To determine if adjunctive N-acetylcysteine 1200 mg twice a day (BID) accelerates sputum culture conversion and normalization of cellular glutathione in tuberculosis (TB), and to assess its potential effects on lung and immune function

This is a randomized controlled, 2-arm, parallel group substudy of the TB-SEQUEL cohort study. It will enrol drug sensitive TB patients with moderately advanced or far advanced pulmonary disease by chest X-ray. Patients providing informed consent will undergo screening evaluations to establish eligibility. Patients meeting all the inclusion and none of the exclusion criteria will be randomized to receive standard TB treatment (2HRZE/4HR) plus NAC 1200 mg BID for months 1-4, or standard treatment alone. During the treatment period patients will undergo safety, efficacy, and biomarker assessments at specified time points. After a final evaluation at 6 months, patients will continue follow-up as a part of the main TB-SEQUEL cohort study.

Inclusion Criteria:

1. Aged 18 to 65 years, male or female
2. Willing and able to provide signed written consent or witnessed oral consent in the case of illiteracy, prior to undertaking any trial related procedures.
3. Body weight (in light clothing without shoes) between 40 and 90 kg.
4. First episode of pulmonary tuberculosis
5. Positive sputum AFB smear with subsequent culture confirmation OR positive Xpert TB/RIF with Ct ≤27.1 [3].
6. RIF susceptibility diagnosed by Xpert TB/RIF OR Hain test
7. Chest radiograph meeting criteria for moderate or far advanced pulmonary tuberculosis [4]
8. If sexually active, willing to use an effective contraceptive method for the duration of tuberculosis treatment
9. HIV-1 seronegative, or if HIV-1 seropositive, CD4 T cell count >220/ul

Exclusion Criteria:

1. Any condition for which participation in the trial, as judged by the investigator, could compromise the well being of the subject or prevent, limit or confound protocol specified assessments

2. Current or imminent (within 24 hr) treatment for malaria.

3. Pregnancy

4. Is critically ill, and in the judgment of the investigator has a diagnosis likely to result in death during the trial or the follow up period.

5. TB meningitis or other forms of severe tuberculosis with high risk of a poor outcome as judged by the investigator.

6. History of allergy or hypersensitivity to any of the trial therapies or related substances, including known allergy or suspected hypersensitivity to rifampin.

7. Having participated in other clinical trials with investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational trial.

8. Prior TB treatment in the preceding 6 months.

9. Angina pectoris requiring treatment with nitroglycerin or other nitrates

10. Cardiac arrhythmia requiring medication, or any clinically significant ECG abnormality, in the opinion of the investigator

11. Random blood glucose >140 mg/dL, or history of unstable Diabetes Mellitus which required hospitalization for hyper- or hypo-glycaemia within the past year prior to start of screening.

12. Use of systemic corticosteroids within the past 28 days.

13. Patients requiring treatment with medications not compatible with rifampin, such as HIV-1 protease inhibitors

14. Subjects with any of the following abnormal laboratory values:

    1. creatinine >2 mg/dL
    2. haemoglobin <8 g/dL
    3. platelets <100x109 cells/L
    4. serum potassium <3.5
    5. aspartate aminotransferase (AST) ≥2.0 x ULN
    6. alkaline phosphatase (AP) >5.0 x ULN
    7. total bilirubin >1.5 mg/dL