STEROID PROTECTION FROM TUBERCULOSIS-ASSOCIATED IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME

Globally over 1 million new cases of Tuberculosis (TB) are reported annually among people infected with the Human Immunodeficiency Virus (HIV-1), with 79% of these cases are located in Sub-Saharan Africa. Although antiretroviral therapy can significantly improve the clinical outcomes of patients co-infected with HIV and TB, this form of treatment can also lead to a complication known as TB-associated Immune Reconstitution Inflammatory Syndrome (TB-IRIS). Once patients commence antiretroviral therapy (ART) there is a rapid recovery of the immune cells, which in some cases can actually worsen the TB disease, even when previous treatments had been effective. The hallmark of TB-IRIS is severe systemic inflammation and the onset of symptoms usually occurs around two weeks after commencing ART. If left untreated, TB-IRIS may be fatal, particularly in patients who have a neurological TB infection.

Prednisone, a corticosteroid, is the only treatment for TB-IRIS that has been evaluated systemically in clinical trials. In a recently completed clinical trial, researchers found that low doses of preventive prednisone prescribed at the time of ART initiation reduced the risk of TB-IRIS by 30%. A large number of clinical samples were collected from these patients to enable us to better understand the underlying causes of TB-IRIS and to develop more effective treatment.

Currently, there is no diagnostic test available for TB-IRIS and treatment options are limited. Preventive steroids can provide some protection, although this is not always the case and some patients may be at risk of adverse side-effects if steroid is used over a prolonged period of time. Consequently, my aim is to develop a biomarker that will enable doctors to identify patients at high risk of developing TB-IRIS so they can more effectively determine the most appropriate dosing regimen for preventive steroid treatment. In addition, I will also investigate how prednisone works to suppress inflammation in patients with TB-IRIS and compare this with a range of novel drugs. This information will help us design and develop a new generation of anti-inflammatory drugs that target TB-IRIS and other inflammatory diseases more effectively and at a lower cost.

Finally, genetics are also known to influence many facets associated with TB including infection, the development of TB-IRIS, and a patient's response to steroids. Therefore, I will investigate whether genetic mutation plays a role in the development of TB-IRIS and the effectiveness of steroid treatments. In short, the research proposed here will significantly improve the diagnosis and treatment of patients suffering from TB-IRIS, with broader implications for the future design of therapeutic drugs to tackle many other inflammatory conditions.

Patients co-infected with HIV-1 and TB are at risk of developing a highly inflammatory complication known as Immune Reconstitution Inflammatory Syndrome (TB-IRIS) upon commencing antiretroviral therapy (ART). There are no validated prognostic biomarkers for TB-IRIS and prednisone is the only treatment that has been evaluated in randomised placebo-controlled trials. A recent trial demonstrated that preventive prednisone given at the time of ART initiation reduced risk of TB-IRIS by up to 30%. Building on the availability of clinical samples from this trial, I aim to investigate how to improve early diagnosis of TB-IRIS and increase the effectiveness of treatment options.

I rationalise that a biomarker signature predictive of patients with high risk of developing TB-IRIS will justify prescription of high dose prophylactic prednisone as its protective benefits outweigh the risk of adverse side-effects. I further argue that drugs targeting biological pathways specific to TB-IRIS pathogenesis may provide better protection against TB-IRIS symptoms. I will perform RNA-Seq and derive transcriptional signatures at each longitudinal timepoint. The transcriptome findings will be complemented with protein profiling in the corresponding plasma. I will dissect the transcriptomic and metabolomics metadata to identify functional pathways associated with TB-IRIS pathogenesis and those related to prednisone's mode of action in suppressing inflammation. Using in vitro experiments I will further investigate whether inhibitors to specific inflammatory signalling pathways may better suppress cytokine/chemokine production than prednisone. Finally, I will also explore if TB-IRIS may be in part due to genetic predisposition. To test this I will perform a target-specific gene polymorphism study on genes with known phenotypic changes, such as those described to associate with TB and TB-IRIS and identify whether not protection from TB-IRIS can be segregated according to genotypes.

A wide range of stakeholders will benefit from my proposed research, as summarised below.

1) Clinical professionals

As of current, there is no standardised test available for the diagnosis or monitoring of TB-IRIS, which means clinicians rely heavily on symptom-based diagnosis and blood chemistry. Consequently, misdiagnosis or underdiagnosis of TB-IRIS is not uncommon as the symptoms of TB-IRIS can be very similar to those of advanced HIV / AIDS. The proposed research therefore aims to identify a predictive biomarker for TB-IRIS, which will have significant potential for commercialisation into standard diagnostic test. This would be a major breakthrough and would revolutionise the way that clinicians and other healthcare professionals diagnose and manage patients at risk of developing TB-IRIS. For example, patients who display a strongly positive biomarker signature may be initiated on high dose steroids at the same time as they commence antiretroviral therapy. Patients who have biomarker signature showing reduced responsiveness to steroid may be put on other anti-inflammatory drugs instead to be better treating the condition. In addition, clinicians will be able to decide when to increase drug dosage or to cease therapy based on signal intensity of the biomarker signature. This will provide the basis of host-directed precision medicine regardless of clinician's past experience in managing TB-IRIS.

2) Patients

The findings of my proposed research have the potential to greatly improve the treatment received by patients suffering from HIV-associated TB. Majority of the patients who developed TB-IRIS have advanced stage of HIV-1 infection / AIDS and their TB-IRIS symptoms may be misdiagnosed as general HIV-1 complications. Without timely and appropriate medication, significant morbidity or even mortality is expected, particularly if patients have extrapulmonary form of TB such as that in the neurological site. Corticosteroid is a widely available and economical drug that can prevent TB-IRIS occurrence. Nevertheless, high dose and/or prolonged use of corticosteroid are not normally prescribed in the first instance as this can increase the risk of HIV-related cancer or other opportunistic infections. With a TB-IRIS specific biomarker that can differentiate between patients who will or will not respond to corticosteroid, clinician will be able to prescribe the most appropriate anti-inflammatory treatment regimens to patients with different risk level of developing TB-IRIS. This will significantly reduce disease morbidity and mortality and improve the overall well being of patients by avoiding unnecessary or ineffective therapies.

3) Medical research community

My research methodology to identify biomarkers in HIV-associated TB may serve as a template for other researchers that are working to identify biomarkers for a range of other diseases. In addition, my proposed research will generate one of the largest and most comprehensive sets of metadata associated with inflammatory diseases. This will represent a highly valuable resource with the potential to help other members of the medical research community working on inflammation, and/or the discovery and development of new drugs to treat a whole host of diseases.

4) Policy makers

The research described in my MRC CDA application has the potential to redefine the diagnosis and treatment regime for TB-IRIS and other inflammatory diseases. As such, policy makers at all levels of government may be able to draw upon my findings to inform assessments of new clinical protocols or novel drugs designed to increase the effectiveness of therapeutic interventions for a range of infectious diseases that lead to inflammation.