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Biomedical subjects

Fiona Lampe

Publications and source records attributed to Fiona Lampe.

14 recordsLinked to original sources
PubMed2005

Treatment exhaustion of highly active antiretroviral therapy (HAART) among individuals infected with HIV in the United Kingdom: multicentre cohort study.

OBJECTIVES: To investigate whether there is evidence that an increasing proportion of HIV infected patients is starting to experience increases in viral load and decreases in CD4 cell count that are consistent with exhaustion of available treatment options. DESIGN: Multicentre cohort study. SETTING: Six large HIV treatment centres in southeast England. PARTICIPANTS: All individuals seen for care between 1 January 1996 and 31 December 2002. MAIN OUTCOME MEASURES: Exposure to individual antiretroviral drugs and drug classes, CD4 count, plasma HIV RNA burden. RESULTS: Information is available on 16,593 individuals (13,378 (80.6%) male patients, 10,340 (62.3%) infected via homosexual or bisexual sex, 4426 (26.7%) infected via heterosexual sex, median age 34 years). Overall, 10,207 of the 16,593 patients (61.5%) have been exposed to any antiretroviral therapy. This proportion increased from 41.2% of patients under follow up at the end of 1996 to 71.3% of those under follow up in 2002. The median CD4 count and HIV RNA burden of patients under follow up in each year changed from 270 cells/mm3 and 4.34 log10 copies/ml in 1996 to 408 cells/mm3 and 1.89 log10 copies/ml, respectively, in 2002. By 2002, 3060 (38%) of patients who had ever been treated with antiretroviral therapy had experienced all three main classes. Of these, around one quarter had evidence of "viral load failure" with all these three classes. Patients with three class failure were more likely to have an HIV RNA burden > 2.7 log10 copies/ml and a CD4 count < 200 cells/mm3. CONCLUSIONS: The proportion of individuals with HIV infection in the United Kingdom who have been treated has increased gradually over time. A substantial proportion of these patients seem to be in danger of exhausting their options for antiretroviral treatment. New drugs with low toxicity, which are not associated with cross resistance to existing drugs, are urgently needed for such patients.

Adolescent↗
PubMed2005

Impact of participant and physician intervention preferences on randomized trials: a systematic review.

CONTEXT: Allocation on the basis of randomization rather than patient choice is the gold standard of unbiased estimates of efficacy in clinical medicine. However, randomly allocating patients to treatments that do not accord with their preferences may influence internal and external validity. OBJECTIVE: To determine whether preferences affect recruitment to trials (external validity) and outcomes in trials (internal validity). DATA SOURCES: We searched MEDLINE, EMBASE, PsycINFO, CINAHL, AMED, and the Cochrane Library for articles published between 1966 and September 2004. We also hand-searched several major medical journals, searched reference lists of relevant articles, and contacted authors of published preference designs. The 2 themes in the first filter of the search strategy were preferences and possible determinants of preferences. STUDY SELECTION: Comprehensive cohorts and 2-stage trials that measured or recorded patient or physician preference, included allocation of participants to random and preference cohorts, and followed up all participants. We excluded trials with no recording of preference; of decision aids; with measurements of preferences for economic analyses; in which patients who refused randomization were followed up without reference to preferences; and of nonclinical populations. DATA EXTRACTION: Up to 4 reviewers independently evaluated the articles, and disagreements were resolved at project steering group meetings. We extracted data on study design, measurement of preference, recruitment, attrition, and summary data on the primary outcome(s) at baseline and each follow-up point. DATA SYNTHESIS: Of 10,023 citations identified, 170 articles met screening criteria and 32 (27 comprehensive cohorts and 5 two-stage trials) were determined to be eligible and were used in the final review. Although treatment preferences led to a substantial proportion of people refusing randomization, there was less evidence of bias in the characteristics of individuals agreeing to be randomized. Differences in outcome across the trials between randomized and preference groups were generally small, particularly in large trials and after accounting for baseline measures of outcome. Therefore, there was little evidence that preferences substantially interfere with the internal validity of randomized trials. CONCLUSIONS: Preferences influence whether people participate in randomized trials, but there is little evidence that they significantly affect validity.

Humans↗
PubMed2005

When to start therapy.

Explore the source record for details and available documents.

Antiretroviral Therapy, Highly Active↗
PubMed2005

Patient preferences in randomised controlled trials: conceptual framework and implications for research.

Patient preferences have recently been highlighted as a potential threat to the validity of randomised controlled trials (RCTs). Although there have been significant methodological and statistical developments in relation to these issues, comparatively little attention has been paid to the development of a conceptual model concerning preferences and their effects on decision-making. This article describes the development of such a model, which was undertaken in parallel with a systematic review of the empirical data concerning preference effects. The model describes the concept of preference in terms of theoretical concepts from the psychological and economics literature, and describes a preliminary model of the development and operation of preferences in the context of RCTs. The paper then examines the implications of the model for informed consent and recruitment procedures. Key issues for future research are also outlined.

Clinical Trials as Topic↗
PubMed2003

Predictive accuracy of the Framingham coronary risk score in British men: prospective cohort study.

OBJECTIVE: To establish the predictive accuracy of the Framingham risk score for coronary heart disease in a representative British population. DESIGN: Prospective cohort study. SETTING: 24 towns in the United Kingdom. PARTICIPANTS: 6643 British men aged 40-59 years and free from cardiovascular disease at entry into the British regional heart study. MAIN OUTCOME MEASURES: Comparison of observed 10 year coronary heart disease mortality and event rates with predicted rates for each individual, using the relevant Framingham risk equation. RESULTS: Of 6643 men, 2.8% (95% confidence interval 2.4% to 3.2%) died from coronary heart disease compared with 4.1% predicted (relative overestimation 47%, P < 0.0001). A fatal or non-fatal coronary heart disease event occurred in 10.2% (9.5% to 10.9%) of the men compared with 16.0% predicted (relative overestimation 57%, P < 0.0001). These relative degrees of overestimation were similar at all levels of coronary heart disease risk, so that overestimation of absolute risk was greatest for those at highest risk. A simple adjustment provided an improved level of accuracy. In a "high risk score" approach, most cases occur in the low risk group. In this case, 84% of the deaths from coronary heart disease and non-fatal events occurred in the 93% of men classified at low risk (< 30% in 10 years) by the Framingham score. CONCLUSION: Guidelines for the primary prevention of coronary heart disease advocate offering preventive measures to individuals at high risk. Currently recommended risk scoring methods derived from the Framingham study significantly overestimate the absolute coronary risk assigned to individuals in the United Kingdom.

Adult↗
PubMed2003

Theoretical rationale for the use of sequential single-drug antiretroviral therapy for treatment of HIV infection.

BACKGROUND: Subpopulations of HIV with mutations associated with resistance to antiretroviral drugs often have reduced replicative capacity, so virus with resistance mutations for all existing and new antiretroviral drugs is likely to be appreciably impaired. Issues of toxicity, quality of life and economics mean that the simultaneous use of all these drugs in combination is unrealistic. We aimed to explore the use of sequential monotherapy regimens using a mathematical model of quasi-species dynamics, to see if these could take advantage of the poor replicative capacity of highly resistant virus. METHODS: We assume for each of seven drugs that a single mutation is associated with the ability to replicate (effective reproductive ratio, R > 1) in the presence of that drug as monotherapy. Parameters included were drug efficacy, the cost of resistance mutations and the number of new target cells arising daily. RESULTS: The use of seven drugs in a daily/weekly sequential monotherapy cycle led to substantial viral suppression (in the presence of all resistant viral subpopulations) for a wider range of parameter values than a continuous five-drug regimen. Although on any one day/week there is a viral subpopulation with R > 1 (e.g. that with resistance only to the current drug), this subpopulation does not have time to grow sufficiently during the short period when that drug is being taken. CONCLUSION: These results provide a rationale for trials of sequential regimens, using as wide a number of drugs with different resistance-associated mutations as possible, as a potential 'resistance-proof' strategy for achieving significant viral load suppression.

Anti-HIV Agents↗
PubMed2002

Human immunodeficiency virus rebound after suppression to <400 copies/mL during initial highly active antiretroviral therapy regimens, according to prior nucleoside experience and duration of suppression.

This study evaluated 1433 human immunodeficiency virus (HIV)-infected patients starting highly active antiretroviral therapy (HAART), 409 (28%) of whom had prior nucleoside experience and achieved an HIV load of <400 copies/mL by 24 weeks of therapy. Three hundred seven patients experienced virus rebound during a total of 2773.3 person-years of follow-up. There was a higher rate of virus rebound among the patients with pre-HAART nucleoside experience (relative hazard [RH], 2.86; 95% confidence interval, 2.22-3.84; P<.0001) and a decreasing rate of virus rebound with increasing duration of virus suppression (i.e., time since achieving a virus load of <400 HIV RNA copies/mL) among both the nucleoside-experienced and naive patients (P<.0001), but the difference between the groups persisted into the third year of follow-up (P=.0007). Even patients who had experienced <2 months of nucleoside therapy before beginning HAART had an increased risk of virus rebound (RH, 1.95; P=.009). It appears that only a small period of pre-HAART nucleoside therapy is sufficient to confer a disadvantage, in terms of risk of virus rebound, that persists for several years.

Adult↗
PubMed2002

Parallel decline of CD8+/CD38++ T cells and viraemia in response to quadruple highly active antiretroviral therapy in primary HIV infection.

OBJECTIVES: To monitor changes in the numbers of CD8 lymphocytes expressing the activated CD38++ phenotype in peripheral blood samples from patients with primary HIV infection (PHI) treated with highly active antiretroviral therapy (HAART). METHODS: Zidovudine, lamivudine, abacavir and amprenavir were initiated during PHI as part of the Quest study. Absolute numbers of CD8+/CD38++ T cells were determined using three-colour flow cytometry, and plasma viral load (VL) was measured using the Roche Amplicor method. RESULTS: The median, pre-therapy CD8+/CD38++ T cell count was 461/mm(3)(interquartile range 216, 974) in 131 patients compared with normal control values of less than 20 cells/mm(3). Levels fell markedly in parallel with VL within the first 2 weeks of HAART initiation, to a median of 47 cells/mm(3) at 28 weeks (median 436 cell decline; P < 0.001). At that time, 80% of patients had a VL less than 50 copies/ml, and 16.3% of all patients had less than 20 CD8+/CD38++ T cells/mm(3). A continued decrease in CD8+/CD38++ T cell count occurred in 67.2% of patients whose VL was maintained below 50 copies/ml (median change from first to last value -18 cells/mm(3); P < 0.001). CONCLUSION: After the initiation of HAART in PHI, CD8+/CD38++ lymphocytes declined rapidly in parallel with VL, and allowed for a normalization of CD8+/CD38++ T cell numbers in a subset of patients at week 28. Cell numbers continued to decline in patients who maintained VL below 50 copies/ml, indicating that the CD8+/CD38++ T cell count may represent a marker of residual viral replication when VL falls below detectable levels after HAART intervention.

Adult↗
PubMed2002

Raised viral load in patients with viral suppression on highly active antiretroviral therapy: transient increase or treatment failure?

OBJECTIVE: To assess the occurrence of viral load greater than 50 copies/ml in patients on highly active antiretroviral therapy (HAART) having achieved less than 50 copies/ml and the chance of whether a viral load greater than 50 copies/ml would lead to a sustained and increasing viral load. DESIGN: A cohort of 553 patients on HAART with viral loads of less than 50 copies/ml were followed. RESULTS: Over a median of 56 weeks 35% of patients experienced a transient increase and 8% virological failure (two consecutive viral loads of > 400 copies/ml). Transient increases and virological failure were more common in those with greater drug experience, and those with initial raised viral load values of more than 400 copies/ml were more likely to have a sustained increase and become virological failures. CONCLUSION: Transient increases in viral load are common, mainly in the 50-400 copies/ml range, and the majority of subsequent viral load estimations show a return to less than 50 copies/ml. A single raised viral load should lead to adherence support and intensified monitoring. Subsequent treatment decisions can then be based on evidence of true virological rebound and failure.

Antiretroviral Therapy, Highly Active↗
PubMed2002

Virological suppression at 6 months is related to choice of initial regimen in antiretroviral-naive patients: a cohort study.

BACKGROUND: Guidelines recommend both protease inhibitor (PI)- and non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens for initial therapy in HIV-positive individuals whilst clinical trial data comparing treatment options remain limited. OBJECTIVE: To assess whether drug selection (PI versus NNRTI) in antiretroviral-naive patients is related to virological response at 6 months within a clinical cohort. DESIGN: Databases from two large clinics were used to identify all treatment-naive patients initiating highly active antiretroviral therapy (PI/ two PI or NNRTI). Statistical models determined the likelihood of suppressing HIV viral load < 500 copies/ml, the risk of treatment failure by 6 months, and factors associated with treatment success. RESULTS: Of 1109 potentially eligible patients 888 met study criteria and were included; 484 were prescribed a PI (40% indinavir, 41% nelfinavir) and 404 were prescribed NNRTI (40% efavirenz, 60% nevirapine). Three treatment arms were compared: efavirenz versus nevirapine versus PI. After stratification by year and centre and adjustment for baseline variables, only treatment group and baseline viral load remained significantly associated with virological suppression at 6 months. Patients on efavirenz were significantly more likely to achieve an undetectable viral load than those on PI or nevirapine. The relative hazard for nevirapine was 0.77 (95% confidence interval, 0.61-0.96, P = 0.02) and that for PI was 0.74 (95% confidence interval, 0.58-0.94, P = 0.01). Efavirenz also performed better in the analysis of treatment failure at 6 months. CONCLUSION: Although observational cohort data may be susceptible to significant bias, this study suggests a better initial virological response for efavirenz compared to either nevirapine or the PI. Clinical trial data is required to confirm these findings.

Adult↗
PubMed2002

Brief report: two-year outcome of a multidrug regimen in patients who did not respond to a protease inhibitor regimen.

In most studies, people who have not responded virologically to a protease inhibitor (PI)-containing regimen have tended to experience poor virologic responses to subsequent regimens. We describe the 2-year viral load, CD4 count, and clinical outcome of a multidrug regimen used in 60 people who had not responded virologically to a PI-containing regimen. At baseline, median CD4 count was 126/mm(3) (nadir 30/mm(3) ) and median viral load was 320,000 copies/mL. A median of five antiretroviral drugs had previously been used, of which a median of two were PIs. Of these patients, 16% had previously used another nonnucleoside reverse transcriptase inhibitor besides efavirenz. The multidrug regimen (median 5 drugs) started most commonly included efavirenz (100%), at least one PI (92%, usually indinavir/ritonavir), didanosine (78%), and hydroxyurea (74%). At year 2, 5 patients had died and 5 had no measure available. Nine patients developed a new AIDS event and 10 patients were known to have stopped all antiretroviral therapy. Thirty-one patients (52% of the whole group, 72% of those remaining on therapy with viral load value available) had viral load <50 copies/mL. Thus, a substantial proportion of patients who had failed to respond virologically to PI-containing regimens can achieve profound and sustained virologic suppression with a multidrug regimen.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes.

BACKGROUND: Treatment strategies for patients in whom HIV replication is not suppressed after exposure to several drug classes remain unclear. We aimed to assess the inter-relations between viral load, CD4-cell count, and clinical outcome in patients who had experienced three-class virological failure. METHODS: We undertook collaborative joint analysis of 13 HIV cohorts from Europe, North America, and Australia, involving patients who had had three-class virological failure (viral load >1000 copies per mL for >4 months). Regression analyses were used to quantify the associations between CD4-cell-count slope, HIV-1 RNA concentration, treatment information, and demographic characteristics. Predictors of death were analysed by Cox's proportional-hazards models. FINDINGS: 2488 patients were included. 2118 (85%) had started antiretroviral therapy with single or dual therapy. During 5015 person-years of follow-up, 276 patients died (mortality rate 5.5 per 100 person-years; 3-year mortality risk 15.3% (95% CI 13.5-17.3). Risk of death was strongly influenced by the latest CD4-cell count with a relative hazard of 15.8 (95% CI 9.28-27.0) for counts below 50 cells per microL versus above 200 cells per microL. The latest viral load did not independently predict death. For any given viral load, patients on treatment had more favourable CD4-cell-count slopes than those off treatment. For patients on treatment and with stable viral load, CD4-cell counts tended to be increasing at times when the current viral load was below 10000 copies per mL or 1.5 log10 copies per mL below off-treatment values. INTERPRETATION: In patients for whom viral-load suppression to below the level of detection is not possible, achievement and maintenance of a CD4-cell count above 200 per microL becomes the primary aim. Treatment regimens that maintain the viral load below 10000 copies per mL or at least provide 1.5 log10 copies per mL suppression below the off-treatment value do not seem to be associated with appreciable CD4-cell-count decline.

Adult↗