Investigating the pathophysiology and contribution of co-infections in fatal HIV-associated tuberculosis. Prof. Graeme Meintjes. Uni of Cape Town
Lead Research Organisation:
Imperial College London
Department Name: Dept of Medicine
Abstract
Among HIV-infected people in Sub-Saharan Africa, tuberculosis (TB) is the commonest cause of death. In 2007 there were an estimated 378,000 deaths due to HIV-associated TB in Africa and 94,000 in South Africa. Many of these deaths occur in young adults. This occurs despite roll-out of antiretroviral therapy (ART) to treat HIV and importantly many patients with HIV-associated TB die after having started TB treatment. It is particularly those patients with HIV-associated TB who are sick enough to require hospitalisation that are most at risk of dying despite TB treatment. In a study of 1006 patients diagnosed with TB at one South African hospital (80% HIV-infected), 19% died in hospital and a further 6% died after discharge. Among hospitalised HIV-infected TB suspects in Uganda, by 2 months 32% had died.
The focus of these studies will be on why these patients die despite treatment for TB. There are few detailed clinical studies that define the mechanisms of death and contributors to death in these patients. We propose an observational study which will involve recruiting 660 patients with HIV-associated TB admitted to GF Jooste Hospital, Cape Town. Patients who are enrolled will be managed according to standard treatment protocols for their TB and ART will be started after 2 weeks. We will perform investigations at study entry and clinical deterioration to address our study hypotheses. We hypothesise that the high mortality in hospitalised HIV-TB patients results from the effects of TB infection itself as well as a number of other factors (other bacterial co-infections, cytomegalovirus infection reactivation in blood, gut dysfunction with entry of bacterial products and bacteria into blood from the gut). These together result in organ dysfunction and cardiovascular collapse, as well as causing worsening of immunosuppression due to the activated immune system being more likely to result in immune cell death. In this study we will be able to establish whether each of these factors (TB infection load, bacterial infections, cytomegalovirus load in blood and gut dysfunction) are associated with deaths in hospitalised HIV-TB patients and what their relative contribution is.
We also propose three substudies. The first will assess the concentrations of TB drugs in the blood of these patients and compare these with HIV-infected and uninfected patients on TB treatment as outpatients. It is possible that TB drug concentrations may be lower in these sick hospitalised patients because of changes in drug absorption in the intestine and this may contribute to deaths, but this has not been properly assessed in a study before. We will also perform post-mortem examinations when relatives consent in order to establish causes and contributors to death, and our findings will be used to develop a TB severity score that will help clinicians in defining prognosis and management strategies in these patients.
The findings of these studies will provide a better understanding of what contributes to the high mortality in these patients and on the basis of the results clinical trials could be designed to test interventions to reduce this mortality. Improved acute management strategies for severe HIV-TB are urgently needed. Based on our study findings, novel therapeutic strategies such as targeted pre-emptive treatment for certain bacterial infections, treatment of high levels of cytomegalovirus infection in blood, treatments that modulate the immune response and adjustments in TB drug doses may be tested in clinical trials.
The focus of these studies will be on why these patients die despite treatment for TB. There are few detailed clinical studies that define the mechanisms of death and contributors to death in these patients. We propose an observational study which will involve recruiting 660 patients with HIV-associated TB admitted to GF Jooste Hospital, Cape Town. Patients who are enrolled will be managed according to standard treatment protocols for their TB and ART will be started after 2 weeks. We will perform investigations at study entry and clinical deterioration to address our study hypotheses. We hypothesise that the high mortality in hospitalised HIV-TB patients results from the effects of TB infection itself as well as a number of other factors (other bacterial co-infections, cytomegalovirus infection reactivation in blood, gut dysfunction with entry of bacterial products and bacteria into blood from the gut). These together result in organ dysfunction and cardiovascular collapse, as well as causing worsening of immunosuppression due to the activated immune system being more likely to result in immune cell death. In this study we will be able to establish whether each of these factors (TB infection load, bacterial infections, cytomegalovirus load in blood and gut dysfunction) are associated with deaths in hospitalised HIV-TB patients and what their relative contribution is.
We also propose three substudies. The first will assess the concentrations of TB drugs in the blood of these patients and compare these with HIV-infected and uninfected patients on TB treatment as outpatients. It is possible that TB drug concentrations may be lower in these sick hospitalised patients because of changes in drug absorption in the intestine and this may contribute to deaths, but this has not been properly assessed in a study before. We will also perform post-mortem examinations when relatives consent in order to establish causes and contributors to death, and our findings will be used to develop a TB severity score that will help clinicians in defining prognosis and management strategies in these patients.
The findings of these studies will provide a better understanding of what contributes to the high mortality in these patients and on the basis of the results clinical trials could be designed to test interventions to reduce this mortality. Improved acute management strategies for severe HIV-TB are urgently needed. Based on our study findings, novel therapeutic strategies such as targeted pre-emptive treatment for certain bacterial infections, treatment of high levels of cytomegalovirus infection in blood, treatments that modulate the immune response and adjustments in TB drug doses may be tested in clinical trials.
Technical Summary
Tuberculosis (TB) is the commonest cause of death among HIV-infected people in Africa. In 2007 there were an estimated 378,000 deaths due to HIV-TB in Africa and 94,000 in South Africa. Many of these deaths occur in young adults. This occurs despite roll-out of antiretroviral therapy and importantly many patients with HIV-TB die after having started TB treatment. The focus of these studies will be on why these patients die despite effective antimicrobial therapy for TB. There are few detailed clinical studies that define the pathophysiology and mechanisms of death in these patients. Improved acute management strategies for severe HIV-TB are urgently needed and these should be evidence-based.
We propose a prospective observational cohort study recruiting 660 hospitalised patients with HIV-TB. We hypothesise that the high mortality in hospitalised HIV-TB patients is the result of a sepsis syndrome driven by a combination of: Mycobacterium tuberculosis (MTB) itself, bacterial co-infections, CMV viraemia, and gut dysfunction with translocation of bacterial products and gram-negative bacteria into blood. Further we hypothesise that this results in organ dysfunction and circulatory collapse, as well as worsening immunosuppression due to immune activation-induced apoptosis of immune cells. We will address the following four specific questions:
1) Is fatal HIV-TB associated with a sepsis syndrome caused by MTB itself resulting in major organ dysfunction and septic shock?
2) Is fatal HIV-TB associated with translocation of gram-negative bacteria and their products from the gastrointestinal tract into blood?
3) Is fatal HIV-TB associated with cytomegalovirus viraemia?
4) Is fatal HIV-TB associated with immune activation-induced apoptosis?
Substudies will be: a pharmacokinetic study to assess the adequacy of rifampicin, isoniazid and pyrazinamide concentrations in hospitalised HIV-TB patients, a postmortem study and the development of an HIV-TB severity score.
We propose a prospective observational cohort study recruiting 660 hospitalised patients with HIV-TB. We hypothesise that the high mortality in hospitalised HIV-TB patients is the result of a sepsis syndrome driven by a combination of: Mycobacterium tuberculosis (MTB) itself, bacterial co-infections, CMV viraemia, and gut dysfunction with translocation of bacterial products and gram-negative bacteria into blood. Further we hypothesise that this results in organ dysfunction and circulatory collapse, as well as worsening immunosuppression due to immune activation-induced apoptosis of immune cells. We will address the following four specific questions:
1) Is fatal HIV-TB associated with a sepsis syndrome caused by MTB itself resulting in major organ dysfunction and septic shock?
2) Is fatal HIV-TB associated with translocation of gram-negative bacteria and their products from the gastrointestinal tract into blood?
3) Is fatal HIV-TB associated with cytomegalovirus viraemia?
4) Is fatal HIV-TB associated with immune activation-induced apoptosis?
Substudies will be: a pharmacokinetic study to assess the adequacy of rifampicin, isoniazid and pyrazinamide concentrations in hospitalised HIV-TB patients, a postmortem study and the development of an HIV-TB severity score.
Planned Impact
There are four major non-academic beneficiaries of this research: clinicians working in hospital settings in sub-Saharan Africa where HIV-TB has become the commonest reason for admission to a medical ward, public health policy makers, people living with HIV and society at large given the economic and broad social impact of HIV-TB deaths.
Clinicians who treat HIV-TB patients urgently need improved acute management strategies and these should be evidence-based. Based on our study findings, novel therapeutic strategies such as targeted gram-negative bacterial prophylaxis, treatment of CMV viraemia, immunomodulatory therapy and improved early TB drug treatment strategies could be tested in clinical trials. By furthering understanding of the causes of death and the contribution of co-infections it is anticipated that the findings will allow for clinical trial to be developed that investigate novel interventions for reducing mortality in hospitalized patients with HIV-TB targeting aetiological factors identified in the observational study we have propose here. The development of an HIV-TB severity score would assist clinicians in defining prognosis of patients on admission and targeting intensive management at those patients with the highest mortality risk.
HIV-TB is a public health priority in sub-Saharan Africa as the condition is one of the leading causes of death among young adults in sub-Saharan Africa. The findings of this study will impact on public health policy. For example, the findings with respect to TB drug pharmacokinetics may lead to strategies to optimize TB drug dosing in patients with severe HIV-TB. We will interact with policy makers to enable study findings to be translated into practice.
The focus of this study is patients with HIV-TB who require hospitalization. These are also the people who in the future will most benefit from the findings of our study. Generally these are people who present with both their HIV disease and their TB late in the course of these diseases. They are very ill and often bedbound when requiring admission with a high mortality risk. However, if these patients are successfully treated through the period of acute illness and are stabilized on TB treatment and then ART, they generally do well in the long term returning to economically-productive lives. The key challenge is to reduce mortality immediately after diagnosis. To do this the causes and mechanisms of these deaths need to be better understood, our aim in these studies.
The HIV pandemic has disproportionately affected South Africa with an estimated prevalence of HIV infection in the general population of 10.9% and approximately 5.5 million South Africans living with HIV. Furthermore it is estimated that approximately 350 000 South Africans die annually with HIV infection (2007 estimate), the majority prematurely in the period of their lives when they are most economically active and heading households. The major cause of death among HIV-infected people is TB. The result is that South Africa has an estimated 1.9 million orphans who have lost one or both parents as a consequence of HIV. Life expectancy has fallen from 62 years in 1990 to 50 years in 2007, with HIV the major contributor to premature mortality. It is estimated that HIV accounted for half of all deaths in SA in 2008. The effect on the macro-economy in terms of death of skilled people, days off work when ill and reduced savings due to investment in caring and treating people with HIV is substantial. Modeling studies have projected that economic growth in Africa will be 0.6 to 1.5% lower between 1990 and 2025 as a consequence of HIV/AIDS. Addressing HIV-TB mortality, understanding the causes and contributors and ultimately defining medical interventions that could reduce acutely mortality among those patients who present with severe HIV-TB could help to mitigate the social and economic impact of this condition.
Clinicians who treat HIV-TB patients urgently need improved acute management strategies and these should be evidence-based. Based on our study findings, novel therapeutic strategies such as targeted gram-negative bacterial prophylaxis, treatment of CMV viraemia, immunomodulatory therapy and improved early TB drug treatment strategies could be tested in clinical trials. By furthering understanding of the causes of death and the contribution of co-infections it is anticipated that the findings will allow for clinical trial to be developed that investigate novel interventions for reducing mortality in hospitalized patients with HIV-TB targeting aetiological factors identified in the observational study we have propose here. The development of an HIV-TB severity score would assist clinicians in defining prognosis of patients on admission and targeting intensive management at those patients with the highest mortality risk.
HIV-TB is a public health priority in sub-Saharan Africa as the condition is one of the leading causes of death among young adults in sub-Saharan Africa. The findings of this study will impact on public health policy. For example, the findings with respect to TB drug pharmacokinetics may lead to strategies to optimize TB drug dosing in patients with severe HIV-TB. We will interact with policy makers to enable study findings to be translated into practice.
The focus of this study is patients with HIV-TB who require hospitalization. These are also the people who in the future will most benefit from the findings of our study. Generally these are people who present with both their HIV disease and their TB late in the course of these diseases. They are very ill and often bedbound when requiring admission with a high mortality risk. However, if these patients are successfully treated through the period of acute illness and are stabilized on TB treatment and then ART, they generally do well in the long term returning to economically-productive lives. The key challenge is to reduce mortality immediately after diagnosis. To do this the causes and mechanisms of these deaths need to be better understood, our aim in these studies.
The HIV pandemic has disproportionately affected South Africa with an estimated prevalence of HIV infection in the general population of 10.9% and approximately 5.5 million South Africans living with HIV. Furthermore it is estimated that approximately 350 000 South Africans die annually with HIV infection (2007 estimate), the majority prematurely in the period of their lives when they are most economically active and heading households. The major cause of death among HIV-infected people is TB. The result is that South Africa has an estimated 1.9 million orphans who have lost one or both parents as a consequence of HIV. Life expectancy has fallen from 62 years in 1990 to 50 years in 2007, with HIV the major contributor to premature mortality. It is estimated that HIV accounted for half of all deaths in SA in 2008. The effect on the macro-economy in terms of death of skilled people, days off work when ill and reduced savings due to investment in caring and treating people with HIV is substantial. Modeling studies have projected that economic growth in Africa will be 0.6 to 1.5% lower between 1990 and 2025 as a consequence of HIV/AIDS. Addressing HIV-TB mortality, understanding the causes and contributors and ultimately defining medical interventions that could reduce acutely mortality among those patients who present with severe HIV-TB could help to mitigate the social and economic impact of this condition.
