Today, several colleagues and I drove out to the Boston Newton Marriott Hotel next to the Charles River and Brandeis University. The occasion was the RePORT tuberculosis meeting organized by Professor Jerry Ellner from BMC. In a chilly basement conference room, a group of distinguished researchers primarily from the US and India were gathering. The sessions ranged from basic science to surveillance/ epidemiology. I think the two highlights from today were David Alland and Peter Cegielski. The speakers included the following people.
- Peter Kim and Sudha Srinivasan from NIH introduced the meeting.
- DJ Christopher from Christian Medical College gave an overview of RePORT India. He also talked about the historic Waverly Hills Tuberculosis Sanatorium (Louisville, Kentucky). I am from Kentucky and I had never heard of this sanatorium!
- Carol Hamilton talked about the Common Protocol and the importance of biomarkers.
- David Alland from Rutgers gave a terrific talk about Xpert.
- He argued that there are a “sea of atypical mutations” brought on by TB treatment that we aren’t routinely detecting. Even with whole genome sequencing, you see the mutations, it is hard to understand their purpose, function. Some mutations may combine, and the patient may develop other mutations, giving resistance above the MIC. For ethambutol, there is evidence that high level resistance is caused by an atypical plus a typical mutation. When we treat patients with drugs, we increase these atypical mutations, causing more low level resistance. This will increase the chance of getting mutations above the breakpoint, leading to drug resistance. When we diagnose patients with TB, we will shift the new atypical mutations, typical mutations, and high level resistance mutations. He argued that we should be surveying these mutations more systematically. Dr. Alland envisions a world where there are centralized high throughput sequencing facilities that constantly survey patients, looking for outbreaks of these mutations we can’t detect by phenotypic DST, that are not cost-effectively detected by genotypic DST. And when we detect an outbreak, we go in with our “swat team” to stop resistance from happening. That is the only way we will be able to control drug resistance, with the exception of a TB vaccine, which don’t see on the horizon…
- In settings of high HIV burden, we know that cycles of nosocomial TB transmission occurred on hospital wards, and this is likely occurring, undetected, anywhere there are concentrated groups of HIV patients.
- Lots of changes are coming soon from the team at Cepheid. For example “Xpert Ultra” the “Xpert Omni.” For the new Xpert Ultra test Cepheid has committed to the same price as current Xpert, and not to increase the cost. Hopefully this will come out in 2016.
- We need to take advantage of the new Xpert machines to improve TB surveillance using the cloud. Privacy/data ownership concerns must be addressed but this has a tremendous potential to give more accurate / up to date estimates of TB incidence correlated with geographic data. Xpert’s information system must be linked to the TB M&E / reporting and recording system, however. This is already being done in South Africa and other countries but we need a much bigger commitment to make this happen, i.e. data analysts, programmers, etc.
- William Jacobs from AECOM talked about so-called “persistors.” He discussed the history of Vitamin C, promoted by Linus Pauling, which may work for killing TB. He emphasized the need to understand the persistence phenotype (MTB persistence is not a homogenous event).
- Kathleen Mcdonough from the Wadsworth Center at the New York State Department of Health spoke about regulatory targets of “CMR”, which may be more important for persistence than for acute TB infection.
- David Sherman from the University of Washington spoke about transcription factors and TB. He explained that transcription factors can alter gene expression to make TB transiently tolerant to bedaquiline.
- Peter Cegielksi spoke about the CDC’s activities in India. During the Q&A he discussed a sobering issue: the epidemiology of drug-resistant TB in India. Apparently there was an evaluation of MDR-TB in India in 2014. The country as a whole is scaling up services for MDR-TB very rapidly. In the past there were about 3 laboratories that could do high quality DST for first line drugs, and now there are about 122. The goal is to scale-up access to DST and appropriate therapy. He said that based on surveillance data there are approximately 100,000 – 200,000 incident cases of MDR-TB in the country per year, and a significant number of INH resistant cases. India still uses WHO standard category 2 regimen treatment regimen for re-treatment cases without doing DST. This will inevitably/unquestionably generate a lot of MDR-TB because there are a lot of patients who are not being cured. About 20% of new TB cases not cured with first treatment, and come back as retreatment cases. The proportion of those with INH resistance is very high, as much as 40%. They are being treated exactly as you shouldn’t do, adding a single drug to a regimen that is failing (standard category 2). All of this is changing, and will likely change rapidly in the next 1-2 years. This is the main “epidemiologic pump” producing MDR-TB. Also, those individuals who develop MDR-TB often seek care from multiple providers, with erratic/ interrupted treatment, wihout consistent effective regimens from start to finish, which leads to XDR-TB, and what was reported in Mumbai the case series of TDR-TB. Best esimtates of XDR are now about 9% – 10% of MDR-TB cases have XDR-TB. My reaction is this is shocking and we need an immediate global response to stop the inappropriate treatment of DR-TB in India and elsewhere (believe me, it’s not just India).
- Bruno Andrade from Salvador, Brazil spoke about matrix metalloproteinases which are selectively induced by MTB infection of human macrophages.
Please forgive me, presenters, if I didn’t get your basic science 100% right. All your lectures were terrific. Also- my friend Tom Yates in the UK tweeted along a few slides about TB transmission.
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