AlpE is a novel drug combination under development for the treatment of TB, with several positive attributes for TBM, including rapid bactericidal activity. The current trial aims to assess the plasma and CSF PK, as well as the safety and tolerability of alpibectir and three doses of Eto in patients with newly diagnosed TBM. Additionally, it is attended to investigate the effect of AlpE on the PK and efficacy of DTG during the first month of antiretroviral treatment (ART) for Human Immunodeficiency Virus (HIV)-positive patients.

Inclusion Criteria:

1. Age ≥ 15 years and < 65 years

2. Diagnosis of TBM defined as "definite" or "probable", using criteria proposed by the Tuberculosis Meningitis International Research Consortium.

   • Definite TBM is defined by at least one of the following criteria: acid-fast bacilli (AFB) seen in CSF microscopy, positive CSF M. tuberculosis culture, or positive CSF M. tuberculosis commercial nucleic acid amplification test in the setting of symptoms suggestive of meningitis.
   • Probable TBM is defined using a modified Marais score* Probable TBM: total score* ≥ 12 when neuroimaging is available, or ≥ 10 when neuroimaging is not available. At least 2 points should come from CSF or 2 points from cerebral imaging criteria.

   (*see Appendix 2: Modified Marais Score)

3. Informed consent signed by the patient. For patients with Glasgow Coma Scale (GCS) < 15, the consent of a next of kin/relative will be required, in accordance with applicable local laws and regulations. Deferred consent will be obtained from the participant when their level of consciousness improves, and they have capacity to provide consent. For adolescents below the age of civil majority (as defined in each country), the consent of at least one parent or legal guardian and the assent of the adolescent will be required.

Exclusion Criteria:

1. Having received >14 days of HRZE TB treatment.

2. In people with HIV infection: use of antiretroviral treatment (ART) other than efavirenz- or dolutegravir-based.

3. Glasgow Coma Scale < 10.

4. Body weight measured or estimated: < 40 kg or > 90 kg or BMI > 40 kg/m2.

5. Renal failure (eGFR < 30 mL/min, calculated by CKD-EPI formula).

6. Alanine aminotransferase (ALT) > 5 times the Upper Limit of Normal.

7. Clinical evidence of liver failure or decompensated cirrhosis.

8. For women of childbearing potential, one or more of the following:

   1. Being pregnant, breast-feeding, or intending to breast-feed or conceive a child during the study or within 30 days after the end of treatment visit (D56), OR;
   2. Not willing or able to use highly effective contraceptive methods (as defined per Appendix 7) starting at screening and continuing until 30 days after the end of treatment visit (D56).

9. For male participants: intending to conceive a child or not willing or able to consistently use a barrier method e.g. condoms during all sexual activity from inclusion until 90 days after the end of treatment visit (D56).

   Note: Male participants should be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse.

10. Documented Mtb resistance to rifampicin.

11. Positive Gram-stain, bacterial culture other than Mtb or cryptococcal antigen in the CSF.

12. For HIV positive patients: Presence of cryptococcal antigen in the blood.

13. Inability to collect CSF or contraindication to lumbar puncture (LP).