Systematic Empirical vs. Test-guided Anti-TB Treatment Impact in Severely Immunosuppressed HIV-infected Adults Initiating ART With CD4 Cell Counts <100/mm3 (STATIS)

• All-cause mortality and incidence of invasive bacterial infections [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  The primary endpoint is the composite of (i) 24-week all-cause mortality and (ii) 24-week incidence of invasive bacterial infections
  
  

• Incidence of confirmed/probable/possible TB [ Time Frame: 24 Weeks and 48 weeks ] [ Designated as safety issue: No ]
  
• Incidence of grade 3 or 4 adverse events [ Time Frame: 24 Weeks and 48 weeks ] [ Designated as safety issue: Yes ]
  

• Incidence of TB-associated IRIS [ Time Frame: 24 Weeks and 48 Weeks ] [ Designated as safety issue: No ]
  
• Incidence of AIDS-defining diseases other than TB [ Time Frame: 24 Weeks and 48 Weeks ] [ Designated as safety issue: No ]
  

Settings: Cambodia, Côte d'Ivoire, Uganda, Vietnam. Design: Multicentre, two-arm, unblinded randomized controlled superiority trial.

Objective: To compare the 24-week risk of death and occurrence of invasive bacterial infection between two experimental strategies in HIV-1 infected adults who start ART with a CD4 count <100/mm3: (i) continuous extensive TB screening during follow-up each time the patient present with symptoms, versus (ii) systematic empirical TB treatment started 2 weeks before ART initiation.

Trial strategies:

At inclusion, participants will be randomized 1:1 in two strategies of TB testing and treatment: extensive TB screening, or systematic empirical TB treatment.

Extensive TB screening (arm 1): In this arm:

• TB screening point-of-care tests (Xpert MTB/RIF®, urine LAM) and chest X-ray will be used extensively at randomisation (in all patients) and during follow-up (in patients with signs or symptoms suggestive of TB);
• Only patients who meet standardized criteria for TB at inclusion or during follow-up will receive a standard TB treatment (2ERHZ/4RH);
• ART (tenofovir(TDF)-lamivudine (3TC)/emtricitabine(FTC) or zidovudine (AZT)-lamivudine+ efavirenz) will be started immediately after randomization in patients not put on TB treatment, and 2 weeks after initiation of TB treatment in others.

Systematic empirical TB treatment (arm 2): In this arm:

• TB screening point-of-care tests will not be used;
• All patients will start a 6-month standard TB treatment (2ERHZ/4RH) at randomization; ART (tenofovir-lamivudine/emtricitabine or zidovudine-lamivudine+ efavirenz) will be started 2 weeks after TB treatment initiation.

Both strategies will apply to the first 24 weeks in the trial (intervention period).

From week-24 to week-48, the choice of TB tests and the prescription of TB treatment will be left upon the decision of the investigator in both trial arms.

Inclusion time: 24 months. Follow-up: each patient will be followed 48 weeks. Statistical analysis: the primary analysis will be intention to treat. It will compare the 24-week probability of death or invasive bacterial infection between arms.

Sample size: 1050 participants. This will allow demonstration of a 40% reduction in the 24-week probability of death or invasive bacterial infection in arm 2, compared to arm 1 (α 5%; 1-β 80%).