A randomised controlled trial of 3 strategies for the treatment of ART-naive HIV infected patients with tuberculosis v1

Tuberculosis (TB) is the leading cause of mortality among people with Human Immunodeficiency Virus (HIV) infection, particularly in sub-Saharan Africa. In this setting, around 30% of HIV-positive tuberculosis patients die by 12 months after starting TB treatment. Between 40% and 60% of these deaths occur during the first 2 months after starting TB treatment, and this early mortality appears to be TB-related, rather than related to HIV. For patients with CD4 counts of < 350 cells/mm3, aggressive management of HIV infection using early antiretroviral treatment (ARV) could decrease mortality by restoring, at least for some patients, the CD4 cell mediated immune response to M. tuberculosis, but might also expose patients to severe complications when introduced at the same time as anti-tuberculosis treatment. An alternative approach is to question whether the current standard TB treatment regimen is optimal for HIV-infected patients. Aggressive management of TB in these patients during the first two months of TB treatment with a high dose of rifampicin might result in a decrease in the early HIV/TB mortality, without the negative effects of the early severe complications that can arise from the use of ARV treatment. Clinical trials conducted in Africa are of great importance in order to identify the best approach for reducing mortality in HIV-infected TB patients, given that Africa accounts for an estimated 80% of the world’s HIV-positive TB cases. Our proposed project is a multi-centre, open-label randomised controlled trial whose primary objective is to assess the efficacy of three treatment strategies for HIV-positive TB patients who are ARV-naive and have a CD4 count of ≥50 cells/mm3. The trial will also include a nested pharmacokinetic (PK) study in a sub-sample of patients. The 3 treatment strategies to be evaluated, which correspond to three parallel arms in the trial, are: 1. Early ARV initiation (at 2 weeks after starting TB treatment ) combined with standard TB treatment; 2. Delayed ARV treatment (at 2 months after starting TB treatment) combined with standard TB treatment; and 3. Delayed ARV treatment (at 2 months after starting TB treatment) with a high dose rifampicin regimen during the intensive phase of TB treatment (15mg/Kg instead of 10 mg/Kg) followed by a standard continuation phase. Efficacy will be measured in terms of mortality at 2 and 12 months after the start of TB treatment, and 375 patients will be recruited in each trial arm. The trial will be implemented in three countries in West Africa: Benin, Guinea and Senegal. Collaborating partners in these countries are the national TB programmes of Benin and Senegal, and the service of pneumo-physiology in Conakry, Guinea. There are five other international partners: University of Cape-Town; the Institute of Tropical Medicine (Antwerp); University College London; the Hospital of Tenon in Paris; and the London School of Hygiene and Tropical Medicine. Key aspects of the trial are summarized in the following table.