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Biomedical subjects

D A Cooper

Publications and source records attributed to D A Cooper.

At least 109 records · Page 6Linked to original sources
PubMed1998

Antiretroviral therapy for HIV infection. A knowledge-based approach to drug selection and use.

In the absence of evidence that eradication of HIV from an infected individual is feasible, the established goal of antiretroviral therapy is to reduce viral load to as low as possible for as long as possible. Achieving this with the currently available antiretroviral agents involves appropriate selection of components of combination regimens to obtain an optimal antiviral response. In addition, consideration of a plan for a salvage or second-line regimen is required if initial therapy fails to achieve an optimal response or should loss of virological control occur despite effective initial therapy. Such a planned approach, based on consideration of the likely modes of therapeutic failure (viral resistance, cellular resistance, toxicity) could be called rational sequencing. Choice of therapy should never involve compromise in terms of activity. However, the choice of drug should also be guided by tolerability profiles and considerations of coverage of the widest range of infected cells, compartmental penetration, pharmacokinetic interactions and, importantly, the ability of an agent or combination to limit future therapeutic options through selection of cross-resistant virus. Available clinical end-point data clearly indicate that combination therapy is superior to monotherapy, with clinical and surrogate marker data supporting the use of triple drug (or double protease inhibitor) combinations over double nucleoside analogue combinations. Thus, 3-drug therapy should represent current standard practice in a nontrials setting. Treatment should be considered as early as practical, and may be best guided by measurement of viral load, with a range of other markers having potential utility in individualising treatment decisions. Therapeutic failure may be defined clinically, immunologically or, ideally, virologically, and should prompt substitution of at least 2, and preferably all, components of the treatment regimen. Drug intolerance may also be best managed by rational substitution.

Anti-HIV Agents↗
PubMed1998

Immunological effects of antiretroviral therapy.

The striking decline in HIV load with highly active antiretroviral combination therapy (HAART) is accompanied by substantial improvements in immune function, even in patients with more advanced disease. These include a general reduction in immune activation with increases in total CD4 and CD8 cell counts, memory and naive T cell subsets and antigen responses to certain opportunistic pathogens. At this time, it appears that HAART-induced improvements in function are limited to those T cells that have not yet been completely depleted by HIV. Long-term studies are needed to determine whether complete functional restoration of the repertoire is possible. Clinically, HAART improves survival and reduces progression of HIV disease. Some patients with active opportunistic disorders demonstrate complete or partial resolution of the infection or malignancy. However, persons with subclinical Mycobacterium avium complex or cytomegalovirus retinitis and those with chronic hepatitis B virus infection may sometimes experience acute flares if prophylactic therapy against the underlying disorder is not included in the regimen.

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↗
PubMed1997

Risk of Kaposi's sarcoma and oroanal sexual contact.

After contradictory findings from a number of previous studies, behavioral risk factors for Kaposi's sarcoma were examined in a case-control study of 202 people diagnosed with acquired immunodeficiency syndrome (AIDS) in 1991-1993 in Sydney, Australia. Cases comprised 67 men who developed Kaposi's sarcoma at or after a diagnosis of acquired immunodeficiency syndrome, and controls were 135 people who did not have Kaposi's sarcoma at the time of diagnosis of acquired immunodeficiency syndrome or during follow-up until 1995. Men who developed Kaposi's sarcoma were more likely to report having a history of sexually transmissible diseases and having engaged more frequently than controls in a number of sexual practices with casual partners in the period before they became aware of their human immunodeficiency virus (HIV) infection. However, the only sexual practice reported significantly more often by cases at the 0.05 significance level was insertive oroanal contact with casual partners (odds ratio = 2.6, 95 percent confidence interval 1.3-5.3). This association was not present for insertive oroanal contact with regular partners or for insertive oroanal contact after subjects became aware of their HIV infection. The relation was present both in men who had Kaposi's sarcoma at the time of interview and in those who developed it later. The relation was not affected by adjustment for time of HIV infection and diagnosis or for other sexual practices. These results can be interpreted as supporting the hypothesis that Kaposi's sarcoma in people with HIV is caused by an infectious agent transmitted by oral contact with feces.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Safety and immunogenicity of UBI HIV-1MN octameric V3 peptide vaccine administered by subcutaneous injection.

Twenty-four HIV-seronegative men, at high risk of HIV infection, were recruited into a phase I/II safety and immunogenicity trial of a prototype HIV vaccine. The immunogen was a synthetic, monovalent, octameric HIV-1MN V3 peptide in an aluminum hydroxide (alum) adjuvant. The vaccine had been evaluated previously using a standard 0-, 1-, 6-month intramuscular schedule and was found to stimulate neutralizing antibody in 60-90% of volunteers. Participants were randomized to receive either 500 micrograms (n = 10; high dose) or 100 micrograms (n = 10; low dose) of immunogen or placebo (alum alone; n = 4) at 0, 1, and 6 months by subcutaneous injection. Responses to the immunogen were evaluated by enzyme-linked immunosorbent assay (ELISA)-detectable antibody and by proliferative responses. Safety was monitored by both clinical assessment and regular review with a clinical psychologist. No serious adverse experiences were observed following administration of the assigned medication. One individual (placebo) seroconverted while on study, following exposure to HIV. After the vaccination course only four individuals (three high dose and one low dose) had ELISA-detectable antibody against the immunogen. In the evaluable samples, from 19 volunteers, only 7 vaccine recipients (3 high dose and 4 low dose) had demonstrable lymphoproliferative responses to preparations of the immunogen. Subcutaneous administration of its candidate vaccine was safe but did not result in uniform or robust immunological responses.

AIDS Vaccines↗
PubMed1997

High-dose nevirapine in previously untreated human immunodeficiency virus type 1-infected persons does not result in sustained suppression of viral replication.

High-dose nevirapine treatment has been reported to confer sustained antiretroviral effects, despite a rapid development of resistance. The use of this strategy was evaluated in 20 previously untreated human immunodeficiency virus type 1 (HIV-1) p24 antigenemic persons with CD4 cell counts between 100 and 500/mm3. Treatment consisted of 400 mg of nevirapine, after a 2-week lead-in dose of 200 mg. Rash was the most frequently reported adverse event, occurring in 25%. While sustained declines in p24 antigen levels were observed in the majority, serum HIV-1 RNA load and CD4 cell counts returned to baseline values within 12 weeks in virtually all subjects. The resistance-conferring tyrosine-to-cysteine substitution at reverse transcriptase position 181 was detected after 4 weeks in most subjects. These observations suggest that plasma drug levels attained with high-dose nevirapine were not sufficient to inhibit nevirapine-resistant virus, although they were approximately 2-fold higher than reported IC50 values of resistant virus.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Transmission of human immunodeficiency virus type 1 resistant to nevirapine and zidovudine. Sydney Primary HIV Infection Study Group.

Human immunodeficiency virus type 1 (HIV-1) resistant to the nonnucleoside reverse transcriptase inhibitor nevirapine and to the nucleoside analogue zidovudine was transmitted from a homosexual man to his sex partner. The virus source patient had commenced combination zidovudine and nevirapine therapy 2.5 years prior to his partner's primary HIV infection. He received both therapies for 7 months, then discontinued nevirapine treatment, continuing to receive zidovudine monotherapy for a further 16 months. He had ceased zidovudine therapy 6 months before the time of his partner's seroconversion. Analysis of major and minor isolates obtained from both patients soon after onset of the recipient's primary HIV infection illness confirmed that an HIV-1 variant mutant at codons 70, 98, and 181 of the viral reverse transcriptase was transmitted. This is the first documented case of transmission of HIV-1 resistant to two antiretroviral compounds.

Adolescent↗
PubMed1997

Acute human immunodeficiency virus type 1 disease as a mononucleosis-like illness: is the diagnosis too restrictive?

The purpose of this study was to describe the frequency and duration of clinical features at the time of acute human immunodeficiency virus type 1 (HIV-1) disease in 218 patients with documented symptomatic primary HIV-1 infection. The mean duration of acute HIV-1 disease was 25.1 days (median, 20.0 days) and did not differ by gender, age, and risk factor. The frequency and mean duration of clinical features occurring in >50% of patients were as follows: fever, 77.1% and 16.9 days; lethargy, 65.6% and 23.7 days; cutaneous rash, 56.4% and 15 days; myalgia, 54.6% and 17.7 days; and headache, 50.9% and 25.8 days. Only 15.6% of patients presented with a typical mononucleosis-like illness (MLI) defined as fever, pharyngitis or sore throat, and cervical adenopathy, and 10% had no features of an MLI. A meningitis-like syndrome occurred in 20 patients (9.2%). Acute HIV-1 disease is more diverse than previously reported, and the absence of fever or other MLI features does not rule out acute HIV-1 disease.

Acute Disease↗
PubMed1997

The domestic pig as a model for evaluating olestra's nutritional effects.

Experimental conditions for measuring the effect of the noncaloric fat substitute olestra on the availability of dietary nutrients were established in the weanling domestic pig. To evaluate the tolerance of the pig for dietary fat levels similar to those in the human diet, groups were fed a standard corn-soy-based swine feed with and without 14% (30% of energy) added fat for 4 wk. To evaluate the adequacy of a purified diet to produce good growth, groups of pigs were fed purified diets providing 30% of energy from fat and micronutrients at 1, 1.3 or 1.6 times the NRC's requirements for 5- to 10-kg swine. Cumulative body weight gain, digestible feed efficiency and a lack of adverse effects showed that the pig can tolerate diets providing 30% of energy from fat and that a purified diet providing the NRC's requirements for micronutrients produces growth comparable to a nutritionally complete swine feed. To determine whether tissue concentrations of vitamins A, D, E and K in the pig respond to olestra and dietary concentrations of the vitamins, two groups were fed purified diet providing 1 or 1.6 times the NRC's requirements for micronutrients and 4.8% olestra. Significant increases occurred in the serum concentration of 25-hydroxyergocalciferol and liver concentrations of retinol and alpha-tocopherol with increasing dietary concentrations of the vitamins. Olestra reduced the tissue concentrations of vitamins A, D and E. Prothrombin time was not affected by dietary concentration of either phylloquinone or olestra. To determine the amount of UV light exposure required to produce 50-80% of vitamin D status from vitamin D3, a range typical of humans, two groups of pigs were fed the NRC requirement for vitamin D and exposed to 15 or 45 min/d of UV light. Serum concentration of 25-hydroxycholecalciferol increased with increased exposure time. UV exposure of 1-2 min/d was calculated to be sufficient to produce 50-80% of total vitamin D status from vitamin D3. No antemortem observations indicated an adverse olestra effect.

25-Hydroxyvitamin D 2↗
PubMed1997

Physical or temporal separation of olestra and vitamins A, E and D intake decreases the effect of olestra on the status of the vitamins in the pig.

A study was conducted in the domestic pig to determine 1 ) whether feeding olestra mixed in the diet exaggerated olestra effects on fat-soluble vitamin status compared with the effects of feeding it in a typical snack food, and 2) whether separating olestra consumption temporally from vitamin consumption affected the influence of olestra on vitamin status. Groups of 10 pigs each, five castrated males and five females, were fed 2.2% (wt/wt) olestra for 4 wk in purified diet that provided 1 time the National Research Council's requirements for swine of all micronutrients. The olestra was either mixed in the purified diet or fed in potato chips. The potato chips were given to the pigs at all three feedings, at the noon feeding only, or between the noon and the evening feedings. A control group was fed the purified diet with no olestra. The effects of olestra on indices of vitamin A, D and E status were from 1.7 to 4.5 times greater when olestra was fed three times daily mixed in the diet than when it was fed three times daily in potato chips. Because the effect of olestra on the status of the fat-soluble vitamins was diminished substantially by feeding the olestra in potato chips, it was not possible to conclude definitively how the temporal separation of olestra and vitamin consumption affected the olestra effect on vitamin status.

25-Hydroxyvitamin D 2↗
PubMed1997

Olestra dose response on fat-soluble and water-soluble nutrients in the pig.

Groups of weanling pigs were fed a purified diet containing graded concentrations of olestra ranging from 1.1 to 7.7% (wt/wt) and the NRC's requirements for micronutrients for 12 wk. Each group consisted of 12 pigs, with the exception of the control group, which had 20, with equal numbers of females and castrated males. The purpose of the study was to determine the dose-response effects of olestra on fat-soluble vitamins and selected water-soluble micronutrients. At wk 0, 4, 8 and 12, hematology, clinical chemistry and blood concentrations of vitamins A, E, K and B12, and 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, folate, calcium, iron, zinc and adipose concentration of vitamin E were measured. Cumulative weight gain and feed efficiency were determined weekly. Prothrombin time was measured weekly for the control group and the groups fed 5.5 or 7.7% olestra, and monthly for other groups. Liver concentrations of vitamins A, E, and B12 and iron and bone concentrations of calcium, phosphorus, zinc and ash were measured for 12 pigs killed at wk 0 and for all animals at wk 12. By wk 12, the pigs were eating from 20 to 155 g/d of olestra. Olestra did not affect the pigs' growth or feed efficiency, indicating that the digestion and absorption of macronutrients were unaffected. Olestra reduced tissue concentrations of vitamin A, vitamin E and 25-hydroxyergocalciferol in a dose-responsive manner but did not affect prothrombin time. Olestra had no effect on the status of folate, vitamin B12, zinc or iron. Statistically reduced liver concentrations of vitamin B12 and iron in groups fed 5.5 or 7.7% olestra and a significant trend in bone ash content with olestra intake were possibly due to the poor vitamin A and/or vitamin E status of the pigs.

25-Hydroxyvitamin D 2↗
PubMed1997

Olestra's effect on the status of vitamins A, D and E in the pig can be offset by increasing dietary levels of these vitamins.

Groups of weanling pigs (5 castrated males, 5 females per group) were fed purified diets containing the NRC's requirements for nutrients and 0, 1.1, 4.4 or 7.7% olestra for 12 wk. Graded concentrations of vitamins A, D2 and E were added at each olestra concentration. The primary purpose of the study was to establish relationships between dietary concentration of olestra and the amounts of vitamins A, D2 and E needed to restore tissue concentrations of these vitamins to control concentrations. A secondary purpose was to confirm that olestra does not affect the status of vitamin K or water-soluble nutrients. Liver concentrations of vitamins A, E and B12, iron and zinc and bone concentrations of ash, zinc, calcium and phosphorus, were measured in a group of pigs killed at the start of the study and in all pigs killed at wk 12. Growth, feed efficiency, hematology, clinical chemistry, blood concentrations of retinol, alpha-tocopherol, 25-hydroxyergocalciferol, 25-hydroxycholecalciferol, 1,25-dihydroxyvitamin D, folate, iron, total iron-binding capacity, zinc and calcium and adipose concentration of vitamin E were measured at 4-wk intervals. Prothrombin time was measured weekly for the control and 7.7% olestra groups, monthly for others. Relationships derived from measured tissue concentrations of vitamins A and E showed that constant amounts of the vitamins were required per unit mass of olestra in the diet to restore tissue concentrations to control values. Such a relationship could not be determined for vitamin D because exposure of the pigs to UV light resulted in an apparent interaction between vitamin D2 and vitamin D3. Olestra did not affect growth, digestible feed efficiency, vitamin K status or the status of the water-soluble micronutrients, in agreement with other studies in the pig.

Animals↗
PubMed1997

Nutritional status of pigs fed olestra with and without increased dietary levels of vitamins A and E in long-term studies.

In a 26-wk study, five groups (n = 10) of domestic pigs were fed 0.25, 0.5, 1.1, 3.3 or 5.5% olestra; three groups were fed 0.25% with graded levels of vitamins A and E; and one group was fed 5.5% with added vitamins A and E and exposed to UV light. In a 39-wk study, two groups (n = 10) were fed 0.25% olestra with or without added vitamins A and E. In each study, a control group was fed basal diet with no olestra, and a group was killed at d 0 for base-line nutrient measurements. The diets provided the NRC's requirements of micronutrients for 5- to 10-kg pigs, with the following two exceptions: vitamin D was provided at twice the requirement in the 26-wk study and vitamin K was provided at 20% of the requirement in the 39-wk study. One purpose of the studies was to determine the amounts of vitamins A and E required to restore tissue concentrations of those vitamins to control concentrations. A second purpose was to determine the effects of olestra on the status of vitamins A, D, E, K and B12, and folate, iron, calcium and zinc when pigs eat olestra at intakes similar to estimated human intake for a period covering major growth and developmental phases, including sexual maturation. Olestra reduced tissue concentrations of vitamins A, D and E but did not affect prothrombin time or the status of the water-soluble nutrients. The amount of vitamin A required to restore liver concentration to control concentration was 93 microg retinyl palmitate/g olestra. Restoration levels for serum and liver concentrations of vitamin E were 2.2 and 2.1 mg d-alpha-tocopheryl acetate/g olestra. Olestra did not affect growth or digestible feed efficiency in either study, indicating that the absorption and utilization of macronutrients were unaffected. There were no antemortem observations or changes in clinical chemistry or hematology that would indicate an adverse effect of olestra.

25-Hydroxyvitamin D 2↗