Systemic Empirical TB Therapy No Better Than Targeted Treatment in HIV Patients

By Gene Emery

June 18, 2020

(Reuters Health) - The strategy of routinely treating newly diagnosed HIV patients with drugs to quell tuberculosis, even if the person has no signs or symptoms of TB, is not as effective as treatment based on TB testing, according to a large international trial reported in Thursday's New England Journal of Medicine.

"It is now clear that empirical antituberculosis therapy for persons with advanced HIV infection is a pound of cure that is worse than an ounce of prevention," said Dr. Richard Chaisson in a Journal editorial, citing the significantly higher risk of grade 3 or 4 adverse events in patients treated systematically.

"The issue with the systematic tuberculosis treatment is that it is associated with higher drug-related toxicity. In our mind, it is now not necessary to expose patients to such risk if you can use and repeat the diagnostic tests that were used in our test-guided group," chief author Dr. Francois-Xavier Blanc told Reuters Health in an email.

"The findings show that doctors should test patients before initiating ART (antiretroviral therapy), even in asymptomatic patients, then repeat diagnostic tests over time in the presence of symptoms evocative of tuberculosis, especially during the first weeks following initiation of ART," he said.

The so-called STATIS ANRS trial followed 1,047 volunteers, all with CD4+ T-cell counts below 100 cells per cubic millimeter, who had not previously received antiretroviral therapy.

Half were treated as if they had tuberculosis as well. The other half only received TB treatment if indicated based on a combination of tests -- an Xpert MTB/RIF test, the Alere Determine TB LAM Ag urinary test, and chest radiography. In that second group, patients were given a World Health Organization (WHO) TB questionnaire during follow-up visits and retested for TB if they answered "yes" to any of the four questions or showed symptoms.

The systemic TB treatment "was compared with the most extensive testing strategy we could imagine in these settings," said Dr. Blanc, head of the respiratory medicine department at Nantes University Hospital in France.

After 24 weeks, 44 patients in the empirical treatment group died from any cause or had invasive bacterial disease versus 46 in the guided treatment group.

At that point, all of the patients in the empirical treatment group were tested for TB using the same tests given to volunteers in the guided-treatment group at the beginning of the trial.

At the 48-week mark, the numbers had grown to 56 in the empirical group and 58 in the test-based group, another insignificant difference.

Death rates at 48 weeks were 10.2 per 100 patient years in the empirical group and 10.1 with guided treatment.

There were dramatically fewer cases of tuberculosis in the group where everyone was treated -- 4.2 per 100 patient years compared with a rate of 26.2 with guided treatment -- but the rate of grade 3 or 4 drug-related adverse events was two and a half time higher with empirical treatment.

The rates for high-grade events per 100 patient-years were 9.3 with guided treatment and 24.9 with systemic treatment.

Dr. Blanc said his team saw no difference in the primary outcome between the two groups because the initial screening for TB at the start of the study was so effective.

"These results are very good news for the patients because they show that decreasing mortality is possible, even at an advanced stage of immunosuppression," he said. "Again, both strategies did quite well in this trial. In general, people should not be afraid to start ART, they should start it as soon as possible to avoid being too severely immunosuppressed."

"But even for those who present at an advanced stage of HIV infection, we showed that mortality can be reduced provided that we take into account tuberculosis as part of their clinical management," he said.

Dr. Chaisson of the Johns Hopkins University School of Medicine in Baltimore said it wasn't surprising that fewer patients were ultimately found to have TB in the empirical group when everyone was treated for the disease.

"This trial fits into a suite of studies regarding the strategy of empirical antituberculosis treatment for patients with established and advanced HIV infection and firmly shuts the door on this intuitive but apparently incorrect concept," he said.

There had been hope that treating all such severely immunocompromised patients for TB would be beneficial because as many as 20% of HIV patients in low- and middle-income countries who already have low CD4+ T-cell counts develop tuberculosis within six months after starting antiretroviral therapy.

When HIV patients present in the late stage of their disease, TB and invasive bacterial disease are a frequent cause of death.

Diagnosing TB can be especially difficult in such patients and roughly 251,000 people with HIV die from TB each year, according to WHO.

But Dr. Blanc stressed that despite the difficulty, "it is possible to find it," even in patients with extremely low CD4 counts of 25 per cubic millimeter.

The volunteers for the study were from Uganda, Cambodia, Vietnam and the Ivory Coast.

SOURCES: and The New England Journal of Medicine, online June 17, 2020