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.     

Value of HIV-1 viral load and CD4 lymphocyte count as determinants of progression to AIDS and survival

BACKGROUND: HIV-1 viral load is regarded as a better surrogate marker for progression and death than CD4+ cell counts. Both markers are analysed in a cohort of patients with unknown seroconversion date and advanced HIV infection. PATIENTS AND METHODS: Retrospective cohort analysis of 421 patients, most on antiretroviral therapy, with a median initial CD4+ cell count of 209 x 10(6)/l and a median initial viral load of 4.7 log copies/ml. One thousand two hundred and eighty-six samples were analysed. Univariate and bivariate analysis were performed with initial and sequential CD4+ cell counts and viral load values to estimate the risk of progression and death by Cox regression models. RESULTS: After a median follow up of 763 days, 124 patients developed AIDS and 117 died. Relative risks of progression related to the group that maintained viral load values always < 35,000 copies/ml were: 5-fold (95% CI: 1.4-17.0; p < 0.05) for patients with any viral load value > 35,000 copies/ml but always < 200,000 copies/ml; and 13.6 fold (95% CI: 5.4-34.2; p < 0.0001) for patients who could not maintain viral load < 200.000 copies/ml. CD4+ counts = 100 x 10(6)/l and viral load = 220,000 copies/ml were the threshold values that best fitted to estimate the probability of survival by a bivariate analysis. CONCLUSIONS: The maintenance of sequential viral load values < 35.000 copies/ml is associated with a lower risk of progression. The maintenance of sequential viral load values < 150,000 copies/ml is associated with higher short-term survival rates.     

CD4 cell counts of 200 x 10(6)/1 or below in natural history studies and surveillance: is one enough or are two better?

A retrospective cohort study was performed to examine the extent and clinical significance of misclassification associated with using the current United States AIDS case defining category of an initial CD4 count < or = 200 cells x 10(6)/l (< or = 200) compared with a definition requiring two consecutive counts below this level. The main outcomes examined were the probability of subsequent CD4 counts > 200 x 10(6)/l (> 200) and progression times to AIDS and death. Of the 2025 predominantly male homosexual HIV-positive patients attending two hospital based HIV clinics with initial CD4 cell counts < or = 200, 1524 (75%) subsequently had consecutive counts < or = 200, but only half did so at the next CD4 count. Ten per cent had either no further or only non-consecutive counts < or = 200, and 15% had only one CD4 count available for analysis. The cumulative proportion of patients with a CD4 count > 200 at one year after a first count of < or = 200 was about twice (39%) that observed among the subgroup with at least two consecutive counts < or = 200 (19%). The times from the initial counts of < or = 200 to AIDS and death were also shorter by six months and two months, respectively, in the subgroup with two or more consecutive counts < or = 200. A significant proportion of patients will be prematurely classified as having a CD4 cell count < or = 200 if a single CD4 count below this level is accepted. A definition of two consecutive counts < or = 200 should be adopted in preference to a single count < or = 200 for natural history studies and clinical trials, in which precise estimates of the time to or from a defined CD4 threshold are important. In surveillance programmes, however, such an approach may be impractical because of missing or infrequent serial CD4 counts, although adjustments can be made based on these estimates of premature misclassification.     

Unintegrated circular HIV-1 DNA in the peripheral mononuclear cells of HIV-1-infected subjects: association with high levels of plasma HIV-1 RNA, rapid decline in CD4 count, and clinical progression to AIDS

We observed 36 HIV-infected patients to evaluate whether the presence of tandem 2-long terminal repeat circular unintegrated HIV-1 DNA (2-LTR) in peripheral blood mononuclear cells (PBMC) at baseline was associated with acceleration of HIV disease. Detection of 2-LTR at baseline correlated with high plasma HIV-1 RNA levels (p < .01), recovery of culturable HIV-1 from plasma (p = .02), and progression to AIDS during follow-up (p = .01). More patients with 2-LTR (68%) than without 2-LTR (31%) had a decline in CD4 levels of >50 cells/mm3 over the first 18 months of follow-up (p = .04), and the average annual CD4 decline was 35% in patients with 2-LTR compared with 16% in those without 2-LTR (p = 0.06). Detection of 2-LTR in PBMC at baseline was an independent predictor of high plasma HIV-1 RNA levels and subsequent CD4 cell decline in this cohort of patients with predominantly nonsyncytium-inducing (NSI) isolates at baseline. The presence of 2-LTR in PBMC appears to be reflective of ongoing HIV-1 replication, as measured by plasma HIV-1 RNA levels, and identifies persons at risk for immunologic and clinical decline.     

CD4 cell count as a surrogate endpoint in HIV clinical trials: a meta-analysis of studies of the AIDS Clinical Trials Group

OBJECTIVE: To evaluate initial changes in CD4 cell count as a surrogate endpoint for clinical outcome in HIV-infected patients. DESIGN: Meta-analysis of all relevant Phase II and III randomized clinical trials undertaken by the Adult AIDS Clinical Trials Group. METHODS: Individual patient data were obtained from each clinical trial, and the difference between a pair of treatments in their effect on clinical outcome (AIDS or death, or death alone) during 2 years of follow-up was evaluated. The proportion of treatment effect explained (PTE) was the proportion of this difference explained by the change in CD4 cell count 6 months after starting treatment, evaluated using proportional hazards models. A weighted average PTE across treatment comparisons was obtained. The association between the difference between treatments in clinical outcome, expressed as hazard ratio, and the difference in mean change in CD4 cell count was evaluated using regression analysis. RESULTS: There were 15 clinical trials involving 24 treatment comparisons. The weighted average PTE for both progression to AIDS or death was 0.16 [95% confidence interval (Cl), 0.07-0.26] and for death was 0.10 (95% Cl, 0.00-0.20). There were significant associations between treatment differences in effect on AIDS or death, and on death alone, and the difference in mean change in CD4 cell count. A difference in mean change in CD4 cell count of 30 or 40 x 10(6)/l or more in favor of the test treatment indicated with high probability that there was a corresponding difference in progression to AIDS or death. CONCLUSIONS: The small PTE suggest that other mechanisms of drug action not captured by initial change in CD4 cells are important. CD4 cell count is a weak surrogate endpoint, but has some value as an aid for screening treatments for drug development or preliminary regulatory approval.     

Value of quantification of p24 antigen in plasma as a prognostic marker of survival in a cohort of 251 HIV-positive patients

OBJECTIVE: To analyse plasma p24 antigen as a marker of survival in a cohort of HIV-infected patients whose time of seroconversion is unknown. DESIGN: Prospective cohort study. SETTING: AIDS Unit in a teaching hospital. PATIENTS: 251 patients were studied, most on antiretroviral therapy. Mean initial CD4 cell counts were 376 x 106/ 1 (range: 0.8-1350). 51 cases had been diagnosed previously with AIDS. METHODS: Analysis of survival, according to initial plasma p24 antigen was performed by Kaplan-Meier test. Relative risks were calculated by Cox's proportional hazards model. RESULTS: During a follow-up period of 24 months, 46 patients died. Relative risk (RR) of death related to the group with p24 antigen = < 40 pg/ml was 3.32 when p24 antigen > 40 pg/ml (p = 0.0001). CD4+ cell levels adjusting, the result was 2.47 (CI 95% 1.37-4.46) (p = 0.0027). CONCLUSIONS: Plasma levels of p24 antigen is useful as a marker of the risk of death and it behaves as a independent prognostic marker in our patients. P24 antigen = < 40 pg/ml is associated with a better prognosis.     

The role of complement and gp120-specific antibodies in virus lysis and CD4+ T cell depletion in HIV-1-infected patients

The substantial virus lysis was induced by HIV-1-infected patient serum and normal human complement serum in the presence of purified patient IgG. Non-infected CD4+ T cells coated with the whole virus or with a recombinant HIV-1 envelope gp120 and sensitised with patient IgG were also shown to be susceptible to complement-dependent lysis. The serum level of complement regulatory protein in a fluid phase, the C1-esterase inhibitor, was significantly correlated with serum concentration of C1q-circulating immune complexes (P=0.0062), but inversely with CD4+ T cell count (P < 0.0001). Accordingly, the disease progression in HIV-1-infected patients was significantly correlated with the level of complement activation as determined by serum level of C1-esterase inhibitor (P=0.0001), and inversely correlated with CD4+ cell count (P < 0. 0001) and gp120-specific antibody titre (P=0.0086). These results strongly suggest that the complement activation by gp120-specific antibodies play a very important role in virus clearance, but also in depletion of infected as well as gp120-coated non-infected CD4+ bystander T cells during the course of HIV-1 infection.     

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

The products of a growing number of genes have been shown to display seemingly contradictory functions; namely, the induction of tumorigenesis and the induction of apoptosis. Heregulin's involvement in oncogenesis occurs through its interactions with members of the EGF receptor tyrosine kinase family. Recently one isoform of heregulin, beta2b, was isolated in an in vitro screen for dominant, apoptosis-inducing genes in kidney epithelial cells. Here we show that heregulin is also capable of mediating apoptosis in human and murine mammary tumor cell lines and murine tumors. Furthermore, through transfection of the human breast cancer cell line MCF-7 with the truncated transmembrane/cytoplasmic segment of the heregulin gene, we show that the intracellular region of the heregulin precursor is sufficient for induction of apoptosis. Through the use of DNA fragmentation assays we also show that apoptosis occurs in cell lines established from heregulin-induced mammary gland tumors. TdT addition of digoxigenin labeled nucleotides to 3' OH ends of DNA breaks recapitulated these results in the actual tumors. Finally, over-expression of heregulin is shown to lead to the down-regulation of Bcl-2, an inhibitor of apoptosis. Conversely, the transfection of Bcl-2 into MCF-7 cells inhibits heregulin-mediated programmed cell death.     

Reduction of Th1 cell activity in the peripheral circulation of patients with rheumatoid arthritis after treatment with a non-depleting humanized monoclonal antibody to CD4

Differences in early events during entry and integration of HIV-1 into peripheral blood mononuclear cells (PBMC) might contribute to the absence of AIDS-like disease in chimpanzees as compared to humans. To address this question, we first tested the in vitro susceptibility of human and chimpanzee PBMC for infection with the two HIV-1 isolates III B and RF. The results of these studies revealed that chimpanzee PBMC had a slightly lower capability to support the growth of HIV-1 as compared to human PBMC. This was accompanied by a delayed accumulation of proviral HIV-1 DNA in cultures of HIV-1-infected chimpanzee PBMC. However, no differences between cells of the two species were observed when very early events of HIV-1 infection were studied. Shortly (20 h) after infection chimpanzee and human cells harbored similar amounts of proviral HIV-1 DNA and PBMC of both species behaved comparably with respect to pre-integration latency (i.e. the ability to activate extrachromosomal HIV-1 intermediates in HIV-1 infected quiescent cells at various times after infection). These results strongly suggest that the absence of AIDS-like disease in chimpanzees cannot be correlated with defects in early events of the HIV-1 replicative cycle.     

Multi-center clinical evaluation of combination anorganic bovine-derived hydroxyapatite matrix (ABM)/cell binding peptide (P-15) as a bone replacement graft material in human periodontal osseous defects. 6-month results

A synthetic cell-binding peptide (P-15) combined with anorganic bovine-derived hydroxyapatite bone matrix (ABM) was compared to demineralized freeze-dried bone allograft (DFDBA) and open flap debridement (DEBR) in human periodontal osseous defects in a controlled, monitored, multi-center trial. Following appropriate initial preparation procedures, flap surgery with defect and root debridement was performed. Three osseous defects per patient were treated randomly with one of three procedures after surgical preparation. Appropriate periodontal maintenance schedules were followed, and at 6 to 7 months re-entry flap surgery was performed for documentation and finalization of treatment. Analysis of variation (ANOVA) and t test analyses of patient mean values from 31 patients revealed that the combination ABM/P-15 grafts demonstrated significantly better mean defect fill of 2.8 +/- 1.2 mm (72.3%) versus a mean defect fill of 2.0 +/- 1.4 mm (51.4%) for defects treated with DFDBA (P <0.05) and a mean defect fill of 1.5 +/- 1.3 mm (40.3%) (P <0.05) for defects treated with DEBR. Other hard tissue findings showed similar clinically superior results with the use of ABM/P-15. Relative defect fill results showed 87% positive (50% to 100% defect fill) responses with ABM/P-15, 58% positive responses with DFDBA, and 41% positive responses with DEBR. There were 8 to 9 times more failures (minimal response) with DFDBA and DEBR (26% to 29% frequency) than with ABM/P-15. Soft tissue findings showed no significant differences among treatments except for greater clinical attachment level gain with ABM/P-15 compared to DEBR. These results suggest that the use of the P-15 synthetic cell-binding peptide combined with ABM yields better clinical results than either DFDBA or DEBR. Further studies are needed to determine the relative roles of the ABM and/or the P-15 in these improved results.