Clinical trial NCT01966822: 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
Official title: 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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV-1 Infection
Keywords: Osteoporosis
Bone mineral density
Dual-energy X-ray absorptiometry
HIV infection
Dolutegravir
Integrase inhibitor
Lead sponsor: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
Sponsor class: OTHER
First posted: 2013-10-22
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Compare changes in Bone Mineral Density (BMO) measured by Dual-energy X-ray absorptiometry
timeFrame: From Baseline to week 48
measure: Compare changes in femur T-score measured by DEXA
timeFrame: From Baseline to week 48
measure: Compare changes in lumbar spine (L1-L4) T-score measured by DEXA
timeFrame: From Baseline to week 48
Secondary outcomes:
measure: HIV-1 viral load
timeFrame: Baseline
measure: HIV-1 viral load
timeFrame: week 4
measure: HIV-1 viral load
timeFrame: week 12
measure: HIV-1 viral load
timeFrame: week 24
measure: HIV-1 viral load
timeFrame: week 48
measure: CD4+/CD8+ T lymphocytes count.
timeFrame: Baseline
measure: CD4+/CD8+ T lymphocytes count.
timeFrame: week 4
measure: CD4+/CD8+ T lymphocytes count.
timeFrame: week 12
measure: CD4+/CD8+ T lymphocytes count.
timeFrame: week 24
measure: CD4+/CD8+ T lymphocytes count.
timeFrame: week 48
measure: Genotypic test if virological failure occurs.
timeFrame: From baseline to week 48
measure: Compare changes in total cholesterol
timeFrame: at week 48 relative to baseline values
measure: Compare changes in HDL cholesterol
timeFrame: at week 48 relative to baseline values
measure: Compare changes in LDL cholesterol
timeFrame: at week 48 relative to baseline values
measure: Compare changes in triglyceride levels.
timeFrame: at week 48 relative to baseline values
measure: Compare changes in filtrate glomerular rate by MDRD equation
timeFrame: at week 48 relative to baseline values
measure: Compare changes in creatinine
timeFrame: at week 48 relative to baseline values
measure: Compare changes in albumine/creatinine ratio
timeFrame: at week 48 relative to baseline values
measure: Compare changes in proteinuria/creatinine ratio
timeFrame: at week 48 relative to baseline values
measure: Adverse events related to antiretroviral treatment (Toxicity).
timeFrame: From Baseline to week 48
measure: Patient withdrawal
timeFrame: From Baseline to week 48
measure: Compare changes in osteocalcin
timeFrame: at week 48 relative to baseline values
measure: Compare changes in alkaline phosphatase
timeFrame: at week 48 relative to baseline values
measure: Compare changes in telopeptide
timeFrame: at week 48 relative to baseline values
Other outcomes:
Locations:
city: Badalona
country: Spain
facility: GermansTrias i Pujol Hospital
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
Study officials:
References: