Psychomotor slowing in HIV infection: a predictor of dementia, AIDS and death.

The objective of this study was to determine if sustained decline in psychomotor speed tests is associated with an increased risk of progression to dementia, acquired immunodeficiency syndrome (AIDS), or mortality in human immunodeficiency virus (HIV)-1-infected homosexual men in the Baltimore site of the Multicenter AIDS Cohort-Study (MACS). Clinical and neuropsychological data were obtained on 291 HIV+ homosexual men seen semi-annually over a nine year period (1986-1994). A proportional hazards model was used to assess the predictive value of sustained psychomotor slowing (defined as a 2.0 standard deviation (s.d.) decline in performance on either the Symbol Digit Modalities test or Trailmaking test at two consecutive evaluations). Time-dependent co-variates included in the model were sustained psychomotor slowing, number of attended visits, CD4+ lymphocyte count, hemoglobin and antiretroviral medication use. HIV+ participants with and without sustained psychomotor slowing were compared. Outcome variables were the development of dementia, AIDS and death. HIV+ subjects with sustained psychomotor slowing had an increased hazard of dementia (Risk ratio (RR) = 5.0, P = 0.008), AIDS (RR = 2.4, P = 0.02), and death (RR = 2.0, P = 0.04). A similar analysis using sustained cognitive decline in one domain from a more extensive neuropsychological test battery failed to show any predictive value. Sustained decline in psychomotor performance in HIV infection was predictive of dementia, AIDS and death. This brief neuropsychological test battery may be useful for early detection of HIV+ individuals with a poorer prognosis who may benefit from more aggressive treatment to prevent HIV dementia.

Human T-cell lymphotropic virus type-I infection in the severe combined immunodeficiency mouse.

Human T-cell lymphotropic virus type-I (HTLV-I) is the etiologic agent of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia (ATL). HAM/TSP and ATL occur infrequently among HTLV-I-infected individuals, and rarely develop in the same individual. To study host and viral factors involved in the induction, tissue tropism, as well as pathogenesis of HAM/TSP, peripheral blood lymphocytes (PBL) from 14 patients with HAM/TSP and from 9 controls were introduced into severe combined immunodeficiency (SCID) mice by intraperitoneal injection. Mice were followed for up to 26 weeks. Human IgG was produced from 2 to 14 weeks after reconstitution in all animals. Thirty-two of 44 mice (72%) showed circulating human antibody against the major viral protein products of HTLV-I. Analysis of viral sequences by polymerase chain reaction (PCR) demonstrated HTLV-I sequences in 21/38 (55%) brains and in 7/17 (41%) spinal cords from HTLV-I-hu SCID mice. No animal had clinical evidence of neurological impairment or pathological findings similar to those seen in HAM/TSP. Seven mice who received PBL from Epstein Barr virus (EBV)-seropositive patients developed an intraperitoneal lymphoma. In 2 mice an infiltration of brain by a lymphoblastic tumor of B/T cell type was observed. By PCR, all the tumors were EBV-positive; HTLV-I sequences were detected in 5 of them. Our study suggests that the HTLV-I-hu-SCID mouse provides a potentially valuable system for studying the production, kinetics, and pathogenicity of anti-HTLV-I antibody, and may help clarify the interaction of EBV and retroviruses in the development of disease.

An epidemiologic analysis of Mycobacterium avium complex disease in homosexual men infected with human immunodeficiency virus type 1.

Cofactors associated with the Mycobacterium avium complex (MAC) disease and its prognosis in incident cases of AIDS in homosexuals were studied. We compared 51 men in whom MAC disease developed as the initial AIDS-defining illness (termed AIDS illness hereafter); 157 men who had MAC disease subsequent to another AIDS illness; and 884 men who had only non-MAC AIDS illnesses. MAC disease was the initially diagnosed AIDS illness more often in Baltimore (6.9%) and Los Angeles (5.6%) than in Chicago (2.6%) and Pittsburgh (0) (P < .01). MAC disease also was a more common subsequent AIDS illness in Baltimore (14.3%) and Los Angeles (22.4%) than in Chicago (8.5%) and Pittsburgh (6.5%) (P < .0001). Prophylaxis for Pneumocystis carinii infection increased the occurrence of MAC disease as the initial AIDS illness (from 2.3% to 12.5%; P < .0001). A low white blood cell (WBC) count was slightly more predictive of MAC disease than was a low CD4+ cell count. At 0-6, 7-12, and 13-18 months before diagnosis, the WBC cell counts of 75.0%, 61.1%, and 50.0%, respectively, of those with MAC disease as the initial AIDS illness were < or = 3,400/microL. Men in whom cytomegalovirus disease developed were at higher risk for subsequent MAC disease (relative hazard = 2.65; P < .0001). MAC disease also increased the risk for subsequent cytomegalovirus disease (relative hazard = 3.96; P < .0001).

Cognitive performance after progression to AIDS: a longitudinal study from the Multicenter AIDS Cohort Study.

OBJECTIVE: To describe changes in cognitive functioning before and after development of an acquired immune deficiency syndrome (AIDS)-defining illness or CD4+ lymphocyte count < 200/mm3 in participants in the Multicenter AIDS Cohort Study. METHODS: The study population included participants who either were diagnosed with an AIDS-defining illness (n = 52) or had at least one measurement of CD4+ count < 200/mm3 (n = 57) and who had at least four neuropsychological (NP) evaluations, two or more before and two or more after the AIDS diagnosis. A group of subjects with clinical diagnosis of dementia (n = 29) was also included for comparison. The NP test battery included measures of attention, memory, constructional abilities, and psychomotor speed. Longitudinal data analysis, using the generalized estimating equation, was performed separately for each NP measure. Time was measured in months from the date of clinical AIDS or CD4+ < 200/mm3. RESULTS: Before AIDS< the dementia group showed significant decline (slope different from zero) only on measures of psychomotor speed. For all other measures, there was no evidence of decline in performance before AIDS for the other groups. After development of AIDS, the group with clinical AIDS showed significant decline on psychomotor speed but none on the other cognitive measures. The group with CD4+ < 200/mm3 did not show significant decline on any of the cognitive measures after AIDS. As expected, the dementia group showed significant decline on all measures. Sensory neuropathy was associated with a significant decline in performance on measures of psychomotor speed after AIDS. Antiretroviral therapy was not associated with any measurable changes in NP performance. CONCLUSION: These results are consistent with previous findings showing no significant decline in cognitive functions before AIDS, unless overt dementia is present, and no decline in immunosuppressed subjects who have had no AIDS-defining illness. By contrast, in subjects who have developed clinical AIDS, there is mild decline in fine motor skills but no significant change in other cognitive domains.

Incidence of clinical AIDS conditions in a cohort of homosexual men with CD4+ cell counts < 100/mm3. Multicenter AIDS Cohort Study.

Incidence rates of AIDS illnesses are described among patients with < or = 100 CD4 cells/mm3 grouped by use of antiretrovirals and chemoprophylaxis. Data were obtained from 2646 homosexual men infected with human immunodeficiency virus type 1. Participants were in the Multicenter AIDS Cohort Study during 1985-1993. The incidence rates per 100 person-years for Pneumocystis carinii pneumonia were 47.4 without treatment, 21.5 with antiretrovirals alone, and 12.8 with antiretrovirals combined with chemoprophylaxis. For Kaposi's sarcoma these rates were 23.2, 11.3, and 15.1, respectively. The incidence of some opportunistic infections, including Mycobacterium avium complex, nonretinitis cytomegalovirus disease, and cytomegalovirus retinitis, increased among persons receiving P. carinii pneumonia prophylaxis, because of reduction of this pneumonia and extension of life span. The incidence pattern of AIDS-defining illnesses in patients receiving treatment points to the changing AIDS epidemic and the need for new therapies. The data are particularly relevant to the development and planning of clinical trials and to health care providers.

Temporal trends in the incidence of HIV-1-related neurologic diseases: Multicenter AIDS Cohort Study, 1985-1992.

OBJECTIVE: To describe temporal trends in the incidence of human immunodeficiency virus (HIV)-related neurologic diseases in the Multicenter AIDS Cohort Study from 1985 to 1992. METHODS: The incidence rates of six neurologic disorders were examined: toxoplasmosis, cryptococcal meningitis, primary CNS lymphoma, progressive multifocal leukoencephalopathy, HIV dementia, and sensory neuropathy. Poisson modeling was used to test linear trends over time and the effects of progressive immunosuppression, antimicrobial prophylaxis, and antiretroviral drug therapy. RESULTS: There was an upward temporal trend in all incidence rates, except for HIV dementia. Progressive immunosuppression in the cohort explained all calendar trends except for sensory neuropathy, where an increasing temporal trend remained even after adjusting for CD4+ cell count, and for HIV dementia where a slight decline was noted, although the effects were not statistically significant. We noted a protective trend of antimicrobial prophylaxis on toxoplasmosis and cryptococcal meningitis, but, in contrast, use of antiretroviral agents was not protective against HIV dementia. Men receiving didanosine, zalcitabine, or stavudine were more likely to develop sensory neuropathy. CONCLUSION: Despite the earlier and more widespread use of antimicrobial and antiretroviral agents, neurologic conditions still occurred frequently in this cohort, with annual rates above 1.5 per 100 person-years for HIV dementia and sensory neuropathy. Sensory neuropathy seems to be increasing in incidence and HIV dementia declining slightly in this cohort. As the epidemic matures and more people with profound immunosuppression live longer, the overall incidence of HIV-related neurologic diseases can be expected to rise.

Clinical manifestations of AIDS in the era of pneumocystis prophylaxis. Multicenter AIDS Cohort Study.

BACKGROUND: Among patients infected with human immunodeficiency virus type 1 (HIV-1), early and widespread use of prophylactic regimens against Pneumocystis carinii is changing the pattern of illnesses related to the acquired immunodeficiency syndrome (AIDS). METHODS: We conducted a subcohort analysis of 844 men with AIDS (87 percent of whom have since died) from a prospectively followed cohort of 2592 HIV-1-infected homosexual men. RESULTS: A total of 138 men received prophylaxis before the diagnosis of AIDS, but 39 (28 percent) nevertheless had P. carinii pneumonia at some time. Only four illnesses occurred more frequently in men who received P. carinii prophylaxis before the onset of AIDS: Mycobacterium avium complex disease, which developed in 33.4 percent, as compared with 17.3 percent of the 706 men who did not receive early prophylaxis; wasting syndrome (18.4 percent vs. 6.4 percent); cytomegalovirus disease (44.9 percent vs. 24.8 percent); and esophageal candidiasis (21.3 percent vs. 12.8 percent). Collectively, these four diseases accounted for the initial AIDS-related illness in 42.7 percent of those who received prophylaxis before the onset of AIDS, as compared with 10.7 percent of those who did not. During the three six-month periods before the diagnosis of AIDS (0 to 6, > 6 to 12, and > 12 to 18 months), the geometric mean CD4+ cell counts were 48, 87, and 147 per cubic millimeter, respectively, in men who received prophylaxis against P. carinii, as compared with 118, 211, and 279 per cubic millimeter in those who did not. CONCLUSIONS: M. avium complex disease, esophageal candidiasis, wasting syndrome, and cytomegalovirus disease are more common in HIV-infected patients who have received prophylaxis against P. carinii than in those who have not. Prophylaxis may delay the first AIDS illness for 6 to 12 months.

Dementia in AIDS patients: incidence and risk factors. Multicenter AIDS Cohort Study.

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.

Trends in the incidence of outcomes defining acquired immunodeficiency syndrome (AIDS) in the Multicenter AIDS Cohort Study: 1985-1991.

Incidence of clinical outcomes defining acquired immunodeficiency syndrome (AIDS) may be expected to change as a consequence of progressive immunosuppression and use of chemoprophylaxis before the onset of AIDS. Using Poisson regression methods, we examined trends in the incidence of initial and secondary AIDS-defining illnesses from 1985 to 1991 among 2,627 homosexual men participating in the Multicenter AIDS Cohort Study who were seropositive for human immunodeficiency virus type 1. The incidence of Pneumocystis carinii pneumonia rose steeply until 1987 but has declined since then (p < 0.001), while the other AIDS-defining conditions have showed significant (p < or = 0.039) upward trends. Trends for Kaposi's sarcoma, lymphoma, neurologic disease, and cytomegalovirus/herpes simplex virus infections were explained by progressive immunosuppression, but residual downward and upward trends were present for P. carinii pneumonia and other opportunistic infections (bacterial, fungal, and protozoal infections and wasting syndrome). Despite selection bias, those receiving P. carinii pneumonia chemoprophylaxis showed a significantly lower incidence of P. carinii pneumonia (relative risk = 0.32, 95% confidence interval 0.16-0.63), and the time trends of P. carinii pneumonia were explained by progressive immunosuppression and use of prophylaxis. No significant effects on all other diagnoses were seen in those selected to receive antiretroviral therapy. Secondary diagnoses showed a strongly significant (p < 0.001) increase in non-P. carinii pneumonia and non-Kaposi's sarcoma among those with initial diagnoses of Kaposi's sarcoma. Overall, the trend observed in the incidence of other opportunistic infections underscores the need for developing and testing new strategies to curtail or delay the onset of these diseases.

Clinical factors associated with weight loss related to infection with human immunodeficiency virus type 1 in the Multicenter AIDS Cohort Study.

The relation between a number of potential risk factors and change in body mass index per semester was examined in a community-based cohort of 1,809 homosexual and bisexual men seropositive for human immunodeficiency virus type 1 (HIV-1). The men were followed semiannually for up to 6.5 years between 1984 and 1990. A total of 9,735 person-semesters of observations were available for analysis. A Markov-type autoregressive model, adjusting for previous body mass index, was used to predict the change in body mass index over each person-semester. Overall, the cohort was gaining weight. An asymptomatic participant 1.8 m in height whose CD4+ cell count was > 750/microliters gained a mean of 0.5 kg each person-semester. In bivariate autoregressive models, diarrhea, fever, oral thrush, acquired immunodeficiency syndrome (AIDS), and CD4+ lymphocyte counts of < 100 and 100-199 cells/microliters were all associated with a significant decrease in body mass index. A significant inverse association was also found between change in body mass index and lymphadenopathy and herpes zoster, but when the intercept coefficient was added, no overall decrease in body mass index was seen in these models. In a final multivariate model, diarrhea was less strongly associated with a change in body mass index (p = 0.057), although AIDS (p = 0.009), fever (p = 0.006), thrush (p = 0.002), and a CD4+ lymphocyte count of < 100 cells/microliters (p < 0.001) all remained independently associated with a decrease in body mass index. Lymphadenopathy and a CD4+ lymphocyte count of 100-199 cells/microliters were also significant covariates in the final model, but neither of the beta coefficients exceeded that of the intercept, indicating that they were not independently associated with a decrease in body mass index. These findings suggest that the importance of diarrhea as a cause of HIV-related weight loss may have been over-estimated in previous clinic-based studies. AIDS and nonspecific markers of progression (fever, thrush, and a CD4+ count of < 100 cells/microliters) were the best predictors of weight loss during a semester.

Signs and symptoms of "asymptomatic" HIV-1 infection in homosexual men. Multicenter AIDS Cohort Study.

We investigated the long-term health effects of HIV-1 infection in homosexual men not close to developing AIDS by comparing 916 HIV-1-seropositive (SP) men at least 1.67-3.67 years prior to a clinical AIDS diagnosis to 2,161 HIV-1-seronegative (SN) controls. The SP group reported a higher total of 12 distinct symptoms (fatigue, shortness of breath, night sweats, rash, cough, diarrhea, headache, thrush, skin discoloration, fever, weight loss, and sore throat/mouth) than did the SN group (p < 0.0001), corresponding to at least 5.6 more days/year of such symptoms. The SP group had lower body mass index (p < 0.0001) and lower hemoglobin (p < 0.0001). The SP group was more depressed, as measured by CES-D score (p = 0.047), before knowledge of one's serostatus was likely, and became even further depressed (p = 0.038 for increase in depression) after the HIV-1 serostatus test was accessible to high-risk groups. These associations remained unchanged in multivariate models, incorporating other covariates.

The progression of untreated HIV-1 infection prior to AIDS.

Using a case-control study of untreated men, we investigated the physical, mental, and economic effects of human immunodeficiency virus (HIV-1) infection prior to the diagnosis of acquired immunodeficiency syndrome (AIDS). Beginning 2 to 2.5 years prior to AIDS, case subjects reported more of 12 HIV-1 related symptoms and during the year prior to AIDS, at least 30.6 extra days of these symptoms than did control subjects. Within the 6 months preceding AIDS, case subjects' unemployment rose to 9% (P < or = .05) and depression to 34.2% (P < or = .001). At 6 to 12 months and within 6 months before AIDS, 17.1% and 31.5%, respectively, were anemic, while 37.7% and 64.7% had CD4+ counts less than 200 x 10(6)/L. Diagnosing AIDS at CD4+ counts less than 200 x 10(6)/L could significantly reduce pre-AIDS morbidity. Other implications of these findings are discussed.

Epidemiologic patterns of upper respiratory illness and Pneumocystis carinii pneumonia in homosexual men.

The relationship between self-reported upper respiratory illness symptoms (URI) and human immunodeficiency virus Type 1 (HIV-1) was examined in homosexual men using semiannual visits from 1984 to 1988. Temporal and geographic patterns of Pneumocystis carinii pneumonia (PCP) diagnosis in these men during the same time period are also described. URI, including acute sinusitis, was reported more often by 916 HIV-1-seropositive participants than by 2,161 seronegative participants (32.21 versus 28.86% p less than 0.001). For 387 seropositive subjects who progressed to acquired immunodeficiency syndrome (AIDS), the proportion reporting URI peaked one visit pre-AIDS at a level significantly higher than matched control subjects (0.45 versus 0.28, p less than or equal to 0.001). The peak was higher for those with PCP as an initial diagnosis. Reported URI peaked in winter and troughed in summer, and PCP diagnosis rates peaked and troughed 4 months later, respectively. Cities with the highest reported rates of URI also had the highest proportions of AIDS cases with PCP as an initial diagnosis. No temporal or geographic patterns were observed for other HIV-1-related symptoms or non-PCP AIDS diagnoses. These patterns suggest the possibility of a person-to-person transmission of P. carinii similar to that of other respiratory pathogens, which would imply a need to consider stricter methods to prevent nosocomial transmission of this pathogen in inpatient and outpatient settings. Further investigation of these issues is needed.

Temporal trends in human immunodeficiency virus type 1 seroconversion 1984-1989. A report from the Multicenter AIDS Cohort Study (MACS).

The 5-year temporal trends in human immunodeficiency virus type 1 (HIV-1) seroconversion between 1984 and 1989 among homosexual/bisexual men participating in the Multicenter AIDS Cohort Study (MACS) are reported. Of 3,262 initially seronegative men, 368 (11.3%) had seroconverted by December 31, 1989. Although the incidence of seroconversion declined precipitously during the first 3 years of follow-up (from 4.1% to 0.9% per 6 months), no evidence for a further substantial reduction was noted after mid-1987, since 6-month incidence rates ranged between 0.5% and 1.2%. The Chicago cohort experienced an increase in HIV-1 seroconversion during both semesters of 1989; 2.1% and 1.6% per 6 months, respectively, became newly infected. Other MACS centers did not report such an increase. Center-specific differences were observed by race; black men were at higher seroconversion risk than white men in Baltimore/Washington (relative risk (RR) = 3.4) and Chicago (RR = 2.4), while Hispanic men were at higher risk than white men in Chicago (RR = 3.3). Younger age (less than 35 years) was also associated with HIV-1 seroconversion (RR = 1.5). It is disturbing to report an overall annual seroconversion rate of 1.2% for the 2 years prior to December 31, 1989, as well as evidence for a sustained recent increase in Chicago during 1989. Long-term maintenance of safe-sex behaviors should be the cornerstone of acquired immunodeficiency syndrome prevention among homosexual/bisexual men.