Clinical trial NCT01650558: Daily Trimethoprim-sulfamethoxazole or Weekly Chloroquine Among Adults on ART in Malawi
Official title: Randomized, Open-label Controlled Trial of Daily Trimethoprim-sulfamethoxazole or Weekly Chloroquine Among Adults on Anti-retroviral Therapy in Malawi
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: HIV
Keywords: Malaria
HIV
Prophylaxis
Antiretroviral therapy
Lead sponsor: University of Maryland, Baltimore
Sponsor class: OTHER
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2012-07-26
Enrollment: 1499
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: PREVENTION

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Severe Events
timeFrame: 22-66 months
Secondary outcomes:
measure: Number of Participants With at Least One Detectable HIV Viral Load
timeFrame: Throughout study participation, measured every six months (2-5.5 years).
measure: CD4 Cell Count
timeFrame: Every 6 months for 22-66 months
measure: WHO HIV Stage 2, 3, 4 Illness
timeFrame: 32-66 months
measure: Bacterial Infections and Malaria
timeFrame: 32-66 months
measure: Adverse Events Greater Than or Equal to Grade 3 That Are Related to the Study Product
timeFrame: 32-66 months
Other outcomes:
measure: Bacterial or Malaria Infection With CQ or TS Resistant Organism
timeFrame: 32-66 months
measure: Clinical and Parasitological Response to Antimalarial Therapy
timeFrame: 32-66 months
Locations:
city: Blantyre
country: Malawi
facility: Blantyre Malaria Project Research Clinic
city: Zomba
country: Malawi
facility: Tisungane Clinic
Study officials:
affiliation: University of Maryland, Baltimore
name: Miriam K Laufer, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.