Due to the remarkable progress made in the treatment of HIV infection, the life expectancy of HIV-infected patients in the US has increased dramatically. However, chronic diseases, including lung disease, in this patient population are becoming increasingly common. In HIV-uninfected U.S. adults, asthma is one of the most common respiratory diseases affecting 5-10% of the general population. In patients with HIV infection, the limited data available suggest that asthma prevalence is increased, ranging from 12-25%. However, the diagnosis is often made based upon ICD-9 codes, which are not entirely accurate. If true, this increase may be due, in part, to increases in specific inflammatory mediators such as interleukin-6 (IL-6), a consistently elevated cytokine in numerous HIV disease states. A T-helper 2 (Th2) inflammatory and pro-fibrotic cytokine, interleukin (IL)-6 may drive a Th2 inflammatory phenotype commonly seen in asthma and is persistently elevated despite anti-retroviral therapy (ART). Thus, we hypothesize that HIV-associated asthma in the post-ART era manifests as a Th2 inflammatory phenotype driven, in part, by IL-6, which modulates asthma severity and control. To test this hypothesis, we will first characterize asthma phenotypes and determine asthma prevalence in HIV-infected patients with possible asthma at the Duke and the Durham Veterans'Affairs Infectious Disease Clinics. This will be done through use of electronic health records and through prospectively phenotyping subjects at the Duke Asthma, Allergy and Airway Center using state-of-the-art physiologic techniques, measurements of biomarkers and questionnaires (Aim 1).
In Aim 2, we will determine whether IL- 6 plays a major role in the immunological phenotype of asthma before and after initiation of ART initiation by evaluating asthma severity, control and exacerbations in HIV-infected patients with asthma as compared to a cohort of HIV-uninfected patients with asthma in a six-month longitudinal study. To guide this aim's immunological measures, we will leverage the Duke HIV Biorepository and measure several serum cytokines relevant to inflammatory phenotypes in HIV-infected subjects with asthma including IL-4, IL-5, IL-6, IL-13, IL- 17, IL-23 and interferon gamma. There are also challenges in treating asthma in these patients as most inhaled corticosteroids, first lin therapy for asthma, significantly interact with protease inhibitors and the pharmacoenhancer, cobicistat. Therefore, Aim 3 will determine if HFA beclomethasone diproproniate, an inhaled corticosteroid, can be safely and effectively used to treat asthma in HIV-infected patients receiving ART containing protease inhibitors or cobicistat, in a randomized, placebo controlled trial of three months duration. Through these combined aims, this proposal will not only accurately determine the prevalence and severity of asthma in an HIV-infected population, it will also increase our understanding of the inflammatory phenotypes in the setting of HIV infection and asthma and provide a safe option for therapy that can inform guideline-based asthma management in HIV-infected patients. ?
Thanks to very effective treatment, patients with human immunodeficiency virus (HIV) infection are living longer and now these patients are developing chronic medical conditions, including chronic lung disease. Asthma is the most common chronic lung disease affecting 5-10% of the general population in the United States. Our preliminary analysis and the current literature suggest that asthma prevalence is increased in patients with HIV infection and we hypothesize that this is due, in part, to interleukin (IL)-6 a cytokine that i known to be elevated in HIV-infected patients and remains elevated after anti-retroviral therapy (ART). This proposal will not only accurately determine the prevalence and severity of asthma in an HIV-infected population, it will also increase our understanding of the HIV and asthma inflammatory phenotypes and provide a safe option for therapy that can impact guideline-based asthma management in HIV-infected patients. Therefore, this work is highly relevant to public health.