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CompletedNCT02577042Updated Oct 29, 2020Results posted

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

A Phase 4 interventional study of Raltegravir and PI-based regimen in Aging-related Inflammation in HIV-infected Patients, sponsored by Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia. Completed at 1 site in Spain. Open to participants aged 60 Years to 99 Years. Per ClinicalTrials.gov, last updated 2020-10-29.

Sponsored by Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia · Phase 4, Interventional, and Treatment

Phase
Phase 4
Study type
Interventional
Enrollment
42
Allocation
Randomized
Ages
60 Years to 99 Years
Sex
All
01

Study summary

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

Read the 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.

02

Conditions studied

  • Aging-related Inflammation in HIV-infected Patients

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Keywords

  • Raltegravir
  • protease inhibitors
  • darunavir
  • inflammation
  • statins
  • comorbidities
03

In context

Inflammation

3,439 studies on the registry are indexed under Inflammation; 629 are open to participants now.

This study's enrollment of 42 is below the median of 50 across 2,437 interventional studies indexed under Inflammation.

Browse Inflammation studies →

Lead sponsor

Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia is the lead sponsor of 44 studies on the registry; 4 are open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
60 Years to 99 Years
Sexes eligible
All
Accepts healthy volunteers
No

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

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.
05

Study design

Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
42 participants (actual)

Study arms

  • 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 · Drug: Atorvastatin

  • 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: PI-based regimen · Drug: Atorvastatin

Interventions

  • DrugRaltegravir

    Switching the PI by raltegravir 400mg every 12 hours, plus Kivexa or Truvada, for 24 weeks.

  • DrugPI-based regimen

    Continue with the same PI-based regimen, plus Kivexa or Truvada, for 24 weeks.

  • DrugAtorvastatin

    Atorvastatin, 20mg/day, will be added after 24 weeks of study for 48 weeks

06

What researchers measure

Primary outcomes

  1. 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)

    Time frame: baseline, wk24 and wk72

  2. Changes in Plasma Soluble Markers (D-dimer)

    Changes in plasma soluble markers (D-dimer)

    Time frame: baseline, wk24 and wk72

Other outcomes

  1. Changes in the Inflammatory, Immune and Coagulation

    Changes in the inflammatory, immune and coagulation (intergroup and intragroup )

    Time frame: at week 72 from week 24 to assess the effect of statin

  2. Compare Intergroup and Intragroup Changes in the Inflammatory, Immune and Coagulation

    Compare intergroup and intragroup changes in the inflammatory, immune and coagulation

    Time frame: at week 72 from baseline to assess the effect of PI or raltegravir plus statin

  3. Compare Intergroup and Intragroup Changes in the Inflammatory, Immune and Coagulation

    Compare intergroup and intragroup changes in the inflammatory, immune and coagulation

    Time frame: at week 24 from baseline to asses the effect of PI or raltegravir

  4. Compare Intergroup and Intragroup Changes in Lipid Profile

    Compare intergroup and intragroup changes in lipid profile

    Time frame: at week 72 from week 24 to assess the effect of statin

  5. Compare Intergroup and Intragroup Changes in Lipid Profile

    Compare intergroup and intragroup changes in lipid profile

    Time frame: at week 72 from baseline to assess the effect of PI or raltegravir plus statin

  6. Compare Intergroup and Intragroup Changes in Lipid Profile

    Compare intergroup and intragroup changes in lipid profile

    Time frame: at week 24 from baseline to asses the effect of PI or raltegravir

  7. 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

    Time frame: at week 72 from week 24 to assess the effect of statin

  8. 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

    Time frame: at week 72 from baseline to assess the effect of PI or raltegravir plus statin

  9. 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

    Time frame: at week 24 from baseline to asses the effect of PI or raltegravir

  10. Compare Intergroup and Intragroup Changes in Bone Turnover Markers

    Compare intergroup and intragroup changes in bone turnover markers

    Time frame: at week 72 from week 24 to assess the effect of statin

  11. Compare Intergroup and Intragroup Changes in Bone Turnover Markers

    Compare intergroup and intragroup changes in bone turnover markers

    Time frame: at week 72 from baseline to assess the effect of PI or raltegravir plus statin

  12. Compare Intergroup and Intragroup Changes in Bone Turnover Markers

    Compare intergroup and intragroup changes in bone turnover markers

    Time frame: at week 24 from baseline to asses the effect of PI or raltegravir

  13. Compare Intergroup and Intragroup Changes in Renal Parameters

    Compare intergroup and intragroup changes in renal parameters

    Time frame: at week 72 from week 24 to assess the effect of statin

  14. Compare Intergroup and Intragroup Changes in Renal Parameters

    Compare intergroup and intragroup changes in renal parameters

    Time frame: at week 72 from baseline to assess the effect of PI or raltegravir plus statin

  15. Compare Intergroup and Intragroup Changes in Renal Parameters

    Compare intergroup and intragroup changes in renal parameters

    Time frame: at week 24 from baseline to asses the effect of PI or raltegravir

  16. Viral Load < 50 Copies

    viral load \< 50 copies

    Time frame: at week 72

  17. Viral Load > 50 Copies

    viral load \> 50 copies

    Time frame: through study completion

  18. CD4+/CD8+ T Lymphocytes

    CD4+/CD8+ T lymphocytes

    Time frame: at week 72 from baseline

07

Results

Posted Jun 22, 2020

Participant flow

Participant flow — Overall Study
MilestoneRaltegravir + AtorvastatinPI-based Regimen + Atorvastatin
Started2022
Completed1519
Not completed53

Outcome measures

PrimaryChanges 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)

Time frame:
baseline, wk24 and wk72
Reported as:
Mean · pg/mL
Changes in the Inflammatory Marker IL-6
pg/mLRaltegravir + AtorvastatinPI-based Regimen + Atorvastatin
Baseline42.5 (34.5 to 50.1)40.0 (36.9 to 53.7)
week 2439.3 (34.6 to 49.8)41.1 (36.1 to 53.2)
week 7243.2 (36.8 to 52.9)41.7 (34.7 to 51.5)
PrimaryChanges in Plasma Soluble Markers (D-dimer)

Changes in plasma soluble markers (D-dimer)

Time frame:
baseline, wk24 and wk72
Reported as:
Median · ng/mL
Changes in Plasma Soluble Markers (D-dimer)
ng/mLRaltegravir + AtorvastatinPI-based Regimen + Atorvastatin
Baseline1743 (1459 to 1894)1990 (1574 to 2523)
wk241844 (1547 to 2340)1917 (1552 to 2244)
wk722051 (1656 to 2414)1868 (1438 to 2175)
Other pre-specifiedChanges in the Inflammatory, Immune and Coagulation

Changes in the inflammatory, immune and coagulation (intergroup and intragroup )

Time frame:
at week 72 from week 24 to assess the effect of statin

No measurements were reported for this outcome.

Other pre-specifiedCompare Intergroup and Intragroup Changes in the Inflammatory, Immune and Coagulation

Compare intergroup and intragroup changes in the inflammatory, immune and coagulation

Time frame:
at week 72 from baseline to assess the effect of PI or raltegravir plus statin

No measurements were reported for this outcome.

Other pre-specifiedCompare Intergroup and Intragroup Changes in the Inflammatory, Immune and Coagulation

Compare intergroup and intragroup changes in the inflammatory, immune and coagulation

Time frame:
at week 24 from baseline to asses the effect of PI or raltegravir

No measurements were reported for this outcome.

Other pre-specifiedCompare Intergroup and Intragroup Changes in Lipid Profile

Compare intergroup and intragroup changes in lipid profile

Time frame:
at week 72 from week 24 to assess the effect of statin

No measurements were reported for this outcome.

Other pre-specifiedCompare Intergroup and Intragroup Changes in Lipid Profile

Compare intergroup and intragroup changes in lipid profile

Time frame:
at week 72 from baseline to assess the effect of PI or raltegravir plus statin

No measurements were reported for this outcome.

Other pre-specifiedCompare Intergroup and Intragroup Changes in Lipid Profile

Compare intergroup and intragroup changes in lipid profile

Time frame:
at week 24 from baseline to asses the effect of PI or raltegravir

No measurements were reported for this outcome.

Other pre-specifiedCompare 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

Time frame:
at week 72 from week 24 to assess the effect of statin

No measurements were reported for this outcome.

Other pre-specifiedCompare 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

Time frame:
at week 72 from baseline to assess the effect of PI or raltegravir plus statin

No measurements were reported for this outcome.

Other pre-specifiedCompare 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

Time frame:
at week 24 from baseline to asses the effect of PI or raltegravir

No measurements were reported for this outcome.

Other pre-specifiedCompare Intergroup and Intragroup Changes in Bone Turnover Markers

Compare intergroup and intragroup changes in bone turnover markers

Time frame:
at week 72 from week 24 to assess the effect of statin

No measurements were reported for this outcome.

Other pre-specifiedCompare Intergroup and Intragroup Changes in Bone Turnover Markers

Compare intergroup and intragroup changes in bone turnover markers

Time frame:
at week 72 from baseline to assess the effect of PI or raltegravir plus statin

No measurements were reported for this outcome.

Other pre-specifiedCompare Intergroup and Intragroup Changes in Bone Turnover Markers

Compare intergroup and intragroup changes in bone turnover markers

Time frame:
at week 24 from baseline to asses the effect of PI or raltegravir

No measurements were reported for this outcome.

Other pre-specifiedCompare Intergroup and Intragroup Changes in Renal Parameters

Compare intergroup and intragroup changes in renal parameters

Time frame:
at week 72 from week 24 to assess the effect of statin

No measurements were reported for this outcome.

Other pre-specifiedCompare Intergroup and Intragroup Changes in Renal Parameters

Compare intergroup and intragroup changes in renal parameters

Time frame:
at week 72 from baseline to assess the effect of PI or raltegravir plus statin

No measurements were reported for this outcome.

Other pre-specifiedCompare Intergroup and Intragroup Changes in Renal Parameters

Compare intergroup and intragroup changes in renal parameters

Time frame:
at week 24 from baseline to asses the effect of PI or raltegravir

No measurements were reported for this outcome.

Other pre-specifiedViral Load < 50 Copies

viral load \< 50 copies

Time frame:
at week 72

No measurements were reported for this outcome.

Other pre-specifiedViral Load > 50 Copies

viral load \> 50 copies

Time frame:
through study completion

No measurements were reported for this outcome.

Other pre-specifiedCD4+/CD8+ T Lymphocytes

CD4+/CD8+ T lymphocytes

Time frame:
at week 72 from baseline

No measurements were reported for this outcome.

Adverse events

Collected over From baseline to week 72. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Raltegravir + Atorvastatin0/20 (0%)3/20 (15%)0/20 (0%)
PI-based Regimen + Atorvastatin0/22 (0%)0/22 (0%)0/22 (0%)
Most frequent serious events
Most frequent serious events
EventRaltegravir + AtorvastatinPI-based Regimen + Atorvastatin
increments of creatine kinaseCardiac disorders2/200/22
increment of liver enzymesHepatobiliary disorders1/200/22

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)Raltegravir + AtorvastatinPI-based Regimen + AtorvastatinTotal
<=18 years000
Between 18 and 65 years202242
>=65 years000
Age, Continuous
Age, Continuous(years)Raltegravir + AtorvastatinPI-based Regimen + AtorvastatinTotal
Median49.5 ± 3.551.8 ± 8.250.65 ± 5.85
Sex: Female, Male
Sex: Female, Male(Participants)Raltegravir + AtorvastatinPI-based Regimen + AtorvastatinTotal
Female257
Male181735
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Raltegravir + AtorvastatinPI-based Regimen + AtorvastatinTotal
American Indian or Alaska Native000
Asian000
Native Hawaiian or Other Pacific Islander000
Black or African American000
White202242
More than one race000
Unknown or Not Reported000
Region of Enrollment
Region of Enrollment(participants)Raltegravir + AtorvastatinPI-based Regimen + AtorvastatinTotal
Spain202242
08

Study locations

1 site
  • Germans Trias i Pujol Hospital
    Badalona, Barcelona 08916, Spain
09

References and documents

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. PubMed 32941476 ↗
  • 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. PubMed 27999056 ↗

Study documents

  • Protocol and statistical analysis plan · May 3, 2016

Documents are hosted by the registry — open the source record to download them.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Oct 29, 2020, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT02577042
Lead sponsor
Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
Responsible party
Sponsor
First posted
Oct 16, 2015
Start date
Oct 15, 2015
Primary completion
Jun 4, 2018
Completion
Jun 4, 2018
Results posted
Jun 22, 2020
Last update
Oct 29, 2020

Oversight

Data monitoring committee
No
View the source record on ClinicalTrials.gov ↗

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