By Dr. Geoffrey Modest
The lancet just reported a study looking at a rapid, low-cost urine test to guide TB treatment in HIV-positive individuals in areas with high TB prevalence (see Lancet 2016; 387: 1187).
Background:
- TB is the leading cause of death in people with HIV, accounting for 360K deaths in 2013; post-mortem analysis in resource-limited countries find that TB is the cause of death in about 40% of HIV-infected people, in 85% of cases it is disseminated, and half are undiagnosed at the time of death
- Those with HIV have a higher case-fatality rate when co-infected with TB: increased disseminated extra-pulmonary TB, more severe TB as immunocompromise increases.
- It is harder to diagnose TB in those with advanced immunosuppression, since they often have low bacillary loads in their bodily fluids, reducing the sensitivity of smears and cultures
- There is a urine test detecting the lipoarabinomannan Ag (LAM), a glycolipid antigen of the M tuberculosis cell wall, which reflects hematogenously disseminated TB. It requires 60 ml of urine, takes 25 minutes to get a result, and costs $2.66/test. It has a specificity of approx 94% and a sensitivity of around 56% in a meta-analysis. but, compared to sputum-smear microscopy, it does identify patients with the most severe illness
Details of study:
- 2659 patients (median age 37, 51% female, CD4 of 84, 48% on antiretroviral therapy (ART) at time of hospitalization, 73% on ART by 8-week follow-up) in 10 hospitals in Africa (South Africa, Tanzania, Zambia, Zimbabwe) were randomly assigned to urinary LAM testing, with 2528 ultimately in the modified intention-to-treat analysis
- 8-week mortality was 578 (23%)
- 261 (21%) in the LAM group and 317 (25%) in the no LAM group, an absolute reduction of 4% (1-7%) and relative risk reduction of 17% [RR 0.83 (0.73-0.96, p=0.012]
- Overall sensitivity of LAM was 45.6%, specificity was 88.7%, positive likelihood ratio of 4.03, negative likelihood ratio of 0.61
- But for those with CD4 ≤50, sensitivity of LAM was 63.7%, specificity was 83.2%, positive likelihood ratio of 3.80, negative likelihood ratio of 0.44; and 46% of the deaths happened in those with CD4 ≤50
- The overall % of patients begun on antiTB therapy was much higher in the LAM group (55% on day 1 and up to 91% on day 8) vs those without LAM (40% on day 1 and up to 89% on day 8), p=0.024 for difference.
- In the subgroup of patients with CD4 ≤50, LAM reduced mortality by 29%
- The attending clinicians delayed TB therapy in the no LAM group because they favored a different diagnosis (e.g. bacterial pneumonia), or they were waiting for the results of diagnostic investigations.
Of note, a recent concern has developed with the spread of MDR-TB (multiply drug-resistant) in Daru Island in New Guinea, with a commentary in Lancet Respiratory Medicine (see http://www.thelancet.com/pdfs/journals/lanres/PIIS2213-2600(16)00101-6.pdf ). The spread of TB, especially resistant TB, is referred to as a “time bomb”. And, of rather concerning note, TB is not so common in Daru and most patients with MDR have never taken TB meds (i.e., they did not develop resistance by taking meds, but were infected with a very difficult-to-treat TB infection), and lots of people there got infected (200 people in this 6 km2 island with only 15,000 individuals, i.e., about 1% of the population). This scary outbreak “will almost certainly eclipse those of both the Ebola and the recent Zika virus outbreaks, deemed a global public health emergency, combined”, per the Lancet commentary.
So, I bring up this LAM study for several reasons:
- It seems pretty likely to me that TB really is a ticking time-bomb, and reading this article on LAM is a reality check on this
- TB tends to have the highest morbidity and mortality in resource-poor countries, which have to deal with an array of very expensive and urgent other issues (little things like famine, war, etc.). A couple of days ago the NY Times ran a very concerning article on Vietnam (see http://www.nytimes.com/2016/03/29/health/vietnam-tuberculosis.html ), a country with a remarkably effective TB program (90% cure rate for uncomplicated TB, 75% in drug-resistant cases — with a global average is 50%), where improving outcomes further is getting more expensive (needing to do more outreach into rural areas, finding/treating those addicted to heroin…), but their hospital wards are packed (with more potential to lead to spread of MDR) and their “money is close to running out”
- TB has the potential to develop highly virulent strains, and the above article on New Guinea is shocking at how virulent a multi-drug resistant TB can be (and MDR, of course, is associated with much more cost to control as well as an inherently higher mortality). And the risk of worldwide spread of a virulent and less-treatable TB is much increased as travel becomes easier and more frequent
- We are continually dealing with outbreaks of newer, potentially devastating diseases (e.g., Zika, Chikungunya, Ebola,…) which divert attention and resources from staid old TB
- And LAM really may be a huge benefit in resource-limited countries, where AIDS-related deaths are still very high (i.e., AIDS has not evolved into a chronic disease requiring taking one pill to control, as in the US and many resource-rich countries), and LAM is a cheap and easy test to identify and treat those with likely imminent death
- But even in the US, TB infection in HIV has been increasing, with increasing numbers of observed vs expected cases (see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3122491/ ), noting that the increase in cases in US cities is both from reactivation of latent TB by HIV-related immunocompromise, but that 41% were due to recent transmission
- Now, one might argue that there should just be empiric anti-TB therapy in all HIV-infected patients in TB-endemic areas, given the high prevalence and mortality of HIV-TB coinfection, at least in those with more severe immunocompromise. But, empiric treatment is more complicated, more expensive, and more toxic, especially in areas of MDR, which reinforces the potential benefit of LAM as a test in those co-infected with HIV and even only a remote possibility of hematogenous TB. And, with the very real possibility of TB spreading outside of the currently endemic areas (as now shown in New Guinea), and co-infecting those with HIV, LAM may become a reasonable test in more and more countries around the world.
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