Update on Latent Tuberculosis Testing and Treatment

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It is estimated that 13 to 14 million people in the United States have latent TB infection. <i>Photo Credit: Medical Images RM / Steve Oh, MS CMI.</i>
It is estimated that 13 to 14 million people in the United States have latent TB infection. Photo Credit: Medical Images RM / Steve Oh, MS CMI.

In the United States, a patient receives a new diagnosis of tuberculosis (TB) every hour, with a mortality rate of 5% to 10%, and it is estimated that 13 to 14 million people in the United States have latent TB infection (LTBI).1 More than 80% of patients develop TB years after becoming infected, clearly underscoring the opportunity for prevention with timely testing and treatment. In addition, the treatment regimen in LTBI is shorter and more effective than it was in the past.

Nonetheless, US clinicians have been slow to test and treat patients at risk, likely due in large part to the uncertainty about optimal testing and treatment methods, as well as which patients to test and treat.2 Previous findings demonstrate the effectiveness, safety, and cost-effectiveness of a weekly, self-administered 3-month regimen of rifapentine and isoniazid in patients with LTBI in the United States.3-6

 

However, the cost-effectiveness of this approach in non-US-born patients with comorbidities is unclear. Noting that TB in the United States most commonly affects non-US-born residents, a new study published in JAMA Internal Medicine used a simulation model to examine the health outcomes and cost-effectiveness of testing for and treating LTBI in these patients, with and without comorbid diabetes, HIV, and end-stage renal disease (ESRD).7

The testing strategies included tuberculin skin tests (TSTs), interferon gamma release assays (IGRA), and a combination of both measures. “The results are intended to inform healthcare professionals seeking guidance on LTBI testing and policymakers seeking to recommend cost effective-interventions,” the investigators wrote.

The results show that LTBI testing and treatment prevented TB cases and contributed to increased cost and quality-adjusted life-years (QALYs) across all non-US-born risk populations, as summarized below. 

  • No testing led to the least cost but the worst outcomes
  • The confirm-negative strategy produced the best outcomes
  • The confirm-positive strategy resulted in better outcomes than no testing and was the second least costly approach 
  • TSTs resulted in better outcomes than confirm-positive testing but had a higher cost per QALY compared with IGRA 
  • IGRA led to better outcomes than the confirm-positive strategy

Results for patients with and without comorbidities are shown below.

  • In patients with no comorbidities, IGRA prevented lifetimes TB reactivation 50% of the time vs no testing (0.30% vs 0.60% in the total cohort), with a 332 need-to-treat (NNT) number and an incremental cost-effectiveness ratio (ICER) of $83,000/QALY. The confirm-negative strategy prevented 13% more cases than IGRA, with an NNT of 294 and an ICER of $147,000/QALY.
  • In patients with diabetes, the confirm positive approach prevented 28% of cases vs no testing (0.36% vs 0.50%) with an NNT of 749 and an ICER of $53,000/QALY. IGRA prevented 50% of cases, with an NNT of 409 and an ICER of $120,000/QALY. Confirm negative prevented 56% of cases and was associated with an NNT of 362 and an ICER of $230,000/QALY.
  • Among patients with HIV, confirm-negative prevented 55% of cases (0.72% vs 1.59%), with an NNT of 114 and an ICER of $63,000/QALY.
  • In the ESRD cohort, the “competing risks of death greatly limited remaining life expectancy and therefore also reduced the lifetime risk of TB reactivation,” according to the paper. Although LTBI testing improved QALYs, ICERs for all approaches exceeded $2 million/QALY.

The investigators note that the “choice of strategy depends on payer willingness to pay by population.”

To find out more about LTBI testing and treatment recommendations, Infectious Disease Advisor interviewed Jorge De La Cruz, a representative from the Office of Public Affairs at the California Department of Public Health (CDPH).

Infectious Disease Advisor: What does testing and treatment for latent TB involve? 

CDPH: The first step is to identify the risk of TB. The 3 main risk factors are birth/residence in a country with an elevated TB rate, immunosuppression, and known exposure to someone with infectious TB.

While either the TST or the IGRA can be used for detecting LTBI, the IGRA is the preferred test in patients who are likely to have been vaccinated with Bacillus-Calmette-Guerin (BCG). Prior to starting LTBI treatment, patients who test positive need to have TB disease ruled out by reviewing symptoms and a chest X-ray. If the chest X-ray is abnormal, possibly suggesting TB disease, mycobacterial culture is indicated.

LTBI treatment with a short-course regimen is preferred since treatment completion is more likely and hepatic toxicity is less frequent. The 2 short regimens consist of 12 weekly doses of oral rifapentine INH regimen (3HP) or 4 months daily oral rifampin. Monitoring patients during treatment helps detect adverse events and ensure treatment completion.

Infectious Disease Advisor: What are some potential reasons US clinicians have been slow to test for and treat latent TB? 

CDPH: Since TB has declined in the United States, it is not on the radar of many clinicians. In addition, complex guidelines make it unclear as to who to test, how to test, and how to treat latent TB infection.

Infectious Disease Advisor: What are the main takeaways of this topic for our clinical audience? 

CDPH: First, LTBI testing and treatment has become easier and the evidence for it has become clearer. Increasing comfort and the use of modern tools (IGRA and short LTBI therapy) and focusing on foreign-born and immunosuppressed individuals can prevent TB disease and is economically sound.

Second, by making testing of high-risk groups routine, people at risk for TB will be given the opportunity to know they are infected and get treatment before disease occurs.

Third, in contrast to a number of other conditions, TB can be prevented by one-time testing and treatment of LTBI, rather than ongoing periodic testing.

Infectious Disease Advisor: What should be next steps in terms of research in this area?

CDPH: The development of tests for latent TB infection that are highly predictive and identify who will go on to develop active TB disease is a top priority for research. In addition, shorter treatment regimens for latent TB infection are needed. A Centers for Disease Control and Prevention (CDC) trial  will study the effects of a 6-week course of daily rifapentine beginning in 2018.

References

  1. Miramontes R, Hill AN Yelk, Woodruff RS, et al. Tuberculosis infection in the United States: prevalence estimates from the National Health and Nutrition Examination Survey, 2011-2012. PLoS One; 10:e0140881.
  2. Flood J, Barry PM. Mainstreaming latent tuberculosis infection testing and treatment in the United States: who and how [published online October 16, 2017]. JAMA Intern Med. doi:10.1001/jamainternmed.2017.4916
  3. Sterling TR, Villarino MEBorisov AS , et al; TB Trials Consortium PREVENT TB Study Team. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med. 2011;8;365:2155-2166.
  4. Bliven-Sizemore EESterling TRShang N, et al; TB Trials Consortium. Three months of weekly rifapentine plus isoniazid is less hepatotoxic than nine months of daily isoniazid for LTBI. Int J Tuberc Lung Dis. 2015;19:1039-1044, i-v.
  5. Shepardson D, Marks SM, Chesson H, et al. Cost-effectiveness of a 12-dose regimen for treating latent tuberculous infection in the United States. Int J Tuberc Lung Dis. 2013; 17:1531-1537.
  6. Belknap R, Borisov AS, Holland DP, et al. Adherence to once-weekly self-administered INH and rifapentine for latent TB: iAdhere. Presented at: CROI (Conference on Retroviruses and Opportunistic Infections) 2017. Seattle, Washington, February 23-26, 2015. Abstract 827LB.
  7. Tasillo A, Salomon JA, Trikalinos TA, Horsburgh CR Jr, Marks SM, Linas BP. Cost-effectiveness of testing and treatment for latent tuberculosis infection in residents born outside the United States with and without medical comorbidities in a simulation model [published online October 16, 2017]. JAMA Intern Med. doi:10.1001/jamainternmed.2017.3941
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