title: TSCQ study: a randomized, controlled, open-label trial of daily trimethoprim-sulfamethoxazole or weekly chloroquine among adults on antiretroviral therapy in Malawi: study protocol for a randomized controlled trial.
abstract: Before antiretroviral therapy (ART) became widely available in sub-Saharan Africa, several studies demonstrated that daily trimethoprim-sulfamethoxazole (TS) prophylaxis reduced morbidity and mortality among HIV-infected adults. As a result, the World Health Organization (WHO) recommended administering TS prophylaxis to this group. However, the applicability of the results to individuals taking ART and living in sub-Saharan Africa has not been definitively evaluated. This study aims to determine if TS prophylaxis benefits HIV-infected Malawian adults after a good response to ART. If TS prophylaxis does indeed show benefit, it is important to determine if this is due to its antibacterial and/or antimalarial properties.
  
  
  
  A randomized, controlled, open-label, phase III trial of continued standard of care prophylaxis with daily trimethoprim-sulfamethoxazole (TS) compared to discontinuation of standard of care TS prophylaxis and starting weekly chloroquine (CQ) prophylaxis or discontinuation of standard of care TS prophylaxis. The study will randomize 1400-1500 HIV-infected adults (equally divided over the three study arms) with a nondetectable viral load and a CD4 count of 250/mm(3) or more from antiretroviral therapy clinics in Blantyre and Zomba. The expected rate of primary endpoint events of death and WHO stage 3 and 4 events is 6.8 per 100 person-years of follow-up in all participants. Assuming the number of events follows a Poisson distribution and average participant follow-up after 10 % loss to follow-up is 41.6 months, the study will have approximately 85 % power to rule out a reduction of 35 % or more in primary endpoint events in the TS or CQ arms compared to discontinuation of TS prophylaxis-i.e., to show that discontinuation of TS prophylaxis is noninferior to either TS or CQ, with a noninferiority margin of 35 %. Ethical and regulatory approvals were obtained from the University of Malawi College of Medicine Research Ethics Committee; the Malawi Pharmacy, Medicines and Poisons Board; and the University of Maryland Baltimore Institutional Review Board.
  
  
  
  The study began recruitment activities at the Ndirande site in November 2012. The sponsor agreed to extend and expand the study in early 2015, and a second site, Zomba, was added for recruitment and follow-up in mid-2015.
  
  
  
  ClinicalTrials.gov Identifier: NCT01650558 (registered on 6 July 2012).
  
  
  
  Letter of amendment #1 to the DAIDS-ES 10822 TSCQ Malawi Protocol, Version 4.0, 16 December 2014.
authors.affiliation: Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, 480 W Baltimore St, Room 480, Baltimore, MD, 21218, USA. mlaurens@medicine.umaryland.edu.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Laurens
authors.affiliation: Blantyre Malaria Project, Blantyre, Malawi.
authors.forename: Randy G
authors.initials: RG
authors.lastname: Mungwira
authors.affiliation: Blantyre Malaria Project, Blantyre, Malawi.
authors.forename: Osward M
authors.initials: OM
authors.lastname: Nyirenda
authors.affiliation: Blantyre Malaria Project, Blantyre, Malawi.
authors.forename: Titus H
authors.initials: TH
authors.lastname: Divala
authors.affiliation: Blantyre Malaria Project, Blantyre, Malawi.
authors.forename: Maxwell
authors.initials: M
authors.lastname: Kanjala
authors.affiliation: Blantyre Malaria Project, Blantyre, Malawi.
authors.forename: Francis
authors.initials: F
authors.lastname: Muwalo
authors.affiliation: Blantyre Malaria Project, Blantyre, Malawi.
authors.forename: Felix A
authors.initials: FA
authors.lastname: Mkandawire
authors.affiliation: Blantyre Malaria Project, Blantyre, Malawi.
authors.forename: Lufina
authors.initials: L
authors.lastname: Tsirizani
authors.affiliation: Dignitas International, Zomba, Malawi.
authors.forename: Wongani
authors.initials: W
authors.lastname: Nyangulu
authors.affiliation: Dignitas International, Zomba, Malawi.
authors.forename: Edson
authors.initials: E
authors.lastname: Mwinjiwa
authors.affiliation: Blantyre Malaria Project, Blantyre, Malawi.|College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA.
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Taylor
authors.affiliation: University of Malawi College of Medicine, Blantyre, Malawi.
authors.forename: Jane
authors.initials: J
authors.lastname: Mallewa
authors.affiliation: Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Blackwelder
authors.affiliation: Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, 480 W Baltimore St, Room 480, Baltimore, MD, 21218, USA.
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Plowe
authors.affiliation: Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, 480 W Baltimore St, Room 480, Baltimore, MD, 21218, USA.
authors.forename: Miriam K
authors.initials: MK
authors.lastname: Laufer
authors.affiliation: Dignitas International, Zomba, Malawi.|University of Malawi College of Medicine, Blantyre, Malawi.
authors.forename: Joep J
authors.initials: JJ
authors.lastname: van Oosterhout
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000382:microbiology / Q000401:mortality / Q000469:parasitology / Q000517:prevention & control*; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects; D044966:Anti-Retroviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000962:Antimalarials / Q000008:administration & dosage* / Q000009:adverse effects; D002738:Chloroquine / Q000008:administration & dosage* / Q000009:adverse effects; D004334:Drug Administration Schedule; D015658:HIV Infections / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D006801:Humans; D008288:Malaria / Q000401:mortality / Q000469:parasitology / Q000517:prevention & control*; D008295:Malawi; D011020:Pneumonia, Pneumocystis / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control*; D013997:Time Factors; D016896:Treatment Outcome; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000900:Anti-Bacterial Agents; D044966:Anti-Retroviral Agents; D000962:Antimalarials; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D002738:Chloroquine
keywords: Adult; Africa; Antiretroviral therapy; Chloroquine; HIV infection; Immunosuppression; Longitudinal studies; Malaria; Malawi; Parasitemia; Plasmodium falciparum; Trimethoprim-sulfamethoxazole