Acquired Immunodeficiency Syndrome: Cooper DA

Yeni PG, Hammer SM, Carpenter CC, Cooper DA, Fischl MA, Gatell JM, Gazzard BG, Hirsch MS, Jacobsen DM, Katzenstein DA, Montaner JS, Richman DD, Saag MS, Schechter M, Schooley RT, Thompson MA, Vella S, Volberding PA. · Hôpital Bichat-Claude Bernard, Department of Infectious Diseases, 46 Rue Henri-Huchard, Paris, Cedex 18 France 75877. · JAMA. · Pubmed #12095387 No free full text.

Abstract: OBJECTIVE: New information warrants updated recommendations for the 4 central issues in antiretroviral therapy: when to start, what drugs to start with, when to change, and what to change to. These updated recommendations are intended to guide practicing physicians actively involved in human immunodeficiency virus (HIV)- and acquired immunodeficiency syndrome (AIDS)-related care. PARTICIPANTS: In 1995, physicians with specific expertise in HIV-related basic science and clinical research, antiretroviral therapy, and HIV patient care were invited by the International AIDS Society-USA to serve on a volunteer panel. In 1999, others were invited to broaden international representation. The 17-member panel met regularly in closed meetings between its last report in 2000 and April 2002 to review current data. The effort was sponsored and funded by the International AIDS Society-USA, a not-for-profit physician education organization. EVIDENCE AND CONSENSUS PROCESS: The full panel was convened in late 2000 and assigned 7 section committees. A section writer and 3 to 5 section committee members (each panel member served on numerous sections) identified relevant evidence and prepared draft recommendations. Basic science, clinical research, and epidemiologic data from the published literature and abstracts from recent (within 2 years) scientific conferences were considered by strength of evidence. Extrapolations from basic science data and expert opinion of the panel members were included as evidence. Draft sections were combined and circulated to the entire panel and discussed in a series of full-panel conference calls until consensus was reached. Final recommendations represent full consensus agreement of the panel. CONCLUSIONS: Because of increased awareness of the activity and toxicity of current drugs, the threshold for initiation of therapy has shifted to a later time in the course of HIV disease. However, the optimal time to initiate therapy remains imprecisely defined. Availability of new drugs has broadened options for therapy initiation and management of treatment failure, which remains a difficult challenge.

Dore GJ, Cooper DA. · No affiliation provided · Med J Aust. · Pubmed #11837843 links to  free full text

This publication has no abstract.

Cooper DA, Lange JM. · University of New South Wales, National Centre in HIV Epidemiology and Clinical Research, St Vincent's Hospital Medical Centre, Sydney, Australia. · Lancet Infect Dis. · Pubmed #15219553 No free full text.

Abstract: The peptidic antiretroviral enfuvirtide (Fuzeon) is the first clinically approved antiviral fusion inhibitor and the first antiretroviral that must routinely be administered parenterally. Its extracellular activity results both in activity against current drug-resistant strains of HIV-1 and a low potential for systemic toxicities. As a peptide, enfuvirtide also exhibits few interactions with other antiretrovirals and concomitant medications used in HIV disease. Enfuvirtide shows potent antiretroviral activity and significantly improves medical outcomes in highly treatment-experienced patients with HIV-1 infection, but like other antiretrovirals must be given as part of a carefully selected combination regimen to minimise the risk of emergent drug resistance. Despite its subcutaneous route of administration, clinical data indicate that most patients can accept long-term enfuvirtide treatment with little difficulty or impact on daily activities. The only common adverse event associated with enfuvirtide use is injection-site reactions of generally mild-to-moderate severity, which are seldom treatment-limiting.

Lindbäck S, Vizzard J, Cooper DA, Gaines H. · Department of Infectious Diseases, Karolinska Institute, Huddinge Hospital, S-141 86 Huddinge, Sweden. · J Infect Dis. · Pubmed #10228080 No free full text.

Abstract: 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.

Benson EM, Clarkson J, Law M, Marshall P, Kelleher AD, Smith DE, Patou G, Stewart GJ, Cooper DA, French RA. · Department of Clinical Immunology, ICPMR, Westmead Hospital, Wentworthville, NSW, Australia. · AIDS Res Hum Retroviruses. · Pubmed #10029243 No free full text.

Abstract: 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.

Cooper DA. · National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, NSW 2052, Australia. · Lancet. · Pubmed #18657689 No free full text.

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Boyd MA, Carr A, Ruxrungtham K, Srasuebkul P, Bien D, Law M, Wangsuphachart S, Krisanachinda A, Lerdlum S, Lange JM, Phanuphak P, Cooper DA, Reiss P. · HIV Netherlands Australia Thailand Research Collaboration, Thai Red Cross AIDS Research Centre, Bangkok, Thailand. · J Infect Dis. · Pubmed #16897663 No free full text.

Abstract: BACKGROUND: Body composition changes complicate antiretroviral therapy. Improvements in lipoatrophy after a switch in nucleoside reverse-transcriptase inhibitors (NRTIs) have been demonstrated. We investigated 60 patients switching from failed NRTIs to ritonavir-boosted indinavir and efavirenz. METHODS: Body composition (assessed by dual-energy x-ray absorptiometry scan and by single-slice computed tomography of the abdomen through the level of the fourth lumbar vertebra [L4] and the mid-right thigh) and fasted metabolics were measured at the baseline time-point at switch and at weeks 48 and 96 thereafter. Mitochondrial DNA and RNA were extracted from right-thigh subcutaneous fat and peripheral-blood mononuclear cells (PBMCs) at weeks 0 and 48. The primary end point was the change in mean limb fat over 48 weeks. RESULTS: At week 96, we observed increases in mean (standard deviation [SD]) limb fat (+620 [974] g; P=.003), L4 subcutaneous adipose tissue (+20 [35] cm(2); P<.001), mid-thigh subcutaneous adipose tissue (+5 [10] cm(2); P<.001), and L4 visceral adipose tissue (+11 [34] cm(2); P=.01), but we also observed reduced lean limb mass (-831 [1,100] g; P=.3). Mean (SD) mtDNA content in subcutaneous fat and in PBMCs increased (+109 [274] and +45 [100] copies/cell, respectively). Improved virological control or immune recovery did not explain the results. Triglyceride, total cholesterol, estimated low-density lipoprotein cholesterol, ratio of total cholesterol to high-density lipoprotein cholesterol, and blood glucose levels deteriorated (i.e., had increased by 206%, 67%, 58%, 19%, and 6%, respectively, at week 96). CONCLUSIONS: This regimen was associated with statistically significant but clinically modest increases in peripheral fat, visceral fat, and mitochondrial nucleic acid content. A predominantly adverse metabolic profile developed.

Dore GJ, Cooper DA. · National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney 2010, New South Wales, Australia. · Lancet. · Pubmed #16890810 No free full text.

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Anonymous00074, Yeni P, Cooper DA, Aboulker JP, Babiker AG, Carey D, Darbyshire JH, Floridia M, Girard PM, Goodall RL, Hooker MH, Mijch A, Meiffredy V, Salzberger B. · No affiliation provided · Lancet. · Pubmed #16860698 No free full text.

Abstract: BACKGROUND: Antiretroviral therapy has greatly reduced HIV mortality and morbidity. However, the best sequence of regimens and implications of initial regimen for long-term therapeutic success are not well defined. METHODS: In INITIO, a large international randomised trial, we compared antiretroviral therapy with two nucleoside analogue reverse transcriptase inhibitors (didanosine+stavudine) plus either a non-nucleoside reverse transcriptase inhibitor (efavirenz, EFV) or a protease inhibitor (nelfinavir, NFV), or both (EFV/NFV), in patients with HIV-1 infection who had not previously received antiretroviral drugs. Primary outcomes were proportion with undetectable HIV RNA in plasma, and change in CD4 count from baseline at 3 years. Analyses were by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN44582462. FINDINGS: We followed up 911 participants (297 EFV, 311 NFV, 303 EFV/NFV). At 3 years, the proportion with HIV RNA less than 50 copies per mL was highest in the EFV group (188 [74%] EFV, 162 [62%] NFV, 155 [62%] EFV/NFV; p=0.004). Mean (95% CI) increases in CD4 count were 316x10(6) cells per L (288-343) for EFV, 289x10(6) cells per L (262-316) for NFV, and 274x10(6) cells per L (231-291) for EFV/NFV (p=0.1). Fewer participants in the EFV group than in the other groups stopped adequate antiretroviral therapy for more than 30 days (p=0.005). Participants in the EFV/NFV group had shorter time to stopping the initial regimen (p<0.0001) and to a treatment modifying adverse event (p=0.04) than those in the other groups. INTERPRETATION: Starting antiretroviral therapy with a three-drug/two-class regimen including efavirenz was better than starting with regimens including nelfinavir or efavirenz plus nelfinavir in terms of virological suppression and durability of the initial regimen. The shorter time on adequate antiretroviral therapy or to a treatment-modifying adverse event might explain the absence of additional benefit for the four-drug regimen.

Boyd MA, Aarnoutse RE, Ruxrungtham K, Stek M, van Heeswijk RP, Lange JM, Cooper DA, Phanuphak P, Burger DM. · The HIV Netherlands Australia Thailand Research Collaboration, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand. · J Acquir Immune Defic Syndr. · Pubmed #14526202 No free full text.

Abstract: BACKGROUND: Addition of efavirenz (600 mg) to indinavir/ritonavir (800/100 mg) results in significant decreases in indinavir levels in healthy volunteers. This study evaluated the steady-state pharmacokinetics of indinavir/ritonavir at 800/100 mg twice daily (bid) in combination with efavirenz at 600 mg once daily (qd) in HIV-infected Thai subjects who used this nucleoside-sparing combination in The HIV Netherlands Australia Thailand Research Collaboration 009 study. METHODS: At week 4 of the study, 12-hour pharmacokinetic profiles for indinavir/ritonavir were obtained for 20 HIV-infected subjects. For efavirenz, the concentrations at 12 hours and 24 hours (Cmin) after dosing were assessed. RESULTS: All subjects (10 males and 10 females) completed the study. The geometric mean area under the concentration versus time curve, Cmin, and maximum plasma concentration of indinavir were 45.7 mg/(L. h) (95% confidence interval [CI], 39.8-52.5), 0.32 mg/L (95% CI, 0.24-0.44), and 11.1 mg/L (95% CI, 9.4-13.0), respectively. A >10-fold variation in indinavir Cmin was observed. All subjects had an indinavir Cmin that was at least comparable with the reported mean population Cmin of indinavir at 800 mg thrice daily without ritonavir (0.15 mg/L). The geometric mean concentration at 12 hours and Cmin of efavirenz were 3.1 mg/L (95% CI, 2.5-3.7) and 2.1 mg/L (95% CI, 1.6-2.6), respectively. CONCLUSIONS: Despite the known pharmacokinetic interaction between efavirenz and indinavir/ritonavir, the combination of indinavir/ritonavir at 800/100 mg bid and efavirenz at 600 mg qd results in adequate minimum concentrations of both indinavir and efavirenz for treatment-naive patients.

Wang B, Dyer WB, Zaunders JJ, Mikhail M, Sullivan JS, Williams L, Haddad DN, Harris G, Holt JA, Cooper DA, Miranda-Saksena M, Boadle R, Kelleher AD, Saksena NK. · Retroviral Genetics Laboratory, Centre for Virus Research, Westmead Millennium Institute, Westmead Hospital, University of Sydney, Westmead, New South Wales 2145, Australia. · Virology. · Pubmed #12504566 No free full text.

Abstract: We recently demonstrated that a unique HIV-1-infected nonprogressor was infected with a nonevolving replication-incompetent HIV-1 strain, showing a total absence of viral evolution in vivo. Potent immune responses against HIV-1 were observed in his PBMC, despite an apparent lack of viral replication for at least 8 years. His PBMC resisted superinfection with CCR5, CXCR4, and dual-tropic HIV-1 strains, although highly purified CD4+ T cells supported infection, but without any visible cytopathic effect. Potent noncytolytic CD8+ T cell antiviral activity was shown to protect his PBMC from productive infection. This activity was not mediated by several known chemokines or IFN-gamma, which were produced at high levels after PHA activation of his CD8+ T cells, indicating the action of other CAF-like CD8 factors. This antiviral activity was a memory response, induced by HIV-specific stimulation to similar levels observed by PHA stimulation, but absent in ex vivo resting T cells. Immunological mechanisms associated with this antiviral suppressive activity included vigorous Gag-specific helper T cell proliferative responses and high-level IFN-gamma release by both CD4 and CD8 T cells. These responses were broadly directed against multiple Gag epitopes, both previously reported and some novel epitopes. Strong HIV-specific helper T cell function was also associated with strong neutralizing antibodies. Understanding how to induce these protective immune responses in other individuals could provide a major step forward in the design of effective immunotherapies or vaccines against HIV infection.

Gan SK, Samaras K, Thompson CH, Kraegen EW, Carr A, Cooper DA, Chisholm DJ. · Metabolism and Diabetes Research Program, Garvan Institute of Medical Research, Sydney, Australia. · Diabetes. · Pubmed #12401706 links to  free full text

Abstract: HIV protease inhibitor-related lipodystrophy is characterized by peripheral fat loss, hyperlipidemia, and insulin resistance. Increased availability of lipid to muscle may be one of the mechanisms that induce insulin resistance. Regional fat, intramyocellular lipid (by (1)H-magnetic resonance spectroscopy), serum lipids, and insulin-stimulated glucose disposal (by hyperinsulinemic-euglycemic clamp) were quantified in 10 men who had HIV-1 infection with moderate to severe lipodystrophy and a control group of 10 nonlipodystrophic men who had HIV-1 infection and were naïve to protease inhibitors to examine the effects of lipodystrophy on glucose and lipid metabolism. Lipodystrophic subjects showed lower insulin-stimulated glucose disposal than control subjects (P = 0.001) and had increased serum triglycerides (P = 0.03), less limb fat (P = 0.02), increased visceral fat as a proportion of total abdominal fat (P = 0.003), and increased intramyocellular lipid (1.90 +/- 0.15 vs. 1.23 +/- 0.16% of water resonance peak area; P = 0.007). In both groups combined, visceral fat related strongly to intramyocellular lipid (r = 0.83, P < 0.0001) and intramyocellular lipid related negatively to insulin-stimulated glucose disposal (r = -0.71, P = 0.0005). Fasting serum cholesterol and triglycerides related positively to intramyocellular lipid and visceral fat in lipodystrophic subjects only. The data indicate that lipodystrophy is associated with increased lipid content in muscle accompanying impaired insulin action. The results do not establish causation but emphasize the interrelationships among visceral fat, myocyte lipid, and insulin action.

Vanhems P, Hirschel B, Phillips AN, Cooper DA, Vizzard J, Brassard J, Perrin L. · Laboratoire d'Epidémiologie et de Santé Publique, Université Claude Bernard Lyon 1, 8, av. Rockefeller, 69373 Lyon Cedex 08, France. · J Infect Dis. · Pubmed #10882619 No free full text.

Abstract: The severity and the duration of acute human immunodeficiency virus (HIV) infection (AHI) are associated with a faster rate of progression to AIDS, but the prognostic value of the length of incubation time of AHI (IncAHI), defined as the time between HIV infection and AHI, on progression to AIDS has not been assessed. We explored this issue prospectively in 70 individuals with documented AHI and a known date of HIV infection. The median IncAHI was 21.5 days (range, 5-70 days), and the median duration of AHI was 15.5 days (range, 3-67 days). The adjusted relative hazard of progression to AIDS or to a CD4(+) count <200x103/mL was 4.23 (95% confidence interval [CI], 1.40-12.73; P=.01) for the patients with an IncAHI <21.5 days, compared with those with longer IncAHI, and was 3.53 (95% CI, 1.09-11.36; P=.03) for the patients with a duration of AHI >15.5 days, compared with those with shorter duration. Both IncAHI and duration of AHI were independent predictors of progression. This suggests that early pathogenic events before the onset of AHI influence the rate of HIV disease progression.

Law MG, Li Y, McDonald AM, Cooper DA, Kaldor JM. · National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales, Darlinghurst, Australia. · AIDS. · Pubmed #10708291 No free full text.

Abstract: OBJECTIVE: To estimate the reduction in AIDS incidence, if any, which has occurred in Australia following the availability of new combination antiretroviral treatments from 1995. DESIGN: Analyses were based on national surveillance data. METHODS: Back-projection analyses based on quarterly AIDS counts to the end of 1994 were used to estimate the numbers of AIDS diagnoses which would have occurred if new treatments had not reduced the rate of progression to AIDS. Estimates of the reduction in AIDS diagnoses between 1995 and 1998 were made by subtracting the observed delay-adjusted AIDS counts from the predicted AIDS incidence. RESULTS: AIDS incidence between 1995 and 1998 was estimated to have been reduced by 1093 cases (33%) following the availability of new antiretroviral treatments (95% confidence interval 831 (25%) to 1425 (43%) cases). The majority of this reduction in AIDS incidence was estimated to have occurred during 1997 (434 cases) and 1998 (427 cases). CONCLUSIONS: AIDS incidence in Australia has declined since 1995 coincidental with introduction of new antiretroviral treatments. In particular, the more rapid decline in AIDS incidence since mid-1996 coincided with the availability and widespread uptake of combinations including protease inhibitors.

Dore GJ, Correll PK, Li Y, Kaldor JM, Cooper DA, Brew BJ. · National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Darlinghurst, Australia. · AIDS. · Pubmed #10416530 No free full text.

Abstract: OBJECTIVES: To determine the protective efficacy of highly active antiretroviral therapy (HAART) against AIDS dementia complex (ADC) relative to other initial AIDS-defining illnesses (ADIs), Australian AIDS notification data over recent years were examined. METHODS: All initial ADIs in Australia over the period 1992-1997 were included. Three initial ADI groups were established: ADC; other predominantly central nervous system (CNS) ADIs (toxoplasmosis and cryptococcosis); and non-CNS ADIs. For each ADI grouping, the proportion of total ADls, and median CD4 cell count in the pre-HAART era (1992-1995) were compared with the HAART era (1996 and 1997). RESULTS: Initial ADls peaked in Australia in 1994 (n = 1049), with a gradual decline to 1996 (n = 722), and a marked decline in 1997 (n = 367). ADC constituted 4.4% of initial ADIs over the period 1992-1995, but increased after the introduction of HAART to 6.0% in 1996 and 6.5% in 1997 (P = 0.02). In contrast, the proportion of other CNS ADIs (1992-1995, 8.1%; 1996, 6.0%; 1997, 8.2%; P = 0.41) was stable over the period 1992-1997. The median CD4 cell count at ADC diagnosis increased from 70/mm3 in 1992-1995 to 120/mm3 in 1996 and 170/mm3 in 1997 (P = 0.04). Although the median CD4 cell count also increased significantly over this period for both other CNS ADIs (40-60/mm3; P = 0.02), and non-CNS ADIs (60-70/mm3; P = 0.02), the increase was small. CONCLUSION: A proportional increase in ADC compared with other ADIs and a marked increase in the median CD4 cell count at ADC diagnosis have occurred since the introduction of HAART in Australia. These changes suggest that HAART has a lesser impact on ADC than on other ADIs, with the poor CNS penetration of many antiretroviral agents a possible explanation.

Law MG, de Winter L, McDonald A, Cooper DA, Kaldor JM. · National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Darlinghurst, Australia. · AIDS. · Pubmed #10202833 No free full text.

Abstract: 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.

Cooper DA, Emery S, Cordery DV. · No affiliation provided · J Infect Dis. · Pubmed #18419355 No free full text.

This publication has no abstract.

Vanhems P, Caillat-Vallet E, Hirschel B, Routy JP, Carr A, Vizzard J, Cooper DA, Perrin L, Anonymous00275. · No affiliation provided · AIDS. · Pubmed #12409751 No free full text.

This publication has no abstract.