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Biomedical subjects

A N Phillips

Publications and source records attributed to A N Phillips.

At least 19 recordsLinked to original sources
PubMed1997

Relation between soluble CD30 levels measured soon after HIV seroconversion and disease progression in men with hemophilia.

Soluble CD30 (sCD30) levels within 3 years of HIV seroconversion were studied in 85 hemophilic men infected with HIV. All men were coinfected with hepatitis C virus (HCV). Levels of sCD30 were elevated in these men when compared with controls. These elevated levels did not appear to be a result of treatment with intermediate-purity clotting factor concentrates and were unlikely to be due to HCV coinfection inasmuch as hemophilic patients infected with HCV alone showed only mildly elevated sCD30 levels when compared with those of hemophilic controls uninfected with HCV. Initial sCD30 levels were not significantly associated with progression to any endpoint, although a tendency was present for those with the highest initial levels to progress less rapidly than those with lower values. Despite elevated sCD30 levels in these men, we have not been able to confirm that high sCD30 levels are associated with more rapid HIV progression.

Disease Progression↗
PubMed1997

Regional differences in use of antiretroviral agents and primary prophylaxis in 3122 European HIV-infected patients. EuroSIDA Study Group.

Little is known about how widely HIV-related drugs are used outside controlled clinical trials. We therefore assessed factors associated with use of antiretroviral (ARV) therapy and primary prophylactic regimens to prevent HIV-associated opportunistic infections. Baseline data from a prospective study from May to August 1994, on 3122 consecutive HIV infected patients with a CD4 count <500 cells/microl, followed in 37 centers from 16 European countries, were analyzed. Two thousand and twenty patients (65%) were receiving at least 1 ARV drug at the time of the study. ARV therapy was more frequently used among patients from southern and central Europe as compared with patients from northern Europe, especially among patients with CD4 counts >200 cells/microl (73%, 57%, and 42%, respectively, p < 0.0001). Of patients on ARV therapy, 34% received open-label combination therapy. This proportion was higher in central Europe compared with other regions (27%, 50%, and 31% for southern, central, and northern Europe, respectively, p < 0.0001). Primary prophylaxis against Pneumocystis carinii pneumonia (PCP) was used by 85% of patients with a CD4 count <200 cells/microl, without marked regional differences. In patients without esophageal candidiasis or other invasive fungal infections, antifungal drugs were far less frequently used in patients from southern and central Europe compared with patients from northern Europe (10%, 10%, and 25%, respectively, p < 0.0001). Only 5% of patients with a CD4 count <100 cells/microl received rifabutine as primary prophylaxis against nontuberculous mycobacterioses. ARV and antifungal therapies are used differently in different parts of Europe, whereas primary PCP prophylaxis is uniformly administered to most at-risk patients. U.S. recommendations on the use of antimycobacterial prophylaxis have not been implemented in Europe.

AIDS-Related Opportunistic Infections↗
PubMed1997

Long-term perspective on the prevalent-cohort biases in studies of human immunodeficiency virus progression.

Because considerable information about progression of human immunodeficiency virus (HIV) infection has been provided by studies of cohorts of individuals with prevalent HIV infection, this study was designed to investigate bias due to onset confounding (differential time-since-infection distributions) and differential length-biased sampling in epidemiologic analyses of data from such cohorts. Subjects were participants in the Italian Seroconverters Study, a seroincident cohort of more than 1,200 adults seen at ambulatory care clinics in Italy, with observed HIV seroconversion in 1980-1988. Acquired immunodeficiency syndrome (AIDS) diagnoses, based on the 1987 Centers for Disease Control case definition, and mortality were ascertained through Italian national registries through 1994. To estimate bias in prevalent cohorts, a series of pseudoseroprevalent (PSP) cohorts were drawn by sampling, from among the total seroincident cohort, prevalent AIDS-free subjects in each calendar year. The relative AIDS risk associated with a given covariate was calculated in each PSP cohort and compared with the relative AIDS risk for that covariate in the seroincident cohort. Relative risks were estimated by both the ratio of AIDS incidence densities and the relative AIDS hazards from proportional hazards regression. Differential length bias was not evident, as assessed in the following way: Among 338 individuals with seroconversion dates in 1983-1986, the relative risk of AIDS for subjects born before 1951 compared with those born more recently was 1.67 (95% confidence interval (CI) 1.30-2.14). Although differential length-biased sampling was expected to bias this relative risk toward 1.0, the observed relative risk for earlier birth ranged from 1.79 to 2.86 in 1987-1992 PSP cohorts. Onset bias was observed: Among 644 subjects with seroconversion in 1980-1988, the AIDS relative risk for 1980-1985 seroconverters compared with 1986-1988 seroconverters was 1.09 (95% CI 0.76-1.55). Onset bias was seen in 1988-1990 PSP cohorts (relative risks for early seroconversion = 1.47, 1.46, and 1.34, respectively); in 1991-1992, relative risks were close to the expected value of 1.09, and CIs on relative risks from all PSP cohorts after 1989 included 1.0. Confounding attributable to differential length-biased sampling in prevalent cohorts does not necessarily bias estimates of the impact of covariates on rate of progression to AIDS. Bias can arise when a covariate suspected of affecting AIDS risk is closely linked to date of acquisition of HIV infection. However, onset bias appears to wane as subjects' dates of infection become more remote.

Acquired Immunodeficiency Syndrome↗
PubMed1997

The molecular epidemiology of human immunodeficiency virus type 1 in six cities in Britain and Ireland.

We have sequenced the p17 coding regions of the gag gene from 211 patients infected either through injecting drug use (IDU) or by sexual intercourse between men from six cities in Scotland, N. England, N. Ireland, and the Republic of Ireland. All sequences were of subtype B. Phylogenetic analysis revealed substantial heterogeneity in the sequences from homosexual men. In contrast, sequence from over 80% of IDUs formed a relatively tight cluster, distinct both from those of published isolates and of the gay men. There was no large-scale clustering of sequences by city in either risk group, although a number of close associations between pairs of individuals were observed. From the known date of the HIV-1 epidemic among IDUs in Edinburgh, the rate of sequence divergence at synonymous sites is estimated to be about 0.8%. On this basis we estimate the date of divergence of the sequences among homosexual men to be about 1975, which may correspond to the origin of the B subtype epidemic.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Low production of interferon gamma is related to disease progression in HIV infection: evidence from a cohort of 347 HIV-infected individuals.

A total of 347 HIV-seropositive individuals attending the Department of Infectious Diseases at Rigshospitalet in Copenhagen and 110 age- and sex-matched healthy controls not at risk for HIV infection were included in this study. Interferon gamma (IFN-gamma) production was measured in whole blood of 223 HIV-seropositive individuals (68 had developed AIDS at enrollment) and 99 healthy sex- and age-matched controls 4.5 hr after challenge with phytohemagglutinin. HIV-infected individuals for whom IFN-gamma production was measured were followed with a median follow-up time of 2.89 years (range, 0.02-4.54 years) from the date of enrollment. Survival analysis was performed considering three different end points: (1) a CD4 count below 100 cells/mm3, (2) an AIDS diagnosis defined according to the 1993 Centers for Disease Control definition, and (3) death. The production of IFN-gamma was highly increased in the blood of HIV-infected individuals without AIDS, but decreased in the blood of AIDS patients (both compared to controls). In the HIV-infected individuals, the total production of IFN-gamma was positively correlated with the number of CD8+ T lymphocytes and with the number of CD16+/CD56+ natural killer cells and negatively correlated with serum levels of beta2-microglobulin. Low levels of IFN-gamma production were associated with an increased risk of experiencing a CD4 count below 100 cells/m3 and death, analyzed in both univariate analysis and in multivariate analysis adjusting for CD4 counts and age. Thus, changes in production of IFN-gamma seem to be truly related to the risk for disease progression in HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Survival after a very low (< 5 x 10(6)/l) CD4+ T-cell count in individuals infected with HIV.

OBJECTIVE: To describe survival after a CD4+ T-cell count of less than 5 x 10(6)/l and to identify possible baseline factors associated with outcome. DESIGN: A prospective cohort study. SETTING: A large teaching hospital in North London. PATIENTS AND PARTICIPANTS: Patients treated at the Royal Free Hospital, London, who had at least one reported CD4+ T-cell count of less than 5 x 10(6)/l and were being followed up for clinical care prior to the date of this cell count. MAIN OUTCOME MEASURE: Death. METHODS: Proportional hazards models, Kaplan-Meier analysis. RESULTS: One-hundred and sixty-nine patients were included in the study. The median survival after a very low CD4+ T-cell count was 0.95 years (95% confidence interval, 0.78-1.19), although 20% survived for over 2 years. Older age and a previous AIDS diagnosis were related to poorer outcome. A higher CD8+ T-cell count at baseline was also associated with a better prognosis. CONCLUSIONS: A CD4+ T-cell count of less than 5 x 10(6)/l did not necessarily mean imminent death, with a median survival after this count of just under 1 year. These results will enable clinicians to provide appropriate counselling for patients at this late stage and to plan terminal care.

Adolescent↗
PubMed1997

Antiretroviral treatment and progression to AIDS in HIV seroconverters from different risk groups. HIV Italian Seroconversion Study.

OBJECTIVES: To evaluate the association between time since initiation of pre-AIDS antiretroviral therapy [mainly with zidovudine (ZDV)] and AIDS-free survival in a cohort of HIV seroconverters, and to assess possible differences in this association and in the use of antiretroviral therapy by HIV exposure group. DESIGN: Observational study of HIV-infected individuals, both those treated with antiretroviral therapy and those untreated, enrolled in an ongoing prospective cohort (median follow-up, 5.3. years). SETTING: Sixteen HIV outpatient clinics throughout Italy. PATIENTS: A total of 1,078 individuals infected with HIV through injecting drug use or homo-/heterosexual activity, and with accurately estimated dates of seroconversion. MAIN OUTCOME MEASURES AND METHODS: Kaplan-Meier estimates of the probability of receiving antiretroviral therapy before AIDS. Crude and adjusted relative hazards of AIDS and of death from AIDS using Cox regression models. RESULTS: The cumulative incidence of beginning pre-AIDS antiretroviral therapy within 7 years of seroconversion was 49.2%. Injecting drug users (IDU) were less likely to undergo antiretroviral treatment before AIDS than homosexual men and heterosexual contacts. The adjusted relative hazard of developing AIDS for patients treated with ZDV (relative hazard adjusted for occurrence of acute HIV disease, pre-AIDS HIV-related diseases, CD4 count, and use of prophylaxis for Pneumocystis carinii pneumonia) was 0.57 within the first year of starting zidovudine and 0.92 after 1 year of therapy. Stratifying by HIV exposure category, the adjusted relative hazards of AIDS for individuals who started ZDV less and more than 1 year before AIDS were 0.74 and 0.99 among IDU, 0.31 and 0.89 among homosexual men, and 0.69 and 0.72 among heterosexuals, respectively. Similar results were obtained when using death from AIDS as an endpoint. CONCLUSIONS: IDU began pre-AIDS antiretroviral therapy significantly later than homosexual men and heterosexuals, even after adjusting for CD4 count. Results from this non-randomized study confirm that antiretroviral treatment has only a short-term clinical benefit. There was a stronger association between antiretroviral treatment and lower risk of AIDS in homosexual men than in IDU.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Survival after diagnosis of AIDS: a prospective observational study of 2625 patients. Royal Free/Chelsea and Westminster Hospitals Collaborative Group.

OBJECTIVE: To estimate median survival and changes in survival in patients diagnosed as having AIDS. DESIGN: Prospective observational study. SETTING: Clinics in two large London hospitals. SUBJECTS: 2625 patients with AIDS seen between 1982 and July 1995. MAIN OUTCOME MEASURES: Survival, estimated using lifetable analyses, and factors associated with survival, identified from Cox proportional hazards models. RESULTS: Median survival (20 months) was longer than previous estimates. The CD4 lymphocyte count at or before initial AIDS defining illness decreased significantly over time from 90 x 10(6)/1 during 1987 or earlier to 40 x 10(6)/1 during 1994 and 1995 (P < 0.0001). In the first three months after diagnosis, patients in whom AIDS was diagnosed after 1987 had a much lower risk of death (relative risk 0.44, 95% confidence interval 0.22 to 0.86; P = 0.017) than patients diagnosed before 1987. When the diagnosis was based on oesophageal candidiasis or Kaposi's sarcoma, patients had a lower risk of death than when the diagnosis was based on Pneumocystis carinii pneumonia (0.21 (0.07 to 0.59). P = 0.0030 and 0.37 (0.16 to 0.83), P = 0.016). Three months after AIDS diagnosis, the risk of death was similar in patients whose diagnosis was made after and before 1987 (1.02 (0.79 to 1.31), P = 0.91). There were no differences in survival between patients diagnosed during 1988-90, 1991-3, or 1994-5. CONCLUSIONS: In later years, patients were much more likely to survive their initial illness, but long term survival has remained poor. The decrease in CD4 lymphocyte count at AIDS diagnosis indicates that patients are being diagnosed as having AIDS at ever more advanced stages of immunodeficiency.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Cross-sectional studies in AIDS pathogenesis: how far can they mislead us?

When investigating variables thought to be of potential importance to AIDS pathogenesis, it is common practice to initially carry out a cross-sectional study comparing those with symptomatic disease/low CD4 counts with those with no symptoms/high CD4 counts. While it is widely appreciated that such studies have weaknesses compared with those involving patient follow-up, the particular biases likely to arise in the context of HIV infection have not been formally evaluated. In an attempt to do this, data on HIV progression for 50,000 notional patients who became infected in the years between 1976 (assumed to be the start of the epidemic) and 2010 were simulated under various scenarios. In Scenario 1, we considered a variable called X, which was specified to be associated with more rapid progression of HIV infection. In Scenario 2, we considered a variable Y, which was specified not to be associated with more rapid progression but which tended to change in value as a result of HIV-induced immunosuppression. Variable Z, in Scenario 3, was specified to be associated with more rapid progression and to change in value when severe immunosuppression developed. Cross-sectional analyses evaluating the association between variables X, Y, and Z and the CD4 count/presence of AIDS were performed for data as of 1980, 1985, 1995, 2000, 2005, and 2010 to assess the extent to which the true role of the three variables could be ascertained. For Scenario 1, cross-sectional analyses performed on these data later in the epidemic falsely suggested that variable X was not related to HIV progression. Variable Y in Scenario 2 falsely appeared to be related to HIV progression, due to the inability of the cross-sectional design to distinguish the fact that changes in variable Y were as a result of immunosuppression and not a possible cause of it. In Scenario 3, variable Z showed a relationship with the presence of AIDS for which the typical interpretation would lead to the suggestion that its effect is in the reverse direction to that which was, in fact, the case. In conclusion, as the HIV epidemic progresses, cross-sectional studies will increasingly tend to give misleading results. Most importantly, it is incorrect to conclude that variables found to have no association with HIV disease stage in such studies are not of potential importance to pathogenesis.

Acquired Immunodeficiency Syndrome↗
PubMed1997

The relationship between beta-2-microglobulin, CD4 lymphocyte count, AIDS and death in HIV-positive individuals.

The relationship, in 539 individuals infected with the human immunodeficiency virus (HIV), between two prognostic markers, the CD4 count and beta-2-microglobulin (B2M), and the development of the acquired immunodeficiency syndrome (AIDS) and death was investigated. Cox proportional hazards models were used to determine the risk of AIDS or death. In a multivariate model which adjusted for demographic factors and treatment, the most recent measurements of B2M (relative hazard (RH) 1.37 per g/l higher) and CD4 count (RH 2.17 per log-unit lower) were both significantly associated with the development of AIDS. Similarly, in a multivariate model which additionally adjusted for the development of AIDS as a time dependent covariate, there was a strong relationship with risk of death for the most recent measurements of B2M (RH 1.34 per g/l higher), and CD4 lymphocyte count (RH 1.91 per log-unit lower). A difference in the level of B2M could be used among patients with similar CD4 counts as an indicator of increased risk of progression to AIDS or death. Using the most recent values of these markers provides a better estimate of the risk of AIDS or death, compared to the more common method of analysis, where baseline values of the markers are used.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Is there a general tendency for CD4 lymphocyte decline to speed up during human immunodeficiency virus infection? Evidence from the Italian Seroconversion Study.

It has been suggested that the rate of CD4 cell decline accelerates in parallel with decreasing numbers of cells; however, the statistical literature suggests the opposite. CD4 cells were counted about every 6 months in a cohort of 1264 human immunodeficiency virus-infected subjects (the Italian Seroconversion Study cohort). Kaplan-Meier analysis was used to estimate the time for CD4 cells to decline by 100 cells/mm3, conditional on reaching predefined levels. In addition, CD4 cell counts were modeled as a function of time since seroconversion in individuals with > or = 5 counts. Kaplan-Meier survival times for a 100 cell/mm3 decrease in CD4 cells increased as lower counts were reached (log rank test, P < .001). The shape of the overall fitted curve of the CD4 cell counts does not suggest an increasing rate of decline. Data from the Italian Seroconversion Study cohort do not show a general tendency for accelerating CD4 cell decline in association with lower counts.

CD4 Lymphocyte Count↗
PubMed1997

Survival of AIDS patients according to type of AIDS-defining event. The AIDS in Europe Study Group.

BACKGROUND: There are known to be wide differences in the prognosis of patients with a diagnosis of AIDS. In this study of 6578 patients with AIDS form 17 European centres, we develop a ranking of AIDS-defining illnesses, and determine how well this ranking holds after adjustment for potential confounding variables. METHODS: Survival from each AIDS-defining event was calculated and ranked using Kaplan-Meier estimation of median survival. Cox proportional hazards models with each disease modelled as a time dependant covariate were used to determine the risk of death after each diagnosis, before and after adjustment for potential confounders. RESULTS: Median survival after an initial AIDS-defining diagnosis of progressive multifocal leukoencephalopathy and malignant lymphoma was particularly poor (2 and 5 months respectively), while the longest median survival occurred after initial AIDS-defining illnesses of Kaposi's sarcoma and extrapulmonary tuberculosis (17 and 22 months respectively) Patients diagnosed with a primary brain lymphoma had shorter median survival times than patients with a peripheral lymphoma (median survival of 1 month and 4 months respectively P < 0.0001). In general, median survival in patients with cutaneous Kaposi's sarcoma (skin, oral) was between two and four times longer than patients with systemic involvement The ranking of diseases was found to be generally similar after adjustment for all potential confounders. CONCLUSIONS: AIDS-defining events can be grouped into three categories with median survival after diagnosis of < 6 months. 6-12 months and > 12 months. The assigned ranking of disease would not be altered by prognostic factors such as age or CD4 lymphocyte count. These results have important implications in the design of clinical trials and patient management.

AIDS-Related Opportunistic Infections↗
PubMed1997

The association between hepatitis C virus genotype and human immunodeficiency virus disease progression in a cohort of hemophilic men.

Patients coinfected with both hepatitis C virus (HCV) and the human immunodeficiency virus (HIV) have more rapid progression of HCV infection; however, little is known about the effect of coinfection with HCV on the progression of HIV disease. This study assessed the association between infection with different HCV genotypes on progression to AIDS and death in a cohort of men with hemophilia. Patients infected with HCV type 1 experienced a more rapid progression to both AIDS (P = .009) and death (P = .007) than did those infected with other types. This effect was largely independent of age at seroconversion, hemophilia diagnosis, and changes in CD4 cell count over the follow-up period. These results suggest an association between HCV genotype and progression of HIV disease, which, if confirmed, could have important implications for the treatment and care of patients coinfected with both HIV and HCV.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Correspondence between the effect of zidovudine plus lamivudine on plasma HIV level/CD4 lymphocyte count and the incidence of clinical disease in infected individuals. North American Lamivudine HIV Working Group.

OBJECTIVES: To investigate whether apparently beneficial changes in plasma HIV RNA level and CD4 lymphocyte count that are induced by antiretroviral therapy are associated with a corresponding clinical benefit. METHODS: For 620 patients in two randomized, double-blind trials of lamivudine (3TC) and zidovudine (ZDV) plasma HIV RNA and CD4 lymphocyte count changes were compared in patients randomized to 3TC plus ZDV and patients randomized to other treatment arms. The effect of therapy on the HIV RNA level and CD4 count was compared with the effect of therapy on clinical endpoints over the same time period. RESULTS: Median baseline values for all subjects were 42 420 copies/ml for HIV RNA and 277 x 10(6)/l for CD4 count. During the trial a significantly lower HIV RNA level and higher CD4 count was sustained in the ZDV/3TC group compared with the other group, with a difference in the median area under the curve from baseline per month of follow-up of 0.38 log10 copies/ml HIV RNA and 0.18 log2 x 10(6)/l CD4 cells (P < 0.001 in each case). For patients who were initially asymptomatic or in CDC stage B, the adjusted relative hazard (RH) of AIDS for a twofold lower CD4 count was 3.14 [95% confidence interval (CI), 1.44-6.83] and for a 10-fold higher HIV RNA level was 3.22 (1.20-8.59). The RH progression to AIDS expected with ZDV/3TC compared with the control treatments, given the observed effects of treatment on CD4 cell counts and HIV RNA levels, is 0.52, whereas the observed value was 0.16 (0.03-0.74). After adjustment for HIV RNA and CD4 changes over time the observed RH of progression to AIDS for ZDV/3TC treatment compared with controls was increased to 0.36 and was no longer significant (95% CI, 0.07-1.85). CONCLUSION: In this analysis of two trials, the effects of ZDV/3TC in reducing plasma HIV RNA and raising peripheral blood CD4 counts were associated with concurrent clinical benefits and the effect of treatment on these markers could account for at least part of the clinical benefits of therapy that were observed.

Anti-HIV Agents↗
PubMed1997

Increased losses of CD4+CD45RA+ cells in late stages of HIV infection is related to increased risk of death: evidence from a cohort of 347 HIV-infected individuals.

OBJECTIVE: To examine changes in the distribution of CD4+CD45RA+ (naive) and CD4+CD45RO+ (memory) lymphocytes in various stages of HIV infection and the effect of these changes on disease progression. DESIGN AND METHODS: Expression of CD45RA+ and CD45RO+ on CD4+ lymphocytes was analysed by flow cytometry in a prospectively followed cohort of 300 HIV-infected individuals (median follow-up time, 2.90 years; range, 0.02-4.54 years) and in a group of 102 age- and sex-matched uninfected controls. Survival analysis was performed considering AIDS development and death as endpoints. RESULTS: The median CD4+CD45RA+/CD45RO+ ratio was 1.3 (25-75% quartiles, 0.9-2.4) in controls; it was increased to 1.8 (1.1-2.5) in 40 HIV-infected individuals with CD4+ cell counts > 500 x 10(6)/l (P < 0.05); it was similar at 1.4 (0.8-2.0) in 106 HIV-infected individuals with CD4+ cell counts of 200-500 x 10(6)/l; and it was decreased to 0.9 (0.5-1.4) in 154 HIV-infected individuals with CD4+ cell counts < 200 x 10(6)/l (P < 10[-6]). When fitted in a Cox model adjusting for the total number of CD4+ cells and age a lower concentration of CD4+CD45RA+ cells was associated with an increased risk of dying. The concentration of CD4+CD45RO+ cells was not significantly associated with AIDS or death in age- and CD4+ cell count-adjusted Cox models. CONCLUSIONS: This study confirms a selective loss of memory CD4+ cells early in HIV infection followed by increased loss of naive CD4+ cells in later stages of the infection. The loss of naive CD4+ cells seems to be important in the pathogenesis of terminal HIV infection.

CD4 Antigens↗