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Tuberculosis (TB) is a leading cause of death in HIV-infected individuals. There are insufficient data correlating concentrations of anti-TB drugs with treatment response. We hypothesize that sub-therapeutic concentrations of anti-TB drugs are associated with inadequate TB treatment response to Mycobacterium tuberculosis.
During the study periodic monitoring will be conducted to ensure that the protocol and Good Clinical Practices (GCPs) are being followed.The monitors may review source documents to confirm that the data recorded on CRFs is accurate. The study site may be subject to review by the Institutional Review Board (IRB) and/or appropriate regulatory authorities.
A CRF will be completed for each included subject and will be signed by the investigator or by an authorized staff member to attest that the data is true. Any corrections to entries made in the CRFs, source documents must be dated, initialed and explained (if necessary) and should not obscure the original entry. Qualit assurance will as also be performed regularly on the CRFs.
The primary end point will be analyzed using Time to event (cure, death, relapse etc)analysis and failure rates and hazard ratios will be calculated accordig to categorical drug concentrations with proposed cutt offs.
Secondary end points will be analysed using time to event for occurence of toxicities which will also be corelated to the drug concentrations.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| anti-tuberculosis drugs | Other | Rifampicin, Isoniazid, Ethambutol, Pyrazinamide tablets 3 to 5 tablets once daily for 2 months followed by Rifampicin, Isoniazid 3 to 5 tablets once daily for 4 months |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rifampicin, Isoniazid, Ethambutol, Pyrazinamide | Drug | Rifampicin, Isoniazid, Ethambutol, Pyrazinamide: 3, 4 or 5 tablets daily for weight below 55kg, above 55kg or above 70kg respectively for first 2 months followed by Rifampicin, Isoniazid: 3, 4 or 5 tablets daily for patients' weight below 55kg, above 55kg or above 70kg respectively for 4 months |
| Measure | Description | Time Frame |
|---|---|---|
| clinical outcome | To investigate the association between serum concentrations of antituberculosis drugs and tuberculosis treatment response in HIV-TB-co-infected individuals. | At the end of treatment (6 months after enrolmet) |
| Measure | Description | Time Frame |
|---|---|---|
| Cmax | To investigate the steady-state pharmacokinetic parameters of anti-TB drugs at different time-points over the course of TB-treatment | At 2 weeks, 8 weeks and 24 weeks after anti-tuberculosis drug initiation |
| Number of adverse events |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Andrew Kambugu, MMED | Contact | +256-414-307000 | 227 | akambugu@idi.co.ug |
| Name | Affiliation | Role |
|---|---|---|
| Barbara Castelnuovo, MD, PhD | Infectious Diseases Institute | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Infectious Diseases Institute | Recruiting | Kampala | Kampala | 256 | Uganda |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19432554 | Background | Chideya S, Winston CA, Peloquin CA, Bradford WZ, Hopewell PC, Wells CD, Reingold AL, Kenyon TA, Moeti TL, Tappero JW. Isoniazid, rifampin, ethambutol, and pyrazinamide pharmacokinetics and treatment outcomes among a predominantly HIV-infected cohort of adults with tuberculosis from Botswana. Clin Infect Dis. 2009 Jun 15;48(12):1685-94. doi: 10.1086/599040. | |
| 15844071 |
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| ID | Term |
|---|---|
| D014376 | Tuberculosis |
| ID | Term |
|---|---|
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
| D001424 | Bacterial Infections |
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| ID | Term |
|---|---|
| D012293 | Rifampin |
| D007538 | Isoniazid |
| D004977 | Ethambutol |
| D011718 | Pyrazinamide |
| ID | Term |
|---|---|
| D012294 | Rifamycins |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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|
|
To assess the safety and tolerability of anti-TB drugs based on the WHO guidelines
| 2 weeks, 8 weeks and 24 weeks after anti-tuberculosis drug initiation |
| ART trough levels | To correlate the effect of anti-TB drugs on plasma concentrations of efavirenz or protease inhibitors and vice versa. | At 2 weeks, 8 weeks and 24 weeks after anti-tuberculosis drug initiation |
| Isoniazid Cmax | To evaluate the effect of acetylator geno-and phenotype (NAT-2 gene) on isoniazid plasma concentrations and toxicity | At 2 weeks, 8 weeks and 24 weeks |
| Weiner M, Benator D, Burman W, Peloquin CA, Khan A, Vernon A, Jones B, Silva-Trigo C, Zhao Z, Hodge T; Tuberculosis Trials Consortium. Association between acquired rifamycin resistance and the pharmacokinetics of rifabutin and isoniazid among patients with HIV and tuberculosis. Clin Infect Dis. 2005 May 15;40(10):1481-91. doi: 10.1086/429321. Epub 2005 Apr 14. |
| 15504887 | Background | Gurumurthy P, Ramachandran G, Hemanth Kumar AK, Rajasekaran S, Padmapriyadarsini C, Swaminathan S, Bhagavathy S, Venkatesan P, Sekar L, Mahilmaran A, Ravichandran N, Paramesh P. Decreased bioavailability of rifampin and other antituberculosis drugs in patients with advanced human immunodeficiency virus disease. Antimicrob Agents Chemother. 2004 Nov;48(11):4473-5. doi: 10.1128/AAC.48.11.4473-4475.2004. |
| 11170964 | Background | Narita M, Hisada M, Thimmappa B, Stambaugh J, Ibrahim E, Hollender E, Ashkin D. Tuberculosis recurrence: multivariate analysis of serum levels of tuberculosis drugs, human immunodeficiency virus status, and other risk factors. Clin Infect Dis. 2001 Feb 1;32(3):515-7. doi: 10.1086/318490. Epub 2001 Jan 25. |
| 17724157 | Background | Gumbo T, Louie A, Deziel MR, Liu W, Parsons LM, Salfinger M, Drusano GL. Concentration-dependent Mycobacterium tuberculosis killing and prevention of resistance by rifampin. Antimicrob Agents Chemother. 2007 Nov;51(11):3781-8. doi: 10.1128/AAC.01533-06. Epub 2007 Aug 27. |
| 30910890 | Derived | Sekaggya-Wiltshire C, Chirehwa M, Musaazi J, von Braun A, Buzibye A, Muller D, Gutteck U, Motta I, Calcagno A, Fehr JS, Kambugu A, Castelnuovo B, Lamorde M, Denti P. Low Antituberculosis Drug Concentrations in HIV-Tuberculosis-Coinfected Adults with Low Body Weight: Is It Time To Update Dosing Guidelines? Antimicrob Agents Chemother. 2019 May 24;63(6):e02174-18. doi: 10.1128/AAC.02174-18. Print 2019 Jun. |
| 29514175 | Derived | Sekaggya-Wiltshire C, von Braun A, Lamorde M, Ledergerber B, Buzibye A, Henning L, Musaazi J, Gutteck U, Denti P, de Kock M, Jetter A, Byakika-Kibwika P, Eberhard N, Matovu J, Joloba M, Muller D, Manabe YC, Kamya MR, Corti N, Kambugu A, Castelnuovo B, Fehr JS. Delayed Sputum Culture Conversion in Tuberculosis-Human Immunodeficiency Virus-Coinfected Patients With Low Isoniazid and Rifampicin Concentrations. Clin Infect Dis. 2018 Aug 16;67(5):708-716. doi: 10.1093/cid/ciy179. |
| 29162063 | Derived | Kwizera R, Parkes-Ratanshi R, Page ID, Sekaggya-Wiltshire C, Musaazi J, Fehr J, Castelnuovo B, Kambugu A, Denning DW. Elevated Aspergillus-specific antibody levels among HIV infected Ugandans with pulmonary tuberculosis. BMC Pulm Med. 2017 Nov 21;17(1):149. doi: 10.1186/s12890-017-0500-9. |
| 28928173 | Derived | Sekaggya-Wiltshire C, Castelnuovo B, von Braun A, Musaazi J, Muller D, Buzibye A, Gutteck U, Henning L, Ledergerber B, Corti N, Lamorde M, Fehr J, Kambugu A. Cohort profile of a study on outcomes related to tuberculosis and antiretroviral drug concentrations in Uganda: design, methods and patient characteristics of the SOUTH study. BMJ Open. 2017 Sep 18;7(9):e014679. doi: 10.1136/bmjopen-2016-014679. |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D047029 | Lactams, Macrocyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |
| D006834 | Hydrazines |
| D009930 | Organic Chemicals |
| D007539 | Isonicotinic Acids |
| D000147 | Acids, Heterocyclic |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D005029 | Ethylenediamines |
| D003959 | Diamines |
| D011073 | Polyamines |
| D000588 | Amines |
| D011719 | Pyrazines |