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HIV & Aging Clinical Recommendations
According to the Global Initiative for Chronic Obstructive Lung Diseases (GOLD), COPD is “characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposures to noxious particles or gases.”(GOLD 2020) COPD is common in PLWH, diagnosed in approximately 15-20%. HIV appears to increase risk for COPD.(Diaz, Clanton et al. 1992, Crothers, Butt et al. 2006, Crothers, Huang et al. 2011, Makinson, Hayot et al. 2018) Although not all studies have found a significant difference in the prevalence of COPD amongst those with and without HIV,(Ronit, Lundgren et al. 2018, Verboeket, Wit et al. 2019) a systematic review and meta-analysis of 30 studies found that the prevalence of COPD was significantly higher in PLWH than in persons without HIV, even after adjusting for cigarette smoking.(Bigna, Kenne et al. 2018)
Emphysema is a frequent manifestation of COPD in PLWH.(Diaz, King et al. 2000, Attia, Akgun et al. 2014, Guaraldi, Besutti et al. 2014) In a Veterans Affairs (VA)-based study, emphysema in PLWH was more severe and diffuse when compared to uninfected persons.(Attia, Akgun et al. 2014) Although HIV was not associated with an increased risk of emphysema in a Danish study (Ronit, Kristensen et al. 2018), the individuals without HIV in this study were significantly older than those with HIV. Further, the PLWH had ART initiated early and had higher CD4+ cell counts than those in the VA-based study. HIV is also associated with a greater risk of chronic bronchitis, another major subtype of COPD that is defined by the presence of cough with sputum production for three months for two consecutive years or more.(Diaz, Wewers et al. 2003)
The major risk factor for COPD is cigarette smoking, but occupational and environmental exposures also contribute. Prior pneumonia, including from bacterial causes, Pneumocystis and tuberculosis, are associated with airflow obstruction on pulmonary function testing.(Morris 2000)(North, Allen et al. 2018, Chin, Rylance et al. 2019) Given their increased incidence in PLWH, pulmonary infections likely play an important role in the risk and progression of COPD in PLWH.
COPD can occur at any CD4 cell count or HIV viral load in HIV-positive persons. However, the risk of COPD is increased in PLWH with a high viral load and lower CD4+ cell counts, even after adjusting for antiretroviral therapy (ART).(Drummond, Kirk et al. 2012, Crothers, McGinnis et al. 2013, Drummond, Merlo et al. 2013, Ronit, Lundgren et al. 2018) Severity of immunocompromise before start of ART, reflected by a nadir CD4+ cell count below 200 cells/µl, and ongoing immune dysfunction, reflected by a low CD4/CD8 ratio (<0.4), are also associated with radiographic emphysema in those with HIV.(Attia, Akgun et al. 2014, Triplette, Attia et al. 2017)
The diagnosis of COPD should be suspected in patients who have chronic cough or sputum production, dyspnea, and/or exposure to risk factors for the disease.(GOLD 2020) The diagnosis of COPD requires spirometry, preferably with bronchodilator testing to demonstrate persistent airflow limitation; the definition of persistent airflow limitation requires that the ratio of the forced expiratory volume in one second (FEV1) to the forced vital capacity (FVC) be less than 0.70; alternatively, an FEV1/FVC that is less than 95% of the lower limit of normal (LLN) can also be used. Among older patients, using a threshold of the FEV1/FVC below the LLN results in fewer false-positive diagnoses of COPD.(Hankinson 1999) Screening spirometry to detect COPD in asymptomatic populations is not recommend, although case-finding to diagnose individuals who have symptoms and risk factors should be pursued. One study implementing screening spirometry in an outpatient clinic for PLWH found a high prevalence of symptoms and exposures consistent with COPD, and approximately one quarter of those who completed spirometry were diagnosed with COPD.(Lambert 2016)
Health care providers should obtain spirometry in PLWH who have chronic respiratory symptoms. Complete pulmonary function testing including measurement of diffusing capacity should also be considered, as PLWH are more likely to have a decrease in diffusing capacity despite relatively normal spirometry.(Gingo 2010) Indeed, PLWH have an increased risk of a moderately to severely impaired diffusing capacity, defined as <60% predicted normal, compared to uninfected persons after adjusting for smoking and other risk factors.(Crothers 2013; Fitzpatrick 2013) A decreased diffusing capacity suggests the presence of emphysema or other disease processes such as pulmonary arterial hypertension or pulmonary fibrosis that interfere with normal gas exchange within the lung. Non-contrast chest CT scan can be helpful to further evaluate respiratory symptoms and distinguish between different diseases that result in impaired diffusing capacity.
COPD may progress more rapidly in PLWH, particularly in current smokers and those with poorly controlled HIV. Amongst injection drug users with HIV, the rate of decline in the FEV1 and the FVC was accelerated in patients with high HIV viral load (defined as >75,000 copies/ml) and with low CD4 cell count (defined as <100 cells/µl), when compared to patients with better controlled HIV disease and to those without HIV infection.(Drummond 2013) Ongoing smoking also increases the rate of lung function decline in PLWH compared to non-smokers, and underscores the importance of smoking cessation in PLWH.(MacDonald, Melzer et al. 2018) PLWH may have a greater risk of COPD exacerbation compared to persons without HIV.(Depp 2016; Lambert 2015) Whether this reflects a greater risk of infection is unclear.
In the absence of data on the treatment of COPD specifically in the setting of HIV infection, current therapy of COPD in PLWH should follow the management guidelines proposed for the general population. In the Global Obstructive Lung Disease (GOLD) 2020 guidelines, therapy for COPD is driven by symptoms and history of exacerbations rather than by severity of airflow limitation, which is graded by the FEV1 % predicted.(GOLD 2020) Symptoms can be assessed using the Medical Research Council (MRC) Dyspnea score, COPD Assessment Test (CAT) or the COPD Control Questionnaire (CCQ); the latter two are more comprehensive whereas the MRC is a single dyspnea item. Smoking cessation should be prioritized for all PLWH, particularly those with COPD. Because COPD in PLWH increases the risk for pneumonia,(Attia, McGinnis et al. 2015) all PLWH with COPD should receive the recommended pneumococcal vaccines (both PCV13 and PPSV23) (CDC 2012; Kim 2017) and yearly inactivated or recombinant influenza vaccine.
Pharmacotherapy is initiated for symptomatic COPD patients with inhaled bronchodilators. For patients who have regular symptoms, monotherapy with a long acting bronchodilator is recommended. Long-acting muscarinic antagonists (LAMA’s) do not have known clinically significant drug-drug interactions with antiretrovirals, and thus can represent first-line bronchodilator therapy for COPD in PLWH. An inhaled long-acting beta-agonist (LABA) is an alternative, second choice. Amongst LABA’s, no clinically significant interactions have been reported between olodateral and formoterol with anti-retroviral medications, but salmeterol can interact with different antiretrovirals to cause QTc prolongation. Combination therapy with a LAMA plus LABA is recommended if symptoms are persistent on monotherapy.
Inhaled corticosteroids (ICS) are primarily reserved for patients who have exacerbations of COPD. ICS can be particularly challenging in PLWH due to drug-drug interactions with antiretrovirals. Protease inhibitors (PIs), particularly ritonavir, have been reported to increase systemic levels of inhaled or intranasal fluticasone and other ICS leading to Cushing syndrome or adrenal suppression when corticosteroids are tapered. Beclomethasone has the least interaction and is the preferred ICS when used in combination with strong CYP3A4 inducers including boosted regimens (cobicistat, ritonavir) and most PIs. Careful monitoring is also required as high-dose ICS are associated with increased risk of oral candidiasis, bacterial pneumonia,(Calverley 2007; Drummond 2008) and tuberculosis.(Brassard 2011) The regular use of systemic steroids for COPD in PLWH should preferably be avoided.
How to tailor therapy for PLWH who have COPD based on frequency of exacerbations is uncertain. For PLWH who have persistent exacerbations despite being on triple inhaled therapy with LABA, LAMA and ICS, roflumilast or azithromycin may be added as per COPD guidelines.(GOLD 2020) As in uninfected individuals with COPD, discontinuation of ICS may be able to be achieved safely with careful monitoring in those who have not had an exacerbation in the past year.(Magnussen, Disse et al. 2014)
COPD is an important contributor to poor physical function in PLWH. Among Veterans infected with HIV, chronic obstructive lung disease (COPD and/or asthma) was among the top comorbid conditions independently associated with self-reported increased physical disability.(Oursler 2006) Airflow limitation, as reflected by a low FEV1, and radiographic emphysema are also associated with decreased 6-minute walk distance in PLWH.(Campo 2014)(Triplette, Attia et al. 2017) Reasons why HIV may result in greater physical limitation in COPD patients are not well understood, but could be related to concomitant comorbidities, muscle loss, and inflammation associated with HIV.
PLWH with COPD should be considered for participation in pulmonary rehabilitation programs. In patients with COPD, physical functioning is significantly improved with participation in pulmonary rehabilitation programs.(Spruit, Singh et al. 2013) In general, pulmonary rehabilitation programs can benefit all COPD patients, although gains tend to be larger in those who are more symptomatic and have more severe disease.(GOLD 2020) Studies support the safety and potential benefit of exercise training in PLWH (O’Brien 2010) although further studies are needed to determine the role and optimal type of exercise training in PLWH, particularly older patients with COPD.
Finally, COPD is associated with several comorbidities that may complicate care, particularly of elderly patients. These include cardiovascular disease, muscle wasting, osteoporosis, malnutrition, depression, anxiety and lung cancer.(Putcha, Drummond et al. 2015) Notably, many of these conditions also occur with increased frequency in PLWH. COPD is also a significant risk factor for increased frailty, decreased physical function and increased mortality in PLWH.(Akgun, Tate et al. 2016, Triplette, Attia et al. 2017, Gingo, Nouraie et al. 2018, Triplette, Justice et al. 2018) As survival improves with effective and early ART, COPD is likely to complicate the care and to adversely impact health-related quality of life, functional status, and mortality in an increasing proportion of PLWH.
Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD). 2017.
Lambert AA, Kirk GD, Astemborski J, Mehta SH, Wise RA, Drummond MB. HIV Infection Is Associated With Increased Risk for Acute Exacerbation of COPD. J Acquir Immune Defic Syndr 2015; 69(1):68-74.
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