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
Condition: Aging-related Inflammation in HIV-infected Patients
MeSH terms: Inflammation
Study type: Interventional
Phase: Phase 4

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
    

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.
    

Intervention name(s): Raltegravir; PI-based regimen; Atorvastatin
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Switching the PI by raltegravir 400mg every 12 hours, plus Kivexa or Truvada, for 24 weeks.; Continue with the same PI-based regimen, plus Kivexa or Truvada, for 24 weeks.; Atorvastatin, 20mg/day, will be added after 24 weeks of study for 48 weeks
Intervention MeSH terms: Raltegravir Potassium; Atorvastatin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Raltegravir; protease inhibitors; darunavir; inflammation; statins; comorbidities