Daily Trimethoprim-sulfamethoxazole or Weekly Chloroquine Among Adults on ART in Malawi (TSCQ)

Randomized, Open-label Controlled Trial of Daily Trimethoprim-sulfamethoxazole or Weekly Chloroquine Among Adults on Anti-retroviral Therapy in Malawi

The purpose of this study is to determine if there is a benefit to taking trimethoprim-sulfamethoxazole (TS) as prophylaxis among HIV positive adults who have viral load suppression and a good clinical response on anti-retroviral therapy (ART). If there is a benefit, then is it due to antimalarial or antibacterial properties.

The investigators hypothesize that there will be a long-term benefit on survival and disease control in the context of prophylaxis and that the benefit will largely be attributed to prevention of malaria. The main study hypothesis is that 1)TS and chloroquine (CQ) will decrease the rates of morbidity and mortality among adults after 6 or more months of ART and 2) CQ prophylaxis will be associated with more prolonged viral suppression and higher CD4 cell counts than TS prophylaxis or no prophylaxis.

Study Overview

• Status: Completed
• Conditions: HIV
• Intervention / Treatment: Drug: Standard of Care prophylaxis; Drug: Chloroquine (CQ) prophylaxis

Detailed Description

This is a randomized, controlled, open-label, phase III trial of standard of care TS prophylaxis and CQ prophylaxis compared to no prophylaxis in adults receiving ART. Adults who have been receiving ART for at least six months with a good clinical response and provide informed consent and fulfill the eligibility criteria will be randomized to one of three arms: (1) to continue standard of care trimethoprim-sulfamethoxazole (TS) prophylaxis, (2) discontinue standard of care TS prophylaxis and begin weekly CQ prophylaxis or (3) discontinue standard of care TS prophylaxis. Participants will be asked to return to the research clinic every four weeks for the first 24 weeks then every 12 weeks thereafter, and any time they are ill to facilitate both active and passive follow-up of the study endpoints. Participation will last for 32 to approximately 66 months. Participants who develop a WHO clinical stage 3 or 4 illness, experience a sustained decline in their CD4 count below 200 cells/mm3, or who experience ART failure will be placed on standard of care TS prophylaxis. Those with confirmed ART failure will be evaluated for second-line therapy according to the Malawi Ministry of Health guidelines.

The study population will include up to 1500 Malawian adults aged 18 years or older living with HIV in or near Blantyre or Zomba, Malawi, Central Africa who have been receiving antiretroviral therapy for at least 6 months with good clinical response to ART, have an undetectable HIV viral load and a CD4 count >250/mm3.

• Study Type: Interventional
• Enrollment (Actual): 1499
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Malawi
  • Blantyre, Malawi
    • Blantyre Malaria Project Research Clinic
  • Zomba, Malawi
    • Tisungane Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18 years or older
• Documented HIV-1 infection
• Initiation of ART through a government-sponsored ART program at least six months prior
• Undetectable HIV viral load (< 400 copies/mL)
• CD4 count > 250/mm3
• TS prophylaxis prescribed for at least the previous 2 months
• Intention to remain in the study area until the end of the study period
• Informed consent from participant
• Female study volunteers of reproductive potential must have a negative urine pregnancy test performed within 20 days before randomization.
• Female study volunteers of reproductive potential who participate in sexual activity that could lead to pregnancy must use contraception (male or female condoms, diaphragm or cervical cap with spermicide, intrauterine device, or hormone-based contraceptive) while receiving their assigned study drug and for one month after stopping the medications.

Exclusion Criteria:

• Severe acute illness (defined as requiring hospitalization at the time of screening or other conditions such as laboratory abnormalities as determined by the investigators)
• Chronic treatment (requiring therapy for > 14 days) or secondary prophylaxis (for toxoplasmosis, Pneumocystis pneumonia, or tuberculosis for example) with any drug with antimalarial or antibacterial activity
• History of hypersensitivity to antifolate drugs or CQ
• Laboratory exclusion criteria
• Hemoglobin < 8.0 gm/dL
• Platelet count < 50,000/mm3
• Absolute granulocyte count < 500/mm3
• Serum alanine aminotransferase (ALT) concentration > 210 U/L for men, >160 U/L for women
• Serum creatinine concentration > 3.3mg/dl (291.7µmol/L) for men, and > 2.7mg/dl (238.7µmol/L) for women)
• History of visual field or retinal changes
• History of preexisting auditory damage
• History of porphyria
• History of psoriasis
• History of liver disease
• History of seizure disorder
• History of glucose-6-phosphate dehydrogenase (G6PD) deficiency
• History of ECG and cardiac conduction abnormality or cardiomyopathy
• History of myopathy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of Care Prophylaxis (TS); Standard of care prophylaxis with daily trimethoprim sulfamethoxazole (TS).	Drug: Standard of Care prophylaxis; Daily trimethoprim sulfamethoxazole; Other Names: Co-trimoxazole; Bactrim
Experimental: Chloroquine (CQ) prophylaxis; Discontinuation of standard of care TS prophylaxis and starting weekly chloroquine prophylaxis	Drug: Chloroquine (CQ) prophylaxis; Discontinue standard of care and start weekly CQ.; Other Names: Aralen
No Intervention: Discontinuation of standard of care; Control arm - Discontinuation of standard of care trimethoprim sulfamethoxazole.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severe Events	Incidence of severe events (composite of death and WHO stage 3 and 4 illness)	22-66 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With at Least One Detectable HIV Viral Load	Number of participants who ever have a detectable viral load (>400 copies/ml).	Throughout study participation, measured every six months (2-5.5 years).
CD4 Cell Count	Number of Participants with at Least One CD4 Count <200	Every 6 months for 22-66 months
WHO HIV Stage 2, 3, 4 Illness	Incidence of any WHO HIV stage 2, 3, or 4 illness	32-66 months
Bacterial Infections and Malaria	Incidence of bacterial infections and malaria	32-66 months
Adverse Events Greater Than or Equal to Grade 3 That Are Related to the Study Product	Occurrence of adverse events that are greater than or equal to Grade 3 that require discontinuation of TS or CQ prophylaxis	32-66 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bacterial or Malaria Infection With CQ or TS Resistant Organism	Occurrence of bacterial or malaria infection with CQ or TS resistant organism	32-66 months
Clinical and Parasitological Response to Antimalarial Therapy	Clinical and parasitological response to antimalarial therapy in cases of uncomplicated malaria	32-66 months

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Miriam K Laufer, MD, MPH, University of Maryland, Baltimore

Publications and helpful links

General Publications

• Laurens MB, Mungwira RG, Nampota N, Nyirenda OM, Divala TH, Kanjala M, Mkandawire FA, Galileya LT, Nyangulu W, Mwinjiwa E, Downs M, Tillman A, Taylor TE, Mallewa J, Plowe CV, van Oosterhout JJ, Laufer MK. Revisiting Co-trimoxazole Prophylaxis for African Adults in the Era of Antiretroviral Therapy: A Randomized Controlled Clinical Trial. Clin Infect Dis. 2021 Sep 15;73(6):1058-1065. doi: 10.1093/cid/ciab252.
• Mungwira RG, Laurens MB, Nyangulu W, Divala TH, Nampota-Nkomba N, Buchwald AG, Nyirenda OM, Mwinjiwa E, Kanjala M, Galileya LT, Earland DE, Adams M, Plowe CV, Taylor TE, Mallewa J, van Oosterhout JJ, Laufer MK; TSCQ Study Team. High burden of malaria among Malawian adults on antiretroviral therapy after discontinuing prophylaxis. AIDS. 2022 Oct 1;36(12):1675-1682. doi: 10.1097/QAD.0000000000003317. Epub 2022 Jul 15.
• Laurens MB, Mungwira RG, Nyirenda OM, Divala TH, Kanjala M, Muwalo F, Mkandawire FA, Tsirizani L, Nyangulu W, Mwinjiwa E, Taylor TE, Mallewa J, Blackwelder WC, Plowe CV, Laufer MK, van Oosterhout JJ. 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. Trials. 2016 Jul 18;17(1):322. doi: 10.1186/s13063-016-1392-3.

Study record dates

Study Major Dates

• Study Start: November 1, 2012
• Primary Completion (Actual): July 31, 2018
• Study Completion (Actual): July 31, 2018

Study Registration Dates

• First Submitted: July 6, 2012
• First Submitted That Met QC Criteria: July 23, 2012
• First Posted (Estimate): July 26, 2012

Study Record Updates

• Last Update Posted (Actual): July 28, 2022
• Last Update Submitted That Met QC Criteria: July 26, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: HIV; Malaria; Prophylaxis; Antiretroviral therapy
• Additional Relevant MeSH Terms: Anti-Infective Agents; Antirheumatic Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Amebicides; Anti-Infective Agents, Urinary; Renal Agents; Chloroquine; Trimethoprim, Sulfamethoxazole Drug Combination
• Other Study ID Numbers: HP-00043360; DAIDS ES-10822; U01AI089342-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO