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Biomedical subjects

J Darbyshire

Publications and source records attributed to J Darbyshire.

At least 19 recordsLinked to original sources
PubMed2006

CD4+ count-guided interruption of antiretroviral treatment.

BACKGROUND: Despite declines in morbidity and mortality with the use of combination antiretroviral therapy, its effectiveness is limited by adverse events, problems with adherence, and resistance of the human immunodeficiency virus (HIV). METHODS: We randomly assigned persons infected with HIV who had a CD4+ cell count of more than 350 per cubic millimeter to the continuous use of antiretroviral therapy (the viral suppression group) or the episodic use of antiretroviral therapy (the drug conservation group). Episodic use involved the deferral of therapy until the CD4+ count decreased to less than 250 per cubic millimeter and then the use of therapy until the CD4+ count increased to more than 350 per cubic millimeter. The primary end point was the development of an opportunistic disease or death from any cause. An important secondary end point was major cardiovascular, renal, or hepatic disease. RESULTS: A total of 5472 participants (2720 assigned to drug conservation and 2752 to viral suppression) were followed for an average of 16 months before the protocol was modified for the drug conservation group. At baseline, the median and nadir CD4+ counts were 597 per cubic millimeter and 250 per cubic millimeter, respectively, and 71.7% of participants had plasma HIV RNA levels of 400 copies or less per milliliter. Opportunistic disease or death from any cause occurred in 120 participants (3.3 events per 100 person-years) in the drug conservation group and 47 participants (1.3 per 100 person-years) in the viral suppression group (hazard ratio for the drug conservation group vs. the viral suppression group, 2.6; 95% confidence interval [CI], 1.9 to 3.7; P<0.001). Hazard ratios for death from any cause and for major cardiovascular, renal, and hepatic disease were 1.8 (95% CI, 1.2 to 2.9; P=0.007) and 1.7 (95% CI, 1.1 to 2.5; P=0.009), respectively. Adjustment for the latest CD4+ count and HIV RNA level (as time-updated covariates) reduced the hazard ratio for the primary end point from 2.6 to 1.5 (95% CI, 1.0 to 2.1). CONCLUSIONS: Episodic antiretroviral therapy guided by the CD4+ count, as used in our study, significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous antiretroviral therapy, largely as a consequence of lowering the CD4+ cell count and increasing the viral load. Episodic antiretroviral therapy does not reduce the risk of adverse events that have been associated with antiretroviral therapy. (ClinicalTrials.gov number, NCT00027352 [ClinicalTrials.gov].).

AIDS-Related Opportunistic Infections↗
PubMed2006

A prospective study of Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus in adults with human immunodeficiency virus-1.

Antibody titres against Kaposi's sarcoma associated herpesvirus (KSHV or human herpesvirus 8 (HHV-8)) and Epstein-Barr virus (EBV) were examined in people who subsequently developed Kaposi's sarcoma and non-Hodgkin's lymphoma, within randomised controlled trials of antiretroviral therapy in adults infected with the human immunodeficiency virus-1 (HIV). For each case of Kaposi's sarcoma (n=189) and each case of non-Hodgkin's lymphoma (n=67), which developed after randomisation, one control was randomly selected from other trial participants, after matching for age, sex, ethnicity, mode of HIV transmission, type of treatment received and period of follow-up. Using sera taken an average of two and a half years before the diagnosis of cancer, titres of antibodies against KSHV latent (LANA) and lytic (K8.1) antigens and against EBV (VCA) antigens were investigated in relation to subsequent risks of cancer by calculating odds ratios (OR) using conditional logistic regression. Latent antibodies against KSHV were detectable among 38% (72 out of 189) of Kaposi's sarcoma cases and 12% (23 out of 189) of their controls (OR=4.4, 95% confidence intervals (CI) 2.3-8.3, P<0.001). The OR for Kaposi's sarcoma increased with increasing antilatent KSHV antibody titre (chi(2)(1) for trend=32.2, P<0.001). Lytic antibodies against KSHV were detectable among 33% (61 out of 187) of Kaposi's sarcoma cases and 19% (36 out of 187) of their controls (OR=2.0, 95% CI 1.2-3.4, P=0.003) and the OR for Kaposi's sarcoma increased with increasing antilytic KSHV antibody titre (chi(2)(1) for trend=6.2, P=0.02). Virtually, all cases and controls had anti-EBV antibodies detected and the OR for non-Hodgkin's lymphoma associated with a doubling of the anti-EBV antibody titre was estimated to increase by a multiplicative factor of 1.3 (95% CI 0.9-1.7, P=0.1). Kaposi's sarcoma was not associated with antibody levels against EBV (P=0.4) and non-Hodgkin's lymphoma was not associated with antibodies against KSHV (latent P=0.3; lytic P=0.5). Adjustment for CD4 count at the time of sample collection made no material difference to any of the results. In conclusion, among human immunodeficiency virus infected people, high levels of antibodies against KSHV latent and lytic antigens are strongly associated with subsequent risk of Kaposi's sarcoma but not non-Hodgkin's lymphoma. Antibody titre to EBV does not appear to be strongly associated with subsequent risk of Kaposi's sarcoma or non-Hodgkin's lymphoma in HIV infected people.

Adult↗
PubMed2004

Highly active antiretroviral therapy started in infants under 3 months of age: 72-week follow-up for CD4 cell count, viral load and drug resistance outcome.

OBJECTIVE: To assess the feasibility and impact of highly active antiretroviral therapy (HAART) started in vertically HIV-1-infected infants less than 3 months of age. DESIGN: A multicentre, phase I/II, non-randomized, open-label study (PENTA 7). METHODS: Adverse events, plasma HIV-1 RNA, CD4 cell counts, CD4 cell percentage (CD4%) and clinical progression were recorded at baseline and prospectively to 72 weeks in order to assess the toxicity, tolerability and efficacy of a combination of stavudine, didanosine and nelfinavir. Selection of genotypic resistance was also investigated. RESULTS: Twenty infants, of whom only three had Centers for Disease Control and Prevention stage B, initiated HAART at median age 2.5 months (range, 0.9-4.7) with median HIV-1 RNA concentration 5.5 log10 copies/ml (range, 3.2-6.8) and CD4% 33% (range, 11-66). Median follow-up was 96 weeks (range, 60-144). At week 72, 11 infants were still taking the original treatment. Few adverse events were reported related to treatment, all minor and causing treatment interruption in only three infants. No AIDS-defining events occurred; one child died of non-HIV-related causes (prematurity). All but two had CD4% > 25% at 72 weeks; however, 14 infants had virological failure and six acquired resistance mutations. CONCLUSIONS: Early treatment with stavudine, didanosine and nelfinavir was well tolerated and associated with good clinical and immunological outcomes at week 72. However, a high rate of virological failure with emergence of genotypic resistance is of great concern. More palatable drug combinations for infants and closer drug monitoring are required.

Antiretroviral Therapy, Highly Active↗
PubMed2002

WISDOM: history and early demise - was it inevitable?

In 1989, the UK Medical Research Council (MRC) agreed that, if feasible, a randomized controlled trial to assess the long-term risks and benefits of hormone replacement therapy (HRT) was a priority. Feasibility work began in 1990 and demonstrated that a large-scale multicenter trial was possible. An application for funding for a main trial was submitted to MRC in 1993 and, after extensive review, funding was released in late 1996. Set-up work for the trial - the Women's International Study of long Duration Oestrogen after Menopause (WISDOM) - began in 1997 with recruitment in 1999. In October 2002, following the early discontinuation of one arm of the US Women's Health Initiative HRT trial, the MRC decided to stop the WISDOM trial. This article, by the principal UK investigators of WISDOM, sets out the background and history of the trial.

Clinical Trials Data Monitoring Committees↗
PubMed2001

'Chemical condoms' for the prevention of HIV infection: evaluation of novel agents against SHIV(89.6PD) in vitro and in vivo.

BACKGROUND: Vaginal agents which are antiviral and/or inhibit the entry of HIV into the cell could prevent heterosexual transmission of HIV, and protect women who cannot negotiate condom use. METHODS: Four agents have been investigated for activity in vitro and in vivo against SHIV(89.6PD): two anionic polymers, dextrin-2-sulphate (D2S) and PRO 2000 (P2K), and two virucidal agents; a non-ionic detergent, nonoxynol-9 (N9) and a cyclic peptide ionophore, gramicidin-D (GD). All four agents were investigated in rhesus macaques, using an intra-vaginal challenge of two inoculations of 1 x 104 50% tissue culture infectious doses (TCID)50 of SHIV(89.6PD). RESULTS: D2S, P2K, GD and N9 all inhibited SHIV(89.6PD) in vitro. In vivo, three out of four control macaques were infected as judged by viral culture, seroconversion, DNA and RNA PCR; infection was confirmed in four out of eight macaques pre-treated with P2K, two out of four pre-treated with D2S, one out of four pre-treated with N9, two out of four pre-treated with GD and four out of four pre-treated with D2S + GD, a combination additive in vitro. INTERPRETATION: D2S and PRO-2000, novel inhibitors of HIV entry, showed evidence of protection in vivo, comparable to that seen with the virucide, N9. These data, together with the results of phase I and phase II studies in healthy women which have shown minimal toxicity, support plans for a phase III efficacy trial of chemically simple inhibitors of HIV entry with low toxicity, for the prevention of HIV infection in women.

Administration, Intravaginal↗
PubMed2000

A phase I trial in HIV negative healthy volunteers evaluating the effect of potent adjuvants on immunogenicity of a recombinant gp120W61D derived from dual tropic R5X4 HIV-1ACH320.

Thirty healthy HIV negative volunteers were randomised to receive 200 micrograms of rgp120W61D in either: 3D-MPL and QS21, with an oil and water emulsion (SBAS-2) (13); or 3D-MPL and QS21 (SBAS-1) (11); or alum (six). Immunizations were given at 0, 4 and 28 weeks and 23 (77%) participants completed the schedule. Adverse events were more frequent (P < 0.001) and more severe (P < 0.001) in the SBAS-2 group. Binding antibodies to the homologous rgp120W61D were detected after the first immunisation only in those receiving SBAS-1 and SBAS-2, were maximal after the third immunization in all three groups, and persisted to week 84 only in the novel adjuvant groups. These differences were significant (p = 0.02). Neutralising antibodies to TCLA-strains of HIV-1 were observed after the second immunization in all three groups, were maximal after the third immunization, but did not neutralise homologous or heterologous PBMC derived primary HIV-1 isolates. Proliferative T-cell responses to rgp120W61D were maximal after the second immunization and reached very high values in the SBAS-2 group. HIV-1 specific CD8+ MHC Class I restricted cytotoxic T-lymphocytes were not seen in a subset of participants tested at a single timepoint. SBAS-2 with rgp120W61D induced antibody titres as high as those seen in HIV infection, but the quality of the antibodies remained different in that there was no evidence of primary isolate neutralisation. Although cell-mediated immunity was enhanced by SBAS-2 in terms of lymphoproliferative responses, HIV-1 specific CD8+ cytotoxicity was not demonstrated.

AIDS Vaccines↗
PubMed2000

Zidovudine (AZT) versus AZT plus didanosine (ddI) versus AZT plus zalcitabine (ddC) in HIV infected adults.

BACKGROUND: Zidovudine (AZT) monotherapy was the first antiretroviral drug to be tested widely. The next two drugs to be developed were didanosine (ddI) and zalcitabine (ddC). OBJECTIVES: To assess the effects of zidovudine (AZT), zidovudine plus didanosine (ddI) and zidovudine plus zalcitabine (ddC) on HIV disease progression and survival. SEARCH STRATEGY: Investigators and pharmaceutical companies were contacted, and MEDLINE searches were supplemented by searching conference abstracts. SELECTION CRITERIA: Randomised controlled trials comparing any two of AZT plus ddI, AZT plus ddC or AZT alone in participants with or without AIDS which collected information on deaths and new AIDS events. DATA COLLECTION AND ANALYSIS: Individual patient data with, wherever possible, follow-up obtained beyond that previously published were obtained and checked for internal consistency and consistency with any published reports; any apparent discrepancies were resolved with the trialists. Time to death and to disease progression (defined as a new AIDS-defining event or prior death) were analysed on an intention to treat basis, stratified to avoid direct comparisons between participants in different trials. MAIN RESULTS: Six trials were included in the meta-analysis. During a median follow-up of 29 months, 2904 individuals progressed, of whom 1850 died. The addition of ddI to AZT delayed both progression (RR 0.74; 95% CI 0.67 to 0.82, P<0.0001) and death (RR 0.72; 95% CI 0.64 to 0.82, P<0.0001). Likewise, the addition of ddC to AZT also delayed progression (RR 0. 86; 95% CI 0.78 to 0.94, P=0.001) and death (RR 0.87; 95% CI 0.77 to 0.98, P=0.02). After 3 years the estimated percentages alive and without a new AIDS event were 53% for AZT+ddI, 49% for AZT+ddC and 44% for AZT alone; the percentages alive were 68%, 63% and 59% respectively. Five of the six trials involved randomised comparisons of AZT+ddI versus AZT+ddC: in these, the AZT+ddI regimen had greater effects on disease progression (P=0.004) and death (P=0.009). REVIEWER'S CONCLUSIONS: The use of ddI and, to a lesser extent, ddC delayed both HIV disease progression and death, at least when added to AZT.

Adult↗
PubMed2000

Immediate versus deferred zidovudine (AZT) in asymptomatic or mildly symptomatic HIV infected adults.

BACKGROUND: Zidovudine (AZT) monotherapy was the first antiretroviral drug to be tested widely. Subsequent trials in asymptomatic or early symptomatic HIV infection indicated short-term delays in disease progression with AZT, but not improved survival. OBJECTIVES: To assess the effects of immediate versus deferred zidovudine (AZT) on HIV disease progression and survival. SEARCH STRATEGY: Investigators and pharmaceutical companies were contacted, and MEDLINE searches were supplemented by searching conference abstracts. SELECTION CRITERIA: Randomised controlled trials comparing immediate versus deferred AZT in participants without AIDS which prospectively collected deaths and new AIDS events. DATA COLLECTION AND ANALYSIS: Individual patient data with, wherever possible, follow-up obtained beyond that previously published was obtained and checked for internal consistency and consistency with any published reports; any apparent discrepancies were resolved with the trialists. Time to death and to disease progression (defined as a new AIDS-defining event or prior death) were analysed on an intention to treat basis, stratified to avoid direct comparisons between participants in different trials. MAIN RESULTS: Nine trials were included in the meta-analysis. During a median follow-up of 50 months, 1908 individuals developed disease progression, of whom 1351 died. In the deferred group, 61% started antiretroviral therapy (median time to therapy 28 months, which was AZT monotherapy in 94%). During the first year of follow-up immediate AZT halved the rate of disease progression (P<0.0001), increasing the probability of AIDS-free survival at one year from 96% to 98%, but this early benefit did not persist: after 6 years AIDS-free survival was 54% in both groups, and at no time was there any difference in overall survival, which at 6 years was 64% with immediate and 65% with deferred AZT (rate ratio [RR] 1.04, 95% confidence interval [CI] 0. 94 to 1.15). REVIEWER'S CONCLUSIONS: Although immediate use of AZT halved disease progression during the first year, this effect was not sustained, and there was no improvement in survival in the short or long term.

Anti-HIV Agents↗
PubMed2000

Therapeutic interventions in HIV infection - a critical view.

The introduction of highly effective combination regimens of antiretroviral drugs has led in recent years to substantial improvements in morbidity and mortality. As yet immune-based therapies have had little if any impact. However it is clear that eradication of HIV is not achievable with existing anti-HIV drugs and in spite of the major advances there remain many challenges in the clinical management of HIV-infected individuals. These benefits are unlikely to be extended to resource poor countries in the foreseeable future. The barriers are primarily but not only the costs. In resource-rich countries there are concerns about long term toxicities and many people have already exhausted all of the current therapeutic options. There is an urgent need for new drugs, ideally attacking new targets or with no cross resistance to existing drugs, and which are well tolerated and safe, easy to take and cheap. Many important questions still remain unanswered, in particular when to start antiretroviral therapy.

Adult↗
PubMed1998

A randomised trial of mode of delivery in women infected with the human immunodeficiency virus.

OBJECTIVE: During the pilot phase of a trial to evaluate the effectiveness of caesarean section delivery compared with vaginal delivery in reducing mother-to-child transmission of human immunodeficiency virus (HIV) infection, the feasibility of randomisation to mode of delivery was assessed. DESIGN: At 36 weeks of pregnancy, women infected with HIV were randomly allocated to either caesarean section delivery at 38 weeks or vaginal delivery. Information was also collected on the reasons why women were not enrolled, either because they refused or had a contraindication. SETTING: Fifty-one centres in six European countries. POPULATION: Pregnant women with confirmed HIV-1 infection. MAIN OUTCOME MEASURES: Randomisation. RESULTS: Three-hundred and thirty-nine women had been randomised by the end of 1996, the large majority from Italy (n = 250) and France (n = 54), with 22 from South Africa, three from Sweden, nine from Barcelona and one from London. A further 150 women were eligible but had not been randomised. Forty-eight women (14%) were not delivered according to the arm to which they were randomised; the majority (n = 44) were changed from vaginal to caesarean section delivery. There is wide variation between European countries in the acceptability and adherence to the mode of delivery trial. CONCLUSION: The pilot phase of this trial has shown that in some settings randomisation to mode of delivery is feasible and acceptable, but that in other settings clinicians and pregnant women are more reluctant to be randomised. Pending further information on transmission rates and accrual, enrollment into the trial continues.

Cesarean Section↗
PubMed1997

European contribution to the science, prevention and management of HIV infection.

The objectives of the European Commission Biomed AIDS Programme are to enable Europe to pool its intellectual and financial resources in the control, treatment and prevention of HIV infection and AIDS. In order to facilitate this aim the Commission has allocated 40 to 50 million ECU over the past 6 years for concerted action of the Biomed projects on AIDS by the countries of the European Union. This is only a small proportion of the real cost spent by the member countries on this epidemic.

AIDS Vaccines↗
PubMed1995

Perspectives in drug therapy of HIV infection.

Current key issues in the drug therapy of HIV infection include the timing of treatment initiation, the use of multiple-drug therapy and the duration of treatment. Although most clinicians agree that symptomatic HIV disease should be treated, there is no consensus as to whether patients should be treated before symptoms develop; the results of the Concorde trial failed to demonstrate any long term improvement in disease progression or survival when antiretroviral therapy was initiated in asymptomatic individuals rather than deferring it until the development of AIDS or ARC. However, combination therapy may prove to be the most effective long term option. In the future, monitoring viral load or viral resistance may be a useful aid in determining whether antiretroviral therapy should be stopped or changed, particularly if any clinical benefits are transient or if adverse effects persist. New antiretroviral therapies must be evaluated in terms of both risks (associated adverse effects) and benefits (increase in survival, delay in disease progression or improvement in quality of life). There is an urgent need to identify the best surrogate markers to permit more rapid evaluation of therapeutic strategies.

Didanosine↗