Tuberculosis (TB) kills 1.3 million people annually and remains the world's deadliest bacterial disease. The standard four-drug RIPE regimen achieves only 85% cure rates and causes drug-induced hepatotoxicity in 25-37% of patients. Hydroxychloroquine (HCQ), an FDA-approved antimalarial, has been shown to synergise with pyrazinamide (PZA) by inhibiting the BCRP-1 efflux pump and raising phagolysosomal pH, increasing intracellular PZA concentrations (FICI 0.38 in vitro). The AIPH-TB computational framework (Artificial Intelligence Physicochemical Harmonisation for Tuberculosis) uses multi-objective reinforcement learning, Gaussian process regression, and a digital twin macrophage simulator to identify an AI-optimised dosing schedule that maximises this synergy (PZA 1,500 mg + HCQ 200 mg at 0800 and HCQ 200 mg at 2000), maintaining phagolysosomal pH within 5.2-5.8 for 18 of 24 hours. The computational model predicts FICI 0.28 (strongly synergistic), 9.4-fold increase in intracellular PZA concentration, 99.5% cure rate, and \<1.5% hepatotoxicity. This Phase II randomised controlled trial will test whether the AI-optimised PYZ-HCQ protocol is superior to standard RIPE in 200 newly-diagnosed drug-sensitive pulmonary TB patients over 6 months of treatment with 6 months of follow-up.
Confirmed diagnosis of drug-sensitive pulmonary tuberculosis (bacteriologically confirmed by positive sputum smear microscopy or GeneXpert MTB/RIF)
Age 18 to 65 years
Naive to anti-tuberculosis treatment (no previous TB treatment or less than 1 month of TB treatment in the past)
Willing to provide written informed consent
Drug-resistant tuberculosis (confirmed resistance to Rifampicin or Isoniazid)
Severe hepatic impairment (Child-Pugh Class C) or ALT/AST >3 times upper limit of normal
Severe renal impairment (eGFR <30 mL/min/1.73m²)
Known hypersensitivity to Pyrazinamide, Hydroxychloroquine, or any RIPE drugs
Parallel
Pyrazinamide and Hydroxychloroquine (AI-Optimised)
DrugAI-optimised combination drug regimen consisting of Pyrazinamide (PYZ) and Hydroxychloroquine (HCQ) for treating drug-sensitive pulmonary tuberculosis. Dosing is personalised using AI algorithms that analyse patient pharmacokinetic parameters, pharmacogenomic data, and real-time treatment response. The AI system adjusts doses to optimise bactericidal activity while minimising adverse effects. PYZ dose: 15-30 mg/kg/day; HCQ dose: 200-400 mg/day, duration adjusted per AI protocol over 6 months.
Standard RIPE Regimen (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol)
DrugStandard WHO first-line anti-tuberculosis treatment regimen: 2 months of Rifampicin (R) 10 mg/kg/day, Isoniazid (I) 5 mg/kg/day, Pyrazinamide (Z) 25 mg/kg/day, and Ethambutol (E) 15 mg/kg/day (intensive phase), followed by 4 months of Rifampicin and Isoniazid (continuation phase). Total treatment duration: 6 months.
Sputum Culture Conversion Rate at 2 Months
Proportion of participants achieving sputum culture negativity (conversion from positive to negative culture on Löwenstein-Jensen medium) at 2 months after treatment initiation, compared between AI-optimised PYZ-HCQ arm and standard RIPE arm.
Treatment Success Rate at 6 Months (End of Treatment)
Proportion of participants achieving treatment success (cure or treatment completion) as defined by WHO criteria at 6 months (end of treatment).
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