Barbara R. Visscher

HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS)

BACKGROUND Although coinfection with HIV-1 and hepatitis B virus (HBV) is common, few long-term studies on liver-disease mortality in coinfected people have been undertaken. Our aim was to examine liver-related mortality among people at risk for HIV-1 and HBV infections. METHODS We used data from a multicentre, prospective cohort study to classify 5293 men who had sex with men, according to their HIV-1 antibody status, ascertained semiannually, and their hepatitis-B surface antigen status (HBsAg), which we ascertained at baseline. Mortality rates were estimated in terms of person-years and Poisson regression methods were used to test for significance of relative risks. FINDINGS 326 (6%) men were HBsAg positive, of whom 213 (65%) were HIV-1 positive. Of the 4967 HBsAg negative men, 2346 (47%) were infected with HIV-1. The liver-related mortality rate was 1.1/1000 person years, and was higher in men with HIV-1 and HBsAg (14.2/1000) than in those with only HIV-1 infection (1.7/1000, p<0.001) or only HBsAg (0.8/1000, p<0.001). In coinfected individuals, the liver-related mortality rate was highest with lower nadir CD4+ cell counts and was twice as high after 1996, when highly active antiretroviral therapy (HAART) was introduced. INTERPRETATION Individuals coinfected with HIV-1 and HBV, especially those with low CD4+ nadir counts, are at increased risk for liver-related mortality, underscoring the importance of prevention, identification, and comprehensive management of hepatitis B in people infected with HIV-1.

Dementia in AIDS patients Incidence and risk factors

We determined incidence and future projections of dementia after AIDS onset in 492 homosexual men with AIDS in the Baltimore/Los Angeles sites of the Multicenter AIDS Cohort Study, 64 of whom developed dementia. We studied various risk factors for dementia, including demographic and clinical features, medical history, markers of immune status before AIDS, and zidovudine use. During the first 2 years after AIDS, HIV dementia developed at an annual rate of 7%. Overall, 15% of the cohort followed through death developed dementia. The median survival after dementia was 6.0 months. Using a proportional hazards model, risk factors for more rapid development of dementia were lower hemoglobin (relative hazard, 0.59 per additional 2 g/dl;p = 0.0005) and body mass index (relative hazard, 0.64 per additional 5 kg/m2; p = 0.05) 1 to 6 months before AIDS, more constitutional symptoms 7 to 12 months before AIDS (relative hazard, 1.68 per additional symptom, p = 0.005), and older age at AIDS onset (relative hazard, 1.60 per decade older; p = 0.009). In a multivariate model, pre-AIDS hemoglobin remained the most significant predictor of dementia. There were no significant risks defined from demographic characteristics, specific AIDS-defining illnesses, zidovudine use before AIDS, or CD4+ lymphocyte count before AIDS. We project that 12 months after the first AIDS diagnosis, 7.1% of survivors will have dementia. The observed association between anemia, low weight, constitutional symptoms, and dementia suggests a role for cytokines inducing both systemic and neurologic disease.

Neuropsychological performance in HIV‐1‐infected homosexual men The Multicenter AIDS Cohort Study (MACS)*

We administered a battery of standardized neuropsychological measures to assess cognitive functions in a group of 769 HIV-1 seronagative, 727 asymptomatic HIV-1 seropositive (CDC Groups 2 and 3), and 84 symptomatic HIV-1 seropositive (CDC Group 4) homosexual/bisexual men enrolled in the Multicenter AIDS Cohort Study (MACS). Measures included tests of attention, memory, and psychomotor speed. Comparison of group means revealed significant differences in performance between HIV-1 seropositive and symptomatic HIV-1 seropositive subjects on measures of memory and on measures with strong motor and psychomotor timed components. These findings support the sensitivity of these neuropsychological instruments for detecting cognitive changes that may be related to HIV-1, and are consistent with other reports of neuropsychological abnormalities in symptomatic HIV-1-infected individuals. Asymptomatic seroropositive men, on the other hand, did not differ significantly from seronegative subjects on any of the neuropsychological measures. Only 5.5% of the asymptomatic HIV-1 seropositive men showed abnormal performance on individual tests. This proportion did not differ significantly from that of seronegative controls. Further, among asymptomatic seropositive subjects, we found no statistically significant differences as a function of duration of HIV infection or level of immune system functioning. Thus, results from this study support the hypothesis that the frequency of neuropsychological abnormalities in asymptomatic HIV-1-infected homosexual men is low, and not statistically different from that of seronegative controls.

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.

RISK FACTORS FOR SEROCONVERSION TO HUMAN IMMUNODEFICIENCY VIRUS AMONG MALE HOMOSEXUALS: Results from the Multicenter AIDS Cohort Study

2507 homosexual men who were seronegative for human immunodeficiency virus (HIV) at enrollment were followed for six months to elucidate risk factors for seroconversion to HIV. 95 (3.8%) seroconverted. Of men who did not engage in receptive anal intercourse within six months before baseline and in the six-month follow-up period, only 0.5% (3/646) seroconverted to HIV. By contrast, of men who engaged in receptive anal intercourse with two or more partners during each of these successive six-month intervals, 10.6% (58/548) seroconverted. No HIV seroconversions occurred in 220 homosexual men who did not practise receptive or insertive anal intercourse within twelve months before the follow-up visit. On multivariate analysis receptive anal intercourse was the only significant risk factor for seroconversion to HIV, the risk ratio increasing from 3-fold for one partner to 18-fold for five or more partners. Furthermore, data for the two successive six-month periods show that men who reduced or stopped the practice of receptive anal intercourse significantly lowered their risk of seroconversion to 3.2% and 1.8%, respectively. Receptive anal intercourse accounted for nearly all new HIV infections among the homosexual men enrolled in this study, and the hazards of this practice need to be emphasised in community educational projects.

Quantitative changes in T helper or T suppressor/cytotoxic lymphocyte subsets that distinguish acquired immune deficiency syndrome from other immune subset disorders

Quantitative measurements of the immune cell subgroups, T helper (Leu 3+/OKT4+) cells and T suppressor/cytotoxic (Leu 2+/OKT8+) cells, were made in patients having acquired immune deficiency syndrome (AIDS) with Kaposis sarcoma and in patients with AIDS and opportunistic infection, as well as in three other relevant populations. These included patients with lymphadenopathy syndrome, e.g., homosexually active males with lymphadenopathy who sought medical care for additional symptoms, and healthy male homosexuals, as well as a control population. Decrease in the number of T helper cells is characteristic of AIDS with Kaposis sarcoma or opportunistic infection. Augmentation of the T suppressor/cytotoxic cell population is rare in AIDS with Kaposis sarcoma but is more frequent in AIDS with opportunistic infection. Augmentation of the T suppressor/cytotoxic cell population, however, may occur in a variety of circumstances, including cytomegalovirus and other viral infections, in healthy, homosexually active males, and in otherwise healthy hemophiliac subjects receiving factor VIII treatment. Reduced T helper:T suppressor/cytotoxic cell ratio can be caused by either decrease in the number of T helper cells or augmentation of the T suppressor/cytotoxic cell population. Lowered T helper:T suppressor/cytotoxic cell ratio does not, by itself, help to distinguish between AIDS and other causes of reduced ratios. Quantitative measurements are needed to define the T subset changes. AIDS is characterized by decrease in the number of T helper cells and reduced T helper:T suppressor/cytotoxic cell ratio. The T helper (Leu 3+) and T suppressor/cytotoxic (Leu 2+) cell subpopulations can change independently. Identification of decrease in the number of T helper cells as an alteration that occurs independently of numerical change in other lymphoid subpopulations, such as T suppressor/cytotoxic cells and B cells, and the close association of the decrease in the number of T helper cells with AIDS are consistent with a distinct pathogenesis (and cause) for AIDS.

Cumulative exposure to nucleoside analogue reverse transcriptase inhibitors is associated with insulin resistance markers in the Multicenter AIDS Cohort Study

Objective:To estimate insulin resistance and its relationship to antiretroviral therapy (ART) in a cohort of HIV-infected persons with comparison to HIV-seronegative controls. Design:Prospective cohort of 533 HIV-infected and 755 HIV-seronegative men in the Multicenter AIDS Cohort Study evaluated at 6-month intervals between 1999 and 2003. Methods:Recent ART exposure was assessed by type of treatment in the preceding 6 months [i.e., no ART, monotherapy, combination ART, or highly active antiretroviral therapy (HAART) with and without a protease inhibitor (PI)]. Cumulative exposure was determined for the three major ART classes and for individual medications within each class. Two endpoints, a modified QUICKI index, 100 × 1/[log10(glucose) + log10(insulin)] and fasting hyperinsulinemia (insulin > 15 μU/ml), were assessed. All statistical models were adjusted for age, body mass index, race, nadir CD4 cell count, hepatitis C serostatus and family history of diabetes mellitus. Results:Each of the HIV-infected groups had higher odds of hyperinsulinemia and lower mean QUICKI than the HIV-seronegative men. Each additional year of exposure to nucleoside analogue reverse transcriptase inhibitors (NRTI) was associated with increased odds of hyperinsulinemia [odds ratio (OR), 1.08; 95% confidence interval (CI), 1.02–1.13) and a lower QUICKI (−0.04; 95% CI, −0.07 to −0.01). Cumulative exposure to non-nucleoside analogue reverse transcriptase inhibitors or PI drugs was not associated with either insulin resistance marker. Of individual medications examined, stavudine was associated with the highest risk of hyperinsulinemia (OR, 1.2; 95% CI, 1.2–1.3). Conclusions:Fasting surrogate markers suggest increased insulin resistance in HIV-infected men, which is related to cumulative NRTI exposure.

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 ones 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.

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.

Computerized and conventional neuropsychological assessment of HIV‐1‐infected homosexual men

We administered a battery of computerized and conventional neuropsychological measures to a group of 507 HIV-1 seronegative, 439 asymptomatic HIV-1 seropositive (Centers for Disease Control [CDC] groups 2 and 3), and 47 symptomatic HIV-1 seropositive (CDC group 4) homosexual/bisexual men enrolled in the Los Angeles center of the Multicenter AIDS Cohort Study. Tasks included multiple measures of attention, reaction time, memory, and psychomotor speed. Comparison of group means revealed significant differences in performance between HIV-1 seronegative and symptomatic HIV-1 seropositive men on computerized measures of choice reaction time and on conventional measures of memory and motor speed. These findings are consistent with previous research in this area and support the sensitivity of both computerized and conventional neuropsychological instruments for detecting cognitive changes found in symptomatic HIV-1-infected individuals. Asymptomatic seropositive men, on the other hand, did not differ significantly from seronegative subjects on any of the computerized or conventional neuropsychological measures. Only 13% of the asymptomatic HIV-1 seropositive men showed abnormal performance on a composite measure of cognitive functioning from the computerized test battery. This proportion did not differ significantly from that of seronegative controls (14%), but was significantly lower than the percentage of abnormal findings observed among symptomatic HIV-1 seropositive subjects (28%). Thus, results from this study support the hypothesis that the frequency of neuropsychological abnormalities in asymptomatic HIV-1-infected homosexual men is low and not statistically different from that of seronegative controls.