Evaluation of Renal Function, Efficacy, and Safety When Switching From Tenofovir/Emtricitabine Plus a Protease Inhibitor/Ritonavir, to a Combination of Raltegravir (MK-0518) Plus Nevirapine Plus Lamivudine in HIV-1 Participants With Suppressed Viremia and Impaired Renal Function (MK-0518-284)

Study Overview
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Brief Summary
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To evaluate changes in renal function, efficacy, and safety when switching from a combination of tenofovir/emtricitabine (TDF/FTC) plus a protease inhibitor/ritonavir (PI/r) to a combination of raltegravir (MK-0518) plus nevirapine plus lamivudine in human immunodeficiency virus (HIV)-1 infected participants with suppressed viremia and impaired renal function.

Official Title
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Switching From Regimens Consisting of a RTV-Boosted Protease Inhibitor Plus TDF/FTC to a Combination of Raltegravir Plus Nevirapine and Lamivudine in HIV Patients With Suppressed Viremia and Impaired Renal Function (RANIA Study) (Pilot Study) Protocol MK-0518-284-03

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Raltegravir (MK-0518)
* Drug: Nevirapine
* Drug: Lamivudine
* Drug: Tenofovir
* Drug: Emtricitabine
* Drug: Lopinavir
* Drug: Ritonavir
* Drug: Atazanavir
* Drug: Darunavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male, or non-pregnant, non-breastfeeding female No previous history of virological failure No previous exposure to non-nucleoside reverse transcriptase inhibitors or integrase inhibitors No previous history of intolerance to lamivudine At least 2 documented plasma HIV-1 RNA <50 copies/mL and no HIV-1 >50 copies/mL in the 12 months before screening Receiving the same protease inhibitor/ritonavir plus tenofovir/emtricitabine combination for at least the 6 months before screening Has no major International Antiviral Society (IAS)-USA mutations on genotype testing performed before starting antiretroviral treatment Sexually-active participants and their partners of child-bearing potential agree to use a medically acceptable method of contraception from 2 weeks before Day 1 and for at least 6 months after the last dose of study drug (postmenopausal women are not required to use contraception; sexually-active male participants with a female partner of child-bearing potential must provide written informed consent to information regarding any pregnancy) Exclusion Criteria: Positive for hepatitis B surface antigen (HBsAg+) or anticipated need for hepatitis C virus treatment Liver cirrhosis Has a history of diabetes mellitus, defined as initiation of antidiabetic treatment or verification of diabetes in a case report form Has any cancer, excluding stable Kaposi Sarcoma Allergy or sensitivity to the investigational product or excipients Female participant who is nursing Female participant who is pregnant or intends to become pregnant Has an active Acquired Immunodeficiency Syndrome (AIDS)-defining event except stable Kaposi Sarcoma or HIV Wasting Syndrome Received any investigational drug within 30 days before screening Participated in any other clinical trial within 30 days before signing informed consent for the current trial

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: Raltegravir plus Nevirapine plus Lamivudine<br>Raltegravir 400 mg oral twice daily for 96 weeks; plus nevirapine 200 mg oral once daily for 14 days followed by nevirapine 200 mg oral twice daily, plus lamivudine 150 mg oral twice daily for 96 weeks | Drug: Raltegravir (MK-0518)<br>* Raltegravir (MK-0518) 400 mg tablets<br>Drug: Nevirapine<br>* Nevirapine (NVP) 200 mg tablets<br>Drug: Lamivudine<br>* Lamivudine (3TC) 150 mg tablets<br>|
| Active Comparator: Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine<br>Tenofovir/emtricitabine 300/200 mg oral once daily plus 1) lopinavir/ritonavir 400/100 mg oral twice daily or 800/200 mg oral once daily, or 2) atazanavir/ritonavir 300/100 mg oral once daily, or 3) darunavir/ritonavir 800/100 mg oral once daily or 600/100 mg oral twice daily | Drug: Tenofovir<br>* Tenofovir disoproxil fumarate (TDF) 300 mg tablets<br>Drug: Emtricitabine<br>* Emtricitabine (FTC) 200 mg tablets<br>Drug: Lopinavir<br>* Lopinavir (LPV) 200 mg tablets<br>Drug: Ritonavir<br>* Ritonavir (r) 100 mg tablets<br>Drug: Atazanavir<br>* Atazanavir (ATV) 300 mg tablets<br>Drug: Darunavir<br>* Darunavir (DAR) 400 mg tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Glomerular Filtration Rate (eGFR) was estimated from the Modification of Diet in Renal Disease (MDRD)-6 equation. The MDRD-6 equation = 198 × [serum creatinine(mg/dL)]^-0.858 × [age]-0.167 × [0.822 if patient is female] × [1.178 if patient is black] × [serum urea nitrogen concentration (mg/dL)]^-0.293 × [urine urea nitrogen excretion (g/d)]^0.249. | Baseline and Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Suppressed Viremia (<50 Copies/mL HIV-1 Ribonucleic Acid [RNA]) at Week 48 | Plasma was to be collected at Week 48 in order to quantify HIV-1 RNA. and identify the percentage of participants with <50 copies/mL HIV-1 RNA. | Week 48 | 
| Percentage of Participants With Suppressed Viremia (<50 Copies/mL HIV-1 RNA) at Week 96 | Plasma was to be collected at Week 96 in order to quantify HIV-1 RNA. and identify the percentage of participants with <50 copies/mL HIV-1 RNA. | Week 96 | 
| Percentage of Participants With Decline in Renal Function at Week 48 | Decline in renal function was to be assessed by evaluating MDRD-6, creatinine clearance and serum phosphate. | Week 48 | 
| Percentage of Participants With Virologic Failure (HIV-1 RNA > 50 Copies/mL) | Plasma was to be collected up to Week 96 in order to quantify HIV-1 RNA, and identify the percentage of participants with >50 copies/mL HIV-1 RNA. | Up to Week 96 | 
| Change From Baseline of HIV-RNA Absolute Values | Plasma was to be collected at baseline and Week 96 in order to determine the change from baseline in HIV-1 RNA. | Baseline and Week 96 | 
| Percentage of Participants With Mutations Associated With Resistance to NRTIs, NNRTIs, INI, at Virological Failure. | Participants were to be identified with mutations associated with Nucleoside/ Nucleotide Reverse Transcriptase Inhibitors (NRTIs), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs), and Integrase Inhibitor (INI). Virological failure is defined as 2 consecutive plasma HIV-1 RNA >200 copies/mL at least two weeks apart while on previous or current ARV therapy. | Up to Week 96 | 
| Change From Baseline in Absolute CD4+ T-lymphocyte Count | Cluster of Differentiation 4 + (CD4+) T-lymphocyte cell counts were to be determined at baseline and Week 96, in order to determine the change from baseline. | Baseline and Week 96 | 
| Percentage of Participants With Altered Liver Enzymes and Lipid Profile | Values of liver enzymes and lipids were to be determined from laboratory tests, in order to identify the percentage of participants classified with altered values. | Up to Week 96 | 
| Percentage of Participants With Altered Values of Tubular Kidney Injury Markers. | Values of tubular kidney injury markers. were to be determined, in order to identify the percentage of participants classified with altered values. | Up to Week 96 | 
| Percentage of Participants Having Changes From Baseline in Metabolic Bone Markers | Changes from baseline in metabolic bone markers, serum Bone Specific Alkaline Phosphatase (s-BSAP) and C-telopeptides of type 1 Collagen (s-CTx), were to be determined, in order to classify the percentage of participants with changes. | Baseline and up to Week 96 | 
| Area Under the Concentration Time Curve From Time 0 the Last Measurement Time t (AUC0-t) for Raltegravir and Nevirapine | Blood samples were to be collected in Week 12 in order to use the trapezoidal method to determine the AUC0-t of Raltegravir and Nevirapine | Week 12: Fasted state (0 h) and 1, 2, 3, 6 and 12 h post-dose | 
| Trough Concentration (Ctrough) for Raltegravir and Nevirapine | Blood samples were to be collected in Weeks 12 and 48 in order to use the trapezoidal method to determine the Ctrough, the lowest concentration reached by the drug before the next dose is administered, of Raltegravir and Nevirapine. | Weeks 12 and 48: at the end of dosing interval at 12 h | 
| Percentage of Participants With Genotypic Resistance at Virologic Failure. | Genotypic resistance measures the presence of particular HIV-1 mutations that give rise to drug resistance. Virological failure is defined as 2 consecutive plasma HIV-1 RNA >200 copies/mL at least two weeks apart while on previous or current ARV therapy. | Up to Week 96 | 
| Percentage of Participants With Adherence to Study Therapy | An Adherence Questionnaire was to be given in order to determine the percentage of participants who adhered to study therapy. | Up to Week 96 | 
| Change From Baseline in Bone Disease Risk Assessment | Bone disease risk assessment was to be based on a Fracture Risk Assessment Tool (FRAX®) score in participants > 40 years old, and the change from baseline determined. | Baseline and week 96 | 
| Change From Baseline in the VACS Index | The Veterans Aging Cohort Risk Index (VACS Index) combines various clinical biomarkers into a cumulative index weighted according to the risk of all-cause mortality. | Baseline and week 96 | 
| Percentage of Participants Experiencing a Decline of Renal Function | Decline in renal function was to be assessed by evaluating MDRD-6, creatinine clearance and serum phosphate. | Up to Week 96 | 
| Change From Baseline in eGFR at Week 96 | Glomerular Filtration Rate (eGFR) was estimated from the Modification of Diet in Renal Disease (MDRD)-6 equation. The MDRD-6 equation = 198 × [serum creatinine(mg/dL)]^-0.858 × [age]-0.167 × [0.822 if patient is female] × [1.178 if patient is black] × [serum urea nitrogen concentration (mg/dL)]^-0.293 × [urine urea nitrogen excretion (g/d)]^0.249. | Baseline and Week 96 |