Study of Options for Second-Line Effective Combination Therapy (SELECT)

Study Overview
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Brief Summary
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The study was conducted on people who were taking their first anti-HIV drug regimen (including an Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), a type of anti-HIV drug) but the drugs in this regimen were not doing a good job of fighting their HIV infection. The main purpose of this study was to compare two other anti-HIV drug regimens to see how well they fight HIV. The study also looked at how well participants tolerate the drug regimens and how safe they are. The study was designed to determine whether taking the combination of lopinavir/ritonavir (LPV/r) plus raltegravir (RAL) works as well as what is usually used for second-line therapy: LPV/r plus the best-available nucleoside (nucleotide) reverse transcriptase inhibitor (NRTI) combination. Testing a regimen that does not include any NRTIs was important because NRTIs may no longer work for patients who received them as part of their first treatment regimen.

Detailed Description
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As more HIV-infected persons start antiretroviral therapy (ART) worldwide, the number needing second-line therapy is increasing. In many settings, an NNRTI-based regimen is the preferred first-line ART, whereas a protease inhibitor (PI)-based regimen is often reserved for second-line ART. Both of these types of regimens usually include two NRTIs. As with initial ART, second-line regimens ideally should be composed of three fully active drugs that have potent anti-HIV activity to maximize the chances of durable viral suppression. However, such a goal may not be achieved with second-line PI-based regimens containing NRTIs because of resistance mutations from first-line therapy that reduce the activity of the NRTI class. The most significant of these mutations include M184V, thymidine analogue mutations (TAMs), Q151M complex, and K65R. The presence of K65R would result in resistance to most NRTIs (leaving only zidovudine (ZDV) and possibly abacavir (ABC) as active second-line options); the presence of multiple TAMs and/or Q151M alone or in complex with other mutations would also result in resistance to most NRTIs. Recent data suggest that patients with isolated M184V-related NRTI resistance who subsequently switch to a boosted PI plus lamivudine (3TC)- or emtricitabine (FTC)-based regimen may achieve HIV-1 RNA suppression without the need to switch to more complex regimens [1]. Detection of an isolated M184V NRTI mutation is possible when resources allow for early diagnosis of virologic failure. However, in many resource-limited settings (RLS) early diagnosis of virologic failure is difficult because of infrequent monitoring of viral load or unavailability of viral load testing. This study intended to provide information applicable to the vast majority of RLS where resistance testing is not used routinely for selection of second-line regimens and PIs not needing refrigeration are preferred. This was a phase III, dual-arm, open-label, randomized, non-inferiority study for participants who were on a failing NNRTI-containing first-line regimen. The study evaluated the difference in virologic failure rate between two treatment arms: Arm A: LPV/r plus RAL Arm B: LPV/r plus best available NRTIs Best available NRTI combinations were selected by the site investigator prior to randomization from a list of combinations approved by the study or in consultation with the A5273 Clinical Management Committee (CMC). The NRTIs provided by the study were FTC/TDF, ABC/3TC/ZDV, ABC/3TC, 3TC/ZDV, ABC, 3TC, and ZDV. Participants took their assigned study therapy until 96 weeks of follow-up or 52 weeks after the last participant was enrolled (protocol amendment), whichever was earlier. This study originally planned to enroll 600 participants (300 per study arm), but the sample size was re-evaluated to 480 participants (240 per study arm), due to emergent data from other studies. Participants were assigned with equal probability to one of the two treatment regimens using permuted blocks. Randomization was stratified by three factors: screening HIV-1 RNA (≥100,000 versus <100,000 copies/mL); screening CD4+ cell count (≥100 versus <100 cells/mm3), and selection of ZDV in the NRTI regimen (yes/no). Furthermore, randomization was balanced by site. During the study, participants were asked to return to the clinic at Weeks 4, 12, 24, and then every 12 weeks. Visits lasted about 30 minutes. At most visits, participants had a physical exam, had their arm, waist and hip circumference measured, and answered questions about their medical condition and any medications they were taking. At some visits, participants completed questionnaires to see how they were feeling, if they had been hospitalized recently, and how well they were taking their anti-HIV drugs, had their blood drawn and were asked to give urine samples. If the participant was female and able to become pregnant, a pregnancy test was taken at any visit that pregnancy was suspected.

Official Title
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Multicenter Study of Options for Second-Line Effective Combination Therapy (SELECT)

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: Lopinavir/ritonavir
* Drug: Lopinavir/ritonavir
* Drug: Raltegravir
* Drug: Emtricitabine/tenofovir disoproxil fumarate
* Drug: Abacavir/lamivudine/zidovudine
* Drug: Abacavir/lamivudine
* Drug: Lamivudine/zidovudine
* Drug: Abacavir
* Drug: Zidovudine
* Drug: Lamivudine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infected Confirmation of first-line virologic failure Certain laboratory values obtained within 45 days prior to study entry. More information on this criterion can be found in the study protocol. Negative pregnancy test within 48 hours prior to study entry. Must refrain from participating in a conception process, and, if participating in sexual activity that could lead to pregnancy, must use at least one acceptable type of contraceptive. More information on this criterion can be found in the study protocol. Karnofsky performance score >= 70 within 45 days prior to study entry. Ability and willingness of participant or legal guardian/representative to provide informed consent. No intention to relocate away from current geographical area of residence for the duration of study participation. Exclusion Criteria: Use of any immunomodulator, HIV vaccine, or other investigational therapy within 45 days prior to study entry, with the exception of a tapering course of corticosteroids as acute therapy for pneumocystis jiroveci pneumonia (PCP) or acute asthma/chronic obstructive pulmonary disease flare and/or prednisone at a daily dose of <10 mg (physiologic replacement dose). If the potential participant has had resistance testing, evidence of broad NRTI cross-resistance that, in the opinion of the investigator, would not allow selection of an effective NRTI combination if the participant were randomized to the LPV/r + best available NRTIs arm. Prior exposure to a Protease Inhibitor. Known history of congenital long QT syndrome, hypokalemia, or planned use of other drugs that prolong the QT interval. Pregnancy or breast-feeding. Known history of chronic hepatitis B virus (HBV) infection or current HBV infection defined by the presence of hepatitis B surface antigen in serum or plasma. Active tuberculosis (TB) requiring treatment with rifampicin. Previously diagnosed malignancies other than basal cell carcinoma and cutaneous Kaposi sarcoma. Requirement for taking any medications that are prohibited with the study drugs. More information on this criterion can be found in the study protocol, section 5.4. Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation. Active drug or alcohol use or dependence or other condition that, in the opinion of the site investigator, would interfere with adherence to study requirements. Serious illness requiring systemic treatment and/or hospitalization until candidate either completes therapy or is clinically stable on therapy, in the opinion of the site investigator, for at least 7 days prior to study entry.

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Experimental: Arm A: LPV/r plus RAL<br>Participants were administered LPV/r plus RAL orally twice daily throughout follow-up. | Drug: Lopinavir/ritonavir<br>* Lopinavir 400mg/ritonavir 100mg (given as two LPV 200mg/RTV 50mg fixed-dose combination tablets) orally twice daily, with or without food, throughout follow-up.<br>* Other names: Kaletra;Drug: Lopinavir/ritonavir<br>* Lopinavir 400mg/ritonavir 100mg (given as three LPV 133.3 mg/RTV 33.3 mg fixed-dose combination soft gelatin capsules) orally twice daily, with food, throughout follow-up.<br>* Other names: LPV/r;Drug: Raltegravir<br>* Raltegravir 400 mg tablet orally twice daily, with or without food, throughout follow-up.<br>* Other names: RAL;|
| Experimental: Arm B: LPV/r plus best available NRTIs<br>Participants were administered LPV/r orally twice daily, plus NRTI options provided by the study, to include the best available NRTIs (listed below) throughout follow-up- FTC/TDF orally twice daily ABC/3TC/ZDV orally twice daily ABC/3TC orally once daily 3TC/ZDV orally twice daily ABC 300mg orally twice daily or 600 mg once daily 3TC orally twice daily ZDV orally twice daily | Drug: Lopinavir/ritonavir<br>* Lopinavir 400mg/ritonavir 100mg (given as two LPV 200mg/RTV 50mg fixed-dose combination tablets) orally twice daily, with or without food, throughout follow-up.<br>* Other names: Kaletra;Drug: Lopinavir/ritonavir<br>* Lopinavir 400mg/ritonavir 100mg (given as three LPV 133.3 mg/RTV 33.3 mg fixed-dose combination soft gelatin capsules) orally twice daily, with food, throughout follow-up.<br>* Other names: LPV/r;Drug: Emtricitabine/tenofovir disoproxil fumarate<br>* Emtricitabine 200 mg/tenofovir disoproxil fumarate 300mg fixed-dose combination tablet orally once daily, with or without food, throughout follow-up.<br>* Other names: FTC/TDF;Drug: Abacavir/lamivudine/zidovudine<br>* Abacavir 300 mg/lamivudine 150 mg/zidovudine 300 mg fixed-dose combination tablet orally twice daily, with or without food, throughout follow-up.<br>* Other names: ABC/3TC/ZDV;Drug: Abacavir/lamivudine<br>* Abacavir 600 mg/lamivudine 300 mg fixed-dose combination tablet orally once daily, with or without food, throughout follow-up.<br>* Other names: ABC/3TC;Drug: Lamivudine/zidovudine<br>* Lamivudine 150 mg/zidovudine 300 mg fixed-dose combination tablet orally twice daily, with or without food, throughout follow-up.<br>* Other names: 3TC/ZDV;Drug: Abacavir<br>* Abacavir 300 mg tablet orally twice daily or 600 mg (given as two 300 mg tablets) once daily, with or without food, throughout follow-up.<br>* Other names: ABC;Drug: Zidovudine<br>* Zidovudine 300 mg tablet orally twice daily, with or without food, throughout follow-up.<br>* Other names: ZDV;Drug: Lamivudine<br>* Lamivudine 150 mg tablet orally twice daily, with or without food, throughout follow-up.<br>* Other names: 3TC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Probability of Virologic Failure by Week 48 | The primary endpoint was time to virologic failure. Virologic failure was defined as confirmed viral load >400 copies/mL at or after week 24. The Kaplan-Meier estimate of the cumulative probability of virologic failure by week 48 was used. | From study entry to week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in CD4+ Cell Count From Baseline to Week 48 | Change in CD4+ cell count was calculated as CD4+ cell count at week 48 minus CD4+ cell count at study entry. | Study entry and week 48 | 
| Number of Participants With HIV-1 Drug Resistance Mutations in Protease, Reverse Transcriptase, and Integrase in Participants With Virologic Failure at Baseline and at Time of Virologic Failure | Mutations were defined as major IAS mutations in the IAS-USA July 2014 list. New mutations were those detected at virologic failure but not at baseline. | From study entry through to week 96 | 
| Number of Participants With Grade 3 or Higher Adverse Event (AE) at Least One Grade Higher Than Baseline | The DAIDS Adverse Event (AE) Grading Table, Version 1.0, December 2004 (Clarification, August 2009) was used for grading of AEs. | From start of randomized treatment to off randomized treatment (up to 96 weeks) | 
| Number of Participants Discontinuing Randomized Treatment for Toxicity | Discontinuation of randomized treatment for toxicity included participant decision to discontinue for low grade toxicity. Within class NRTI changes were not considered discontinuations. | From Start of Randomized Treatment to Off Randomized Treatment (up to 96 weeks) | 
| Number of Participants With a New AIDS-defining Events or Death | AIDS-defining events were those recognized by the Centers for Disease Control (CDC) and World Health Organization (WHO) | From study entry throughout follow-up (up to 96 weeks) | 
| Number of Participants With a Targeted Serious Non-AIDS-defining Event or Death | Serious non-AIDS diagnoses were based on ACTG Appendix 60 Diagnosis Codes | From study entry throughout follow-up (up to 96 weeks) | 
| Percentage of Time Spent in Hospital | The percentage of total study time that participants were in hospital. | From study entry throughout follow-up (up to 96 weeks) | 
| Changes in Fasting Total Cholesterol, High-density Lipoprotein (HDL) Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, Triglycerides, and Glucose From Baseline | Fasting was for 8 hours and the metabolic panel was drawn locally. | Study entry and week 48 |