HIV's influence on TB evolution
Tuberculosis (TB) remains a major global health problem, with 10 million cases and 2 million deaths per year according to the World Health Organization. The only available vaccine is effective in children, but its effect wanes in older children and adults.
People who are already infected with HIV are more susceptible to TB infection, and they often encounter severe complications and experience a much higher mortality rate as a result of their co-infection. The brunt of the co-epidemic of HIV and TB is especially felt in sub-Saharan Africa, a region that also struggles with high rates of poverty and inequality.
While the TB bacteria (Mycobacterium tuberculosis) has been evolving with humans for thousands of years, HIV co-infections create immunological environments within the host that this bacterium has not encountered before and could, therefore, be nudging it to evolve new characteristics.
In one of the first studies to have investigated this possibility, Dr Anastasia Koch from UCT’s Institute of Infectious Disease and Molecular Medicine conducted an evolutionary analysis of M. tuberculosis full genome sequences from HIV uninfected and HIV co-infected individuals. She conducted her research under the supervision of Professor Robert Wilkinson from the Wellcome Centre for Infectious Disease Research in Africa and Associate Professor Darren Martin from Computational Biology, and in collaboration with colleagues from the Institute of Infectious Disease and Molecular Medicine and from the Swiss Tropical and Public Health Institute.
These M. tuberculosis strains were isolated from individuals living in Khayelitsha, a community with among the highest HIV and TB infection rates in the world.
The research team uncovered specific sites within M. tuberculosis genomes where the bacterium may have been forced to evolve in response to HIV co-infections.
Of particular significance was that when these sites were classified according to their function, an unusually large number occurred in parts of the M. tuberculosis genome that provide the genetic information for epitopes. Epitopes are the parts of M. tuberculosis proteins that are recognised by the B and T cells in the human immune system. However, in this study only epitopes that might be recognised by T cells were investigated.
“This is the first time that evolutionary models have been applied to M. tuberculosis whole genome sequence data to detect natural selection that might be influenced by HIV co-infection. An important finding of this work is that natural selection on M. tuberculosis can be detected using these methods, and that HIV may be impacting how M. tuberculosis is presently evolving,” said Koch.
“The influence of HIV on M. tuberculosis epitope evolution could have implications for the design of vaccines to be administered in settings with high rates of HIV-associated TB. However, it is highly desirable that our results are validated on larger datasets in other settings to establish how generalisable our findings are,” she said.
“So it’s extremely important to stress that this requires a lot more work: firstly, to validate our findings in larger cohorts; secondly, to understand exactly how M. tuberculosis is changing during HIV co-infection; and thirdly, to understand how much of an impact this would have on immune recognition of M. tuberculosis.”
Koch hopes that the work will inform thinking around the potential for M. tuberculosis to evolve not just in response to human interventions such as the antibiotics or vaccines that have been used to control this bacterium, but also in response to the largely uncontrollable and ever-changing microbial communities that share humans as their preferred homes.
The research team’s findings appear in the advanced online edition of Molecular Biology and Evolution.
The setting for this study: Khayelitsha, Cape Town. The high rates of HIV and TB in this setting are fuelled by poverty and inequalities in access to healthcare. The picture was taken as part of Eh!woza – a public engagement project that Dr Koch is involved in running.
UCT study shows that urine test is better for diagnosing TB rapidly among HIV-infected patients
A study published this week in the journal BMC Medicine by researchers from the University of Cape Town shows that among hospitalised patients with HIV infection, a simple and inexpensive urine test identified more TB diagnoses in the first 24 hours of admission than rapid sputum-based tests.
This urine test (the Determine TB-LAM assay, similar to a pregnancy test) detects components of the cell wall of the TB bacterium in the urine and takes about 20 minutes to undertake without need for special infrastructure.
One of the researchers on the study, Professor Graeme Meintjes said: "The results of this study build on findings of other UCT researchers that this urine test can reduce mortality among HIV-infected patients admitted to hospital by speeding up the diagnosis of TB.
"The findings of these studies challenge the dogma that the first place to look for TB is in the sputum. Among a select group of patients (HIV-infected patients with very weak immune systems admitted to hospital) a combination of tests is required, including urine and sputum tests, to facilitate a quick diagnosis of TB thereby allowing doctors to start patients with TB on appropriate treatment rapidly."
Historically, the laboratory examination of sputum samples has been the method used to diagnose most cases of TB. However, it is well recognised that this approach often fails in patients with HIV infection. In many of these patients, TB spreads from the lungs to the blood and other organs in the body due to poor immunity.
Additionally, there may be few or no TB bacteria found in their sputum, either because they are too weak or ill to produce a good sputum sample or because of less TB cavity formation in their lungs.
The difficulty of diagnosing TB is particularly true for patients with HIV who are sick enough to be admitted to hospital. Notably, in such patients, it is critically important to make a rapid diagnosis of TB so that treatment may be initiated promptly to avoid deaths.
The study was conducted at GF Jooste Hospital prior to it being decommissioned. A total of 427 consecutive patients with HIV infection admitted to the medical wards were screened for TB using sputum, urine and blood tests. In total, one in three (33%) of these patients were diagnosed with active TB disease. Among patients with TB, sputum microscopy and sputum Xpert diagnosed TB within 24 hours of admission in 19% and 27%, respectively, compared to 38% using the urine Determine TB-LAM assay. The urine test was particularly useful for diagnosing TB in the patients with the lowest CD4 counts or weakest immune systems as well as those who were anaemic.
The main reason that the urine test outperformed the sputum test was because of how difficult it was to obtain a sputum specimen from many patients on admission. Whereas almost all patients, even those were very ill, could provide a urine sample.
The study was led by Professor Steve Lawn, who passed away in September 2016, after a long battle with brain cancer. Professor Lawn, originally from the UK, conducted research in Cape Town from 2004 until the time of his death. He made seminal contributions to understanding the interactions between HIV and TB, the role of antiretroviral therapy in preventing TB in HIV-infected people and the important role of new diagnostic tests in improving the diagnosis of TB in HIV-infected people. Professor Lawn published over 100 papers with UCT colleagues on HIV and TB in leading international journals.
Authors: Stephen D. Lawn, Andrew D. Kerkhoff, Rosie Burton, Charlotte Schutz, Andrew Boulle, Monica Vogt, Ankur Gupta-Wright, Mark P. Nicol, Graeme Meintjes
CIDRI clinical research site in Khayelitsha joins the HVTN702 trial
The Clinical Infectious Diseases Research Initiative (CIDRI) clinical research site located at Site B Community Health Centre in Khayelitsha has been activated as one of the trial sites to participate in the pivotal HVTN702 randomised controlled trial assessing the safety and efficacy of the novel HIV vaccine (ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59). It is one of fifteen sites across South Africa participating in this trial. The other site in Cape Town is Emavundleni in Crossroads run by UCT's Desmond Tutu HIV Centre. The Emavundleni site has been recruiting since late 2016.
The trial aims to enroll 5,400 men and women aged 18-35 years. It is planned that each of the 15 sites will enroll 360 HIV-negative participants over a 2-year period. Each participant will be followed for 2-3 years in the study.
The vaccine used in HVTN 702 is based on the vaccine investigated in the RV144 clinical trial in Thailand. The Thai trial delivered landmark results in 2009: the experimental vaccine regimen it tested was found to be 31 percent effective in preventing HIV infection over the 3.5-year follow-up period after vaccination.
In the HVTN 702 study, the vaccination schedule and vaccine components of the RV144 vaccine regimen have been modified in an attempt to increase the magnitude and duration of the protective immune responses elicited. Funders of the trial are the National Institute for Allergy and Infectious Diseases (NIAID), the Bill & Melinda Gates Foundation, and the South African Medical Research Council (MRC).
The principal investigator at the Khayelitsha site is Professor Graeme Meintjes. The trial staff of over 20 members has worked hard over the past 6 months to prepare the site for the trial in terms of training and developing clinical, regulatory laboratory and pharmacy infrastructure and capacity. A Community Advisory Group (CAG) of 12 community members has also been established and has advised the trial team on strategies for messaging and recruitment in the community. Meintjes said: "This is the first time that the community of Khayelitsha has the opportunity to participate in an HIV vaccine trial. This is fitting given the key role that members of this community have played in the fight against the HIV epidemic through activism and disseminating knowledge about the virus to combat its spread. The ongoing burden of new HIV infections among young people in this and many other communities in South Africa means that its vital to develop and evaluate new prevention methods."
The Khayelitsha HVTN702 trial team at Site B Community Health Centre
PredART trial shows prednisone is safe and effective for preventing TB-IRIS
The findings of the PredART trial were presented at the annual Conference on Retroviruses and Opportunistic Infections (CROI) that took place in Seattle, United States, from 13-16 February 2017. This trial is the first to demonstrate the efficacy and safety of prednisone for preventing the tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) in patients at high risk for this condition.
The trial was conducted as a collaboration between investigators from UCT, Imperial College London and the Institute of Tropical Medicine in Belgium. UCT investigators included Graeme Meintjes (Principal Investigator), Robert J. Wilkinson, Gary Maartens, Cari Stek, Liz Blumenthal, Friedrich Thienemann and Charlotte Schutz. The main funder of the trial was the the European and Developing Countries Clinical Trials Partnership (EDCTP), with co-funding received from the South African National Department of Science and Technology and the Wellcome Trust.
TB-IRIS is the most frequent complication of starting antiretroviral therapy in patients with advanced HIV being treated for active TB disease (it affects up to 50% of such patients). It manifests with recurrent or new inflammatory features of TB during the first few weeks of ART resulting in clinical deterioration frequently necessitating hospital admission. Patients complain of recurrence of their TB symptoms, and may develop enlarging lymph glands in their neck, TB abscesses or worsening of their chest X-rays.
The trial was conducted at Site B clinic in Khayelitsha at the Clinical Infectious Diseases Research Initiative (CIDRI) clinical research facility. It was a randomized, double-blind, placebo-controlled trial: 240 patients who were HIV-infected with a CD4 T-cell count of 100 cells/mm3 or lower, who had never received ART previously and were recently diagnosed with TB disease were enrolled. All participants received TB treatment and ART. Participants were randomized in a 1:1 ratio to receive prednisone for 4 weeks or identical placebo for 4 weeks started at the same time as their ART medication, and followed intensively for a further 8 weeks. A moderate dose of prednisone was used: 40mg per day for 2 weeks followed by 20mg per day for 2 weeks. Prednisone is a corticosteroid anti-inflammatory drug that is widely used for the treatment of conditions such as asthma and certain forms of arthritis.
The primary comparison was the proportion of participants who were diagnosed with TB-IRIS. In participants who received prednisone there was a significant (30%) relative reduction in the risk of developing TB-IRIS: 46.7% of patients in the placebo arm developed TB-IRIS compared with 32.5% in the prednisone arm. There was a trend towards fewer hospital admissions in the prednisone-treated participants.
Also important is that prednisone appeared to be safe in these patients with advanced HIV. Adverse events and severe infections were not more common in the prednisone-treated participants. One case of Kaposi’s sarcoma (an HIV-related cancer) occurred: this was in a patient in the placebo arm who stopped taking ART.
Prednisone is a cheap and readily accessible drug in developing world settings. In this trial, it was demonstrated that it reduces the incidence of TB-IRIS by 30% in patients on TB treatment at high risk for TB-IRIS starting ART. It was also safe. These findings provide the first evidence of an effective strategy for reducing the risk of developing TB-IRIS which is a very common early complication of ART in South Africa.
CROI press conference:
Short film about PredART trial made in 2015 by EDCTP:
PredART trial clinical team meeting at Site B clinic in Khayelitsha where the trial was conducted.
Chest X-ray worsening due to TB-IRIS: the first X-ray was taken prior to ART, the second when the patient presented with TB-IRIS.
Ambitious new project ‘Predict-TB’ aims to cut treatment duration in majority of patients
Current treatment of TB is long, complicated to administer, and can have severe side-effects. To prevent recurrence of the disease after treatment is stopped patients undergoing treatment must take a combination of different antibiotics for at least 6 months– this often leads to improper adherence, which consequently can result in the development of multi-drug-resistant TB (MDR). Treatment for drug-resistant TB can take up to two years, and is yet more complex, expensive, and toxic. The staggering cost of curing MDR-TB poses a significant challenge to governments, health systems, and other payers – and still, many patients are unable to even access treatment. Among those who do receive treatment for MDR TB, only 50% survive.
Thus, shortening of standard treatment is a main priority of current TB research. Previous studies of treatment shortening, usually to 4 months, have all been unsuccessful when compared to standard 6-month treatment. Six-month courses cure 95% of patients and shorter courses only 80-85% of patients. This still means, however, that most patients are cured after 4 months - but we cannot currently know beforehand which patients belong to that group. If it were possible to identify the patients who only require 4-month therapy, we would be able to reduce treatment duration in the vast majority of patients.
This is precisely what the Predict-TB consortium wants to do:
Over the next five years, the consortium, led by Prof. Clifton Barry from the US National Institutes of Health and Prof. Gerhard Walzl from Stellenbosch University in South Africa, is planning to develop a smart set of treatment stopping criteria, and a point-of-care device to measure immunological markers that can contribute to the decision making. The group will perform an ambitious phase 2B clinical trial in South Africa and China, looking at demographic, radiographic, bacteriologic and immunologic parameters, to answer two key questions:
- can those patients who cure with shorter treatment duration be identified? and
- what combination of parameters can best identify these patients?
This new method – if successful – could be a true game changer, advancing treatment standards from the current practice of "one size fits all" to precision-guided individualised therapy, which would allow for shortened treatment in a significant proportion of drug sensitive TB patients.
Millions of patients could benefit from a much shorter treatment. This will not only make their lives much easier: Reducing the TB burden will have a beneficial effect on the economic situation in many developing countries, and less drug resistance will benefit public health on a global scale.
The Predict-TB project will receive over 20 million EUR funding from the EDCTP, the Bill & Melinda Gates Foundation through the Foundation for the National Institutes of Health, National Institutes of Health, the National Science Foundation of China (NSFC) and China Ministry of Science and Technology (MOST).