Impact of anti-retroviral therapy and pneumocystis carinii pneumonia prophylaxis on the pattern of AIDS illnesses and AIDS survival in the Western Australian HIV Cohort Study: 1983 - 1992

OBJECTIVE: To evaluate the impact of antiretroviral therapy (ART) and Pneumocystis prophylaxis use on (a) the incidence of Pneumocystis carinii pneumonia (PCP) and CD4+ T-cell counts at AIDS, (b) the patterns of AIDS illnesses and (c) survival after AIDS. DESIGN: Prospective, longitudinal, observational study of all 230 patients diagnosed with AIDS in Western Australia to 1 January 1993. RESULTS: Of 230 patients with AIDS, 74 (32%) had begun both ART and PCP prophylaxis before AIDS and 135 (59%) had received neither therapy before AIDS. Patients treated with ART and PCP prophylaxis were less likely than untreated patients to have PCP as the first AIDS diagnosis (treated 28% versus non-treated 60%, p = 0.0001 Fisher's exact test) and once this was taken into account were also less likely to have Kaposi's sarcoma (KS) (17% versus 42.5%, p = 0.0003). Following adjustment for the reduction in PCP and KS the distribution of other AIDS illnesses was similar in the treated and untreated groups. In multivariate models treatment with ART and PCP prophylaxis before AIDS was associated with reduction in PCP as the first AIDS illness (p Acquired Immunodeficiency Syndrome/*DRUG THERAPY/IMMUNOLOGY/ MORTALITY Antiviral Agents/*THERAPEUTIC USE Australia/EPIDEMIOLOGY AIDS-Related Opportunistic Infections/COMPLICATIONS/*PREVENTION & CONTROL Cohort Studies CD4 Lymphocyte Count Human Longitudinal Studies Pneumonia, Pneumocystis carinii/COMPLICATIONS/*PREVENTION & CONTROL Prospective Studies Survival Rate

The clinical utility of measuring cutaneous delayed-type hypersensitivity (DTH) responses in HIV-infected patients

Aim: To determine the value of and indications for measuring cutaneous DTH responses to evaluate cellular immune function in HIV-infected patients. Methods: Data on DTH responses, CD4 T-cell percentages and opportunistic infections (OIs) were analysed from patients in the Western Australian HIV Cohort Study (WAHCS) database. DTH responses were measured using the Multitest CMI method and results expressed as a Multitest score. Results: Multitest scores declined progressively in all patients who developed AIDS with the greatest decline commencing at about 20-25% CD4 T-cells. By multivariate analysis DTH had prognostic value in predicting the time to both AIDS and death independantly of %CD4 T-cells, particularly in patients with 10-19% CD4 T-cells RH=0.728 per 5mm for both, p=0.002 and 0.004 respectively). Furthermore, patients with a Multitest score of greater than 5 n=127) at the time of first reaching less than 20% CD4 T-cells, had a median survival of 70.7 months compared with 36.5 months in patients with a Multitest score of less than 5 (n=83) [p=0.0016, log rank test]. Measurement of Multi-test scores in 68 patients at or within the 50 days prior to developing an OI demonstrated that 73% of 41 patients with pneumocystis pneumonia (PCP) were anergic, including 3 with greater than 20% and 5 with 10-20% CD4 T-cells. All but one of the other PCP patients has a Multitest score of less than 5. Multi-test scores in patients with greater than 10% CD4 T-cells who developed PCP were significantly lower than in randomly selected patients matched for %CD4 T-cells who had never had an OI (p is less than 0.05, Mann-Whitney). In patients with OIs other than PCP (n=27), 89% had Multitest scores of less than 5 but all except one, who had tuberculosis, also had less than 10% CD4 T-cells. Conclusion: Measurement of DTH responses has additional value to quantitation of CD4 T-cells in determining (a) the prognosis of HIV-infected patients1, and (b) the susceptibility of patients to PCP, especially patients with 10-20% CD4 T-cells, as well as having clinical utility in demonstrating restoration of cell-mediated immunity (CMI) by zidovudine2, including CMI to pathogenic mycobacteria3,4

Delayed type hypersensitivity (DTH) responses to tuberculin after zidovudine in immunodeficient HIV infected patients predict subsequent mycobacterium avium intracellulare infection

No abstract availabl

Detection of subclinical Mycobacterium avium intracellulare complex infection in immunodeficient HIV-infected patients treated with zidovudine

Objective: To test the hypothesis that subclinical Mycobacterium avium intracellulare complex (MAC) infection may result in the development of a tuberculin response in immunodeficient HIV-infected individuals treated with zidovudine. Design: Longitudinal, observational study. Setting: The Western Australian HIV Cohort Study; a prospective, single centre, population-based observational study of the natural history of HIV disease. Patients: Forty-nine patients with impaired delayed-type hypersensitivity (DTH) responses and negative tuberculin responses in whom DTH responses were augmented within 6 months of starting zidovudine therapy. Outcome measures: Progression to disseminated MAC infection stratified according to the presence or absence of a tuberculin response in the first 6 months of zidovudine therapy. Results: Twenty-nine of the patients developed a post-zidovudine tuberculin response. None of the tuberculin non-responders developed disseminated MAC infection during the study period; the Kaplan-Meier probability estimate of disseminated MAC infection was 50% at 24 months and reached 100% 40 months after zidovudine was commenced in tuberculin responders. All patients with disseminated MAC infection had become anergic to all antigens, including tuberculin, before diagnosis. The probability of a post-zidovudine tuberculin response was related to the severity of peripheral blood CD4+ T-cell depletion, rising from an estimated 20% at 20% CD4+ T cells to 100% at <= 1% CD4+ T cells. Conclusions: The restoration of a cellular immune response against subclinical MAC infection can be demonstrated by measuring the DTH response to tuberculin in patients with impaired DTH augmented by zidovudine therapy. The findings suggest that MAC infection is almost inevitable, but often asymptomatic, in profoundly immunodeficient HIV-infected patients and that a prolonged subclinical phase of MAC infection is usual

Zidovudine-induced restoration of cell-mediated immunity to mycobacteria in immunodeficient HIV-infected patients

Objective: To describe a localized form of Mycobacterium avium intracellulare (MAI) infection occurring concurrently with the restoration of cutaneous delayed-type hypersensitivity (DTH) responses to mycobacterial antigens after commencement of ziclovudine therapy in immunodeficient HIV-infected patients. Patients: The first 108 Western Australian patients with a CD4+ T-cell count of <200 $$ 106/1 and/or symptomatic disease to be given zidovudine (ZDV), of whom 72 had adequate DTH data. Methods: DTH responses to seven antigens were measured by the 'Multitest' method before and on at least two occasions during the 6 months after commencing ZDV. All patients were reviewed at regular intervals and clinical events recorded. Results: Of the 64 patients who were anergic to tuberculin before commencing ZDV, 27 (42%) developed a DTH response to tuberculin after ZDV. Four of the nine patients with a 'Multitest' tuberculin response of >=8mm and one patient who developed a positive Mantoux test to M. avium purified protein derivative developed an illness characterized by localized MAI infection, lymphadenopathy and/or severe fevers after 1-2 weeks. Conclusion: The development of localized MAI infection and/or fevers shortly after commencing ZDV in immunodeficient HIV-infected patients may reflect restoration of cellular immunity to mycobacterial antigens in some patients rather than early failure of therapy or hypersensitivity to ZDV

Heterogeneity of HIV induced cellular immune defects predisposing to opportunistic infections

No abstract availabl

Cerebral mass lesions due to cytomegalovirus in patients with AIDS: Report of two cases

No abstract availabl

Statistical issues in the evaluation of markers of HIV progression

Contemporary survival analytic praxis affords several methods for both appraising and extending the Cox proportional hazards model. With regard assessment a variety of diagnostic plots based on martin-gale and related residuals are available. One extension, additive proportional hazards models, allows sums of univariate smooth functions of the covariates as a generalization of the Cox model linear predictor. A complementary method, tree-structured survival analysis, is adept at identifying homogenous subgroups having distinct survival patterns. We apply this array of techniques to an evaluation of markers of HIV disease progression. Issues concerning survival analysis from seroprevalent cohort data are described. Little used measures of partial dependence for censored data are invoked in this context. Results from the Western Australian HIV Cohort Study indicate that delayed-type hypersensitivity skin tests augment CD4 cell counts in predicting time-to-AIDS and time-to-death

Major histocompatibility complex genes influence the outcome of HIV infection

Several alleles at multiple HLA loci have been found to be associated with infection with human immunodeficiency virus (HIV): HLA A1; B8, B35; Cw7, Cw4; DR1, DR3 and DQ1, are associated with particular disease manifestations and/or disease progression. Furthermore, in a pilot study we have shown an increase in the frequency of C4 null alleles and suggested that all the reported HLA alleles could reflect association with a limited number of ancestral haplotypes (AHs). On this occasion, we studied 122 Caucasoid patients classified according to Centers for Disease Control (CDC) criteria. The control group consisted of 67 seronegative homosexual or bisexual males at risk of developing HIV infection. C4 null alleles were unequivocally present in 58% of patients in CDC IV compared with 33% of the seronegative subjects (x2 = 5.65, p < 0.05). Furthermore, C4 null alleles could be excluded in only 8% and 16% of CDC III and IV, respectively, but in 30% of the seronegative subjects. An increased frequency of three AHs largely accounted for the increases in C4 null and HLA alleles. To examine the role of specific AHs we undertook a longitudinal analysis of a subgroup of 26 patients who seroconverted under observation. Seventeen of these patients were followed for 32 to 63 months. All seven patients with the 8.1 AH (A1, CW7, B8, BfS, C4AQ0, C4B1, DR3, DQ2) developed low CD4 lymphocyte counts (<450 × 106/l) compared with only 2 of 10 patients without this haplotype (p < 0.002). All three deaths occurred in patients with the 8.1 AH. The acquired immunodeficiency syndrome developed in three further cases with either 8.1- or B35- bearing (35.x) haplotypes. Sequential CD4/8 ratios showed an early and progressive decline in individuals with 8.1 or 35.x. Since the 8.1 and 35.x AHs contain deletions of the central major histocompatibility complex (MHC) genes, we suggest that the genes affecting HIV infection and progression are within the central MHC region