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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV-1 Infection
• Intervention / Treatment: Drug: Dolutegravir, 50mg every 24 hours; Drug: Protease Inhibitor/ritonavir

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 3

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08025
    • Hospital De La Santa Creu I Sant Pau
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • GermansTrias i Pujol Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. HIV-infected patients over 18 years.
2. In current antiretroviral therapy with abacavir and lamivudine (Kivexa) plus ritonavir-boosted PI, at least 6 months.
3. Viral suppression (HIV RNA <50 copies / ml) for at least 12 months.
4. T-score ≤ -1 evaluated by DEXA (done in the last 6 months).
5. Signed informed consent.
6. In potential childbearing women, commitment to use barrier contraceptive method throughout the study.

Exclusion Criteria:

1. Suspected or documented resistance to integrase inhibitors or reverse transcriptase inhibitors, nucleoside analogues.
2. Osteoporosis / osteopenia secondary (testosterone deficiency, thyroid disease ...), except vitamin D deficiency
3. Treatment with bisphosphonates in the last 6 months.
4. Have used integrase inhibitors
5. Pregnant or breastfeeding.
6. 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%)
7. Patients with severe hepatic dysfunction (Class B or C) according to the Child-Pugh classification
8. Patients infected with hepatitis B virus (HBV) who can not use entecavir or telbivudine.
9. Patients infected with hepatitis C virus (HCV) in which is expected to begin treatment during the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dolutegravir 50mg; Dolutegravir 50mg every 24 hours + Kivexa (ABC+3TC)	Drug: Dolutegravir, 50mg every 24 hours; Dolutegravir, 50mg every 24 hours
Active Comparator: Protease Inhibitor/ritonavir; Protease Inhibitor/ritonavir + Kivexa (ABC+3TC)	Drug: Protease Inhibitor/ritonavir; Protease Inhibitor/ritonavir

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Actual): October 1, 2015
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: October 7, 2013
• First Submitted That Met QC Criteria: October 21, 2013
• First Posted (Estimate): October 22, 2013

Study Record Updates

• Last Update Posted (Estimate): November 30, 2015
• Last Update Submitted That Met QC Criteria: November 27, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Keywords: Osteoporosis; Dolutegravir; HIV infection; Bone mineral density; Dual-energy X-ray absorptiometry; Integrase inhibitor
• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Integrase Inhibitors; Integrase Inhibitors; Viral Protease Inhibitors; Ritonavir; Protease Inhibitors; Dolutegravir; HIV Protease Inhibitors
• Other Study ID Numbers: OSTEODOLU