Inclusion Criteria:
* Pulmonary TB (among participants with or without history of prior TB treatment) identified within 5 days prior to entry by:
* At least one sputum specimen positive for M. tuberculosis by molecular TB assay (Xpert) or line probe assay \[LPA\]) OR
* At least one sputum specimen positive (1+ or greater) for acid-fast bacilli (AFB) on smear microscopy
* Note: TB diagnosis for purposes of meeting inclusion criterion can be from a study testing laboratory or from an outside laboratory, as long as it is from a sputum sample collected within 5 days prior to entry.
* Pulmonary TB diagnosed without known INH resistance (e.g., by LPA or Xpert) and without known RIF resistance (e.g., by either LPA or Xpert).
* Absence of HIV-1 infection, as documented by any licensed rapid HIV test or HIV-1 enzyme or chemiluminescence immunoassay (E/CIA) test kit, within 30 days prior to entry OR HIV-1 infection, documented by any licensed rapid HIV test or HIV-1 E/CIA test kit at any time prior to entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen or plasma HIV-1 RNA viral load. Two or more HIV-1 RNA viral loads of \>1,000 copies/mL are also acceptable as documentation of HIV-1 infection.
* For participants living with HIV, CD4+ cell count ≥100 cells/mm\^3, obtained within 30 days prior to study entry at any network-approved non-US laboratory that is Immunology Quality Assessment (IQA) certified.
* For participants living with HIV must be currently receiving or planning to initiate antiretroviral therapy (ART) at or before study week 8.
* A verifiable address or residence readily accessible to facilitate directly observed therapy (DOT), and willingness to inform the study team of any change of address during the treatment and follow-up period.
* The following laboratory values obtained at or within 5 days prior to entry by any US laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent, or at any network-approved non-US laboratory that operates in accordance with Good Clinical Laboratory Practice (GCLP) and participates in appropriate external quality assurance programs.
* Serum or plasma alanine aminotransferase (ALT) ≤3 times the upper limit of normal (ULN)
* Serum or plasma total bilirubin ≤2.5 times ULN
* Serum or plasma creatinine ≤2 times ULN
* Serum or plasma potassium ≥3.5 mEq/L and ≤5.5 mEq/L
* Absolute neutrophil count (ANC) ≥650/mm\^3
* Hemoglobin ≥7.0 g/dL
* Platelet count ≥50,000/mm\^3
* For females of reproductive potential, negative serum or urine pregnancy test within 5 days prior to entry by any US clinic or laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent, or is using a point of care (POC)/CLIA-waived test, or at any network-approved non-US laboratory or clinic that operates in accordance with Good Clinical Laboratory Practice (GCLP) and participates in appropriate external quality assurance programs.
* Female participants of reproductive potential must agree not to participate in the conception process (i.e., active attempt to become pregnant, in vitro fertilization), and if participating in sexual activity that could lead to pregnancy, must agree to use at least one reliable nonhormonal method of contraception, as listed below, while on study treatment and for 30 days after stopping study medications.
* Acceptable forms of contraception include:
* Condoms
* Intrauterine device or intrauterine system
* Cervical cap with spermicide
* Diaphragm with spermicide
* Note: Hormonal birth control alone is not acceptable, as it may not be sufficiently reliable in combination with RPT or RIF.
* Female participants who are not of reproductive potential must have documentation of menopause (i.e., at least 1 year amenorrheic), hysterectomy, or bilateral oophorectomy or bilateral tubal ligation.
* Documentation of Karnofsky performance score ≥50 within 30 days prior to entry.
* Documentation of either the presence or absence of advanced disease as determined by chest X-ray within 5 days prior to entry.
* Ability and willingness of participant to provide informed consent.
Exclusion Criteria:
* More than 5 days of treatment directed against active TB for the current TB episode preceding study entry.
* Pregnant or breast-feeding.
* Unable to take oral medications.
* Current receipt of clofazimine or bedaquiline or known receipt of clofazamine or bedaquiline at any time in the past.
* Corrected QT based on the Fridericia correction method (QTcF) interval \>450 ms for men or \>470 ms for women within 30 days prior to entry.
* Weight \<30 kg.
* Current or planned use within 6 months following enrollment of one or more of the following medications: HIV protease inhibitors, HIV entry and fusion inhibitors, HIV non-nucleoside reverse transcriptase inhibitors (other than EFV), elvitegravir/cobicistat, bictegravir, quinidine, procainamide, amiodarone, sotalol, disopyramide, ziprasidone, or terfenadine.
* Current extrapulmonary TB, in the opinion of the site investigator.
* Current or history of known personal or family long QT syndrome.
* Known allergy/sensitivity or any hypersensitivity to components of study TB drugs or their formulation.
* Active drug, alcohol use or dependence; or mental illness (e.g., major depression) that, in the opinion of the site investigator, would interfere with adherence to study requirements.
* Known history of acute intermittent porphyria.
* Other medical conditions (e.g., severe uncontrolled diabetes, liver or kidney disease, blood disorders, peripheral neuritis, chronic diarrhea) in which the current clinical condition of the participant is likely to prejudice the response to, or assessment of, treatment.
