HIV Infections
Conditions
Keywords
second line therapy, combination antiretroviral therapy, first-line failure, AIDS, treatment experienced
Brief summary
The investigators hypothesize that following virological failure of a standard NNRTI+2N(T)RTI regimen second-line antiretroviral therapy consisting of ritonavir-boosted lopinavir and 2N(T)RTIs will offer comparable efficacy to that provided by ritonavir-boosted lopinavir and raltegravir. The study will be conducted for 96-weeks with the primary endpoint analyzed after 48-weeks. The primary endpoint is virological: a comparison of virological suppression in plasma \< 200 copies/mL between the randomized arms after 48 weeks. Secondary and exploratory endpoints include virological, immunological, safety, clinical, metabolic, drug adherence, drug resistance and quality of life.
Detailed description
In HIV-infected subjects who have virologically failed first-line antiretroviral therapy comprising 2N(t)RTI + NNRTI a regimen of second-line therapy incorporating ritonavir-boosted lopinavir and raltegravir provides comparable (i.e., non-inferior) antiretroviral efficacy over 48 weeks to a regimen containing ritonavir-boosted lopinavir and 2-3N(t)RTIs. Eligible patients will be randomised to one of two arms: I. ritonavir boosted lopinavir (LPV/r) 200mg/50mg 4 tabs once daily or 2 tabs twice daily + 2-3N(t)RTIs II. ritonavir boosted lopinavir (LPV/r) 200mg/50mg 4 tabs once daily or 2 tabs twice daily + raltegravir 400 mg twice daily The primary objective of this study is to compare the virological efficacy of the two strategies as measured by the proportion of participants with HIV RNA \< 200 copies/mL 48 weeks after randomisation. Secondary objectives include virological, immunological, safety and antiretroviral therapy endpoints. Exploratory endpoints include clinical, metabolic, drug resistance, medication adherence and quality of life endpoints.
Interventions
DRUGraltegravir
400 mg raltegravir tablet taken every 12 hours
DRUG2N(t)RTI
2N(t)RTIs as prescribed
2 heat-stable tablets of ritonavir-boosted lopinavir taken every 12 hours
Sponsors
Kirby Institute
Merck Sharp & Dohme LLC
Abbott
amfAR, The Foundation for AIDS Research
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
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 at least 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 (at least 7 days apart) HIV RNA results of greater then 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/microlitres * hemoglobin \< 7.0 g/decilitres * platelet count \< 50,000 cells/microlitres * ALT great than 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 hospitalization 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 |
|---|---|
| Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization | 48 weeks following randomization |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population | 48 weeks | The per- protocol population includes those participants who fulfil the protocol in the terms of the eligibility, interventions, and outcome assessment |
| Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population, Non-completer Classed as Failure | 48 weeks | The non-completer classed as failure analysis will include all randomised participants; participants who meet the following criteria will be defined as failures: i. week 48 HIV RNA being above each threshold ii. has missing HIV-1 RNA data for any reason iii. stops randomly assigned therapy |
| Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population, Baseline VL >100,000 Copies Per mL | 48 weeks | The difference between treatment arms in proportion of participants with plasma HIV RNA \< 200 copies/mL 48 weeks after randomization, per-protocol population: stratified analysis by baseline plasma viral load (less than or equal to 100,000 copies per mL or \>100,000 copies per mL) on those participants who fulfil the protocol in the terms of the eligibility, interventions, and outcome assessment |
| Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population, VL Less Than or Equal to 100,000 Copies Per mL | 48 weeks | The per- protocol population includes those participants who fulfil the protocol in the terms of the eligibility, interventions, and outcome assessment |
Countries
Argentina, Australia, Chile, France, Germany, Hong Kong, India, Ireland, Malaysia, Mexico, New Zealand, Nigeria, Peru, Singapore, South Africa, Taiwan, United Kingdom
Contacts
STUDY_CHAIRDavid A Cooper, MD
Kirby Institute
STUDY_CHAIRBrian Gazzard, MD
St. Stephen's Trust
Participant flow
Recruitment details
Recruitment took place from Mar-2010 till Sept-2011 at 37 sites in Argentina, Australia, Chile, UK, France, Hong Kong, India, Israel, Malaysia, Mexico, Peru, Nigeria, Singapore, South Africa, and Thailand. The sites had to be clinical facilities with a cohort of suitable patients and able to do protocol-mandated procedures.
Pre-assignment details
558 participants were enrolled in the study. 14 were excluded because of unverifiable data at one site and 3 dropped out before analysis, never received study treatment
Participants by arm
| Arm | Count |
|---|---|
| Ritonavir-boosted Lopinavir and 2N(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 | 271 |
| Ritonavir-boosted Lopinavir and Raltegravir Lopinavir /ritonavir + raltegravir: LPV/r 200mg/50mg 4 tabs once daily or 2 tabs twice daily + raltegravir 400mg 1 tablet twice daily | 270 |
| Total | 541 |
Baseline characteristics
| Characteristic | Ritonavir-boosted Lopinavir and 2N(t)RTI | Ritonavir-boosted Lopinavir and Raltegravir | Total |
|---|---|---|---|
| Age, Continuous | 39 years STANDARD_DEVIATION 8.81 | 38.55 years STANDARD_DEVIATION 8.84 | 38.78 years STANDARD_DEVIATION 8.82 |
| Region of Enrollment Africa | 100 participants | 96 participants | 196 participants |
| Region of Enrollment Australia | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Europe | 1 participants | 2 participants | 3 participants |
| Region of Enrollment South America | 53 participants | 59 participants | 112 participants |
| Region of Enrollment Southeast Asia | 116 participants | 113 participants | 229 participants |
| Sex: Female, Male Female | 115 Participants | 128 Participants | 243 Participants |
| Sex: Female, Male Male | 156 Participants | 142 Participants | 298 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| other Total, other adverse events | 243 / 271 | 232 / 270 |
| serious Total, serious adverse events | 23 / 271 | 24 / 270 |
Outcome results
Primary
Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization
Time frame: 48 weeks following randomization
Population: modified intention-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ritonavir-boosted Lopinavir and 2N(t)RTI | Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization | 219 participants |
| Ritonavir-boosted Lopinavir and Raltegravir | Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization | 223 participants |
Secondary
Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population
The per- protocol population includes those participants who fulfil the protocol in the terms of the eligibility, interventions, and outcome assessment
Time frame: 48 weeks
Population: Per protocol
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ritonavir-boosted Lopinavir and 2N(t)RTI | Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population | 211 participants |
| Ritonavir-boosted Lopinavir and Raltegravir | Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population | 211 participants |
Secondary
Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population, Baseline VL >100,000 Copies Per mL
The difference between treatment arms in proportion of participants with plasma HIV RNA \< 200 copies/mL 48 weeks after randomization, per-protocol population: stratified analysis by baseline plasma viral load (less than or equal to 100,000 copies per mL or \>100,000 copies per mL) on those participants who fulfil the protocol in the terms of the eligibility, interventions, and outcome assessment
Time frame: 48 weeks
Population: Baseline viral load \>100,000 copies per mL
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ritonavir-boosted Lopinavir and 2N(t)RTI | Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population, Baseline VL >100,000 Copies Per mL | 31 participants |
| Ritonavir-boosted Lopinavir and Raltegravir | Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population, Baseline VL >100,000 Copies Per mL | 39 participants |
Secondary
Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population, Non-completer Classed as Failure
The non-completer classed as failure analysis will include all randomised participants; participants who meet the following criteria will be defined as failures: i. week 48 HIV RNA being above each threshold ii. has missing HIV-1 RNA data for any reason iii. stops randomly assigned therapy
Time frame: 48 weeks
Population: Non-completer classes as failure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ritonavir-boosted Lopinavir and 2N(t)RTI | Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population, Non-completer Classed as Failure | 208 participants |
| Ritonavir-boosted Lopinavir and Raltegravir | Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population, Non-completer Classed as Failure | 210 participants |
Secondary
Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population, VL Less Than or Equal to 100,000 Copies Per mL
The per- protocol population includes those participants who fulfil the protocol in the terms of the eligibility, interventions, and outcome assessment
Time frame: 48 weeks
Population: Baseline viral load \<=100,000 copies per mL
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ritonavir-boosted Lopinavir and 2N(t)RTI | Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population, VL Less Than or Equal to 100,000 Copies Per mL | 188 participants |
| Ritonavir-boosted Lopinavir and Raltegravir | Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization, Per-protocol Population, VL Less Than or Equal to 100,000 Copies Per mL | 184 participants |