HIV, Tuberculosis
Conditions
Keywords
HIV, Tuberculosis, Treatment Naive
Brief summary
The purpose of this study is twofold: (1) to assess the feasibility and safety of fixed dose combination zidovudine/lamivudine/abacavir in HIV infected subjects with tuberculosis in a resource-limited setting, and (2) to assess the impact of delayed versus early initiation strategies for fixed dose combination zidovudine/lamivudine/abacavir on the rate of tuberculosis-associated immune reconstitution inflammatory syndromes.
Interventions
DRUGFixed dose combination zidovudine/lamivudine/abacavir
All subjects will receive fixed dose combination zidovudine(300 mg) / lamivudine (150 mg) / abacavir (300 mg) by mouth twice daily. Medications will be provided as long as deemed beneficial by the site investigator and study subject for up to two years. Toxicity substitutions are allowed per protocol.
Sponsors
Kilimanjaro Christian Medical Centre, Tanzania
Kibongoto National Tuberculosis Hospital, Tanzania
GlaxoSmithKline
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
13 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HIV Infection is documented by rapid HIV test or any licensed enzyme-linked immunosorbent assay (ELISA) test kit and confirmed with a different sample. * Men or women admitted to Kibongoto or Marangu Hospitals with (a) recent (within 56 days) smear positive tuberculosis (pulmonary or extrapulmonary,) (b)total lymphocyte count \<1,200/mm3, and (c) less than 14 days of antituberculous therapy. * Antiretroviral naive with the exception of regimens used to prevent mother-to-infant transmission of HIV during pregnancy. * The following laboratory values obtained within 45 days prior to study entry: absolute neutrophil count (ANC) \>=700/mm³, hemoglobin \> 8 g/dL in women; \>9 g/dL in men, serum creatinine \<= 1.5 times upper limits of normal, AST \<5 times upper limits of normal. * For all women of reproductive potential (who have not reached menopause or undergone hysterectomy, bilateral oophorectomy, or tubal ligation), a negative urine pregnancy test within 48 hours of to study. * All subjects must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate) and if participating in sexual activity that could lead to pregnancy, the female subject/male partner must use condoms (male or female) without a spermicidal agent. * Not intending to relocate out of area for the duration of study participation. * Willingness of subject to adhere to follow up schedule. * Men and women \>= age 13. * Ability and willingness of subject or legal guardian/representative to give written consent.
Exclusion criteria
* Serious illness, other than tuberculosis, that requires systematic treatment and/or hospitalization, until either completion of therapy or clinical stability on therapy in the opinion of the investigator for at least 14 days prior to study entry. Oral and vaginal candidiasis, mucocutaneous herpes simples, and other illnesses which are minor in the opinion of the site investigator are exceptions * Diagnosis of or suspicion of tuberculosis of the central nervous system. * \> 14 days of antituberculous therapy prior to screening. * \> 28 days of antituberculous therapy for active tuberculosis within the 6 months prior to screening. * Recent past (within 28 days of study entry) or planned use of corticosteroids. * Any condition that in the opinion of the investigator would compromise the subject's ability to participate in the study. * Radiation or systemic chemotherapy within 45 days of entry. * Any immunomodulator, HIV vaccine, or other investigational therapy within 30 days prior to study entry. * Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements. * Allergy/sensitivity to any study drugs or their formulations.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Serious Adverse Events (SAEs) | 104 weeks | Feasibility and safety of fixed dose combination zidovudine/lamivudine/abacavir in HIV-infected subjects with tuberculosis in a resource-limited setting as assessed by the number of serious adverse events. Serious adverse events included any untoward medical occurrence that resulted in death, was considered life-threatening, required inpatient hospitalization or prolongation of existing hospitalization beyond what was required in the study, or resulted in persistent or resulted in significant disability/incapacity. |
| Tuberculosis-immune Reconstitution Inflammatory Syndrome Events | 104 weeks | Tuberculosis-immune reconstitution inflammatory syndrome was defined by the protocol as: a) new persistent fevers (temperature \>101.5 degrees Fahrenheit) developing after the initiation of antiretroviral therapy, and not believed to be associated with antiretroviral therapy and without an identifiable source, b) marked worsening or emergence of intrathoracic lymphadenopathy, pulmonary infiltrates or pleural effusions on radiologic examination, or c) worsening or emergence of lymphadenopathy on serial examinations or worsening of other tuberculous lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma HIV Ribonucleic Acid (RNA) Level < 400 Copies/ml | 104 Weeks | The number of subjects with plasma HIV RNA level \<400 copies/ml. |
| HIV RNA Level < 50 Copies/ml | 104 Weeks | The number of subjects with plasma HIV RNA level \<50 copies/ml. |
Countries
Tanzania
Participant flow
Recruitment details
Enrollment began in June 2004 and was completed in September 2005. Patients were enrolled at one of two hospitals in the Kilimanjaro Region of Tanzania.
Participants by arm
| Arm | Count |
|---|---|
| Early Initiation of fixed dose combination zidovudine (300 mg)/lamivudine (150 mg)/abacavir (300 mg) administered orally twice daily, beginning 2 weeks after commencing antituberculous therapy | 35 |
| Delayed Initiation of fixed dose combination zidovudine (300 mg)/lamivudine (150 mg)/abacavir (300 mg) administered orally twice daily, beginning 8 weeks after commencing antituberculous therapy | 35 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Clinical failure | 0 | 1 |
| Overall Study | Death | 2 | 1 |
Baseline characteristics
| Characteristic | Delayed | Early | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 1.0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0.0 Participants |
| Age, Categorical Between 18 and 65 years | 35 Participants | 34 Participants | 69.0 Participants |
| Age Continuous | 36.7 years | 36.0 years | 36.2 years |
| Region of Enrollment Tanzania | 35 participants | 35 participants | 70.0 participants |
| Sex: Female, Male Female | 17 Participants | 12 Participants | 29.0 Participants |
| Sex: Female, Male Male | 18 Participants | 23 Participants | 41.0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 35 | 0 / 35 |
| serious Total, serious adverse events | 12 / 35 | 7 / 35 |
Outcome results
Primary
Number of Serious Adverse Events (SAEs)
Feasibility and safety of fixed dose combination zidovudine/lamivudine/abacavir in HIV-infected subjects with tuberculosis in a resource-limited setting as assessed by the number of serious adverse events. Serious adverse events included any untoward medical occurrence that resulted in death, was considered life-threatening, required inpatient hospitalization or prolongation of existing hospitalization beyond what was required in the study, or resulted in persistent or resulted in significant disability/incapacity.
Time frame: 104 weeks
Population: Intention to treat.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Early | Number of Serious Adverse Events (SAEs) | 12 Events |
| Delayed | Number of Serious Adverse Events (SAEs) | 7 Events |
Primary
Tuberculosis-immune Reconstitution Inflammatory Syndrome Events
Tuberculosis-immune reconstitution inflammatory syndrome was defined by the protocol as: a) new persistent fevers (temperature \>101.5 degrees Fahrenheit) developing after the initiation of antiretroviral therapy, and not believed to be associated with antiretroviral therapy and without an identifiable source, b) marked worsening or emergence of intrathoracic lymphadenopathy, pulmonary infiltrates or pleural effusions on radiologic examination, or c) worsening or emergence of lymphadenopathy on serial examinations or worsening of other tuberculous lesions.
Time frame: 104 weeks
Population: Intention to treat.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Early | Tuberculosis-immune Reconstitution Inflammatory Syndrome Events | 0 Events |
| Delayed | Tuberculosis-immune Reconstitution Inflammatory Syndrome Events | 0 Events |
Secondary
HIV RNA Level < 50 Copies/ml
The number of subjects with plasma HIV RNA level \<50 copies/ml.
Time frame: 104 Weeks
Population: Intent to Treat, missing = failure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Early | HIV RNA Level < 50 Copies/ml | 23 Participants |
| Delayed | HIV RNA Level < 50 Copies/ml | 26 Participants |
Secondary
Plasma HIV Ribonucleic Acid (RNA) Level < 400 Copies/ml
The number of subjects with plasma HIV RNA level \<400 copies/ml.
Time frame: 104 Weeks
Population: Intention to Treat Analysis, missing = failure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Early | Plasma HIV Ribonucleic Acid (RNA) Level < 400 Copies/ml | 26 Participants |
| Delayed | Plasma HIV Ribonucleic Acid (RNA) Level < 400 Copies/ml | 31 Participants |