The effect of changing the definition of AIDS on the modeling of AIDS.
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Biomedical subjects
Publications and source records attributed to L Kingsley.
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In natural history studies of human immunodeficiency virus type 1 (HIV-1) infection a substantial proportion of participants are seropositive at time of enrollment in the study. These participants form a prevalent subcohort. Estimation of the unknown times since exposure to HIV-1 in the prevalent subcohort is of primary importance for estimation of the incubation time of AIDS. The subset of the cohort that tested negative for antibody to HIV-1 at study entry and was observed to seroconvert forms the incident subcohort that provides longitudinal data on markers of maturity (that is, duration) of infection. We use parametric life table regression models incorporating truncation to describe the conditional distribution (imputing model) of the times since seroconversion given a vector of the markers of maturity. Using the fitted model and the values of the markers of maturity of infection provided by the seroprevalent subcohort at entry into the study, we can impute the unknown times since seroconversion for the prevalent subcohort. We implement multiple imputation based on a model-robust estimate of the covariance matrix of parameters of the imputing model to provide confidence intervals for the geometric mean of the time since seroconversion in the prevalent subcohort, and to compare maturity of infection of cohorts recruited in different cities. The accuracy of imputation is further validated by comparisons of imputation-based estimates of AIDS incubation distribution in the seroprevalent subcohort with more direct estimates obtained from the seroincident subcohort.
This study evaluated the self-reported patterns of handedness among a large subsample (n = 1612) of the gay/bisexual men comprising the Multicenter AIDS Cohort Study (MACS). There was a small but significant elevation in left-handedness among gay/bisexual men compared to available normative data. However, there were no differences within the cohort in measures of immune function, self-reported autoimmune disorders, asthma, or hay fever, although there was an association between handedness and allergy. Performance on neuropsychological tests also did not differ as a function of handedness.
OBJECTIVE: To assess the presence of covert HIV-1 infection. SETTING: High-risk seronegative homosexual men from the Pittsburgh portion of the Multicenter AIDS Cohort Study were examined for the presence of HIV-1 infection. PATIENTS, PARTICIPANTS: Ten men (group 1) were examined prospectively for the presence of HIV-1 in their freshly-obtained peripheral blood mononuclear cells (PBMC). Furthermore, cryopreserved PBMC from 26 men (group 2) at their first visit (1984-1985) were examined retrospectively for the presence of HIV-1. MAIN OUTCOME MEASURES: PBMC samples from groups 1 and 2 were examined for HIV-1 by polymerase chain reaction (PCR) using gag, env and strong-stop (long terminal repeat) specific primers. In addition, fresh PBMC samples from group 1 were examined for HIV-1 by virus culture. RESULTS: None of the 10 PBMC samples from group 1 were positive for virus culture and PCR. Only one of the 26 men from group 2 was positive for gag and strong-stop DNA sequences. This PCR-positive, seronegative subject was found to be negative for HIV-1 by PCR at follow-up visits up to 48 months later. None of 15 seronegative, low-risk homosexual men and 12 seronegative heterosexual men were found to be PCR-positive for HIV-1. However, six HIV-1-seropositive men were positive by PCR for gag, env, and strong-stop HIV-1 DNA sequences. CONCLUSIONS: These results suggest a low prevalence of covert HIV-1 infection in high-risk seronegative homosexual men in our geographic area.
The authors studied the historical spread of human immunodeficiency virus type 1 (HIV-1) infection in homosexual/bisexual men and projected its future spread in these men using data from an AIDS-free cohort recruited during late 1984 in Baltimore, Maryland; Chicago, Illinois; Los Angeles, California; and Pittsburgh, Pennsylvania. Dates of preentry seroconversion in HIV-1 seroprevalent men were estimated using study entry values of hematologic variables influenced by HIV-1 infection. The authors used survival methods incorporating truncation to determine numbers/dates of seroconversion for men with a pre-1984 AIDS diagnosis who were selectively excluded by design from the 1984 AIDS-free cohort. Overall, the annual seroconversion hazard rose progressively from 0.4% in 1978 to 13.8% in 1983, dropped to 4.6% in 1985, and remained relatively stable at 1.1-2.2% from 1986 to 1990. By January 1990, almost 46% of men who were seronegative in 1978 had seroconverted. The authors estimated historical rates of spread by city, age, education, and ethnicity to examine the effects of these factors in the early and continuing stages of the HIV-1 epidemic. There were striking differences among cities with respect to pre-1985 seroconversion rates but not with respect to post-1985 seroconversion rates. Age, education, and ethnicity were all associated with 1978-1990 seroconversion rates. Future seroconversion among homosexual men was predicted assuming that the "stabilized" 1986-1990 hazards (stratified by age) observed here will be representative of future rates. Truncated Kaplan-Meier methods gave the probability of a seronegative 20-year-old man's remaining seronegative in subsequent years. Such a man has a 20.2% chance of seroconverting before reaching the age of 25 years (a 4.4% yearly hazard). The annual hazard drops to 2.5% between 25 and 30 years, to about 1.5% between 30 and 45 years, and to 1.0% between 45 and 55 years. The overall probability of seroconversion prior to age 55 years is about 50%, with seroconversion still continuing at and after age 55. Given that this cohort consists of volunteers receiving extensive anti-HIV-1 transmission education, the future seroconversion rates of the general homosexual population may be even higher than those observed here.
A prospective multicenter study was undertaken to isolate human immunodeficiency virus type 1 (HIV-1) from 45 homosexual men for a period of 30 months after seroconversion. Efficiency of HIV-1 isolation from peripheral blood mononuclear cells was relatively stable over time, ranging from 64% at the time of seroconversion to more than 82% after 18 months of seroconversion. However, Kaplan-Meier analysis of HIV-1 culture data indicates that the cumulative proportion of HIV-1 culture positivity at 3, 6, 12, and 18 months after seroconversion was 62, 65, 84, and 92%, respectively. No significant correlation was observed between the presence of HIV-1 p24 antigen in serum, or numbers of CD4+ and CD8+ blood lymphocytes, and HIV-1 isolation within this period of time. These data suggest that HIV-1 viremia in homosexual men gradually increases to almost 100% culture positivity by 18 months after seroconversion.
We examined whether 644 homosexual men who engaged in receptive anal intercourse were at particularly elevated risk for seroconversion if they also possessed specific behavioral, health or psychosocial vulnerability characteristics. Of 11 potential factors examined, heavy drinking, moderate to heavy drug use, and younger age were significantly related to seroconversion. These variables were also associated with an increased number of sexual partners, anonymous sex, and failure to use condoms.
108 seropositive homosexual men were examined for associations between HLA phenotype and progression of human immunodeficiency virus type 1 (HIV-1) infection. Among men of predominantly European ethnic origin, 49 with very rapid 2-year declines in CD4+ lymphocyte counts showed significant differences in antigen frequencies from 59 men matched for ethnic background, study centre, and initial CD4+ cell count but with little or no decline in CD4+ cells. Relations of varying strength (odds ratios 6.1-10.3) were seen with several HLA antigens often linked in the A1-Cw7-B8-DR3 haplotype. The strongest relation was with the A1, Cw7, B8 combination (odds ratio 10.3). Associations between these antigen combinations and development of AIDS were weaker. The frequency of HLA A24 was also significantly higher in rapid than in slow decliners (odds ratio 4.3). These findings strengthen the suggested link between the product of a gene in the A1-Cw7-B8-DR3 haplotype and HIV-1-related disease.
Human immunodeficiency virus (HIV) p24 antigenemia was assessed in a longitudinal study of 52 homosexual men who developed serum antibody to HIV. Antibody seroconversion to HIV as defined by a positive HIV enzyme immunoassay (EIA) confirmed by Western (immuno-) blot was associated with three major patterns of HIV antigenemia. In the first pattern, a transient antigenemia was noted 6 (six subjects) and 12 (one subject) months prior to detection of antibody by HIV EIA and Western blot in 7 (13.5%) of the 52 men. Use of an EIA employing a recombinant envelope protein (ENV9) was able to detect antibody in four of these seven men at the time of this early antigenemia. In the second pattern, HIV p24 antigenemia occurred in 8 (15.4%) of the 52 subjects within the first 12 months after HIV antibody seroconversion. No p24 antigen was detected in the 37 (71.1%) remaining subjects. CD4+ cell numbers were lower in antigen-positive men before and after antibody seroconversion. Development of acquired immunodeficiency syndrome (AIDS) or AIDS-related complex was strongly associated with evidence of persistent p24 antigenemia during the early, postseroconversion period. HIV p24 antigenemia may be of value in determining appropriate cohorts for drug therapy trials for subjects with early-phase HIV infection.
The authors administered the Center for Epidemiological Studies Depression (CES-D) Scale to 4,954 homosexual men in the Multicenter AIDS Cohort Study. HIV antibody status at enrollment was a less important predictor of psychological distress than were reported physical symptoms. Multivariate analysis showed an association between a high score on each CES-D Scale component and the number of self-reported possible AIDS- or HIV-related symptoms, perceived lymphadenopathy, and absence of "someone to talk to about serious problems." This relationship between self-reported physical symptoms and psychological distress suggests a possible etiologic relationship between perceived AIDS risk and psychological symptoms in men at risk of AIDS.
Specific cellular immune responses to human immunodeficiency virus type 1 (HIV-1) were assessed in mononuclear leukocyte cultures from homosexual men with documented, early phase HIV-1 infection. Cell cultures from men with a mean duration of 1.3 yr (range, 0.3 to 2.2 yr) of HIV-1 infection were treated with UV-inactivated, whole, purified HIV-1 Ag together with various concentrations of rIL-2. Cell supernatants were harvested after 5-day incubation and assayed for IFN activity against encephalomyocarditis virus in human WISH cells. IFN subtypes were characterized by neutralization of antiviral activity with antiserum specific for human IFN-gamma and IFN-alpha. Results showed that cultures from 68% (17 of 25) of the HIV-1-seropositive subjects produced "immune" IFN-gamma in response to whole HIV-1 Ag plus rIL-2. IFN-gamma was induced in only 20% (5 of 25) of cultures treated with HIV-1 Ag alone. Enhancement of HIV-1-specific IFN-gamma production by rIL-2 was synergistic rather than additive in that titers induced by the mixture were consistently higher than the sum of IFN titers induced by HIV-1 or rIL-2 alone. This effect was not demonstrable in cultures from 18 HIV-1-seronegative men. Similarly, HIV-1-immune specific augmentation of IFN-gamma production by rIL-2 was noted for PENV9, a recombinant HIV-1 envelope glycoprotein gp41 and gp120 fragment. Production of IFN-gamma may be an important, HIV-1-immune specific parameter in the host response to this retrovirus.
We conducted a study to assess the effect of human immunodeficiency virus (HIV) infection on humoral immunity. Fifty-five homosexual men and 19 heterosexual men had four- to six-week postimmunization antibody responses measured to trivalent influenza vaccine and 23-valent pneumococcal vaccine. The homosexual men were divided into three groups: 20 asymptomatic HIV-seronegative men, 10 asymptomatic HIV-seropositive men, and 25 HIV-seropositive men with persistent generalized lymphadenopathy. Antibody responses to influenza antigens in the subgroups of homosexual men did not significantly differ from those of heterosexual controls. The IgG antibody responses to pneumococcal capsular types 9N and 18C in men with lymphadenopathy, and type 18C in HIV-seronegative homosexual men, were lower than those of heterosexual controls. Otherwise, responses to other ten capsular types showed no significant differences. There was no evidence of an immunosuppressive effect of vaccination on T-cell numbers, or deterioration of clinical status associated with vaccination. This study demonstrates that HIV-infected homosexual men, asymptomatic or with persistent generalized lymphadenopathy, are able to mount appropriate antibody responses to two commonly used vaccines.
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A cohort of 181 patients with hemophilia A (149) and hemophilia B (32) cared for at the Hemophilia Center of Western Pennsylvania was followed to determine human immunodeficiency virus (HIV) seroprevalence, seroconversion rate, and clinical and immunologic correlates of HIV infection. By December 1986, 82 (45%) were HIV seropositive, and of these, ten (12%) had developed AIDS, 28 (34%) had symptomatic HIV infection (CDC class III, IV), of whom 14 (17%) had AIDS-related complex (ARC), and 44 (54%) had asymptomatic HIV infection (CDC class II). The HIV seropositive group included 82% of those treated with factor VIII concentrate (97% severe, 5% moderate), 48% of those treated with factor IX concentrate (92% severe, 8% moderate), 10% of those treated with cryoprecipitate (67% severe, 33% moderate), and none of those treated with fresh frozen plasma. Based on 77 serially sampled HIV seropositive hemophiliacs (1977 to 1986), peak seroconversion occurred in 1982, with 14% (11 of 77) occurring since 1984. With increasing time from seroconversion, both T4 lymphocyte number and function (the latter measured by growth in soft agar [T colony assay]) progressively declined; T4 number declined to 135 +/- 26/mm3 (SEM), and colony count declined 1193 +/- 537 (control 3851 +/- 387) by 5 years after seroconversion. In those developing AIDS, total T4 fell below 100/mm3 (33 +/- 8/mm3) at diagnosis. In this cohort, the overall AIDS incidence is 5.5% (12% among the HIV seropositive) and in those seropositive 5 or more years, the AIDS incidence approaches 32%.
Physical examination by a single clinician showed that 17 of 51 asymptomatic homosexual men and 19 of 26 men with persistent lymphadenopathy had linear telangiectasias in a broad, crescent distribution across the chest. The telangiectasias were commonly associated with erythema in the same distribution. Of the 36 men with telangiectasias, 25 were positive for serum antibody to the human immunodeficiency virus (HIV), whereas only 15 of 41 men without telangiectasias were seropositive (p = 0.001). Biopsy studies of supraclavicular skin from 6 of the men with HIV antibody and telangiectasias showed a characteristic pattern of dilated blood vessels with a perivascular small-cell infiltrate; no endothelial proliferation was noted. This histopathologic pattern was not consistently observed in HIV-seronegative men regardless of whether they had telangiectasias. These data show that telangiectasias of the upper chest are a relatively common finding in homosexual men and that they are significantly, although not exclusively, associated with HIV infection.
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