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.”