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A N Phillips

Publications and source records attributed to A N Phillips.

At least 163 records · Page 9Linked to original sources
PubMed1994

CD4 lymphocyte count as a determinant of the time from HIV seroconversion to AIDS and death from AIDS: evidence from the Italian Seroconversion Study.

OBJECTIVES: It is well established that a low CD4 lymphocyte count is strongly associated with an increased risk of AIDS in HIV infection. We attempted to determine whether the link is sufficiently strong that the wide inter-person variability in times from HIV infection to AIDS can be explained solely by differences in CD4 count experience. METHODS: We followed 1090 HIV-infected individuals for up to 12.8 years from seroconversion (median, 3.5 years; 25% for more than 5.2 years). The median interval between last negative and first positive anti-HIV tests was 9 months. A median of four CD4 counts per subject were measured. RESULTS: Individuals with CD4 lymphocyte counts above 250 x 10(6)/l cells experienced an AIDS incidence rate of one per 339 years (0.3 per 100 years; 10 cases in 3394 person-years), compared with one per 6 years in those whose count had declined below this level (17.2 per 100 years; 96 cases in 559 person-years) and one per year in those whose count had declined below 50 x 10(6)/l (100.0 per 100 years; 41 cases in 41 person-years). The AIDS rate increased by an average of 33% [relative rate, 1.33; 95% confidence interval (CI), 1.20-1.49; P = 0.0001] with every year from seroconversion; one per 46 years (2.2 per 100 years) for people seropositive for less than 5 years compared with one per 14 years (7.3 per 100 years) for those seropositive for more than 5 years. After adjusting for the tendency for CD4 lymphocyte counts to be higher soon after seroconversion, the relative rate declined to 1.07 (95% CI, 0.94-1.22) per year from seroconversion (P = 0.32). This result was similar when those infected through sharing injecting equipment, homosexual sex, and other routes were considered separately. The relative rate per year from seroconversion for death due to AIDS fell from 1.41 (P = 0.0001) to 1.00 (P = 0.99) after adjusting for CD4 count. CONCLUSIONS: Most of the inter-person variability in time from HIV infection to AIDS appears to result from differences in CD4 lymphocyte counts. HIV infection appears to cause AIDS and death largely by its ability to induce CD4 lymphocytopaenia or some closely correlated abnormality.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Beta-2 microglobulin as a predictor of prognosis in HIV-infected men with haemophilia: a proposed strategy for use in clinical care.

Whilst the prognostic value of serum beta-2 microglobulin (s-beta 2m) is well documented, the lack of a simple strategy for its use means that it is rarely ever measured in clinical practice. The prognosis associated with s-beta 2m at two different points in HIV infection, as defined by the CD4 count, was studied in a cohort of 111 men with haemophilia registered at the Royal Free Hospital School of Medicine, London. At CD4 counts of 0.5 and 0.2 x 10(9)/l, a raised s-beta 2m level was significantly associated with an increased risk of developing AIDS (P = 0.002 and 0.022 respectively, adjusted for the patient's age). Kaplan-Meier progression rates to AIDS by 4.5 years after a CD4 count of 0.5 x 10(9)/l were 57% (95% CI 32-82%) in those with s-beta 2m levels of 3 mg/l or more, but 20% (95% CI 4-36%) in those with s-beta 2m levels of less than 3 mg/l. By 3.5 years after a CD4 count of 0.2 x 10(9)/l, Kaplan-Meier progression rates to AIDS were 75% (95% CI 52-98%) in those with s-beta 2m levels of 3.8 mg/l or more, and 47% (95% CI 29-66%) in those with s-beta 2m levels of less than 3.8 mg/l. In the absence of acute viral infections, a raised s-beta 2m indicates those who will tend to progress to AIDS more rapidly than those with lower s-beta 2m levels and the same CD4 count. S-beta 2m levels in general are likely to be higher in haemophilia patients than in other, non-haemophilic risk groups. Whilst care should be taken, therefore, when applying our chosen cut-off values to non-haemophilic patients, our findings support the introduction of prophylaxis and antiviral therapies at a higher CD4 count in those with raised s-beta 2m levels relative to other patients in the same risk group whilst delaying treatment in those with lower CD4 counts, but relatively normal s-beta 2m levels.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Acquired immunodeficiency syndrome (AIDS) risk in recent and long-standing human immunodeficiency virus type 1 (HIV-1)-infected patients with similar CD4 lymphocyte counts.

The loss of CD4 lymphocytes is known to be an important component of human immunodeficiency virus type 1 (HIV-1) pathogenesis. It remains unclear, however, whether the importance of the CD4 lymphocyte count is such that individuals who have been infected for widely different lengths of time, but for whom the CD4 lymphocyte count is the same, have the same risk of developing acquired immunodeficiency syndrome (AIDS). The authors directly addressed this question for 111 HIV-1-infected hemophiliacs who had been followed for up to 12 years from seroconversion and for whom a median of 16 CD4 lymphocyte counts had been made. Thirty-eight patients had developed AIDS by January 1, 1992. As of August 1, 1985, the time from seroconversion to AIDS ranged from 3 weeks to almost 6 years. The risk of AIDS increased with time from seroconversion (relative hazard = 1.25 per year; p = 0.09). CD4 lymphocyte count was strongly related to time from seroconversion and also to the risk of AIDS (relative hazard = 3.25 per 100/mm3; p < 0.00005). In a bivariate Cox regression model, the relative hazard for time from seroconversion fell markedly towards unity (1.05; p = 0.7), while that for CD4 lymphocyte count remained unchanged. This suggests that time from seroconversion is a relevant factor in HIV-1 infection only insofar as it provides information as to the probable degree of loss of CD4 lymphocytes. If the number of these cells is known, time from seroconversion seems to be of little additional value in assessing the risk of AIDS. This finding has implications for the clinical assessment of individual patient prognosis, for the design of epidemiologic studies of HIV-1 infection, and for our understanding of how HIV-1 causes disease.

Acquired Immunodeficiency Syndrome↗
PubMed1993

New AIDS definition.

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Acquired Immunodeficiency Syndrome↗
PubMed1993

The design of prospective epidemiological studies: more subjects or better measurements?

Prospective epidemiological studies which seek to relate potential risk factors to the risk of disease are subject to appreciable biases which are often unrecognized. The inability to precisely measure subjects' true values of the risk factors under consideration tends to result in bias towards unity in the univariate relative risks associated with them--the more imprecisely a risk factor is measured, the greater the bias. When correlated risk factors are measured with different degrees of imprecision the adjusted relative risk associated with them can be biased towards or away from unity. When designing a new prospective study cost considerations usually limit the total number of subject-evaluations that are available. The usual design approach is to maximize the study size and evaluate each subject on one occasion only. An alternative approach involves recruitment of a smaller number of subjects so that each can be evaluated on more than one occasion, thus resulting in a more precise measure of subjects' risk factor values and hence less bias in the relative risk estimates. In this paper we use a simulation approach to show that under conditions that prevail for most major prospective epidemiological studies the latter approach is actually more likely to produce accurate relative risk estimates. This emphasizes the importance of bias due to exposure measurement imprecision and suggests that attempts to anticipate and control it be given at least as high a priority as that given to sample size assessment in the design of epidemiological studies.

Causality↗
PubMed1993

Lymphocyte activation in HIV-1 infection. I. Predominant proliferative defects among CD45R0+ cells of the CD4 and CD8 lineages.

OBJECTIVES AND DESIGN: The proliferative defects of CD4 and CD8 cells taken from 474 HIV-1-seropositive individuals during various stages of disease were quantitated. Phytohaemagglutinin (PHA) and soluble anti-CD3 were used in optimal mitogenic concentrations in the presence of recombinant interleukin-2 (rIL-2) and conditioned medium, and the proliferation of cells from HIV-1-seropositive donors was assessed in co-culture with HIV-1-seronegative cells in order to exclude effects of cytokine deficiency. Defects within the CD45RA+ ('unprimed') and CD45R0+ ('primed') T-cell populations were also investigated. METHODS: Quantitative immunofluorescence and double and triple labelling in flow cytometry were performed for (1) CD25 (IL-2 receptor alpha chain) expression, (2) lymphocyte and T-cell survival, and (3) blast transformation and proliferation--in relation to the original input of cells for each subpopulation. RESULTS: T cells from normal and HIV-1-seropositive donors were CD25+ at day 1. In HIV-1-seropositive patients a variable number of CD4 and CD8 lymphocytes failed to further increase CD25, and died as a sign of activation-associated lymphocyte death (AALD). Forty-two per cent of asymptomatic subjects, including 32% of those with CD4 cell counts > 400 x 10(6)/l, showed a poor blast transformation (< 30% blasts). Cells from HIV-1-seropositive donors showed poor blast responses when co-cultured with HIV-1-seronegative cells; both CD4 and CD8 cells were handicapped. In asymptomatic HIV-1-seropositive people T cells with the CD45R0+ RA- ('primed') phenotype were three to five times more vulnerable to AALD than the CD45RA+ RO- ('unprimed') cells. In patients in Centers for Disease Control and Prevention (CDC) disease stage IV both CD45R0+ and -RA+ populations were severely affected. CONCLUSIONS: This is the first quantitative analysis to demonstrate that in HIV-1 infection mitogen-stimulated CD45R0+ ('primed') T cells preferentially die upon activation. Both the CD4 and CD8 lineages are affected, as seen in animal models of graft versus host disease. AALD may explain defects of immunological memory. The analysis of AALD may be a suitable assay for studying whether antiviral drugs influence the proliferative responses of lymphocytes.

CD3 Complex↗
PubMed1993

CD8 lymphocyte counts and serum immunoglobulin A levels early in HIV infection as predictors of CD4 lymphocyte depletion during 8 years of follow-up.

OBJECTIVE: To assess the ability of the CD8 lymphocyte count and immunoglobulin (Ig) A level, measured at the early stage of HIV infection when the CD4 lymphocyte count remains relatively high, to predict the future rate of CD4 lymphocyte loss and hence the risk of AIDS. DESIGN: Cohort of recently infected haemophiliacs with relatively high CD4 lymphocyte counts followed for up to 8.5 years from baseline measurement of CD8 lymphocyte counts and IgA levels. SETTING: A regional haemophilia centre based in a major teaching hospital. PATIENTS: Eighty-four of 111 patients with haemophilia who seroconverted to HIV between 1979 and 1985 in whom CD8 lymphocyte counts and IgA levels were measured soon after seroconversion (mean, 2.7 years; maximum, 5 years) while CD4 lymphocyte counts remained relatively high (median, 600 x 10(6)/l; minimum, 300 x 10(6)/l). OUTCOME MEASURES: Development of severe immunodeficiency defined by a CD4 lymphocyte count falling below 50 x 10(6)/l, and AIDS. RESULTS: Individuals with high CD8 counts (P < 0.008) and high IgA levels (P < 0.003) at baseline experienced a more rapid rate of CD4 lymphocyte loss than those with low baseline levels. A score was derived to combine the predictive ability of CD8 count and IgA level. Estimated proportions with CD4 counts below 50 x 10(6)/l after 8 years of follow-up were 100, 30 and 14% for those with high, intermediate and low baseline scores, respectively. The CD8/IgA score showed similar ability to predict the future occurrence of AIDS (P < 0.0001; log-rank test). CONCLUSION: Immune activation seen in HIV infection, as reflected by raised CD8 counts and IgA levels, appears to be linked to the process of CD4 lymphocyte depletion. Measurement of these markers in the years following infection, when CD4 lymphocyte counts remain high, provides a first indication of a patient's long-term prognosis.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Immunodeficiency and the risk of death in HIV infection.

OBJECTIVE: To describe the rate of development of immunodeficiency in human immunodeficiency virus (HIV) infection and to relate this to the risk of death. DESIGN: Inception cohort followed up for up to 12 years from HIV seroconversion until January 1, 1992. SETTING: A regional hemophilia center based in a major teaching hospital. PATIENTS: All 111 patients with hemophilia who seroconverted to HIV-1 between 1979 and 1985 were registered at the center. Patients have been closely followed up clinically and immunologically. OUTCOME MEASURES: Development of immunodeficiency, defined by a CD4 lymphocyte count falling beneath 0.20 and 0.05 x 10(9)/L, and death. RESULTS: Kaplan-Meier estimates suggest that almost half (46%; 95% confidence interval [CI], 26% to 66%) of patients alive 12 years after seroconversion will have a CD4 lymphocyte count that has remained above 0.05 x 10(9)/L. Thirty-five percent (95% CI, 22% to 48%) remain above 0.20 x 10(9)/L. Thirty-seven patients died of HIV-related causes, and there was a 52% probability (95% CI, 35% to 69%) of HIV-related mortality by 12 years from seroconversion. Mortality risk was closely associated with severe immunodeficiency. There was only a 15% chance (95% CI, 6% to 25%) of HIV-related death occurring before a CD4 count of below 0.05 x 10(9)/L had been reached. There was an average of one HIV-related death per 96.7 patient-years of observation before the CD4 count had fallen below 0.05 x 10(9)/L, as compared with one death per 2.5 patient-years of observation after the CD4 count had fallen below this level (P < .0001). CONCLUSIONS: In patients with HIV infection who are closely followed up, the risk of death is low before the CD4 lymphocyte count has fallen to 0.05 x 10(9)/L, a count many patients remain above up to 12 years after seroconversion.

CD4-Positive T-Lymphocytes↗