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

Study Status: Not yet recruiting
Recruit Status: Not yet recruiting
Study Type: Interventional

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 o

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 (clinic

Detailed Summary:

Background Bacterial infections account for a large proportion of global morbidity and mortality. While antimicrobial drugs have helped save millions from the consequences of these infections, emerging antimicrobial resistance now threatens to reverse those gains. The HIV-epidemic renders large populations drastically more susceptible to bacterial infections, particularly in Sub-Saharan Africa, where HIV is rampant and health-systems to deal with the consequences are insufficient. Indiscriminate use of antimicrobials is thought to be the main driving force behind emerging resistance. The opportunistic infection Pneumocystis jirovecii pneumonia (PJP) is a major cause of mortality among HIV-infected people with low immunity. Continuous cotrimoxazole preventive therapy (CPT) has proved to reduce morbidity and mortality from PJP globally, as well as in Africa where the burden of HIV is largest [Anglaret 1999, Mermin 2004]. The impact of this large-scale antibiotic use on emergence of antimicrobial resistance in Africa remains unclear. In a recent literature review, Sibanda and colleagues [Sibanda 2011] found only two studies specifically designed to answer the question of whether CPT induced resistance in common bacterial pathogens [Hamel 2008, Gill 2008], and 15 other studies that assessed the question as sub-analyses of studies designed for other purposes. The two targeted studies both assessed resistance in pneumococci, one finding increased resistance to clindamycin in the CPT group [Gill 2008], neither finding any difference in resistance to penicillin. While most of the other 15 studies assessed penicillin-resistance in pneumococci and methicillin-resistance in Staphylococcus aureus (MRSA), only two studies evaluated the effect on Gram-negative bacteria [Martin 1999, Dar 2003]. Among these, the study from San Francisco [Martin 1999] showed significantly higher temporal increase from 1988 to 1995 in resistance to cotrim
Sponsor: University of Bergen

Current Primary Outcome:

  • 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
  • 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
  • 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


Original Primary Outcome: Same as current

Current Secondary Outcome: 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


Original Secondary Outcome: Same as current

Information By: University of Bergen

Dates:
Date Received: March 8, 2017
Date Started: March 30, 2017
Date Completion: September 30, 2018
Last Updated: March 17, 2017
Last Verified: March 2017