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

NCT03087890 | Completed Phase 4 DMC

• 4 other identifiers: REK2015/540TZ16CT007NIMRlHQ/R.SaJVol. 1X121442015-10-27/AEC/Vol.X/54
• Study Type: interventional
• Target: 537
• Locations: 1 country
• Sites: 6

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.

Conditions

HIV-1-infection; Pneumocystis Pneumonia; Opportunistic Infections; Preventive Therapy; Antibiotic Side Effect

Keywords

Microbial drug resistance; Beta-lactamase; Cotrimoxazole; Trimethoprim-sulfamethoxazole; Tanzania

Outcome Measures

Primary Outcomes (3)

• Change in carriage of resistant bacteria in gut and/or nose by week 2

  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

  From baseline to day 14

• Change in carriage of resistant bacteria in gut and/or nose by 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

  From baseline to week 24

• Change in carriage of resistant bacteria in gut and/or nose by 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

  From baseline to week 48

Secondary Outcomes (3)

• Adverse events

  From baseline to 48 weeks

• Mortality

  From baseline to 48 weeks

• Morbidity

  From baseline to 48 weeks

Other Outcomes (2)

• Difference in carriage of resistant bacteria in gut and/or nose between HIV positive patients and HIV negative controls

  At baseline

• Difference in carriage of resistant bacteria in gut and/or nose between HIV positive patients with CD4 counts above and below 350

  At baseline

Study Arms (2)

Cotrimoxazole

ACTIVE COMPARATOR

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Cotrimoxazole DRUG

Patients will receive preventive treatment with 2 tablets cotrimoxazole (80 mg trimethoprim, 400mg sulfamethoxazole) daily for 48 weeks

Also known as: Trimethoprim - sulfamethoxazole

Cotrimoxazole

Placebo DRUG

Patients will receive 2 tablets placebo daily for 48 weeks

Also known as: Placebo tablet with no active drug

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

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

Sponsors & Collaborators

• University of Bergen: lead
• Haukeland University Hospital: collaborator
• Muhimbili University of Health and Allied Sciences: collaborator
• Helse Vest: collaborator

Study Sites (6)

Amana Regional Referral Hospital

Dar es Salaam, Tanzania

Location

Mbagala District Hospital

Dar es Salaam, Tanzania

Location

Mnazimmoja Health Centre

Dar es Salaam, Tanzania

Location

Mwananyamala Regional Referral Hospital

Dar es Salaam, Tanzania

Location

Pasada Upendano

Dar es Salaam, Tanzania

Location

Temeke Regional Referral Hospital

Dar es Salaam, Tanzania

Location

Related Publications (17)

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  PMID: 36803640 DERIVED

• Manyahi J, Moyo SJ, Aboud S, Langeland N, Blomberg B. Predominance of PVL-negative community-associated methicillin-resistant Staphylococcus aureus sequence type 8 in newly diagnosed HIV-infected adults, Tanzania. Eur J Clin Microbiol Infect Dis. 2021 Jul;40(7):1477-1485. doi: 10.1007/s10096-021-04160-2. Epub 2021 Feb 14.

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  PMID: 32653726 DERIVED

MeSH Terms

Conditions

Pneumonia, Pneumocystis; Opportunistic Infections

Interventions

Trimethoprim, Sulfamethoxazole Drug Combination

Condition Hierarchy (Ancestors)

Lung Diseases, Fungal; Mycoses; Bacterial Infections and Mycoses; Infections; Pneumocystis Infections; Respiratory Tract Infections; Pneumonia; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Sulfamethoxazole; Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Sulfanilamides; Aniline Compounds; Amines; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Trimethoprim; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Study Officials

• Joel Manyahi, MD

  Muhimbili University of Health and Allied Sciences

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: March 8, 2017
• First Posted: March 23, 2017
• Study Start: March 30, 2017
• Primary Completion: July 25, 2019
• Study Completion: July 25, 2019
• Last Updated: October 2, 2019

Record last verified: 2019-10

Locations

TA (6)