Showing papers by "David A. Cooper published in 1996"
TL;DR: In every pair studied, the transmitted variant(s) represents only a minor population in the semen of the corresponding transmitter, thereby providing evidence that HIV-1 selection indeed occurs during sexual transmission.
Abstract: To explore the mechanism of sexual transmission of human immunodeficiency virus type 1 (HIV-1), we compared HIV-1 gp120 sequences in longitudinal samples from five acute seroconvertors with those from their corresponding sexual partners (transmitters). We used a quantitative homoduplex tracking assay to compare the overall genetic composition of HIV-1 quasispecies in each transmission pair and to track the transmitted viruses during the acute and asymptomatic stages of HIV-1 infection. In the chronically infected transmitters, HIV-1 variants in genital secretions differed from those in blood and variants in cells differed from those in cell-free plasma, indicating remarkable sequence heterogeneity in these subjects as well as compartmentalization of the virus in different bodily sites. Conversely, two of five seroconvertors had only a few related variants and three of five harbored only one viral population, indicating that in these subjects the transmitted viruses were typically homogeneous. Transmitted viruses were evident in the donor's seminal plasma (one of five cases) and even more so in their seminal cells (three of five cases), suggesting that both cell-associated and cell-free viruses can be transmitted. In every pair studied, the transmitted variant(s) represents only a minor population in the semen of the corresponding transmitter, thereby providing evidence that HIV-1 selection indeed occurs during sexual transmission.
450 citations
TL;DR: Treatment with ritonavir produced alterations in the immune system that included changes in T cell subset distribution and increases in CD4 and CD8 lymphocyte numbers and of lymphocyte function.
Abstract: Effects of a human immunodeficiency virus (HIV) type 1 protease inhibitor, ritonavir, were evaluated in 21 patients enrolled in a phase I/II study. The magnitude and rates of CD4 and CD8 lymphocyte increase, changes in subsets of CD4 and CD8 lymphocytes, and proliferative responses to mitogen and antigens were analyzed. Significant increases were noted in CD4 and CD8 lymphocyte counts; numbers of CD4CD45RO lymphocytes increased significantly by week 1 of therapy. Increases in the CD4CD45RA subset were observed at week 4. Reductions in the percentage of CD4 and CD8 lymphocytes expressing CD38 were noted. Increases in proliferative responses to phytohemagglutinin were noted in 6 of 7 patients and correlated with duration of virus load suppression. Increased responses to recall antigens and to HIV-specific proteins were observed. Treatment with ritonavir produced alterations in the immune system that included changes in T cell subset distribution and increases in CD4 and CD8 lymphocyte numbers and of lymphocyte function.
328 citations
TL;DR: Although this trial was not designed as a clinical end-point study, patients assigned to zidovudine plus didanosine combination therapy experienced a significant delay in time to first AIDS-defining event or death compared with those assigned toZidovUDine monotherapy.
Abstract: A randomized controlled study was done to determine whether initial combination therapy with zidovudine and zalcitabine or zidovudine and didanosine would delay the emergence of zidovudine-resistant virus. Human immunodeficiency virus (HIV)-1-infected patients with <300 CD4 cells/mm 3 and <4 weeks of prior zidovudine therapy were randomized to zidovudine, zidovudine plus zalcitabine, or zidovudine plus didanosine. Combination therapy did not delay the emergence of zidovudine-resistant virus isolates. However, combination therapy resulted in a significant increase in CD4 cells through 72 weeks compared with zidovudine monotherapy and a greater and more sustained decline in serum HIV-I RNA. Although this trial was not designed as a clinical end-point study, patients assigned to zidovudine plus didanosine combination therapy experienced a significant delay in time to first AIDS-defining event or death compared with those assigned to zidovudine monotherapy.
88 citations
TL;DR: Nevirapine exhibits significant although transient anti-HIV activity in ZDV-pretreated patients but its use is frequently associated with a hypersensitivity reaction.
Abstract: OBJECTIVES: Nevirapine is a non-nucleoside reverse transcriptase inhibitor of HIV-1 which exhibits synergy in vitro with zidovudine (ZDV) and also is active against ZDV-resistant HIV. We evaluated the activity and safety of nevirapine in combination with ZDV in patients receiving long-term ZDV therapy. METHODS: We conducted a randomized, open-label, controlled 28-week study of nevirapine (200 mg daily for 2 weeks followed by 200 mg twice daily for 26 weeks) and continued ZDV (500-600 mg daily) versus continued ZDV alone in 49 HIV-1 p24 antigenaemic patients with CD4+ lymphocyte counts < 500 x 10(6)/l and who had been treated with ZDV for at least 6 months.
RESULTS: Addition of nevirapine to ZDV resulted in a significant and rapid reduction in circulating RNA load (mean, 0.65), a mean CD4+ lymphocyte rise of 34 x 10(6)/l, a reduction in serum beta 2-microglobulin and a median fall in immune complex dissociated p24 antigen levels of 69%. These changes remained statistically significant for 4, 4, 12 and at least 28 weeks, respectively. The principal adverse event due to nevirapine was a hypersensitivity reaction comprising rash with or without fever and mucositis in eight (32%) patients, which was dose-limiting in seven patients. CONCLUSION: Nevirapine exhibits significant although transient anti-HIV activity in ZDV-pretreated patients but its use is frequently associated with a hypersensitivity reaction.
83 citations
TL;DR: The CD8+ lymphocyte proliferation observed with protease inhibitor therapy could result in improved suppression of HIV replication by the immune system and should be confirmed in a prospective trial comparing protease inhibitors with both nucleoside and non-nucleoside analog therapies.
Abstract: CD8+ T lymphocytes may mediate important host responses to human immunodeficiency virus (HIV) infection by human leukocyte antigen (HLA)-restricted cytotoxicity and production of soluble HIV suppressor factors. CD8+ lymphocytes are also important for the suppression of many latent pathogens responsible for opportunistic disease in HIV-infected patients. There has been no systematic analysis of the responses of CD8+ lymphocyte counts to antiretroviral therapy. We compared CD8+ lymphocyte responses in seven trials of nucleoside or non-nucleoside analog reverse transcriptase inhibitors and in two trials of ritonavir, a HIV protease inhibitor. Nucleoside analog and non-nucleoside analog reverse transcriptase inhibitor monotherapy resulted in no substantial changes in CD8+ counts relative to baseline or placebo. Combination nucleoside analog therapy resulted in variable peak responses (-145 to +240 cells/mm3), which remained significantly above baseline for 0 to 12 weeks. In contrast, ritonavir monotherapy caused a peak increase of 892 CD8+ cells/mm3, which remained significantly above baseline for 32 weeks. There was a significant correlation (Rs 0.61, p = 0.01) between the peak CD4+ cell and CD8+ responses to each therapy, but no significant correlation between the peak viral load responses and peak CD8+ cell responses. These findings suggest that the greater CD8+ response seen with ritonavir may be due to its specific inhibition of HIV protease and also that the CD8+ response is dependent on new CD4+ cell production. The CD8+ lymphocyte proliferation observed with protease inhibitor therapy could result in improved suppression of HIV replication by the immune system and should be confirmed in a prospective trial comparing protease inhibitors with both nucleoside and non-nucleoside analog therapies.
53 citations
TL;DR: The decline in incidence and later occurrence of KS suggest several hypotheses, including declining prevalence or reduced virulence of a KS cofactor, according to a retrospective cohort of people diagnosed with AIDS over the period 1983–1994.
Abstract: Objective: To explore trend 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 150x106/l (P = 0.02). A decline in median CD4 T-lymphocyte count at KS diagnosis was seen, from 67x106/l in 1984-1987 to 20x106/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.
42 citations
TL;DR: Primary infection with zidovudine-resistant variants of HIV-1 was not associated with a more severe symptomatic primary illness or more rapid CD4 cell decline at 1 year after infection.
Abstract: Human immunodeficiency virus type 1 (HIV-1) variants with reduced in vitro sensitivity to zidovudine, conferred by specific mutations in the viral reverse transcriptase, emerge during prolonged therapy. Late-stage disease and declining CD4 cell count are associated with more rapid emergence of these resistant variants. Isolates of HIV-1 from seroconverters were screened for the zidovudine-resistance marker mutation at codon 215. HIV-1 with the altered genotype was detected in 5 (8.2%) of 61 patients soon after onset of symptomatic primary illness and from the sex partner of 1 patient. These transmitted resistant viruses were either replaced by strains susceptible to zidovudine within a few months of infection or persisted for up to 1 year in the absence of prolonged zidovudine therapy. The resistant genotype persisted in 3 of 5 seroconverters but in 2 patients had reverted to wild type at 48 and 52 weeks. Primary infection with zidovudine-resistant variants of HIV-1 was not associated with a more severe symptomatic primary illness or more rapid CD4 cell decline at 1 year after infection.
42 citations
25 citations
TL;DR: Bile acid malabsorption can be demonstrated in some cases of HIV associated chronic diarrhoea and a therapeutic trial of a bile sequestering agent in patients whose symptoms are not well controlled using conventional anti-diarrhoeal agents is suggested.
Abstract: Aims: To look for the presence of bile acid malabsorption in HIV infected patients with chronic diarrhoea and determine whether bile sequestering agents may have a role in palliating this common problem.
Methods: Nineteen HIV infected patients with chronic diarrhoea (duration >one month) poorly controlled on conventional treatment were investigated using the seven day retention of 75seleno-23-homocholic acid taurine (SeHCAT) as a measure of bile acid loss from the enterohepatic circulation. Patients with evidence of bile acid malabsorption were offered cholestyramine.
Results: Sixteen (84%) had evidence of bile acid malabsorption (<15% retention at seven days). Ten of the 16 patients with bile acid malabsorption had terminal ileal biopsies -six had ileitis and four normal histology, suggesting that malabsorption is not always related to terminal ileitis. Thirteen patients with bile acid malabsorption have been treated with cholestyramine and 11 have reported a symptomatic response.
Conclusions: Bile acid malabsorption can be demonstrated in some cases of HIV associated chronic diarrhoea and we suggest a therapeutic trial of a bile sequestering agent in patients whose symptoms are not well controlled using conventional anti-diarrhoeal agents.
16 citations
TL;DR: The risk of nosocomial transmission of tuberculosis is significant in institutions caring for HIV-infected patients even in countries with a low prevalence of tuberculosis infection, and highlights the importance of adherence to tuberculosis control guidlines.
Abstract: Objective : To investigate a possible outbreak of tuberculosis in an outpatient HIV treatment facility in Sydney, Australia. Design : Following the diagnosis of pulmonary tuberculosis in an attendee, a prospective screening program was instituted to investigate the potential outbreak. Methods : Screening of 89 potentially exposed patients included chest radiographs (n = 89), and sputum examination (n = 37) over a period of 23 weeks. Results : No cases of tuberculosis were detected by the screening program. However, three (3.4%) of this cohort developed pulmonary tuberculosis between 8 and 10 weeks following the diagnosis of the index case. The incidence of active tuberculosis during the follow-up period (median, 7.4 months) was 5.3 per 100 person years and represents the lower limit of possible tuberculous infection, as both latent infection, and undiagnosed tuberculosis among those who died could not be excluded. Mycobacterium tuberculosis strains isolated from the index case and three subsequent cases were found to be identical by DNA typing. Conclusion : Nosocomial transmission of tuberculosis in an outpatient treatment setting has been demonstrated. The risk of nosocomial transmission of tuberculosis is significant in institutions caring for HIV-infected patients even in countries with a low prevalence of tuberculosis infection, and highlights the importance of adherence to tuberculosis control guidlines.
16 citations
TL;DR: Nevirapine is a potent antiretroviral agent whose use, especially as monotherapy, may be limited by rapid onset of resistance as well as by hypersensitivity reactions, however, virologic features of nevirapine suggest that it may be useful in combination therapy with zidovudine or other antireTrovirals, including for patients infected with zirconia-resistant strains HIV.
Abstract: Nevirapine is a non-nucleoside reverse transcriptase inhibitor specific for HIV-1.1,2 This review will focus on some clinically important aspects of the pharmacology and virology of nevirapine, as well as adverse events and the results of some completed clinical studies.
TL;DR: High-dose ddI at 375 mg twice daily significantly increases the probability of an NSI phenotype over the short term in patients with advanced HIV disease, suggesting that ddI may be selective against the faster-replicating virus.
Abstract: Progression to AIDS in patients harboring human immunodeficiency virus type 1 (HIV-1) isolates expressing a syncytium-inducing (SI) phenotype is faster than in those in whom the virus expresses a non-SI (NSI) phenotype. Zidovudine monotherapy does not appear to alter this outcome. To examine the role of didanosine (ddI) monotherapy in phenotype expression, HIV-1 isolates from 73 patients receiving ddI for up to 72 weeks were analyzed. After 12 weeks, the number of isolates expressing an NSI phenotype was 29% higher than at the start of treatment. Patients receiving high-dose ddI (375 mg twice daily) were significantly more likely to express the NSI phenotype at 12 weeks than patients who received low-dose ddI (100 mg twice daily), even after adjustment for phenotype and CD4 cell count at baseline, suggesting that ddI may be selective against the faster-replicating virus. ddI at 375 mg twice daily significantly increases the probability of an NSI phenotype over the short term in patients with advanced HIV disease.
TL;DR: The dosages of CEOP in cohort 1 defined the MTD however, the cohort 2 doses with filgrastim and antiretroviral therapy gave an encouraging response, acceptable toxicities and merit further study.
01 Sep 1996
TL;DR: A pilot project in informal settlements in Khayelitsha, Cape Town, South Africa, to use community-based distribution (CBD) for contraceptive delivery and preliminary findings reveal a range of problems including limited hours of operations and long waiting lines.
Abstract: This article describes a pilot project in informal settlements in Khayelitsha Cape Town South Africa to use community-based distribution (CBD) for contraceptive delivery. The article presents preliminary findings from a baseline survey conducted among a sample of 696 women and 679 men in all CBD areas. The pilot program began in March 1996. Most people lived in informal housing with or without access to services. Three nongovernmental organizations (NGOs) piloted the program. Qualitative and quantitative studies were conducted to determine the nature of contraceptive services and the response of the population to these services. Qualitative studies included in-depth interviews with key staff at five contraceptive clinics and health NGOs serving the target areas. Findings reveal a range of problems including limited hours of operations and long waiting lines. Services focused on injectables. Quality of care problems included perceived side effects limited client information poor client-staff relations and limited follow-up. A number of clinic problems would be reduced with CBD distribution. The survey among the suburbs of Harare Makhaza Site B and Griffiths Mxenge in August 1995 and February 1996 reveals that men and women differed in the desired family size. Respondents had less children than they preferred. Support was strongly in favor of contraception. Contraceptive use was 66%. 83% were using injectables. 75% reported that the method choice was made by the provider. Almost all believed that germs caused sexually transmitted diseases but there was misinformation on transmission modes.
Journal Article•
TL;DR: Zidovudine (AZT) is not the only drug with some effect on HIV but new agents and better-directed use of established agents can delay progression of the disease and prevent the onset of symptoms for some time.
Abstract: Zidovudine (AZT) is not the only drug with some effect on HIV. New agents and better-directed use of established agents can delay progression of the disease and prevent the onset of symptoms for some time.
Journal Article•
TL;DR: Overall, the Australian system works well, but it remains in conflict with political pressures to cut costs.
Abstract: AIDS: Australia's policies regarding AIDS-related services are progressive As a result, most Australians enjoy approximately equal access to care, regardless of income; only those physically distant from health care facilities receive diminished services The health care system is funded through general revenue taxes, currently at 14 percent of income The chargeback system for physicians allows them to either accept the governments pre-set fees for services, or add a surcharge As a result, some physicians have reduced the quality of services so that they can see more patients per day Generally, the Australian history of HIV/AIDS care coincides with the culture of providing safety nets and systems that are fair and equitable Australia was a pioneer in needle and syringe exchange programs Drug trials in Australia have been hampered by both a small potential market for the drugs (Australians account for only one percent of the market for worldwide pharmaceuticals) and by a regulatory climate that is difficult for the drug manufacturers to work in Overall, the Australian system works well, but it remains in conflict with political pressures to cut costs