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.
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 TB-IRIS 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.
*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.
For further enquiries please contact Graeme Meintjes
(PredART Principal Investigator)