Although the HIV pandemic fuels tuberculosis (TB) outbreaks, it does not drive the development and transmission of multidrug resistance in TB patients as previously suspected, found a large international collaboration.
The findings, from a collaboration between scientists from Norwegian Institute of Public Health, University College London, ANLIS Carlos Malbrán, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Hospital Muñiz and Imperial College London, also show that TB drug resistance is not more likely to evolve in HIV-positive patients compared with HIV-negative patients.
“It is already known that a parallel HIV pandemic amplifies the TB epidemic, with ongoing efforts around the world to tackle these potentially fatal diseases,” said lead author Dr Vegard Eldholm, a research fellow at the Norwegian Institute of Public Health, in Oslo. “Among the estimated 1.5m people who died from TB in 2015, about 200,000 cases involved multidrug-resistant TB and 400,000 were HIV-co-infected. However, it is not clear exactly how much of an effect HIV has had on drug resistance in the most common form of TB, Mycobacterium tuberculosis.”
To explore the effect of HIV coinfection on M. tuberculosis drug resistance, Eldholm and his team analysed the genomes of 252 TB isolates from patients belonging to the largest outbreak of multidrug-resistant TB in South America to date.
The isolates were collected from patients with HIV from the mid-1990s until 2009. The team used the genomes to create a time-labelled phylogenetic tree, a diagram showing the inferred evolutionary relationships among the mutations within the sampled patients. They then applied a new mathematical model optimised for TB to reconstruct how the disease spread among individuals.
Finally, they combined the results of both methods to estimate the length of the TB latent period – the time from infection to infectiousness – and identify the patients in whom TB strains evolved into drug resistance mutations.
“We saw no significant differences in the rate at which mutations occur in the genomes of strains in HIV-positive and -negative patients. This suggests that drug resistance is not more likely to evolve in HIV-positive patients,” said co-corresponding author Dr Francois Balloux, a professor of computational systems biology at University College London.
While the team’s reconstruction of disease transmission among individuals did not reveal a significant effect of HIV co-infection on the ability of patients to transmit TB, their estimates of TB latency confirmed that HIV co-infection accelerates the development of active TB.
“HIV prevents some cells from doing their job in the immune system, meaning the body is unable to fight off a large number of infections,” Eldholm explained. “The disease therefore provides TB with a pool of susceptible hosts, amplifying the rate of coinfection. Indeed, for this reason, HIV patients at a major hospital in Buenos Aires, Argentina, played a central role in fuelling South America’s largest multidrug-resistant TB epidemic in the early 1990s,” he added.
The tuberculosis (TB) epidemic is fueled by a parallel Human Immunodeficiency Virus (HIV) epidemic, but it remains unclear to what extent the HIV epidemic has been a driver for drug resistance in Mycobacterium tuberculosis (Mtb). Here we assess the impact of HIV co-infection on the emergence of resistance and transmission of Mtb in the largest outbreak of multidrug-resistant TB in South America to date. By combining Bayesian evolutionary analyses and the reconstruction of transmission networks utilizing a new model optimized for TB, we find that HIV co-infection does not significantly affect the transmissibility or the mutation rate of Mtb within patients and was not associated with increased emergence of resistance within patients. Our results indicate that the HIV epidemic serves as an amplifier of TB outbreaks by providing a reservoir of susceptible hosts, but that HIV co-infection is not a direct driver for the emergence and transmission of resistant strains.
Vegard Eldholm, Adrien Rieux, Johana Monteserin, Julia Montana Lopez, Domingo Palmero, Beatriz Lopez, Viviana Ritacco, Xavier Didelot, Francois Balloux