No Benefit of Empiric Tuberculosis Treatment in Advanced HIV

Pam Harrison

July 27, 2015

VANCOUVER, British Columbia — Whether patients with advanced HIV receive empiric treatment for tuberculosis (TB), which they frequently die from, or isoniazid preventive therapy, there is no difference in mortality rates, new research suggests.

"What this study shows is that empiric treatment for TB doesn't give you any excess toxicity and it's as safe as isoniazid preventive therapy, but it doesn't give you any mortality benefit either," said Mina Hosseinipour, MD, from the University of North Carolina at Chapel Hill.

"When you evaluate which patients are dying early in antiretroviral therapy programs, you see it's patients with CD4 cell counts below 50 copies/mm³, those who have anemia, and those with a low body mass index. And when you look at presumed causes of death, TB comes out as one of the big ones," she told Medscape Medical News.

"You also see that these patients are developing TB shortly after they start antiretroviral therapy, so antiretroviral therapy allows TB to unmask itself," she explained.

For their study, Dr Hosseinipour and her colleagues reasoned that "if the same people who are getting TB are dying of it," these patients likely have undiagnosed TB.

The results were presented during the 8th International AIDS Society Conference.

The Reducing Early Mortality and Early Morbidity by Empiric Tuberculosis Treatment Regimens — or REMEMBER — study was an open-label strategy trial that involved HIV-infected adults with a CD4 count below 50 cells/mm³ and no active TB. The median CD4 count at study entry was 18 cells/mm³.

REMEMBER Study

Almost one-third of the 1368 patients screened before study entry were excluded because screening indicated either active or suspected TB, Dr Hosseinipour reported.

Eligible patients were randomized to one of two treatment groups: 424 received an efavirenz-based antiretroviral regimen plus a four-drug fixed-dose empiric TB treatment for 8 weeks followed by a two-drug fixed-dose regimen for another 16 weeks; and 426 received the same regimen plus isoniazid 300 mg daily for 24 weeks.

 
You can be confident using isoniazid and prevent TB in these high-risk patients.
 

The primary end point — mortality at 24 weeks — was the same in the empiric and the isoniazid groups (5.3% vs 5.2%), Dr Hosseinipour reported. And the time to the primary end point was essentially identical in the 2 groups.

In a sensitivity analysis, there was no mortality difference between the two treatment groups when patients were stratified by the presence or absence of poor prognostic factors or CD4 cell count (less than 25 cells/mm³ vs more than 25 cells/mm³).

"Our causes of death were primary HIV infection and HIV-related diagnoses," which accounted for 89% of deaths in the empiric group and 50% of deaths in the isoniazid group, Dr Hosseinipour said.

Time to death and progression of AIDS were more rapid in the empiric group than in the isoniazid group, although not significantly so.

There were more cases of TB in the empiric group than in the isoniazid group. The excess of TB cases in the empiric group began to emerge as early as 2 weeks into the study. This divergence suggests that at the study outset, there was more TB in the empiric group by virtue of chance, she pointed out.

The investigators recorded 33 incident cases of TB in the empiric group and 19 in the isoniazid group, the majority of which were extrapulmonary in nature.

"Virologic suppression was essentially equal between the arms," Dr Hosseinipour pointed out, "and the median change in CD4 cell counts was also the same."

Toxicity — determined by grade 3 or 4 signs, symptoms, and laboratory values — was equal in the two treatment groups, and new diagnoses occurred in about half of the patients in each group.

"The current WHO policy advocating routine TB screening and isoniazid preventive therapy is sufficient to markedly reduce mortality in a patient population at high risk for death, and there is no added benefit from empiric TB treatment in a setting of systematic TB screening," Dr Hosseinipour concluded.

Isoniazid preventive therapy is not routinely being used in most countries because there is a concern that if only isoniazid is used in patients with undiagnosed TB, drug resistance will ensue, she told Medscape Medical News.

However, the REMEMBER study indicates that if patients are given a standard TB symptom screen plus further evaluation if symptoms are present, "you can be confident using isoniazid and prevent TB in these high-risk patients," she said.

Great Success

This study is actually a great success, not a disappointment, said Richard Chaisson, MD, from the Johns Hopkins Center for Tuberculosis Research and Center for AIDS Research in Baltimore.

"What it shows is that by screening people with advanced HIV infection for TB and providing isoniazid preventive therapy, survival is much better than previously seen, and the use of four-drug anti-TB therapy is not necessary or helpful," he told Medscape Medical News.

This is entirely consistent with the recent TEMPRANO study, Dr Chaisson explained. In that study of African patients with higher CD4 counts, the level of protection against progression of AIDS was the same in patients treated with isoniazid preventive therapy and those treated with antiretroviral therapy (N Engl J Med. Published online July 20, 2015). However, the two treatments were additive for the prevention of tuberculosis.

Dr Hosseinipour has disclosed no relevant financial relationships. Dr Chaisson reports serving as a consultant for Merck.

8th International AIDS Society (IAS) Conference. Abstract MOAB0205LB. Presented July 20, 2105.

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