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Physicians in charge of HIV-infected patients are increasingly being faced to previously unrecognized comorbid conditions such as atherosclerosis and cardiovascular events, loss of renal function, osteopenia/osteoporosis and bone fractures or non-AIDS-defining cancers (1-4). The incidence of these conditions seems to be higher than in the general population but there are controversial data about if these diseases appear at a younger age in HIV-infected patients.
The investigators propose a strategy for treatment of elderly HIV-infected patients with a double impact on systemic inflammation and age-related co-morbidities by switching the protease inhibitors by raltegravir, a integrase inhibitor with a neutral effect on lipid and bone metabolism, and adding an statin because of their anti-inflammatory effect. For safety reasons, only patients with maintained viral suppression (documented indetectable viral load for 1 year or more), and no history of virological failure to integrase inhibitors or suspected or documented resistance mutations to the integrase or retrotranscriptase will be candidates for the study.
Interleukin -6 and D-dimer are biomarkers that most strongly predict mortality in treated HIV infection and sCD14, sCD163 are soluble markers of monocyte activation that reflect a key source of inflammation and coagulation in HIV infection and predict mortality (26,27). For that reasons, these markers were chosen to determine changes on them after the introduction of the statin and the change of antiretrovirals
Physicians in charge of HIV-infected patients are increasingly being faced to previously unrecognized comorbid conditions such as atherosclerosis and cardiovascular events, loss of renal function, osteopenia/osteoporosis and bone fractures or non-AIDS-defining cancers (1-4).
The incidence of these conditions seems to be higher than in the general population but there are controversial data about if these diseases appear at a younger age in HIV-infected patients.
Different pathogenic mechanisms are involved in the increased risk of comorbidities. First, the increased life expectancy of the HIV-infected population. The number of elderly HIV+ individuals is dramatically increasing, and nowadays, approximately one-half of the people living with HIV in the United States are age 50 or older (5). In this sense, aging itself is a condition associated with a chronic inflammation and immune senescence, contributing to accelerate age-related morbidity. Second, the persistent inflammatory state and activation of the immune system also induced by the HIV-infection, per se. This condition amplifies the risk of age-related morbidity (6-9). Finally, antiretroviral-related toxicities contribute to accelerate the apparition of some of these diseases such as the dyslipidemia and cardiovascular events (mainly associated with the protease inhibitors use), renal damage or low bone mineral density (especially by tenofovir and probably also by protease inhibitors).
As a consequence, one of the current aims of HIV management is the management of chronic non-infectious co-morbidities in an increasingly older and more complex population. The use of the newest and more safety antiretroviral drugs is a mandatory strategy, especially in this elderly population, to achieve a maintained viral suppression. However, there are many published studies showing higher levels of inflammation even in patients under a viral suppression, in comparison with general population. Regarding this condition, the investigators currently lack effective interventions to potently block this inflammatory status. Although some initial data are published about this regard, data in elderly HIV-infected people are lacking.
Based on these data, the investigators propose a strategy for treatment of elderly HIV-infected patients with a double impact on systemic inflammation and age-related co-morbidities by switching the protease inhibitors by raltegravir, a integrase inhibitor with a neutral effect on lipid and bone metabolism, and adding an statin because of their anti-inflammatory effect. For safety reasons, only patients with maintained viral suppression (documented indetectable viral load for 1 year or more), and no history of virological failure to integrase inhibitors or suspected or documented resistance mutations to the integrase or retrotranscription will be candidates for the study.
Raltegravir is an antiretroviral drug that received approval by the U.S. Food and Drug Administration (FDA) in 2007. It was the first of a new class of HIV drugs, the integrase inhibitors, and exhibited rapid, potent and durable antiretroviral activity in antiretroviral naïve patients and in treatment-experienced patients with drug-resistant HIV-1 (10-12). Raltegravir has demonstrated a neutral effect on lipid and renal parameters, and a better impact on bone mineral density (13) and lipid profile than protease inhibitors (14).
Statins are lipid-lowering drugs that also exert anti-inflammatory effects, and have immune-modulatory properties. Recent studies in HIV-infected population have suggested that statins have an anti-inflammatory effect, evaluated by inflammatory markers (15-21), and that the statin use is associated with a lower risk of non-AIDS defining morbidities and malignancies and mortality (22-25). But limited data have been published, mainly based on retrospective studies, and no clinical recommendations are available. The investigators propose the use of atorvastatin to study the anti-inflammatory effect measuring changes in inflammatory markers and some clinical conditions. Atorvastatin was chosen due to the low drug-drug interactions of this statin and ritonavir and the low cost. Since very few data are available about the effect of statins on inflammatory markers and clinical conditions, a intermediate dose (20 mg per day) was selected.
IL-6 and D-dimer are biomarkers that most strongly predict mortality in treated HIV infection and sCD14, sCD163 are soluble markers of monocyte activation that reflect a key source of inflammation and coagulation in HIV infection and predict mortality (26,27). For that reasons, these markers were chosen to determine changes on them after the introduction of the statin and the change of antiretrovirals.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Raltegravir + Atorvastatin | Experimental | Switching the PI by raltegravir, plus Kivexa or Truvada, for 24 weeks. After that, atorvastatin, 20mg/day, will be added for 48 weeks |
|
| PI-based regimen + Atorvastatin | Active Comparator | Continue with the same PI-based regimen, plus Kivexa or Truvada, for 24 weeks. After that, atorvastatin, 20mg/day, will be added for 48 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Raltegravir | Drug | Switching the PI by raltegravir 400mg every 12 hours, plus Kivexa or Truvada, for 24 weeks. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Changes in the Inflammatory Marker IL-6 | Switching the PI by raltegravir, plus Kivexa or Truvada for 24 weeks. After that, atorvastatin, 20mg/day has been added for 48 weeks. (intergroup and intragroup) | baseline, wk24 and wk72 |
| Changes in Plasma Soluble Markers (D-dimer) | Changes in plasma soluble markers (D-dimer) | baseline, wk24 and wk72 |
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| Measure | Description | Time Frame |
|---|---|---|
| Changes in the Inflammatory, Immune and Coagulation | Changes in the inflammatory, immune and coagulation (intergroup and intragroup ) | at week 72 from week 24 to assess the effect of statin |
| Compare Intergroup and Intragroup Changes in the Inflammatory, Immune and Coagulation |
Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Germans Trias i Pujol Hospital | Badalona | Barcelona | 08916 | Spain |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32941476 | Derived | Negredo E, Jimenez M, Puig J, Loste C, Perez-Alvarez N, Urrea V, Echeverria P, Bonjoch A, Clotet B, Blanco J. A randomized pilot trial to evaluate the benefit of the concomitant use of atorvastatin and Raltegravir on immunological markers in protease-inhibitor-treated subjects living with HIV. PLoS One. 2020 Sep 17;15(9):e0238575. doi: 10.1371/journal.pone.0238575. eCollection 2020. | |
| 27999056 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Raltegravir + Atorvastatin | Switching the PI by raltegravir, plus Kivexaâ or Truvada, for 24 weeks. After that, atorvastatin, 20mg/day, will be added for 48 weeks Raltegravir: Switching the PI by raltegravir 400mg every 12 hours, plus Kivexa or Truvada, for 24 weeks. Atorvastatin: Atorvastatin, 20mg/day, will be added after 24 weeks of study for 48 weeks |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 3, 2016 |
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| PI-based regimen | Drug | Continue with the same PI-based regimen, plus Kivexa or Truvada, for 24 weeks. |
|
| Atorvastatin | Drug | Atorvastatin, 20mg/day, will be added after 24 weeks of study for 48 weeks |
|
Compare intergroup and intragroup changes in the inflammatory, immune and coagulation |
| at week 72 from baseline to assess the effect of PI or raltegravir plus statin |
| Compare Intergroup and Intragroup Changes in the Inflammatory, Immune and Coagulation | Compare intergroup and intragroup changes in the inflammatory, immune and coagulation | at week 24 from baseline to asses the effect of PI or raltegravir |
| Compare Intergroup and Intragroup Changes in Lipid Profile | Compare intergroup and intragroup changes in lipid profile | at week 72 from week 24 to assess the effect of statin |
| Compare Intergroup and Intragroup Changes in Lipid Profile | Compare intergroup and intragroup changes in lipid profile | at week 72 from baseline to assess the effect of PI or raltegravir plus statin |
| Compare Intergroup and Intragroup Changes in Lipid Profile | Compare intergroup and intragroup changes in lipid profile | at week 24 from baseline to asses the effect of PI or raltegravir |
| Compare Intergroup and Intragroup Changes in Lumbar and Femoral BMD and T-score Measured by DEXA | Compare intergroup and intragroup changes in lumbar and femoral BMD and t-score measured by DEXA | at week 72 from week 24 to assess the effect of statin |
| Compare Intergroup and Intragroup Changes in Lumbar and Femoral BMD and T-score Measured by DEXA | Compare intergroup and intragroup changes in lumbar and femoral BMD and t-score measured by DEXA | at week 72 from baseline to assess the effect of PI or raltegravir plus statin |
| Compare Intergroup and Intragroup Changes in Lumbar and Femoral BMD and T-score Measured by DEXA | Compare intergroup and intragroup changes in lumbar and femoral BMD and t-score measured by DEXA | at week 24 from baseline to asses the effect of PI or raltegravir |
| Compare Intergroup and Intragroup Changes in Bone Turnover Markers | Compare intergroup and intragroup changes in bone turnover markers | at week 72 from week 24 to assess the effect of statin |
| Compare Intergroup and Intragroup Changes in Bone Turnover Markers | Compare intergroup and intragroup changes in bone turnover markers | at week 72 from baseline to assess the effect of PI or raltegravir plus statin |
| Compare Intergroup and Intragroup Changes in Bone Turnover Markers | Compare intergroup and intragroup changes in bone turnover markers | at week 24 from baseline to asses the effect of PI or raltegravir |
| Compare Intergroup and Intragroup Changes in Renal Parameters | Compare intergroup and intragroup changes in renal parameters | at week 72 from week 24 to assess the effect of statin |
| Compare Intergroup and Intragroup Changes in Renal Parameters | Compare intergroup and intragroup changes in renal parameters | at week 72 from baseline to assess the effect of PI or raltegravir plus statin |
| Compare Intergroup and Intragroup Changes in Renal Parameters | Compare intergroup and intragroup changes in renal parameters | at week 24 from baseline to asses the effect of PI or raltegravir |
| Viral Load < 50 Copies | viral load < 50 copies | at week 72 |
| Viral Load > 50 Copies | viral load > 50 copies | through study completion |
| CD4+/CD8+ T Lymphocytes | CD4+/CD8+ T lymphocytes | at week 72 from baseline |
| Derived |
| Negredo E, Estrada V, Domingo P, Gutierrez MD, Mateo GM, Puig J, Bonjoch A, Ornelas A, Echeverria P, Estany C, Toro J, Clotet B. Switching from a ritonavir-boosted PI to dolutegravir as an alternative strategy in virologically suppressed HIV-infected individuals. J Antimicrob Chemother. 2017 Mar 1;72(3):844-849. doi: 10.1093/jac/dkw504. |
| FG001 |
| PI-based Regimen + Atorvastatin |
Continue with the same PI-based regimen, plus Kivexa or Truvada, for 24 weeks. After that, atorvastatin, 20mg/day, will be added for 48 weeks. PI-based regimen: Continue with the same PI-based regimen, plus Kivexa or Truvada, for 24 weeks. Atorvastatin: Atorvastatin, 20mg/day, will be added after 24 weeks of study for 48 weeks |
| COMPLETED |
|
| NOT COMPLETED |
|
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Raltegravir + Atorvastatin | Switching the PI by raltegravir, plus Kivexaâ or Truvada, for 24 weeks. After that, atorvastatin, 20mg/day, will be added for 48 weeks Raltegravir: Switching the PI by raltegravir 400mg every 12 hours, plus Kivexa or Truvada, for 24 weeks. Atorvastatin: Atorvastatin, 20mg/day, will be added after 24 weeks of study for 48 weeks |
| BG001 | PI-based Regimen + Atorvastatin | Continue with the same PI-based regimen, plus Kivexa or Truvada, for 24 weeks. After that, atorvastatin, 20mg/day, will be added for 48 weeks. PI-based regimen: Continue with the same PI-based regimen, plus Kivexa or Truvada, for 24 weeks. Atorvastatin: Atorvastatin, 20mg/day, will be added after 24 weeks of study for 48 weeks |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
| ||||||||||||||||||
| Age, Continuous | Median | Standard Deviation | years |
| |||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||||
| Region of Enrollment | Number | participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Changes in the Inflammatory Marker IL-6 | Switching the PI by raltegravir, plus Kivexa or Truvada for 24 weeks. After that, atorvastatin, 20mg/day has been added for 48 weeks. (intergroup and intragroup) | Posted | Mean | Inter-Quartile Range | pg/mL | baseline, wk24 and wk72 |
|
|
| ||||||||||||||||||||||||||||||||||||
| Primary | Changes in Plasma Soluble Markers (D-dimer) | Changes in plasma soluble markers (D-dimer) | Posted | Median | Inter-Quartile Range | ng/mL | baseline, wk24 and wk72 |
|
| |||||||||||||||||||||||||||||||||||||
| Other Pre-specified | Changes in the Inflammatory, Immune and Coagulation | Changes in the inflammatory, immune and coagulation (intergroup and intragroup ) | Data were not collected | Posted | at week 72 from week 24 to assess the effect of statin |
|
| |||||||||||||||||||||||||||||||||||||||
| Other Pre-specified | Compare Intergroup and Intragroup Changes in the Inflammatory, Immune and Coagulation | Compare intergroup and intragroup changes in the inflammatory, immune and coagulation | Data were not collected | Posted | at week 72 from baseline to assess the effect of PI or raltegravir plus statin |
|
| |||||||||||||||||||||||||||||||||||||||
| Other Pre-specified | Compare Intergroup and Intragroup Changes in the Inflammatory, Immune and Coagulation | Compare intergroup and intragroup changes in the inflammatory, immune and coagulation | Data were not collected | Posted | at week 24 from baseline to asses the effect of PI or raltegravir |
|
| |||||||||||||||||||||||||||||||||||||||
| Other Pre-specified | Compare Intergroup and Intragroup Changes in Lipid Profile | Compare intergroup and intragroup changes in lipid profile | Data were not collected | Posted | at week 72 from week 24 to assess the effect of statin |
|
| |||||||||||||||||||||||||||||||||||||||
| Other Pre-specified | Compare Intergroup and Intragroup Changes in Lipid Profile | Compare intergroup and intragroup changes in lipid profile | Data were not collected | Posted | at week 72 from baseline to assess the effect of PI or raltegravir plus statin |
|
| |||||||||||||||||||||||||||||||||||||||
| Other Pre-specified | Compare Intergroup and Intragroup Changes in Lipid Profile | Compare intergroup and intragroup changes in lipid profile | Data were not collected | Posted | at week 24 from baseline to asses the effect of PI or raltegravir |
|
| |||||||||||||||||||||||||||||||||||||||
| Other Pre-specified | Compare Intergroup and Intragroup Changes in Lumbar and Femoral BMD and T-score Measured by DEXA | Compare intergroup and intragroup changes in lumbar and femoral BMD and t-score measured by DEXA | Data were not collected | Posted | at week 72 from week 24 to assess the effect of statin |
|
| |||||||||||||||||||||||||||||||||||||||
| Other Pre-specified | Compare Intergroup and Intragroup Changes in Lumbar and Femoral BMD and T-score Measured by DEXA | Compare intergroup and intragroup changes in lumbar and femoral BMD and t-score measured by DEXA | Data were not collected | Posted | at week 72 from baseline to assess the effect of PI or raltegravir plus statin |
|
| |||||||||||||||||||||||||||||||||||||||
| Other Pre-specified | Compare Intergroup and Intragroup Changes in Lumbar and Femoral BMD and T-score Measured by DEXA | Compare intergroup and intragroup changes in lumbar and femoral BMD and t-score measured by DEXA | Data were not collected | Posted | at week 24 from baseline to asses the effect of PI or raltegravir |
|
| |||||||||||||||||||||||||||||||||||||||
| Other Pre-specified | Compare Intergroup and Intragroup Changes in Bone Turnover Markers | Compare intergroup and intragroup changes in bone turnover markers | Data were not collected | Posted | at week 72 from week 24 to assess the effect of statin |
|
| |||||||||||||||||||||||||||||||||||||||
| Other Pre-specified | Compare Intergroup and Intragroup Changes in Bone Turnover Markers | Compare intergroup and intragroup changes in bone turnover markers | Data were not collected | Posted | at week 72 from baseline to assess the effect of PI or raltegravir plus statin |
|
| |||||||||||||||||||||||||||||||||||||||
| Other Pre-specified | Compare Intergroup and Intragroup Changes in Bone Turnover Markers | Compare intergroup and intragroup changes in bone turnover markers | Data were not collected | Posted | at week 24 from baseline to asses the effect of PI or raltegravir |
|
| |||||||||||||||||||||||||||||||||||||||
| Other Pre-specified | Compare Intergroup and Intragroup Changes in Renal Parameters | Compare intergroup and intragroup changes in renal parameters | Data were not collected | Posted | at week 72 from week 24 to assess the effect of statin |
|
| |||||||||||||||||||||||||||||||||||||||
| Other Pre-specified | Compare Intergroup and Intragroup Changes in Renal Parameters | Compare intergroup and intragroup changes in renal parameters | Data were not collected | Posted | at week 72 from baseline to assess the effect of PI or raltegravir plus statin |
|
| |||||||||||||||||||||||||||||||||||||||
| Other Pre-specified | Compare Intergroup and Intragroup Changes in Renal Parameters | Compare intergroup and intragroup changes in renal parameters | Data were not collected | Posted | at week 24 from baseline to asses the effect of PI or raltegravir |
|
| |||||||||||||||||||||||||||||||||||||||
| Other Pre-specified | Viral Load < 50 Copies | viral load < 50 copies | Data were not collected | Posted | at week 72 |
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| Other Pre-specified | Viral Load > 50 Copies | viral load > 50 copies | Data were not collected | Posted | through study completion |
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| |||||||||||||||||||||||||||||||||||||||
| Other Pre-specified | CD4+/CD8+ T Lymphocytes | CD4+/CD8+ T lymphocytes | Data were not collected | Posted | at week 72 from baseline |
|
|
From baseline to week 72
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Raltegravir + Atorvastatin | Switching the PI by raltegravir, plus Kivexaâ or Truvada, for 24 weeks. After that, atorvastatin, 20mg/day, will be added for 48 weeks Raltegravir: Switching the PI by raltegravir 400mg every 12 hours, plus Kivexa or Truvada, for 24 weeks. Atorvastatin: Atorvastatin, 20mg/day, will be added after 24 weeks of study for 48 weeks | 0 | 20 | 3 | 20 | 0 | 20 |
| EG001 | PI-based Regimen + Atorvastatin | Continue with the same PI-based regimen, plus Kivexa or Truvada, for 24 weeks. After that, atorvastatin, 20mg/day, will be added for 48 weeks. PI-based regimen: Continue with the same PI-based regimen, plus Kivexa or Truvada, for 24 weeks. Atorvastatin: Atorvastatin, 20mg/day, will be added after 24 weeks of study for 48 weeks | 0 | 22 | 0 | 22 | 0 | 22 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| increments of creatine kinase | Cardiac disorders | DAIDS AE GRADING TA | Systematic Assessment |
| |
| increment of liver enzymes | Hepatobiliary disorders | DAIDS AE GRADING TA | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Director of Clinical Trials | Fundació Lluita contra la SIDA | +34 93 497 84 14 | enegredo@flsida.org |
| Jun 3, 2020 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D007249 | Inflammation |
| ID | Term |
|---|---|
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000068898 | Raltegravir Potassium |
| D000069059 | Atorvastatin |
| ID | Term |
|---|---|
| D011760 | Pyrrolidinones |
| D011759 | Pyrrolidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011758 | Pyrroles |
| D001393 | Azoles |
| D006538 | Heptanoic Acids |
| D005227 | Fatty Acids |
| D008055 | Lipids |
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| >=65 years |
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| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| week 72 |
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