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. Study protocol

Abstract

Cotrimoxazole preventive therapy (CPT) is recommended for prevention of morbidity and mortality due to Pneumocystis jirovecii pneumonia (PJP) and other infections in HIV positive patients with low immunity. In industrial countries, it is recommended start CPT in any patient with CD4 counts below 200/μL, and, conversely, to stop CPT when immunity is 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 that CPT be started at a higher threshold, i.e. for any patient with CD4 count below 350/μL, as well as for patients with clinical stage 3 or 4. In the setting with high prevalence of malaria and bacterial infections, it is recommended that all patients with HIV start CPT regardless of CD4 counts and clinical stage. Conversely, WHO recommends continued CPT until the patient is virologically and immunologically stable with CD4 counts above 350/μL, and indefinitely prolonged CPT in settings with high prevalence of malaria and bacterial infections. 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 multidrugresistant gut bacteria. The proposed randomized clinical trial (RCT) 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 (VCT) 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.