HIV Clinical Trial
Official title:
DNA Sequencing of MDR TB in Eastern Siberia
This is protocol is generated in response to the exploratory R21 from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) for US-Russia collaborative research in HIV/tuberculosis (TB). Given the exploratory focus of the protocol and the short time frame of funding (2 years) we will study TB in Irkutsk, in Eastern Siberia. Irkutsk is one of the hardest-hit areas in all of the Russian Federation for drug-resistant TB and poor TB outcomes. Specifically, the investigators will examine the factors of anti-TB drug pharmacokinetics, TB drug-resistance mutations and virulent/transmissible M. tuberculosis sublineages. This foundational work will inform future diagnostic strategies and therapeutic regimens.
Status | Recruiting |
Enrollment | 630 |
Est. completion date | November 2018 |
Est. primary completion date | November 2018 |
Accepts healthy volunteers | No |
Gender | Both |
Age group | 15 Years and older |
Eligibility |
Inclusion Criteria: - All patients suspected of TB at Irkutsk Dispensary/Irkutsk AIDS Center. - age >15 years Exclusion Criteria: - Pregnancy (self reported) - Prisoner or ward of the state |
Observational Model: Case-Only, Time Perspective: Prospective
Country | Name | City | State |
---|---|---|---|
Russian Federation | Institute of Epidemiology & Microbiology of Scientific Center | Timiryazeva | Irkutsk |
Lead Sponsor | Collaborator |
---|---|
University of Virginia |
Russian Federation,
Bobkov A, Kazennova E, Khanina T, Bobkova M, Selimova L, Kravchenko A, Pokrovsky V, Weber J. An HIV type 1 subtype A strain of low genetic diversity continues to spread among injecting drug users in Russia: study of the new local outbreaks in Moscow and Irkutsk. AIDS Res Hum Retroviruses. 2001 Feb 10;17(3):257-61. — View Citation
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. — View Citation
Dymova MA, Kinsht VN, Cherednichenko AG, Khrapov EA, Svistelnik AV, Filipenko ML. Highest prevalence of the Mycobacterium tuberculosis Beijing genotype isolates in patients newly diagnosed with tuberculosis in the Novosibirsk oblast, Russian Federation. J Med Microbiol. 2011 Jul;60(Pt 7):1003-9. doi: 10.1099/jmm.0.027995-0. Epub 2011 Mar 24. — View Citation
Heysell SK, Houpt ER. The future of molecular diagnostics for drug-resistant tuberculosis. Expert Rev Mol Diagn. 2012 May;12(4):395-405. doi: 10.1586/erm.12.25. Review. — View Citation
Heysell SK, Moore JL, Keller SJ, Houpt ER. Therapeutic drug monitoring for slow response to tuberculosis treatment in a state control program, Virginia, USA. Emerg Infect Dis. 2010 Oct;16(10):1546-53. doi: 10.3201/eid1610.100374. — View Citation
Heysell SK, Mtabho C, Mpagama S, Mwaigwisya S, Pholwat S, Ndusilo N, Gratz J, Aarnoutse RE, Kibiki GS, Houpt ER. Plasma drug activity assay for treatment optimization in tuberculosis patients. Antimicrob Agents Chemother. 2011 Dec;55(12):5819-25. doi: 10.1128/AAC.05561-11. Epub 2011 Oct 3. — View Citation
Millán-Lou MI, Alonso H, Gavín P, Hernández-Febles M, Campos-Herrero MI, Copado R, Cañas F, Kremer K, Caminero JA, Martín C, Samper S. Rapid test for identification of a highly transmissible Mycobacterium tuberculosis Beijing strain of sub-Saharan origin. J Clin Microbiol. 2012 Feb;50(2):516-8. doi: 10.1128/JCM.06314-11. Epub 2011 Nov 23. — View Citation
Peloquin CA, Nitta AT, Burman WJ, Brudney KF, Miranda-Massari JR, McGuinness ME, Berning SE, Gerena GT. Low antituberculosis drug concentrations in patients with AIDS. Ann Pharmacother. 1996 Sep;30(9):919-25. — View Citation
Shenoi S, Heysell S, Moll A, Friedland G. Multidrug-resistant and extensively drug-resistant tuberculosis: consequences for the global HIV community. Curr Opin Infect Dis. 2009 Feb;22(1):11-7. doi: 10.1097/QCO.0b013e3283210020. Review. — View Citation
Swaminathan S, Rekha B. Pediatric tuberculosis: global overview and challenges. Clin Infect Dis. 2010 May 15;50 Suppl 3:S184-94. doi: 10.1086/651490. Review. — View Citation
Zhdanova S, Heysell SK, Ogarkov O, Boyarinova G, Alexeeva G, Pholwat S, Zorkaltseva E, Houpt ER, Savilov E. Primary multidrug-resistant Mycobacterium tuberculosis in 2 regions, Eastern Siberia, Russian Federation. Emerg Infect Dis. 2013 Oct;19(10):1649-52. doi: 10.3201/eid1910.121108. — View Citation
* Note: There are 11 references in all — Click here to view all references
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | TB drug-susceptibility testing | For subjects suspected of TB, sputum samples or other leftover sputum/blood specimens will be screened by GeneXpert and if positive, cultured for TB and the cultured specimen subjected to drug-susceptibility testing by conventional qualitative resistance and minimum inhibitory concentration (MIC), sequencing for drug-resistance mutation and spoligotyping for sublineage identification. Primary analysis will include standard sensitivity/specificity of each drug-mutation compared to conventional qualitative resistance and then median/range MIC values among isolates with/without mutation for improved discrimination. | The participants will be followed for the duration of hospital stay, an expected average of 12 weeks. | No |
Secondary | The proportion of patients below the expected Cmax range | For subjects ultimately initiating TB treatment, the pharmacokinetic parameters to be tested against the MIC for each TB drug in the patient's regimen include peak (Cmax) and area under the concentration-time curve (AUC). Parameters will be compared to the expected ranges for each drug and expressed as both a population value and at the individual level (proportion of patients below the expected range for each drug). | The participants will be followed for the duration of hospital stay, an expected average of 12 weeks. | No |
Secondary | The proportion of patients below the expected AUC range | For subjects ultimately initiating TB treatment, the pharmacokinetic parameters to be tested against the MIC for each TB drug in the patient's regimen include peak (Cmax) and area under the concentration-time curve (AUC). Parameters will be compared to the expected ranges for each drug and expressed as both a population value and at the individual level (proportion of patients below the expected range for each drug). | The participants will be followed for the duration of hospital stay, an expected average of 12 weeks. | No |
Secondary | Correlation of Cmax with the primary outcome | For subjects ultimately initiating TB treatment, the pharmacokinetic parameters to be tested against the MIC for each TB drug in the patient's regimen include peak (Cmax) and area under the concentration-time curve (AUC). Parameters will be compared to the expected ranges for each drug and expressed as both a population value and at the individual level (proportion of patients below the expected range for each drug). | The participants will be followed for the duration of hospital stay, an expected average of 12 weeks. | No |
Secondary | Correlation of AUC with the primary outcome | For subjects ultimately initiating TB treatment, the pharmacokinetic parameters to be tested against the MIC for each TB drug in the patient's regimen include peak (Cmax) and area under the concentration-time curve (AUC). Parameters will be compared to the expected ranges for each drug and expressed as both a population value and at the individual level (proportion of patients below the expected range for each drug). | The participants will be followed for the duration of hospital stay, an expected average of 12 weeks. | No |
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