Are HIV-infected patients with rapid CD4 cell decline a subgroup who benefit from early antiretroviral therapy?

We have developed a model to determine whether asymptomatic HIV-infected individuals who have a rapid CD4 cell decline are a subgroup who might benefit from early antiretroviral therapy. Data were obtained from a subgroup of participants in the Concorde and EACG020 trials, two randomized, double-blind, comparative trials of immediate (IMM) versus deferred (DEF) zidovudine therapy in asymptomatic HIV-infected individuals. The subgroup comprised 297 patients (IMM = 154, DEF = 143) who had at least one CD4 cell count before and after randomization. The median CD4 cell count at randomization was 491 x 10(6)/L, and the median follow-up was 61 months. The rate of CD4 decline before and after randomization was estimated using multi-level linear regression analysis, and patients were stratified into quartiles according to the rate of CD4 cell decline before randomization. Outcome measures were the development of AIDS, a 50% drop in CD4 count from the baseline, and death. A Cox proportional hazards model was used to examine whether the effect of zidovudine on disease progression varied according to the previous rate of CD4 decline. We found that a more rapid rate of CD4 decline before randomization was associated with a greater reduction in the rate of CD4 decline following IMM antiretroviral therapy (r = -0.5, P = 0.03). The greatest risk reduction in disease progression with IMM antiretroviral therapy was seen in the quartile of patients with the highest rate of CD4 decline (> or = 26 x 10(6) cells/L per 6 months) (hazards ratio (HR) = 0.61, 95% CI = 0.35-1.05). However, this effect was statistically significant in only the Concorde trial (HR = 0.48, 95% CI = 0.29-0.89). In contrast, we found no evidence in the EACG020 trial of any trend towards greater benefit in those with the most rapid CD4 cell decline. These findings suggest that asymptomatic patients with rapid CD4 cell decline are a subgroup likely to benefit from early antiretroviral therapy. This analytic approach should now be replicated in trials of combination therapy, and these should include viral load data.     

CALLA-positive myeloma: an aggressive subtype with poor survival

Detailed immunotyping was carried out on 21 direct myeloma bone marrow aspirates and eight human myeloma cell lines. Four previously untreated common acute lymphoblastic leukemia antigen (CALLA)-positive myeloma patients were identified and six of eight cell lines (75%) were also positive. CALLA positivity, as part of an immature B phenotype, was found to correlate with very aggressive clinical disease: median survival six months v 56 months for the CALLA-negative group.     

Changes in acquired immunodeficiency syndrome-related lymphoma since the introduction of highly active antiretroviral therapy

Clinical data on 7840 HIV-positive patients, representing 43 745 patient-years of follow-up, has been collected. All patients with ARL since 1986 (n = 150) were assessed at presentation for prognostic factors and outcomes recorded. Comparisons are made between cases in the pre-HAART era (1988-1995), and the HAART era (1996-1999). Statistical models are used to calculate the incidence of ARL and factors predicting its development. The incidence of ARL has not changed over time (3 to 7 of 1000 patients per year, P = .933), but contributes to a greater percentage of first AIDS-defining illnesses (ADI) in the HAART era (P < or = .0001). Older age, nadir CD4 count, and no prior HAART use, predict the development of ARL. There has been no change in stage at presentation, presence of B symptoms, performance status, or marrow involvement between the 2 time cohorts or between patients with or without prior HAART exposure. Similarly, there is no difference in survival duration between the pre-HAART and HAART era (log rank P = .15) or specifically in patients treated with HAART before ARL diagnosis (log rank P = .12). The use of HAART has not yet been shown to influence the incidence or survival of ARL. However, because nadir CD4 count and use of HAART are independent predictors of ARL development, this may translate into a future fall in new cases. (Blood. 2000;96:2730-2734)     

Characterization and quantitation of the circulating forms of serum transferrin receptor using domain-specific antibodies

To characterize the nature of the immunoreactive transferrin receptor in human serum, antisera were developed to peptide sequences of the extracellular domain of human transferrin receptor between amino acids 107 and 120 and the intracellular domain between amino acids 40 and 54. Antisera against the extracellular domain exhibited reactivity against both purified intact receptor and immunopurified circulating receptor, whereas antisera against the intracellular domain reacted only with intact receptor. Using competitive binding enzyme-linked immunosorbent assays, transferrin receptor in ultracentrifuged sera from normal subjects and patients with sickle cell anemia could be detected with antisera against the extracellular but not the intracellular domain. When the pellet obtained by ultracentrifugation of these sera was assayed after solubilization in 1% teric (polyoxyethylene-9-lauryl ether), only 0.6% of total serum receptor was detected in normal subjects and 3.8% in subjects with sickle cell disease. Roughly equal amounts of this pelleted immunoactivity were detected with antibodies against the extracellular and intracellular domains. These results indicate that less than 1% of transferrin receptor in normal human sera is intact receptor consistent with an exosomal origin and that virtually all circulating transferrin receptor is in the form of a truncated extracellular domain.     

Selective laser trabeculoplasty (SLT) performed by optometrists—enablers and barriers to a shift in service delivery

Background/objectivesTo explore the acceptability, training requirements, enablers and barriers of optometrist-delivered SLT.Subjects/methodsOptometrists, fellowship and consultant grade ophthalmologists, hospital managers and patients were interviewed using pre-defined topic guides. Interviews were audio-recorded, transcribed, and subjected to thematic analysis. Overarching themes were defined by the study aims and the topic guides; subthemes were derived from the interview data.ResultsSixty-six participants (three managers, eight glaucoma specialist consultant ophthalmologists, seven clinical glaucoma fellows, 12 optometrists (two of them performing SLT), two ophthalmic nurses and 34 patients) participated in the study. Overarching themes (and subthemes) were: necessity of non-medical SLT delivery, clinical practice and training, advantages, disadvantages, concerns, challenges, community delivery of SLT, patient values and other healthcare professionals that could also deliver SLT.ConclusionsCertain clinical pre-requisites, such as gonioscopy and independent prescribing rights, were perceived as necessary for undertaking SLT training. An optometrist-delivered SLT service was expected to benefit the NHS, but there was an identified need of a standardised training scheme and robust governance. Patients were accepting of an optometrist-delivered SLT service in the hospital eye service.Subject terms: Health services, Glaucoma     

Dysfunction and infection of freshly isolated blood myeloid and plasmacytoid dendritic cells in patients infected with HIV-1

Recently it has been shown that the 2 populations of blood dendritic cells (DCs), termed plasmacytoid (pcDCs) and myeloid (myDCs), are reduced in HIV-1 infection. This study aimed to determine whether these 2 populations are targets for HIV-1 infection and whether their ability to stimulate T-lymphocyte proliferation is affected. Highly purified populations of myDCs and pcDCs were isolated from the blood of antiretroviral treatment-naive patients and assessed for the level of HIV provirus by polymerase chain reaction (PCR). We show that both populations are targets for HIV-1 infection as indicated by the presence of provirus in 12 of 14 pcDC and 13 of 14 myDC samples tested. A proportion of this provirus is integrated in myDCs. The ability of both myDCs and pcDCs from HIV-1-infected patients to stimulate allogeneic T-lymphocyte proliferation in a 6-day mixed leukocyte reaction was severely impaired, but was not mediated by secondary infection of T lymphocytes. Thus, in addition to depletion, both myeloid and plasmacytoid DCs are infected and show impaired functional capacity. These findings suggest that infection, depletion, and dysfunction of dendritic cells may contribute to the immunosuppression associated with HIV-1 disease.     

The paradox of improved antiretroviral therapy in HIV: potential for nutritional modulation?

Chronic infection with HIV type 1 is associated with alterations in macronutrient metabolism, specifically elevated plasma lipids, glucose and reduced insulin sensitivity. These alterations are most severe in patients at the later stages of AIDS, indicating a relationship with disease progression. Recently, a metabolic syndrome, termed lipodystrophy, has been described in successfully-treated HIV patients in whom the altered macronutrient metabolism of HIV infection appears to be amplified markedly, with concurrent alterations in adipose tissue patterning. This syndrome presents a paradox, as before the development of highly-active antiretroviral therapy (HAART) the most severe perturbations in metabolism were observed in the sickest patients. Now, the patients that respond well to therapy are showing metabolic perturbations much greater than those seen before. The implications of this syndrome are that, whilst life expectancy may be increased by reducing viral load, there are concomitant increases in the risk of cardiovascular disease, diabetes and pancreatitis within this patient population. The aetiology of the syndrome remains unclear. In a collaborative trial with the Chelsea and Westminster Hospital in London we have used stable-isotope-labelled fatty acids to examine the hypothesis that treatment with HAART causes a delayed clearance of dietary lipid from the circulation, resulting in the retention of lipid within plasma and the downstream changes in insulin and glucose homeostasis. This hypothesis would indicate a role for low-fat diets, exercise and drugs that reduce plasma lipid or insulin resistance, in modulating the response to antiretroviral therapy in HIV infection.