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R Detels

Publications and source records attributed to R Detels.

At least 55 records · Page 3Linked to original sources
PubMed1999

Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage.

To define predictors of survival time in late human immunodeficiency virus type 1 (HIV-1) disease, long- and short-duration survivors were studied after their CD4+ T cells fell to </=50/mm3. Immune activation of CD4+ and CD8+ T cells, as measured by elevated cell surface expression of CD38 antigen, was strongly associated with shorter subsequent survival (P</=.002). The naive CD45RA+CD62L+ T cell reserve was low in all subjects and did not predict survival (P=.34 for CD4+ and.08 for CD8+ cells). Higher virus burden correlated with CD8+ but not CD4+ cell activation and, after correcting for multiple comparisons, was not associated with shorter survival (P=.02). All of the patients' viruses used CCR5, CXCR4, or both, and coreceptor usage did not predict survival (P=. 27). Through mechanisms apparently unrelated to higher virus burden, immune activation is a major determinant of survival in advanced HIV-1 disease.

ADP-ribosyl Cyclase↗
PubMed1999

Stability of plasma levels of cytokines and soluble activation markers in patients with human immunodeficiency virus infection.

Cytokine and immune activation marker levels in plasma are valuable measurements of immune status and treatment effects in human immunodeficiency virus (HIV) infection and AIDS. Five populations representing various stages of disease were studied: controls, 2 AIDS groups with <50/mm3 CD4 cells, and 2 groups of HIV-positive subjects-1 with stable CD4 T cells (median, 545/mm3) and 1 with >100/mm3 CD4 cell decline in 1 year. Relatively stable levels of tumor necrosis factor (TNF)-alpha, soluble TNF receptor (R)II, soluble interleukin-2R, neopterin, and beta2-microglobulin (beta2M) were documented over 5-8 weeks in patients with AIDS and for 1-4 years in the other groups. beta2M was generally the most stable marker. Interferon-gamma levels, however, fluctuated substantially. Individuals, whether normal or HIV-positive, maintain characteristic plasma levels of cytokines and immune activation markers. Thus, documented changes, in excess of the variability observed in this study, are likely to be significant indicators of change in disease status or effects of therapy.

Adult↗
PubMed1999

Variables that affect assays for plasma cytokines and soluble activation markers.

Cytokines and soluble immune activation markers that reflect cytokine activities in vivo are increasingly being measured in plasma, serum, and other body fluids. They provide useful diagnostic and prognostic information as well as insight into disease pathogenesis. Assays of neopterin, beta2-microglobulin, soluble interleukin-2 receptor, and soluble tumor necrosis factor receptor type II as well as of the cytokines tumor necrosis factor alpha and gamma interferon (IFN-gamma) were evaluated by using serum and plasma samples of human immunodeficiency virus (HIV)-positive and HIV-negative subjects. Many factors were found to influence the outcomes of these assays. Substantial differences in apparent levels of analytes were frequently found when enzyme-linked immunosorbent assay (ELISA) kits from different manufacturers were used. In some cases, differences were found in the standards provided by separate manufacturers. Furthermore, the analytic results from different lots of ELISA kits supplied by single manufacturers differed by as much as 50%. The need for uniformity in the standards for quantitative assays was clearly illustrated. International reference standards are available for cytokines but not for soluble cytokine receptors or soluble activation markers. Marker levels in serum or in plasma were similar except those for IFN-gamma. Most of the analytes were stable under several storage conditions. Thus, batch testing of frozen stored samples is feasible. The findings indicate that for longitudinal studies, the levels of cytokines and immune activation markers in plasma or serum should be measured by using preverified reagents from one manufacturer. The quality of laboratory performance can have an impact on clinical relevance. Proficiency testing and external quality assurance programs can help to develop the needed consensus.

Antigens, CD↗
PubMed1999

Knowledge of HIV/AIDS among health care workers in China.

This study was designed to assess knowledge of AIDS among health professionals in China via a cross-sectional survey. A self-administered questionnaire requesting demographic characteristics and basic AIDS knowledge was given to health professionals in 11 provinces, cities, and autonomous regions. Questionnaires were completed by 1,400 of 1,500 (93%) health professionals surveyed. The percentages of correct answers ranged from 3% to 68%. Findings included that public health workers had more knowledge than clinicians; having attended training workshops was not associated with an adequate levels of knowledge; and knowledge differed by professional level and by the geographic region in which they worked. Although most health professionals questioned knew that AIDS is caused by an infectious agents, their knowledge of transmission routes, the "window period" and the length of the incubation period is still inadequate. Thus, health professionals in China urgently need both more training and more effective training. The effectiveness of future HIV/AIDS workshops should be evaluated.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Association of HLA profiles with early plasma viral load, CD4+ cell count and rate of progression to AIDS following acute HIV-1 infection. Multicenter AIDS Cohort Study.

BACKGROUND: Host genetic factors, such as HLA alleles, play an important role in mediating the course of HIV-1 disease progression through largely undefined mechanisms. OBJECTIVES: To examine the association of HLA markers with HIV-1 RNA plasma viral load and other factors associated with course of disease progression in HIV-1 infection. DESIGN AND METHODS: A group of 139 HIV-1 seroconverters from the Multicenter AIDS Cohort Study had been typed for a variety of HLA markers. HIV-1 RNA plasma viral load was measured from frozen plasma specimens obtained approximately 9 months following seroconversion. CD4+ cell counts were available from the same study visit. Statistical analysis was performed using survival techniques and linear regression models to quantify the relative associations of an HLA score profile, HIV-1 RNA plasma viral load, CD4+ cell count and age with each other and with rate of progression to AIDS and death. RESULTS: Cox proportional hazards models showed statistically significant differences in time to AIDS by HLA score profile category per unit increase [relative hazard (RH), 0.64; P < 0.0001], HIV-1 RNA plasma viral load per 10-fold increase (RH, 2.04; P = 0.0003), and CD4+ cell count per 100 cell (x 10(6)/l) increase (RH, 0.90; P = 0.02). Multivariate linear regression showed that viral load was 39% lower (P = 0.0001) for each unit increase in HLA score profile and 13% lower (P = 0.002) for each 100 cell (x 10(6)/l) increase in CD4+ cell count. CONCLUSION: The means by which the HLA score profile influences the time to AIDS is probably through immunologic responses that affect the rate of HIV-1 replication, as manifested by the HIV-1 RNA plasma viral load during the first 6-12 months following acute infection.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration. Multicenter AIDS Cohort Study Investigators.

CONTEXT: Time to development of acquired immunodeficiency syndrome (AIDS) and time to death have been extended with the increased use of combination therapy and protease inhibitors. Cohort studies following up persons with human immunodeficiency virus (HIV) infection in periods characterized by different therapies offer the opportunity to estimate therapy effectiveness at the population level. OBJECTIVE: To assess the effectiveness of self-reported, long-term potent antiretroviral therapy in a cohort of 536 men whose duration of HIV infection was known (seroconverters). DESIGN: Cohort study. The cohort was compared for time to development of AIDS and time to death in 1984 to 1990, 1990 to 1993, 1993 to July 1995, and July 1995 to July 1997 when the major treatments were no therapy, monotherapy, combined therapy, and potent antiretroviral therapy, respectively. Survival analysis methods with time zero set as the date of seroconversion and incorporating staggered entries into each period were used. Mean CD4 cell change, stratified by infection duration, was determined for each period using a random effects model. SETTING: The Multicenter AIDS Cohort Study (MACS) in 4 urban areas (Baltimore, Md; Chicago, III; Los Angeles, Calif; and Pittsburgh, Pa). PARTICIPANTS: A total of 5622 men who were 18 years or older were enrolled into MACS. Of the 5622, there were 2191 HIV-positive individuals at enrollment. Of the 3431 men who were HIV-negative, 536 were observed to seroconvert and were followed up for up to 13 years. The group of 536 who seroconverted constituted the study population. MAIN OUTCOME MEASURES: Time from seroconversion to development of AIDS and to death and change in CD4 cell count. RESULTS: A total of 231 seroconverters developed AIDS, and 200 men died. Using 1990 to 1993 as the reference period, the relative hazard of AIDS was 1.04 (95% confidence interval [CI], 0.73-1.48) during 1993 to July 1995 and 0.35 (95% CI, 0.20-0.61) during July 1995 to July 1997. Relative hazards of death were 0.87 (95% CI, 0.58-1.31) and 0.62 (95% CI, 0.38-1.01 ) for the same periods. The relative time (the factor by which times are contracted or expanded) to development of AIDS was 0.97 (95% CI, 0.86-1.09) for 1993 to July 1995 and 1.63 (95% CI, 1.40-1.89) for July 1995 to July 1997. Relative survival time for 1993 to July 1995 was 1.01 (95% CI, 0.91-1.12) and for July 1995 to July 1997 was 1.21 (95% CI, 1.07-1.36) relative to 1990 to 1993. The rate of CD4 cell count decline in July 1995 to July 1997 was significantly lower (P<.05) compared with the previous 2 periods. CONCLUSIONS: In the calendar period when potent antiretroviral therapy was introduced, the time to development of AIDS and time to death were extended, and rate of CD4 cell count decline was arrested.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Immunologic effects of combined protease inhibitor and reverse transcriptase inhibitor therapy in previously treated chronic HIV-1 infection.

OBJECTIVE: To evaluate the efficacy of combination protease and reverse transcriptase inhibitor therapy in correcting HIV-1-induced lymphocyte subset abnormalities in previously treated adults. DESIGN: A 48-week observational study of lymphocyte subsets in 12 participants in the Multicenter AIDS Cohort Study who were already taking at least one reverse transcriptase inhibitor and added a protease inhibitor to their treatment regimen. Comparison groups were HIV-seronegative homosexual men, HIV-seronegative heterosexual men, and homosexual HIV-1-infected men who were long-term non-progressors. METHODS: Three-color immunofluorescence and monoclonal antibodies were used to assess HIV-1-induced lymphocyte subset alterations related to immune deficiency and immune activation. Plasma HIV-1 RNA levels were monitored to assess suppression of viral replication. RESULTS: CD4+ cell counts significantly increased and lymphocyte activation measured as CD38 and HLA-DR expression on CD8+ T cells significantly decreased by 48 weeks. CD4+ cell values remained abnormal even in those who were fully suppressed. Some T-cell activation markers decreased to levels observed in long-term non-progressors. The increase in CD4+ T-cell numbers reached a plateau by week 24, but the increase in resting HLA-DR- CD38-T cells was sustained through week 48. Proportions of CD45RA+ CD62L-selectin+ and CD28+ CD4+ T-cell subsets and Fas expression were not abnormal at baseline compared with seronegative homosexual controls. CONCLUSIONS: The most significant impact of suppression of viral replication was reversal of T-cell activation. However, normalization of lymphocyte subset perturbations associated with chronic HIV-1 infection was not achieved after 1 year of treatment with current combination antiretroviral regimens. More profound viral suppression, therapy for longer than 1 year, or immunologic augmentation may be needed to fully reverse the abnormalities.

Adult↗
PubMed1998

Prognostic significance of plasma markers of immune activation, HIV viral load and CD4 T-cell measurements.

OBJECTIVE: To evaluate the prognostic significance for AIDS occurrence of plasma levels of immune activation markers in comparison with and in conjunction with HIV viral load and CD4 T-cell measurements. DESIGN: A retrospective analysis was conducted of three plasma activation markers, the soluble tumor necrosis factor (TNF) receptor II (TNF-RII), neopterin and soluble interleukin-2 receptor levels, and of CD4 T-cell levels and plasma HIV viral load. SUBJECTS: The participants were 659 men taking part in the University of California Los Angeles Multicenter AIDS Cohort Study who were HIV-seropositive but AIDS-free in 1985. MAIN OUTCOME MEASURE: Clinically defined AIDS within 3 years. Failure time statistical regression models for the time to development of AIDS were used to assess prognostic capacity of the parameters alone and in combination. RESULTS: All the markers had prognostic capability. The levels of the three plasma activation markers correlated well with each other (median r = 0.61). They related less well with HIV RNA plasma levels (median r = 0.50) and least well with CD4 cell levels (median r = 0.36). Furthermore, plasma marker levels were shown to be able to stratify patients for prognosis within all the major categories of CD4 T-cell and HIV RNA levels. CONCLUSIONS: Plasma levels of soluble TNF-RII and other soluble markers of immune activation have prognostic capabilities which are different from HIV and CD4 T-cell levels. Combination of a single plasma activation marker measurement (such as soluble TNF-RII) with CD4 T-cell levels improved the prognostic capability of each. A new graphic technique for presenting prognostic capability indicated that plasma soluble TNF-RII and CD4 cell levels are better prognostic factors than HIV plasma level with CD4 cells < 200 x 10(6)/l. Inexpensive tests for one of the plasma activation markers, such as soluble TNF-RII or neopterin, can be useful for evaluations of HIV disease course, especially when expensive equipment, technical expertise and funding required for flow cytometry and for HIV load measurements are not readily available.

Antigens, CD↗
PubMed1998

Identification of inflections in T-cell counts among HIV-1-infected individuals and relationship with progression to clinical AIDS.

Studies of circulating T (CD3(+)) lymphocytes have shown that on a population basis T-cell numbers remain stable for many years after HIV-1 infection (blind T-cell homeostasis), but decline rapidly beginning approximately 1.5-2.5 years before the onset of clinical AIDS. We derived a general method for defining the loss of homeostasis on the individual level and for determining the prevalence of homeostasis loss according to HIV status and the occurrence of AIDS in more than 5,000 men enrolled in the Multicenter AIDS Cohort Study. We used a segmented regression model for log10 CD3(+) cell counts that included separate T-cell trajectories before and after a time (the T-cell inflection point) where the loss of T-cell homeostasis was most likely to have occurred. The average slope of CD3(+) lymphocyte counts before the inflection point was close to zero for HIV- and HIV+ men, consistent with blind T-cell homeostasis. After the inflection point, the HIV+ individuals who developed AIDS generally showed a dramatic decline in CD3(+) cell counts relative to HIV- men and HIV+ men not developing AIDS. A CD3(+) cell decline of greater than 10 percent per year was present in 77% of HIV+ men developing AIDS but in only 23% of HIV+ men with no onset of AIDS. Our findings at the individual level support the blind T-cell homeostasis hypothesis and provide strong evidence that the loss of homeostasis is an important mechanism in the pathogenesis of the severe immunodeficiency that characterizes the late stages of HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1998

A study of sexual behavior among rural residents of China.

OBJECTIVE: Although the recent spread of HIV/AIDS and other sexually transmitted diseases (STDs) in China has been associated with sexual activities, little information has been available about sexual behavior in rural areas with high HIV prevalence. Studies identifying high-risk sexual behaviors are needed to formulate effective prevention programs. METHODS: A cross-sectional study design was used to measure sexual activities using a two-stage cluster sampling method. A two-part anonymous questionnaire was used. Sensitive questions related to sexual behavior were administered using a tape recorder, earphones, and an answer sheet which did not include the text. RESULTS: In total, 1057 subjects were interviewed. Among 886 sexually active individuals, 7.8% had >1 sexual partner, 22.8% had premarital sex, 2.4% had anal intercourse, 4.1% had oral intercourse, and 2.3% had both anal and oral intercourse. Less than 2% reported past or current sexually transmitted diseases. Overall, 10.4% used condoms; only 11.2% for every sexual act. History of premarital and extramarital sex was higher in younger people. CONCLUSIONS: Sexual norms in rural China are changing rapidly and high-risk sexual behavior among young rural residents is increasing. Strategies to prevent HIV/AIDS should include education to promote delayed onset of sexual activity, safer sexual behavior, and condom use.

Adolescent↗
PubMed1998

Factors associated with survival following secondary AIDS: 1988 to 1995.

The second AIDS-defining condition diagnosed chronologically is referred to in this report as the secondary AIDS diagnosis. In this study, we examined survival following a secondary AIDS diagnosis using demographic and clinical factors known within 1 year before secondary AIDS diagnosis. In a prospective cohort of 2412 HIV-seropositive homosexual men observed in the Multicenter AIDS Cohort Study (MACS), 609 presented with a secondary AIDS diagnosis between January 1, 1988 and March 31, 1995. To analyze the data, we used survival analysis methods including the Kaplan-Meier product-limit estimator and extended Cox models that allow for nonproportional hazards. The median survival time after a secondary diagnosis was 10.3 months. Rapidity of progression from an initial AIDS diagnosis to a secondary diagnosis was not associated with survival. Drug treatment did not show a beneficial effect because of confounding by indication (i.e., selection bias) and limited efficacy on advanced disease of treatments available prior to 1995. However, a beneficial effect was captured by the use of calendar periods as a proxy measure for the relative exposure to drug treatments. Later calendar year of secondary diagnosis, secondary Kaposi's sarcoma, and higher CD4+ cell count were found to be significantly (p < .05) associated with longer survival time. However, secondary AIDS diagnosis was a significant factor only in the short term. Using secondary Pneumocystis carinii pneumonia as the reference diagnosis, the relative hazard of death 3 months after the time of secondary Kaposi's sarcoma diagnosis was 0.56 (95% confidence interval [CI] = 0.36-0.89) whereas the relative hazard after concurrently diagnosed multiple secondary illnesses was 2.06 (95% CI = 1.26-3.38). After approximately 1 year from the secondary diagnosis, the type of diagnosis was no longer significantly associated with survival.

Acquired Immunodeficiency Syndrome↗
PubMed1998

CD8+ T-lymphocyte activation in HIV-1 disease reflects an aspect of pathogenesis distinct from viral burden and immunodeficiency.

The CD8+ T-cell response is central to control and eventual elimination of persistent viral infections. Although it might be expected that CD8+ T-cell activation would be associated with a better clinical outcome during viral infections, in long-term HIV-1 infection, high levels of CD8+ T-cell activation are instead associated with faster disease progression. In this study, cell surface expression of CD38, a flow cytometric marker of T-cell activation of CD8+ T cells, had predictive value for HIV-1 disease progression that was in part independent of the predictive value of plasma viral burden and CD4+ T-cell number. Measurements of CD38 antigen expression on CD8+ T cells in HIV-1-infected patients may be of value for assessing prognosis and the impact of therapeutic interventions. The pathogenetic reason why CD8+ T-cell activation is associated with poor outcome in HIV-1 disease remains unknown. Possibly CD8+ T-cell activation contributes to immunologic exhaustion, hyporesponsiveness of T cells to their cognate antigens, or perturbations in the T-cell receptor repertoire.

ADP-ribosyl Cyclase↗
PubMed1998

Accelerated changes (inflection points) in levels of serum immune activation markers and CD4+ and CD8+ T cells prior to AIDS onset.

The trajectories of change in CD4+ and CD8+ lymphocytes and serum neopterin and beta2-microglobulin (beta2M) levels were determined in 158 HIV-seropositive individuals during 5.5 years before a clinical AIDS diagnosis. Each patient was evaluated separately using a two-piece regression model with seven possible change points to identify any adverse change (inflection point) in the slopes of each immunologic marker of HIV infection. Two categories of subjects were distinguished for each marker--those with statistically significant inflection points and those who demonstrated a steady progression of changes to AIDS. Fifty-nine percent had an inflection point for CD4+ T cells. The frequency of inflection points for CD8+ was 49%, for serum neopterin -48% and for beta2M -38%. Inflection points were found over a 4-year span. Three distinctive categories of inflection points were observed on the basis of their independent occurrence: one was in CD4+ T cells, another in CD8+ T cells, and a third in the serum markers of immune activation. The inflection point for CD4+ usually occurred prior to those for CD8+ T cells (p=.0002). The HIV-positive persons with inflection points were diagnosed with AIDS when immunologic parameters were significantly more abnormal than in those with steady progression (p < .0003). Thus, these two groups differed in the course of immune changes and in the levels of immune abnormalities associated with the occurrence of clinical AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. ALIVE Study, Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC)

Stromal-derived factor (SDF-1) is the principal ligand for CXCR4, a coreceptor with CD4 for T lymphocyte cell line-tropic human immunodeficiency virus-type 1 (HIV-1). A common polymorphism, SDF1-3'A, was identified in an evolutionarily conserved segment of the 3' untranslated region of the SDF-1 structural gene transcript. In the homozygous state, SDF1-3'A/3'A delays the onset of acquired immunodeficiency syndrome (AIDS), according to a genetic association analysis of 2857 patients enrolled in five AIDS cohort studies. The recessive protective effect of SDF1-3'A was increasingly pronounced in individuals infected with HIV-1 for longer periods, was twice as strong as the dominant genetic restriction of AIDS conferred by CCR5 and CCR2 chemokine receptor variants in these populations, and was complementary with these mutations in delaying the onset of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1998

The effects of establishment practices, knowledge and attitudes on condom use among Filipina sex workers.

The findings for a baseline assessment for a community-based HIV/STD prevention intervention for commercial sex workers (CSWs) and managers of the establishments that employ them in the Philippines is presented in this study. CSW knowledge, attitudes, behaviours and establishment policies concerning HIV prevention were assessed. Baseline assessments are part of an iterative process that will be used to modify the planned intervention. The preliminary findings point to the importance of an intervention that stresses changes in establishment policies and expectations as a means of reducing risk behaviours associated with HIV/STD transmission.

Adolescent↗
PubMed1998

Increased immune activation precedes the inflection point of CD4 T cells and the increased serum virus load in human immunodeficiency virus infection.

The temporal relationship of serum levels of human immunodeficiency virus (HIV) RNA and of immune activation products in 10 HIV-seropositive persons who showed an accelerated decline (inflection point) in CD4 T cell counts and went on to develop AIDS and in 10 matched controls without inflection point were examined. Cases and controls did not differ statistically at the baseline time point for this study. CD4 cell inflection points occurred 18-30 months before AIDS development. Serum levels of soluble tumor necrosis factor receptor II, soluble interleukin-2 receptor, beta2-microglobulin, and neopterin increased significantly > or = 6 months before the CD4 cell inflection point. In contrast, increases in mean HIV RNA levels occurred at the time of the CD4 cell inflection point. These data are consistent with the view that in vivo immune activation precedes the increases in virus load and is followed by an accelerated and rapid loss of CD4 lymphocytes.

Acquired Immunodeficiency Syndrome↗