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Biomedical subjects

D A Cooper

Publications and source records attributed to D A Cooper.

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

Comprehensive classification of symptoms and signs reported among 218 patients with acute HIV-1 infection.

Acute HIV-1 illness presents a wide range of clinical manifestations. We assessed a classification and data reduction of clinical features among 218 patients with acute HIV-1 infection enrolled in four prospective seroincidence studies. Factor analysis allows the definition of eight factors based on groups of symptoms and signs: gastrointestinal transit disturbances, weight loss/abdominal pain, lymphadenopathy, myalgia/arthralgia, neurologic features, constitutional and mucocutaneous features, oral candidiasis, and anorexia/pharyngitis. These groups reflected the main target systems involved at the time of acute HIV-1 disease. Grouping of symptoms and signs based on groups of patients is potentially more informative than observations made on individual patients. It might facilitate diagnosis, suggest pathogenic mechanisms and reduce the number of variables for characterizing acute HIV-1 illness.

Acute Disease↗
PubMed1999

Kaposi's sarcoma-associated herpesvirus: a sexually transmissible infection?

We examined sexual behavior as a risk factor for Kaposi's sarcoma-associated herpesvirus (KSHV) infection and examined the relation between KSHV seropositivity and development of KS in cross-sectional and cohort studies of 130 homosexual men diagnosed with AIDS in Sydney, Australia during the period from 1991 to 1993. KSHV serology was measured using antibody tests to latency-associated nuclear antigen (LANA) and lytically expressed open reading frame (ORF) 65.2. In the cross-sectional analysis, 52% (68) of study subjects were KSHV-seropositive by either assay. KSHV-seropositive men were significantly more likely to be seropositive to both herpes simplex type 2 (odds ratio [OR] 3.0; 95% confidence interval [CI], 1.2-7.5 for LANA and OR 2.8; 95% CI, 1.3-6.0 for ORF 65) and hepatitis A virus (OR 2.2; 95% CI, 1.1-4.5 for ORF 65). KSHV-seropositive men reported nonsignificantly more casual sexual partners and were nonsignificantly more likely to report insertive oroanal contact with casual partners. These data suggest that KSHV might be sexually transmitted among homosexual men. Men were observed until October 1996 for development of KS. Those seropositive to either KSHV assay at baseline were more likely than the seronegative to develop KS during follow-up (rate ratio [RR] 4.4; 95% CI, 1.9-10.2). Of those seropositive for KSHV, 53% developed KS.

AIDS-Related Opportunistic Infections↗
PubMed1999

AIDS diagnoses at higher CD4 counts in Australia following the introduction of highly active antiretroviral treatment.

OBJECTIVES: To assess whether AIDS cases in Australia have been diagnosed at higher CD4 counts since the widespread availability of highly active antiretroviral treatment (HAART) in mid-1996. METHODS: Data on the CD4 count at AIDS diagnosis for AIDS cases diagnosed between 1 January 1992 and 31 December 1997, and reported to the National AIDS Registry in Australia by 31 March 1998, were analysed. The median CD4 count at AIDS diagnosis, and the proportions of AIDS diagnoses with a CD4 count above 100 cells/microl, and above 200 cells/microl, were calculated by the year of diagnosis, both for all AIDS-defining illnesses, and for each illness separately. Analyses were also stratified by the time interval between HIV and AIDS diagnoses (less than or equal to, or more than, 3 months) because people diagnosed with HIV close to the diagnosis of AIDS would generally not have received any antiretroviral treatment before the diagnosis of AIDS, and so no trends in CD4 counts at the diagnosis of AIDS would be expected in this group. RESULTS: There was an increase in CD4 count at AIDS diagnosis in 1996 and 1997, although this increase was only apparent for AIDS-defining illnesses other than Pneumocystis carinii pneumonia (PCP), and was limited to AIDS cases diagnosed with HIV more than 3 months before AIDS. In cases of AIDS other than PCP, and diagnosed with HIV more than 3 months before AIDS, the median CD4 count increased from 50 cells/microl in 1995 to 80 cells/microl in 1996 and 134 cells/microl in 1997. CONCLUSIONS: There has been an increase in the CD4 count at AIDS diagnosis for most AIDS-defining illnesses in Australia coincident with the widespread availability of HAART.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Therapeutic vaccination with p24-VLP and zidovudine augments HIV-specific cytotoxic T lymphocyte activity in asymptomatic HIV-infected individuals.

This study evaluates the impact of therapeutic vaccination with p24-VLP and zidovudine on the induction or maintenance of HIV-specific cytotoxic lymphocyte activity in a cohort of asymptomatic patients with CD4 counts greater than 400 cells/microl. In a dummy, randomized, phase II clinical trial of the therapeutic vaccine, participants were randomized to one of three arms for 6 months: p24-VLP (500 microg) in alum monthly plus zidovudine 200 mg tds, alum adjuvant plus zidovudine, or p24-VLP plus placebo. Subjects were studied for a total of 52 weeks from baseline. Monitoring included viral load, CD4 and CD8 counts, markers of immune activation, delayed-type hypersensitivity (DTH) skin testing, and cytotoxic T lymphocyte (CTL) measurement. The nine subjects who received p24-VLP and zidovudine had an augmentation and/or broadening of their CTL response compared with baseline (p = 0.004). The eight subjects receiving p24-VLP and seven subjects receiving zidovudine did not have a statistically significant increase or broadening of CTL activity. The augmentation of the CTL response in the subjects who received p24-VLP and zidovudine was not associated with a decline in viral load or an increase in CD8 counts. This study suggests that HIV-specific CTL activity can be augmented in HIV-infected individuals receiving p24-VLP and zidovudine, supporting the hypothesis of therapeutic vaccination in the presence of antiretroviral therapy.

AIDS Vaccines↗
PubMed1999

Efficacy and safety of combination therapy with delavirdine and zidovudine: a European/Australian phase II trial.

The objective of the study was to investigate the safety and antiviral effect of three delavirdine dose regimens or placebo in combination with zidovudine in patients who were already taking zidovudine. Eighty-nine symptomatic HIV-1 seropositive individuals with CD4 cell counts between 50 and 350 cells/microl were included in this trial The influence of combination therapy on viral susceptibility to both zidovudine and delavirdine was investigated. Death or the occurrence, or re-occurrence of an AIDS-defining illness was considered as a clinical endpoint. The addition of delavirdine to the antiretroviral treatment regimen resulted in a significant, but transient, reduction in virus load, as determined by quantitative RNA measurements. CD4+ cell count did not change significantly. Susceptibility to zidovudine remained unchanged after 12 weeks of combination therapy, while 70% of the patients demonstrated a substantial decrease (> 10-fold) in sensitivity to delavirdine. Two patients suffered from an AIDS-defining disease during the study. No deaths occurred. Generally, the drug appeared to be safe. Skin rash was the most frequently observed adverse event (52%). In most patients the rash either resolved spontaneously or was treated successfully with a short course of antihistamines. The definite place of the compound in the management of HIV disease, in particular when given in combination with other antiretroviral agents, remains to be further explored.

Anti-HIV Agents↗
PubMed1999

Effect of protease therapy on cytokine secretion by peripheral blood mononuclear cells (PBMC) from HIV-infected subjects.

The viral load reduction seen in patients with late stage HIV infection treated with the protease inhibitor, ritonavir, is accompanied by increases in the in vitro proliferative responses generated by PBMC. The present study was undertaken to investigate which lymphocyte subsets generated these responses and the effects of therapy on cytokine production. Lymphoproliferation following phytohaemagglutinin (PHA) stimulation was studied by thymidine incorporation, and production of IL-2, interferon-gamma (IFN-gamma) and IL-4 was assessed by ELISA in 12 patients receiving ritonavir and seven receiving placebo in the context of randomized, blinded clinical trials. CD4+ cell-depleted and CD8+ cell-depleted subsets were obtained from PBMC by immunomagnetic bead depletion. At week 4 of therapy a two-fold or greater increase in proliferative responses was observed in 9/12 subjects receiving therapy, compared with 0/7 receiving placebo. Similarly there was a significant increase in IL-2 and IFN-gamma production of 2.7-fold (P = 0.02) and 1.7-fold (P = 0.03), respectively, in the treatment group compared with those receiving placebo. No change in IL-4 production was observed. Despite these increases, cytokine responses post-therapy were still reduced compared with both healthy controls and asymptomatic HIV-infected subjects. Increases in proliferative response and IL-2 production were greater in the CD8+ cell-depleted population than in the CD4+ cell-depleted population, whereas increases in IFN-gamma production were derived from the CD4+ cell-depleted population.

CD4-Positive T-Lymphocytes↗
PubMed1999

Long-term prognosis following zidovudine monotherapy in primary human immunodeficiency virus type 1 infection.

Eighty-five subjects with symptomatic primary (P) human immunodeficiency virus (HIV) type 1 infection were analyzed in a retrospective cohort study to investigate the long-term clinical benefit of antiretroviral treatment during PHIV infection. Zidovudine treatment was initiated (PHIV treatment group) in 21 persons a median of 9 days after onset of PHIV symptoms and continued for a median of 55 days (range, 21-99). Sixty-four subjects did not receive early antiretroviral treatment (PHIV nontreatment group). After follow-up for 3-10 years, 33 subjects had developed AIDS and 22 subjects had died of AIDS. The median times for progression to AIDS and death were 6.4 and 9.1 years, respectively. Progression rates did not differ between the PHIV treatment and nontreatment groups. Zidovudine treatment initiated during PHIV infection did not improve long-term outcome after symptomatic PHIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1999

CD8+ anti-human immunodeficiency virus suppressor activity (CASA) in response to antiretroviral therapy: loss of CASA is associated with loss of viremia.

CD8+ anti-human immunodeficiency virus (HIV) suppressor activity (CASA) defines the noncytolytic suppression of HIV mediated by secreted soluble factors. Changes in CASA in patients receiving combination antiretroviral therapy have not been described. Thirty-two HIV-infected patients receiving mono- or dual therapy for 52 weeks followed by highly active antiretroviral therapy (HAART) for a further 52 weeks were analyzed. T cell number and functional subsets, cutaneous delayed-type hypersensitivity, and plasma HIV RNA were assessed in 17 patients for CASA. Prior to therapy, CASA correlated inversely with HIV RNA (P<.001). Dual therapy yielded greater and more sustained changes in CASA than monotherapy, but HAART decreased CASA to levels observed in HIV-uninfected individuals. The magnitude of HIV RNA suppression correlated significantly with a decrease in activated CD8+ T lymphocytes (CD38+HLA-DR+), increases in naive CD4+ T lymphocytes (CD45RA+62L+), and increases in the delayed-type hypersensitivity score. However, changes in CASA did not correlate with changes in any T lymphocyte subset. CASA increases with improving immune function but appears more dependent on ongoing HIV replication.

Anti-HIV Agents↗
PubMed1999

Potent antiretroviral therapy of primary human immunodeficiency virus type 1 (HIV-1) infection: partial normalization of T lymphocyte subsets and limited reduction of HIV-1 DNA despite clearance of plasma viremia.

Antiretroviral therapy commenced during primary human immunodeficiency virus type 1 (HIV-1) infection (PHI) may limit the extent of viral replication and prevent early loss of HIV-specific CD4 lymphocyte function. We studied the effect of current standard therapy (2 nucleoside analogues and a protease inhibitor) in 16 patients with symptomatic PHI. In the 13 patients who completed 1 year of treatment, plasma HIV RNA was <50 copies/mL and median CD4 cell counts were comparable to HIV-uninfected controls, with naive (CD45RA+CD62L+), primed (CD45RO+), and T cell receptor Vbeta subsets all within normal ranges. However, HIV-1 DNA levels in treated and untreated PHI patients were similar. Furthermore, CD8 cell counts remained elevated, including activated (CD38+HLA-DR+), replicating (Ki-67+), and cytotoxic (perforin+CD28-) lymphocytes. In conclusion, early antiretroviral therapy resulted in clearance of viremia and prevented loss of crucial CD4 subsets. The persistence of HIV-1 DNA together with increased CD8 T lymphocyte turnover and activation indicate continued expression of viral antigens.

Adult↗
PubMed1999

Dual efficacy of lamivudine treatment in human immunodeficiency virus/hepatitis B virus-coinfected persons in a randomized, controlled study (CAESAR). The CAESAR Coordinating Committee.

The efficacy and safety of lamivudine in persons coinfected with human immunodeficiency virus (HIV) type 1 and hepatitis B virus (HBV) were examined in the CAESAR study, a randomized placebo-controlled trial assessing the addition of lamivudine (150 mg 2x/day) or lamivudine (150 mg 2x/day) plus loviride (100 mg 3x/day) to zidovudine-containing background antiretroviral treatment. Baseline hepatitis B surface antigen (HBsAg) results were available for 1790 study subjects, of whom 122 (6.8%) tested positive. Retrospective analyses for serial HBV DNA, HBsAg, and hepatitis B e antigen (HBeAg) were performed on stored sera from 118 HBsAg-positive subjects. HBV DNA and HBeAg were present in 83% and 63%, respectively. At weeks 12 and 52, median log10 HBV DNA change was -2.0 and -2.7, respectively, in the lamivudine arms, compared with no reduction among placebo recipients (P<.001). A trend to lower alanine transferase level, and delayed progression of HIV-1 disease (relative hazard, 0.26; 95% confidence interval, 0.08-0.80) were also seen in the lamivudine arms, compared with the placebo group.

Acetamides↗
PubMed1999

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.

Adult↗
PubMed1999

Demographic, dietary and lifestyle factors differentially explain variability in serum carotenoids and fat-soluble vitamins: baseline results from the sentinel site of the Olestra Post-Marketing Surveillance Study.

Biochemical measures of nutrients or other dietary constituents can be an important component of nutritional assessment and monitoring. However, accurate interpretation of the nutrient concentration is dependent on knowledge of the determinants of the body pool measured. The purpose of this study was to identify the determinants of serum carotenoid and fat-soluble vitamin concentrations in a large, community-based sample (n = 1042). Multiple linear regression analysis was used to examine effects of demographic characteristics (age, sex, race/ethnicity, education), health-related behavior (exercise, sun exposure, smoking, alcohol consumption), and intake (diet, supplements) on serum retinol, 25-hydroxyvitamin D, alpha-tocopherol, phylloquinone, and carotenoid concentrations. Age, sex, race/ethnicity, vitamin A intake, and alcohol consumption were found to be determinants of serum retinol concentration. Race/ethnicity, vitamin D intake, body mass index, smoking status, and sun exposure were determinants of serum 25-hydroxyvitamin D concentration. Determinants of serum alpha-tocopherol were age, sex, race/ethnicity, alpha-tocopherol intake, serum cholesterol, percentage of energy from fat (inversely related), supplement use, and body mass index. Age, sex, phylloquinone intake, serum triglycerides, and supplement use were determinants of serum phylloquinone concentration. Primary determinants of serum carotenoids were age, sex, race/ethnicity, carotenoid intake, serum cholesterol, alcohol consumption, body mass index, and smoking status. Overall, the demographic, dietary, and other lifestyle factors explained little of the variability in serum concentrations of retinol (R2 = 0.20), 25-hydroxyvitamin D (R2 = 0.24), and the carotenoids (R2 = 0.15-0.26); only modest amounts of the variability in serum phylloquinone concentration (R2 = 0.40); and more substantial amounts of the variability in serum alpha-tocopherol concentration (R2 = 0.62).

Adult↗
PubMed1999

Dietary carotenoids and lung cancer: a review of recent research.

Several hundred carotenoid research studies have been published since 1996, when two major intervention trials showed a lack of protective effect of beta-carotene supplements against lung cancer. Recent epidemiologic studies continue to show an association between high dietary intake of beta-carotene and lower risk of lung cancer. New research is attempting to clarify the apparently contradictory results of intervention and epidemiologic studies. Promising areas of investigation include characterizing biologic activities of carotenoids and gaining further insight into whether they may serve primarily as markers for a healthy lifestyle or diet.

Animals↗
PubMed1999

Dietary carotenoids and certain cancers, heart disease, and age-related macular degeneration: a review of recent research.

Key epidemiologic studies show associations between high dietary intakes of certain carotenoid-containing fruits and vegetables and reduced risk of prostate cancer, breast cancer, head and neck cancers, cardiovascular disease, and age-related macular degeneration, although overall the evidence is inconsistent. Little is known about the potential biochemical mechanisms whereby carotenoids might protect against disease, and human intervention trials are limited to high dose beta-carotene, which is not protective against lung cancer or cardiovascular disease. Authoritative scientific organizations continue to emphasize increased consumption of fruits and vegetables but do not make specific recommendations for carotenoids because of a lack of data that directly link them to disease reduction.

Breast Neoplasms↗
PubMed1999

Immune reconstitution in HIV-1 infected subjects treated with potent antiretroviral therapy.

The introduction of potent antiretroviral drug regimens contributed to a decline in HIV-1 associated morbidity and mortality. Clinical observations of spontaneous remission of previously untreatable opportunistic infections in subjects on highly active antiretroviral therapy (HAART) reflect the substantial degree of immune reconstitution which can be achieved by those therapies. A biphasic increase of CD4+ T lymphocytes has been reported including naive (CD45RA+) and memory (CD45RO+) cell subsets. Proliferative lymphocyte responses to recall antigens and mitogens are enhanced over time, while T lymphocyte activation is largely reduced and T cell receptor (TCR) repertoires are partly restored. Proliferative lymphocyte responses specific to HIV-1 antigens, in contrast, remain weak. A complete normalisation of HIV-1 associated immunological alterations has not been reported so far, but the observation period of subjects on potent antiretroviral therapies is still relatively short.

AIDS-Related Opportunistic Infections↗
PubMed1998

A model of primary HIV-1 infection.

We construct a model based on biological principles of the interaction of HIV-1 with the CD4+ T cells at primary infection. Most of the parameters are obtained from the literature, the remainder from fitting the output of the model to data from seven patients. On the basis of the model we find that initial viral containment is due to an effective immune response. The viral level after the initial peak, a surrogate marker of disease progression, was determined by the rate of reactivation of memory cells. Differences in this rate may occur because of inter- or intra-individual differences in the capability of memory cells to recognise and dispose of variants of HIV, either due to immune escape mutations within the virus or because the virus directly inhibits reactivation. With no choice of parameters could direct and indirect killing produce the gradual loss in CD4+ T cells with the observed viral behaviour. The loss of CD4+ T cells is perhaps due to defective expansion of activated cells of both HIV specific and nonspecific cells. As less memory cells are produced as a result then this compartment decreases and hence so do naive numbers through less reversion of memory cells to the naive phenotype.

Adult↗
PubMed1998

HIV disease progression in Australia in the time of combination antiretroviral therapies.

OBJECTIVE: To examine the effect of recent developments in antiretroviral therapy on HIV disease progression and survival. DESIGN: Retrospective cohort study. PARTICIPANTS AND SETTING: Two cohorts of people with HIV were defined retrospectively from the records of a large immunology laboratory. The first cohort were subjects whose CD4+ T cell counts had dropped to 200 x 10(6)/L during 1990, and the second were subjects whose CD4+ T cell counts had dropped to 200 x 10(6)/L in 1994. MAIN OUTCOME MEASURES: HIV disease progression and survival was determined over a minimum three years of follow-up for each cohort (i.e., 1990-1993; 1994-1997). RESULTS: 346 subjects were included in the analysis (193 subjects from 1990 and 153 from 1994). The relative risk of progression to AIDS in the 1994 cohort compared with the 1990 cohort was 0.57 (95% confidence interval, 0.35-0.91; P = 0.018) and the relative risk of death was 0.20 (95% confidence interval, 0.08-0.49; P < 0.001). CONCLUSIONS: There were 43% fewer AIDS cases and 80% fewer deaths in the time following the increased availability of combination antiretroviral therapy in Australia.

Adult↗