Vascular risk factors, HIV serostatus, and cognitive dysfunction in gay and bisexual men.

BACKGROUND: The purpose of this study was to evaluate the relationship between cognitive performance, risk factors for cardiovascular and cerebrovascular disease (CVD), and HIV infection in the era of highly active antiretroviral therapy. METHODS: We evaluated the cognitive functions of men enrolled in the cardiovascular disease substudy of the Multicenter AIDS Cohort Study who were aged > or =40 years, with no self-reported history of heart disease or cerebrovascular disease. Results from comprehensive neuropsychological evaluations were used to construct composite scores of psychomotor speed and memory performance. Subclinical CVD was assessed by measuring coronary artery calcium and carotid artery intima-media thickness (IMT), as well as laboratory measures, including total cholesterol, fasting glucose, glycosylated hemoglobin, glomerular filtration rate (estimated), and standardized blood pressure and heart rate measures. RESULTS: After accounting for education, depression, and race, carotid IMT and glomerular filtration rate were significantly associated with psychomotor speed, whereas IMT was associated with memory test performance. HIV serostatus was not significantly associated with poorer cognitive test performance. However, among the HIV-infected individuals, the presence of detectable HIV RNA in plasma was linked to lower memory performance. CONCLUSIONS: These findings suggest that HIV infection may not be the most important predictor of cognitive performance among older gay and bisexual men in the post-highly active antiretroviral therapy era, at least among those with access to medical care and to appropriate medications. Medical factors associated with normal aging are significantly associated with performance on neuropsychological tests, and good clinical management of these factors both in HIV-infected individuals and those at risk for infection may have beneficial effects in the short term and could reduce the risk of subsequent cognitive decline.

Evidence that anoreceptive intercourse with ejaculate exposure is associated with rapid CD4 cell loss.

OBJECTIVE: To determine whether ejaculate exposure through anoreceptive intercourse is associated with rapid CD4 cell loss. DESIGN: Self-reported behavioral, demographic data and blood samples were gathered longitudinally at ten semiannual visits from individuals participating in the Multicenter AIDS Cohort Study (MACS). PATIENTS/PARTICIPANTS: A group of 937 HIV-seropositive men who were continuously followed for four to ten semiannual visits. OUTCOME MEASURES: A loss of 10% or more in CD4 cells between the first two of any three consecutive semiannual visits that was followed by a 10% or greater loss between the second and third visits. RESULTS: A period of rapid CD4 cell loss over three semiannual visits occurred in 389 of the 937 (42%) HIV-seropositive men studied. Men who reported one or more anoreceptive intercourse partners with whom they were exposed to ejaculate (RAI-E) during the 12 months immediately preceding their visits were more than twice as likely to show this rapid CD4 cell loss compared with men with no such partners. CONCLUSIONS: The association between RAI-E partnerships and rapid CD4 cell loss suggests factors associated with ejaculate exposure (e.g., sexually transmitted diseases) may hasten the clinical progression of HIV disease. It is suggested that infectious diseases, which are known to be associated with ejaculate exposure, may be the causal factor underlying the association between RAI-E partnerships and rapid CD4 cell loss in these men, although the presence of these diseases was not ascertained in these data. HIV-infected individuals should be cautioned against unprotected anoreceptive intercourse.

AIDS onset at high CD4+ cell levels is associated with high HIV load.

To identify factors associated with development of AIDS at high CD4+ cell levels a nested case-control study using data from the Multicenter AIDS Cohort Study (MACS) was conducted. HIV-1-infected men who developed AIDS with > or =300/mm3 CD4+ cells (AIDS men) were compared to men who had > or =300/mm3 of CD4+ cells, but remained AIDS free for at least 2 years. The AIDS men had higher plasma HIV-1 RNA levels (mean 10(5.02) vs. 10(4.42), p<0.01) and neopterin levels (mean 18.3 vs. 11.5 units/ml, p<0.05) before the AIDS diagnosis than did the AIDS-free men. A significantly higher proportion of the AIDS men reported genital herpes within the year prior to their initial AIDS diagnosis than did the AIDS-free men (21.9 vs. 4.4%, p<0.05). The higher viral load at relatively high CD4+ cell levels in men who subsequently developed AIDS within 6 months supports the hypothesis that elevated levels of HIV precede CD4+ decline and are the major factor in determining risk of AIDS even at high levels of CD4+ cell levels.

Negative HIV-specific expectancies and AIDS-related bereavement as predictors of symptom onset in asymptomatic HIV-positive gay men.

This study examined negative HIV-related expectancies, AIDS-related bereavement, and the interaction of expectancies and bereavement as predictors of the onset of significant HIV-related symptoms among previously asymptomatic HIV-positive gay men. From a longitudinal psychobiological investigation, 72 men were selected who had been HIV-positive and asymptomatic from study entry (approximately 3 years). Participants were followed for an additional 2 1/2 to 3 1/2 years after psychosocial assessment, with symptom status assessed every 6 months. The interaction of negative HIV-specific expectancies and bereavement was a significant predictor of symptom onset. Negative HIV-specific expectancies predicted the subsequent development of symptoms among bereaved men, controlling for immunological status, use of zidovudine, high-risk sexual behavior, substance use, and depression.

Virologic, immunologic, and immune activation markers as predictors of HIV-associated weight loss prior to AIDS. Multicenter AIDS Cohort Study.

OBJECTIVES: To study weight patterns among HIV-positive men and associations of baseline HIV RNA, CD4+ lymphocyte count, and serum levels of neopterin and beta2-microglobulin with subsequent weight loss prior to AIDS. METHODS: A cohort of 1558 homosexual men from the Multicenter AIDS Cohort Study comprised the main study population. Marker values obtained using samples from a baseline visit in 1984 to 1985 were associated with weight patterns and risk of weight loss events over 10 years of follow-up. To investigate the impact of protease inhibitor (PI) therapy on weight patterns, a separate analysis was conducted for men who initiated such therapy in 1995 to 1996. RESULTS: In general, HIV-positive men demonstrated a striking tendency toward weight loss, with a rate of decline that increased over time. Distinct variations in this pattern were observed according to baseline HIV RNA levels. Each marker considered was independently predictive of weight loss events. Following use of PIs, 68 men showed a tendency toward increased weight, compared with men who did not use PIs. CONCLUSIONS: Although baseline virologic, immunologic, and immune activation markers all predicted weight loss events in AIDS-free HIV-positive men, HIV RNA displayed the best discrimination. Shifts in weight patterns observed in this cohort after PI therapy call for further attention to nutritional and body changes as the duration of therapy increases.

Estimating the effect of zidovudine on Kaposi's sarcoma from observational data using a rank preserving structural failure-time model.

Researchers commonly express scepticism about using observational data to estimate the effect of a treatment on an outcome the treatment is intended to affect. In this paper, we consider using data from the Multicenter AIDS Cohort Study (MACS) to determine whether zidovudine prevents the development of Kaposi's sarcoma among HIV-positive gay men. Several methodologic issues common to observational data characterized the study: information on potentially important confounders was missing at some study visits; investigators did not always know the time of changes in treatment level, nor the value of confounders at that time, and the censoring process depended strongly on time-varying covariates related to outcome. We describe application to our data of Robins' paradigm for defining, modelling and estimating the effect of a time-varying treatment and show how to modify his approach to deal with the methodologic issues we have mentioned. Further, we demonstrate that relative risk regression is less well equipped to deal with these issues. We compare our results to the findings from randomized trials, and conclude that observational studies may sometimes be useful in evaluating the effect of treatment on an intended outcome.

Constitutional symptoms and health-related quality of life in patients with symptomatic HIV disease.

PURPOSE: To assess the severity of constitutional symptoms in persons with human immunodeficiency virus (HIV) infection, and their relationship to health-related quality of life (HRQOL). PATIENTS AND METHODS: Two hundred five HIV-infected patients (93% male, 26% African American, 28% Latino, 39% white, 7% other ethnicity) with diarrhea, fever, or weight loss were studied at a county hospital and a Veterans Administration hospital in southern California. Consenting subjects were administered a battery that included 11 scales measuring various aspects of health-related quality of life and detailed questions about six constitutional symptoms or symptom complexes (myalgias, exhaustion, anorexia/nausea/vomiting, night sweats, fever, and weight loss) as well as about other manifestations of HIV disease. RESULTS: Constitutional symptoms except weight loss were all strongly related to all measures of quality of life. On 0 (worst) to 100 (best) point scales, mean scores ranged from 34 (for individuals having all five symptoms other than weight loss) to 78 (for those with none) for physical function, 43 to 79 for emotional well-being, and 36 to 73 for social function. Adjustment for helper T-lymphocyte counts, duration of illness, and demographic characteristics did not diminish these associations. CONCLUSION: The presence, number, and severity of constitutional symptoms in HIV disease is strongly related to health-related quality of life in symptomatic HIV-infected individuals. Identifying and treating these very common symptoms has the potential to improve quality of life in these patients.

Effect of treatment with zidovudine on subsequent incidence of Kaposi's sarcoma.

Despite much investigation of zidovudine, little has been reported regarding its effect on the development of most individual AIDS-defining illnesses, including Kaposi's sarcoma (KS). We used observational data from the Multicenter AIDS Cohort Study (MACS) to estimate the effect of zidovudine use on the subsequent incidence of KS. To do this, we examined and adjusted for predictors of zidovudine use. CD4 lymphocyte counts, the development of HIV-related symptoms and AIDS, and changes in these factors were important predictors of zidovudine use. We used these associations to control for confounding by these and other factors with the G-estimation approach. We found no evidence that zidovudine use affected the time to KS in the MACS; the point estimate (95% confidence interval [CI]) for increase in time to KS was zero (-28%-68%). The relative risk was 1.0 (95% CI, 0.54-1.84). Randomized trials suggest that zidovudine may prevent KS. We discuss possible explanations for differences between results.

Social relationships and immune processes in HIV seropositive gay and bisexual men.

This three-year longitudinal study assessed the association between social relationships and human immunodeficiency virus (HIV) progression in individuals at risk for morbidity and mortality due to acquired immune deficiency syndrome (AIDS). Two-hundred five HIV seropositive men without AIDS completed measures of social integration and loneliness at baseline. Blood samples used to assess CD4 T-lymphocyte levels were collected at baseline and at six-month intervals for a three-year follow-up period. Contrary to expectation, lower levels of baseline loneliness predicted more rapid declines in CD4 levels over the follow-up period. This association was independent of baseline CD4 values, negative affect, and health practices. A series of mediational analyses revealed that sexual behavior, medication use, bereavement, coping, and a number of other variables were not mechanisms through which loneliness affected the immune system. Loneliness was not associated with time to AIDS diagnosis or time to AIDS-related mortality. These findings are consistent with the emerging view that social relationships can have deleterious, as well as protective, influences on health outcomes.

Causal attributions predict rate of immune decline in HIV-seropositive gay men.

Research has suggested that attributions-the perceived causes of events-may affect psychological and physical health and the immune system. The authors hypothesized that attributions reflecting negative beliefs about the self, the future, and control would affect helper T cell (CD4) decline and onset of AIDS in individuals with HIV, either directly or through associations with psychological states such as depression. HIV+ gay men (N = 86) participated in a structured interview from which causal attributions were extracted and coded. Attributing negative events to aspects of the self significantly predicted faster CD4 decline over 18 months following the interview, controlling for potential psychological, behavioral, social, and health mediators such as depression and health behavior. However, attributions did not predict AIDS diagnosis during the study period. The results support the idea that causal attributions related to beliefs about the self may have an influence on the immune system.

Elevated physical health risk among gay men who conceal their homosexual identity.

This study examined the incidence of infectious and neoplastic diseases among 222 HIV-seronegative gay men who participated in the Natural History of AIDS Psychosocial Study. Those who concealed the expression of their homosexual identity experienced a significantly higher incidence of cancer (odds ratio = 3.18) and several infectious diseases (pneumonia, bronchitis, sinusitis, and tuberculosis; odds ratio = 2.91) over a 5-year follow-up period. These effects could not be attributed to differences in age, ethnicity, socioeconomic status, repressive coping style, health-relevant behavioral patterns (e.g., drug use, exercise), anxiety, depression, or reporting biases (e.g., negative affectivity, social desirability). Results are interpreted in the context of previous data linking concealed homosexual identity to other physical health outcomes (e.g., HIV progression and psychosomatic symptomatology) and theories linking psychological inhibition to physical illness.

Persistently seronegative men from whom HIV-1 has been isolated are genetically and immunologically distinct.

Studies in both monkeys and humans have suggested that transient infection with HIV-1 can occur without provoking a measurable humoral immune response. The objective of this study was to look for genetic and immunologic correlates of transient HIV-1 infection in antibody-negative men from whom HIV-1 had been isolated. The distributions of MHC class I, class II, and TAP (transporter protein associated with antigen processing) region genes were compared between 23 persistently seronegative men from whom HIV-1 was isolated at least once (isol+/Ab-) and 137 men who seroconverted. A subset of 13 of the 23 isol+/Ab- men were compared to 27 seronegative men for distribution of CD25+CD4+ and CD25+CD8+ cells in the absence of exogenous immunologic stimulation. The prevalences of the TAP1.4, and a combination of TAP1.4, and TAP2.3 variants were significantly higher in the isol+/Ab- men. The proportion of CD8+ cells that expressed CD25+ antigen was also significantly higher in the isol+/Ab- men than in the seronegative men. We conclude that isol+/Ab- men may be genetically and immunologically distinct from HIV-1 susceptible men. We hypothesize that activated CD8+ cells may have cleared HIV-1 infection in these men through genetically mediated influences of the TAP genes on the presentation of peptides by HLA class I molecules.

Accelerated course of human immunodeficiency virus infection in gay men who conceal their homosexual identity.

Research linking psychological inhibition to physical illness led us to examine whether human immunodeficiency virus (HIV) infection might progress more rapidly among gay men who conceal their homosexual identity than among those who do not. We also sought to determine whether any accelerated course of HIV infection among "closeted" gay men might be attributable to differences in health-relevant behavior (e.g., health practices, sexual behavior) or psychosocial characteristics (e.g., depression, anxiety, social support, repressive coping style). Data came from a longitudinal psychosocial study associated with the Los Angeles site of the Multicenter AIDS Cohort Study. Eighty gay men, HIV-seropositive but otherwise healthy at study entry (CD4 T lymphocytes = 30-60% of total lymphocytes), were examined at 6-month intervals for 9 years. Indicators of HIV progression included time to a critically low CD4 T lymphocyte level (15% of total peripheral blood lymphocytes), time to AIDS diagnosis, and time to AIDS mortality. On all measures, HIV infection advanced more rapidly in a dose-response relationship to the degree participants concealed their homosexual identity. Sample characteristics and statistical controls ruled out explanations based on demographic characteristics, health practices, sexual behavior, and antiretroviral therapy. Mediational analyses indicated that observed effects were not attributable to differences in depression, anxiety, social support, or repressive coping style. HIV infection appears to progress more rapidly in gay men who conceal their homosexual identity. These results are consistent with hypotheses about the health effects of psychological inhibition, but further research is required to definitively identify the psychosocial, behavioral, and physiological mechanisms underlying these findings.

Outcomes in 248 patients who had diagnostic evaluations for epilepsy surgery.

Surgery for intractable epilepsy is a widely used treatment that is not readily assessed by randomised trials. We evaluated the impact of epilepsy surgery on seizures, medication use, employment, and the quality of life in 248 adults and adolescents consecutively referred to one medical centre between 1974 and 1990. Outcomes were determined through self-administered questionnaire and medical record review for 202 surgery and 46 non-surgery patients whose treatment was usually determined by the presence or absence of an epileptogenic focus. Surgery and non-surgery patients differed at baseline only in median monthly seizure frequency (surgery lower than non-surgery). After adjustment for baseline covariates, surgery patients at follow-up had greater decline in average monthly seizure frequency (-11.9 vs - 1.5; difference -10.4, 95% CI -20.5, -0.3) and took fewer antiepileptic medications (average number 1.4 vs 2.0; difference -0.67, 95% CI -0.94, -0.40). Although quality-of-life scores were higher (p < 0.05) with surgery on 5 of 11 scales that were administered only at follow-up, there were no significant differences in employment status or prospectively assessed quality of life. Relative to a non-surgery group, patients treated surgically had better seizure control with less antiepileptic medication. The impact of epilepsy surgery on quality of life and employment needs to be assessed in larger prospective studies.

Bartonella (Rochalimaea) antibodies, dementia, and cat ownership among men infected with human immunodeficiency virus.

To determine the association between recent human immunodeficiency virus (HIV)-associated dementia and serum antibodies to Bartonella (Rochalimaea) henselae, we performed a nested case control study within the Multicenter AIDS Cohort Study in Los Angeles. We measured serum IgG and IgM antibodies to B. henselae with use of enzyme immunoassay in 369 HIV-seropositive and HIV-seronegative participants with and without recent neuropsychological deterioration. Data on pet ownership were also collected. IgM antibodies to B. henselae were strongly associated with neuropsychological decline or dementia (OR = 6.6;95% CI = 1.4-31.9;P = .02). Those participants with IgM antibodies to B. henselae were 1.7 times more likely to develop HIV-associated dementia (HAD) or neuropsychological decline over the next 5 years. At least 4% of the new cases of HAD and neuropsychological decline were due to bartonella infection. Cat ownership was associated with the presence of IgM antibodies to B. henselae (OR = 6.4;95% CI = 1.3-30.8;p = .02) and with neuropsychological decline and dementia (OR = 2.4;95% CI = 1.2-5.1;P = .02). This finding suggests that some cases of HAD and neuropsychological decline are associated with potentially treatable B. henselae infections.

Long-term survivors with HIV-1 infection: incubation period and longitudinal patterns of CD4+ lymphocytes.

To characterize long-term survival with HIV-1, we need to estimate the proportion of seroconverters remaining free from clinical AIDS for long periods. We predict that approximately 13% of homosexual/bisexual men infected at a young age may remain so for > 20 years. Since studies have not followed individuals for such periods, long-term survivors must be characterized using stability of immunologic markers. In a cohort of 1,809 seropositive men followed since 1984-85, 15% (187/1,214) of those with at least two consecutive visits early in the study showed no decline in CD4+ cell count. From these, 67 men with long follow-up and no use of zidovudine were identified as cases to investigate correlates of protection against HIV-1-induced immunodepletion. Two matched control subgroups, one with moderate and one with rapid CD4+ lymphocyte decline, produced 56 triplets of individuals to be contrasted. Analysis of data from early in the study on demographics, sexual behavior, and sexually transmitted diseases revealed no significant differences among the three groups. Men showing no decline in CD4+ lymphocytes persistently showed a healthier profile with respect to onset of clinical AIDS, survival, and concomitant hematologic variables. Moderate decliners had rates of clinical AIDS and death significantly higher than those in the stable group but lower than the fast decliners.

Resistance to HIV-1 infection. Multicenter AIDS Cohort Study.

Men from the Multicenter AIDS Cohort Study were classified as "susceptible" and "resistant" to HIV infection. Resistant men were still HIV antibody negative in 1993 and were estimated to have had > 45 different anal intercourse partners (median, 92; range, 46-504) in the 2.5 years before visit 2 (1985). Susceptible men were seroconverters who were estimated to have had < 13 different anal partners (median, 4; range, 0-12). Leukocyte groups were compared between the two groups of men. Values were excluded for 12 months before the first antibody-positive visit in the susceptible men. White blood cells, polymorphonuclear neutrophils, total lymphocyte count, CD8+ percentage and number, and CD3+ and CD4+ number were higher in the resistant men. Logistic regression analyses were used to develop 50 bivariate models. Higher levels of neutrophils and CD8+ cells were included in four of the six best-fitting bivariate models, suggesting that each is associated with resistance to HIV-1 infection. These results support the hypothesis that CD8+ cells may modulate the outcome of HIV-1 exposure.

A longitudinal study of cytomegalovirus infection in human immunodeficiency virus type 1-seropositive homosexual men: molecular epidemiology and association with disease progression.

Cytomegalovirus (CMV) isolates from 234 asymptomatic human immunodeficiency type 1 (HIV-1)-positive men were analyzed for molecular relatedness using junctional hybridization. Of isolates shed simultaneously at two or more body sites, 36% from 22 men were different. Of 180 isolates collected from 67 men over 15 months, different strains were isolated serially from 27 men (40%), most from semen. After follow-up of 58 months (mean), the relative hazard of HIV infection progressing to AIDS was 1.8 (95% confidence interval [CI], 0.9-3.7) for men shedding the same strain of CMV and 3.0 (95% CI, 1.4-6.1) for men shedding different strains compared with men not shedding CMV in semen. The prevalence of CMV-specific IgM was higher in men shedding different versus same CMV strains (32% vs. 18%; P = .244). Thus, presence of multiple CMV strains in HIV-1-positive homosexual men is associated with progression to AIDS, possibly via activation of HIV-1-infected CD4 cells.

Realistic acceptance as a predictor of decreased survival time in gay men with AIDS.

Although theoretical accounts of adaptation in the terminally ill suggest that realistic acceptance of one's disease is adaptive, some investigations suggest that such responses are associated with increased mortality. This prospective psychobiological investigation involved 74 gay men with AIDS. Six scores reflecting responses to disease were derived from a detailed psychosocial questionnaire. One pattern of response, Realistic Acceptance, was a significant predictor of decreased survival time. Median estimated survival time for participants with low Realistic Acceptance scores was 9 months greater than for participants with high Realistic Acceptance scores. This effect was not accounted for by time since diagnosis with AIDS, self-reported health status, number of CD4 T lymphocyte cells, psychological distress, age, education, initial diagnosing condition, use of AZT, smoking, or alcohol and drug use.