HIV-1 RNA levels and development of clinical disease in two different adolescent populations

HIV infection rates in American youth continue to increase unabated. As adolescent-specific therapeutic interventions are planned, information on HIV infection's course and its predictors becomes critically important for valid and precise study design. We report on age-specific disease rates stratified by estimated time since infected and predictors of HIV disease progression through four clinical categories in two distinct adolescent populations. Adolescents with hemophilia infected through contaminated blood products showed disease progression rates of 18 to 23 events per 100 person-years (PYs) by age and years infected. Predictors of first progression included HIV-1 RNA >30,000 copies/ml (rate ratio [RR], 2.4; 95% confidence interval [CI], 1.5-3.9), antiretroviral monotherapy (RR, 2.4; 95% CI, 1.7-3.3); Latino/a ethnicity (RR, 2.2; 95% CI, 1.2-4.2) and initial intermediate clinical status (RR, 1.9; 95% CI, 1.3-2.9). Sexually-infected adolescents >18 years who had been infected >3 to 6 years had a disease progression rate of 16 events per 100 PY. For these youths, the sole predictor of first progression was viral load (VL) (RR for VL >30,000 copies per ml, 8.4; 95% CI, 2.8-25.1). This article examines the predictive capacity of viral load and evaluates other cofactors for disease progression in different adolescent populations. These data will be of value in clinical trial design.     

Declining immune function in children and adolescents with hemophilia and HIV infection: effects on neuropsychological performance. Hemophilia Growth and Development Study

OBJECTIVE: To determine whether declines in immune functioning are associated with changes in neuropsychological performance in children and adolescents with hemophilia who are infected with the human immunodeficiency virus (HIV). METHODS: Participants were 333 males with hemophilia, ages 6-19 years at entry. A baseline and four annual neuropsychological evaluations were given. A longitudinal growth curves analysis of data was performed to detect changes associated with declining immune function. The cohort was stratified into four groups: (1) HIV- (n = 126); (2) HIV+, average of first two and last two CD4 counts > or = 200, (n = 106; High CD4 group); (3) HIV+, average first two counts > or = 200, average last two counts < 200 (n = 41; CD4 Drop group); and (4) HIV+, average first two and last two counts < 200 (n = 60; Low CD4 group). RESULTS: There were significant differences among the four groups over time in nonverbal intelligence, perceptual/performance skills, nonverbal memory, academic achievement, and language. The Low CD4 group consistently showed the greatest decrement in performance. On measures showing a practice effect for repeated measurements, the Low CD4 group participants' scores remained stable over time, suggesting opposing effects of practice and HIV-related declines. Lowered academic performance relative to IQ was found in all groups. CONCLUSIONS: Declines in neuropsychological functioning are directly related to declines in immune functioning in HIV+ children, adolescents, and young adults with hemophilia. Hemophilia itself may be a risk factor for academic underachievement.     

Longitudinal neurological follow-up of a group of HIV-seropositive and HIV-seronegative hemophiliacs: results from the hemophilia growth and development study

BACKGROUND: Boys and young men with hemophilia treated with factor infusions before 1985 had a substantial risk of acquiring the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome. This study was designed to assess the effects of HIV and hemophilia per se on neurological function in a large cohort of subjects with hemophilia, and to investigate the relationships between neurological disease and death during follow-up. METHODS: Three hundred thirty-three boys and young men (207 HIV seropositive and 126 HIV seronegative) were evaluated longitudinally in a multicenter, multidisciplinary study. Neurological history and examination were conducted at baseline and annually for 4 years. The relationship between neurological variables, HIV serostatus, CD4+ cell counts, and vital status at the conclusion of the study was examined using logistic regression models. RESULTS: The risks of nonhemophilia-associated muscle atrophy, behavior change, and gait disturbance increased with time in immune compromised HIV-seropositive subjects compared with HIV seronegative or immunologically stable HIV-seropositive subjects. The risk of behavior change in immune compromised HIV-seropositive hemophiliacs, for example, rose to 60% by year 4 versus 10% to 17% for the other study groups. Forty-five subjects (13.5%), all of whom were HIV seropositive, died by year 4. Subjects who died had had increased risks of hyperreflexia, nonhemophilia-associated muscle atrophy, and behavior change. CONCLUSIONS: These results indicate that immune compromised, HIV-seropositive hemophiliacs have high rates of neurological abnormalities over time and that neurological abnormalities were common among subjects who later died. By contrast, immunologically stable HIV-seropositive subjects did not differ from the HIV-seronegative participants. Hemophilia per se was associated with progressive abnormalities of gait, coordination, and motor function.     

Response to measles, mumps, and rubella revaccination among HIV-positive and HIV-negative children and adolescents with hemophilia. Hemophilia Growth and Development Study.

The effect of human immunodeficiency virus (HIV) infection on response to measles, mumps, and rubella revaccination in children and adolescents with hemophilia was evaluated. Antibody levels of measles, mumps, and rubella were assayed at baseline and two annual examinations in 207 HIV-positive and 126 HIV-negative hemophiliacs participating in the Hemophilia Growth and Development Study (HGDS). Response to revaccination was analyzed for participants whose antibody levels were below the cut-off at the start of a year-long observation period. Among HIV-positive participants, antibody levels were below cut-off in 52 subjects for measles, in 71 for mumps, and in 96 for rubella. Among HIV-negative participants, antibody levels were low in 23 subjects for measles, in 23 for mumps, and in 31 for rubella. For measles and mumps antigens, revaccination was associated with a significant increase in redraw antibody levels for HIV-negative participants. Although there was an increase in the mean measles titers for revaccinated HIV-positive participants, it was not significant. Revaccination was associated with an increase in rubella antibodies in HIV-positive and HIV-negative participants. Revaccination with measles and mumps was associated with an increase in antibody levels in HIV-negative participants but not in HIV-positive participants. Both HIV-positive and HIV-negative participants responded to rubella revaccination with an increase in antibody levels.     

Cost and outcome: comparisons of two alternative bypassing agents for persons with haemophilia A complicated by an inhibitor

The development of inhibitory antibodies to factor VIII is a serious complication of haemophilia. Two haemostatic agents with different bypassing mechanisms have been used in the treatment of patients with inhibitors: activated prothrombin complex concentrate (aPCC) and recombinant factor VIIa (rFVIIa). The objective was to compare cost and outcome of aPCC and rFVIIa in the treatment of joint bleeds. The analyses were based on the FENOC (FEIBA NovoSeven Comparative Study) crossover study where 48 patients used aPCC and rFVIIa to treat two joint bleeds. Incremental cost-effectiveness ratios were calculated for three outcome measures and the variation in cost was analyzed using two alternative regression methods. Results were subjected to sensitivity analyses. Key determinants of cost were prescribed dose, bodyweight and treatment in addition to protocol. The cost of aPCC was on average lower than rFVIIa. At all but one time point, patients rated slightly higher (but not statistically significantly) percentages of treatment efficacy and stopping of the bleed by aPCC. The reported reduction in pain from start of treatment up to 48 hours varied considerably among individuals. The different relative prices in the US, Turkey and Sweden mattered, but did not reverse the main results. In conclusion, the cost per episode was significantly lower for aPCC. The large individual-level variation in reduction of pain supports decisions that consider the individual patient's experience and that accept trade-offs between cost and reduction in pain rather than focusing on cost only.     

F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort

Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in haemophilia A. It has been suggested that differences in the distribution of FVIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Data from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1 + H2) and inhibitor risk among individuals of genetically determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and human leucocyte antigen (HLA) were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Haplotype 3 was associated with higher inhibitor risk among those genetically identified (N = 49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N = 223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Haplotype 3 was not an independent predictor of inhibitor risk. Furthermore, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual.     

Evaluation of IL10, IL19 and IL20 gene polymorphisms and chronic hepatitis B infection outcome

Hepatitis B virus (HBV) infection remains a serious global health problem despite the availability of a highly effective vaccine. Approximately 5% of HBV-infected adults develop chronic hepatitis B, which may result in liver cirrhosis or hepatocellular carcinoma. Variants of interleukin-10 (IL10) have been previously associated with chronic hepatitis B infection and progression to hepatocellular carcinoma. Single nucleotide polymorphisms (SNP; n = 42) from the IL10, IL19 and IL20 gene regions were examined for an association with HBV infection outcome, either chronic or recovered, in a nested case-control study of African Americans and European Americans. Among African Americans, three nominally statistically significant SNP associations in IL10, two in IL20, and one haplotype association were observed with different HBV infection outcomes (P = 0.005-0.04). A SNP (rs1518108) in IL20 deviated significantly from Hardy-Weinberg equilibrium in African Americans, with a large excess of heterozygotes in chronic HBV-infected cases (P = 0.0006), which suggests a strong genetic effect. Among European Americans, a nominally statistically significant SNP association in IL20 and an IL20 haplotype were associated with HBV recovery (P = 0.01-0.04). These results suggest that IL10 and IL20 gene variants influence HBV infection outcome and encourage the pursuit of further studies of these cytokines in HBV pathogenesis.     

Virologic and clinical features of primary infection with human parvovirus 4 in subjects with hemophilia: frequent transmission by virally inactivated clotting factor concentrates

BACKGROUND: Human parvovirus 4 (PARV4) is a newly discovered parvovirus prevalent in injecting drug users and other groups with histories of parenteral exposure including persons with hemophilia exposed to non–virally inactivated clotting factor concentrates. To investigate its potential ongoing transmission to persons with hemophilia treated with plasma‐derived, virally inactivated clotting factors, we screened a large cohort of persons with hemophilia for antibody seroconversion to PARV4 over a 5‐year observation period. STUDY DESIGN AND METHODS: Samples from 195 persons with hemophilia enrolled in the Hemophilia Growth and Development Study cohort were screened for PARV4 antibodies at the start and end of a 5‐year period of treatment with exclusively virally inactivated clotting factor concentrates. Samples collected at intermediate time points from subjects seroconverting over the study period were screened to narrow down the seroconversion time and investigate immunoglobulin (Ig)M responses, duration of acute viremia, and clinical presentations. RESULTS: PARV4 seroprevalence at the outset of the study was 44%. Over the observation period, nine subjects (seven human immunodeficiency virus positive) seroconverted for anti‐PARV4 (incidence, 1.7%/year). Infected subjects showed relatively prolonged durations of viremia (mean, 7 months) and weak, transient IgM responses during acute infections. Clotting factors inactivated by solvent/detergent or by wet or dry heat were infectious. The most common clinical presentations were rashes and exacerbation of hepatitis. CONCLUSION: This study identifies PARV4 as a transfusion‐transmissible agent that is resistant to viral inactivation. Of concern, infections may still regularly occur in those exposed to plasma‐derived blood products. Urgent evaluation of the incidence of PARV4 in treated individuals and disease associations of PARV4 infections is required.