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

Study Overview
=================
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.

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

Conditions
-----------------
HIV

Intervention / Treatment
-----------------
* Drug: Standard of Care prophylaxis
* Drug: Chloroquine (CQ) prophylaxis


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HIV, Malaria, Prophylaxis, Antiretroviral therapy