Serologic response to hepatitis B vaccine in HIV infected and high-risk HIV uninfected adolescents in the REACH cohort. Reaching for Excellence in Adolescent Care and Health.

PURPOSE: To evaluate hepatitis B (HBV) vaccine response rates in HIV infected and high-risk HIV uninfected youth and examine associations with responsiveness in the HIV infected group. METHODS: Cohorts within the Reaching for Excellence in Adolescent Care and Health (REACH) study population were defined based on receipt of HBV vaccine both retrospectively and prospectively. Sero-responsiveness was determined by HBsAb measurements. Testing was done for HBsAg, HBsAb, and HBcAb. For HBsAb, a value of > 10 International Units per liter was considered a positive response, and the data were collected as either positive or negative from each of the reporting laboratories. Covariates of responsiveness were explored in univariate and multivariate models for each cohort. RESULTS: Sixty-one subjects had received a three-dose vaccination course at the time of entry into REACH. HIV uninfected subjects had significantly higher rates of response by serology compared with HIV infected subjects (70% vs. 41.1%; chi(2) = .05; RR = .586, 95% CI: .36-.96). By the time of an annual visit 43 subjects had received three vaccinations with at least one occurring in the study period. The rates of response were similar for the HIV infected and uninfected groups (37.1% vs. 37.5%) in this cohort. Univariate and multivariate analysis in the prospective HIV infected group (N = 35) found an association between elevated CD8(+)/CD38(+)/HLA-DR(+) T cells and lack of HBV vaccine responsiveness (6.7% vs. 60%; chi(2) = .03; RR = .12, 95% CI: .02- .55). CONCLUSIONS: The poor HBV vaccine response rate in the HIV uninfected high-risk adolescents was unexpected and suggests that HBV vaccination doses have not been optimized for older adolescents. This is the first report of decreased responsiveness in HIV infected subjects being associated with elevated CD8(+)/CD38(+)/HLA(-)DR(+) T cells and suggests that ongoing viral replication and concomitant immune system activation decreases the ability of the immune system in HIV infected subjects to respond to vaccination.

Performance of antigens used in detecting delayed-type hypersensitivity in adolescents infected with the human immunodeficiency virus.

We examined the performance of delayed-type hypersensitivity (DTH) antigens employing a new Candida albicans product in a human immunodeficiency virus (HIV)-infected and nonanergic adolescent population. Diameters of induration (in millimeters) for three intradermally applied antigens (C. albicans, tetanus toxoid, and mumps) were compared in a population of HIV-infected 12 to 18 year olds at study entry in a national multicenter study of HIV disease progression. CD4+ T-cell counts were measured in quality-controlled laboratories. The influence of past immunization, gender, and clinical status on antigen reactivity was evaluated with contingency table comparisons and relative risk estimation. Nearly one-half of the 123 eligible subjects were untreated, and almost three-quarters were early in HIV disease by clinical indicators. There was no statistically significant difference in reactivity by past immunization status. Candida antigen (CASTA; Greer Laboratories) evoked DTH response in a significantly higher number of males and females at every level of induration (largest P value, 0.049 for male comparisons; all P values, <0.001 for females) and in subjects with early and intermediate HIV disease at every level of induration (all P values, <0.0001) than either tetanus or mumps antigens. No two-antigen combination was as useful as all three antigens across either gender or clinical categories, although candida and tetanus was the most useful two-antigen combination at indurations of <3 mm. The superior performance of a new C. albicans antigen may extend the utility of DTH assessment in monitoring immune function.

The closeout process for a clinical trial terminated early for lagging enrollment and inadequate follow-up.

Closeout of a clinical trial, whether carried out to its original completion of full accrual and attendant follow-up or stopped prematurely because of early indications of efficacy or adverse toxicity, presents challenges in many areas. Closing a clinical trial that fails to adequately accrue and/or successfully follow up patients may exacerbate these problems. The issues involved in the early termination of the Low-Dose Oral Alpha Interferon Trial are described. Control Clin Trials 2001;22:49-55

The prevalence of anergy in human immunodeficiency virus-infected adolescents and the association of delayed-type hypersensitivity with subject characteristics.

PURPOSE: To examine the prevalence of anergy in HIV-infected adolescents and factors associated with its occurrence. METHODS: Anergy was defined as less than 2mm induration to each of three intradermally applied antigens (Candida albicans, tetanus toxoid, and mumps) between 24 and 96 hours in a population of HIV-infected adolescents aged 12-18 at entry in a national multicenter study of HIV disease progression. CD4(+) T-cell counts and plasma HIV-1 RNA were measured in quality controlled laboratories. Factors associated with the probability of anergy were examined with contingency table comparisons, tree-structured classification, and logistic regression analyses. RESULTS: Overall prevalence of anergy in this clinic-based population of 167 was 11% [7% in males and 12% in females (p = 0.57)]. The sole significant predictor of anergy was decreased CD4(+) T-cell count (p = 0.005). CONCLUSION: The prevalence of anergy is low in this HIV-infected population compared to older infected cohorts. The occurrence of differential rates of anergy in particular age and sex groupings that may be related to intrinsic immunologic differences requires further study.

Relationship of CD4+ T cell counts and HIV type 1 viral loads in untreated, infected adolescents. Adolescent Medicine HIV/AIDS Research Network.

The REACH Project (Reaching for Excellence in Adolescent Care and Health) of the Adolescent Medicine HIV/AIDS Research Network was designed as a study of an adolescent cohort composed of HIV-1-infected and -uninfected subjects. The goal of the analysis presented was to examine the relationship of CD4+ T cell counts and HIV-1 plasma viral loads in adolescents. The CD4+ T cell counts of 84 HIV+ subjects who were 13 to 19 years of age were measured at the clinical sites, using ACTG standardized techniques. HIV-1 viral loads in frozen plasma were determined by the NASBA/NucliSens assay at a central laboratory. Past and current treatment with antiretroviral drugs was determined by medical record abstraction and interview data. The slope of the line generated by regressing log10 HIV-1 RNA (copies/ml) versus CD4+ T cell counts of REACH subjects who are antiretroviral drug naive was negative and significantly different than zero. A negative association has also been reported for antiretroviral drug-naive, adult males in the Pittsburgh Men's Study, a component of MACS (Pitt-MACS) (Mellors J, et al.: Science 1996;272:1167). These data show that in adolescents, as in adults, HIV-1 RNA concentrations are correlated with corresponding absolute CD4+ T cell count. The slopes of the lines generated with data from each cohort were different (p = 0.003). In addition to age, there are sex and racial differences in the makeup of the two cohorts. Any or all of these differences may affect the slopes of the lines.

Cytokine profile in genital tract secretions from female adolescents: impact of human immunodeficiency virus, human papillomavirus, and other sexually transmitted pathogens.

Quantitative enzyme-linked immunosorbent assays were used to measure interleukin (IL)-2, IL-10, and IL-12 in cervical secretions from female adolescents with and without sexually transmitted infections. Compared with human immunodeficiency virus [HIV]-negative patients, HIV-positive patients had higher concentrations of IL-10 (118.2 pg/mL vs. 34.5 pg/mL; P=.002) and IL-12 (175.5 pg/mL vs. 85.1; P=.03). IL-2 concentrations were not statistically different. Furthermore, genital tract infections were predictors of IL-10 and IL-12 concentrations. Coinfection with HIV and human papillomavirus predicted the highest IL-10 concentrations; coinfection with HIV, human papillomavirus, and other sexually transmitted pathogens predicted the highest IL-12 concentrations. The data indicate that concomitant infection of the genital tract with HIV and other viral, bacterial, or protozoan pathogens influences the local concentrations of some immunoregulatory cytokines.

Prevalence of and risks for cervical human papillomavirus infection and squamous intraepithelial lesions in adolescent girls: impact of infection with human immunodeficiency virus.

CONTEXT: Data suggest that in adults, human papillomavirus (HPV) infections and their sequalae, squamous intraepithelial lesions (SILs), occur more commonly among human immunodeficiency (HIV)-infected women because of the HIV-associated CD4+ T-cell immunosuppression. Since adolescents are more likely to be early in the course of HIV and HPV infections, the study of both infections in this age group may help elucidate their initial relationship. OBJECTIVE: To examine the prevalence of and risks for cervical HPV infection and SILs by HIV status in a population of adolescent girls. PARTICIPANTS: Subjects recruited at each of the 16 different US sites participating in a national study of HIV infection in adolescents. MAIN OUTCOME MEASURES: Cervical HPV DNA findings using polymerase chain reaction detection techniques and Papanicolaou smear from baseline visits. Infection with HPV was categorized into low- (rarely associated with cancer) and high- (commonly associated with cancers) risk types. RESULTS: Of 133 HIV-infected girls, 103 (77.4%) compared with 30 (54.5%) of 55 noninfected girls were positive for HPV (relative risk [RR], 1.4; 95% confidence interval [CI], 1.1-1.8). The risk was for high-risk (RR, 1.8; 95% CI, 1.2-2.7) but not low-risk (RR, 1.2; 95% Cl, 0.4-3.9) HPV types. Among the girls with HPV infection, 21 (70.0%) of the non-HIV-infected girls had normal cytologic findings compared with only 29 (29.9%) of the HIV-infected girls (P<.001). Multivariate analysis showed that HIV status was a significant risk for HPV infection (odds ratio [OR], 3.3; 95% CI, 1.6-6.7) and SIL (OR, 4.7; 95% CI, 1.8-14.8), but CD4 cell count and viral load were not associated with infection or squamous intraepithelial lesions. Only 9 girls had a CD4+ T-cell count of less than 0.2 cell X 10(9)/L. CONCLUSIONS: High prevalence of HPV infection in both groups underscores the risky sexual behavior in this adolescent cohort. Rates of HPV infection and SILs were higher among HIV-infected girls, despite similar sexual risk behaviors and the relatively healthy state of our HIV-infected group. Infection with HIV may enhance HPV proliferation through mechanisms other than CD4 immunosuppression, particularly early in the course of HIV infection.

A multicenter, randomized, controlled trial of three preparations of low-dose oral alpha-interferon in HIV-infected patients with CD4+ counts between 50 and 350 cells/mm(3). Division of AIDS Treatment Research Initiative (DATRI) 022 Study Group.

To evaluate the effectiveness of low-dose oral alpha-interferon (alpha-IFN), 247 HIV-infected study subjects received placebo, Alferon LDO, Veldona, or Ferimmune in a randomized, double-blind trial. Subjects had CD4+ counts between 50 and 350 cells/mm3 and HIV-related symptoms at entry. Study subjects rated the severity of eight symptoms using a symptom burden index (SBI). Study endpoints included changes in SBI, weight, CD4+ count, and Karnofsky score between baseline and the 24-week visit. The SBI outcome and weight were measured in 99 and 106 study subjects, respectively, at both the baseline and 24-week visits. Baseline SBI scores ranged from 5.4 to 7.9 in the four arms. No clinically important or statistically significant differences were found among the four arms with regard to SBI or weight change over the 24-week period. There were also no significant differences among the arms for CD4+ cell count and Karnofsky score. Few adverse reactions were noted in any arm, and there were no significant differences between arms. Although the trial was designed to enroll 560 study subjects and was prematurely terminated because of slow accrual and discontinuations of participants, the small differences among the arms in the primary and secondary endpoints do not support claims of efficacy for the measures studied.

Febrile seizures: is the EEG a useful predictor of recurrences?

We examined the predictive value of a paroxysmal EEG in children with febrile seizures seen at the University Pediatric Clinic, Skopje, Macedonia, between 1982 and 1984. This was the only facility providing EEG or neurologic consultation for children in Macedonia, and almost all children in the area who experienced a febrile seizure were referred to this facility. EEGs were classified as epileptiform if they contained spikes and sharp waves or spike wave complexes, which were either focal or generalized, and were considered abnormal for age and state. Nonspecifically abnormal was defined as focal or generalized slowing excessive for age and state. Follow-up visits were scheduled at 6-month intervals; mean follow-up time was approximately 23 months. In order to determine whether clearly abnormal EEG features would predict recurrences, we compared the recurrences in 170 children with initial normal-appearing EEGs with 99 children with initial paroxysmal EEGs. There was no significant difference in risk of recurrence of febrile seizures between the two groups; increase in recurrence risk was determined primarily by younger age. The EEG did not add information regarding the likelihood of recurrence of febrile seizures.

Posttraumatic Amnesia as a predictor of outcome after severe closed head injury. Prospective assessment.

OBJECTIVES: To identify the demographic and clinical variables related to the duration of posttraumatic amnesia after severe closed head injury; to evaluate the usefulness of posttraumatic amnesia duration in predicting outcome at the time of hospital discharge and at 6 months after injury. SETTING: Four clinical centers located in primary care hospitals. PATIENTS: Three hundred fourteen severely injured subjects aged 16 years or older who did not have trauma as a result of a penetrating injury and came out of coma before hospital discharge. INTERVENTIONS: Approximately half of the subjects were administered phenytoin sodium for some period after termination of coma; 17% were administered dexamethasone and 41% morphine sulfate. MAIN OUTCOME MEASURES: Galveston Orientation and Amnesia Test scores defined the duration of posttraumatic amnesia. The Glasgow Outcome Scale was used to grade outcome at the time of hospital discharge and at 6 months. RESULTS: Older age, low initial Glasgow Coma Scale score, nonreactive pupil(s), coma duration, and use of phenytoin were associated with a longer duration of posttraumatic amnesia. Poor pupillary response, time in coma, and duration of posttraumatic amnesia and use of phenytoin was predictive of the 6-month outcome. CONCLUSIONS: The results support the prognostic usefulness of prospectively measuring duration of posttraumatic amnesia after termination of coma. Pending replication, our findings suggest that posttraumatic amnesia duration may be a useful surrogate outcome measure for clinical trials involving interventions for acute head injury.

Childhood neurological disorders in twins.

In order to examine neurological outcome in twins, a multi-centre prospective cohort study of infants was used. Women entered at the first prenatal visit, with follow-up of offspring to the age of 7 years. Outcome measures were death, cerebral palsy, seizure disorders including neonatal, febrile or nonfebrile, and intelligence quotient. Among a total of 52,364 livebirths, there were 1079 twins. Overall, rates of fetal or neonatal death and cerebral palsy were higher in twins. Neonatal and febrile seizures occurred with similar frequency in twins as in singletons. Although twins were much more likely than singletons to be low in birthweight, twins < 2500 g were not at higher risk for cerebral palsy than low birthweight singletons. The risk of cerebral palsy and of nonfebrile seizure disorders was similar in monozygous and dizygous pairs, and in like-sex and unlike-sex pairs. Death of one twin was associated with higher rates of cerebral palsy and of nonfebrile seizure disorders in survivors, but not with lowered intelligence. Data from this cohort suggest that low birthweight and survival status of the co-twin are dominant predictors of childhood neurological morbidity in twins.

Risk factors for seizure recurrence in children with febrile seizures: a pooled analysis of individual patient data from five studies.

To reassess the relations between postulated risk factors and seizure recurrence after a first febrile seizure (FS), the individual data from five follow-up studies that used similar definitions of FSs and risk factors were pooled and reanalyzed. The risk of frequent recurrent seizures and of the occurrence of complex seizures in previously healthy, untreated children was studied. Seizure recurrence hazard was described as a function of the child's attained age. The influence of various risk factors on the recurrence hazard was assessed, with control for other factors. Of a total of 2496 children with 1410 episodes of recurrent seizures, 32% had one, 15% had two, and 7% had three or more recurrent seizures after a first FS; 7% had a complex seizure. The hazard of recurrent seizures was highest between the ages of 12 and 24 months. After a first and a second recurrence, the risk of further FSs was two and two and one-half times higher, respectively. A history of febrile or unprovoked seizures in a first-degree family member and a relatively low temperature at the time of the first seizure were also associated with an increased risk of subsequent recurrences. Young age at onset (< 12 months), a family history of unprovoked seizures, and a partial initial FS were all associated with an increased risk of complex seizures. A higher recurrence rate in clinic-based studies compared with population-based studies could not be explained by a difference in the presence of the risk factors studied. Thus other factors must influence seizure recurrence after an initial FS.

Selection bias in observational and experimental studies.

There has been a heightened awareness of the dangers of selection bias over the past two decades. Certainly coverage in statistical and 'statistics for medicine', and epidemiology textbooks have allocated pages to warn investigators and readers of investigations to be aware of its presence. The scientific community has not, however, yet accepted the necessity for critical assessment of the method of sample selection in the planning and execution of studies as a fundamental underpinning of observational and experimental studies. To wit, we are faced with a plethora of research studies receiving funding, being published in peer-reviewed journals and influencing future studies, that may be reporting entirely spurious associations. It is the intent of this paper to present examples of selection bias in a variety of areas which have resulted in misleading or entirely incorrect results. We hope to help make such research scientifically 'politically incorrect' to the degree that the scientific community 'just says no' to such studies, either proposed or reported.

Differential postmorbidity mortality in observational studies of risk factors for neurologic disorders.

Selection bias may be introduced in case-control or cross-sectional studies, and the impact on the observed associations may be dramatic. Many authors have examined this issue primarily in the context of subject source (e.g. referral bias). The potential bias encountered when a risk factor associated with outcome is also associated with an increase in mortality among cases greater than that among those not developing the disease (e.g. selective survival) is examined here. The potential for selective survival bias arising in observational studies is demonstrated in studies of the etiology of neonatal seizures and Parkinson's disease.

Observational data bases in neurological disorders: selection bias and generalization of results.

Observational data bases in the neurological disorders may be an important source of information on etiology and natural history. The ability to make valid generalizations of results from a data base to the general population of patients with a particular disorder is not, however, guaranteed. The design or analysis of the study may result in selection biases that make inferences untenable. Examples are presented which demonstrate the potential for bias limiting the validity of inferences beyond the sample observed.

Does phenobarbital used for febrile seizures cause sleep disturbances?

The effect of phenobarbital on total sleep time, night awakenings, and lengthy awakenings was examined as part of a randomized trial of children with febrile seizures; information about sleep patterns was gathered by parental observation. Children were between ages 8-36 months at enrollment and were examined subsequently for 2 1/2 years. Night awakenings were not more common in children assigned to phenobarbital except for those who were poor sleepers at the beginning of the study. Total sleep time was no different in children assigned to phenobarbital than in those assigned to placebo. It is concluded that sleep problems reported in most young children with febrile seizures treated with phenobarbital did not exceed those reported in children treated with placebo, but a subset of predisposed children did experience an increase in night awakenings.

Perinatal 'TORCH' infections identified by serology: correlation with abnormalities in the children through 7 years of age.

A matched case-control methodology was used to assess the risk for a wide range of abnormalities in children associated with serological evidence for 'TORCH' infections in the mothers. Specimens were selected from the large bank of sera from the approximately 54,000 pregnant women who participated in the Collaborative Perinatal Project. There was no clear association between any of the antigens studied and any specific damage to the child. These 'negative' findings are consistent with the absence of frequent significant effects due to these agents in the second and third trimesters of pregnancy.

Revised estimate of the prevalence of multiple sclerosis in the United States.

Using three adjustments, we have revised a 1976 prevalence count for multiple sclerosis in the United States. The adjustments were made to data from a US national survey; they used 1990 population projections from the US Bureau of the Census, and results of investigations conducted in Weld and Larimer Countries, Colorado, and Olmsted County, Minnesota. It is estimated that approximately 250,000 to 350,000 persons in the United States in 1990 had physician-diagnosed multiple sclerosis.

Febrile seizures: clinical characteristics and initial EEG.

We examined the relationship between clinical characteristics and EEG classification in all children with febrile seizures examined at the University Pediatric Clinic, Skopje, Yugoslavia between 1982 and 1984. This is the only facility in Macedonia providing EEG or neurologic consultation for children. EEGs were classified as paroxysmally abnormal if they contained spikes, sharp waves, or spike-wave complexes considered abnormal for age. In all, 22% of the 676 children had an abnormal initial EEG. The most common basis for classification as abnormal was spike-wave complexes greater than 3 Hz; the next most common basis was the presence of spikes. Birth weight, gender, accompanying illness, and family history of seizures, and whether the index seizure was single or multiple were not associated with differences in rate of abnormal EEG. Clinically focal index seizures and longer duration were associated with EEG abnormality. Number of previous febrile seizures was associated with an increasing rate of EEG abnormality, from 18% in children with no previous seizures to 63% in those with four or more previous seizures. Age at EEG was linearly related to likelihood of paroxysmal EEG abnormality, both for the total cohort and for the 376 children with no previous seizures. In the total cohort, logistic regression identified leading predictors of abnormal initial EEG to be older age, number of previous febrile seizures, preexisting motor abnormality, and focal seizures. For children with a first febrile seizure, leading predictors were focal seizure, older age, and preexisting motor abnormality.