Genetic testing sites for TB are recommended for Africa

Compared to alternatives, whole genome testing is a faster, more accurate and potentially life-saving way to find out whether specific types of medication used against the lung disease tuberculosis (TB) will help a particular patient. Such tests must be available in countries with many TB patients.

TB has become a treatable disease but drug-resistant tuberculosis is unfortunately becoming a worldwide problem making the control of the disease even more difficult than before.

Drug-resistant tuberculosis occurs because some forms of Mycobacterium tuberculosis, the bacteria that causes TB, have become resistant to many of the standard medicines that doctors normally prescribe to patients. This means that the bacteria have become too clever for the very medicines that were manufactured to kill it. Unfortunately, it also means that these medicines no longer work for everybody.

Before they can receive medication, TB patients must therefore be tested to find out whether they might have a form of drug-resistant tuberculosis, which would mean they need special medication. One option is drug-susceptibility tests which can take weeks to perform and are not very accurate because they can only tell whether one or two types of the most common TB medicine will work for a patient or not.

Newer “whole genome” testing works much better and can be done within days to find out whether around 19 types of TB medicines will work for a patient or not. It considers the genetic information contained in the whole of a patient’s DNA code, and not only parts of it.

Researchers from across the world completed the study at a time when whole genome testing methods were not yet widely available in the countries that had the highest numbers of tuberculosis patients.

The researchers wanted to show just how many drug-resistant patients were not accurately diagnosed and treated adequately because the tests used in their countries were not accurate or comprehensive enough.

They took another look at samples previously obtained from 582 TB patients from seven countries who all have high numbers of TB cases: Côte d’Ivoire, Democratic Republic of the Congo, Kenya, Nigeria and South Africa (all in Africa), Peru (in South America) and Thailand (in Asia). The patients all also had HIV.

The researchers already knew the results of the drug-susceptibility tests that were previously done using these samples. The samples were then retested using whole genome testing methods in laboratories in Switzerland and the United States of America.

The researchers then compared the results of the two types of tests. They found that the drug-susceptibility tests did not correctly pick up that 130 (22%) of the 582 patients indeed had drug-resistant TB. In the process, around 15% of patients did not receive the right treatment. This happened for patients in all seven countries. They then looked at the results of only 530 of the patients. Of these, 63 (12%) died and 77 (15%) did not receive the right treatment.

As shown in other studies, whole genome testing is by far a better way to control tuberculosis in general, and drug-resistant TB specifically.

The findings support the World Health Organization’s stance at the time that countries with high volumes of TB patients should have whole genome testing sites too. It will ensure quicker and more accurate testing, and better treatment. 

A possible weakness of the study was that the samples of patients did not only have tuberculosis but were also HIV positive. After the study was done between 2013 and 2016, more drug-resistant tests already became available.

The lives of many more TB patients can be saved in Africa and other poorer regions of the world by building whole genome testing sites in these countries. Governments should therefore invest in such facilities. 

It will help local doctors to accurately diagnose whether a patient has drug-resistant TB or not, and to therefore prescribe the right treatment for individual patients.

Abstract

Background Drug resistance threatens global tuberculosis control. We aimed to examine mortality in patients with tuberculosis from high-burden countries, according to concordance or discordance of results from drug susceptibility testing done locally and whole-genome sequencing (WGS).

Methods In this multicentre cohort study, we collected pulmonary Mycobacterium tuberculosis isolates and clinical data from individuals with tuberculosis from antiretroviral therapy programmes and tuberculosis clinics in Côte d’Ivoire, Democratic Republic of the Congo, Kenya, Nigeria, Peru, South Africa, and Thailand, stratified by HIV status and drug resistance. Sites tested drug susceptibility using routinely available methods. WGS was done on Illumina HiSeq 2500 in the USA and Switzerland, and TBprofiler was used to analyse the genomes. We included individuals aged 16 years or older with pulmonary tuberculosis (bacteriologically confirmed or clinically diagnosed). We analysed mortality in multivariable logistic regression models adjusted for sex, age, HIV status, history of tuberculosis, and sputum positivity.

Findings Between Sept 1, 2014, and July 4, 2016, of 634 patients included in our previous analysis, we included 582 patients with tuberculosis (median age 33 years [IQR 27–43], 225 [39%] women, and 247 [42%] HIV-positive). Based on WGS, 339 (58%) isolates were pan-susceptible, 35 (6%) monoresistant, 146 (25%) multidrug-resistant, and 24 (4%) pre-extensively drug-resistant (pre-XDR) or XDR. The analysis of mortality was based on 530 patients; 63 (12%) died and 77 (15%) patients received inappropriate treatment. Mortality ranged from 6% (18 of 310) in patients with pan-susceptible tuberculosis to 39% (nine of 23) in patients with pre-XDR or XDR tuberculosis. The adjusted odds ratio for mortality was 4·92 (95% CI 2·47–9·78) among undertreated patients, compared with appropriately treated patients.

Interpretation In seven countries with a high burden of tuberculosis, we observed discrepancies between drug resistance patterns obtained locally and WGS. The underdiagnosis of drug resistance resulted in inappropriate treatment and higher mortality. WGS can provide accurate and detailed drug resistance information required to improve the outcomes of drug-resistant tuberculosis in high-burden settings. Our results support WHO’s call for point-of-care tests based on WGS.

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