Monitoring and modelling prognosis in the era of HAART (Extension to Strategic Grant G0100221)

Lead Research Organisation: University of Bristol
Department Name: Social Medicine

Abstract

Highly effective treatments, consisting of a combination of different drugs, are now available for people infected with HIV. These treatments have dramatically reduced the risk of acquired immune deficiency syndrome (AIDS) and the risk of death. Since 1996, when these treatments became available, causes of death among adults dying with or due to HIV-infection have changed. The aim of the ART Cohort Collaboration (ART-CC) is to study rates of serious diseases and death in HIV-infected patients who have started combination therapy. The collaboration is coordinated by a small team at Bristol University, and admininistered by a steering committee of cohort representatives. Our most recent dataset contains data on 45,000 HIV-infected individuals combined from 16 cohort studies (studies in which HIV-infected individuals have been followed over time). The present grant covers the period February 2008 to January 2011. Our objectives are (1) To describe the risk of AIDS, AIDS-defining illnesses and deaths from all causes and specific causes in patients starting combination therapy; (2) To define groups of illnesses that have similar implications for the subsequent risk of death, and to propose a classification of these illnesses that is relevant now that effective treatments are available; (3) To examine causes of death in the era of effective treatment, and death rates compare with the general population; (4) To use data from both cohort studies and clinical trials to compare different drug regiments; (5) To examine how outcomes differ between regions, studies, and settings and to conduct comparisons with a sister collaboration in low-income countries. We will derive updated datasets twice during the period covered by the present application. An expert committee will classify causes of death. We will compare mortality rates in HIV-infected individuals with those in the general population. The results of this research will be of direct relevance to the care of HIV-infected patients.

Technical Summary

Highly active antiretroviral therapy (HAART) has substantially improved the prognosis of HIV-infected patients, but has to be continued indefinitely once initiated. 90% of HIV-infected people live in resource-poor settings. HAART has resulted in a shift in the causes of death among adults dying with or due to HIV-infection. Randomized controlled trials (RCTs) of antiretroviral drugs typically examine differences or equivalence in short-term surrogate markers: the extent to which such effects can be extrapolated to clinical outcomes is unclear.

The aim of the ART Cohort Collaboration (ART-CC) is to examine the prognosis of HIV-infected, antiretroviral-na?ve patients starting HAART, with a focus on clinical events (AIDS-defining conditions, death and cause-specific mortality). The collaboration is coordinated by a small team at Bristol University, and admininistered by a steering committee of cohort representatives. Our most recent dataset contains data on 45,000 HIV-infected individuals combined from 16 cohort studies. In the present proposal, we request funding from February 2008 to January 2011.

Our objectives are (1) To describe the risk of progression to AIDS, AIDS-defining events (ADEs), and deaths from all causes and specific causes in treatment na?ve patients starting HAART; (2) To define groups of ADEs with comparable prognostic significance, and to propose a classification for the HAART era; (3) To examine causes of death in the era of HAART, and how cause-specific and all-cause mortality compare with the general population; (4) To examine the relationship between the effects of different HAART regimens on short-term, surrogate outcomes and those on longer term clinical outpoints; (5) To examine how outcomes differ between regions, cohorts, and settings and to conduct comparisons with a sister collaboration in low-income countries.

We will derive updated datasets twice during the period covered by the present application. The development of prognostic models will use our previously published methods. We will examine the prognostic importance of different AIDS-defining events for subsequent mortality. An expert committee will classify causes of death. We will use actuarial methods to compare mortality rates in HIV-infected individuals with those in the general population. We will compare the estimated effects of different initial HAART regimens using data from both RCTs and ART-CC. We will use meta-analytic approaches to examine heterogeneity between regions, cohorts and settings. The results of this research will be of direct relevance to the care of HIV-infected patients.

Publications

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ART-LINC Collaboration Of International Databases To Evaluate AIDS (IeDEA) (2008) Antiretroviral therapy in resource-limited settings 1996 to 2006: patient characteristics, treatment regimens and monitoring in sub-Saharan Africa, Asia and Latin America. in Tropical medicine & international health : TM & IH

 
Guideline Title Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
Description DHHS Panel on Antiretroviral Guidelines
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact The most recent US guidelines on antiretroviral therapy for HIV-infected individuals cite papers from the ART Cohort Collaboration, including and extensive discussion of our 2009 Lancet paper on timing of antiretroviral therapy (19361855) and our 2007 paper on 5 year prognosis (17502729)
 
Guideline Title Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel
Description US HIV treatment guidelines
Geographic Reach North America 
Policy Influence Type Citation in clinical guidelines
 
Description project grant
Amount £568,241 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 02/2012 
End 01/2015
 
Title Prognostic model 
Description Our website at www.art-cohort-collaboration.org provides a prognostic model for use by patients and their carers. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2007 
Provided To Others? Yes  
Impact The web site has been accessed tens of thousands of times 
URL http://www.art-cohort-collaboration.org
 
Description CNICS 
Organisation University of Alabama at Birmingham
Country United States 
Sector Academic/University 
PI Contribution Statistical modelling.
Collaborator Contribution Data contributed to opportunistic infection modelling.
Impact dataset
Start Year 2013
 
Description COHERE 
Organisation National Institute of Health and Medical Research (INSERM)
Department INSERN (1053) (Université Bordeaux Segalen)
Country France 
Sector Academic/University 
PI Contribution Scientific advice.
Collaborator Contribution Management of database and scientific advice.
Impact Published papers by ART-CC used data managed by COHERE.
Start Year 2010
 
Description COHERE 
Organisation University of Copenhagen
Department Copenhagen HIV Programme (CHIP)
Country Denmark 
Sector Academic/University 
PI Contribution Scientific advice.
Collaborator Contribution Management of database and scientific advice.
Impact Published papers by ART-CC used data managed by COHERE.
Start Year 2010
 
Description HIV-CAUSAL 
Organisation Harvard University
Department Harvard T.H. Chan School of Public Health
Country United States 
Sector Academic/University 
PI Contribution Statistical modelling and data.
Collaborator Contribution Data and statistical modelling.
Impact Paper of effect of ART.
 
Description IEDEA South Africa 
Organisation National Institutes of Health (NIH)
Country United States 
Sector Public 
PI Contribution The IEDEA collaboration is a global network of HIV cohort collaborations funded by the US National Institutes of Health. Sterne and May are collaborators with the IEDEA Southern Africa collaboration (Principal Investigator Matthias Egger)
Collaborator Contribution Comparative analyses of data from low and high income settings
Impact IEDEA South Africa is a collaboration of HIV clinic cohorts in Sub Saharan Africa, funded by the US National Institutes of Health, with which we collaborate closely. The following publications have resulted from this collaboration: 18981768, 18670668, 18373510, 18240981, 19142294
Start Year 2007
 
Description IeDEA Southern Africa 
Organisation University of Bern
Country Switzerland 
Sector Academic/University 
PI Contribution Prognostic modelling for pediatric HIV patients and comparative prognosis for adults comparing mortality with Europe and North America.
Collaborator Contribution Data and statistical modelling.
Impact publications as listed.
 
Description IeDEA Southern Africa 
Organisation University of Cape Town
Country South Africa 
Sector Academic/University 
PI Contribution Prognostic modelling for pediatric HIV patients and comparative prognosis for adults comparing mortality with Europe and North America.
Collaborator Contribution Data and statistical modelling.
Impact publications as listed.
 
Description IeDEA West Africa 
Organisation International Epidemiologic Databases to Evaluate AIDS (IeDEA)
Department IeDEA West Africa Region
Country Central African Republic 
Sector Charity/Non Profit 
PI Contribution Prognostic modelling methodology for HIV-1 and HIV-2 modelling
Collaborator Contribution Prognostic modelling methodology for HIV-1 and HIV-2 modelling
Impact Paper in Press
Start Year 2012
 
Description NA-ACCORD 
Organisation Johns Hopkins University
Department Johns Hopkins Bloomberg School of Public Health
Country United States 
Sector Academic/University 
PI Contribution Statistical modelling
Collaborator Contribution Data for project on opportunistic infections
Impact dataset
Start Year 2013
 
Description SwissRe 
Organisation Swiss Re
Country Switzerland 
Sector Private 
PI Contribution Expertise in HIV epidemiology, statistics, and data.
Collaborator Contribution Expertise in insurance, analysis.
Impact Paper on insurability 23449349 AIDS 2013 Insurability of hiv-positive people treated with antiretroviral therapy in europe: collaborative analysis of hiv cohort studies.
Start Year 2010
 
Description UKCHIC 
Organisation University College London
Department Faculty of Population Health Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboratively worked on 2 studies on life expectancy of people treated for HIV infection. Analysed data, wrote papers, and presented at conferences. Collaborated on subtypes analysis.
Collaborator Contribution Supplied data, expertise on HIV.
Impact 2 life expectancy papers subtypes paper in press with AIDS
Start Year 2009
 
Description Conference on Retroviruses and Opportunistic Infections 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Attended the Conference on Retroviruses and Opportunistic Infections every year to present work, support team members and lead the ART-CC collaboration in its work on HIV-1 patients. This is a major, international conference with an audience of around 4,000 researchers in the field of opportunistic infections and retroviruses.
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016
URL http://www.croiconference.org/
 
Description Media appearances 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Television and radio appearances by Sterne, describing improved life expectancy of HIV-infected individuals, following publication of article in the Lancet (18657708)

Wider knowledge of the benefits of antiretroviral therapy
Year(s) Of Engagement Activity 2008
 
Description Press conference 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Appeared at a press conference during the 2009 Conference on Retrovirus and Opportunistic Infections, to describe work examining when HIV-infected individuals should start antiretroviral therapy

Coverage on several web sites providing information to HIV infected patients
Year(s) Of Engagement Activity 2009
 
Description Press coverage 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Press releases from BMJ, British HIV Association and Bristol University after publication of paper on life expectancy in BMJ (pubmed 21990260). These resulted in 2 page artice in the Independent, article in Bristol Evening Post, front page item on BBC news website, Reuters articles (India and China), Nursing Times, National AIDS Treatment Advocacy Project (USA), Twitter and numerous other coverage on internet newsletters.

Wider knowledge of impact of late diagnosis and treatment on life expectancy on those with HIV. This should translate into increased testing for HIV and earlier treatment at higher CD4 counts with improved survival.
Year(s) Of Engagement Activity 2011
 
Description Radio interviews 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Two radio interviews by May in news programmes on subject of life expectancy in HIV positive individuals after publication of paper in BMJ (pubmed 21990260).

Wider knowledge of the benefits of testing and diagnosis early in the course of HIV disease so yhat antiretroviral therapy can be received in accordance with guidelines and lengthen life expectancy.
Year(s) Of Engagement Activity 2011