART suggests residual HIV-1 replication, and spread continues even in patients successfully suppressing detectable viral RNA.

Coping with the HIV epidemic 1982–2007: 25‐year outcomes of the Hershey Haemophilia Cohort

Coping with the HIV epidemic 1982–2007: 25‐year outcomes of the Hershey Haemophilia Cohort

Correlates of Spontaneous Clearance of Hepatitis C Virus among HIV-Infected Persons with Hemophilia.

Up to the late 1980s, hepatitis C virus (HCV) infected the majority of people with hemophilia (PWH) in the United States (US), via contaminated plasma clotting factor therapy. Approximately two-thirds of the HCV-infected PWH in the US also were infected with human immunodeficiency virus (HIV). The Second Multicenter Hemophilia Cohort Study (MHCS-II) investigated complications of HCV and HIV infections in people with hemophilia. From 2001 - 2005, data and specimens were collected from 2561 anti-HCV positive participants, including 763 who were co-infected with HIV. These data were analyzed for correlates of spontaneous HCV clearance.Results. Of the 763 HIV-positive, anti-HCV-positive participants, 285 were eliminated from the analysis because they had received interferon treatment to clear HCV, lacked HCV treatment data, or lacked sufficient specimens to determine HCV clearance status. Of the remaining 478 interferon-untreated participants, 61 (12.8%) had cleared HCV RNA from plasma. HCV had cleared in 8.6% of the 116 who were never infected with hepatitis B virus (HBV), 11.6% of 207 with resolved HBV infection, and 8.9% of 124 with missing HBV status (P≥ 0.41). In contrast, HCV had cleared in 16 (51.6%) of the 31 participants with chronic HBV surface antigen (HBsAg) in serum. Adjusted for gender and race, HCV clearance was increased 7.4-fold (95% CI 3.7 - 15.0) for those with chronic HBsAg. In the HBsAg negative group, HCV clearance was significantly lower among participants of African ancestry (1.6%, p=0.01) and was significantly lower in PWH with severe compared to mild or moderate coagulopathy (8.2% vs 15.9%, p=0.02). Clearance was unrelated to type of initial clotting factor replacement therapy, year of birth, year of primary HCV infection, age at primary HCV infection, age at HIV infection, and year of enrollment in the cohort. HCV clearance occurred in 2 (12.5%) of the 14 participants in whom primary HCV infection occurred after or within one year of HIV infection, compared to 9.1% when HCV infection occurred more than one year before HIV (p=0.65). HCV clearance was unrelated to CD4 count at cohort enrollment, history of immunologically or clinically defined AIDS, and detection of HIV RNA in plasma at cohort enrollment. HCV clearance tended to be higher among the 231 participants on HAART (12.6%) than in those on less intensive (9.1%), anomalous (6.7%) or no anti-HIV therapy (6.5%, Ptrend=0.07), although when restricted to non-African ancestry males, HIV therapy was not associated with clearance (Ptrend=0.26).Conclusion. Unlike in HIV-negative people with hemophilia, HCV clearance in the current study was unrelated to age at or year of primary HCV infection. We were unable to evaluate repeated exposure to and likely re-infection with HCV, although the lower clearance in patients with severe hemophilia, who would have been treated, and thus exposed more frequently, supports the hypothesis of lower clearance with re-infection. While reduced overall, spontaneous HCV clearance was markedly increased by the presence of chronic HBsAg carriage. These findings will increase our understanding of interactions between these viruses and may lead to improved approaches to treatment of co-infected patients.

HCV quasispecies evolution: association with progression to end-stage liver disease in hemophiliacs infected with HCV or HCV/HIV

AbstractPatients with inherited bleeding disorders who received clotting factor concentrates before 1987 have high rates of hepatitis C virus (HCV) or HCV/HIV infection. We evaluated HCV quasispecies evolution in longitudinally collected specimens comparing those from patients with progression to end-stage liver disease (ESLD; cases) to those with compensated chronic hepatitis (controls). Plasma samples were obtained from the National Cancer Institute Multicenter Hemophilia Cohort Study. Controls were matched for age, sex, infection duration, and presence/absence of HIV. Samples from early infection were compared to those obtained after onset of ESLD in the cases. The first hypervariable (HVR1) and core proteincoding regions were amplified, subcloned, and sequenced. Complexity and diversity were determined. More than 700 sub-clones from 10 pairs of patients (8 with HIV) followed over approximately 9.3 years were evaluated. HVR1 complexity narrowed over time in the cases, whereas it increased in controls (P = .01). Similar trends were observed for diversity within HVR1 and the core region (P = .04). HCV-infected patients with inherited bleeding disorders undergo quasispecies evolution over time. Evolution patterns differ for progressors and nonprogressors. Further understanding of these mechanisms may help identify factors related to progression rate and treatment response.

Cellular HIV-1 DNA load predicts HIV-RNA rebound and the outcome of highly active antiretroviral therapy

To assess whether cellular HIV-1 DNA prior to highly active antiretroviral therapy (HAART) initiation predicts its outcome. Patients included all 51 hemophiliacs of the Greek component of the Multicenter Hemophilia Cohort Study who had initiated HAART and for whom cryopreserved lymphocyte samples before HAART initiation were available. Cellular HIV-1 DNA quantification was performed by a molecular beacon-based real-time PCR assay in multiple samples per patient with a median (interquartile range) follow-up of 76 (45-102) weeks. The median (range) baseline HIV-1 DNA load was 297 (< 10 to 3468) copies per 1 x 10(6) peripheral blood mononuclear cells. Baseline HIV-1 DNA load did not predict initial virological response (VR). None of the patients with initial VR and baseline HIV-1 DNA load at or below the median experienced a subsequent virological rebound, while the cumulative probability of virological rebound by week 104 was 55% among those with HIV-1 DNA load greater than the median (P < 0.008). Cellular HIV-1 DNA load was the only parameter associated with sustained virological response as shown by univariate or multivariate analyses [adjusted odds ratio (95% confidence interval) 0.197 (0.048-0.801) per 1 log10 increase in DNA copies, P = 0.023]. Low cellular HIV-1 DNA load is a marker of sustained virological response in patients with initial VR and it can reliably predict the long-term success of HAART.

Quantitation of human immunodeficiency virus type 1 DNA forms with the second template switch in peripheral blood cells predicts disease progression independently of plasma RNA load.

There are several forms of human immunodeficiency virus type 1 (HIV-1) DNA in peripheral blood T cells and lymph nodes in untreated HIV-1-infected individuals and in patients whose plasma HIV-1 RNA levels are suppressed by long-term combination antiretroviral therapy. However, it remains to be established whether the concentration of HIV-1 DNA in cells predicts the clinical outcome of HIV-1 infection. In this report, we measured the concentration of HIV-1 DNA forms which has undergone the second template switch (STS DNA) and 2-long-terminal-repeat DNA circles in peripheral blood mononuclear cell (PBMC) samples. To do this, we used molecular-beacon-based real-time PCR assays and studied 130 patients with hemophilia in the Multicenter Hemophilia Cohort Study. We assessed the influence of baseline HIV-1 STS DNA levels on the progression of HIV-1 disease in the absence of combination antiretroviral therapy by Kaplan-Meier and Cox regression analysis. Among the patients who progressed to AIDS, the median levels (interquartile ranges) of STS HIV-1 DNA in PBMC were significantly higher than those of patients who remained AIDS free during the 16 years of follow-up (1,017 [235 to 6,059] and 286 [31 to 732] copies per 10(6) PBMC, respectively; P < 0.0001). Rates of progression to death and development of AIDS varied significantly (log rank P < 0.001) by quartile distribution of HIV-1 STS DNA levels. After adjustment for age at seroconversion, baseline CD4(+) T-cell counts, plasma viral load, and T-cell-receptor excision circles, the relative hazards (RH) of death and AIDS were significantly increased with higher HIV-1 STS DNA levels (adjusted RH, 1.84 [95% confidence interval (CI), 1.30 to 2.59] and 2.62 [95% CI, 1.75 to 3.93] per 10-fold increase per 10(6) PBMC, respectively). HIV-1 STS DNA levels in each individual remained steady in longitudinal PBMC samples during 16 years of follow-up. Our findings show that the concentration of HIV-1 STS DNA in PBMC complements the HIV-1 RNA load in plasma in predicting the clinical outcome of HIV-1 disease. This parameter may have important implications for understanding the virological response to combination antiretroviral therapy.

Characterization of high-risk HIV-1 seronegative hemophiliacs.

Mechanisms that protect most high-risk HIV-1 seronegative (HRSN) persons are not well understood. Among hemophiliacs from the Multicenter Hemophilia Cohort Study who remained HIV-1 seronegative despite a high (94%) risk for acquisition of HIV-1 infection, only 7/43 were homozygous for the protective CCR5 Delta32 polymorphism. Among the remainder, neither CCR5 density nor beta-chemokine production, nor in vitro susceptibility to infection with the HIV-1 isolate JR-FL could distinguish HRSN hemophiliacs from healthy controls. When compared to lymphocytes of healthy controls not at risk for HIV-1 infection, diminished spontaneous lymphocyte proliferation was seen in lymphocytes of HRSN hemophiliacs as well as in lymphocytes of hemophiliacs not at risk for HIV-1 infection. Surprisingly sera/plasmas obtained from high-risk HIV-1 seropositve hemophiliacs prior to seroconversion more often contained alloreactive antibodies than date-matched sera/plasmas obtained from HRSN hemophiliacs. Thus alloreactivity may predispose to acquisition of HIV-1 infection after parenteral exposure.

Virus load and risk of heterosexual transmission of human immunodeficiency virus and hepatitis C virus by men with hemophilia. The Multicenter Hemophilia Cohort Study.

A high human immunodeficiency virus (HIV) load may increase the probability of HIV transmission by sexual contact, but the association of virus load of hepatitis C virus (HCV) with risk of HCV transmission is uncertain. HIV and HCV virus loads were examined in hemophilic men, as were risks of HIV and HCV transmission to their female partners in a hemophilia cohort in which most subjects are dually infected. A higher HIV load was associated with an increased risk of HIV transmission (odds ratio [OR], 1.31 per log10 increase in virus load). A higher HCV load was associated, although not significantly, with an increased risk of HCV transmission (OR, 1. 42 per log10). HCV load was higher among dually infected men than in those infected with HCV alone (P=.001). However, much larger studies are needed to clearly show whether HIV/HCV coinfection significantly increases the risk of HCV transmission to female partners.

Effect of recent thymic emigrants on progression of HIV-1 disease

The concentration of T-cell receptor-rearrangement excision DNA circles (TREC) in peripheral-blood T cells is a marker of recent thymic emigrant alphabeta T cells. We studied the predictive ability of measurements of TREC for clinical outcome in HIV-1-infected individuals. We measured TREC in peripheral-blood mononuclear cells with a real-time PCR assay. We studied 131 Greek participants in the Multicenter Hemophilia Cohort Study who had known HIV-1 seroconversion dates. The prognostic value of baseline TREC, CD4 T-cell count, and HIV-1 RNA concentration was assessed by Kaplan-Meier and Cox's regression analysis. Four participants had progressed to AIDS by first blood sampling. Among the remaining 127 individuals, the median value of TREC per 10(6) cells was 6900 (IQR 2370-15604). Baseline TREC values were lower in the 53 who progressed to AIDS than in those who did not (geometric mean 2843 [95% CI 1468-5504] vs 6560 [4723-9113] per 10(6) cells; p=0.017). The relative hazard of AIDS, adjusted for plasma viral load, CD4 T-cell count, and age at seroconversion was 1.44 (95% CI 1.04-2.01; p=0.031) per ten-fold increase in TREC; that for death was 1.52 (1.12-2.06; p=0.007). The adjusted relative hazards of death were 2.91 (1.91-4.44; p<0.001) per ten-fold increase in plasma HIV-1 RNA load and 1.20 (1.04-1.38; p=0.014) per 100-cell decrease in CD4 T-cell count. The concentration of TREC in the peripheral T-cell pool complements HIV-1 RNA load and CD4 T-cell count in predicting the rate of HIV-1 disease progression. Recent thymic emigrants have a role in the pathogenesis of HIV-1 disease.

Estimating the cumulative incidence of HIV infection among persons with haemophilia in the United States of America.

We used complementary approaches to estimate the cumulative incidence of infection with the human immunodeficiency virus (HIV) among persons with haemophilia in the United States of America. One approach, ratio estimation, divided the cumulative number of haemophiliacs diagnosed with acquired immunodeficiency syndrome (AIDS) in the United States by the corresponding cumulative proportion with AIDS among HIV-positive subjects in the Multicenter Hemophilia Cohort Study (MHCS). The other approach, back-calculation, reconstructed past HIV incidence from national surveillance of AIDS using essentially non-parametric estimates of the hazard functions for AIDS and for pre-AIDS death. We derived confidence intervals that fully incorporated uncertainty about the hazard functions. Results from the two approaches were consistent. Around 9200 haemophiliacs became infected during the course of the epidemic. Of them, around 7000 were living with HIV or AIDS as of 31 December 1992 and at least 5630 as of 31 December 1995. Credible calculations for this group must account for those who die before AIDS and for the significantly longer incubation times in those infected as children or adolescents. The consistency of back-calculation and cohort data in haemophiliacs supports the use of back-calculation to estimate prevalence in other populations.

Parvovirus B19 quiescence during the course of human immunodeficiency virus infection in persons with hemophilia.

To detect and characterize parvovirus B19 infection during the course of progressive immune deficiency from human immunodeficiency virus (HIV), ten subjects enrolled in the Multicenter Hemophilia Cohort Study were followed for 6.4 to 15 years from HIV seroconversion through extreme immune deficiency. Four to five sera or plasma samples from each subject, collected at predetermined CD4+ lymphocyte levels, were tested for immunoglobulin G (IgG) and M (IgM) B19 antibodies and DNA. All 42 samples were positive for B19 IgG antibodies, and three were weakly positive for IgM antibodies. Only one sample, collected coincident with HIV seroconversion, was unequivocally positive for B19 DNA. No persistent hematologic adverse effects of B19 infection were observed. Thus, although B19 IgG antibodies are highly prevalent among HIV-infected persons with hemophilia or related disorders, B19 viremia and its hematologic consequences were not detected, even with severe depletion of CD4+ lymphocytes. If primary B19 infection occurs after immune deficiency, however, the consequences may be more adverse.

Survival after AIDS diagnosis in a cohort of hemophilia patients. Multicenter Hemophilia Cohort Study.

We studied factors affecting survival after the diagnosis of AIDS in a cohort of 1253 patients with hemophilia. The nature of the AIDS-defining condition was found to be as important as age at seroconversion and CD4+ lymphocyte level in predicting survival. A multivariate analysis yielded estimates of median survival for groups defined by age at seroconversion (0 through 15, 16 through 69), CD4+ lymphocyte count (<100 cells/microl versus > or = 100 cells/microl), and 10 AIDS-defining disease groups. Estimates of median survival after a single AIDS-defining condition ranged from 3 to 51 months, depending on the diseases. Median survival after a second AIDS-defining condition was about 1.5- to 2.0-fold shorter than after an initial, isolated AIDS-defining condition. HIV-related neurologic disease (i.e., AIDS dementia complex or multifocal leukoencephalopathy) was a notable exception. It correlated with the shortest estimates of median survival (3 to 9 months), and this poor prognosis was no worse for patients who had a second AIDS-defining condition. The results of this analysis were consistent in most respects with other published analyses of factors affecting survival. These findings may be useful in the clinical care of persons with AIDS and in estimating the number of persons alive who have had a particular AIDS-defining disease.

Thrombocytopenia in HIV-infected and uninfected hemophiliacs. Multicenter Hemophilia Cohort study.

To determine the incidence and prognostic significance of thrombocytopenia among hemophiliacs, we analyzed clinical and hematologic data from the Multicenter Hemophilia Cohort study. Nineteen percent of HIV-infected subjects had thrombocytopenia (platelet count of <100,000/mm3) noted at least once, compared to 3% of HIV-uninfected subjects. For HIV-infected subjects, the prevalence of thrombocytopenia rose in the first 5 years after seroconversion and was twice as common in subjects age >35 years compared to younger subjects. The risk increased after an AIDS-defining illness, particularly among older subjects, nearly one-half of whom had thrombocytopenia within 1 year after AIDS. When adjusted for age and CD4-positive lymphocyte counts, thrombocytopenia was associated with an increased risk of death [relative risk (RR) 1.7, 95%CI = 1.2-2.3] but with little change in the risk of progression to AIDS (RR = 1.2, 95%CI = 0.8-1.7). Treatment with zidovudine was associated with a decreased risk of thrombocytopenia (RR = 0.5, 95%CI = 0.3-0.7). Although 59 HIV-infected subjects died of hemorrhage, only 11 (19%) of the 59 had a reported platelet count of <50,000/mm3, and only 2 (3%) of the deaths were temporally associated with thrombocytopenia. Thus, the risk of death was increased for thrombocytopenic HIV-infected hemophiliacs but this was not explained by an increased risk of developing AIDS and was rarely associated with death from bleeding.

Thrombocytopenia in HIV‐infected and uninfected hemophiliacs

To determine the incidence and prognostic significance of thrombocytopenia among hemophiliacs, we analyzed clinical and hematologic data from the Multicenter Hemophilia Cohort study. Nineteen percent of HIV-infected subjects had thrombocytopenia (platelet count of <100,000/mm3) noted at least once, compared to 3% of HIV-uninfected subjects. For HIV-infected subjects, the prevalence of thrombocytopenia rose in the first 5 years after seroconversion and was twice as common in subjects age >35 years compared to younger subjects. The risk increased after an AIDS-defining illness, particularly among older subjects, nearly one-half of whom had thrombocytopenia within 1 year after AIDS. When adjusted for age and CD4-positive lymphocyte counts, thrombocytopenia was associated with an increased risk of death [relative risk (RR) 1.7, 95%Cl = 1.2–2.3] but with little change in the risk of progression to AIDS (RR = 1.2, 95%Cl = 0.8–1.7). Treatment with zidovudine was associated with a decreased risk of thrombocytopenia (RR = 0.5, 95%Cl = 0.3–0.7). Although 59 HIV-infected subjects died of hemorrhage, only 11 (19%) of the 59 had a reported platelet count of <50,000/mm3, and only 2 (3%) of the deaths were temporally associated with thrombocytopenia. Thus, the risk of death was increased for thrombocytopenia HIV-infected hemophiliacs but this was not explained by an increased risk of developing AIDS and was rarely associated with death from bleeding. Am. J. Hematol. 54:296–300, 1997. © 1997 Wiley-Liss, Inc.

Dose of Non-Heat-Treated Factor VIII Concentrate and HIV-1 RNA Levels-Reply

In Reply. —Dr Montoro and colleagues recategorized our data and used a test for linear trend instead of the more conservative overall Mantel-Haenszel ϰ2test that we used. They point out that subjects who received lower annual doses of non-heat-treated factor VIII concentrate (between 1978 and 1984) had somewhat higher HIV-1 RNA levels. An association between lower factor VIII dose and higher HIV-1 RNA levels would be consistent with a recent report by Montoro et al that lower factor-concentrate dose was associated with faster progression to AIDS in 225 HIV-1-infected Spanish hemophiliac patients.1Therefore, we examined the relationship between factor VIII dose, HIV-1 RNA levels, and time to development of AIDS in our study, the Multicenter Hemophilia Cohort Study (MHCS). Although only a small subset of MHCS subjects were tested for HIV-1 RNA, data on factor VIII dose and clinical outcome were available for 1094 HIV-1-infected adults and children. As