Pulmonary diseases, especially pneumonia, have been among the most frequent complications of HIV since early in the AIDS epidemic [1–3]. In parallel with other complications of HIV, the spectrum of pulmonary diseases currently reflects a substantial burden of non-AIDS-defining chronic diseases as HIV-infected patients are aging on antiretroviral therapy (ART) [4–9]. A leading cause of global mortality [10,11], chronic obstructive pulmonary disease (COPD) is the most common chronic lung disease diagnosed in HIV-infected patients, encountered in approximately 20% of patients in different cohorts [4,6,8,9,12]. However, our understanding of the impact of chronic HIV infection on lung health over time remains incomplete. Does HIV cause a unique impairment in lung health, or is HIV a ‘second hit’ to accelerate the toxic effects of other exposures such as cigarette smoking to cause typical diseases like COPD? Or, is the increased burden of lung diseases in HIV merely explained by a greater prevalence of smoking, drug use, respiratory infections, and other exposures that are common in many HIV-infected populations?
To date, whether HIV infection is an independent risk factor for chronic lung diseases, particularly COPD, remains uncertain. Cross-sectional studies in HIV-infected and uninfected persons comparing the prevalence of COPD, defined by the presence of fixed airflow obstruction on spirometry, have had somewhat conflicting results [6,8]. Disentangling the effects of numerous behavioral, environmental, and occupational exposures, and the contribution of comorbid conditions from those of HIV infection on lung health is challenging, particularly in cross-sectional analyses.
The current work by Drummond et al.  in this month's issue of AIDS expands our knowledge of the effects of HIV infection on lung health with one of the first longitudinal studies of lung function decline in HIV-infected compared to demographically and behaviorally similar HIV-uninfected persons in the combination ART era. They examined the effect of HIV infection, specifically HIV viral load and CD4 cell count, on lung function decline in a cohort of injection drug users, the AIDS Linked to the IntraVenous Experience (ALIVE) study.
Several findings from the study will be important both to clinicians caring for HIV-infected patients and to researchers trying to understand the causes of HIV-associated lung disease. First, absolute values of airflow, namely, the forced expiratory volume in 1 second (FEV1) and the forced vital capacity (FVC), were significantly lower in HIV-infected compared with uninfected participants in analyses adjusted for demographic, behavioral, and clinical factors; whether this is because of a prior period of accelerated decline in lung function such as from earlier episodes of pneumonia, or due to a lower attainment of overall lung function such as from earlier initiation of smoking or childhood illness, or for other reasons, is not known. Second, the rate of decline in lung function, as measured by the change in FEV1 and the FVC, was similar in HIV-infected and uninfected drug users overall. The decrease in FEV1 was nonsignificantly higher, and the decrease in FVC was greater, but of borderline significance in HIV-infected individuals (P = 0.05). Given the nearly universal smoking history and high rate of current drug use, the decrements in lung function over time are overall surprisingly small. There may have also been differences in prescription of bronchodilators that had an unmeasured effect on the results, and bronchodilator testing was not administered during spirometry.
The most intriguing finding is that despite the lack of difference in lung function decline in the overall HIV-infected population compared to HIV-uninfected, when stratified by HIV disease severity, a higher HIV viral load (defined as >75 000 copies/ml) and a lower CD4 cell count (considering absolute values as well as CD4%) were associated with a greater rate of decline in both FEV1 and FVC over time. HIV-infected participants with CD4 cell counts of 200 cells/μl and below were significantly more likely to have a greater decline in FEV1 and FVC over time compared to HIV-uninfected individuals. In contrast, decline in lung function was similar in HIV-infected persons with CD4 cell count above 200 cells/μl and those without HIV. These data raise the possibility that ART and better control of HIV may ameliorate the decline in lung function in HIV, although previous studies have found an association of ART with worse airway obstruction [9,14] and time-updated ART use was not significantly associated with change in lung function in the current analyses.
Residual confounding in human studies always remains as a potential explanation for these findings. However, Drummond et al. assessed other risk factors in a rigorous fashion and utilized time-updated covariates to account for factors such as current smoking status, recent HIV disease severity, and intercurrent respiratory infection . In particular, increased risk for pneumonia in patients with poorly controlled HIV could certainly mediate rate of decline in lung function. Notably, the incidence of pneumonia was low, especially in those with CD4 cell counts below 100. However, assuming that capture of pneumonia events was complete, these data support that the association of HIV viremia and/or immunodeficiency with greater lung function decline is independent of pneumonia and other major confounders.
These findings raise a number of intriguing questions. Why is uncontrolled HIV disease associated with a greater risk of decline in lung function? Is the association with higher HIV viral load due to effects of the virus itself, accompanying inflammation, and/or immune activation? Does poorly controlled HIV increase the risk for colonization with microorganisms that may play a role in COPD pathogenesis (such as with Pneumocystis)? Furthermore, is the effect of HIV viremia or immunodeficiency more important, and is there an independent effect of ART initiation? In analyses grouped by combined CD4 and viral load levels, decline in FEV1 appeared more strongly associated with HIV RNA greater than 75 000 copies/ml, whereas decline in FVC appeared more strongly associated with CD4 cell counts below 100 cells/μl.
Taken together, these data suggest that HIV viremia and immunodeficiency may contribute to different lung diseases. Although the predominant effect seems to be an increase in airflow obstruction over time, not all disease in HIV-infected individuals may represent COPD. Additional studies are needed with evaluation of full pulmonary function inclusive of bronchodilator testing, lung volumes, and diffusing capacity paired with chest computed tomography scans to better understand the physiology and disease processes driving the decrease in airflow (i.e., FEV1, FVC). Furthermore, whether similar declines in FEV1 and FVC will be seen in HIV-infected cohorts with a lower prevalence of injection drug use requires investigation.
A final important finding of this study to highlight is the documented increase in individuals with airflow obstruction in the cohort over time. At baseline, 16% of the cohort met spirometric criteria for airflow obstruction (defined as an FEV1/FVC<70%). During follow-up, the proportion of individuals with airflow obstruction increased to 23% at last visit. Although markers of HIV disease control were associated with more rapid decline in FEV1 and FVC, the magnitude of decrement in FEV1 decline was greater. Overall, these data confirm that the burden of chronic lung disease, particularly obstructive disease, in HIV-infected populations is increasing over time.
What are the implications for clinical care? The management of chronic lung diseases such as COPD in HIV-infected populations has not been well defined as there have been no large-scale trials of COPD therapies in HIV-infected individuals. COPD is a major cause of morbidity in HIV-infected patients: it is a strong risk factor for hospitalization , a leading cause of respiratory failure in critically ill HIV-infected patients , and is associated with significantly worse health-related quality of life . Whether current guidelines for management of COPD and other chronic lung diseases in HIV-uninfected patients can be applied to those with HIV infection is uncertain and requires further study.
Two conclusions, however, are clear: given that approximately 40–50% of HIV-infected patients smoke compared to 20% in the general population , smoking-related comorbidities with a long latency of onset such as COPD will become increasingly common as HIV-infected patients are aging; and increased efforts to improve smoking cessation in HIV-infected populations are urgently needed. The study by Drummond et al.  underscores the importance of COPD in HIV and the need for increased awareness and understanding of obstructive lung diseases in this population.
Conflicts of interest
There are no conflicts of interest.
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