HIV
Conditions
Brief summary
The use of anti HIV drugs (ART), and in particular a class of drugs known as nucleoside reverse transcriptase inhibitors (N(t)RTI), has been associated with changes in body fat and in particular loss of peripheral fat in the limbs. Low bone mineral density and osteoporosis are also common in HIV-infected patients. There appears to be some association between ART and bone loss, but this is poorly understood and requires further research. The SECOND-LINE study provides an opportunity to examine if a new anti-HIV drug (raltegravir) can result in greater increase in limb fat than a drug regimen containing N(t)RTI, which is currently standard of care. This study also provides an opportunity to examine if additional bone loss occurs with the second regimen of anti-HIV drugs and whether non-N(t)RTI regimens of ART used in second line therapy result in more or less bone loss than use of other classes of anti-HIV drugs such as protease inhibitors or N(t)RTI combinations. It is hypothesized that subjects randomised into Raltegravir arm will demonstrate greater increases in limb fat and smaller reductions in bone density at the proximal femur over 48 weeks than those randomised into the control arm (LPV/r + 2-3N(t)RTIs).
Interventions
LPV/r 200mg/50mg 4 tabs once daily or 2 tabs twice daily
DRUG2-3N(t)RTI
DRUGraltegravir
raltegravir 400mg 1 tablet twice daily.
Sponsors
Kirby Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Second-Line main study identifier: NCT00931463 Inclusion Criteria: 1. HIV-1 positive by licensed diagnostic test 2. Aged 16 years or older (or minimum age as determined by local regulations or as legal requirements dictate) 3. Have received first antiretroviral regimen consisting of an NNRTI plus 2N(t)RTIs for ≥ 24 weeks 4. No change in antiretroviral therapy within 12 weeks prior to screening 5. Failed first-line NNRTI + 2N(t)RTI combination therapy according to virological criteria defined by two consecutive (≥7 days apart) HIV RNA results of \> 500 copies/mL 6. No prior or current exposure to HIV protease inhibitors and/or HIV integrase inhibitors 7. Able to provide written informed consent
Exclusion criteria
1. The following laboratory variables: * absolute neutrophil count (ANC) \< 500 cells/µL * hemoglobin \< 7.0 g/dL * platelet count \< 50,000 cells/µL * ALT \> 5 x ULN 2. Pregnant or nursing mothers 3. Participants with active viral hepatitis B infection defined by the presence in serum of hepatitis B surface antigen 4. Use of immunomodulators within 30 days prior to screening 5. Use of any prohibited medications (rifampicin, midazolam, triazolam, cisapride, pimozide, amiodarone, dihydroergotamine, ergotamine, ergonovine, methylergonovine, astemizole, terfenadine, vardenafil, and St. John's wort) 6. Intercurrent illness requiring hospitalisation 7. Active opportunistic disease not under adequate control in the opinion of the site Principal Investigator 8. Participants with current alcohol or illicit substance abuse that in the opinion of the site Principal Investigator might adversely affect participation in the study 9. Participants deemed by the site Principal Investigator unlikely to be able to remain in follow-up for the protocol-defined period
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Mean Bone Mineral Density Changes From Baseline to 48 Weeks as Measured by DXA Scan | 48 weeks |
| Mean Limbs Fat Changes From Baseline to 48 Weeks as Measured by DXA Scan | 48 weeks |
Secondary
| Measure | Time frame |
|---|---|
| Mean Total Body Fat Changes From Baseline to 48 Weeks as Measured by DXA Scan | 48 weeks |
| Mean Triglycerides Changes From Baseline to 48 Weeks | 48 weeks |
| Mean Total Cholesterol Changes From Baseline to 48 Weeks | 48 weeks |
| Mean Glucose Changes From Baseline to 48 Weeks | 48 weeks |
Countries
Argentina, India, Malaysia, South Africa, Thailand
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1. Lopinavir / Ritonavir + 2-3N(t)RTI Lopinavir / ritonavir + 2-3N(t)RTI: LPV/r 200mg/50mg 4 tabs once daily or 2 tabs twice daily + 2-3 N(t)RTI | 102 |
| Arm 2. Lopinavir /Ritonavir + Raltegravir Lopinavir /ritonavir + raltegravir: LPV/r 200mg/50mg 4 tabs once daily or 2 tabs twice daily + raltegravir 400mg 1 tablet twice daily. | 108 |
| Total | 210 |
Baseline characteristics
| Characteristic | Arm 1. Lopinavir / Ritonavir + 2-3N(t)RTI | Arm 2. Lopinavir /Ritonavir + Raltegravir | Total |
|---|---|---|---|
| Age, Continuous | 38.6 years INTER_QUARTILE_RANGE 7.8 | 38.9 years INTER_QUARTILE_RANGE 7.7 | 38.8 years INTER_QUARTILE_RANGE 7.8 |
| Sex: Female, Male Female | 47 Participants | 63 Participants | 110 Participants |
| Sex: Female, Male Male | 55 Participants | 45 Participants | 100 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Mean Bone Mineral Density Changes From Baseline to 48 Weeks as Measured by DXA Scan
Time frame: 48 weeks
Population: 97 participants reached week 48 in 2-3N(t)RTI arm. 107 reached week 48 in the RAL arm (1 death)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm 1. Lopinavir / Ritonavir + 2-3N(t)RTI | Mean Bone Mineral Density Changes From Baseline to 48 Weeks as Measured by DXA Scan | -5.2 percentage change |
| Arm 2. Lopinavir /Ritonavir + Raltegravir | Mean Bone Mineral Density Changes From Baseline to 48 Weeks as Measured by DXA Scan | -2.9 percentage change |
Primary
Mean Limbs Fat Changes From Baseline to 48 Weeks as Measured by DXA Scan
Time frame: 48 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm 1. Lopinavir / Ritonavir + 2-3N(t)RTI | Mean Limbs Fat Changes From Baseline to 48 Weeks as Measured by DXA Scan | 15.7 percentage change |
| Arm 2. Lopinavir /Ritonavir + Raltegravir | Mean Limbs Fat Changes From Baseline to 48 Weeks as Measured by DXA Scan | 21.1 percentage change |
Secondary
Mean Glucose Changes From Baseline to 48 Weeks
Time frame: 48 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm 1. Lopinavir / Ritonavir + 2-3N(t)RTI | Mean Glucose Changes From Baseline to 48 Weeks | -0.04 mmol/L |
| Arm 2. Lopinavir /Ritonavir + Raltegravir | Mean Glucose Changes From Baseline to 48 Weeks | -0.1 mmol/L |
Secondary
Mean Total Body Fat Changes From Baseline to 48 Weeks as Measured by DXA Scan
Time frame: 48 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm 1. Lopinavir / Ritonavir + 2-3N(t)RTI | Mean Total Body Fat Changes From Baseline to 48 Weeks as Measured by DXA Scan | 1.4 kg |
| Arm 2. Lopinavir /Ritonavir + Raltegravir | Mean Total Body Fat Changes From Baseline to 48 Weeks as Measured by DXA Scan | 2.1 kg |
Secondary
Mean Total Cholesterol Changes From Baseline to 48 Weeks
Time frame: 48 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm 1. Lopinavir / Ritonavir + 2-3N(t)RTI | Mean Total Cholesterol Changes From Baseline to 48 Weeks | 0.4 mmol/L |
| Arm 2. Lopinavir /Ritonavir + Raltegravir | Mean Total Cholesterol Changes From Baseline to 48 Weeks | 0.6 mmol/L |
Secondary
Mean Triglycerides Changes From Baseline to 48 Weeks
Time frame: 48 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm 1. Lopinavir / Ritonavir + 2-3N(t)RTI | Mean Triglycerides Changes From Baseline to 48 Weeks | 0.6 mmol/L |
| Arm 2. Lopinavir /Ritonavir + Raltegravir | Mean Triglycerides Changes From Baseline to 48 Weeks | 0.8 mmol/L |