Biomedical subjects
Publications and source records attributed to D R Hoover.
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The possibility that an agent in addition to the human immunodeficiency virus (HIV) may contribute to the etiology of non-Hodgkin's lymphoma in persons with acquired immunodeficiency syndrome (AIDS) was studied using participants from the Multicenter AIDS Cohort Study (MACS) of homosexual and bisexual men enrolled in 1984-1985 and also in 1987-1991. A nested case-control analysis was conducted. The primary source of information on potential exposures and characteristics of the participants was the baseline study entry interview that was conducted prior to the development of AIDS. A total of 84 cases of non-Hodgkin's lymphoma were identified and compared with 527 participants who developed AIDS but had no evidence of cancer. The groups were similar for most sociodemographic characteristics as well as sexual activity and past history of antecedent illnesses. Although the non-Hodgkin's lymphoma cases reported less frequent use of recreational drugs and cigarettes compared with other persons with AIDS, these differences were not significant. Non-Hodgkin's lymphoma cases reported more frequent intake of aspirin during the week before the interview. However, there were no differences between the comparison groups for long-term aspirin intake or intake of other analgesics. The absence of any specific and strong association between non-Hodgkin's lymphoma and the various behavior-related activities and exposures considered in this analysis suggests that these factors are not related to a second agent in the etiology of HIV-induced non-Hodgkin's lymphoma. The possibility that a very common agent in this study population or that differences in the nature of the immune dysfunction resulting from HIV infection could act as a cofactor for HIV-induced non-Hodgkin's lymphoma cannot be excluded.
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OBJECTIVE: To estimate the incidence and prevalence of cytomegalovirus retinitis (CMV-R) in late-stage human immunodeficiency virus type 1 disease. DESIGN: Cohort study. SETTING: The Multicenter AIDS Cohort Study, an ongoing 10-year study of human immunodeficiency virus type 1-infected homosexual men with semiannual visits and CD4+ cell testing. STUDY PARTICIPANTS: Three hundred sixty-seven human immunodeficiency virus type 1-infected men from the Multicenter AIDS Cohort Study who were receiving zidovudine and Pneumocystis carinii prophylaxis and who had CD4+ cell counts fall below 0.10 x 10(9)/L (100/microL). MAIN OUTCOME MEASURES: Kaplan-Meier-type estimates for various longitudinal quantifications of incidence and prevalence of CMV-R were obtained. RESULTS: Among these 367 individuals, cytomegalovirus disease developed in 103, of whom 73 (71%) had ocular complications. At 4 years after the first CD4 cell count ( < 0.10 x 10(9)/L), the probability for these subjects to have (1) remained living without CMV-R was 11%, (2) died without experiencing CMV-R was 66%, (3) experienced CMV-R and be living was 6%, and (4) experienced CMV-R and died was 18%. During these 4 years, there was a 25% chance for the development of CMV-R and, on average, 0.211 person-years of CMV-R morbidity. Among those subjects in whom CMV-R developed, about 19% did have CMV-R before a CD4+ cell count of less than 0.05 x 10(9)/L ( < 50/microL) was observed, and 81% had CMV-R after the CD4+ cell count reached this threshold. CONCLUSION: These estimates may be relevant to current clinical practice and help in allocating resources and planning for treatment and prophylaxis against cytomegalovirus disease.
The objective of this study was to describe the prevalence and course of depressive symptoms before AIDS in HIV-infected homosexual men. A descriptive and comparative analysis of data from HIV-infected and -uninfected homosexual men in the Multicenter AIDS Cohort Study was performed. The Center for Epidemiologic Studies Depression Scale (CES-D) was the primary measure of depressive symptoms. The prevalence of depressive symptoms and CES-D caseness estimates in the AIDS-free HIV-infected homosexual men were stable over time. Small differences between HIV seropositive and seronegative men were detected on the CES-D and on three of its subscales. These were mostly accounted for by less hope, and by more fearfulness, insomnia, and anorexia in the seropositive cohort. We concluded that there does not appear to be an overall increase in depressive symptoms in HIV-infected homosexual men from the time of infection until prior to AIDS. However, this group of men consistently report specific depressive symptoms more often. Implications of these findings for the clinical care of HIV-infected patients is discussed.
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The relationship between cell-associated infectious human immunodeficiency virus type 1 (HIV) load (infectious units/10(6) peripheral blood mononuclear cells [IUPM]) and phenotypes of CD4+ and CD8+ lymphocytes was studied. IUPM were measured in 242 HIV-infected homosexual men by quantitative microculture and T cell subsets by two-color flow cytometry. In multivariate analysis, IUPM correlated negatively with CD4+ lymphocyte level and with a diagnosis of AIDS and positively with the proportion of CD8+ lymphocytes expressing the activation marker CD38. After adjusting for level of CD4+ lymphocytes, men with AIDS had significantly lower IUPM than those without AIDS. The correlation between IUPM and CD4+ lymphocyte level was largely explained by correlation with level of CD4+ lymphocytes with resting phenotypes (HLA-DR-, CD38-) rather than with those expressing HLA-DR and CD38. Thus, subsets of CD4+ lymphocytes may vary in cell-associated infectious HIV content at different stages of HIV infection.
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To determine if use of antiherpes drugs protects against the development of AIDS-associated Kaposi's sarcoma (KS), data from 935 homosexual men with AIDS from the Multicenter AIDS Cohort Study were analyzed. In nested case-control analysis, neither acyclovir use for human immunodeficiency virus infection (odds ratio [OR], 0.84; 95% confidence interval [CI], 0.56-1.26; P = .39) nor acyclovir use for any indication (OR, 1.02; 95% CI, 0.76-1.38; P = .89) was associated with a reduced risk of KS as initial AIDS diagnosis. In longitudinal analysis, acyclovir was also not protective against developing KS as a late manifestation of AIDS (after initial non-KS AIDS diagnosis). Among men with cytomegalovirus disease, ganciclovir use (relative risk [RR], 0.56; 95% CI, 0.22-1.44; P = .23) and foscarnet use (RR, 0.40; 95% CI, 0.051-3.10; P = .38) were associated (although not significantly) with a reduced risk of KS. Thus, acyclovir use does not appear to reduce the risk of KS, but further study of other antiherpes drugs such as ganciclovir and foscarnet is warranted.
To assess the effect of human immunodeficiency virus (HIV) immunosuppression on ongoing hepatitis C virus (HCV) infection, CD4 lymphocyte counts and serum concentrations of HCV RNA, HIV RNA, and alanine aminotransferase (ALT) were evaluated among members of a cohort of injecting drug users (IDUs). With 100 participants randomly selected at various stages of HIV-related immunosuppression, serum HCV RNA concentrations increased with age (P = .007) and were higher in HIV-positive IDUs with 201-500 (P = .026) and 51-200 (P = .004) CD4 cells/mL than in HIV-negative participants. Among 27 HCV-infected IDUs who acquired HIV infection, serum HCV RNA concentrations varied between semiannual visits by a mean of 0.45 logs, increasing by 0.60 logs after HIV seroconversion (P < .0001), by 0.12 logs each subsequent year (P = .006), and by 0.36 logs per log increase in CD4 cells (P = .01). Serum ALT levels were similar between HIV-positive (40.1 IU/mL) and HIV-negative (45.4 IU/mL) patients (P > .10). While HIV infection and possibly HIV progression are associated with increased HCV RNA levels, other factors appear to affect biochemical and virologic markers of HCV infection in some dually infected persons.
To determine if vaccination induces replication of human immunodeficiency virus type 1 (HIV-1), 42 HIV-1-infected subjects with CD4 cell counts of 200-500 cells/microL were randomized to receive influenza vaccine or saline placebo. Infectious cell-associated and plasma HIV-1 RNA virus load were measured twice at baseline and then at 7, 10, 14, and 30 days after injection by quantitative microculture and branched DNA amplification. The ratios of the geometric mean plasma HIV-1 load of the four follow-up visits compared with baseline in vaccine (n = 28) and placebo (n = 14) recipients were similar (1.05 [95% confidence interval, 0.80-1.37] for vaccine; 0.96 [95% confidence interval, 0.68-1.33] for placebo; P = .90). The geometric mean ratios of plasma virus load at each follow-up visit to baseline did not differ significantly from 1.0 for each group. Infectious cell-associated virus load measures yielded similar results. CD4 cell counts declined similarly in both groups at 6 months. Influenza vaccination did not increase HIV-1 load in this controlled clinical trial.
OBJECTIVES: Kaposi's sarcoma-associated herpesvirus (KSHV), a newly discovered human gammaherpesvirus, is found in the majority of KS lesions from patients with and without AIDS. Peripheral blood mononuclear cells (PBMC) were examined for KSHV DNA to determine whether viral infection precedes onset of this neoplasm. DESIGN: Randomized and blinded case-control study of prospectively collected PBMC samples from ongoing cohort studies. METHODS: Paired PBMC drawn before and after KS onset from 21 AIDS-KS patients were compared to paired PBMC from 23 high-risk HIV-infected homo-/bisexual patients who did not develop KS and to a single PBMC sample from 19 low-risk, HIV-infected hemophiliac patients. Extracted DNA samples were amplified by polymerase chain reaction (PCR) using two non-overlapping nested primer sets to control for potential PCR contamination. RESULTS: In all comparisons, patients who went on to develop KS were significantly more likely to show evidence of KSHV infection prior to onset of KS than either control group. Of PBMC samples from AIDS-KS patients drawn prior to KS, 52% were positive for KSHV DNA whereas both high- and low-risk control groups had lower rates of PBMC infection (9-13%). KSHV infection can precede KS onset by up to 21 months among AIDS-KS patients. CONCLUSIONS: AIDS-KS patients are significantly more likely to show evidence of KSHV infection in PBMC prior to KS onset than control HIV-infected patients. Because identical PBMC samples from cases and controls were examined blindly, these results are not caused by a bias in tissue sampling. Homo-/bisexual and hemophiliac AIDS patients who do not develop KS appear to have a low prevalence of infection. These findings indicate that KSHV infection is specifically associated with the subsequent development of KS in AIDS patients.
It is widely assumed that the time since human immunodeficiency virus (HIV) infection is an important indicator of HIV disease stage, yet for most infected individuals the date of infection is unknown. We consider whether marker values, such as CD4 lymphocyte number or percent and levels of serum beta2 microglobulin or serum neopterin, render time since infection unimportant for predicting the residual time to acquired immunodeficiency syndrome (AIDS) diagnosis. The Multicenter AIDS Cohort Study (MACS) contains a subsample of homosexual men whose date of HIV seroconversion is known within +/-6 months and who provide data for this analysis. From this subsample, we extract two overlapping data subsets. The first subset consists of 370 persons whose 3,723 study visits include complete data on the cellular markers CD4 lymphocyte number and percent for a period of 9 years. The second consists of 272 persons whose 1,593 visits include complete information on cellular markers and on the serological markers beta2-microglobulin and neopterin for a period of 5 1/2 years. We model the residual time to AIDS diagnosis with a regression model, in which cellular and serologic markers are the explanatory covariates (independent variables) and the residual time to AIDS is the responses variable (dependent variable). A robust estimate of the variance-covariance matrix corrects for the dependence of repeated measurements in the same individual. In the case of CD4 number and percent, the results indicate that time since infection is of none or at most little importance if the marker value is known, suggesting that time since infection can be adequately replaced by the combination of marker values. However, the serological markers alone do not eliminate the importance of the time since infection.
OBJECTIVE: The authors sought to determine whether rates of depressive symptoms change from early- to late-stage HIV-1 infection and to determine the predictors of depressive symptoms as AIDS develops. METHOD: The data for this study were from 911 HIV-seropositive men-community volunteers from four U.S. cities-who entered the 10-year Multicenter AIDS Cohort Study without a diagnosis of AIDS and subsequently developed AIDS. The subjects underwent semiannual follow-ups during the study period. The outcome measures-overall depressive symptoms, nonsomatic depressive symptoms, syndromal depression, and severe depression-were assessed over the 5 years before and the 2 years after AIDS diagnosis from responses on the Center for Epidemiologic Studies Depression Scale (CES-D Scale). RESULTS: Depressive symptoms were stable over time from month 60 to month 18 before AIDS developed. However, beginning 12-18 months before AIDS diagnosis, there was a significant rise in all measures of depression, which reached a plateau within 6 months before AIDS developed. At this plateau, there was a 45% increase in mean CES-D Scale scores above baseline. An elevated CES-D Scale score in the earlier stages of infection, a self-report of AIDS-related symptoms (such as rash and lymphadenopathy), concurrent unemployment, cigarette smoking, and limited social supports were consistent predictors of higher rates of depression as AIDS developed. CONCLUSIONS: There is a dramatic, sustained rise in depressive symptoms as AIDS develops, beginning as early as 18 months before clinical AIDS is diagnosed. Prior depression, HIV-disease-related factors, and psychological stressors contribute to this rise. This robust phenomenon invites further characterization.
Weight loss is commonly associated with increased morbidity and mortality in individuals with human immunodeficiency virus (HIV) infection. We performed a nested case-control study of 26 HIV-infected subjects recruited from a cohort of gay men enrolled in the Multicenter Acquired Immunodeficiency Syndrome Cohort Study. To test the hypothesis that hormonal changes precede and may induce the wasting syndrome, we performed a nested case-control study and analyzed serum gonadal steroids and GH in samples of HIV-infected men with or without weight loss, uncomplicated by diarrhea or ever having an opportunistic infection. We studied 13 cases (mean age +/- SD, 45 +/- 7.2 yr) with a mean weight loss of 13 +/- 3.6%, considered to have the wasting syndrome by Centers for Disease Control criteria (weight loss of > 10%) and 13 controls matched for age and duration of follow-up. Serum bioavailable testosterone (T) levels decreased in the case group (P < 0.05) before the definition of wasting was attained, although weight loss had already begun. More impressive declines occurred in serum T (P = 0.012), free T (P = 0.0025), and bioavailable T (P < 0.0001) during the 6 months immediately before documentation of wasting. These changes were concurrent with an increase in serum FSH (P = 0.0135) without a change in serum LH. We conclude that a decline in bioavailable T occurs early in the course of events leading to wasting, suggesting that changes in gonadal hormones may contribute to the multifactorial etiology of the wasting syndrome.
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.
OBJECTIVE: To determine whether racial differences exist in the rate of CD4 lymphocyte decline in HIV-1-infected homosexual men. DESIGN: Prospective cohort study. STUDY POPULATION: Non-Hispanic white (n = 321) and black (n = 102) HIV-1-seropositive homosexual and bisexual men were recruited from the Baltimore/Washington, DC metropolitan areas between 1984-1985 and 1987-1990, and evaluated semiannually. MAIN MEASUREMENTS: Changes in CD4 lymphocyte count and CD4 percentage over time were analysed using linear regression methods for the 271 white and 69 black participants who had at least four semiannual CD4 lymphocyte measurements. RESULTS: Rate of decline in CD4 lymphocyte count over 6 months was much slower among black than white seroprevalent men at all levels of baseline CD4 count (baseline 201-400 x 10(6)/l: + 0.24 versus -17.7 x 10(6)/l; 401-600 x 10(6)/l: -11.3 versus -23.9 x 10(6)/l; 601-800 x 10(6)/l: -15.1 versus -35.2 x 10(6)/l; > 800 x 10(6)/l: -4.3 versus -42.7 x 10(6)/l for black versus white, respectively), although this was only statistically significant for the lowest and highest strata of baseline CD4 count. These racial differences persisted after adjustment for recruitment period (1984-1985 or 1987-1990), follow-up duration, age and zidovudine therapy or Pneumocystis carinii pneumonia prophylaxis. Similar findings were observed among the 70 white and 11 black seroconverters. Black participants were also less likely than a subgroup of white participants matched on baseline CD4 lymphocyte count to be HIV-1 p24 antigen-positive. However, after acid dissociation of samples initially p24 antigen-negative, there were no significant differences in the prevalence of p24 antigenemia at enrollment or after 1 year of follow-up. CONCLUSIONS: This analysis suggests a more gradual decline in CD4 lymphocyte count among black than white Americans. The clinical significance of and reasons for this are unclear, but the lower prevalence of p24 antigenemia due to immune complexing among black Americans suggests that racial differences in the immune response to HIV may exist. Additional studies are needed to validate these findings in a larger cohort of non-whites, and to assess their relationship with other measures of cell-mediated immune function.
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