HIV
Conditions
Keywords
Malaria, HIV, Prophylaxis, Antiretroviral therapy
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.
Interventions
DRUGStandard of Care prophylaxis
Daily trimethoprim sulfamethoxazole
DRUGChloroquine (CQ) prophylaxis
Discontinue standard of care and start weekly CQ.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
University of Maryland, Baltimore
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Severe Events | 22-66 months | Incidence of severe events (composite of death and WHO stage 3 and 4 illness) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With at Least One Detectable HIV Viral Load | Throughout study participation, measured every six months (2-5.5 years). | Number of participants who ever have a detectable viral load (\>400 copies/ml). |
| CD4 Cell Count | Every 6 months for 22-66 months | Number of Participants with at Least One CD4 Count \<200 |
| WHO HIV Stage 2, 3, 4 Illness | 32-66 months | Incidence of any WHO HIV stage 2, 3, or 4 illness |
| Bacterial Infections and Malaria | 32-66 months | Incidence of bacterial infections and malaria |
| Adverse Events Greater Than or Equal to Grade 3 That Are Related to the Study Product | 32-66 months | Occurrence of adverse events that are greater than or equal to Grade 3 that require discontinuation of TS or CQ prophylaxis |
Other
| Measure | Time frame | Description |
|---|---|---|
| Bacterial or Malaria Infection With CQ or TS Resistant Organism | 32-66 months | Occurrence of bacterial or malaria infection with CQ or TS resistant organism |
| Clinical and Parasitological Response to Antimalarial Therapy | 32-66 months | Clinical and parasitological response to antimalarial therapy in cases of uncomplicated malaria |
Countries
Malawi
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Standard of Care Trimethoprim Sulfamethoxazol (TS) Prophylaxis Participants will continue standard of care daily TS prophylaxis (two tablets each of 80 mg trimethoprim and 400 mg sulfamethoxazole or one tablet each of 160 mg trimethoprim and 800 mg sulfamethoxazole). | 500 |
| Chloroquine (CQ) Prophylaxis Participants will discontinue standard of care trimethoprim sulfamethoxazol prophylaxis and start weekly CQ prophylaxis at 300 mg.. | 500 |
| Discontinuation of Standard of Care (Control Arm) Participants will discontinue standard of care trimethoprim sulfamethoxazol prophylaxis and receive no prophylaxis. | 499 |
| Total | 1,499 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 10 | 6 | 8 |
| Overall Study | Lost to Follow-up | 10 | 13 | 6 |
| Overall Study | Migration out of study area | 61 | 71 | 56 |
| Overall Study | Non-compliant participant | 1 | 0 | 2 |
| Overall Study | Physician Decision | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 3 |
Baseline characteristics
| Characteristic | Chloroquine (CQ) Prophylaxis | Discontinuation of Standard of Care (Control Arm) | Total | Standard of Care Trimethoprim Sulfamethoxazol (TS) Prophylaxis |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 19 Participants | 29 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 496 Participants | 480 Participants | 1470 Participants | 494 Participants |
| Age, Continuous | 38.7 years STANDARD_DEVIATION 9.6 | 39.4 years STANDARD_DEVIATION 10.1 | 39.1 years STANDARD_DEVIATION 9.8 | 39.1 years STANDARD_DEVIATION 9.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 500 Participants | 499 Participants | 1499 Participants | 500 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Malawi | 500 participants | 499 participants | 1499 participants | 500 participants |
| Sex: Female, Male Female | 374 Participants | 386 Participants | 1135 Participants | 375 Participants |
| Sex: Female, Male Male | 126 Participants | 113 Participants | 364 Participants | 125 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 10 / 500 | 6 / 500 | 8 / 499 |
| other Total, other adverse events | 488 / 500 | 483 / 500 | 488 / 499 |
| serious Total, serious adverse events | 72 / 500 | 99 / 500 | 116 / 499 |
Outcome results
Primary
Severe Events
Incidence of severe events (composite of death and WHO stage 3 and 4 illness)
Time frame: 22-66 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard of Care Trimethoprim Sulfamethoxazol (TS) Prophylaxis | Severe Events | 3.3 Events per 100 participant-years |
| Chloroquine (CQ) Prophylaxis | Severe Events | 4.2 Events per 100 participant-years |
| Discontinuation of Standard of Care (Control Arm) | Severe Events | 4.2 Events per 100 participant-years |
p-value: <=0.0595% CI: [0.89, 1.82]Poisson
p-value: <=0.0595% CI: [0.89, 1.83]Poisson
Secondary
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
Time frame: 32-66 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard of Care Trimethoprim Sulfamethoxazol (TS) Prophylaxis | Adverse Events Greater Than or Equal to Grade 3 That Are Related to the Study Product | 0 Events per 100 participant-years |
| Chloroquine (CQ) Prophylaxis | Adverse Events Greater Than or Equal to Grade 3 That Are Related to the Study Product | 0.24 Events per 100 participant-years |
| Discontinuation of Standard of Care (Control Arm) | Adverse Events Greater Than or Equal to Grade 3 That Are Related to the Study Product | 0 Events per 100 participant-years |
Secondary
Bacterial Infections and Malaria
Incidence of bacterial infections and malaria
Time frame: 32-66 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard of Care Trimethoprim Sulfamethoxazol (TS) Prophylaxis | Bacterial Infections and Malaria | 27.8 Events per 100 participant-years |
| Chloroquine (CQ) Prophylaxis | Bacterial Infections and Malaria | 37.4 Events per 100 participant-years |
| Discontinuation of Standard of Care (Control Arm) | Bacterial Infections and Malaria | 36.3 Events per 100 participant-years |
p-value: <=0.0595% CI: [1.11, 1.55]Poisson
p-value: <=0.0595% CI: [1.14, 1.58]Poisson
Secondary
CD4 Cell Count
Number of Participants with at Least One CD4 Count \<200
Time frame: Every 6 months for 22-66 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard of Care Trimethoprim Sulfamethoxazol (TS) Prophylaxis | CD4 Cell Count | 24 Participants |
| Chloroquine (CQ) Prophylaxis | CD4 Cell Count | 23 Participants |
| Discontinuation of Standard of Care (Control Arm) | CD4 Cell Count | 27 Participants |
p-value: <=0.0595% CI: [0.66, 1.93]Fisher Exact
p-value: <=0.0595% CI: [0.55, 1.68]Fisher Exact
Secondary
Number of Participants With at Least One Detectable HIV Viral Load
Number of participants who ever have a detectable viral load (\>400 copies/ml).
Time frame: Throughout study participation, measured every six months (2-5.5 years).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard of Care Trimethoprim Sulfamethoxazol (TS) Prophylaxis | Number of Participants With at Least One Detectable HIV Viral Load | 24 Participants |
| Chloroquine (CQ) Prophylaxis | Number of Participants With at Least One Detectable HIV Viral Load | 36 Participants |
| Discontinuation of Standard of Care (Control Arm) | Number of Participants With at Least One Detectable HIV Viral Load | 33 Participants |
p-value: <=0.0595% CI: [0.83, 2.3]Fisher Exact
p-value: <=0.0595% CI: [0.91, 2.49]Fisher Exact
Secondary
WHO HIV Stage 2, 3, 4 Illness
Incidence of any WHO HIV stage 2, 3, or 4 illness
Time frame: 32-66 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard of Care Trimethoprim Sulfamethoxazol (TS) Prophylaxis | WHO HIV Stage 2, 3, 4 Illness | 4.0 Events per 100 participant-years |
| Chloroquine (CQ) Prophylaxis | WHO HIV Stage 2, 3, 4 Illness | 5.7 Events per 100 participant-years |
| Discontinuation of Standard of Care (Control Arm) | WHO HIV Stage 2, 3, 4 Illness | 5.8 Events per 100 participant-years |
p-value: <=0.0595% CI: [1.07, 2]Poisson
p-value: <=0.0595% CI: [1.04, 1.96]Poisson
Other Pre-specified
Bacterial or Malaria Infection With CQ or TS Resistant Organism
Occurrence of bacterial or malaria infection with CQ or TS resistant organism
Time frame: 32-66 months
Other Pre-specified
Clinical and Parasitological Response to Antimalarial Therapy
Clinical and parasitological response to antimalarial therapy in cases of uncomplicated malaria
Time frame: 32-66 months