Multicentre Study To Assess Changes In Bone Mineral Density Of The Switch From Protease Inhibitors To Dolutegravir In HIV-1-Infected Subjects With Low Bone Mineral Density

Study Overview
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Brief Summary
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Protease inhibitors (PI) have been associated with an acceleration of bone mineral density loss in HIV-infected individuals because of an enhanced osteoclast activity, although some controversial data have been also published. A first study suggest an increase of bone mineral density after switching from PI to raltegravir, the first generation integrase inhibitor, but there are no more data about this subject. Based on data that PI decrease bone mineral density by accelerating osteoclast cells and that the discontinuation of this drugs could improve bone mineralization, we propose a randomized prospective multicenter study to assess the impact of switching from PI to dolutegravir on bone mineral density in patients with low bone mineral density receiving a PI-containing regimen. At the same time, the study will help to assess the antiviral efficacy and safety of a PI-sparing regimen including dolutegravir as a simplification strategy in virologically suppressed patients.

Detailed Description
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The second generation integrase inhibitor dolutegravir has demonstrated good virological and immunological outcomes in antiretroviral-naive subjects, compared with efavirenz, (SPRING 1 study). As well, it is active against HIV strains resistant to first-generation inhibitors raltegravir and elvitegravir in heavily treatment-experienced patients (VIKING study). Additionally, it was safe and well tolerated after two years of use. It is administered once daily with no need for boosting, no food requirements and has a long half-life. The easy posology and its pharmacokinetics, together with the antiviral potency, make this drug a good alternative as a simplification approach. However, no clinical data are available supporting the switch of protease inhibitors or no nucleoside reverse transcriptase inhibitors to dolutegravir in virologically suppressed HIV-treated subjects. Protease inhibitors (PI) have been associated with an acceleration of bone mineral density loss in HIV-infected individuals because of an enhanced osteoclast activity, although some controversial data have been also published. A first study suggest an increase of bone mineral density after switching from PI to raltegravir, the first generation integrase inhibitor, but there are no more data about this subject. Based on data that PI decrease bone mineral density by accelerating osteoclast cells and that the discontinuation of this drugs could improve bone mineralization, we propose a randomized prospective multicenter study to assess the impact of switching from PI to dolutegravir on bone mineral density in patients with low bone mineral density receiving a PI-containing regimen. At the same time, the study will help to assess the antiviral efficacy and safety of a PI-sparing regimen including dolutegravir as a simplification strategy in virologically suppressed patients.

Official Title
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MULTICENTRE STUDY TO ASSESS CHANGES IN BONE MINERAL DENSITY OF THE SWITCH FROM PROTEASE INHIBITORS TO DOLUTEGRAVIR IN HIV-1-INFECTED SUBJECTS WITH LOW BONE MINERAL DENSITY

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: Dolutegravir, 50mg every 24 hours
* Drug: Protease Inhibitor/ritonavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-infected patients over 18 years. In current antiretroviral therapy with abacavir and lamivudine (Kivexa) plus ritonavir-boosted PI, at least 6 months. Viral suppression (HIV RNA <50 copies / ml) for at least 12 months. T-score ≤ -1 evaluated by DEXA (done in the last 6 months). Signed informed consent. In potential childbearing women, commitment to use barrier contraceptive method throughout the study. Exclusion Criteria: Suspected or documented resistance to integrase inhibitors or reverse transcriptase inhibitors, nucleoside analogues. Osteoporosis / osteopenia secondary (testosterone deficiency, thyroid disease ...), except vitamin D deficiency Treatment with bisphosphonates in the last 6 months. Have used integrase inhibitors Pregnant or breastfeeding. Patients with alanine aminotransferase (ALT)> 5 times the upper limit of normal (ULN) or ALT ≥ 3 times ULN and bilirubin ≥ 1.5 times ULN (direct bilirubin> 35%) Patients with severe hepatic dysfunction (Class B or C) according to the Child-Pugh classification Patients infected with hepatitis B virus (HBV) who can not use entecavir or telbivudine. Patients infected with hepatitis C virus (HCV) in which is expected to begin treatment during the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Dolutegravir 50mg<br>Dolutegravir 50mg every 24 hours + Kivexa (ABC+3TC) | Drug: Dolutegravir, 50mg every 24 hours<br>* Dolutegravir, 50mg every 24 hours<br>|
| Active Comparator: Protease Inhibitor/ritonavir<br>Protease Inhibitor/ritonavir + Kivexa (ABC+3TC) | Drug: Protease Inhibitor/ritonavir<br>* Protease Inhibitor/ritonavir<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare changes in Bone Mineral Density (BMO) measured by Dual-energy X-ray absorptiometry |  | From Baseline to week 48 | 
| Compare changes in femur T-score measured by DEXA |  | From Baseline to week 48 | 
| Compare changes in lumbar spine (L1-L4) T-score measured by DEXA |  | From Baseline to week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HIV-1 viral load |  | Baseline | 
| HIV-1 viral load |  | week 4 | 
| HIV-1 viral load |  | week 12 | 
| HIV-1 viral load |  | week 24 | 
| HIV-1 viral load |  | week 48 | 
| CD4+/CD8+ T lymphocytes count. |  | Baseline | 
| CD4+/CD8+ T lymphocytes count. |  | week 4 | 
| CD4+/CD8+ T lymphocytes count. |  | week 12 | 
| CD4+/CD8+ T lymphocytes count. |  | week 24 | 
| CD4+/CD8+ T lymphocytes count. |  | week 48 | 
| Genotypic test if virological failure occurs. |  | From baseline to week 48 | 
| Compare changes in total cholesterol |  | at week 48 relative to baseline values | 
| Compare changes in HDL cholesterol |  | at week 48 relative to baseline values | 
| Compare changes in LDL cholesterol |  | at week 48 relative to baseline values | 
| Compare changes in triglyceride levels. |  | at week 48 relative to baseline values | 
| Compare changes in filtrate glomerular rate by MDRD equation |  | at week 48 relative to baseline values | 
| Compare changes in creatinine |  | at week 48 relative to baseline values | 
| Compare changes in albumine/creatinine ratio |  | at week 48 relative to baseline values | 
| Compare changes in proteinuria/creatinine ratio |  | at week 48 relative to baseline values | 
| Adverse events related to antiretroviral treatment (Toxicity). |  | From Baseline to week 48 | 
| Patient withdrawal |  | From Baseline to week 48 | 
| Compare changes in osteocalcin |  | at week 48 relative to baseline values | 
| Compare changes in alkaline phosphatase |  | at week 48 relative to baseline values | 
| Compare changes in telopeptide |  | at week 48 relative to baseline values | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osteoporosis, Bone mineral density, Dual-energy X-ray absorptiometry, HIV infection, Dolutegravir, Integrase inhibitor