Standard Versus Double Dose Dolutegravir in Patients With HIV-associated Tuberculosis
Condition: HIV Infections; Tuberculosis
MeSH terms: Tuberculosis
Study type: Interventional
Phase: Phase 2

Summary: 
      The investigators propose to conduct a phase 2 randomised (1:1) double-blind
      placebo-controlled trial of the dolutegravir-lamivudine-tenofovir fixed dose combination
      tablet daily with an additional 50 mg dose of dolutegravir/matching placebo taken 12 hours
      later in ART-naïve or fisrt-line interrupted HIV-infected patients on rifampicin-based
      anti-tuberculosis therapy. The hypothesis is that virologic outcomes with standard dose
      dolutegravir-based ART will be acceptable in patients on rifampicin-based anti-tuberculosis
      therapy.
    

Detailed description: 
      Dolutegravir is being rolled out to replace efavirenz in first-line antiretroviral therapy
      (ART) in low-middle income countries (LMICs) because it is more effective, better tolerated,
      and has a considerably higher genetic barrier to resistance.

      Tuberculosis is the commonest cause of HIV-related morbidity and mortality in LMICs.
      Rifampicin, which is a key component of anti-tuberculosis therapy, induces genes that are
      important in the metabolism and transport of dolutegravir. The resulting drug-drug
      interaction between dolutegravir and rifampicin significantly reduces dolutegravir exposure,
      which can be overcome by increasing the dose of dolutegravir to 50 mg 12 hourly.

      The additional dose of dolutegravir will be difficult to implement in high burden settings.
      Furthermore, the additional dolutegravir tablet increases pill burden and costs. If standard
      dose dolutegravir is shown to be effective in patients with tuberculosis this would sweep
      away one of the major barriers to its implementation in LMICs. There are three lines of
      evidence to support studying standard dose dolutegravir in patients with HIV-associated
      tuberculosis.

      First, there are compelling pharmacokinetic and pharmacodynamic data supporting the
      therapeutic efficacy of lower dolutegravir exposure. Second, the investigators have conducted
      a drug-drug interaction study of dolutegravir dosed at 50 mg or 100 mg once daily in healthy
      volunteers with rifampicin. Although, as expected, concomitant rifampicin significantly
      reduced dolutegravir exposure at both doses, all dolutegravir trough concentrations on
      rifampicin were above the protein-adjusted 90% inhibitory concentration (PA IC90). Third,
      exposure to the first-generation integrase inhibitor raltegravir is also significantly
      reduced with concomitant rifampicin. A phase 2 study in patients with HIV-associated
      tuberculosis showed that virologic outcomes were similar with standard and double dose
      raltegravir. It is plausible that findings could be similar with dolutegravir.

      The hypothesis is that virologic outcomes with standard dose dolutegravir-based ART will be
      acceptable in patients on rifampicin-based anti-tuberculosis therapy. If the proportion of
      participants who achieve virological suppression on standard dose dolutegravir is acceptable,
      this would pave the way for a phase 3 trial of dolutegravir 50 mg daily versus an appropriate
      standard of care regimen, like efavirenz-based ART, in patients with HIV-associated
      tuberculosis.
    

Intervention name(s): Placebo; Dolutegravir 50 mg
Intervention type(s): Other; Drug
Intervention description(s): Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily is not given with a supplementary dose of dolutegravir 50 mg.; Dolutegravir-lamivudine-tenofovir fixed-dose combination tablet daily is given with a supplementary dose of dolutegravir 50 mg.
Other intervention name(s): Tivicay 50 mg
Intervention MeSH terms: Dolutegravir
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Parallel assignment of randomised groups with stratification by ART-naïve versus first-line interrupter status
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Antiretroviral therapy; Dolutegravir; Rifampicin; Tuberculosis; Drug-drug interaction