A Trial of 2 Options for Second Line Combination Antiretroviral Therapy Following Virological Failure of a Standard Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI)+2N(t)RTI First Line Regimen

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomised Open-label Study Comparing the Safety and Efficacy of Ritonavir Boosted Lopinavir and 2-3N(t)RTI Backbone Versus Ritonavir Boosted Lopinavir and Raltegravir in Participants Virologically Failing First-line NNRTI/2N(t)RTI Therapy

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: raltegravir
* Drug: 2N(t)RTI
* Drug: Ritonavir-boosted lopinavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 positive by licensed diagnostic test Aged 16 years or older (or minimum age as determined by local regulations or as legal requirements dictate) Have received first antiretroviral regimen consisting of an NNRTI plus 2N(t)RTIs for at least 24 weeks No change in antiretroviral therapy within 12 weeks prior to screening 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 No prior or current exposure to HIV protease inhibitors and/or HIV integrase inhibitors Able to provide written informed consent Exclusion Criteria: 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 Pregnant or nursing mothers Participants with active viral hepatitis B infection defined by the presence in serum of hepatitis B surface antigen Use of immunomodulators within 30 days prior to screening Use of any prohibited medications (rifampicin, midazolam, triazolam, cisapride, pimozide, amiodarone, dihydroergotamine, ergotamine, ergonovine, methylergonovine, astemizole, terfenadine, vardenafil, and St. John's wort) Intercurrent illness requiring hospitalization Active opportunistic disease not under adequate control in the opinion of the site Principal Investigator Participants with current alcohol or illicit substance abuse that in the opinion of the site Principal Investigator might adversely affect participation in the study Participants deemed by the site Principal Investigator unlikely to be able to remain in follow-up for the protocol-defined period

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ritonavir-boosted lopinavir and 2N(t)RTI<br>This is the current standard of care for second line therapy following failure of standard first-line NNRTI+2N(t)RTIs according to WHO guidelines. | Drug: 2N(t)RTI<br>* 2N(t)RTIs as prescribed<br>* Other names: nucleosides, nucleotides, nuncleoside backbone;Drug: Ritonavir-boosted lopinavir<br>* 2 heat-stable tablets of ritonavir-boosted lopinavir taken every 12 hours<br>* Other names: Aluvia, Kaletra;|
| Experimental: Ritonavir-boosted lopinavir and raltegravir<br>This is an experimental arm which is likely to be fully active in the presence of N(t)RTI mutations and which preliminary evidence suggests should be potent and durable. | Drug: raltegravir<br>* 400 mg raltegravir tablet taken every 12 hours<br>* Other names: Isentress;Drug: Ritonavir-boosted lopinavir<br>* 2 heat-stable tablets of ritonavir-boosted lopinavir taken every 12 hours<br>* Other names: Aluvia, Kaletra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Plasma HIV RNA < 200 Copies/mL 48 Weeks After Randomization |  | 48 weeks following randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 48 weeks | 
| 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 | 48 weeks | 
| 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 | 48 weeks | 
| 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 | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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second line therapy, combination antiretroviral therapy, first-line failure, AIDS, treatment experienced