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Impact of Cotrimoxazole Use in Immunocompetent HIV Patients on Carriage of Antimicrobial Resistant Bacteria (CoTrimResist)

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ClinicalTrials.gov Identifier: NCT03087890
Recruitment Status : Recruiting
First Posted : March 23, 2017
Last Update Posted : April 5, 2018
Sponsor:
Collaborators:
Haukeland University Hospital
Muhimbili University of Health and Allied Sciences
Helse Vest
Information provided by (Responsible Party):
University of Bergen

Brief Summary:
Cotrimoxazole preventive therapy (CPT) is recommended for prevention of morbidity and mortality due to Pneumocystis pneumonia and other infections in HIV positive patients with low immunity. Common clinical practice is to start CPT in any patient with CD4 counts below 200/µL, and, conversely, to stop CPT when immunity has been restored by antiretroviral treatment to CD4 counts above 200/µL or when viral suppression has been documented for 3 months. However, the latest WHO guidelines widely expands the indication for CPT by advocating for settings with high prevalence of malaria and bacterial infections, that all patients with HIV start CPT regardless of CD4 counts and clinical stage. Furthermore, WHO recommends these patients to continue CPT indefinitely regardless of evidence of immune restoration (The recommendation is for settings with high prevalence of malaria and bacterial infections, not for high-income countries). There is limited scientific evidence to recommend prolonged CPT, as studies have shown it is associated with modestly reduced morbidity due to pneumonia, meningitis and malaria, but no corresponding reduction in mortality. The impact of such a large increase in antibiotic use on the emergence of antimicrobial resistance has not been thoroughly considered. Our previous studies in Tanzania showed that multidrug-resistant bacteria frequently cause bloodstream infections with resultant very high case-fatality rates. As genes encoding for multiple antibiotic resistance traits are transferred by plasmids together with resistance towards cotrimoxazole, prolonged CPT will likely favor the selection of carriage of multidrug-resistant gut bacteria. The proposed randomized clinical trial is designed to assess whether prolonged CPT in HIV-positive patients results in increased fecal carriage of multi-drug resistant gut microbes or increased nasal carriage of methicillin-resistant Staphylococcus aureus (MRSA). Secondary endpoints are morbidity (clinical events, hospitalizations) and mortality. Stool specimens, nasal swabs and clinical data will be collected from persons attending voluntary counseling and testing facilities and HIV-clinics in Dar es Salaam, Tanzania. The study results may have important impact on public health in terms of assisting development of rational recommendations for CPT use, and may help prevent emerging antibiotic resistance.

Condition or disease Intervention/treatment Phase
HIV-1-infection Pneumocystis Pneumonia Opportunistic Infections Preventive Therapy Antibiotic Side Effect Drug: Cotrimoxazole Drug: Placebo Phase 4

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 500 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Patients with newly diagnosed hiv-1 infection and good immunological status defined as CD4 counts of >350 pr microliter, will be randomised to receive cotrimoxazole (160mg/800mg) daily or placebo for 48 weeks. Rectal and nasal swabs will be collected on day 0, 14, week 24 and week 48. The swabs will be analysed for the presence of bacterial species with focus on certain multidrug-resistant bacteria such as ESBL (extended spectrum beta-lactamase)-producing Gram negative bacteria, MRSA (methicillin-resistant Staphylococcus aureus) and VRE (Vancomycin-resistant enterococci). Patients will also be monitored closely on monthly visits to assess for any adverse events.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Patients in one study arm will receive 2 tablets daily of Cotrimoxazole (trimethoprim 80mg + sulfamethoxazole 400mg), these tablets are purchased locally in Tanzania, and are the same as used for pneumocystis preventive therapy under the National AIDS control programme. Participants in arm 2 will receive 2 placebo tablets daily. These tablets have been manufactured by Kragero Tablettproduksjon AS, Norway, and care has been taken to make them look as similar as possible to the locally purchased cotrimoxazole tablets from Tanzania. Neither study participants, care providers, investigators or outcome assessors will know which patients receive cotrimoxazole or placebo
Primary Purpose: Prevention
Official Title: Randomized Clinical Trial to Assess Whether the Duration of Cotrimoxazole Preventive Therapy in HIV Patients With CD4 Counts >350 CD4 Cells/µL by Antiretroviral Treatment Influences the Rate of Carriage of Multidrug-resistant Bacteria
Actual Study Start Date : March 30, 2017
Estimated Primary Completion Date : October 30, 2018
Estimated Study Completion Date : October 30, 2018


Arm Intervention/treatment
Active Comparator: Cotrimoxazole
Patients in the Cotrimoxazole study arm will receive 2 tablets daily of Cotrimoxazole (trimethoprim 80mg + sulfamethoxazole 400mg), these tablets are purchased locally in Tanzania, and are the same as used for pneumocystis preventive therapy under the National AIDS control programme.
Drug: Cotrimoxazole
Patients will receive preventive treatment with 2 tablets cotrimoxazole (80 mg trimethoprim, 400mg sulfamethoxazole) daily for 48 weeks
Other Name: Trimethoprim - sulfamethoxazole

Placebo Comparator: Placebo
Participants in the Placebo arm will receive 2 placebo tablets daily. These tablets have been manufactured by Kragero Tablettproduksjon AS, Norway, and care has been taken to make them look as similar as possible to the locally purchased cotrimoxazole tablets from Tanzania. Neither study participants, care providers, investigators or outcome assessors will know which patients receive cotrimoxazole or placebo
Drug: Placebo
Patients will receive 2 tablets placebo daily for 48 weeks
Other Name: Placebo tablet with no active drug




Primary Outcome Measures :
  1. Change in carriage of resistant bacteria in gut and/or nose by week 2 [ Time Frame: From baseline to day 14 ]
    Change in the proportion who carry antibiotic-resistant bacteria, including presence of extended-spectrum beta-lactamase (ESBL) producing gram-negative bacteria or vancomycin-resistant enterococci (VRE) on microbiological examination of fecal swab, or methicillin-resistant Staphylococcus aureus (MRSA) on microbiological examination of nasal swab, from baseline to day 14

  2. Change in carriage of resistant bacteria in gut and/or nose by week 24 [ Time Frame: From baseline to week 24 ]
    Change in the proportion who carry antibiotic-resistant bacteria, including presence of extended-spectrum beta-lactamase (ESBL) producing gram-negative bacteria or vancomycin-resistant enterococci (VRE) on microbiological examination of fecal swab, or methicillin-resistant Staphylococcus aureus (MRSA) on microbiological examination of nasal swab, from baseline to week 24

  3. Change in carriage of resistant bacteria in gut and/or nose by week 48 [ Time Frame: From baseline to week 48 ]
    Change in the proportion who carry antibiotic-resistant bacteria, including presence of extended-spectrum beta-lactamase (ESBL) producing gram-negative bacteria or vancomycin-resistant enterococci (VRE) on microbiological examination of fecal swab, or methicillin-resistant Staphylococcus aureus (MRSA) on microbiological examination of nasal swab, from baseline to week 48


Secondary Outcome Measures :
  1. Adverse events [ Time Frame: From baseline to 48 weeks ]
    Adverse events graded as a) light, b) moderate, c) severe, d) life-threatening or e) fatal will be registered through patients' monthly visits to clinic and additional follow-up as required

  2. Mortality [ Time Frame: From baseline to 48 weeks ]
    All cause mortality

  3. Morbidity [ Time Frame: From baseline to 48 weeks ]
    Documented episode of malaria, pneumonia, diarrhea and hospital admission


Other Outcome Measures:
  1. Difference in carriage of resistant bacteria in gut and/or nose between HIV positive patients and HIV negative controls [ Time Frame: At baseline ]
    Difference in the proportion who carry antibiotic-resistant bacteria, including presence of extended-spectrum beta-lactamase (ESBL) producing gram-negative bacteria or vancomycin-resistant enterococci (VRE) on microbiological examination of fecal swab, or methicillin-resistant Staphylococcus aureus (MRSA) on microbiological examination of nasal swab, between HIV positive patients and HIV negative controls

  2. Difference in carriage of resistant bacteria in gut and/or nose between HIV positive patients with CD4 counts above and below 350 [ Time Frame: At baseline ]
    Difference in the proportion who carry antibiotic-resistant bacteria, including presence of extended-spectrum beta-lactamase (ESBL) producing gram-negative bacteria or vancomycin-resistant enterococci (VRE) on microbiological examination of fecal swab, or methicillin-resistant Staphylococcus aureus (MRSA) on microbiological examination of nasal swab, between HIV positive patients with CD4 counts above and below 350



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Only patients who provide written informed consent will be included
  • Patients aged 18 years or older with newly diagnosed HIV-infection and CD4 counts of ≥ 350 per microliter will be included for randomisation to receive placebo or cotrimoxazole preventive treatment.
  • Persons testing hiv negative at the participating clinics will be included as additional control group but not randomised to interventions
  • Persons testing hiv-positive and having impaired immunity with CD4 count below will be included as additional control group but not randomised for intervention. This group will routinely receive cotrimoxazole prophylaxis from the national AIDS control program, and not followed-up further in this study.

Exclusion Criteria:

  • CD4<350 per microliter at enrollment
  • Patients allergic to cotrimoxazole
  • Children under age of 18 years
  • Pregnant women

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03087890


Contacts
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Contact: Bjorn Blomberg, MD, PhD +4793262119 bjorn.blomberg@uib.no
Contact: Nina Langeland, MD, PhD +4755582087 nina.langeland@uib.no

Locations
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Tanzania
Amana Regional Referral Hospital Recruiting
Dar es Salaam, Tanzania
Contact: Joel Manyahi, MD    +255712251709    manyahijoel@yahoo.com   
Contact: Bjorn Blomberg, MD, PhD    +4793262119    bjorn.blomberg@uib.no   
Mbagala District Hospital Recruiting
Dar es Salaam, Tanzania
Contact: Joel Manyahi, MD    +255712251709    manyahijoel@yahoo.com   
Contact: Bjorn Blomberg, MD, PhD    +4793262119    bjorn.blomberg@uib.no   
Mnazimmoja Health Centre Recruiting
Dar Es Salaam, Tanzania
Contact: Joel Manyahi, MD    +255712251709    manyahijoel@yahoo.com   
Contact: Bjorn Blomberg, MD, PhD    +4793262119    bjorn.blomberg@uib.no   
Mwananyamala Regional Referral Hospital Recruiting
Dar es Salaam, Tanzania
Contact: Joel Manyahi, MD    +255712251709    manyahijoel@yahoo.com   
Contact: Bjorn Blomberg, MD, PhD    +4793262119    bjorn.blomberg@uib.no   
Pasada Upendano Recruiting
Dar es Salaam, Tanzania
Contact: Joel Myanyahi, MD    +255712251709    manyahijoel@yahoo.com   
Contact: Bjørn Blomberg, MD, PhD    +4793262119    bjorn.blomberg@uib.no   
Temeke Regional Referral Hospital Recruiting
Dar es Salaam, Tanzania
Contact: Joel Manyahi, MD    +255712251709    manyahijoel@yahoo.com   
Contact: Bjorn Blomberg, MD, PhD    +4793262119    bjorn.blomberg@uib.no   
Sponsors and Collaborators
University of Bergen
Haukeland University Hospital
Muhimbili University of Health and Allied Sciences
Helse Vest
Investigators
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Principal Investigator: Joel Manyahi, MD Muhimbili University of Health and Allied Sciences

Additional Information:
Publications:

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Responsible Party: University of Bergen
ClinicalTrials.gov Identifier: NCT03087890     History of Changes
Other Study ID Numbers: REK2015/540
TZ16CT007 ( Other Identifier: Tanzania Food and Drugs Authority )
NIMRlHQ/R.SaJVol. 1X12144 ( Other Identifier: National Institute for Medical Research, Tanzania )
2015-10-27/AEC/Vol.X/54 ( Other Identifier: Muhimbili University of Health and Allied Sciences )
REK2015/540 ( Other Identifier: Regional Committee for Medical Ethics, Western Norway )
First Posted: March 23, 2017    Key Record Dates
Last Update Posted: April 5, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: There are currently no plans for sharing data with other researchers.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by University of Bergen:
Microbial drug resistance
Beta-lactamase
Cotrimoxazole
Trimethoprim-sulfamethoxazole
Tanzania

Additional relevant MeSH terms:
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Trimethoprim, Sulfamethoxazole Drug Combination
Anti-Infective Agents, Urinary
Anti-Infective Agents
Renal Agents
Antiprotozoal Agents
Antiparasitic Agents
Anti-Dyskinesia Agents
Anti-Bacterial Agents
Infection
Communicable Diseases
Pneumonia, Pneumocystis
Opportunistic Infections
Pneumonia
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Lung Diseases, Fungal
Mycoses
Pneumocystis Infections
Virus Diseases
Parasitic Diseases
Trimethoprim
Sulfamethoxazole
Antimalarials
Folic Acid Antagonists
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP2C8 Inhibitors
Cytochrome P-450 Enzyme Inhibitors