Prognosis of HIV-positive patients treated with antiretroviral therapy: comparative analyses and treatment strategies
Lead Research Organisation:
University of Bristol
Department Name: Social Medicine
Abstract
Highly effective treatments consisting of combinations of different drugs are now available for HIV-positive people and have dramatically reduced the risk of acquired immune deficiency syndromes (AIDS) and death since their introduction in 1996. Increasing numbers of patients have been treated for many years, but outcomes in these people remain unclear, patterns of cause of death have changed, and new predictors of outcomes are emerging. Randomised clinical trials are the best way to examine treatment effects, but most trials in the field rely on outcomes that are measurements from blood tests (rather than AIDS and death, which are of more interest to patients and doctors) and recruit small numbers of patients followed for a short length of time. Trials often exclude sicker patients, and cannot estimate the effectiveness of drugs in important subgroups such as women, those aged >50 years, or ethnic minorities. Many questions relating to treatment strategies cannot be, or have not been, answered in trials. Therefore information about long term outcomes and effects of treatment in patient subgroups must largely rely on large collaborations of HIV cohorts - studies in which groups of HIV positive people are followed over time.
This application seeks funding for the ART Cohort Collaboration (ART-CC), an international collaboration that combines data from 19 HIV cohort studies from Europe and North America. It is coordinated by a small team at Bristol University, and administered by a steering committee of representatives from the contributing studies with expertise in HIV medicine, clinical epidemiology and medical statistics, and patient representatives. We will work within European and North American regional collaborations, which will provide considerable value for money because we can take advantage of their data management systems, and also ensure that we have a distinct and unique research agenda. We expect to combine data on at least 100,000 patients. We will work with collaborations in Southern and West Africa in order to compare outcomes among patients treated in these settings, in which resources for treatment and health care are limited, with outcomes among patients treated in Europe and North America. We will update our datasets annually during the period covered by the application.
Our objectives are: (A) Examine the prognosis of patients on treatment for AIDS, deaths from all causes and deaths from specific causes, focusing on prognosis over many years, the role of new factors that predict AIDS and death, and prognosis from some years after starting treatment; (B) Examine differences in prognosis between regions and settings including the roles of gender and ethnic group; (C) Estimate life expectancy, defined as the average number of additional years a person will live, from the time of starting treatment and separately for groups of patients with different characteristics; (D) Conduct collaborative work on prognosis in low income settings, such as sub-Saharan Africa, where the majority of HIV-positive people live. We will use statistical methods that mimic randomised trials using cohort data to: (E) Investigate strategies for regimen modification (switching) in patients in whose blood HIV-1 virus can be detected, and examine risk factors for and prognosis according to the type of regimen change; (F) Estimate the adverse effects of missed doses or interruptions to treatment on clinical outcomes; (G) Examine the best time to start treatment for HIV in patients who also require treatment for other specific infections that occur when the immune system has been damaged and that affect the central nervous system.
Based on our past experience, we expect the results of this research to be of direct relevance to the care of HIV-positive people and to be incorporated into treatment guidelines. We will provide online risk and life expectancy calculators, as well as summaries for patients, on the study web site.
This application seeks funding for the ART Cohort Collaboration (ART-CC), an international collaboration that combines data from 19 HIV cohort studies from Europe and North America. It is coordinated by a small team at Bristol University, and administered by a steering committee of representatives from the contributing studies with expertise in HIV medicine, clinical epidemiology and medical statistics, and patient representatives. We will work within European and North American regional collaborations, which will provide considerable value for money because we can take advantage of their data management systems, and also ensure that we have a distinct and unique research agenda. We expect to combine data on at least 100,000 patients. We will work with collaborations in Southern and West Africa in order to compare outcomes among patients treated in these settings, in which resources for treatment and health care are limited, with outcomes among patients treated in Europe and North America. We will update our datasets annually during the period covered by the application.
Our objectives are: (A) Examine the prognosis of patients on treatment for AIDS, deaths from all causes and deaths from specific causes, focusing on prognosis over many years, the role of new factors that predict AIDS and death, and prognosis from some years after starting treatment; (B) Examine differences in prognosis between regions and settings including the roles of gender and ethnic group; (C) Estimate life expectancy, defined as the average number of additional years a person will live, from the time of starting treatment and separately for groups of patients with different characteristics; (D) Conduct collaborative work on prognosis in low income settings, such as sub-Saharan Africa, where the majority of HIV-positive people live. We will use statistical methods that mimic randomised trials using cohort data to: (E) Investigate strategies for regimen modification (switching) in patients in whose blood HIV-1 virus can be detected, and examine risk factors for and prognosis according to the type of regimen change; (F) Estimate the adverse effects of missed doses or interruptions to treatment on clinical outcomes; (G) Examine the best time to start treatment for HIV in patients who also require treatment for other specific infections that occur when the immune system has been damaged and that affect the central nervous system.
Based on our past experience, we expect the results of this research to be of direct relevance to the care of HIV-positive people and to be incorporated into treatment guidelines. We will provide online risk and life expectancy calculators, as well as summaries for patients, on the study web site.
Technical Summary
Antiretroviral therapy (ART) dramatically reduces rates of AIDS and death in HIV-positive people in Europe, North America and low-income settings, particularly those who start early and attain viral suppression. However mortality rates still exceed those in the general population, and there are increasing numbers of older patients and those treated for many years. Predictors of prognosis are changing to include factors beyond conventional markers of HIV disease progression: long term outcomes remain unclear. This application seeks funding for a collaboration of 19 European and North American HIV cohort studies. Working within regional collaborations, we plan to combine data on >100000 treated patients and compare outcomes with those in Southern and West Africa. Objectives are: A) Examine prognosis for AIDS and deaths from all and specific causes among patients on ART, focusing on non-HIV biomarkers, additional CD4 measures, co-infections, new measures of and interactions with HIV virus burden, and HIV-1 subtype; B) Investigate heterogeneity in outcomes between regions and settings; C) Estimate life expectancy overall and in subgroups; D) Conduct collaborative work on prognosis in low-income settings (comparison of mortality in S. Africa, Europe and N. America allowing for incomplete death ascertainment, and prognosis for HIV-2 in W. Africa). We will use causal inference methods to examine optimal treatment strategies including E) strategies for regimen modification (switching) in patients with virological failure of first ART regimen; F) effect of non-adherence to ART on treatment failure and progression to AIDS and death; G) optimal timing of ART in patients presenting with specific CNS AIDS-defining opportunistic infections such as cryptococcal meningitis and toxoplasmic encephalitis. We expect our research results to be of direct relevance to the care of HIV-positive people and to be published in high impact journals and incorporated in treatment guidelines.
Planned Impact
Our research programme aims to provide information that will be directly useful to patients and health professionals making decisions about antiretroviral therapy (ART). An improved understanding of factors predicting prognosis among treated patients will help doctors and other health professionals improve and optimise care for high-risk patients and guide patients on ways to improve their prognosis. Our previous work has directly influenced, and been highly cited in, national and international treatment guidelines on treatment of HIV-positive people, and the objectives of our current application address questions of direct relevance to formulation of future guidelines. We will respond to requests for additional analyses from those writing guidelines (for example, the World Health Organisation (WHO)).
Prognostic models are important in enabling policy-makers and those planning health services to predict levels of care that will be needed by an increasing and aging population of treated HIV-positive people. Defining the burden of morbidity and mortality associated with HIV in the era of combination ART will help future planning of both health service provision and social welfare. ART is an expensive treatment that has to be taken for life, but costs may reduce as some drugs come off-patent in the coming years. Our work will assist in studies of the optimum choice of initial ART regimen, balancing effects on rates of AIDS and death, regimen durability, and costs.
Our work on heterogeneity will provide insights into the influence of health systems on outcomes, and an improved understanding of differences between patient groups (for example, according to sex or ethnicity) will enable targeting of groups in which outcomes are sub-optimal, for example because of imperfect adherence, presence of modifiable risk factors or a need for improved treatment of comorbidities.
Estimates of life-expectancy will enable health professionals to answer one of the most common questions asked by patients considering starting ART, or changing or interrupting their regimen - "How long have I got to live?". We will work with the insurance industry to promote life insurance for treated HIV-positive people, by providing estimates in the form required for actuarial calculations.
Comparisons between outcomes of ART in high and low income settings are key to identifying problems of delivering ART in low income settings (for example, very high early mortality), as well as demonstrating that excellent outcomes can be achieved with much more limited resources than are available in Europe or North America.
Randomised clinical trials (RCTs) underpin decisions about optimal treatments and treatment strategies, but many questions about ART cannot be, or have not yet been, addressed in RCTs. The best available alternative is to conduct analyses of cohort studies using methods that mimic RCTs and can hence provide causal inferences, based on strong but clearly defined assumptions. We will use these methods to answer questions about effects of ART regimen modification (switching), non-adherence to ART, and the optimal timing of ART. Results of this work will again be directly useful to health professionals and patients making treatment decisions.
Prognostic models are important in enabling policy-makers and those planning health services to predict levels of care that will be needed by an increasing and aging population of treated HIV-positive people. Defining the burden of morbidity and mortality associated with HIV in the era of combination ART will help future planning of both health service provision and social welfare. ART is an expensive treatment that has to be taken for life, but costs may reduce as some drugs come off-patent in the coming years. Our work will assist in studies of the optimum choice of initial ART regimen, balancing effects on rates of AIDS and death, regimen durability, and costs.
Our work on heterogeneity will provide insights into the influence of health systems on outcomes, and an improved understanding of differences between patient groups (for example, according to sex or ethnicity) will enable targeting of groups in which outcomes are sub-optimal, for example because of imperfect adherence, presence of modifiable risk factors or a need for improved treatment of comorbidities.
Estimates of life-expectancy will enable health professionals to answer one of the most common questions asked by patients considering starting ART, or changing or interrupting their regimen - "How long have I got to live?". We will work with the insurance industry to promote life insurance for treated HIV-positive people, by providing estimates in the form required for actuarial calculations.
Comparisons between outcomes of ART in high and low income settings are key to identifying problems of delivering ART in low income settings (for example, very high early mortality), as well as demonstrating that excellent outcomes can be achieved with much more limited resources than are available in Europe or North America.
Randomised clinical trials (RCTs) underpin decisions about optimal treatments and treatment strategies, but many questions about ART cannot be, or have not yet been, addressed in RCTs. The best available alternative is to conduct analyses of cohort studies using methods that mimic RCTs and can hence provide causal inferences, based on strong but clearly defined assumptions. We will use these methods to answer questions about effects of ART regimen modification (switching), non-adherence to ART, and the optimal timing of ART. Results of this work will again be directly useful to health professionals and patients making treatment decisions.
Publications
Mugglin, C.
(2012)
Immunodeficiency at the start of ART: Global view
Davies MA
(2014)
Prognosis of children with HIV-1 infection starting antiretroviral therapy in Southern Africa: a collaborative analysis of treatment programs.
in The Pediatric infectious disease journal
Antiretroviral Therapy Cohort Collaboration
(2017)
Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies.
in The lancet. HIV
GBD 2015 HIV Collaborators
(2016)
Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980-2015: the Global Burden of Disease Study 2015.
in The lancet. HIV
Trickey A
(2017)
Methodological and statistical issues related to analysis of survival - Authors' reply
in The Lancet HIV
Brilleman SL
(2016)
Joint longitudinal hurdle and time-to-event models: an application related to viral load and duration of the first treatment regimen in patients with HIV initiating therapy.
in Statistics in medicine
Palmer Tom M.
(2015)
Fitting fixed- and random-effects meta-analysis models using structural equation modeling with the sem and gsem commands
in STATA JOURNAL
Trickey A
(2016)
Cause-Specific Mortality in HIV-Positive Patients Who Survived Ten Years after Starting Antiretroviral Therapy.
in PloS one
Suthar A
(2017)
Antiretroviral therapy and population mortality: Leveraging routine national data to advance policy
in PLOS Medicine
Johnson L
(2017)
Estimating the impact of antiretroviral treatment on adult mortality trends in South Africa: A mathematical modelling study
in PLOS Medicine
Balestre E
(2016)
Immunologic response in treatment-naïve HIV-2-infected patients: the IeDEA West Africa cohort.
in Journal of the International AIDS Society
Pettit AC
(2018)
Increased non-AIDS mortality among persons with AIDS-defining events after antiretroviral therapy initiation.
in Journal of the International AIDS Society
Womack J
(2017)
A novel strategy to reduce very late HIV diagnosis in high-prevalence areas in South-West England: serious incident audit.
in Journal of public health (Oxford, England)
Ingle SM
(2018)
Identifying Risk of Viral Failure in Treated HIV-Infected Patients Using Different Measures of Adherence: The Antiretroviral Therapy Cohort Collaboration.
in Journal of clinical medicine
IeDEA And ART Cohort Collaborations
(2014)
Immunodeficiency at the start of combination antiretroviral therapy in low-, middle-, and high-income countries.
in Journal of acquired immune deficiency syndromes (1999)
Caniglia EC
(2016)
When to Monitor CD4 Cell Count and HIV RNA to Reduce Mortality and AIDS-Defining Illness in Virologically Suppressed HIV-Positive Persons on Antiretroviral Therapy in High-Income Countries: A Prospective Observational Study.
in Journal of acquired immune deficiency syndromes (1999)
May MT
(2015)
Injection Drug Use and Hepatitis C as Risk Factors for Mortality in HIV-Infected Individuals: The Antiretroviral Therapy Cohort Collaboration.
in Journal of acquired immune deficiency syndromes (1999)
Gras L
(2019)
Determinants of Restoration of CD4 and CD8 Cell Counts and Their Ratio in HIV-1-Positive Individuals With Sustained Virological Suppression on Antiretroviral Therapy.
in Journal of acquired immune deficiency syndromes (1999)
Fox MP
(2012)
Rates and predictors of failure of first-line antiretroviral therapy and switch to second-line ART in South Africa.
in Journal of acquired immune deficiency syndromes (1999)
May MT
(2014)
Cohort profile: Antiretroviral Therapy Cohort Collaboration (ART-CC).
in International journal of epidemiology
May MT
(2012)
Heterogeneity in outcomes of treated HIV-positive patients in Europe and North America: relation with patient and cohort characteristics.
in International journal of epidemiology
ChĂȘne G
(2017)
Cohort Profile: Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord.
in International journal of epidemiology
Cain LE
(2016)
Using observational data to emulate a randomized trial of dynamic treatment-switching strategies: an application to antiretroviral therapy.
in International journal of epidemiology
Trickey A
(2020)
Cause-specific mortality after diagnosis of cancer among HIV-positive patients: A collaborative analysis of cohort studies.
in International journal of cancer
Young J
(2018)
Antiretroviral pill count and clinical outcomes in treatment-naïve patients with HIV infection.
in HIV medicine
Satre DD
(2021)
The relationship of smoking and unhealthy alcohol use to the HIV care continuum among people with HIV in an integrated health care system.
in Drug and alcohol dependence
Nakagawa F
(2013)
Life expectancy living with HIV: recent estimates and future implications.
in Current opinion in infectious diseases
Costagliola D
(2016)
Survival in individuals living with HIV.
in Current opinion in HIV and AIDS
May MT
(2016)
Mortality According to CD4 Count at Start of Combination Antiretroviral Therapy Among HIV-infected Patients Followed for up to 15 Years After Start of Treatment: Collaborative Cohort Study.
in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
Description | Collaborative Research in HIV/AIDS, Alcohol, and Related Comorbidities (Collaborative U01) - National Institute on Alcohol Abuse and Alcoholism |
Amount | $8,045,723 (USD) |
Funding ID | 1U01AA026209-01 |
Organisation | National Institutes of Health (NIH) |
Sector | Public |
Country | United States |
Start | 09/2017 |
End | 09/2023 |
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 | 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 | 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 | WADA |
Organisation | University of Bordeaux |
Country | France |
Sector | Academic/University |
PI Contribution | Collaborative analysis of data on HIV-2 infected persons in West Africa |
Collaborator Contribution | Data, medical expertise, statistical analyses. |
Impact | paper in press |
Start Year | 2012 |
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 | MRC Centenary celebrations |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Type Of Presentation | Workshop Facilitator |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Gave 2 round table presentations and discussions as part of an evening of showcasing MRC research. Raised public awareness of HIV issues. |
Year(s) Of Engagement Activity | 2013 |