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THE PredART TRIAL: A RANDOMIZED CONTROLLED TRIAL OF PREDNISONE FOR
THE PREVENTION OF THE PARADOXICAL TUBERCULOSIS-ASSOCIATED IMMUNE
RECONSTITUTION INFLAMMATORY SYNDROME (TB-IRIS)
Investigators: Graeme Meintjes (Principal Investigator), Cari Stek, Liz
Blumenthal, Friedrich Thienemann, Charlotte Schutz, Jozefien Buyze, Gary
Maartens, Robert J. Wilkinson, Lut Lynen on behalf of the PredART trial team
Late Breaker Abstract 81, to be presented at the Conference on Retroviruses
and Opportunistic Infections (CROI), Seattle, Washington, on 15 February 2017
at 11h15 Pacific Time.
NEWS STORY EMBARGOED UNTIL PRESENTATION GIVEN
Background: HIV and Tuberculosis
Untreated HIV infection is associated with progressive weakening of the body’s
immune system. This predisposes a person infected with HIV to other serious
infections. In countries of sub-Saharan Africa the most common co-infection
complicating HIV is tuberculosis (TB). In these countries it is common for people
to present to the health services with symptoms of TB and be newly diagnosed
with both HIV infection and active TB disease simultaneously. In such patients, TB
treatment is first started followed by antiretroviral therapy (ART) a few weeks
later.
Previous studies have shown that patients with TB and a very weakened immune
system due to HIV (especially those with a CD4 T cell count less than 50
cells/mm3) should start TB treatment followed within 2 weeks by ART – if there is
a delay to starting ART increased deaths result.
Background: TB-IRIS
The most common complication of starting ART in HIV-infected patients on
treatment for TB is a condition called the TB-associated Immune Reconstitution
Inflammatory Syndrome (or “TB-IRIS” for short). This condition manifests with
recurrent or worsening symptoms and inflammatory signs of TB during the first
few weeks of ART. It is thought that improving immune function on ART drives
inflammation directed at TB bacteria or their breakdown products still present in
the lungs and other organs causing clinical deterioration. Common features
include recurrence of cough and night sweats, enlarging lymph nodes in the neck
and worsening of chest radiograph features of TB. About a quarter of patients
who develop TB-IRIS require hospital admission. Major risk factors include a low
CD4 T-cell count and starting ART soon after TB treatment.
The PredART trial
Thus in patients with HIV and TB and a low CD4 T-cell count it is imperative to
start ART soon after TB treatment to reduce deaths, but this paradoxically
increases the risk for TB-IRIS. To date no effective preventive medications for TBIRIS have been identified. In this trial we evaluated whether prednisone could
safely reduce the risk of TB-IRIS in such patients. Prednisone is a corticosteroid
anti-inflammatory drug that is widely used for the treatment of conditions such as
asthma and certain forms of arthritis. It costs less than US$3 for a month’s supply
in South Africa.
The trial was known as the PredART trial. It was a randomized, double-blind,
placebo-controlled trial conducted in HIV-TB clinics in Khayelitsha township, Cape
Town, South Africa. 240 patients who were HIV-infected with a CD4 T-cell count
of 100 cells/mm3 or lower, who had never received ART previously and were
recently diagnosed with TB disease were enrolled. All participants received TB
treatment and ART. Participants were randomized in a 1:1 ratio to receive
prednisone for 4 weeks or identical placebo for 4 weeks started at the same time
as their ART medication, and followed intensively for a further 8 weeks. A
moderate dose of prednisone was used: 40mg per day for 2 weeks followed by
20mg per day for 2 weeks.
The primary comparison was the proportion of participants who were diagnosed
with TB-IRIS. In participants who received prednisone there was a significant 30%
relative reduction in the risk of developing TB-IRIS: 47% of patients in the placebo
arm developed TB-IRIS compared with 33% in the prednisone arm. There was also
a trend towards fewer hospital admissions in the prednisone-treated participants.
Also important is that prednisone appeared to be safe in these patients with
advanced HIV. Adverse events and severe infections were not more common in
the prednisone-treated participants. One case of Kaposi’s sarcoma (an HIV-related
cancer) occurred: this was in a patient in the placebo arm who stopped taking
ART.
Prednisone is a cheap and readily accessible drug in developing world settings. In
this trial, we have demonstrated that it reduces the risk of developing TB-IRIS by
30% in patients on TB treatment at high risk for TB-IRIS starting ART. It was also
safe. The findings of this trial provide the first evidence of an effective strategy for
reducing the risk of this very common complication of starting ART in HIV-infected
patients also being treated for TB.
The trial was conducted by investigators from the University of Cape Town,
Institute of Tropical Medicine (Antwerp), and Imperial College London. It was
funded by the European and Developing Countries Clinical Trials Partnership
(EDCTP), with co-funding from the South African National Department of Science
and Technology and the Wellcome Trust.
For further enquiries please contact Graeme Meintjes (PredART Principal
Investigator): [email protected]
Dated: 12 February 2017
PredART trial clinical site team meeting at Site B Khayelitsha