Acquired Immunodeficiency Syndrome: Gazzard BG

Yeni PG, Hammer SM, Carpenter CC, Cooper DA, Fischl MA, Gatell JM, Gazzard BG, Hirsch MS, Jacobsen DM, Katzenstein DA, Montaner JS, Richman DD, Saag MS, Schechter M, Schooley RT, Thompson MA, Vella S, Volberding PA. · Hôpital Bichat-Claude Bernard, Department of Infectious Diseases, 46 Rue Henri-Huchard, Paris, Cedex 18 France 75877. · JAMA. · Pubmed #12095387 No free full text.

Abstract: OBJECTIVE: New information warrants updated recommendations for the 4 central issues in antiretroviral therapy: when to start, what drugs to start with, when to change, and what to change to. These updated recommendations are intended to guide practicing physicians actively involved in human immunodeficiency virus (HIV)- and acquired immunodeficiency syndrome (AIDS)-related care. PARTICIPANTS: In 1995, physicians with specific expertise in HIV-related basic science and clinical research, antiretroviral therapy, and HIV patient care were invited by the International AIDS Society-USA to serve on a volunteer panel. In 1999, others were invited to broaden international representation. The 17-member panel met regularly in closed meetings between its last report in 2000 and April 2002 to review current data. The effort was sponsored and funded by the International AIDS Society-USA, a not-for-profit physician education organization. EVIDENCE AND CONSENSUS PROCESS: The full panel was convened in late 2000 and assigned 7 section committees. A section writer and 3 to 5 section committee members (each panel member served on numerous sections) identified relevant evidence and prepared draft recommendations. Basic science, clinical research, and epidemiologic data from the published literature and abstracts from recent (within 2 years) scientific conferences were considered by strength of evidence. Extrapolations from basic science data and expert opinion of the panel members were included as evidence. Draft sections were combined and circulated to the entire panel and discussed in a series of full-panel conference calls until consensus was reached. Final recommendations represent full consensus agreement of the panel. CONCLUSIONS: Because of increased awareness of the activity and toxicity of current drugs, the threshold for initiation of therapy has shifted to a later time in the course of HIV disease. However, the optimal time to initiate therapy remains imprecisely defined. Availability of new drugs has broadened options for therapy initiation and management of treatment failure, which remains a difficult challenge.

Phillips AN, Gazzard BG, Clumeck N, Losso MH, Lundgren JD. · Department of Primary Care and Population Sciences, Royal Free and University College Medical School, London NW3 2PF. · BMJ. · Pubmed #17218713 No free full text.

This publication has no abstract.

Stebbing J, Wildfire A, Portsmouth S, Powles T, Thirlwell C, Hewitt P, Nelson M, Patterson S, Mandalia S, Gotch F, Gazzard BG, Bower M. · Departments of Oncology and HIV Medicine, Chelsea and Westminster Hospital, London, UK. · Ann Oncol. · Pubmed #14581275 links to  free full text

Abstract: BACKGROUND: Murine data indicate that angiogenesis is central to the aetiopathogenesis of Kaposi's sarcoma (KS). Therefore, we measured angiogenic cytokines and growth factors in patients with AIDS-related KS during treatment with both antiretrovirals and second-line paclitaxel chemotherapy. Cytokines measured included tumour necrosis factor-alpha (TNF-alpha), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and the interleukins IL-2, -6 and -12. PATIENTS AND METHODS: Enzyme-linked immunosorbent assays (ELISAs) were carried out to measure plasma cytokine levels in 17 patients with AIDS-related KS who had progressed within 6 months of receiving liposomal anthracyclines and were treated with paclitaxel 100 mg/m(2) every 2 weeks. Measurements were carried out before progression, at commencement and at the completion of paclitaxel. RESULTS: The objective response rate to paclitaxel was 71% (95% confidence interval 60% to 81%). In 17 patients with AIDS-related KS, we observed eight partial responses and four complete responses. Patients with AIDS Clinical Trial Group stage T1 disease had higher plasma VEGF (P = 0.05) and lower plasma TNF-alpha levels (P = 0.05) than patients with earlier stage T0 KS. There were no correlations between plasma cytokines (bFGF, VEGF, TNF-alpha, and IL-2,-6 and -12) and the CD4 and CD8 cell counts or HIV-1 RNA viral load. Response to paclitaxel was associated with a fall in plasma IL-6 levels (P = 0.04) but no change in other cytokines. There were no significant changes in CD4, CD8, CD16/56, CD19 cell counts and HIV-1 viral loads during chemotherapy. CONCLUSIONS: Angiogenic cytokines may correlate with KS disease extent but not with cellular immune function or HIV viraemia. Response to paclitaxel therapy correlates with a fall in plasma IL-6 levels and recent data indicate this may be a surrogate marker of KS-associated herpesvirus viral load. Overall, clinical response in KS correlates poorly with known angiogenic cytokines.

Miao YM, Hayes PJ, Gotch FM, Barrett MC, Francis ND, Gazzard BG. · HIV/GUM Directorate, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, United Kingdom. · J Infect Dis. · Pubmed #11930313 No free full text.

Abstract: Reduced intestinal CD4 T cell numbers and gastrointestinal disease are common features of acquired immunodeficiency syndrome (AIDS). Duodenal lymphocyte densities and mucosal addressin cell adhesion molecule (MAdCAM)-1 expression were analyzed in patients with AIDS after highly active antiretroviral therapy (HAART). Compared with human immunodeficiency virus (HIV)-seronegative individuals, HAART-naive patients with AIDS displayed reduced duodenal CD4 T cell densities. After HAART, AIDS patients with opportunistic intestinal pathogens displayed greater increases in duodenal lamina propria (LP) CD4 T cell densities than patients without such infections. Duodenal MAdCAM-1 expression was elevated in all HAART-naive patients with AIDS but remained elevated only in the intestinal pathogen group after HAART. The data suggest that, in HIV-1 infection, lymphocyte migration to the intestine may be promoted by increased MAdCAM-1 expression. After HAART, opportunistic intestinal pathogens maintain elevated MAdCAM-1 expression, which results in prominent increases in LP CD4 T cell densities in the absence of HIV-mediated CD4 T cell destruction.

Thomas PD, Pollok RC, Gazzard BG. · Department of HIV/GUM Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. · HIV Med. · Pubmed #11737325 No free full text.

Abstract: BACKGROUND AND AIMS: The role of non-cytomegalovirus (CMV) enteric viral infection in causing diarrhoea in patients with human immunodeficiency virus (HIV) is poorly understood. We aimed to investigate the prevalence of these infections in acute and chronic diarrhoea. METHODS: Stool specimens from 377 HIV-infected patients presenting with diarrhoea were studied prospectively for evidence of non-CMV enteric viral infection. Patients with diarrhoea underwent investigation for gastrointestinal pathogens, including electron microscopic examination of stool for enteric viruses. We collected data on patients in whom enteric virus was identified and examined the association of enteric virus infection with diarrhoeal symptomatology. RESULTS: Eighty-nine (10.3%) stool specimens from 60 (15.9%) HIV+ individuals were positive for coronavirus (n = 13, 22%), rotavirus (n = 11, 18%), adenovirus (n = 30, 50%) and small round structured viruses (n = 5, 8%) or dual infection (n = 2, 3%). Thirty-four of 52 (65%) patients available for analysis had acute diarrhoea, and 18/52 (35%) had chronic diarrhoea. Twenty-three of 52 (44%) patients had a concurrent gut pathogen. After exclusion of concurrent pathogens enteric viral infections were found to be significantly associated with acute as opposed to chronic diarrhoea (P = 0.004). The presence of adenovirus colitis was significantly more likely to be associated with chronic diarrhoea (15/21 cases) than adenovirus isolated from stool alone (9/23 cases) (P = 0.03). There was a trend towards an association between adenovirus colitis and colonic cytomegalovirus infection (P = 0.06). CONCLUSION: Enteric viral infection is strongly associated with acute diarrhoea in patients with HIV. Light microscopic examination of large bowel biopsies can identify adenovirus colitis which is significantly associated with chronic diarrhoea, and in addition may facilitate gastrointestinal co-infection with CMV.

Walsh JC, Horne R, Dalton M, Burgess AP, Gazzard BG. · St. Stephen's Centre, Chelsea & Westminster Healthcare NHS Trust, London, UK. · AIDS Care. · Pubmed #11720641 No free full text.

Abstract: The objective of the study was to define common reasons for non-adherence (NA) to highly active antiretroviral therapy (HAART) and the number of reasons reported by non-adherent individuals. A confidential questionnaire was administered to HIV-seropositive patients taking proteinase inhibitor based HAART. Median self-reported adherence was 95% (n = 178, range = 60-100%). The most frequent reasons for at least 'sometimes' missing a dose were eating a meal at the wrong time (38.2%), oversleeping (36.3%), forgetting (35.0%) and being in a social situation (30.5%). The mean number of reasons occurring at least 'sometimes' was 3.2; 20% of patients gave six or more reasons; those reporting the lowest adherence reported a significantly greater numbers of reasons (rho = - 0.59; p < 0.001). Three factors were derived from the data by principal component analysis reflecting 'negative experiences of HAART', 'having a low priority for taking medication' and 'unintentionally missing doses', accounting for 53.8% of the variance. On multivariate analysis only the latter two factors were significantly related to NA (odds ratios 0.845 and 0.849, respectively). There was a wide spectrum of reasons for NA in our population. The number of reasons in an individual increased as adherence became less. A variety of modalities individualized for each patient are required to support patients with the lowest adherence.

Ives NJ, Gazzard BG, Easterbrook PJ. · Academic Department of HIV/GU Medicine, The Guy's, King's and St. Thomas' School of Medicine, Weston Education Centre, King's College Hospital, Cutcombe Road, London, SE5 9RT, UK. · J Infect. · Pubmed #11531320 No free full text.

Abstract: OBJECTIVES: To quantify the progressive impact of combination antiretroviral therapy (ART) on the incidence of AIDS-defining illnesses (ADIs) over a 9-year period. METHODS: Retrospective cohort study. Eligible patients were 1538 AIDS-free, HIV-1-positive patients attending a large HIV clinic in west London who were at risk of developing AIDS because their CD4 count had declined to < or =350 x 10(6)/l cells during the period 1 January 1990 and 31 December 1998. Incidence rates for the 12 most frequent ADIs were compared for two time periods, 1990-1995 (pre-HAART) and 1996-1998 (post-HAART), using Poisson regression methods. Multivariate Poisson regression models were used to examine the contribution of ART and HAART to any observed temporal trends in incidence rates. RESULTS: After a median follow-up of 35 months, 450 (29%) patients had developed AIDS. Between the two time periods there was a significant decrease in the incidence of Pneumocystis carinii pneumonia (PCP) by 35% (4.11 per 100 person-years in 1990-1995 vs. 2.67 in 1996-1998;P= 0.007), Kaposi's sarcoma by 34% (3.27 vs. 2.17;P= 0.022) and cryptosporidiosis by 60% (0.76 vs. 0.31;P= 0.029). A non-significant reduction in incidence was observed for cryptococcosis by 45% (0.81 vs. 0.45;P= 0.11), oesophageal candidiasis by 29% (3.34 vs. 2.39;P= 0.053) and mycobacterium avium complex by 18% (1.58 vs. 1.29;P= 0.4), and a non-significant increase was observed for tuberculosis by 17% (0.62 vs. 0.73;P= 0.66) and non-Hodgkins lymphoma (NHL) by 51% (0.43 vs. 0.65;P= 0.31). The incidence of cerebral toxoplasmosis, cytomegalovirus, recurrent bacterial chest infections and dementia remained stable. There was a clear stepwise reduction in the incidence of PCP, Kaposi's sarcoma and cryptosporidiosis with the use of non-H AART and HAART regimens relative to no ART. In a multivariate analysis, the use of ART and HAART explained the progressive decrease in incidence of PCP and Kaposi's sarcoma. CONCLUSIONS: The incidence of most ADIs has decreased over the last 9 years. The striking reduction in the inci-dence of PCP and Kaposi's sarcoma since 1996 can be attributed to the use of combination ART and particularly HAART. The non-significant increase in the incidence of NHL and tuberculosis needs confirmation in other patient cohorts.

Pearson IC, Baker R, Sullivan AK, Nelson MR, Gazzard BG. · Department of HIV Medicine, Chelsea & Westminster Hospital, Fulham Road, London SW10 9NH, UK. · Int J STD AIDS. · Pubmed #11368827 No free full text.

Abstract: Meningococcal infection is believed to be rare in HIV-positive individuals. We present 2 cases from our reference caseload within the last 10 years.

Psychd ST, Troop M, Burgess AP, Button J, Goodall R, Flynn R, Gazzard BG, Catalán J, Easterbrook PJ. · Psychological Medicine Unit, South Kensington & Chelsea Mental Health Centre, Chelsea & Westminster Hospital, London, UK. · Int J STD AIDS. · Pubmed #11089788 No free full text.

Abstract: This study investigated the contribution of psychological factors to disease progression among long-term HIV-1 infected gay men. Participants completed self-report measures including coping strategies, life events, social support, personality and psychological morbidity and were followed clinically for up to 30 months. Cox proportional hazards survival analyses were carried out to CD4<200 x 106/1 and AIDS-related complex (ARC) or AIDS diagnosis controlling for viral load, antiretroviral drug use and CD4 count. Only acceptance coping was a significant predictor of time to ARC or AIDS diagnosis: the risk of ARC or AIDS was almost 5 times greater for those scoring within the lowest tertile compared with those scoring in the highest tertile (HR=4.7, 95% CI 1.8-12.3).

Matthews GV, Bower M, Mandalia S, Powles T, Nelson MR, Gazzard BG. · Department of HIV Medicine, Chelsea and Westminster Hospital, London, United Kingdom. · Blood. · Pubmed #11023505 links to  free full text

Abstract: 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)

Neild PJ, Amadi A, Ponikowski P, Coats AJ, Gazzard BG. · Cardiac Department, Fazakerley Hospital, Liverpool, UK. · Int J Cardiol. · Pubmed #10962112 No free full text.

Abstract: OBJECTIVE: Heart rate variability (HRV) is a marker of cardiovascular autonomic tone, and is also known to be reduced in association with cardiac dysfunction. Abnormal autonomic function tests are common in HIV infected individuals, but the contribution of heart disease to such findings is not known. Spectral analysis of heart rate variability is a sensitive technique for measurement of cardiovascular autonomic function, which also allows differential assessment of parasympathetic and sympathetic components. The aim of this study was to characterise the nature of autonomic dysfunction in patients with AIDS and to compare our findings with those seen in HIV seronegative patients with established heart disease. METHODS: HRV was measured prospectively by spectral analysis in 10 subjects with dilated cardiomyopathy (age 45.7+/-6.9 years), 10 subjects with AIDS and no clinical evidence of heart disease (age 37.9+/-5.4 years), and 10 healthy HIV seronegative controls (age 41.7+/-13.9 years). RESULTS: All components of HRV were reduced in subjects with cardiomyopathy (P<0.005), and markedly so in subjects with AIDS (P<0. 0001) compared with controls. CONCLUSIONS: HIV infection may be associated with severe global autonomic dysfunction, which is not related to heart disease.

Hayes PJ, Miao YM, Gotch FM, Gazzard BG. · Department of Immunology, Imperial College School of Medicine, London, UK. · Clin Exp Immunol. · Pubmed #10444267 links to  free full text

Abstract: CD4 and CD8 lymphocyte numbers in the gut lamina propria are grossly altered in HIV-1 infection, out of proportion to alterations in the circulation. Such alterations in lymphocyte counts in the tissues may be due to altered leucocyte migration from the blood. One factor affecting leucocyte migration is adhesion molecule expression. Levels of adhesion molecule expression on peripheral CD4 and CD8 lymphocytes, monocytes and neutrophils from HIV-1-infected (AIDS and non-AIDS) and low-risk control individuals were compared. CD11a, CD62L, CD44, CD49d and beta7 integrin expression were examined by FACS analysis of fresh whole blood. Significant alterations in adhesion molecule expression were detected in HIV infection. The most striking alterations were observed in the CD8 lymphocyte population. CD11a expression was increased and CD62L and CD44 decreased. The CD4 lymphocyte population followed a similar, though less striking, pattern of alteration in adhesion molecule expression. Neutrophils displayed significantly reduced expression of both CD11a and CD62L, but only after onset of AIDS. Monocytes from infected individuals without AIDS displayed a different pattern of altered adhesion molecule expression compared with individuals with AIDS. These findings suggest that in HIV infection, leucocyte functions, such as migration, which require adhesion molecules are abnormal.

Davis PA, Corless DJ, Gazzard BG, Wastell C. · Department of Academic Surgery, Chelsea and Westminster Hospital, London, UK. · Dig Surg. · Pubmed #9949269 No free full text.

Abstract: The number of individuals in the UK who are HIV seropositive is increasing as is their presentation with abdominal complications. Poor wound healing following anorectal surgery in HIV-positive patients has been well reported. This study reviews the incidence of wound complications following laparotomy. The hospital records of all HIV-positive patients who underwent laparotomy at a London teaching hospital over a 10-year period were reviewed and compared to an equal number of matched non-HIV patients. Between April 1986 and April 1996, 64 laparotomies were carried out on 53 patients. There was a significantly greater incidence of wound complications (chi2 = 12.75, 1 d.f., p = 0.0003) and wound breakdown (chi2 = 10.45, 1 d.f., p = 0.012) in the HIV group following laparotomy than in the non-HIV control group.