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S Mead,
M Ranopa,
G S Gopalakrishnan,
A G B Thompson,
P Rudge,
S Wroe,
A Kennedy,
F Hudson,
A MacKay, J H Darbyshire,
J Collinge,
A S Walker
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ABSTRACT: Human prion diseases are heterogeneous but invariably fatal neurodegenerative disorders with no known effective therapy. PRION-1, the largest clinical trial in prion disease to date, showed no effect of the potential therapeutic quinacrine on survival. Although there are several limitations to the usefulness of survival as an outcome measure, there have been no comprehensive studies of alternatives.
To address this we did comparative analyses of neurocognitive, psychiatric, global, clinician-rated, and functional scales, focusing on validity, variability, and impact on statistical power over 77 person-years follow-up in 101 symptomatic patients in PRION-1.
Quinacrine had no demonstrable benefit on any of the 8 scales (p > 0.4). All scales had substantial numbers of patients with the worst possible score at enrollment (Glasgow Coma Scale score being least affected) and were impacted by missing data due to disease progression. These effects were more significant for cognitive/psychiatric scales than global, clinician-rated, or functional scales. The Barthel and Clinical Dementia Rating scales were the most valid and powerful in simulated clinical trials of an effective therapeutic. A combination of selected subcomponents from these 2 scales gave somewhat increased power, compared to use of survival, to detect clinically relevant effects in future clinical trials of feasible size.
Our findings have implications for the choice of primary outcome measure in prion disease clinical trials. Prion disease presents the unusual opportunity to follow patients with a neurodegenerative disease through their entire clinical course, and this provides insights relevant to designing outcome measures in related conditions.
Neurology 11/2011; 77(18):1674-83. · 8.31 Impact Factor
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P Munderi,
A S Walker,
C Kityo,
A G Babiker,
F Ssali,
A Reid, J H Darbyshire,
H Grosskurth,
P Mugyenyi,
D M Gibb,
C F Gilks
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ABSTRACT: Triple nucleoside reverse transcriptase inhibitor regimens have advantages as first-line antiretroviral therapy (ART), avoiding hepatotoxicity and interactions with anti-tuberculosis therapy, and sparing two drug classes for second-line ART. Concerns exist about virological potency; efficacy has not been assessed in Africa.
A safety trial comparing nevirapine with abacavir was conducted in two Ugandan Development of Antiretroviral Therapy in Africa (DART) centres: 600 symptomatic antiretroviral-naïve HIV-infected adults with CD4 counts <200 cells/microL were randomized to zidovudine/lamivudine plus abacavir or nevirapine (placebo-controlled to 24-week primary toxicity endpoint, and then open-label). Documented World Health Organization (WHO) stage 4 events were independently reviewed and plasma HIV-1 RNA assayed retrospectively. Exploratory efficacy analyses are intention-to-treat.
The median pre-ART CD4 count was 99 cells/microL, and the median pre-ART viral load was 284 600 HIV-1 RNA copies/mL. A total of 563 participants (94%) completed 48 weeks of follow-up, 25 (4%) died and 12 (2%) were lost to follow-up. The randomized drug was substituted in 21 participants (7%) receiving abacavir vs. 34 (11%) receiving nevirapine (P=0.09). At 48 weeks, 62% of participants receiving abacavir vs. 77% of those receiving nevirapine had viral loads <50 copies/mL (P<0.001), and mean CD4 count increases from baseline were +147 vs. +173 cells/microL, respectively (P=0.006). Nine participants (3%) receiving abacavir vs. 16 (5%) receiving nevirapine died [hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.24-1.25; P=0.15]; 20 receiving abacavir vs. 32 receiving nevirapine developed new or recurrent WHO 4 events or died (HR=0.60; 95% CI 0.34-1.05; P=0.07) and 48 receiving abacavir vs. 68 receiving nevirapine developed new or recurrent WHO 3 or 4 events or died (HR=0.67; 95% CI 0.46-0.96; P=0.03). Seventy-one participants (24%) receiving abacavir experienced 91 grade 4 adverse events compared with 130 events in 109 participants (36%) on nevirapine (P<0.001).
The clear virological/immunological superiority of nevirapine over abacavir was not reflected in clinical outcomes over 48 weeks. The inability of CD4 cell count/viral load to predict initial clinical treatment efficacy is unexplained and requires further evaluation.
HIV Medicine 02/2010; 11(5):334-44. · 3.01 Impact Factor
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P Yeni,
D A Cooper,
J P Aboulker,
A G Babiker,
D Carey, J H Darbyshire,
M Floridia,
P M Girard,
R L Goodall,
M H Hooker,
A Mijch,
V Meiffredy,
B Salzberger
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ABSTRACT: 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.
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.
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.
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.
The Lancet 07/2006; 368(9532):287-98. · 38.28 Impact Factor
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ABSTRACT: To assess the clinical utility of phenotypic resistance testing in addition to genotypic resistance testing among HIV-1-infected patients experiencing virologic failure and with limited therapeutic options.
Multicenter randomized trial.
Patients were eligible if a decision had been made to switch antiretroviral therapy, the most recent HIV-1 RNA plasma viral load (VL) exceeded 2000 copies/mL, and the clinician was unable to select a potent regimen of 3 or more drugs without access to a resistance test. Subjects were randomized to genotypic resistance testing alone (G arm) or to genotypic plus phenotypic testing (G + P arm). Patients had access to resistance testing at any time during follow-up (minimum of 1 year) according to the original allocation. The primary end point was change in plasma VL from baseline at 12 months.
Three hundred eleven patients were recruited between February 2000 and July 2001. At baseline, mean VL and CD4 count were 4.23 log10 copies/mL and 275 cells/mm, respectively, and subjects had previous exposure to a mean of 7.7 antiretroviral drugs. There was no appreciable difference between the study arms in the drug regimens prescribed after randomization. Mean reduction in VL load at 12 months was similar in the 2 arms (G: 1.37 log10 reduction, G + P: 1.28 log10 reduction; P = 0.77), as was the proportion of subjects with VL <50 copies/mL (G: 35%, G + P: 27%).
The study did not demonstrate added value of phenotypic resistance testing in conjunction with genotypic resistance testing in patients with limited therapeutic options.
JAIDS Journal of Acquired Immune Deficiency Syndromes 04/2005; 38(5):553-9. · 4.43 Impact Factor
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ABSTRACT: Several methods for the estimation and comparison of rates of change in longitudinal studies with staggered entry and informative drop-outs have been recently proposed. For multivariate normal linear models, REML estimation is used. There are various approaches to maximizing the corresponding log-likelihood; in this paper we use a restricted iterative generalized least squares method (RIGLS) combined with a nested EM algorithm. An important statistical problem in such approaches is the estimation of the standard errors adjusted for the missing data (observed data information matrix). Louis has provided a general technique for computing the observed data information in terms of completed data quantities within the EM framework. The multiple imputation (MI) method for obtaining variances can be regarded as an alternative to this. The aim of this paper is to develop, apply and compare the Louis and a modified MI method in the setting of longitudinal studies where the source of missing data is either death or disease progression (informative) or end of the study (assumed non-informative). Longitudinal data are simultaneously modelled with the missingness process. The methods are illustrated by modelling CD4 count data from an HIV-1 clinical trial and evaluated through simulation studies. Both methods, Louis and MI, are used with Monte Carlo simulations of the missing data using the appropriate conditional distributions, the former with 100 simulations, the latter with 5 and 10. It is seen that naive SEs based on the completed data likelihood can be seriously biased. This bias was largely corrected by Louis and modified MI methods, which gave broadly similar estimates. Given the relative simplicity of the modified MI method, it may be preferable.
Statistics in Medicine 11/2003; 22(20):3161-75. · 1.88 Impact Factor
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ABSTRACT: Many cohort studies and clinical trials are designed to compare rates of change over time in one or more disease markers in several groups. One major problem in such longitudinal studies is missing data due to patient drop-out. The bias and efficiency of six different methods to estimate rates of changes in longitudinal studies with incomplete observations were compared: generalized estimating equation estimates (GEE) proposed by Liang and Zeger (1986); unweighted average of ordinary least squares (OLSE) of individual rates of change (UWLS); weighted average of OLSE (WLS); conditional linear model estimates (CLE), a covariate type estimates proposed by Wu and Bailey (1989); random effect (RE), and joint multivariate RE (JMRE) estimates. The latter method combines a linear RE model for the underlying pattern of the marker with a log-normal survival model for informative drop-out process. The performance of these methods in the presence of missing data completely at random (MCAR), at random (MAR) and non-ignorable (NIM) were compared in simulation studies. Data for the disease marker were generated under the linear random effects model with parameter values derived from realistic examples in HIV infection. Rates of drop-out, assumed to increase over time, were allowed to be independent of marker values or to depend either only on previous marker values or on both previous and current marker values. Under MACR all six methods yielded unbiased estimates of both group mean rates and between-group difference. However, the cross-sectional view of the data in the GEE method resulted in seriously biased estimates under MAR and NIM drop-out process. The bias in the estimates ranged from 30 per cent to 50 per cent. The degree of bias in the GEE estimates increases with the severity of non-randomness and with the proportion of MAR data. Under MCAR and MAR all the other five methods performed relatively well. RE and JMRE estimates were more efficient(that is, had smaller variance) than UWLS, WLS and CL estimates. Under NIM, WLS and particularly RE estimates tended to underestimate the average rate of marker change (bias approximately 10 per cent). Under NIM, UWLS, CL and JMRE performed better in terms of bias (3-5 per cent) with the JMRE giving the most efficient estimates. Given that markers are key variables related to disease progression, missing marker data are likely to be at least MAR. Thus, the GEE method may not be appropriate for analysing such longitudinal marker data. The potential biases due to incomplete data require greater recognition in reports of longitudinal studies. Sensitivity analyses to assess the effect of drop-outs on inferences about the target parameters are important.
Statistics in Medicine 01/2002; 20(24):3715-28. · 1.88 Impact Factor
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ABSTRACT: Age is a major determinant of mortality for many diseases including HIV infection, yet the effect of age is rarely studied directly. In this article, we review what is known about the effect of age at seroconversion on HIV disease progression and survival prior to the widespread use of HAART before describing appropriate methods for adjusting for background mortality in more detail. We then investigate the impact of HAART on the effect of age at seroconversion on mortality and consider the estimation of the age effect in seroprevalent cohorts with regard to lack of knowledge of the true age at infection. Finally, we discuss mechanisms by which age at seroconversion might impact on disease progression and death. Throughout, we use published results by the Collaborative Group on AIDS Incubation and HIV Survival (CGAIHS), and published results and data from the Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE) for illustration.
Journal of Clinical Epidemiology 01/2002; 54 Suppl 1:S16-21. · 4.27 Impact Factor
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ABSTRACT: A national survey of tuberculosis was conducted in England and Wales in 1998 to obtain detailed information on the occurrence of the disease and recent trends. This survey also piloted the methodology for enhanced tuberculosis surveillance in England and Wales and investigated the prevalence of HIV infection in adults with tuberculosis.
Clinical and demographic data for all cases diagnosed during 1998 were obtained, together with microbiological data where available. Annual incidence rates in the population were estimated by age, sex, ethnic group, and geographical region using denominators from the 1998 Labour Force Survey. Incidence rates in different subgroups of the population were compared with the rates observed in previous surveys. The tuberculosis survey database for 1998 was matched against the Communicable Disease Surveillance Centre HIV/AIDS database to estimate the prevalence of HIV co-infection in adult patients with tuberculosis.
A total of 5658 patients with tuberculosis were included in the survey in England and Wales (94% of all formally notified cases during the same period), giving an annual rate of 10.93 per 100 000 population (95% CI 10.87 to 10.99). This represented an increase of 11% in the number of cases since the survey in 1993 and 21% since 1988. In many regions case numbers have remained little changed since 1988, but in London an increase of 71% was observed. The number of children with tuberculosis has decreased by 10% since 1993. Annual rates of tuberculosis per 100 000 population have continued to decline among the white population (4.38) and those from the Indian subcontinent, although the rate for the latter has remained high at 121 per 100 000. Annual rates per 100 000 have increased in all other ethnic groups, especially among those of black African (210) and Chinese (77.3) origin. Over 50% of all patients were born outside the UK. Recent entrants to the UK had higher rates of the disease than those who had been in the country for more than 5 years or who had been born in the UK. An estimated 3.3% of all adults with tuberculosis were co-infected with HIV.
The epidemiology of tuberculosis continues to change in England and Wales and the annual number of cases is rising. More than one third of cases now occur in young adults and rates are particularly high in those recently arrived from high prevalence areas of the world. The geographical distribution is uneven with urban centres having the highest rates. The increase in the number of cases in London is particularly large. Tuberculosis in patients co-infected with HIV makes a small but important contribution to the overall increase, particularly in London. To be most effective and to make the most efficient use of resources, tuberculosis prevention and control measures must be based on accurate and timely information on the occurrence of disease. A new system of continuous enhanced tuberculosis surveillance was introduced in 1999, based on the methodology developed in this national survey.
Thorax 04/2001; 56(3):173-9. · 6.84 Impact Factor
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ABSTRACT: We illustrate the use of marginal methods for the analysis of multivariate failure-time data using a large trial in HIV infection in which the composite endpoint of AIDS or death incorporates more than 20 events with varying severity. Multivariate failure-time methods are required to investigate whether treatment delays development of new AIDS events. AIDS events can be grouped and treatment effects estimated using only the first event to occur in each group for each individual. Alternatively, all events can be included by fitting a separate baseline hazard for development of each event, and restricting treatment effects to be common within groups of events. In either case, model-based or minimum-variance estimates of the overall effect of treatment can be constructed. The covariance matrix for the treatment-effect estimates can be used in multiple testing procedures. Results from the Delta trial suggest that combination antiretroviral therapy with AZT plus either ddI or ddC may delay progression to more severe AIDS events compared to AZT monotherapy. These late events are generally untreatable and prophylaxis is not available. Trials are not generally powered to detect treatment effects on individual events making up a composite endpoint, and therefore all analyses are exploratory rather than providing definitive evidence. However, marginal multivariate models provide an easily available approach for modeling the effect of covariates on multiple disease processes, and allow the likely effects of treatment to be presented in a manner which is easily understood. They can be used in a variety of ways to explore different patterns of treatment effects and are also useful for testing multiple hypotheses regarding treatment effects on several different composite endpoints.
Controlled Clinical Trials 05/2000; 21(2):75-93.
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ABSTRACT: We develop analysis methods for clinical trials with time-to-event outcomes which correct for treatment changes during follow-up, yet are based on comparisons of randomized groups and not of selected groups. A causal model relating observed event times to event times that would have been observed under other treatment scenarios is fitted using the semi-parametric approach of Robins and Tsiatis (avoiding assumptions about the relationship between treatment changes and prognosis). The methods are applied to the Concorde trial of immediate versus deferred zidovudine, to investigate how the results would have differed if no participant randomized to deferred zidovudine had started treatment before reaching ARC or AIDS. We consider issues relating to model choice, non-constant treatment effects and censoring.
Statistics in Medicine 11/1999; 18(19):2617-34. · 1.88 Impact Factor
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ABSTRACT: To assess the practical significance of the following sources of bias for estimates of the AIDS incubation period in a large seroconverter cohort: estimation of the time of seroconversion; presentation with an HIV-related illness; preferential inclusion of survivors; loss to follow-up and analysis cut-off date; the inclusion of Kaposi's sarcoma as an AIDS event; death without an AIDS diagnosis; and representativeness of the HIV population.
Standard non-parametric survival methods were used to estimate the AIDS incubation period distribution. The practical importance of each type of bias was assessed using various sensitivity analyses.
The potential sources of bias of most practical importance in this study were the right-censoring strategy and that due to lack of documentation of a negative HIV antibody test. Five different right-censoring strategies gave estimates of the median time to AIDS ranging from 8.1 to 10.8 years for the 1202 individuals enrolled in the UK Register of HIV Seroconverters. HIV-infected persons with a history of a previous antibody negative test which could not be verified appeared to progress to AIDS more rapidly than persons with such verification (Relative risk = 1.8, 95% confidence intervals = 1.3-2.3).
As a number of possible causes of bias can impact on results, care must be taken to document them and control for them wherever possible. In our study, this was particularly relevant in relation to the documentation of a previous HIV antibody negative test and the choice of analysis cut-off dates. As methods may differ between cohorts, comparison of the published results from one cohort with those of another may be misleading.
AIDS 11/1999; 13(14):1943-51. · 6.24 Impact Factor
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ABSTRACT: Many cohort studies and clinical trials have designs which involve repeated measurements of disease markers. One problem in such longitudinal studies, when the primary interest is to estimate and to compare the evolution of a disease marker, is that planned data are not collected because of missing data due to missing visits and/or withdrawal or attrition (for example, death). Several methods to analyse such data are available, provided that the data are missing at random. However, serious biases can occur when missingness is informative. In such cases, one needs to apply methods that simultaneously model the observed data and the missingness process. In this paper we consider the problem of estimation of the rate of change of a disease marker in longitudinal studies, in which some subjects drop out prematurely (informatively) due to attrition, while others experience a non-informative drop-out process (end of study, withdrawal). We propose a method which combines a linear random effects model for the underlying pattern of the marker with a log-normal survival model for the informative drop-out process. Joint estimates are obtained through the restricted iterative generalized least squares method which are equivalent to restricted maximum likelihood estimates. A nested EM algorithm is applied to deal with censored survival data. The advantages of this method are: it provides a unified approach to estimate all the model parameters; it can effectively deal with irregular data (that is, measured at irregular time points), a complicated covariance structure and a complex underlying profile of the response variable; it does not entail such complex computation as would be required to maximize the joint likelihood. The method is illustrated by modelling CD4 count data in a clinical trial in patients with advanced HIV infection while its performance is tested by simulation studies.
Statistics in Medicine 06/1999; 18(10):1215-33. · 1.88 Impact Factor
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ABSTRACT: The Concorde trial compared immediate (Imm) with deferred (Def) AZT monotherapy in asymptomatic HIV-positive participants. Haematological and immunological markers and weight were measured throughout, and correlated with clinical endpoints. Markers associated with disease progression (CD4 lymphocyte count and percentage, platelets, p24 antigen and beta 2 microglobulin favoured Imm: those associated with toxicity (haemoglobin, neutrophils and white cell count) favoured Def. CD8 and total lymphocyte count did not differ significantly between groups. In multivariate analysis, the combination of baseline CD4, p24 antigen and beta 2m was the best baseline predictor of disease. Including change in CD4 and beta 2m at 12 weeks, or changes over follow-up in these markers significantly improved the fit. Markers were also incorporated into the definition of 'clinical' endpoints. Hazard ratio estimates from end-points that included CD4 < 50 and CD4 < 25 were closest to those for AIDS or death alone, but added very few extra events. Use of other landmark CD4 counts (100 or greater) or relative decreases in counts (25% or more) increased the number of events, but overestimated the effect of immediate AZT. Although AZT had a beneficial effect on the surrogate markers of efficacy evaluated, these changes did not predict clinical outcome, nor could the markers be usefully incorporated into an endpoint definition.
QJM: monthly journal of the Association of Physicians 06/1998; 91(6):423-38. · 2.33 Impact Factor
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R S Tedder,
S Kaye,
C Loveday,
I V Weller,
D Jeffries,
J Norman,
J Weber,
M Bourelly,
R Foxall,
A Babiker, J H Darbyshire
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ABSTRACT: Virological assays for human immunodeficiency virus type 1 load and drug resistance can broadly be divided into culture-based and molecular biology-based methods. Culture-based methods give a direct measure of infectious virus load and phenotypic drug resistance, whereas molecular biology-based methods are indirect, assaying nucleic acid levels to determine virus load and point mutations associated with drug resistance. We have compared culture-based and non-culture-based methods for patients enrolled in a placebo-controlled trial of zidovudine (the Concorde Trial). Virus loads were assayed by culture of peripheral blood mononuclear cells (PBMCs) or quantitative PCR, and drug resistance was assayed in culture or in a quantitative, PCR-based point mutation assay. The rates of detection of viremia and drug resistance were higher by PCR than by culture for this population of subjects. Comparison of the virus loads by the two measures showed a good correlation for virus loads in PBMCs but a poor correlation for virus loads in plasma. The latter result probably reflected the inaccuracies of culture in assaying plasma with the low infectious virus titers seen in the study population. The concordance of phenotypic and genotypic drug resistance methods was high, with all phenotypically resistant isolates having at least one resistance-associated mutation and with no mutations being found in a drug-sensitive isolate. Genomic resistance scores (weighted sums of levels of resistance mutations) showed good correlations with the levels of phenotypic resistance, and both resistance measures were observed to increase as the duration of exposure to drug increased. Overall, non-culture-based methods were shown to correlate well with culture-based methods and offer a low-cost, high-throughput alternative. However, culture-based methods remain the final arbiters of infectious virus load and phenotypic drug resistance and are unlikely to be superseded entirely.
Journal of Clinical Microbiology 04/1998; 36(4):1056-63. · 4.15 Impact Factor
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ABSTRACT: The geographical distribution of tuberculosis in England and Wales and changes since 1983 were examined using data from the 1988 and 1993 national surveys of tuberculosis notifications.
Notification rates for England and Wales in 1988 and 1993 were calculated for geographical areas using Office for National Statistics (ONS) mid year population estimates. Those for the standard regions and the Greater London boroughs were calculated for the main ethnic groups. Those for the counties and local authorities were calculated for all ethnic groups combined. These were compared using data from the 1983 national survey as a baseline.
Wide regional variations in notification rates persist with Greater London having the highest rates. Rates in the ethnic group from the Indian subcontinent (ISC) were high in all regions, whilst those of the white ethnic group varied fourfold. Twenty seven of the 33 London boroughs showed increased rates in 1993 compared with 1988. In general, those local authority areas with high rates had high proportions of notifications in individuals of ISC ethnic origin, emphasising the continuing important contribution of ethnic minority groups to local tuberculosis rates. The number of local authority areas with notification rates four times the national average increased, but the number of areas with low or zero rates increased even more.
The distribution of tuberculosis in England and Wales continues to vary markedly by geographical area. The distribution is becoming increasingly polarised with a growth in the number of areas with very high rates of notifications and a greater increase in the number of areas with very few notifications. Patients from ethnic minorities continued to contribute a substantial and increasing proportion of all reported tuberculosis cases in most regions in 1988 and 1993. These findings have important implications for the provision of tuberculosis services in England and Wales.
Thorax 04/1998; 53(3):176-81. · 6.84 Impact Factor
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ABSTRACT: A national survey of tuberculosis notifications in England and Wales was carried out in 1993 to determine the notification rate of tuberculosis and the trends in the occurrence of disease by ethnic group in comparison with the findings of similar surveys in 1978/79, 1983, and 1988. The prevalence of HIV infection in adults notified with tuberculosis in the survey period was also estimated.
Clinical, bacteriological, and sociodemographic information was obtained on all newly notified cases of tuberculosis in England and Wales during the six months from 2 January to 2 July 1993. The prevalence of HIV infection in 16-54 year old patients with tuberculosis notified throughout 1993 was assessed using "unlinked anonymous" testing supplemented by matching of the register of patients with tuberculosis with that of patients with AIDS reported to the PHLS AIDS centre. Annual notification rates were calculated using population estimates from the 1993 Labour Force Survey.
A total of 2706 newly notified patients was eligible for inclusion in the survey of whom 2458 were previously untreated the comparable figures for 1988 were 2408 and 2163. The number of patients of white ethnic origin decreased from 1142 (53%) in 1988 to 1088 (44%) in 1993 whereas those of patients of Indian, Pakistani, or Bangladeshi (Indian subcontinent (ISC)) ethnic origin increased from 843 (39%) in 1988 to 1014 (41%) and those of "other" (non-white, non-ISC) ethnic origins increased from 178 (8%) to 356 (14%). The largest increase was seen in the black African ethnic group from 37 in 1988 to 171 in 1993. Forty nine per cent of patients had been born abroad and the highest rates were seen in those who had recently arrived in this country. The overall annual notification rate for previously untreated tuberculosis in England and Wales increased between 1988 and 1993 from 8.4 to 9.2 per 100,000 population. The rate declined in the white, Indian, and black Caribbean ethnic groups and increased in all other groups. In the white group the rate of decline has slowed since the last survey: in several age groups the rates were higher in 1993 than 1988 but the numbers in these groups were small. Thirty six (4.1%) of the 882 previously untreated respiratory cases were resistant to isoniazid and three (0.3%) to isoniazid and rifampicin. Sixty two (2.3%) adults aged 16-54 years were estimated to be HIV-infected. Evidence of under-reporting of HIV positive tuberculosis patients was found.
The number of cases and annual notification rate for previously untreated tuberculosis increased between 1988 and 1993. Although the decline in rates in the white population has continued, the rate of decline has slowed. The high rates in the ISC ethnic group population have continued to decline since 1988 whereas rates in the black African group have increased. An increased proportion of cases were found among people born abroad, particularly those recently arrived in this country. In previously untreated cases the level of drug resistance remains low and multi-drug resistance is rare. A small proportion of adults with tuberculosis were infected with HIV but there may be selective undernotification of tuberculosis in these patients.
Thorax 01/1998; 52(12):1060-7. · 6.84 Impact Factor
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ABSTRACT: The Concorde trial compared two policies of therapy with zidovudine (ZVD) in individuals with asymptomatic HIV infection: immediate or deferred ZDV. Participants in both groups could stop their blinded trial therapy for several reasons and/or could start open-label ZDV. The difference in survival and disease progression between the two groups was estimated allowing for treatment changes.
The relationship between latest CD4 count, treatment changes and time to AIDS-related complex (ARC), AIDS or death was investigated using time-updated proportional hazards models, but these models gave seriously biased estimates of the effect of ZDV. Therefore, a method based on the comparison of the randomized groups was used. A model relating a participant's events times to the treatment actually received was used to estimate what would have been observed if the deferred group had not received ZDV before ARS or AIDS, and to explore alternative policies for starting Pneumocystis carinii pneumonia (PCP) prophylaxis.
The major treatment changes during the trial were the termination of blinded therapy because of adverse events or personal reasons (575 out of 1749 participants), starting open-label ZDV (745 participants), and starting PCP prophylaxis (613 participants). Starting open-label ZDV and PCP prophylaxis were strongly related to latest CD4 count. The uncorrected hazard ratios for immediate compared with deferred groups were 0.89 for time to ARC, AIDS or death [95% confidence interval (CI), 0.75-1.05], 1.01 for time to AIDS or death (95% CI, 0.82-1.24), and 1.26 for time to death (95% CI, 0.93-1.70). After correction for treatment changes, these hazard ratios were 0.79 (95% CI, 0.57-1.11), 1.01 (95% CI, 0.81-1.26), and 1.37 (95% CI, 0.91-2.08), respectively. Correction for PCP prophylaxis made little difference to the results.
Open-label ZDV before ARC or AIDS in the deferred group was likely to have diluted any differences between the immediate and deferred groups. After correction for this dilution, both the estimated benefit of immediate treatment in delaying progression to ARC, AIDS or death and the estimated disadvantage of immediate treatment in accelerating death were somewhat increased, but both remained consistent with chance alone. This study demonstrated the large potential bias inherent in non-randomization-based methods of analysis of clinical trials.
AIDS 08/1997; 11(8):999-1006. · 6.24 Impact Factor
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ABSTRACT: To determine whether healthcare workers in England and Wales are at increased risk of tuberculosis and to examine the frequency of drug resistance in this population.
Comparison of notification rates by occupation obtained from national tuberculosis notification surveys in 1988 and 1993, with denominators from the 1991 census.
People with notified tuberculosis in professional and associate professional occupations from the two surveys.
Rates of notified tuberculosis in health professionals (mainly doctors) and health associate professionals (mainly nurses) compared with rates in other professional and associate professional occupations, adjusted for ethnic group, sex, and age.
119 cases of tuberculosis were identified in healthcare workers, including 61 nurses and 42 doctors. The crude notification rate in healthcare workers was 11.8 per 100,000 per year (95% confidence interval 9.8 to 14.1) compared with 3.3 per 100,000 per year (2.9 to 3.6) in other professional and associate professional occupations; rate ratios were higher (range 1.7 to 3.2) in all ethnic groups. The relative risk adjusted for ethnic group, sex, and age was 2.4 (95% confidence interval 2.0 to 3.0), slightly higher for health professionals (2.7 (1.9 to 3.8)) than for associate professionals (2.0 (1.5 to 2.6)). No multiple drug resistant strains of tuberculosis were identified in healthcare workers.
Better detection and notification of cases of tuberculosis in healthcare workers may account for some of the apparent increased risk, but these findings imply that tuberculosis remains a hazard for healthcare workers and highlight the importance of ensuring that occupational health monitoring and protection workers are not neglected.
BMJ 09/1996; 313(7056):522-5. · 14.09 Impact Factor
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The Lancet 05/1995; 345(8957):1115. · 38.28 Impact Factor
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ABSTRACT: A study was designed to determine the extent of the interaction between tuberculosis and human immunodeficiency virus infection in England and Wales.
Data were obtained from the United Kingdom national AIDS surveillance and the Medical Research Council tuberculosis notification surveys in England and Wales (1983 and 1988). The proportion of patients reported with AIDS known to have had tuberculosis and the proportion of patients notified with tuberculosis known to have HIV infection were estimated.
Of the 4360 patients with AIDS reported by 30 June 1991, 200 (4.6%) were in patients reported to have had tuberculosis. Only one of the 3002 patients (0.03%) reported in the 1983 survey of tuberculosis notifications in England and Wales was known to be infected with HIV compared with nine of 2163 patients (0.42%) in the 1988 survey.
Although the reported number of cases of HIV infection with tuberculosis in this country is increasing it remains small. Complete reporting of cases of AIDS and notification of cases of tuberculosis are essential to enable the two infections to be monitored as the HIV epidemic develops. Special studies, such as those reported here, will need to be undertaken regularly to assess the future extent of the interaction.
Thorax 04/1993; 48(3):199-203. · 6.84 Impact Factor
