Biomedical subjects

S A Mallal

Publications and source records attributed to S A Mallal.

At least 19 recordsLinked to original sources

PubMed2005

Killer immunoglobulin-like receptors and HLA act both independently and synergistically to modify HIV disease progression.

Variation in the host response to infection by pathogens including HIV-1 may be conferred by polymorphic genetic factors such as HLA and killer immunoglobulin-like receptors (KIR) genes. Here, we examined KIR and HLA genotype effects on pretreatment viral load, rate of CD4(+) T-cell decline and progression to AIDS among adult HIV-1-infected patients within the Western Australian HIV Study Cohort. In this study, carriage of KIR genes within the 'B' haplotype (eg KIR2DS2) was specifically associated with a more rapid CD4(+) T-cell decline over time and progression to AIDS. In contrast, KIR gene repertoire had no effect on pretreatment viral load while selected HLA alleles (eg HLA-B*5701, HLA-B*2705) demonstrated significant protective effects on viremia. Furthermore, interactions between specific HLA and KIR genes did appear to influence HIV disease progression. The results suggest that host genetic variation within the HLA and KIR gene complexes have clinically relevant effects on the course of HIV-1/AIDS, acting independently as well as synergistically to modify disease progression at multiple levels.

Acquired Immunodeficiency Syndrome↗

PubMed2001

Effects of CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on HIV-1 disease progression: An international meta-analysis of individual-patient data.

BACKGROUND: Studies relating certain chemokine and chemokine receptor gene alleles with the outcome of HIV-1 infection have yielded inconsistent results. OBJECTIVE: To examine postulated associations of genetic alleles with HIV-1 disease progression. DESIGN: Meta-analysis of individual-patient data. SETTING: 19 prospective cohort studies and case-control studies from the United States, Europe, and Australia. PATIENTS: Patients with HIV-1 infection who were of European or African descent. MEASUREMENTS: Time to AIDS, death, and death after AIDS and HIV-1 RNA level at study entry or soon after seroconversion. Data were combined with fixed-effects and random-effects models. RESULTS: Both the CCR5-Delta32 and CCR2-64I alleles were associated with a decreased risk for progression to AIDS (relative hazard among seroconverters, 0.74 and 0.76, respectively; P = 0.01 for both), a decreased risk for death (relative hazard among seroconverters, 0.64 and 0.74; P < 0.05 for both), and lower HIV-1 RNA levels after seroconversion (difference, -0.18 log(10) copies/mL and -0.14 log(10) copies/mL; P < 0.05 for both). Having the CCR5-Delta32 or CCR2-64I allele had no clear protective effect on the risk for death after development of AIDS. The results were consistent between seroconverters and seroprevalent patients. In contrast, SDF-1 3'A homozygotes showed no decreased risk for AIDS (relative hazard for seroconverters and seroprevalent patients, 0.99 and 1.03, respectively), death (relative hazard, 0.97 and 1.00), or death after development of AIDS (relative hazard, 0.81 and 0.97; P > 0.5 for all). CONCLUSIONS: The CCR5-Delta32 and CCR2-64I alleles had a strong protective effect on progression of HIV-1 infection, but SDF-1 3'A homozygosity carried no such protection.

Acquired Immunodeficiency Syndrome↗

PubMed2001

Chronic hyperlactatemia in HIV-infected patients taking antiretroviral therapy.

OBJECTIVE: To determine the prevalence, course and risk factors for hyperlactatemia in HIV-infected patients. DESIGN: A prospective, longitudinal study of venous lactate concentrations over an 18-month period in 349 participants of the Western Australian HIV Cohort Study. RESULTS: In 516 patient-years of observation, two patients experienced severe fulminant lactic acidosis (lactate > 5 mmol/l) and hepatic steatosis attributable to nucleoside analogue reverse transcriptase inhibitors (NRTI). A further five patients with lesser elevations of lactate (2.8-4.1 mmol/l) but with symptoms of nausea or abdominal discomfort and evidence of hepatic steatosis had NRTI therapy revised, with relief of symptoms and a fall in lactate levels. Most remaining patients on highly active antiretroviral therapy (HAART) had mild, chronic, asymptomatic hyperlactatemia, with mean lactate level between 1.5 mmol/l and 3.5 mmol/l most commonly. Longitudinal data was analysed in a non-linear mixed effects growth model which indicated that average lactate levels rose after the start of HAART but tended to stabilise at low-grade elevation, with an average 0.23 mmol/l greater long term level in stavudine users compared with zidovudine users (p < 0.01). A multiple linear regression model showed that the association between stavudine and higher lactate level was not confounded by longer duration of total NRTI exposure. Risk of hyperlactatemia was not significantly associated with use of other NRTIs, protease inhibitors, non-nucleoside analogue reverse transcriptase inhibitors or multiple immunological and virological factors in multivariate analyses. CONCLUSIONS: Chronic, compensated, asymptomatic hyperlactatemia is common in patients taking HAART. Decompensated, life-threatening lactic acidosis/hepatic steatosis is rare. Treatment with stavudine appears to be the predominant risk factor for development of chronic hyperlactatemia.

Acidosis, Lactic↗

PubMed2000

Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection.

BACKGROUND: Progressive subcutaneous fat wasting, fat accumulation, dyslipidaemia and insulin resistance in HIV-infected patients on antiretroviral therapy has been attributed to the long-term toxicity of HIV protease inhibitors (PI). More recently, fat wasting has been observed in patients who have never taken a PI, implicating an independent effect of nucleoside analogue reverse transcriptase inhibitor (NRTI) therapy. OBJECTIVES: To determine the relative contribution of NRTI and PI, as well as any other factors, to fat wasting in HIV-infected patients. DESIGN: Longitudinal cohort study involving 277 participants of the Western Australian HIV Cohort Study. METHODS: The time to onset of clinically apparent fat wasting in patients receiving different antiretroviral regimens was compared using standardized clinical criteria. Regional fat measured by dual energy X-ray absorptiometry (DEXA) in 161 patients was also compared. The average rate of percentage fat reduction was estimated in 70 patients who had consecutive DEXA scans at approximately 6-monthly intervals. Multiple confounding factors were considered in the analyses. RESULTS: Progressive subcutaneous fat wasting, indistinguishable from that described in PI-treated patients, does occur in PI-naive, NRTI-treated patients. In patients taking triple combination antiretroviral therapy, age (relative risk = 1.052 per year; P < 0.0001), white race (relative risk = 3.9; P = 0.023), longer duration of dual NRTI therapy prior to addition of PI (relative risk = 1.021 per month; P = 0.0046) and increased cumulative time on stavudine-containing regimens compared with time on zidovudine-containing regimens (relative risk = 1.085 per month; P < 0.0001) are associated with increased risk of fat wasting. Stavudine increases the risk of fat wasting by 265% per year compared with zidovudine. However PI therapy is associated with faster progression to clinically apparent wasting compared with dual NRTI therapy without PI. The results of DEXA scanning supports these clinical data and suggest a non-linear decline in fat over time. CONCLUSIONS: NRTIs do have an independent contribution to fat wasting, but PI are the predominant influence and may act synergistically with NRTIs. NRTIs appear to predispose individuals to slowly progressive fat loss, which is markedly accelerated when a PI and NRTIs are combined. Of the NRTIs, stavudine leads to an earlier onset of clinically apparent fat wasting compared with zidovudine. Fat wasting associated with NRTI use may be a manifestation of mitochondrial toxicity, which may be exacerbated by PI use.

Absorptiometry, Photon↗

PubMed2000

Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy.

BACKGROUND: To determine if infectious disease events in HIV-infected patients treated with highly active antiretroviral therapy (HAART) are a consequence of the restoration of pathogen-specific immune responses, a single-centre retrospective study of all HIV-infected patients commencing HAART prior to 1 July 1997 was undertaken to determine the incidence, characteristics and time of onset of disease episodes in HAART responders (decrease in plasma HIV RNA of > 1 log10 copies/mL). METHODS: Baseline and post-therapy changes in CD4 T-cell counts and HIV RNA were compared in patients with and without disease and delayed-type hypersensitivity responses to mycobacterial antigens were measured in selected patients. RESULTS: Thirty-three of 132 HAART responders (25%) exhibited one or more disease episodes after HAART, related to a pre-existent or subclinical infection by an opportunistic pathogen. Disease episodes were most often related to infections by mycobacteria or herpesviruses but hepatitis C virus (HCV), molluscum contagiosum virus and human papilloma virus were also implicated. They were most common in patients with a baseline CD4 T-cell count of < 50/uL and occurred most often during the first 2 months of therapy and when CD4 T-cell counts were increasing. Mycobacteria- and HCV-related diseases were associated with restoration of pathogen-specific immune responses. CONCLUSIONS: We conclude that improved immune function in immunodeficient patients treated with HAART may restore pathogen-specific immune responses and cause inflammation in tissues infected by those pathogens.

AIDS-Related Opportunistic Infections↗

PubMed2000

Uptake of HIV testing and treatment in an isolated population with access to free and universal healthcare.

This Western Australian study analysed clinical information from 344 people with AIDS, and experiential data from a sample of 36 people with AIDS to investigate 2 relevant issues: the timing of HIV testing and uptake and experiences of HIV drug treatment. We found that the proportion of people presenting with AIDS before being diagnosed with HIV infection ('AIDS-presenters') fell from 47% in 1985-1987 to 20% in 1991-1993. Since antiretroviral therapy (ART) became available in 1987, two-thirds of Western Australian people with AIDS who knew of their HIV infection prior to the development of AIDS have consistently elected to take recommended HIV treatment. Four phases of the treatment experience were identified. It is concluded that 'AIDS-presentation' is unlikely to reduce further and that the timing of testing and issues of treatment acceptance are only understood when the experiences of people with illness are examined using a patient-centred approach.

Acquired Immunodeficiency Syndrome↗

PubMed1998

The Western Australian HIV Cohort Study, Perth, Australia.

The efficacy of primary prophylactic treatment for opportunistic infections can be estimated in an observational cohort study by adjusting for clinical and laboratory markers of the immunodeficiency (e.g., oral candidiasis, CD4%, lymphocyte cell counts) as time-dependent co-variates (providing that the treatment does not directly alter the markers). However, the CD4 cell count provides an incomplete measure of the protective immune response, and the efficacy of treatment may be underestimated if there is inadequate adjustment for the severity of immunodeficiency. Unlike prophylactic therapies, the efficacy of which remains relatively constant over time, antiretroviral therapy may produce only transient or time-limited benefits. This problem can be minimized by allowing the effect of antiretroviral therapy to vary over time in Cox proportional hazards models (i.e., to allow the antiretroviral therapy coefficient to change over time). Another difficulty is that CD4 cell counts may underestimate the degree of immunodeficiency after prolonged zidovudine (AZT) monotherapy. If post-antiretroviral therapy CD4 cell counts are used to adjust for the stage of immunodeficiency, it may therefore be helpful to adjust for the duration of antiretroviral therapy with the CD4 cell count at the time of starting antiretroviral therapy. It is interesting to consider statistical models of progressive HIV-induced immunodeficiency in the context of the evolution of host immunity. HIV infection results in the loss of the relatively recently evolved adaptive CD4 T cell-mediated immunity to intracellular parasites. The infected host may compensate for this by making greater use of phylogenetically ancient, more innate protective responses. Because these compensatory responses are polymorphic, this results in the appearance of differences between individuals in the immune response to HIV as the disease progresses. Data from the Western Australia HIV Cohort Study support a two-stage model of immunopathology. The first stage of this model involves a loss of mucosal immunity and occurs at a variable CD4 cell count (of between 400 cells/mm3 and zero), and is marked by a loss of cutaneous delayed-type hypersensitivity responses and oral candidiasis, seborrheic dermatitis, and Pneumocystis carinii pneumonia. The second stage of the model involves a loss of systemic immunity and requires profound CD4 T-cell lymphopenia (CD4 cell count <50 cells/mm3), and is marked by infections such as cytomegalovirus and disseminated Mycobacterium avium infection. The influence of HLA type on the risk for such opportunistic infections becomes apparent during this late phase.

AIDS-Related Opportunistic Infections↗

PubMed1997

Trends in incidence of AIDS illnesses in Australia from 1983 to 1994: the Australian AIDS cohort.

To assess time trends in incidence of AIDS illnesses in Australia, a retrospective cohort of people diagnosed with AIDS from January 1, 1983 to December 31, 1994 in three HIV medicine units in Sydney, Melbourne, and Perth was established. Data on initial and subsequent AIDS illnesses were available for 2580 AIDS cases, or 45% of Australian AIDS notifications over the study period. Males represented 97.2% of the cohort, and HIV exposure category was homosexual contact for 89.9%. Subcohorts were formed by interval of AIDS diagnosis: 1983 through 1987, 1988 through 1990, and 1991 through 1994, with estimation of cumulative risk for each AIDS illness by the Kaplan-Meier method. The cumulative risk declined for Pneumocystis carinii pneumonia (PCP) (p < 0.0001) and for Kaposi's sarcoma (KS) (p < 0.0001); PCP cumulative risk estimates 2 years following AIDS diagnosis were 70% for people diagnosed with AIDS in 1983 through 1987 and 48% in 1991 through 1994, and KS cumulative risk estimates 2 years following AIDS diagnosis were 44% in 1983 through 1987 and 32% in 1991 through 1994. In contrast, cumulative risk increased from 34% to 40% for cytomegalovirus (CMV) disease (p = 0.005), from 47% to 50% for Mycobacterium avium complex (MAC) (p < 0.0001), and from 26% to 33% for esophageal candidiasis (p < 0.0001). Corresponding to this changing spectrum of AIDS illness has been an increase in severity of immunodeficiency at AIDS, with median CD4 cell count declining from 54 cells/mm3 in 1983 through 1987 to 34/mm3 in 1991 through 1994 (p = 0.002).

AIDS Dementia Complex↗

PubMed1996

Declining incidence and later occurrence of Kaposi's sarcoma among persons with AIDS in Australia: the Australian AIDS cohort.

OBJECTIVE: To explore trends in cumulative incidence of Kaposi's sarcoma (KS) and the level of immunodeficiency at KS diagnosis among people with AIDS in Australia. SETTING: Three hospital-based HIV units. STUDY POPULATION: Retrospective cohort of 2580 people diagnosed with AIDS over the period 1983-1994, representing 45% of cases of AIDS in Australia over this period. METHODS: Data including date and CD4 T-lymphocyte count of KS diagnosis was abstracted from medical records. KS occurring as both an initial and subsequent AIDS illness was included. Three subcohorts were defined based on interval of AIDS diagnosis: 1983-1987, 1988-1990, 1991-1994. Cumulative risk estimates for KS development were calculated by the Kaplan-Meier method. RESULTS: KS was diagnosed in 716 people (27.8%), and in 451 (63%) of these as the initial AIDS illness. There was a decline over time in cumulative incidence of KS (P < 0.0005); the cumulative risk of KS at 1 year after AIDS diagnosis declined from 35% for those diagnosed with AIDS during 1983-1987 to 25% for 1991-1994. This decline was not due to a decline in homosexual HIV exposure category, and was independent of CD4 T-lymphocyte count at AIDS. In multivariate analysis independent risk factors for KS development were year of AIDS diagnosis (P = 0.003), male homosexuality (P = 0.003), and CD4 T-lymphocyte count at AIDS greater than 150 x 10(6)/l (P = 0.02). A decline in median CD4 T-lymphocyte count at KS diagnosis was seen, from 67 x 10(6)/l in 1984-1987 to 20 x 10(6)/l for 1991-1994 (P < 0.0005). CONCLUSION: The decline in incidence and later occurrence of KS suggest several hypotheses, including declining prevalence or reduced virulence of a KS cofactor.

AIDS-Related Opportunistic Infections↗

PubMed1995

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

Cytomegalovirus (CMV) is an increasingly important opportunistic pathogen in patients with HIV infection and advanced immune deficiency. Neurological complications due to CMV cause significant morbidity but may be treatable with specific anti-viral therapy: cerebral mass lesions are not a generally recognised manifestation. We report two patients with CMV encephalitis presenting as a cerebral mass lesion, with simultaneous occurrence of a pleuro-pulmonary mass also caused by CMV in one case, and with concurrent polyradiculomyelopathy in the other. The spectrum of previously reported clinical and radiological features of CNS involvement in AIDS is discussed. CMV should be considered in the differential diagnosis of cerebral mass lesions in patients with HIV infection and severe immune deficiency so that anti-viral therapy can be rapidly deployed.

AIDS-Related Opportunistic Infections↗

PubMed1994

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 < or = 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.

AIDS-Related Opportunistic Infections↗

PubMed1994

Severity and outcome of Pneumocystis carinii pneumonia (PCP) in patients of known and unknown HIV status.

Of 170 Western Australian patients who had their first AIDS-defining illness between 1 January 1983 and 31 December 1991, 61 (36%) were of unknown HIV antibody status (AIDS presenters), while 109 (64%) were of known HIV antibody status (HIV presenters). Pneumocystis carinii pneumonia (PCP) was less common as the AIDS-defining illness in HIV presenters (41% versus 62%, p = 0.005). In this study of 70 patients with PCP as the index AIDS diagnosis, 36 were HIV presenters and 34 were AIDS presenters. Ten HIV presenters were taking prophylaxis at the time PCP manifested. The duration of symptoms of cough or dyspnea before the diagnosis of PCP was shorter, and the arterial PO2 measurement on admission was higher in those on prophylaxis, and a lower proportion of patients on prophylaxis required hospital admission (p < or = 0.05 for all comparisons). Furthermore, the CD4 counts at diagnosis of PCP were lower in patients taking PCP prophylaxis (mean 26 x 10(6)/L) than in patients who were not (mean 94 x 10(6)/L, p = 0.007). Of seven patients who died of PCP, none were receiving treatment for HIV disease before AIDS presentation. These findings suggest that PCP is prevented or deferred in patients receiving care for HIV disease and is less severe as a result of early diagnosis and treatment.

Acquired Immunodeficiency Syndrome↗

PubMed1992

Exposure to blood borne infections in health care workers.

OBJECTIVE: To determine the incidence and nature of occupational exposures to blood and body fluids in health care workers. DESIGN: 332 reports of occupational exposure were analysed and are presented. SETTING: A major teaching hospital. PARTICIPANTS: All staff at Royal Perth Hospital who reported an occupational exposure to blood or body fluids to the Department of Clinical Immunology between 1 January 1990 and 31 August 1991. OUTCOME MEASURES: The rate of reported occupational exposure according to staff category, nature of exposure, HIV status of source patient, activity at the time of exposure and compliance with infection control measures. RESULTS: 332 reports from 323 health care workers were received, giving an overall incidence of 6.1 per 100 full time equivalent (FTE) years. Nursing staff (9.4/100 FTE years) and medical staff (9.0/100 FTE years) reported exposure more frequently than housekeeping staff (2.5/100 FTE years) or paramedical staff (2.3/100 FTE years) (P < 0.001). The rate of exposure to HIV antibody positive patients was only 0.24/100 FTE years. Needlestick or other blood contaminated sharps injuries accounted for 83.4% (277/332) of reports and failure to observe universal precautions for 34.0% of reports. Insertion and operation of parenteral lines (24%) and performing operations (15.4%) were the activities most often associated with occupational exposure. No occupationally acquired infections were observed. Despite the immediate availability of zidovudine, acceptance by health care workers with high risk occupational exposure was low (18.8%). CONCLUSIONS: Occupational exposure to blood and body fluids is common among health care workers but most exposures confer a low risk of blood borne infection. The introduction of an occupational exposure assessment program has many benefits, including optimal management of injuries and acquisition of data on infection control measures, and may protect health care institutions from false claims for compensation.

Blood↗

PubMed1992

Epidemiology of late presentation of HIV infection in Western Australia.

OBJECTIVE: To determine the incidence of and reasons for late presentation of patients infected with the human immunodeficiency virus (HIV), and the demographic characteristics of these late presenters, who first seek medical attention when they have an illness that defines the acquired immunodeficiency syndrome (AIDS). DESIGN: Retrospective analysis of clinical and demographic data relating to 106 sequential AIDS diagnoses in Western Australia. Surviving patients were questioned during routine medical and social work interviews to identify the reasons for late presentation. SETTING: Royal Perth Hospital, the sole specialist referral centre for the management of infection with the human immunodeficiency virus (HIV) in Western Australia. PARTICIPANTS: All patients presenting or referred to Royal Perth Hospital with an AIDS-defining condition between 1 January 1988 and 1 July 1991. RESULTS: Forty-one of 106 (39%) patients presenting with an AIDS-defining condition had known of their HIV status for eight weeks or less (late presenters). The proportion of late presenters decreased from 61% in 1988 to 34% in 1989 (P less than 0.05). Six of the 41 late presenters died during their initial admission compared with only one of the 65 early presenters (P less than 0.02). Sixty-six per cent of late presenters compared with only 35% of early presenters had pneumocystis pneumonia as their AIDS-defining condition (P less than 0.01). There was no significant difference in age at diagnosis of AIDS, martial status, sex or risk factors between the early and late presentation groups. Reasons given for late presentation included lack of knowledge of advances in the treatment of HIV infection, concerns about confidentiality and beliefs that sexual behaviour had been relatively "safe" from risk of HIV infection. CONCLUSIONS: While the proportion of patients presenting late is decreasing, late presentation continues to be a problem. Reasons for delayed presentation are not entirely clear, but can be explained in terms of psychosocial and physiological influences. How and to what degree each of these contribute to timing of presentation is yet to be determined.

AIDS Serodiagnosis↗

PubMed1992

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 zidovudine therapy in immunodeficient HIV-infected patients. PATIENTS: The first 108 Western Australian patients with a CD4+ T-cell count of < 200 x 10(6)/l 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 > or = 8 mm 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. CONCLUSIONS: 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.

AIDS-Related Opportunistic Infections↗

PubMed1991

Major histocompatibility complex (MHC) complement deficiency, ancestral haplotypes and systemic lupus erythematosus (SLE): C4 deficiency explains some but not all of the influence of the MHC.

In 1982 we reported that among Caucasians with systemic lupus erythematosus (SLE) there is an increased frequency of C4A null. As this allele occurs on the HLA-A1,B8,BfS, C4AQO,B1,DR3 (8.1) supratype, we suggested this accounted for the reported association of B8 and DR3. Since then we have shown that many supratypes including 8.1 identify unique segments of DNA conserved from a common but remote ancestor. Many of these ancestral haplotypes (AH), including 8.1, carry disease genes and some bear C4 null. We have therefore tested the hypothesis that in SLE C4 null alleles are directly involved by examining (1) whether all or only some AH bearing C4 null alleles are increased, (2) whether C4 null is increased in all racial groups examined, and (3) whether C4 null is associated with the presence of antinuclear antibodies (ANA) in the absence of SLE. We performed HLA and complement allotyping on 62 Australian Caucasians and 9 Australian aborigines with SLE and on the 10 out of 133 healthy individuals with 7 or more international units of ANA. Our data confirm an association of C4A null in Australian Caucasians (gene frequency 0.30 versus 0.15 in controls) and show an increased frequency of C4B null in Australian aborigines (gene frequency 0.33 versus 0.22). A review of an extensive literature shows C4A and/or C4B null are increased in all racial groups examined. On the other hand, the HLA-A3,B7,BfS,C4A3,B1,DR2 (7.1) AH rather than C4 null is associated with ANA in health. Our data indicate that while C4 nulls contribute to MHC susceptibility, other genes are likely to be involved.

Alleles↗

PubMed1990

Major histocompatibility complex genes influence the outcome of HIV infection. Ancestral haplotypes with C4 null alleles explain diverse HLA associations.

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 (chi 2 = 5.65, p less than 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 (less than 450 x 10(6)/l) compared with only 2 of 10 patients without this haplotype (p less than 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.

Alleles↗

PubMed1983

Treatment of cryptorchidism with pulsatile luteinizing hormone-releasing hormone (LH-RH).

This preliminary report describes a new method of treating bilateral cryptorchidism that may modify the need for surgical intervention. Four of five boys (3 1/2, 3 1/2, 7, 11 and 12 1/2 years of age) given hourly subcutaneous pulses of luteinizing hormone-releasing hormone (LH-RH, 10 to 100 micrograms/day, given in a 3-min pulse every hour) showed evidence of testicular descent after 3 to 19 weeks. The battery-operated, programmable syringe driver was well tolerated by the boys, and the daily insertion of the scalp-vein needles was managed at home by their parents.

Child↗