Study of the Effect of Atorvastatin for Reducing Aging-related Complication in HIV-infected Patients Older Than 45 Years Receiving a Protease Inhibitor-based Regimen Versus a Raltegravir-based Regimen

Study of the Effect of Atorvastatin for Reducing "Inflaming" (Aging-related Complication) in HIV-infected Patients Older Than 45 Years Receiving a Protease Inhibitor-based Regimen Versus a Raltegravir-based Regimen

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

Study Overview

• Status: Completed
• Conditions: Aging-related Inflammation in HIV-infected Patients
• Intervention / Treatment: Drug: Raltegravir; Drug: Atorvastatin; Drug: PI-based regimen

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Germans Trias I Pujol Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient having a diagnosis of HIV-1 infection.
• Age 45 years old.
• Current highly active antiretroviral therapy including Truvada or Kivexa plus a ritonavir boosted PI started at least 3 months before.
• Maintained undetectable plasma HIV-1 RNA (VL < 50 copies/mL) for at least 12 months.
• Voluntary written informed consent.

Exclusion Criteria:

• History of virological failure to integrase inhibitors.
• Suspected or documented resistance mutations to the integrase, as well as NRTI-related mutations that may impact nucleoside activity in current regimen.
• Systemic concurrent process such as coinfection with hepatitis C or B, acute systemic infection within the last 4 months, neoplasm, chronic inflammatory process, etc.
• Treatment with other drugs with anti-inflammatory, anticoagulant or antiplatelet effect (for instance corticosteroids, aspirin, etc…)
• Therapy with statins within the last 6 months.

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: Raltegravir + Atorvastatin; Switching the PI by raltegravir, plus Kivexa or Truvada, for 24 weeks. After that, atorvastatin, 20mg/day, will be added for 48 weeks	Drug: Raltegravir; Switching the PI by raltegravir 400mg every 12 hours, plus Kivexa or Truvada, for 24 weeks.; Drug: Atorvastatin; Atorvastatin, 20mg/day, will be added after 24 weeks of study for 48 weeks
Active Comparator: 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.	Drug: Atorvastatin; Atorvastatin, 20mg/day, will be added after 24 weeks of study for 48 weeks; Drug: PI-based regimen; Continue with the same PI-based regimen, plus Kivexa or Truvada, for 24 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Other Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

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

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2015
• Primary Completion (Actual): June 4, 2018
• Study Completion (Actual): June 4, 2018

Study Registration Dates

• First Submitted: October 7, 2015
• First Submitted That Met QC Criteria: October 15, 2015
• First Posted (Estimate): October 16, 2015

Study Record Updates

• Last Update Posted (Actual): October 29, 2020
• Last Update Submitted That Met QC Criteria: October 7, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: comorbidities; inflammation; darunavir; statins; Raltegravir; protease inhibitors
• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; HIV Integrase Inhibitors; Integrase Inhibitors; Atorvastatin; Raltegravir Potassium
• Other Study ID Numbers: RALATOR