The Centers for Disease Control and Prevention operates two TB research consortia—the TB Trials Consortium and the TB Epidemiologic Studies Consortium. In a May 18 symposium, four speakers shared the results of several studies being conducted under their auspices.
Presenters discussed opportunities for prevention of TB among the foreign-born; the PREVENT TB trial, which tested the effectiveness of a new preventive TB treatment regimen; interferon-gamma release assays (IGRA) in the diagnosis of latent tuberculosis infection (LBTI) in healthcare workers; and the use of rifapentine for TB treatment.
TB Identification in Immigrants
One study looked at how new guidelines may improve identification of people with TB coming to the United States.
In a TB Epidemiologic Studies Consortium study on opportunities for prevention of TB among the foreign-born, researchers collected data via three areas—from in-person interviews, data from the CDC’s Division of Global Migration and Quarantine, and clinical data from the required TB reporting form.
According Amy Davidow, PhD, associate professor in the Department of Preventive Medicine and Community Health at the New Jersey Medical School, Newark, participants were foreign-born and diagnosed with TB between April 2005 and January 2007. They selected random samples from 20 sites throughout the United States and from two sites in Canada.
While participants were from traditional immigrant gateways, such as California, Texas, New York, New Jersey and Chicago, they also were from emerging and re-emerging areas, such as North Carolina, Georgia and Seattle. In all, they recruited 1,454 individuals with active TB, and 981 had pulmonary TB.
Dr. Davidow noted that visa status at interview showed that 310 were undocumented, and 961 were documented with visas of various types. The majority of the 183 with unknown visa types were from New York, which has an ordinance preventing the collection of such data.
Participants in the study entered the United States under the Division of Global Migration and Quarantine (DGMQ) Technical Instructions, which requires a chest X-ray for those over 15. If they are suspected to have active TB and are smear negative (Class B1 smear negative), suspected to have inactive TB (Class B2 no smears) or not suspected to have TB (Non B), they can enter the U.S.
Post-entry, Class B1 and B2 entrants are recommended for follow-up with the local health department, and those classified as Non B screened have no follow-up. Civil surgeons screen others stateside if they desire a visa class adjustment, for example.
“What we wondered is what proportion of the people who entered the country under the old instructions [1991] would have been potentially identifiable under new instructions?” Dr. Davidow said.
The New Technical Instructions issued in 2007 call for cultures and drug susceptibility testing in addition to three AFB smears. The researchers found that DGMQ screening identifies a low proportion of active pulmonary tuberculosis among the foreign-born population diagnosed for TB in the United States, and that the New Technical Instructions emphasizing AFB sputum cultures may improve DGMQ identification.
They also found that the majority of pulmonary TB cases arise among subjects who have not gone through DGMQ-testing or arise less than six months after DGMQ-testing.
Dr. Davidow added that new approaches to identifying latent TB infection and ensuring treatment initiation and completion are needed.
PREVENT TB
One of the largest U.S. government clinical trials on latent TB treatment, the TB Trials Consortium PREVENT TB study (also known as Study 26), was a non-placebo controlled, randomized clinical trial of high-risk clients, who were followed for 33 months. They were randomized to one of two treatments.
The first arm (9H) was a self-administered daily dose of isoniazid taken for nine months (n=3,745; 270 doses; INH 5-15 mg/kg, 300 mg maximum,). The second arm (3HP) involved a once-weekly dose of rifapentine and isoniazid taken for three months (12 doses) and given with supervision (n=3,986; 900 mg maximum of rifapentine; INH 15-25 mg/kg, 900 mg maximum).
Participants over age 2 were categorized as follows: tuberculin skin test (TST)-positive close contacts of a culture-confirmed TB case; TST-converters; HIV-infected with positive TST or a known close contact to TB case regardless of TST; or TST-positive with fibrosis on chest X-ray consistent with prior untreated TB. Or they were children age 2-4 years with positive TST or close contact with a culture-confirmed TB case.
Carol Hamilton, MD, MHS, senior scientist in health and developmental sciences at FHI in Durham, N.C., reported that 22 patients developed TB. Fifteen were in the 9H group and seven were in the 3HP group.
“The cumulative TB rate showed that the 9H arm continued to accrue cases to the end of our follow-up, whereas most of our cases that occurred in the 3HP arm generally occurred earlier,” she said.
Sixty-nine percent of participants completed the 9H regimen, and 82 percent completed the 3HP regiment. Those who for any reason permanently discontinued the drug regimen numbered 31 percent of 9H and 18 percent of 3HP enrollees. These numbers were 3.6 percent and 4.7 percent for drug discontinuation due to an adverse event and 1.0 percent and 0.8 percent due to death, respectively.
Looking ahead, Dr. Hamilton said that the team would scale up their research with “an eye toward observation of any adverse events that might be seen in the field” and that studies are underway looking at dosing in a self-administered manner.
LTBI Testing in Healthcare Workers
Another study compared the effectiveness of three testing methods for latent tuberculosis infection (LTBI) in healthcare workers. In this TB Epidemiologic Studies Consortium study (Task Order 18), researchers employed three testing scenarios: TST with an initial two-step assessment using Tubersol; QuantiFERON-TB Gold in-tube (QFT) and T-Spot TB testing.
This longitudinal study was conducted at four sites (Denver, Houston, Baltimore and New York) with 2,500 adult healthcare workers undergoing routine LTBI screening. Investigators excluded those who had current or prior active TB or a TST within the prior six months. Data collection began in February 2008, with serially testing conducted over an 18-month period. Follow-up was completed in March 2011.
Females made up 75 percent of the subjects, the median age was 36 years, and 83 percent were born in the United States. Job categories were nurse, physician or physician assistant, laboratory technician, social worker/therapist, administrative/clerical and other. Their levels of contact varied.
Charles Daley, MD, head of the Division of Mycobacterial and Respiratory Infections and a professor of medicine at National Jewish Health in Denver, noted that of all the TST participants, 6.64 percent were positive at baseline, 2.2 percent were positive at six months, 1.17 percent were positive at 12 months, and 0.64 were positive at 18 months.
“The number of patients was 2,500 at baseline, but by the time we got to 18 months, only 1,709 had skin tests,” said Dr. Daley, adding that was due to dropouts and refusals of additional skin testing.
In the QFT group, the positive rates at baseline, six, 12 and 18 months were 5.6 percent, 6.8 percent, 6 percent and 5.8 percent. The T-Spot TB group showed positive results of 6.7 percent, 7.9 percent, 7.3 percent and 8.4 percent during those time periods. The borderline group over time was between 3 percent and 4 percent. Indeterminate rates throughout this time also remained fairly stable in the QFT and T-Spot TB groups.
The researchers also found higher conversion rates with interferon-gamma release assays than with the skin test and that reversion is common in all three of tests.
Rifapentine in TB Treatment
The final presenter, Stefan Goldberg, MD, medical officer with the CDC’s Division of TB Elimination, looked at some of TB Trial Consortium rifapentine studies, including Study 29.
Study 29 was a randomized, Phase II clinical trial assessing the antimicrobial activity and safety of substitution of rifapentine for rifampin in a standard intensive phase TB treatment regimen of 531 patients
Investigators found that in liquid and solid culture media, the rifapentine arm was slightly higher, but not statistically significant, Dr. Goldberg said.
“One subtle analysis showed that in non-cavitary patients (liquid media), we had 83 percent converting on rifapentine, and the solid media 100 percent converted on rifapentine,” he said.
As culture conversions accumulated, there was no difference between the two arms on solid or liquid cultures. The numbers of patients who discontinued their involvement nearly mirrored in each arm.
A slightly higher number of adverse events occurred, though not statistically significant in the rifapentine group (18.1 percent versus 22.6 percent). There were three deaths, all in the rifapentine arm. Two of these were immediately after enrollment from severe complications of TB, and one was later and due to an HIV complication.
“We concluded that the activity of the rifapentine regimen was not superior to that of the rifampin regimen, based on the endpoint of culture status at completion of the intensive phase,” said Dr. Goldberg.
He added that a regimen containing rifapentine 10 mg/kg administered five days/week without concomitant food for approximately eight weeks was safe and well tolerated, but that additional trials are needed to define the optimal dose of rifapentine and its role in TB treatment.