Using isoniazid alone to prevent the development of active tuberculosis (TB) in people with advanced HIV disease was equally effective and better tolerated than a common four-drug empirical TB regimen, according to a study published in the March 19 edition of The Lancet in advance of World TB Day. Another study in the same issue found that a new inexpensive urine test has the potential to help reduce TB-related mortality by enabling faster treatment.
Isoniazid preventive therapy
As described in the first article, Mina Hosseinipour of the University of North Carolina at Chapel Hill and fellow investigators with the AIDS Clinical Trials Group A5274 REMEMBER study team conducted a randomised trial comparing isoniazid preventive therapy versus multi-drug empirical TB therapy for HIV-positive outpatients starting antiretroviral therapy (ART) with a CD4 cell count of less than 50 cells/mm3.
TB is a leading killer of people with HIV and in resource-limited settings many people with HIV who start ART late, after they have already developed advanced immune suppression, die within the first six months on treatment, often due to TB, the study authors noted as background.
Long-standing World Health Organisation (WHO) guidelines recommend isoniazid preventive therapy for HIV-positive adults without active TB. However, sub-clinical tuberculosis can be difficult to diagnose in people with advanced HIV disease – and complex tests can take weeks – so more intensive multi-drug TB treatment is commonly given on an empirical or default basis, in part because using isoniazid alone could lead to drug resistance if a patient has unrecognised active TB.
The REMEMBER study recruited 850 participants from 18 outpatient research clinics in 10 countries (Brazil, Haiti, India, Kenya, Malawi, Peru, South Africa, Uganda, Zambia and Zimbabwe) between October 2011 and June 2014. Just over half (53%) were men and the median age was 36 years. The participants had advanced HIV disease with a median baseline CD4 count of just 18 cells/mm3.
In contrast, the Temprano trial, which previously showed that isoniazid preventive therapy and early ART reduced the risk of illness and death, looked at people with higher CD4 counts, including about 40% each with >500 and 350-500 cells/mm3.
Before inclusion, REMEMBER participants were screened for TB using a symptom screen, locally available diagnostics and the GeneXpert MTB/RIF assay if available. People with confirmed or suspected TB were excluded, as were those with serious liver or kidney function abnormalities.
Participants were randomly assigned to either the isoniazid preventive therapy group, which received 300mg daily isoniazid monotherapy for 24 weeks, or the empirical therapy group, which received a standard four-drug TB regimen of isoniazid, rifampin, ethambutol and pyrazinamide for eight weeks, followed by isoniazid and rifampin for 16 more weeks. In addition, all participants in both groups received ART. The primary endpoint was survival at 24 weeks after randomisation.
After 24 weeks of treatment, 22 participants (5%) in each group died – mostly due to HIV-related complications – or had unknown status, for an absolute difference of only 0.06%, showing that isoniazid alone worked as well as the combination empirical TB regimen. However, people in the isoniazid-only group had less overall ‘disease burden’ and were less likely to either die or experience HIV disease progression (53 vs 72 participants, respectively).
Grade 3 or 4 signs or symptoms – such as weight loss, diarrhoea or fever – occurred in 46 people (11%) in the isoniazid preventive therapy group and 50 people (12%) in the empirical therapy group. Grade 3 or 4 laboratory abnormalities occurred in 97 participants in the isoniazid group and 99 in the empirical therapy group – both 23%. Among people who developed active TB, drug resistance was uncommon in both groups (three cases in each).
“Empirical tuberculosis therapy did not reduce mortality at 24 weeks compared with isoniazid preventive therapy in outpatient adults with advanced HIV disease initiating antiretroviral therapy,” the researchers concluded. “The low mortality rate of the trial supports implementation of systematic tuberculosis screening and isoniazid preventive therapy in outpatients with advanced HIV disease.”
“We actually underestimated the benefit of isoniazid preventive therapy in this highly vulnerable population, so what this trial found was that you could do a good job of screening for tuberculosis using locally available measures and safely put patients on isoniazid,” senior investigator Amita Gupta of Johns Hopkins Bloomberg School of Public Health stated in a press release. “Our results even suggest the four-drug strategy is actually doing more harm than isoniazid-alone therapy because study participants found it less tolerable and stopped using it.”
Isoniazid alone is of course more affordable than a multi-drug regimen, she added: “On average, the cost of isoniazid is pennies per pill, while it can be 6 times more expensive to try to diagnose and treat TB in each patient.”
Low-cost urine test
In a second study described in the same issue, Jonny Peter of the University of Cape Town and colleagues assessed a point-of-care urine-based lipoarabinomannan (LAM) assay, and evaluated the effect on mortality of a LAM-guided TB treatment initiation strategy for people with HIV.
This randomised trial was conducted at 10 hospitals in Africa (four in South Africa, two in Tanzania, two in Zambia and two in Zimbabwe). The study screened 8728 HIV-positive adults between January 2013 and October 2014. Eligible participants had at least one TB symptom (fever, cough, night sweats or self-reported weight loss) severe enough to require hospitalisation. Those who received any TB medications within the prior 60 days were excluded.
The researchers randomly assigned 2659 of these patients to receive treatment based on either the LAM assay plus routine diagnostic tests (smear microscopy, Xpert-MTB/RIF and culture) or the diagnostics tests alone. Some people did not receive their allocated treatment or were excluded from analysis, leaving 1257 in the LAM group and 1271 in the no-LAM group for the final modified intention-to-treat analysis.
In the LAM group, trained nurses performed the LAM test at bedside upon enrolment. If the test was positive they made a recommendation to start TB treatment, and the attending physician made an independent decision about whether or not to start.
Overall all-cause mortality at eight weeks after hospital discharge was 21% (261 patients) in the LAM group and 25% (317 patients) in the no-LAM group, an absolute reduction of 4%. The risk ratio, adjusted for country, was 0.83 – a relative risk reduction of 17%.
A larger proportion of patients in the LAM group compared to the no-LAM group were treated for TB (52 vs 47%) and more started treatment within the first three days (79 vs 69%).
The LAM test had a sensitivity (proportion correctly diagnosed with TB) of 46% and a specificity (proportion with TB correctly ruled out) of 90%.
There were no adverse events associated with LAM testing.
“Bedside LAM-guided initiation of anti-tuberculosis treatment in HIV-positive hospital inpatients with suspected tuberculosis was associated with reduced 8-week mortality,” the study authors concluded. “The implementation of LAM testing is likely to offer the greatest benefit in hospitals where diagnostic resources are most scarce and where patients present with severe illness, advanced immunosuppression, and an inability to self-expectorate sputum.”
“This is the first trial of any diagnostic test for tuberculosis to show a reduction in the number of deaths,” senior author Keertan Dheda of the University of Cape Town said in a Lancet press release. “The reduction in mortality is likely to be because urine-testing, in conjunction with routine testing, resulted in a greater proportion of patients starting tuberculosis treatment early.”
The Alere Determine LAM test costs less than US$3 and produces results in 25 minutes. WHO conditionally recommended it – leaving it up to doctors and health systems – last November.
“Importantly, we found that the test was particularly effective in identifying tuberculosis among patients with advanced HIV infection who are most vulnerable to advanced TB disease,” Dheda added. “The absolute reduction in mortality was small at 4%, but with 300,000 patients with HIV dying from tuberculosis in Africa every year, implementing this low cost, rapid, bedside test could potentially save thousands of lives annually.”
Hosseinpour MS et al. Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial. The Lancet 387(10024):1198-1209, 2016.
Peter JG et al. Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: a pragmatic, parallel-group, multicountry, open-label, randomised controlled trial. The Lancet 387(10024):1187-1197, 2016.