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Biomedical subjects

B Gazzard

Publications and source records attributed to B Gazzard.

At least 73 records · Page 4Linked to original sources
PubMed1999

Highly active anti-retroviral therapy (HAART) prolongs time to treatment failure in Kaposi's sarcoma.

OBJECTIVE: To evaluate the impact of highly active antiretroviral therapy (HAART) on Kaposi's sarcoma. DESIGN: Retrospective study of patients who had received systemic or local treatment for AIDS-related Kaposi's sarcoma who subsequently commenced HAART. METHODS: Case note review to determine time to treatment failure for Kaposi's sarcoma before and after starting HAART. Time to treatment failure was calculated from the end of last therapy to the start of the next new treatment for Kaposi's sarcoma. RESULTS: The cohort contained 78 patients. Only 38% had good risk Kaposi's sarcoma (stage T0I0) at presentation. The median time to treatment failure before starting HAART was 0.5 years. Initial HAART therapy was three or more drugs including a protease inhibitor for 38 (49%), three or more drugs without a protease inhibitor for 27 (35%) and a two-drug protease combination for 13 (16%). The median follow-up after starting HAART was 12 months (range, 0.5-52 months) and anti-Kaposi's sarcoma treatment has been required for 24 (31%) patients. The median time to treatment failure for Kaposi's sarcoma from the start of HAART is 1.7 years. This is statistically longer than the time to treatment failure for the same cohort of patients before they started HAART (log rank chi2 = 16.5, P < 0.0001). The serum HIV RNA viral load (VL) at the time of Kaposi's sarcoma progression revealed virological failure of HAART (defined as VL > 5000 copies/ml) in 14 of 24 (58%) and good control (VL < 200 copies/ml) in five of 24 (21%). CONCLUSION: HAART is associated with prolonged time to treatment failure in Kaposi's sarcoma. Progression of Kaposi's sarcoma while on HAART is not necessarily associated with virological failure as determined by rising viral RNA titre.

Adult↗
PubMed1999

The influence of nutritional and metabolic status on progression from asymptomatic HIV infection to AIDS-defining diagnosis.

BACKGROUND: Changes in body weight and lean tissue increase morbidity and mortality during AIDS; however there are few data on the effect of alterations in nutrition and metabolism on disease progression at earlier stages of HIV infection. OBJECTIVES: To assess whether change in weight, lean tissue or skeletal muscle affects progression to AIDS; to assess prospectively the effects of recognized alterations in nutrition and metabolism in asymptomatic HIV-seropositive men on disease progression; and to examine prospectively changes in nutrition and metabolism at AIDS-defining diagnosis. METHODS: A group of 104 asymptomatic HIV-seropositive men were recruited and prospectively examined at 3-monthly intervals between April 1993 and September 1995. Nutritional status and metabolism were examined using indirect calorimetry, dual energy X-ray absorptiometry and urine excretion of simple sugars. Time-fixed and time-dependent Cox's proportional hazard models were fitted to calculate risks of developing a first AIDS diagnosis, weight loss or death. RESULTS: During the study period, 31 subjects had a first AIDS diagnosis of whom 26 were fully assessed. Changes in nutrition and metabolism do not affect disease progression in asymptomatic HIV infection. However, subjects with a reduction in body weight and basal metabolic index tend to have a higher risk of progression to AIDS-defining diagnosis, independent of CD4 count. There is a significant decrease in all body tissue compartments, a decrease in excretion of urinary sugars and significant increase in resting energy expenditure and fat oxidation associated with a first AIDS diagnosis. CONCLUSION: Change in metabolic and nutritional status at the asymptomatic stage of HIV infection does not influence disease progression significantly, although there is a trend suggesting weight loss has an independent effect on outcome. There is a cachectic response to AIDS-defining opportunistic infection or tumour.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Induction of HIV-1-specific T cell responses by administration of cytokines in late-stage patients receiving highly active anti-retroviral therapy.

Highly active anti-retroviral therapy (HAART) is associated with reduction in the morbidity and mortality of patients with advanced HIV-1 disease. The ability of such treatment to improve immune responses against HIV-1 and opportunistic pathogens is variable and limited. Addition of cytokine immunotherapy to this treatment may improve immune responses. IL-2 with or without granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered to HIV-1+ individuals receiving HAART with undetectable viral loads, and CD4 counts < 100 cells/microl. In one patient presenting with Mycobacterium avium complex (MAC) infection, we evaluated the effect of cytokine immunotherapy on lymphocyte phenotype; plasma viral load; proliferative responses to mitogens, recall and HIV-1 antigens; cytokine production and message in response to non-specific and specific stimuli; and natural killer (NK) cell activity. Proliferation assays were performed in two similar patients. Before cytokine immunotherapy the predominant CD8+ population was mainly CD28-. No proliferation or IL-2 production was seen in response to mitogens, recall or HIV-1 antigens; and no HIV-1 peptide-specific interferon-gamma (IFN-gamma)-secreting cells were present. Low levels of IL-4 were detected in response to antigens to which patients had been exposed, associated with up-regulated expression of costimulatory molecules influenced by IL-4. Following IL-2 administration, loss of IL-4 was associated with increased NK cell activity and HIV-1 peptide-specific and non-specific IFN-gamma-producing cells. Proliferative responses associated with IL-2 production and responsiveness were only seen after subsequent concomitant administration of GM-CSF with IL-2. These changes mirrored clinical improvement. An imbalance of lymphocyte subsets may account for immune unresponsiveness when receiving HAART. Restoration of responses following immunotherapy suggests a shift towards a lymphocyte profile with anti-pathogen activity.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Identification of human herpesvirus 8-specific cytotoxic T-cell responses.

Human herpesvirus 8 (HHV-8) (or Kaposi's sarcoma-associated herpesvirus) is implicated in the etiopathogenesis of Kaposi's sarcoma (KS) and certain lymphoproliferations. The introduction of more effective therapies to treat human immunodeficiency virus infection has led to a decline in the incidence of KS and also in the resolution of KS in those already affected. This suggests that cellular immune responses including cytotoxic T lymphocytes (CTLs) could play a vital role in the control of HHV-8 infection and in KS pathogenesis. Here we elucidate HLA class I-restricted, HHV-8-specific cellular immune responses that could be important in the control of HHV-8 infection and subsequent tumor development. We show the presence of CTLs against HHV-8 latent (K12), lytic (K8.1), and highly variable (K1) proteins in infected individuals.

AIDS-Related Opportunistic Infections↗
PubMed1999

Small intestinal transit, absorption, and permeability in patients with AIDS with and without diarrhoea.

BACKGROUND: Diarrhoea in AIDS is associated with anorexia and weight loss. The importance of gastrointestinal transit in such symptoms has not been addressed. AIMS: To assess jejunal to caecal transit times in subjects with AIDS related diarrhoea and weight loss and correlate these with measures of absorptive capacity and intestinal permeability. METHODS: Jejunal to caecal transit times were assessed in 20 seronegative controls and 60 HIV seropositive subjects from serum analysis of 3-O-methyl-D-glucose and sulphapyridine after ingestion of the monosaccharide and sulphasalazine in aqueous solution. The method also allows an estimation of gastric emptying times for liquids. Intestinal absorptive capacity and permeability were assessed by a combined test using 3-O-methyl-D-glucose, D-xylose, L-rhamnose, and lactulose. RESULTS: Gastric emptying was significantly delayed in all groups of patients with AIDS. Mean jejunal to caecal transit times were not significantly different between controls (246 (62) minutes) and patients without diarrhoea (AIDS, well: 278 (103) minutes; AIDS, wasting: 236 (68) minutes), cytomegalovirus colitis (289 (83) minutes), pathogen negative diarrhoea (192 (100) minutes), or microsporidiosis (190 (113) minutes), although 30% of patients had values below the control range. Patients with cryptosporidiosis differed significantly from controls (135 (35) minutes, p<0.0001), seven of 10 having rapid transit times. Absorptive capacity was reduced and intestinal permeability significantly increased in AIDS, but did not correlate significantly with transit times. CONCLUSION: Small bowel transit is accelerated in many patients with AIDS, particularily in protozoal diarrhoea, but is not the sole explanation for malabsorption of monosaccharides.

AIDS-Related Opportunistic Infections↗
PubMed1999

Erythrocyte glutathione deficiency in symptom-free HIV infection is associated with decreased synthesis rate.

Although several studies have documented intra- and extracellular glutathione (GSH) deficiency in asymptomatic human immunodeficiency virus (HIV) infection, the mechanisms responsible for the altered GSH homeostasis remain unknown. To determine whether decreased synthesis contributes to this alteration of GSH homeostasis, a primed-constant infusion of [2H2]glycine was used to measure the fractional and absolute rates of synthesis of GSH in five healthy and five symptom-free HIV-infected subjects before and after supplementation for 1 wk with N-acetylcysteine. The erythrocyte GSH concentration of the HIV-infected group was lower (P < 0.01) than that of the control group (1.4 +/- 0.16 vs. 2.4 +/- 0.08 mmol/l). The smaller erythrocyte GSH pool of the HIV-infected group was associated with a significantly slower (P < 0.01) absolute synthesis rate of GSH (1.15 +/- 0.14 vs. 1.71 +/- 0.15 mmol. l-1. day-1) compared with controls. Cysteine supplementation elicited significant increases in both the absolute rate of synthesis and the concentration of erythrocyte GSH. These results suggest that the GSH deficiency of HIV infection is due in part to a reduced synthesis rate secondary to a shortage in cysteine availability.

Acetylcysteine↗
PubMed1999

The acute-phase protein response to human immunodeficiency virus infection in human subjects.

Although several studies have shown that asymptomatic human immunodeficiency virus infection elicits an increase in whole body protein turnover, it is not known whether this increased protein turnover includes changes in the kinetics of acute-phase proteins (APPs). To answer this question, we measured 1) the plasma concentrations of four positive (C-reactive protein, alpha1-antitrypsin, haptoglobin, and fibrinogen) and four negative APPs [albumin, high-density lipoprotein (HDL)-apolipoprotein (apo) A1, transthyretin, and retinol-binding protein] and 2) the fractional (FSR) and absolute (ASRs) synthesis rates of three positive and three negative APPs using a constant intravenous infusion of [2H5]phenylalanine in five subjects with symptom-free acquired immunodeficiency syndrome (AIDS) and five noninfected control subjects. Compared with the values of the controls, the plasma concentrations, FSRs, and ASRs of most positive APPs were higher in the AIDS group. The negative APPs had faster FSRs in the AIDS group, there was no difference between the ASRs of the two groups, and only HDL-apoA1 had a lower plasma concentration. These results suggest that symptom-free AIDS elicits an APP response that is different from bacterial infections, as the higher concentrations and faster rates of synthesis of the positive APPs are not accompanied by lower concentrations and slower rates of synthesis of most of the negative APPs.

Acute-Phase Proteins↗
PubMed1999

The picture of future therapy.

Highly active antiretroviral therapy (HAART) consisting of 2 nucleoside reverse transcriptase inhibitors (NRTIs) in combination with a protease inhibitor (PI) or a non nucleoside reverse transcriptase inhibitor (NNRTI) is now regarded as the standard of care in the treatment of HIV infection. However, over the next few years it is anticipated that clinician will become increasingly concerned with the quality of clinical data, the cost of treatment and virological failure. Several causes of virological failure have already been identified including compliance, toxicity, pharmacokinetic interactions, resistance and lack of potency. Many studies have been performed to investigate new combination regimens and new drugs to find solutions to these problems. In addition, new targets for antiviral drugs are also being investigated.

Drug Therapy, Combination↗
PubMed1999

Interactive debate.

An interactive voting session at the end of the European symposium on evolving therapies provided an opportunity for panel discussion on various therapeutic options based on a series of case studies. The interactive voting and subsequent discussion focused on the preferred options for first-line, second-line and salvage therapy. In addition, issues of compliance and drug resistance were addressed. All case studies were entirely hypothetical and were projected into the future when it is anticipated that today's investigational drugs are likely to be available for general use.

Anti-HIV Agents↗
PubMed1998

1998 revision to the British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals. BHIVA Guidelines Writing Committee.

When the British HIV-1 Association (BHIVA) guidelines on the treatment of HIV-seropositive individuals with antiretrovirals were published in The Lancet in April 1997, it was clear that they would require updating on a frequent basis. The guidelines have been useful in ensuring that viral-load testing and combination therapy is widely available in the UK. However, standards of treatment are rapidly changing as new evidence becomes available. Since formulation of the guidelines, data from two large clinical endpoint studies have been presented that show superior clinical benefit for the use of triple therapy compared with dual therapy in treatment of both naive individuals and patients who have been given zidovudine. Here we update the BHIVA guidelines with a consensus drawn from a wide range of UK medical opinion. The guidelines include input from groups representing individuals living with HIV-1. A more detailed reflection of these views may be found in publications such as the National AIDS Manual and the AIDS Treatment Project's Doctor fax.

Anti-HIV Agents↗
PubMed1998

The incidence of AIDS-defining illnesses in 4883 patients with human immunodeficiency virus infection. Royal Free/Chelsea and Westminster Hospitals Collaborative Group.

BACKGROUND: Acquired immunodeficiency syndrome (AIDS)-defining illnesses are known to occur at different levels of immunosuppression, and the incidence of diagnoses may also vary according to the CD4 lymphocyte count strata. Information about the incidence of disease at different levels of immunosuppression would help clinicians monitoring patients and would allow prophylaxis to be targeted at the most appropriate population. METHODS: Between 1982 and July 1995, 4883 patients testing positive for the human immunodeficiency virus were seen at either the Royal Free or Chelsea and Westminster Hospitals in London, England. The incidence of each diagnosis, both overall and stratified by CD4 lymphocyte count, was calculated using a person-years analysis. Patients who had no CD4 lymphocyte counts measured during follow-up were excluded from the analysis. RESULTS: During a median follow-up period of 27.6 months, 3875 AIDS-defining illnesses were reported in 1713 patients. The incidence of AIDS-defining illnesses ranged from 6.22 per 100 person-years of follow-up for Pneumocystis carinii pneumonia (95% confidence interval, 5.74-6.70) to 0.37 for extrapulmonary tuberculosis (95% confidence interval, 0.26-0.48). The incidence of each AIDS-defining illness increased as the CD4 lymphocyte count declined; diagnoses such as cytomegalovirus and Mycobacterium avium-intracellulare complex infection had a low incidence at CD4 lymphocyte counts above 0.05x10(9)/L (50/mm3), while Kaposi sarcoma, P carinii pneumonia, and esophageal candidiasis had a high incidence throughout all CD4 lymphocyte count strata. CONCLUSIONS: This study provides important information about the risk of AIDS-defining illnesses at lower CD4 lymphocyte counts, enabling disease-specific prophylaxis to be targeted at the most appropriate population. In the future, as more prophylactic therapies are developed, this study will provide historical data of the incidence of diseases before specific prophylaxis was introduced.

AIDS-Related Opportunistic Infections↗
PubMed1998

Summary of the II International Symposium on Cytomegalovirus.

Human cytomegalovirus (HCMV) is a highly species-specific DNA virus belonging to the Betaherpesvirinae subfamily of the herpesviridae family. Like other herpesviruses, primary infection with HCMV is followed by persistence of the virus in a latent form. The sites of latency are still largely undefined, but they probably include bone marrow progenitor cells and peripheral blood monocytes. From these sites, the virus can reactivate, resulting in renewed shedding of the virus, or, in immunocompromized persons, development of disease. Humans are the only reservoir of HCMV and transmission occurs by person-to-person contact. Infection with HCMV is common. In most developed countries, HCMV seroprevalence steadily increases after infancy and 10-20% of children are infected before puberty. In adults, the prevalence of antibodies ranges from 40 to 100%. Although HCMV has a world-wide distribution, infection with HCMV is more common in the developing countries and in areas of low socioeconomic conditions, which is predominantly related to the closeness of contacts within these populations. Except for a mononucleosis-like illness in some persons, infection with HCMV rarely causes disease in immunocompetent individuals. However, HCMV can cause severe morbidity and mortality in congenitally infected newborns and immunocompromized patients, most notably transplant-recipients and HIV-infected persons. This article provides a review of the information presented at the Second International Symposium on Cytomegalovirus organized and convened by The Macrae Group (New York City, NY) in Acapulco, Mexico on 24-28 April 1998. During this symposium, the state-of-the-art knowledge on diagnosis, treatment and prophylaxis of HCMV infections were discussed, and, based on this information, attempts to highlight the future directions in basic and clinical research areas that need to be stimulated to facilitate advancement in prevention and treatment of CMV disease.

AIDS-Related Opportunistic Infections↗
PubMed1998

Cytomegalovirus (CMV) infection in AIDS patients is associated with a CD3 receptor-mediated T cell hyporesponsiveness.

HIV+ individuals with human CMV (HCMV) reactivation have a CD3 receptor-mediated T cell hyporesponsiveness when compared with CD4-matched HIV+ and HCMV- control groups. The impairment of proliferation was not reversed by exogenous IL-2. A typical increase in NFkappaB expression was observed following cross-linking of the CD3 receptor, but did not lead to increased CD25 cell surface expression or cell proliferation. The HCMV-induced non-responsiveness was not observed when cells were stimulated with phorbol esters. Lymphocytes cultured with media collected from cell cultures infected with HCMV showed a dose-dependent inhibition in the total T cell population even though cells staining dually for CD8/57 increased in number. The altered growth factor requirements of CD8/57+ cells may therefore account for their presence in AIDS and patients following bone marrow transplantation.

AIDS-Related Opportunistic Infections↗