Europe-Africa Research Network for Evaluation of Second-line Therapy

Study Overview
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Brief Summary
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The trial aim is to ascertain what, if anything, needs to be combined with a boosted protease inhibitor (bPI) backbone in second-line therapy in order to maximize the chance of a good clinical outcome following WHO-defined failure on a first-line nucleoside reverse transcriptase inhibitor (NRTI) and NNRTI-containing regimen with probable extensive NRTI and NNRTI resistance mutations.

Detailed Description
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The standard of care for second-line HIV therapy in patients who have failed a first-line NNRTI-based regimen is to combine a boosted protease inhibitor (bPI) with two (new) NRTIs. However, patients failing first-line therapy in roll-out programmes often have extensive NRTI resistance mutations that may compromise the efficacy of the NRTI drugs used in second-line therapy and it is likely that the virological potency of the second-line regimen is mostly due to the bPI. It is possible that the contribution of the NRTI drugs to efficacy may be outweighed by additional toxicity and cost. It is also possible that replacing the NRTI drugs with a new class of drug (integrase inhibitors) will improve outcome from second-line therapy, although if the boosted protease inhibitor alone is providing close to optimal response, incremental gains from adding a new class may be small. The principal aims are to determine whether, in patients failing a first-line NRTI and NNRTI-containing regimen: The use of bPI plus raltegravir (an integrase inhibitor) is superior to standard of care (bPI plus 2 new NRTIs) in achieving good HIV disease control at 96 weeks after randomisation The use of bPI monotherapy, preceded by a 12-week induction period in combination with raltegravir, is non-inferior to standard of care in achieving good HIV disease control at 96 weeks after randomisation

Official Title
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A Randomised Controlled Trial to Evaluate Options for Second-line Therapy in Patients Failing a First-line 2NRTI + NNRTI Regimen in Africa

Conditions
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Human Immunodeficiency Virus, HIV

Intervention / Treatment
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* Drug: Aluvia + 2NRTIs
* Drug: Aluvia + raltegravir
* Drug: Aluvia monotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously documented HIV infection on at least one standard antibody-based test Age 12 years and above Taking 2NRTI + NNRTI-based regimen continuously for at least 12 months Naive to protease inhibitor therapy Good adherence to ART in the 12 weeks prior to screening defined as missing medication on no more than 3 days in the prior month Clinically stable and receiving treatment for any known opportunistic infections HIV treatment failure defined by one or more of clinical, immunological or virological criteria defined in the protocol, including VL and CD4 at screening visit Willing and able to give informed consent Able to attend for regular study follow up visits Exclusion Criteria: Any major clinical contra-indications to the use of bPI, the NRTIs that are available to be selected for a second-line regimen or raltegravir Known Hepatitis B carrier (Hepatitis B surface antigen positive if tested) Requires concomitant medication with known major interactions with study drugs for which drug substitutions or dose alterations are not available or acceptable Women who are currently pregnant or breastfeeding Current participation in another clinical trial involving a treatment intervention (may be permitted in some circumstances, but must be discussed with MRC CTU) Life expectancy of less than one month in the opinion of the treating physician

Ages Eligible for Study
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Minimum Age: 12 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: bPI + 2NRTIs<br> | Drug: Aluvia + 2NRTIs<br>* Aluvia (lopinavir/ritonavir 400mg/100mg), twice daily The choice of NRTIs will be at the discretion of the managing clinician and based on the local standard of care and drug availability, taking into account patient's previous drug exposure and side effects on first-line therapy.<br>|
| Experimental: bPI + raltegravir<br> | Drug: Aluvia + raltegravir<br>* Aluvia (lopinavir/ritonavir 400mg/100mg) twice daily raltegravir (400mg) twice daily<br>|
| Experimental: bPI monotherapy<br> | Drug: Aluvia monotherapy<br>* Aluvia (lopinavir/ritonavir 400mg/100mg) twice daily raltegravir (400mg) twice daily for the first 12 weeks only<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Good HIV disease control defined as a composite endpoint consisting of all of: - No new WHO stage 4 events - CD4 count >250 cells/mm3 - viral load <10,000 copies/ml or >10,000 copies/ml with no PI resistance mutations |  | week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Good HIV disease control |  | week 144 | 
| Proportion with CD4 cell count >250 cells/mm3 |  | week 96 and week 144 | 
| Proportion with new or recurrent WHO stage 4 event |  | week 96 and week 144 | 
| Proportion of patients with plasma viral load <50 copies |  | week 48, week 96 and week 144 | 
| Adverse events |  | During trial | 
| Quality of life change from randomisation |  | During trial | 
| Neurocognitive function change from randomisation |  | during trial | 
| Healthcare costs |  | During trial | 
| Proportion with serious non-AIDS events |  | Week 96 and week 144 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human Immunodeficiency virus, second line therapy, raltegravir, aluvia, monotherapy, integrase inhibitor, protease inhibitor, Randomized Controlled Trial