The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis


Summary

Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms—including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions—are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues.

Conclusion

MDR tuberculosis, XDR tuberculosis, and resistance beyond XDR tuberculosis remains a major threat to global tuberculosis control because of the increasing burden it creates on health-care systems, economies, and societies, the threat to health-care workers in tuberculosis-endemic countries, the high mortality, and the unsustainably high costs of treating drug-resistant tuberculosis. Additionally, the development of totally drug-resistant or programmatically incurable tuberculosis has raised several ethical and medicolegal challenges. The global epidemiology of drug-resistant tuberculosis shows a worrying increase in the prevalence and incidence of drug-resistant tuberculosis in several countries and regions. Also, the proportion of cases of tuberculosis that are MDR and fluoroquinolone-resistant or aminoglycoside-resistant—ie, pre-XDR—or that are programmatically incurable has increased greatly. New molecular tools such as next-generation whole-genome sequencing are shedding further light on the transmission, diagnosis, and pathogenesis of drug-resistant tuberculosis.522Particularly, several lines of evidence challenge the traditional view that resistance is acquired through non-adherence promoted by poor programmatic functioning. Although adherence is clearly important for the prevention of drug-resistant tuberculosis, several other factors that promote pharmacokinetic mismatch drive the acquisition of drug-resistant tuberculosis even when adherence is good. However, newer methods to enable whole-genome sequencing directly from sputum and to assess its effect on clinical outcomes are needed.

Furthermore, a paradigm shift is required to take testing from the clinical setting into the community, thus promoting active case finding, and the detection of the undiagnosed and unsuspected cases of community-based drug-resistant tuberculosis. Newer drugs have improved the efficacy of the treatment of MDR and XDR tuberculosis, and therefore the prognosis, but resistance amplification will need to be minimised through strengthening tuberculosis programmes and other innovative approaches to prevent pharmacokinetic mismatch. Novel ways to reduce or eliminate the transmission of drug-resistant tuberculosis and to understand the fundamental biology of transmission are urgently required. These key messages are summarised in panel 11, and timeline-orientated research priorities and goals for drug-resistant tuberculosis are shown in table 15. All these priorities will need to be urgently addressed in tandem with the strengthening of health systems, reduction of poverty, and changing of political will.

Key messages

  • Resistance to antituberculosis drugs is a global problem of considerable public health importance that threatens to derail efforts to eradicate the disease. Advocacy is needed in national and transnational fora to ensure the urgency of the situation is understood and that appropriate funding is made available.

  • Practices for the management of individual patients in settings with a high tuberculosis burden are not sufficient to prevent the emergence, amplification, and spread of drug-resistant tuberculosis. These practices include empirical treatment with standardised second-line drug regimens for people who are found to have rifampicin-resistant tuberculosis.

  • Access to drug resistance testing is scarce in most countries and urgently needs to be expanded to allow curative second-line treatment regimens to be implemented.

  • Knowledge regarding the safe use—including dose and length of treatment—of new and repurposed drugs must be improved through clinical trials.

  • Models of care for people with drug-resistant tuberculosis, including programmatically incurable disease, must ensure that the rights and dignity of individual patients are respected.

  • Assessment of the performance, health effects, and potential economic benefits of molecular tools such as genome sequencing for detecting resistance, must be accelerated to facilitate effective implementation.

  • Greater investment is needed in the development of new drugs and diagnostics.

Source:Lancet

Education, breastfeeding and gender affect the microbes on our bodies.


Trillions of microbes live in and on our body. We don’t yet fully understand how these microbial ecosystems develop or the full extent to which they influence our health. Some provide essential nutrients, while others cause disease. A new study now provides some unexpected influences on the contents of these communities, as scientists have found that life history, including level of education, can affect the sorts of microbes that flourish. They think this could help in the diagnosis and treatment of disease.

The more the merrier.

A healthy human provides a home for about 100 trillion bacteria and other microbes. These microbes are known as the microbiome, and normally they live on the body in communities, with specialised populations on different organs.

Evolution has assured that both humans and bacteria benefit from this relationship. In exchange for somewhere to live, bacteria protect their hosts from harmful pathogens. Past analysis of the gut microbiome has shown that, when this beneficial relationship breaks down, it can lead to illnesses such as Crohn’s disease, a chronic digestive disorder.

You’ve been swabbed

One of the largest research projects looking at the delicate connection between humans and their resident microbes is called the Human Microbiome Project (HMP). As part of the project, hundreds of individuals are being sampled for microbes on various parts of their bodies, with the hope that the data will reveal interesting relationships.

In the new study, published in Nature, Patrick Schloss at the University of Michigan and his colleagues set out to use data from the HMP to investigate whether events in a person’s life could influence their microbiome.

Their data came from 300 healthy individuals, with men and women equally represented, ranging in age between 18 and 40. Life history events, such as level of education, country of birth, diet, and recent use of antibiotics were among 160 data pieces were recorded. Finally, samples were swabbed from 18 places across the body to analyse their microbiome communities at two different time intervals, 12 to 18 months apart.

Those swabs underwent genomic analysis. A select group of four bacterial communities were selected to test what proportion of each was found on different body parts. That data was then compared with life history events. Only three life history events out of about 160 tested could be associated with a specific microbial community. These were: gender, level of education, and whether or not the subject was breastfed as a child.

This complicated issue may help diagnosis and treatment of illnesses. “If a certain community of bacteria is associated with a specific life history trait,” Schloss said, “it is not such a stretch to imagine that there may be microbiome communities associated with illnesses such as cancer.”

To be sure, these associations are only correlations. Neither Schloss nor hundreds of other scientists working on microbiome data can be sure why certain communities end up on certain body parts of only certain individuals. “We really don’t have a good idea for what determines the type of community you’ll have at any given body site,” Schloss said.

Lack of such knowledge means that Schloss cannot explain odd correlations, such as why women with a baccalaureate degree have specific communities in their vaginal microbiome. Because level of education is also associated with a range of other factors such as wealth and social status – we can’t know that it is only education affecting the vaginal microbiome. Janneke Van de Wijgert at the University of Liverpool said, “I think that it is impossible to tease out the individual effects of education, sexual behaviour, vaginal hygiene behaviour, ethnicity, and social status.”

Van de Wijgert believes the data has other limitations. “The study population of a mere 300 was homogenous and healthy – young, white women and men from Houston and St Louis – which likely means that much additional microbiome variation has been missed.”

With better tools, genomic data analysis has substantially improved since the project launched in 2008. Van de Wijgert thinks that future studies need to sample a lot more individuals and look for changes at shorter time intervals.

She is hopeful that microbiome data can be used to improve medicine, make it more tailored to individual. But before manipulations of the microbiome are used to treat illnesses, she said, it should be confirmed that the offending bacteria communities cause – and are not symptom of – disease. If the bacteria causes an illness, then efforts can be made – such as a change in diet or microbial transplant – to treat disease.

The Conversation

HIV Treatment as Prevention: Optimising the Impact of Expanded HIV Treatment Programmes.


Resources for expanding ART in the short term may be limited, so the question is how to generate the most prevention benefit from realistic potential increases in the availability of ART. Although not a formal systematic review, here we review different ways in which access to ART could be expanded by prioritising access to particular groups based on clinical or behavioural factors. For each group we consider (i) the clinical and epidemiological benefits, (ii) the potential feasibility, acceptability, and equity, and (iii) the affordability and cost-effectiveness of prioritising ART access for that group. In re-evaluating the allocation of ART in light of the new data about ART preventing transmission, the goal should be to create policies that maximise epidemiological and clinical benefit while still being feasible, affordable, acceptable, and equitable.

 

Source: PLOS

 

 

 

 

 

 

HIV Treatment as Prevention: Principles of Good HIV Epidemiology Modelling for Public Health Decision-Making in All Modes of Prevention and Evaluation.


Public health responses to HIV epidemics have long relied on epidemiological modelling analyses to help prospectively project and retrospectively estimate the impact, cost-effectiveness, affordability, and investment returns of interventions, and to help plan the design of evaluations. But translating model output into policy decisions and implementation on the ground is challenged by the differences in background and expectations of modellers and decision-makers. As part of the PLoS Medicine Collection “Investigating the Impact of Treatment on New HIV Infections”—which focuses on the contribution of modelling to current issues in HIV prevention—we present here principles of “best practice” for the construction, reporting, and interpretation of HIV epidemiological models for public health decision-making on all aspects of HIV. Aimed at both those who conduct modelling research and those who use modelling results, we hope that the principles described here will become a shared resource that facilitates constructive discussions about the policy implications that emerge from HIV epidemiology modelling results, and that promotes joint understanding between modellers and decision-makers about when modelling is useful as a tool in quantifying HIV epidemiological outcomes and improving prevention programming.

Source: PLOS.