Safety and Effectiveness of Raltegravir Plus Darunavir/Ritonavir in Treatment-Naive HIV-Infected Adults

Study Overview
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Brief Summary
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The purpose of this study is to assess the effectiveness and safety of an antiretroviral therapy (ART) regimen consisting of raltegravir (RAL) and darunavir (DRV)/ritonavir (RTV) as first-line therapy in treatment-naïve participants.

Detailed Description
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Despite the remarkable strides made in the treatment of HIV-1-infected persons over the last decade, current first-line ART regimens are imperfect. The ideal combination, unlike some current first-line options, would have uncompromised efficacy in the presence of transmitted drug-resistant variants. The primary purpose of this study is to estimate the cumulative proportion of ART-naive participants experiencing virologic failure at or prior to week 24 after initiating raltegravir (RAL) plus darunavir/ritonavir (DRV/RTV). The study will last 52 weeks. All participants will follow the same treatment schedule and take RAL plus DRV/RTV orally daily for the duration of the trial. After entry, all participants will have scheduled visits at weeks 1, 4, 12, 24, 36, 48, and 52. Medical/medication history, blood and urine collection, and liver function tests will occur at screening. A targeted physical exam and concomitant medications history will occur at all study visits. Blood and urine collection and liver function tests will occur at most study visits. For females, a pregnancy test will occur at screening and study entry. RAL and DRV were provided by the study. RTV was not provided by the study.

Official Title
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A Pilot Efficacy and Safety Trial of Raltegravir Plus Darunavir/Ritonavir for Treatment-Naive HIV-1-Infected Subjects

Conditions
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HIV-1 Infections

Intervention / Treatment
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* Drug: Raltegravir
* Drug: Darunavir/Ritonavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1-infected Plasma HIV-1 RNA of at least 5,000 copies/mL within 90 days prior to study entry HIV genotype (for reverse transcriptase and protease) performed at any time prior to study entry. More information on this criterion can be found in the protocol. ARV drug-naive. More information on this criterion can be found in the protocol. Negative result from a hepatitis B surface antigen test performed within 90 days prior to study entry Agree to use one form of medically-accepted contraceptive throughout the study and for 60 days after stopping study treatment. More information on this criterion can be found in the protocol. Exclusion Criteria: Serious illness requiring systemic treatment and/or hospitalization for at least 7 days prior to study. More information on this criterion can be found in the protocol. Screening HIV genotype obtained any time prior to study entry with more than one DRV resistance-associated mutation [RAM] (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, I84V, and L89V) or L76V alone Known major integrase inhibitor RAM(s), including N155H, Q148H/R/K, Y143C/R, and G140S Severe renal insufficiency requiring hemodialysis or peritoneal dialysis Treatment with immunomodulators within 30 days prior to study entry. More information on this criterion can be found in the protocol. Current medications that are prohibited with any study medications. More information on this criterion can be found in the protocol. Known allergy/sensitivity to study drugs or their formulations. A history of sulfa allergy is not an exclusion. Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with the study. Certain abnormal laboratory results. More information on this criterion can be found in the protocol. Pregnant or breastfeeding

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RAL + DRV/RTV<br>Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks | Drug: Raltegravir<br>* 400 mg tablet taken orally twice daily<br>* Other names: RAL;Drug: Darunavir/Ritonavir<br>* 800 mg Darunavir/100 mg Ritonavir tablet taken orally once daily<br>* Other names: DRV/RTV;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants With Virologic Failure After Initiating RAL Plus DRV/RTV at or Prior to Week 24 | Virologic failure is defined as: at week 12, confirmed plasma HIV-1 RNA >= 1000 copies/ml or confirmed rebound from the week 4 value by >0.5 log10 copies/ml (for subjects with week 4 value <= 50 copies/ml, confirmed rebound to >50 copies/ml); at week 24 or later, confirmed value > 50 copies/ml. Viral load confirmation was scheduled 7-35 days after initial virologic failure. The proportion was estimated using Kaplan-Meier method. An adaptation of Greenwood's variance estimate was used in constructing the confidence interval. | From start of study treatment to week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants With Virologic Failure or Off Study Treatment Regimen or Death at or Prior to Week 24 | The proportion of participants with virologic failure (see primary outcome measure for definition) and/or premature treatment discontinuation/modification and/or death was estimated using Kaplan-Meier method. An adaptation of Greenwood's variance estimate was used in constructing the confidence interval. | From start of study treatment to Week 24 | 
| Change in Plasma HIV-1 RNA From Baseline to Week 1 | Results report the week 1 change from baseline (week 1 - baseline) in HIV-1 RNA. Baseline HIV-1 RNA was computed as the mean of the log10 HIV-1 RNA values at pre-entry and study entry. | Baseline and week 1 | 
| Proportion of Participants With Plasma HIV-1 RNA < 50 Copies/ml or <200 Copies/ml at Week 24 | Results report the percentage of participants with plasma HIV-1 RNA < 50 copies/ml or <200 copies/ml at week 24. | From start of study treatment to week 24 | 
| Proportion of Participants With Plasma HIV-1 RNA <50 Copies/ml or <200 Copies/ml at Week 48 | Results report the percentage of participants with plasma HIV-1 RNA <50 copies/ml or <200 copies/ml at week 48. | From start of study treatment to week 48 | 
| Proportion of Participants Who Experienced Signs/Symptoms or Laboratory Toxicities Grade 3 or Higher, or of Any Grade Which Led to a Permanent Change or Discontinuation of Study Treatment | Signs, symptoms and laboratory values were graded according to the Division of AIDS Adverse Event Grading System. Results report the percentage of participants who had grade 3 or higher events, or events of any grade which led to a permanent change or discontinuation of study treatment, which occurred any time from start of treatment to end of treatment. | From start of study treatment to week 52 | 
| Number of Participants With Pretreatment Drug Resistance | Results report the number of participants who had resistance to non-nucleoside reverse transciptase inhibitors (NNRTI), nucleoside reverse transciptase inhibitors (NRTI) and protease inbitors (PI) based on genotypic resistance testing done prior to participant's entry into the study. Participants are classified into one (and only one category) based on the maximum number of drug class resistance seen for the participant. | At screening | 
| Number of Participants With Integrase Drug Resistance at Virologic Failure | Results report the number of participants who had integrase resistance mutation(s) detected at the time of virologic failure. | From 12 weeks after starting study treatment to week 52 | 
| Number of Participants With Protease Drug Resistance at Virologic Failure | Results report the number of participants who had protease resistance mutation(s) detected at the time of virologic failure. | From 12 weeks after starting study treatment to week 52 | 
| Number of Participants With Perfect Overall Adherence by Self Report | At each study visit, adherence was measured in terms of the number of missed doses each participant had over a 4-day recall for each drug. Adherence for all study visit weeks were combined for an overall measure of adherence. Participants who had zero missed doses on all weeks in all drugs while on study were classified as having an overall perfect adherence. | From one week after starting study treatment to week 52 | 
| Changes in Fasting Total Cholesterol, High-density Lipoprotein and Triglyceride at Week 24 | Results report the week 24 change from week 0 (week 24 - week 0) fasting total cholesterol, high-density lipoprotein and triglyceride. | From start of study treatment through week 24 | 
| Change in Fasting Low-density Lipoprotein at Week 24 | Results report the week 24 change from week 0 (week 24 - week 0) fasting low-density lipoprotein (LDL). For participants whose calculated fasting LDL and direct fasting LDL were both reported, only the calculated fasting LDL was used. Direct fasting LDL was reported when the participant had high fasting triglyceride. | From start of study treatment through week 24 | 
| Changes in Fasting Total Cholesterol, High-density Lipoprotein and Triglyceride at Week 48 | Results report the week 48 change from week 0 (week 48 - week 0) fasting total cholesterol, high-density lipoprotein and triglyceride. | From start of study treatment through week 48 | 
| Change in Fasting Low-density Lipoprotein at Week 48 | Results report the week 48 change from week 0 (week 48 - week 0) fasting low-density lipoprotein (LDL). For participants whose calculated fasting LDL and direct fasting LDL were both reported, only the calculated fasting LDL was used. Direct fasting LDL was reported when the participant had high fasting triglyceride. | From start of study treatment through week 48 | 
| Change in CD4 Count at Week 48 | Results report the week 48 change from baseline (week 48 - baseline) in CD4 count. Baseline CD4 count was computed as the mean of CD4 count values at pre-entry and study entry. | From start of study treatment through week 48 | 
| Plasma Trough Concentration of Raltegravir | Plasma trough concentrations (ng/ml) of Raltegravir (RAL) below the detection limit (10 ng/ml) were replaced by half the corresponding lower limit of quantitation. Geometric mean of trough concentrations obtained within the prescribed trough time (within 9-15 hours after the last RAL dose) was computed for each participant. For participants who experienced virologic failure (see primary outcome measure definition), only those concentrations on or before virologic failure confirmation were used in the geometric mean computation. | From start of study treatment to week 52 | 
| Plasma Trough Concentration of Darunavir | Plasma trough concentrations (ng/ml) of Darunavir (DRV) below the detection limit (50 ng/ml) were replaced by half the corresponding lower limit of quantitation. Geometric mean of trough concentrations obtained within the prescribed trough time (within 20-28 hours after the last DRV dose) was computed for each participant. For participants who experienced virologic failure (see primary outcome measure definition), only those concentrations on or before virologic failure confirmation were used in the geometric mean computation. | From start of study treatment to week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment Naive