Predicting progression to AIDS: combined usefulness of CD4 lymphocyte counts and p24 antigenemia

PURPOSE: To investigate the combined usefulness of CD4 lymphocyte counts and human immunodeficiency virus type 1 (HIV-1) p24 antigen in predicting progression to the acquired immunodeficiency syndrome (AIDS). PATIENTS AND METHODS: CD4 lymphocyte counts and HIV-1 p24 antigen status were evaluated over a 4-year period in 518 HIV-1-seropositive men enrolled in the Multicenter AIDS Cohort Study in Chicago. RESULTS: Twenty-six percent (134 of 518) of the HIV-1-seropositive cohort had detectable p24 antigen during the study period. Men with p24 antigenemia experienced a more rapid decline in CD4 lymphocyte counts than men who were persistently p24 antigen-negative (p less than 0.01). Mean CD4 lymphocyte counts at first detection of p24 antigen were 406 and 455 cells/microL for men with incident and prevalent antigenemia, respectively. Antigen was detected in 61% (63 of 103) of the men who progressed to AIDS and in only 17% (71 of 415) of the men who did not (p less than 0.0001). The 4-year estimated cumulative AIDS incidence was 86%, 63%, and 21% for men with entry CD4 counts less than 200, 200 to 399, and 400 or more cells/microL, respectively. Presence of p24 antigenemia was strongly associated with more rapid disease progression within each of these CD4 groupings (p less than 0.0001). CONCLUSION: Our data indicate that p24 antigenemia can first be detected with moderate CD4 cell depletion, is associated with a more rapid decline in the CD4 lymphocyte population, and combined with CD4 lymphocyte counts is useful in identifying individuals at significantly greater risk of disease progression. Our findings provide important information for assessing HIV-1 disease prognosis over a 4-year period.     

The natural history of human immunodeficiency virus infection in a haemophilic cohort

112 haemophilic patients infected with HIV were followed up with clinical and laboratory assessment between 1 December 1979 and 30 November 1988. Sixty-six (59%) of the patients developed HIV-related clinical symptoms and 22 (20%) developed AIDS. Twenty (18%) of the patients developed p24 antigenaemia. Amongst the 59 patients whose date of seroconversion could be estimated the calculated 8-year cumulative incidence of AIDS was 40% (symptoms 73%). For the whole cohort of 112 patients, the median slope of linear regression of the absolute T4 lymphocyte count was steeper for those with AIDS (-0.113 x 10(9)/l per year) than for those without AIDS (-0.054 x 10(9)/l per year) (P less than 0.02). While 15 cases of AIDS developed during 58 patient-years of follow up after falling below a T4 lymphocyte count of 0.2 x 10(9)/l, only two cases occurred during 450 patient-years before reaching this count. Thus the decline of the T4 lymphocyte count to 0.2 x 10(9)/l may be an appropriate additional end-point for the assessment of new treatments for asymptomatic patients infected with HIV.     

Impact of tuberculosis on the course of HIV-infected patients with a high initial CD4 lymphocyte count.

OBJECTIVE: To assess the influence of tuberculosis (TB) on the progression of human immunodeficiency virus (HIV) infection in patients without immunological impairment. MATERIAL AND METHODS: In an observational study of retrospective cohorts, the evolution of 28 HIV-infected patients with TB and a CD4 lymphocyte count >500 x 10(6) cells/l was compared with 56 HIV-infected patients without TB. Each case was paired with two controls by CD4 lymphocyte count (+/-50 x 10(6)/l) and date of starting follow-up (+/-6 months). The progression of HIV infection was evaluated as: 1) immunological progression: time to CD4 lymphocyte count <200 x 10(6)/l; 2) clinical progression: time to development of acquired immune-deficiency syndrome (AIDS), excluding TB; 3) survival; and 4) global disease progression: time to the first defined event in 1, 2 and/or 3. The times to these events were estimated using Kaplan Meier curves. RESULTS: There were no significant differences between the cohorts for age, sex and risk group. Faster immunological impairment (RR 2.94; 95%CI 1.46-8.6; P < 0.01), greater progression to AIDS (RR 4.01; 95%CI 1.66-9.69; P < 0.01), lower survival (RR 3.89; 95%CI 1.53-9.87; P < 0.05) and higher global disease progression (RR 2.82; 95%CI 1.57-5.09; P < 0.01) were found in the cohort of TB patients. These associations were still significant after adjustment for CD4 lymphocyte counts. CONCLUSION: The diagnosis of TB in HIV-infected patients with a high initial CD4 lymphocyte count (>500 x 10(6)/l) was related to greater progression to AIDS and shorter survival.     

Prognostic indicators for the development of AIDS in HIV antibody positive haemophiliac patients: results of a three-year longitudinal study

In February 1986, 40 out of 75 adult patients with haemophilia A attending St. James's University Hospital were human immunodeficiency virus (HIV) antibody positive. Over a three-year period these patients were prospectively studied with regard to possible prognostic indicators for the development of the acquired immune deficiency syndrome (AIDS). Using the Centres for Disease Control (CDC) classification of HIV infection, 17 patients (42.5%) developed group 4 disease during this time, giving an actuarial three-year progression rate of 44%, and 5 patients (12.5%) died. The following parameters measured at recruitment were found independently to predict progression to AIDS: a serum beta 2-m level of greater than 3.5 mg/l, (chi 2 = 15.95, P less than 0.001), a serum IgA level of greater than 4.5 milligram(s) (chi 2 = 6.08, P less than 0.02) and p24 antigenaemia (chi 2 = 5.7, P less than 0.05). The actuarial three-year progression rate in those patients abnormal by two or more of these parameters was 100% (n = 7), compared to only 7% in patients who were normal by all three values (n = 15). CD4+ lymphocyte counts and CD4+:CD8+ ratios were significantly lower in HIV positive compared with HIV negative patients (P less than 0.01), but did not predict the development of AIDS.     

Progression to AIDS in the majority of asymptomatic HIV-infected people

Sixty-eight asymptomatic HIV-seropositive people with a CD4 lymphocyte count above 400/mm3 at the first examination were followed up every year over a 3-year period, by monitoring the biological markers of AIDS (CD4 lymphocyte decrease, loss of anti-p24 or anti-p17 antibodies, positive p24 antigenemia, increase of erythrocyte sedimentation rate, and of serum levels of immunoglobulin G. immunoglobulin A, neopterin and beta 2-microglobulin). The percentages of subjects positive for at least one marker at the first, second, third and fourth examinations were 66, 88, 94 and 97%, respectively. The increase in the number of markers with time was significant (chi-square test; P less than 0.001). This increase suggests a progression to AIDS in the majority of asymptomatic seropositive subjects, even those without a decreased CD4 lymphocyte count.     

Increased levels of activated subsets of CD4 T cells add to the prognostic value of low CD4 T cell counts in a cohort of HIV-infected drug users

OBJECTIVE: To identify subsets of CD4 T lymphocytes that can predict the development of AIDS and to assess whether increased levels of these cellular markers could provide additional independent prognostic information to the CD4 T cell count and plasma HIV-1-RNA levels. DESIGN AND METHODS: In a prospective study, a cohort of 85 HIV-positive intravenous drug users [clinical categories of the CDC classification A (n = 48) and B (n = 37)] were followed for a period of 37+/-13 months. Memory and activated CD4 and CD8 T cells were quantitated by three-colour flow cytometry at baseline and expressed as a percentage of total CD4 and CD8 lymphocytes. Clinical evaluations were performed at 6 month intervals. The relationships between these lymphocyte subsets and progression to AIDS were studied using Kaplan-Meier plots and proportional hazards regression models. RESULTS: After adjustment for the level of CD4 T cells and plasma HIV-1-RNA levels, the elevation in the subset CD4+CD38+DR+ was the marker within the functionally distinct subsets of CD4 T lymphocytes with additional prognostic value in bivariate Cox regression models. In multivariate models, increased percentages of CD4+CD38+DR+ T cells provided the strongest independent prognostic information for progression to AIDS (relative hazard, 1.07; P < 0.0001). CONCLUSION: Our results suggest that high levels of CD4+CD38+HLA-DR+ T cells reflect the increasing degree of CD4 T cell activation during the progression of HIV infection, and could be used together with the CD4 T cell and HIV-RNA levels to evaluate more accurately the progressive cellular immune impairment associated with the risk of progression to AIDS.     

Clinical signs and laboratory markers in predicting progression to AIDS in HIV-1 infected patients.

In a prospective longitudinal study 89 men with HIV-1 infection were observed for a mean time of 51 months with regard to clinical signs and laboratory findings predictive of progression to AIDS/opportunistic infection (OI). In a bivariate regression analysis the clinical signs showing a significant relation to AIDS development were: dermatitis of the face, yellow toe nail changes, hairly leukoplakia and oral candidiasis. The laboratory findings significantly associated with progression to AIDS were: decrease of the relative and absolute number of CD4 lymphocytes, decrease of the CD4/CD8 ratio, HIV p24 antigenaemia, lack of anti-HIV p24, elevated erythrocyte sedimentation rate, anaemia and elevated serum-beta-2-microglobulin. The relative number (%) of CD4 cells was found superior to the absolute number and the CD4/CD8 ratio. In a multivariate regression analysis decrease of CD4 lymphocytes and lack of anti-HIV p24 were independently associated with subsequent AIDS/OI development.     

Prediction of progression to AIDS by analysis of CD4 lymphocyte counts in a haemophilic cohort

Serial CD4 lymphocyte counts were recorded in 112 anti-HIV-positive haemophiliacs who were followed for up to 8 years after seroconversion. The patients remained at low risk of developing AIDS until their CD4 lymphocyte count fell to 0.25 X 10(9)/l. From this point, the risk increased as their count approached zero. Using this result and on the assumption (which is evaluated) that the underlying trend over time in CD4 lymphocyte counts is linear, the predicted rate of progression to AIDS was calculated for the cohort. It was estimated that 73% (95% confidence limits 60-86%) of the cohort will develop AIDS within 15 years of HIV-seropositivity. During 8 years of follow-up, this cohort had shown similar rates of progression to AIDS to other cohorts--haemophilic and otherwise--suggesting that this estimate may well have general applicability. The method described could be used to plan the provision of health-care resources for groups of anti-HIV-positive patients as it allows the number of new cases of AIDS to be predicted year by year, even when the patients' dates of seroconversion are unknown.     

Immune activation markers and AIDS prognosis.

Four assays for serum levels of cellular products of immune activation were examined as prognostic markers for AIDS in a prospective study of asymptomatic HIV-seropositive homosexual men. Baseline serum values of beta 2-microglobulin (beta 2M), neopterin, soluble CD8 (sCD8), and soluble interleukin-2 receptor (sIL-2R) for 185 men were examined univariately and multivariately as predictors of AIDS during 36 months of follow-up. Thirty-three cases of AIDS (18%) were diagnosed during the follow-up period. All four assays correlated highly with each other (r = 0.48-0.63), and all four were good univariate predictors of AIDS and comparable to CD4 lymphocyte count. beta 2M, neopterin, and sCD8 predicted AIDS independently of both CD4 count and HIV p24 antigen or p24 antibody in multivariate analysis. Within the range of CD4 count 200-499 x 10(6) cells/l, an immune activation marker used in combination with an assay for p24 antigen identifies those at 3-6% risk of AIDS over 36 months (low risk on both assays) and those at 63-86% risk (high risk on both assays). These results can be used to guide physicians and patients making decisions about treating asymptomatic HIV infection with zidovudine in individuals with CD4 lymphocyte count of 200-499 x 10(6) cells/l.     

The Progression of HIV disease in a haemophilic cohort followed for 12 years

A cohort of haemophilic patients who seroconverted to HIV-1 between October 1979 and July 1985 has been followed to 1 January 1992. The median age at initial seropositivity was 24 years with a range of 2–77 years. By January 1992, 38/111 (34%) had developed AIDS and 39/111 (35%) had died (four of liver failure including one hepatoma). Using Kaplan-Meier plots, the calculated progression to AIDS at 12 years is 45% (95% CI 31, 58): for age > 25 years 63% (95% CI 45, 82), age < 25 years 32% (95% CI 15, 48) P = 0.0001; CMV positive 68% (95% CI 48, 87) CMV –ve 20% (95% CI 8, 32) P = 0.0009. The 12-years progression rate to CD4+0.2 or AIDS is 66% (95% CI 55, 76). 21/34 (63%) of patients who are p24 antigen positive have developed AIDS compared to 17/77 (22%) who are p24 antigen negative (=0.0001). 19/34 (56%) and 20/77 (23%) of those p24 positive and negative respectively have died ( P = 0.007). Before antiviral and prophylactic treatment for asymptomatic patients there were nine AIDS cases in 3.84 years experience with CD4 + <0.05 (1/0.43 years) and since treatment, 10 AIDS cases in 18.22 years (1/1.8 years). Age, CMV status and p24 remain strongly predictive of disease progression. Treatment appears to reduce the incidence of AIDS.     

Natural history of advanced HIV disease in patients treated with zidovudine. The Zidovudine Epidemiology Study Group.

OBJECTIVE: To describe the natural history of advanced HIV disease in patients treated with zidovudine. DESIGN: Longitudinal, observational study. SETTING: Twelve academic and community-based sites. PATIENTS, PARTICIPANTS: Eight hundred and sixty-three patients with AIDS or AIDS-related complex (ARC) with a CD4+ lymphocyte count less than 250 x 10(6)/l, who first received zidovudine between 15 April 1987 and 14 April 1988. MAIN OUTCOME MEASURES: Survival, progression to AIDS and first development of specific opportunistic illness. RESULTS: Median survival after initiation of zidovudine therapy ranged from greater than 900 days in patients with a baseline CD4+ lymphocyte count greater than or equal to 150 x 10(6)/l to 560 days in patients with a CD4+ lymphocyte count less than 50 x 10(6)/1. Other factors associated significantly with poorer survival were diagnosis of AIDS (versus ARC), baseline age greater than or equal to 40 years, hematocrit less than 35%, and diminished functional status. In patients with ARC at enrollment, median time of progression to AIDS ranged from 810 days in patients with a CD4+ lymphocyte count greater than or equal to 150 x 10(6)/l to 310 days in patients with a CD4+ lymphocyte count less than 50 x 10(6)/l. Rates of development of specific opportunistic infections or neoplasms and HIV encephalopathy were determined for different baseline CD4+ lymphocyte count ranges. Myelosuppression was significantly more common in patients with CD4+ lymphocyte counts greater than or equal to 100 x 10(6)/l. Sixty-five per cent of patients with a CD4+ lymphocyte count greater than or equal to 100 x 10(6)/l and 51% with a CD4+ lymphocyte count less than 100 x 10(6)/l continued to receive zidovudine 2 years after starting therapy. CONCLUSIONS: We describe the natural history of a cohort of patients treated with zidovudine for advanced HIV disease. These CD4+ lymphocyte count-stratified estimates of disease progression should provide prognostic information useful in the clinical management of advanced disease and the design of future studies.     

Relationships among the detection of p24 antigen, human immunodeficiency virus (HIV) RNA level, CD4 cell count, and disease progression in HIV-infected individuals with hemophilia

The aim of this study was to assess the relationships among the detection of p24 antigen, human immunodeficiency virus (HIV) RNA level, CD4 cell count, and disease progression in 111 males with hemophilia who were infected with HIV for < or =20 years. Sixty-four individuals (58%) developed p24 antigenemia a median of 11.6 years after seroconversion. The time to first detection of p24 antigen was shorter among those who were older (P=.04) and those with a high initial HIV RNA level (P=.006). The median HIV RNA level and CD4 cell count at the time of the detection of p24 antigen were 4.95 log(10) copies/mL and 100 cells/mm(3), respectively. In univariate analyses, p24 antigenemia was associated with more-rapid progression to AIDS (relative hazard [RH], 5.50; P=.0001). The effect was reduced (RH, 1.85; P=.06) after adjusting for CD4 cell counts and HIV RNA levels during follow-up, age, and calendar year. A significant relationship between p24 antigenemia and death was nonsignificant after adjusting for CD4 cell count.     

HIV／AIDS患者血浆病毒载量及外周血T淋巴细胞亚群的变化

目的：观察国内HIV／AIDS患者血浆病毒载量和外周血CD4^ 、CD8^ T淋巴细胞的变化，探讨这些变化的临床意义。方法：选择未经抗病毒治疗的HIV／AIDS患者124例，用bDNA法检测血浆病毒载量，并用流式细胞仪检测外周血CD4^ 、CD8^ T淋巴细胞。结果：AIDS患者的血浆病毒载量明显高于HIV感染者，血浆病毒载量与CD4^ 细胞计数呈显著负相关，但其最高峰位于CD4^ 细胞计数100／μl处，然后随着CD4^ 细胞计数的下降而减少。CD4^ T细胞计数为AIDS组＜HIV组＜正常对照组：HIV感染者的CD8^ T细胞计数显著高于正常组和AIDS组，而AIDS患者CD8^ T细胞数则随着CD4^ T细胞减少而下降。结论：血浆病毒载量随着疾病进展而显著升高，但在疾病晚期则有所降低。外周血CD4^ T细胞计数随着疾病的进展而进行性减少；CD8^ T细胞计数在感染早期显著升高，进入晚期则减少。在评价HIV感染者和AIDS患者病情时，应结合病毒载量、CD4^ 、CD8^ T细胞计数综合分析。     

Prognostic value of single measurements of beta-2-microglobulin, immunoglobulin A in HIV disease after controlling for CD4 lymphocyte counts and plasma HIV RNA levels

The interrelationships between the CD4 lymphocyte count, plasma viral load [human immunodeficiency virus (HIV) RNA], beta-2-microglobulin (beta2-M) and immunoglobulin A (IgA) and the mortality risk was explored in 234 HIV-infected individuals (median CD4 count 230 cells/mm3, range 1-1,247). Product-moment correlation analysis was used to study the association between beta2-M, IgA and HIV RNA. A proportional hazards Cox model was used to estimate the relative hazard (RH) of death. Both beta2-M (r = 0.49, p < 0.0001) and IgA (r = 0.42, p < 0.0001) were positively correlated with HIV RNA. High beta2-M levels were associated with an increased risk of death in both univariate Cox analysis and after adjustment for HIV RNA, CD4 lymphocyte count and age [RH = 1.16 per 100 nmol/l higher beta2-M, 95% confidence interval (CI) 1.05-1.27]. Raised IgA levels were associated with shorter survival in individuals with a CD4 count above 50 cells/mm3 in univariate analysis as well as after adjusting for age and CD4 lymphocyte count (RH = 1.19 per 10 micromol/l higher IgA, 95% CI 1.01-1.39). However, this association was no longer significant after further adjusting for HIV RNA. In conclusion, beta2-M levels provided additional prognostic information for survival to the information obtained by CD4 count and HIV RNA levels, whereas serum IgA only was a weak prognostic marker in this fairly progressed cohort.     

Predictive markers of AIDS: a follow-up of lymphocyte subsets and HIV serology in a cohort of patients with lymphadenopathy

From 1982 to 1985, 89 HIV-1 seropositive men with persistent generalized lymphadenopathy (PGL) were enrolled into a prospective longitudinal study. In February 1988, after a mean observation time of 45 months, 23 patients had progressed to AIDS with opportunistic infection (AIDS/OI), 4 had developed Kaposi's sarcoma, 47 had developed HIV-related symptoms, 14 still had PGL as only symptom, and 1 was lost to follow-up. Patients with CD4 lymphocytes less than or equal to 0.40 x 10(9)/l as well as patients with HIV antigenaemia and those lacking antibodies to p24 all had a significantly higher risk of developing AIDS/OI within 30 months of observation than other patients. HIV antigen was present in 70% and antibodies to p24 were lacking in 61% of the patients at the time of AIDS/OI diagnosis. All but one (96%) of the AIDS/OI patients had CD4 numbers less than or equal to 0.20 x 10(9)/l at the same time. The estimated median time to AIDS/OI in patients with HIV antigenaemia was 21 months and in patients lacking p24 antibodies 27 months. In patients with CD4 numbers less than or equal to 0.20 and 0.40 x 10(9) cells/l the estimated median time to AIDS/OI was 14 months and longer than 30 months, respectively.     

Anaemia is an independent predictive marker for clinical prognosis in HIV-infected patients from across Europe. EuroSIDA study group.

OBJECTIVES: To describe changes in haemoglobin over time and to determine the joint prognostic value of the current haemoglobin, CD4 lymphocyte count and viral load among patients from across Europe. PATIENTS: The analysis included 6725 patients from EuroSIDA, an observational, prospective cohort of patients with HIV from across Europe. METHODS: Normal haemoglobin was defined as haemoglobin greater than 14 g/dl for men and 12 g/dl for women; mild anaemia was 8-14 g/dl for men and 8-12 g/dl for women; severe anaemia was defined as less than 8 g/dl for both males and females. Linear regression techniques were used to estimate the annual change in haemoglobin; standard survival techniques were used to describe disease progression and risk of death. RESULTS: At recruitment to the study, 40.4% had normal levels of haemoglobin, 58.2% had mild anaemia and 1.4% had severe anaemia. At 12 months after recruitment, the proportion of patients estimated to have died was 3.1% [95% confidence interval (CI) 2.3-3.9] for patients without anaemia, 15.9% for patients with mild anaemia (95% CI 14.5-17.2) and 40.8% for patients with severe anaemia (95% CI 27.9-53.6; P < 0.0001). In a multivariate, time-updated Cox proportional hazards model, adjusted for demographic factors, AIDS status and each antiretroviral treatment as time-dependent covariates, a 1 g/dl decrease in the latest haemoglobin level increased the hazard of death by 57% [relative hazard (RH) 1.57; 95% CI 1.41-1.75; P < 0.0001], a 50% drop in the most recent CD4 lymphocyte count increased the hazard by 51% (RH 1.51; 95% CI 1.35-1.70; P < 0.0001) and a log increase in the latest viral load increased the hazard by 37% (RH 1.37; 95% CI 1.15-1.63; P = 0.0005). CONCLUSIONS: Severe anaemia occurred infrequently among these patients but was associated with a much faster rate of disease progression. Among patients with similar CD4 lymphocyte counts and viral load, the latest value of haemoglobin was a strong independent prognostic marker for death.     

CD8+ T lymphocytes and progression to AIDS in HIV-infected men: some observations

The relationship between CD8+ lymphocyte counts and progression to AIDS was studied in 340 HIV-1-seropositive men participating in a population-based prospective study. Overall, the relative hazard for developing AIDS during 60 months of observation was slightly elevated (1.08, P = 0.003), indicating an 8% increase in risk of progression for every 100 CD8+ cell count increment. When the data were analyzed in relation to date of diagnosis, the relative hazard was depressed (0.90, P less than 0.001) for the period 6 months prior to diagnosis, but was close to 1.0 for the period 6-36 months prior to diagnosis. These findings suggest a complex relationship between CD8+ cell counts and progression to AIDS, with the possibility that various subsets of the CD8+ compartment play different roles.     

Fungal infection as a risk factor for HIV disease progression among patients with a CD4 count above 200/microl in the era of cART

The identification of clinical risk factors for AIDS in patients with preserved immune function is of significant interest. We examined whether patients with fungal infection (FI) and CD4 cell count >or=200/microl were at higher risk of disease progression in the era of cART. 11,009 EuroSIDA patients were followed from their first CD4 cell count >or=200/microl after 1 January 1997 until progression to any non-azoles/amphotericin B susceptible (AAS) AIDS disease, last visit or death. Initiation of antimycotic therapy (AMT) was used as a marker of FI and was modelled as a time-updated covariate using Poisson regression. After adjustment for current CD4 cell count, HIV-RNA, starting cART and diagnosis of AAS-AIDS, AMT was significantly associated with an increased incidence of non-AAS-AIDS (IRR=1.55, 95% CI 1.17-2.06, p=0.0024). Despite low incidence of AIDS in the cART era, FI in patients with a CD4 cell count >or=200/microl is associated with a 55% higher risk of non-AAS-AIDS (95% confidence interval 1.17-2.06, p=0.0024). These data suggest that patients with FI are more immune compromized than would be expected from their CD4 cell count alone. FI can be used as a clinical marker for disease progression and indirect indicator for initiation/changing cART in settings where laboratory facilities are limited.