Change In CD4 Cell Count Research Articles

Concorde: MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection

Concorde is a double-blind randomised comparison of two policies of zidovudine treatment in symptom-free individuals infected with human immunodeficiency virus (HIV): (a) immediate zidovudine from the time of randomisation (Imm); and (b) deferred zidovudine (Def) until the onset of AIDS-related complex (ARC) or AIDS (CDC group IV disease) or the development of persistently low CD4 cell counts if the clinician judged that treatment was indicated. Between October, 1988, and October, 1991, 1749 HIV-infected individuals from centres in the UK, Ireland, and France were randomly allocated to zidovudine 250 mg four times daily (877 Imm) or matching placebo (872 Def). Follow-up was to death or Dec 31,1992 (total 5419 person-years; medians 3·3 years) and only 7% of the 1749 had not had a full clinical assessment after July 1, 1992. Of those allocated to the Def group, 418 started zidovudine at some time during the trial, 174 (42%) of them at or after they were judged by the clinician to have developed ARC or AIDS (nearly all confirmed subsequently) and most of the remainder on the basis of low CD4 cell counts. Those in the Imm group spent 81% of the time before ARC or AIDS on zidovudine compared with only 16% for those in the Def group. Despite the large difference in the amount of zidovudine between the two groups and the fact that the number of clinical endpoints (AIDS and death) in Concorde (347) outnumbers the total of those in all other published trials in symptom-free and early symptomatic infection, there was no statistically significant difference in clinical outcome between the two therapeutic policies. The 3-year estimated survival probabilities were 92% (95% Cl 90-94%) in Imm and 94% (92-95%) in Def (log-rank p=0·13), with no significant differences overall or in subgroup analyses by CD4 cell count at baseline. Similarly, there was no significant difference in progression of HIV disease: 3-year progression rates to AIDS or death were 18% in both groups, and to ARC, AIDS, or death were 29% (Imm) and 32% (Def) (p=0·18), although there was an indication of an early but transient clinical benefit in favour of Imm in progression to ARC, AIDS, or death. However, there was a clear difference in changes in CD4 cell count over time in the two groups. Median changes from baseline at 3 months were + 20 cells/μL (Imm) and -9 cells/μL (Def), a difference of 29 cells/μL (95% Cl 16-42; p < 0·0001) which persisted for up to 3 years. Thus such persistent differences in CD4 cell count do not necessarily imply long-term differences in clinical outcome. 6 participants had life-threatening adverse events that were judged to be possibly drug related: 4 occurred on trial capsules before unblinding (3 on zidovudine, 1 on placebo) and 2 occurred on open zidovudine. Despite a daily dose of 1 g of zidovudine, the frequency of severe haematological and other adverse events on trial therapy was low but significantly higher in the Imm group: 16 Imm and 2 Def participants stopped trial drug for haematological events and the estimated proportions with haemoglobin dropping below 10 g/dL were 5% and 1%, respectively, at 1 year and 8% and 2%, respectively, at 3 years. Another 83 (9%) Imm and 36 (4%) Def participants stopped for other adverse events, predominantly gastrointestinal or neurological symptoms (headaches) or malaise. The results of Concorde do not encourage the early use of zidovudine in symptom-free HIV-infected adults. They also call into question the uncritical use of CD4 cell counts as a surrogate endpoint for assessment of benefit from long-term antiretroviral therapy.

Immune Status of Human Immunodeficiency Virus Seropositive and Seronegative Hemophiliacs Infused for 3.5 Years With Recombinant Factor VIII

AbstractRecent studies suggest that treatment of hemophiliacs with highly purified factor VIII concentrates may preserve immune function. To test this hypothesis, we prospectively studied 51 hemophilic patients (21 human immunodeficiency virus [HIV] seropositive and 30 seronegative) who were on home therapy exclusively with recombinant factor VIII (Kogenate, Miles Laboratory, Berkeley, CA) for 3.5 years. Patients, all of whom had been previously treated with plasma-derived factor VIII concentrates, were monitored every 6 months with T-lymphocyte subsets and β2-microglobulin levels. Mean rate of change in absolute CD4 cell counts, calculated from regression slopes for individual patients, showed a small but statistically significant decrease over the 3.5-year study period for HIV seropositive hemophiliacs. No decrease in CD4 cell counts was seen in HIV seronegative hemophiliacs when the data for children under age 6 years were excluded from the analysis, β2-microglobulin levels and CD8 cell counts remained unchanged. These data show stability of immunologic parameters in HIV seronegative hemophiliacs, and a small decrease in CD4 cell counts in HIV seropositive hemophiliacs treated with recombinant factor VIII.

Immune status of human immunodeficiency virus seropositive and seronegative hemophiliacs infused for 3.5 years with recombinant factor VIII. The Kogenate Study Group

Recent studies suggest that treatment of hemophiliacs with highly purified factor VIII concentrates may preserve immune function. To test this hypothesis, we prospectively studied 51 hemophilic patients (21 human immunodeficiency virus [HIV] seropositive and 30 seronegative) who were on home therapy exclusively with recombinant factor VIII (Kogenate, Miles Laboratory, Berkeley, CA) for 3.5 years. Patients, all of whom had been previously treated with plasma-derived factor VIII concentrates, were monitored every 6 months with T-lymphocyte subsets and beta 2-microglobulin levels. Mean rate of change in absolute CD4 cell counts, calculated from regression slopes for individual patients, showed a small but statistically significant decrease over the 3.5-year study period for HIV seropositive hemophiliacs. No decrease in CD4 cell counts was seen in HIV seronegative hemophiliacs when the data for children under age 6 years were excluded from the analysis. beta 2- microglobulin levels and CD8 cell counts remained unchanged. These data show stability of immunologic parameters in HIV seronegative hemophiliacs, and a small decrease in CD4 cell counts in HIV seropositive hemophiliacs treated with recombinant factor VIII.

T-Lymphocyte Subsets in Intravenous Drug Users With HIV-1 Infection

To the Editor. —Margolick et al 1 recently reported a median change in CD4 cell count of 7.47/μL per 6 months among HIV-1 infected IVDUs. No significant difference in loss of CD4 cells over time was observed between active users and ex-users. Previous reports in the United States 2 and in Italy 3 had revealed much higher rates of CD4 cell loss in IVDUs. The Multicenter Prospective HIV Study of Rome is collecting information on over 4000 HIV-1 seropositive IVDUs for a longitudinal study of the natural history of HIV-1 infection. We have analyzed data from the San Giovanni Hospital subcohort where 734 HIV-1 seropositive subjects have been clinically and immunologically evaluated since 1985. Of these, 495 had injection of drugs as their chief risk behavior for HIV-1 infection. As of January 31, 1992, a total of 280 IVDUs (56.6%) had returned for at least one follow-up visit and had

Progressive slowing of reaction time and increasing cerebrospinal fluid concentrations of quinolinic acid in HIV-infected individuals

Neuropsychological functioning and cerebrospinal fluid concentrations of an endogenous neurotoxin, quinolinic acid (QUIN) were evaluated in 52 HIV-positive individuals (71% without constitutional symptoms) and 33 HIV-seronegative controls (including 15 psychiatric patients with adjustment disorders). Although the HIV-positive subjects did not differ from controls on standard neuropsychological tests, simple and choice reactions times (RT) were slow at initial evaluation (P less than 0.01) and became progressively slower at 6-month re-evaluation (P less than 0.05). Cerebrospinal fluid (CSF) QUIN was elevated at initial evaluation and increased during the 6-month interval (P less than 0.05). Moreover, during this 6-month interval, progressive slowing of RT was highly correlated with increasing levels of CSF QUIN (r = 0.85, df = 15, P less than 0.0001) but not with changes in mood, constitutional symptoms, or CD4 cell count. These findings suggest that RT may provide a sensitive behavioral measure of relatively early central nervous system involvement in HIV-infected individuals and that QUIN may play an important role in the pathogenesis of HIV-related neurological dysfunction.

Detection of Infectious Immune Complexes in Human Immunodeficiency Virus Type 1 (DIV-l) Infections: Correlation with Plasma Viremia and CD4 Cell Counts

The detection of infectious immune complexes in plasma after human immunodeficiency virus (HIV) infection may be useful as a surrogate marker of progression of disease and may help in understanding the pathogenesis of AIDS. Polyethylene glycol (PEG) precipitates of plasma were tested for the presence of HIV p24 antigen and infectious virus. Results were compared with data from cell and plasma cultures, plasma p24 antigen, CD4 cell counts, and stage of disease. PEG precipitation increased the detection rate of the p24 antigen assay from 38.3% to 58.7%. There was a significant correlation between precipitable p24 antigen and plasma viremia, changes in CD4 cell counts, and progression of disease. The sensitivity of the PEG-precipitable p24 antigen assay versus traditional p24 antigen testing was 59.0% and the specificity 91.7%. The assay was reproducible and may be a useful determinant of viral load, clinical progression, and antiretroviral efficacy.