Epidemiology and Social
The effect of HIV infection on longitudinal lung function decline among IDUs: a prospective cohort
Drummond, Michael Bradleya; Merlo, Christian A.a; Astemborski, Jacquieb; Kalmin, Mariah M.c; Kisalu, Annamarieb; Mcdyer, John F.d; Mehta, Shruti H.b; Brown, Robert H.a,e; Wise, Robert A.a; Kirk, Gregory D.a,b
aDepartment of Medicine, School of Medicine, Johns Hopkins University
bDepartment of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
cDepartment of Epidemiology, School of Public Health and Health Services, George Washington University, Washington, District of Columbia
dDepartment of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
eDepartment of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
Correspondence to Michael Bradley Drummond, MD, MHS, Division of Pulmonary and Critical Care Medicine, 5501 Hopkins Bayview Circle, JHAAC 4B.70, Baltimore, MD 21224, USA. Tel: +1 410 550 6431; fax: +1 410 550 8050; e-mail: email@example.com
Received 17 October, 2012
Revised 11 December, 2012
Accepted 21 December, 2012
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).
Objective: As survival with HIV infection improves, HIV-infected individuals appear to be susceptible to development of chronic diseases, including restrictive and obstructive lung diseases. We sought to determine the independent association of HIV infection on lung function decline.
Design: Longitudinal analysis of the AIDS Linked to the Intravenous Experience study, an observational cohort of current and former IDUs.
Methods: Generalized estimating equations were used to determine the effects of markers of HIV infection on adjusted annual change in forced expiratory volume in one second (FEV1) and forced vital capacity (FVC).
Results: A total of 1064 participants contributed 4555 spirometry measurements over a median follow-up time of 2.75 years. The mean age of the cohort was 48 years; nearly, two-thirds were men and 85% current smokers. After adjustment, the overall annual decline of FEV1 and FVC between HIV-infected and uninfected persons did not differ. However, there was a 76 ml/year greater rate of decline in FEV1 and 86 ml/year greater rate of decline in FVC among HIV-infected participants with viral load more than 75 000 copies/ml compared with HIV-uninfected individuals (P < 0.01). Similarly, HIV-infected individuals with CD4 cell count less than 100 cells/μl had a 57 ml/year more rapid decline in FEV1 and 86 ml/year more rapid decline in FVC than HIV-uninfected participants (P = 0.018 and P = 0.001, respectively).
Conclusion: Markers of poorly controlled HIV disease are independently associated with accelerated annual lung function decline, with decrements in both FEV1 and FVC. These findings highlight the need for optimized HIV antiretroviral therapy in addition to smoking cessation among HIV-infected individuals with tobacco dependence.
The advancement of antiretroviral therapy (ART) has led to improved survival and longer life expectancy for persons living with HIV infection [1–3]. Subsequently, there is an increased recognition of development of age-associated chronic diseases (e.g. cardiovascular, metabolic, renal, neurological) and non-AIDS-defining malignancies occurring in these individuals [4–8]. Emerging data suggest an increased prevalence of chronic lung disease in HIV-infected individuals, the spectrum of which includes both chronic airflow obstruction and restrictive lung disease [9–12]. HIV infection has been shown to increase the diagnosis of self-reported and administratively diagnosed COPD [13,14]. We have previously shown that the odds of airflow obstruction were increased more than three-fold among HIV-infected individuals with the highest plasma viral load independent of smoking compared with epidemiologically similar HIV-negative individuals . Respiratory infections, increased in HIV-infected individuals, are associated with restrictive lung disease . Beyond these cross-sectional reports, few studies have evaluated longitudinal lung function decline among HIV-infected persons [12,16]. Because earlier studies were prior to widespread ART availability and recent studies were limited by small numbers of persons, short duration of follow-up and lack of HIV-negative comparator groups, the independent effect of HIV disease markers on lung function decline remains unanswered.
The AIDS Linked to the Intravenous Experience (ALIVE) study is a longitudinal cohort of persons with a history of injecting drugs with or at-risk for HIV infection followed in Baltimore, Maryland, since 1988 . The ALIVE study collects behavioural, clinical and laboratory data at regular 6-month intervals and recently instituted serial spirometric measures into the data collection protocol. With nearly ubiquitous cigarette smoking and substantial prevalence of respiratory symptoms and obstructive lung disease (OLD) [18–20], ALIVE represents an appropriate population to examine the effect of HIV infection on changes in lung function. In the current study, we used longitudinal data from ALIVE to determine the independent association of HIV infection on lung function decline over almost 3 years of observations. We hypothesized that HIV infection, particularly more advanced HIV disease, would be associated with accelerated lung function decline. Some of these results have been previously presented at the 19th Conference on Retroviruses and Opportunistic Infections and published in an abstract form .
Materials and methods
As described previously [17,22], since 1988, ALIVE has recruited residents of Baltimore, Maryland, who were at least 18 years of age and had a history of injection drug use into biannual follow-up. At each study visit, both HIV-infected and uninfected participants completed standardized interviewer and computerized questionnaires, a clinical examination, and provided blood samples. Since 2007, participants performed prebronchodilator spirometry testing at each study visit. We performed a longitudinal analysis of 1064 participants who contributed at least two spirometry measurements between January 2007 and December 2010. The study was approved by the IRB of Johns Hopkins University. All participants provided written informed consent.
Demographic, behavioural, clinical and laboratory data were collected contemporaneously with spirometry measurements. Smoking patterns, injection drug use and ART use were determined by self-report. Respiratory infections were identified through standardized medical record review and were classified as bacterial, Pneumocystis, or other (e.g. viral, tuberculosis or multifactorial). Prebronchodilator spirometry forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) was performed using KOKO pneumotachometers (nSpire Health Inc, Longmont, Colorado, USA). All spirograms were automatically assessed by a computer software for accordance with American Thoracic Society guidelines . Any spirogram identified as potentially of poor quality was reviewed by two pulmonologists and excluded if effort and reproducibility criteria were not met. Percentage-predicted values were calculated using standard formulas . OLD was defined as an FEV1/FVC ratio less than 0.70 .
All data are presented as mean (standard deviation) for normally distributed data and median [interquartile range (IQR)] for nonnormally distributed data. To determine the independent association of markers of HIV infection on longitudinal lung function decline, linear regression models of FEV1, FVC and FEV1/FVC ratio with generalized estimating equations  with an exchangeable correlation structure and robust estimation of variance were used. Predictors were selected on the basis of an association with FEV1 decline in univariate analysis and by relevance based on literature review. Final models included age, race, sex, BMI, baseline pack-years smoking (defined as the reported number of years smoked throughout life * average packs per day smoked), time varying current smoking status (current vs. nonsmoker updated biannually), time varying injection drug use updated biannually and prior respiratory infection updated biannually. Markers of HIV disease (HIV serostatus, viral load, CD4 cell count) and ART use were modelled as time-varying covariates, updated at biannual visits. Annual change in lung function decline (ml/year) was assessed via the interaction of the spirometric measure and time. HIV viral load was modelled categorically at clinical thresholds (<400 vs. 400–75 000 vs. >75 000 copies/ml). CD4 cell count was also considered categorically (<100, 100–200, >200 cells/μl). Models evaluated HIV-infected persons overall and stratified by disease markers compared with HIV-uninfected persons as the reference group; similar analysis was also performed among HIV-infected persons only. For data presentation, graphs of modelled absolute FEV1 and FVC decline (expressed in millilitre) vs. follow-up time were generated after centring values for the covariates of a typical participant (50-year-old African-American male current smoker with 20 pack-year smoking history, BMI 25 kg/m2 and no history of pneumonia) as well as time-updated HIV serum viral load and CD4 cell count. A P value of less than 0.05 was used to infer statistical significance. Stata version 12.0 (Stata Corp, College Station, Texas, USA) and SAS software (SAS Institute Inc., Cary, North Carolina, USA) were used for statistical analyses.
A total of 97% of eligible ALIVE participants completed spirometry testing, with 1064 participants contributing 4555 spirometry measurements over a median follow-up time of 2.75 years (range 0.5–3.9 years). We found no differences in distribution of sex, race, HIV status, viral load category, current injection drug use or current smoking comparing those with and without spirometry measurements. Age was different between those who did and did not complete spirometry (median 51.6 years for those without spirometry; P = 0.04). For the cohort with spirometry data, at baseline, the mean age was 48 ± 7 years; nearly, two-thirds were men and 91% were black (Table 1). Almost all participants reported ever smoking cigarettes (94%) and most were current cigarette smokers (85%). Although all participants had a history of injecting drugs, 40% reported active injection drug use in the prior 6 months. Nearly 40% reported ever smoking cocaine, heroin or marijuana. At baseline, 169 (16%) met spirometric criteria for OLD. The proportion of individuals with OLD increased to 23% at last visit, with 109(10%) of the 895 without OLD at baseline meeting spirometric criteria at final visit. At baseline, the FEV1/FVC was 0.77 ± 0.08, baseline FEV1 was 92% predicted and FVC 3.65 ± 0.94 l. At baseline, 316 (30%) were HIV-infected with 230 (74%) having a CD4 cell count of more than 200 cells/μl, 55% were currently receiving HAART and 148 (47%) had an HIV RNA viral load of less than 400 copies/ml. At baseline, a total of 129 clinically confirmed respiratory infections had occurred. During follow-up, 60 respiratory infections occurred, with 28 (47%) occurring in HIV-negative individuals, 20 (33%) in HIV-infected individuals with CD4 cell count more than 200 cells/μl, seven (11%) in HIV-infected individuals with CD4 cell count between 100 and 199 cells/μl, and five (8%) in HIV-infected individuals with CD4 cell count less than 100 cells/μl.
Effect of HIV infection on absolute forced expiratory volume in one second and forced vital capacity levels
Female sex, older age, black race and higher BMI were independently associated with lower absolute FEV1 and FVC (see Table, Supplemental Digital Content 1, http://links.lww.com/QAD/A304, which displays the adjusted effect of demographic, behavioural and clinical factors on absolute FEV1 and FVC). In this group of nearly ubiquitous smokers and after adjusting for age (collinear with pack-years), increasing pack-years of smoking history and smoking status were not independently associated with lower absolute FEV1 or FVC. Prior respiratory infection resulted in 106 ml lower absolute FEV1 [95% confidence interval (CI) −162 to −48.8 ml; P < 0.001] and 96.5 ml lower absolute FVC (95% CI −167 to −26.4 ml; P = 0.007). Each year of time from initial spirometry was associated with a lower FEV1 but not with a lower FVC. After adjusting for these demographic, behavioural and clinical factors, HIV infection was independently associated with a 154 ml lower absolute FEV1 (95% CI −221 to −86 ml) and 210 ml lower absolute FVC (95% CI −288 to −132 ml) compared with HIV-uninfected individuals (P < 0.001 for both estimates).
Markers of HIV disease and annual rate of decline of forced expiratory volume in one second and forced vital capacity
In order to assess the association of advanced HIV disease on annual FEV1 and FVC decline, we incorporated HIV disease markers into adjusted models (Table 2). The annual rate of FEV1 decline in HIV-infected individuals was −35.8 ml/year (95% CI −51.2 to −20.3 ml/year) compared with −23.6 ml/year (95% CI −32.6 to −14.7 ml/year) among HIV-uninfected participants, with a difference in slopes of 12.2 ml/year (95% CI −28.1 to 3.78 ml/year; P = 0.135). The annual rate of FVC decline in HIV-infected persons was −9.29 ml/year (95% CI −25.1 to 6.5 ml/year), in HIV-uninfected persons +8.0 ml/year (95% CI −26.4 to 18.7 ml/year), with the difference in slopes of 17.3 ml/year (95% CI −34.3 to −0.33 ml/year; P = 0.05). Figure 1 graphically represents the impact of HIV infection on modelled FEV1 and FVC over time by centring the other covariates to represent the typical participant in this cohort (50-year-old African-American current smoker with a 20 pack-year smoking history, BMI of 25 kg/m2 and no history of respiratory infection). Although HIV-infected persons had a lower absolute FEV1 and FVC at study entry, the annual rate of FEV1 decline did not differ compared with HIV-uninfected individuals.
Recognizing that HIV status alone does not accurately model the range of severity of HIV disease in this cohort, additional models were examined that incorporated HIV viral load and CD4 cell count levels (Table 2). Compared with HIV-uninfected individuals, HIV-infected individuals with a plasma viral load of 75 000 copies/ml or less had a similar adjusted annual FEV1 decline (−23.5 vs. −29.9 ml/year; P = 0.44). However, HIV-infected participants with a viral load of more than 75 000 copies/ml experienced a substantially greater adjusted annual FEV1 decline compared with HIV-uninfected individuals (−99.1 vs. −23.5 ml/year; P = 0.004), with a difference of 75.6 ml/year (95% CI 23.8–127 ml/year). The difference in annual FEV1 decline between HIV-infected individuals with viral load of 75 000 copies/ml or less and HIV-infected individuals with viral load of more than 75 000 copies/ml was also significantly greater (69.2 ml/year; 95% CI 15.3–123 ml/year; P = 0.012). Similar results were observed when examining the effect of HIV viral load level on annual FVC decline (Table 2). HIV-infected participants with a viral load of more than 75 000 copies/ml demonstrated a greater adjusted annual FVC decline compared with HIV-uninfected individuals (−74.0 vs. 8.24 ml/year; P = 0.008), with a difference of 85.7 ml/year (95% CI 35.8–136 ml/year; Fig. 2).
When stratifying HIV-infected persons by the degree of immunodeficiency, individuals with lower CD4 cell counts experienced a more rapid decline in FEV1 and FVC (Table 2 and Fig. 3). Although HIV-infected individuals with CD4 cell count more than 200 cells/μl had similar adjusted annual FEV1 and FVC decline compared with HIV-uninfected persons, HIV-infected participants with CD4 cell counts between 100 and 200 cells/μl experienced a 34.4 ml/year (95% CI 1.63–67.1 ml/year; P = 0.04) greater decline in FEV1 and 34.3 ml/year (95% CI −1.5 to 70.1 ml/year; P = 0.06) greater decline in FVC compared with HIV-uninfected individuals. HIV-infected individuals with the lowest CD4 cell counts (<100 cells/μl) had the most rapid adjusted annual FEV1 and FVC decline. There was no difference in annual FEV1 or FVC decline comparing HIV-infected individuals with CD4 cell count between 100 and 200 cells/μl with HIV-infected individuals with CD4 cell count more than 200 cells/μl. However, HIV-infected individuals with CD4 cell count less than 100 cells/μl experienced a greater decline in FEV1 and FVC than HIV-infected individuals with CD4 cell count of more than 200 cells/μl (P = 0.031 and P = 0.003, respectively). There were no differences in the annual rates of decline of FEV1 or FVC comparing HIV-infected participants with CD4 cell count of less than 100 cells/μl with HIV-infected persons with CD4 cell counts between 100 and 200 cells/μl.
To differentiate whether higher viral load or lower CD4 cell count may represent the primary contributor to FEV1 and FVC decline, we evaluated models incorporating groups classified by combined CD4 cell count/viral load levels (Table 2). Although a dose–response relationship in annual FEV1 decline was observed with lower CD4 cell counts, this relationship was not significantly different from HIV-uninfected persons if HIV-infected individuals had HIV RNA levels of 75 000 copies/ml or less. In contrast, HIV-infected persons with viral load more than 75 000 copies/ml had significantly more rapid annual FEV1 decline compared with HIV-uninfected persons irrespective of CD4 cell count (−90.8 ml/year for CD4 cell count >100 cells/μl; 95% CI −145 to −36.2 ml/year; P = 0.017 and -125 ml/year for CD4 cell count <100 cells/μl; 95% CI −220 to −30.4 ml/year; P = 0.037). In contrast, when examining the effect of combined CD4 cell count/viral load levels on FVC decline, strata with CD4 cell count of less than 100 cells/μl had more rapid annual decline than HIV-uninfected persons. This association was present irrespective of viral load level.
Sensitivity analyses were performed to determine the effect of incorporating other potential confounders of relationship between HIV and lung function decline. The association between markers of HIV disease and annual decline in FEV1 or FVC did not change when including history of smoked drugs, time varying ART use or hepatitis C antibody status into models. To explore whether specific types of respiratory infections (bacterial, Pneumocystis) differentially impacted our findings, we performed sensitivity analyses with models including only bacterial or only Pneumocystis infections, and found no difference from our primary findings. When incorporating CD4 cell count% rather than absolute CD4 cell count, similar associations with lung function decline were observed. There was no association between markers of HIV infection and annual rate of change in FEV1/FVC ratio (see Table, Supplemental Digital Content 2, http://links.lww.com/QAD/A304, which displays the adjusted effect of markers of HIV infection on annual FEV1/FVC ratio).
In this analysis of 4555 spirometry measurements obtained on 1064 individuals with or at-risk for HIV infection over a median of 2.75 years, we found a strong effect of poorly controlled HIV disease independently contributing to accelerated lung function decline. Specifically, HIV-infected individuals with plasma viral load exceeding 75 000 copies/ml had a more rapid annual decline in FEV1 and FVC than in those with controlled HIV disease or without HIV infection. Similarly, the annual loss in FEV1 and FVC of HIV-infected individuals with CD4 cell counts less than 100 cells/μl was greater than HIV-infected individuals, with CD4 cell count exceeding 200 cells/μl or HIV-uninfected individuals. Importantly, the effect of poorly controlled HIV disease was independent of factors known to contribute to longitudinal lung function decline, including age, smoking habits and respiratory infections. As well, although there were decrements in both FEV1 and FVC over time associated with HIV infection, the magnitude of effect on FEV1 decline exceeded that of FVC. These observations provide further evidence to the emerging body of literature that accelerated lung disease is a complication of HIV infection. Both obstructive and restrictive processes are implicated in chronic lung disease associated with poorly controlled HIV infection. In addition, these findings highlight the need for optimizing HIV treatment among HIV-infected individuals with tobacco dependence and suggest a potential benefit of maintaining lung function through achieving viral suppression.
Our findings of accelerated longitudinal lung function decline in poorly controlled HIV infection extend the previously described cross-sectional associations between HIV infection and OLD [11,13,14]. Previously, we demonstrated that higher plasma viral load was independently associated with the presence of airflow obstruction . In this analysis, we again see a strong independent effect of higher viral load on adverse lung outcomes. As well, we observed that low CD4 cell counts predicted accelerated FEV1 and FVC decline over time, although the viral load effect appeared to be the dominant factor associated with accelerated FEV1 decline while CD4 effects contribute to FVC decline. In addition to predicting AIDS progression and death , our findings suggest that CD4 cell count and viral load can also predict lung function decline in the setting of HIV.
Although the highly prevalent tobacco use among ALIVE participants does not allow for robust modelling of potential additive effects of smoking and HIV infection on lung function decline, this characteristic of the ALIVE cohort does allow for isolation of the effects of HIV infection independent of smoking. In this analysis, HIV-infected individuals with elevated viral load or reduced CD4 cell counts had a more rapid annual FEV1 decline on the order of 55–76 ml/year compared with those with controlled HIV infection or without HIV. Studies comparing the rates of decline of FEV1 in the general population have reported that current smoking results in an annual FEV1 decline of approximately 35–45 ml compared with former or nonsmokers [28,29]. Thus, the effect of uncontrolled HIV infection on FEV1 decline in this analysis was of greater magnitude than the impact of smoking reported in the general population. Our findings demonstrate that uncontrolled HIV infection is at least as powerful a contributor to lung function decline as cigarette smoking in HIV-uninfected populations, and may even exceed the deleterious effects of current tobacco use.
There are potential immune mechanisms to explain the association between HIV disease severity and accelerated lung function decline. Systemic immune activation has been correlated with HIV progression and may play an important role in lung disease progression similar to that described in the gastrointestinal tract . The HIV-specific adaptive immune T-cell response may contribute to injurious pulmonary CD8+ T-cell alveolitis [27,31,32]. In addition, behavioural effects may contribute to this association, including differential access to medical care or engagement in high-risk behaviours among those persons with uncontrolled HIV infection. The unique strength of the ALIVE cohort is that the HIV-negative comparator group is similar in other measured and unmeasured confounders, allowing for HIV associations with lung function decline. Although epidemiological studies, such as the one presented, cannot ultimately determine causal pathways, the findings we describe highlight the need for increased exploration of the role of HIV in chronic lung disease, increased awareness of potential for undiagnosed lung disease during HIV clinical encounters and targeted smoking cessation in this high-risk cohort.
Another potential explanation for the association between more severe HIV infection and accelerated lung function decline is the increased risk of respiratory infections in this population. Prior studies have established that lung function decline in HIV is accelerated in the setting of bacterial and Pneumocystis respiratory infections [12,16]. In an HIV-infected cohort followed for an average of 3.7 years, it was shown that bacterial pneumonia and Pneumocystis infections resulted in a 109–264 ml fall in FEV1 and 117–254 ml fall in FVC, which was not regained over time . We observed a similar magnitude of association with prior respiratory infections. Because of the standardized medical record abstraction of respiratory infections in the ALIVE cohort, we are able to account for this confounding factor in analyses. Our observations of more rapid annual decline in FEV1 and FVC with worse HIV control persisted after adjusting for bacterial and Pneumocystis infections, suggesting that accelerated decline is largely attributable to HIV infection, rather than a secondary consequence of respiratory infections. Despite this, respiratory infections may predispose to progressive restrictive lung disease, resulting in decrements of both FEV1 and FVC. The observation that the FVC is not falling at a greater rate than FEV1 suggests this is not simply a restrictive process resulting in secondary FEV1 fall. In this cohort, decrements in FEV1 and FVC observed with HIV disease are likely multifactorial, related to obstructive ventilatory defects from tobacco use as well as restrictive defects related to prior infection.
This study has some limitations. The ALIVE cohort is composed of predominantly urban, African-American smokers who are currently or were previously engaged in injection drug use. Thus, these findings may not be generalizeable to other populations. Postbronchodilator spirometry testing was not obtained, nor was bronchodilator use prior to spirometry assessed. Variable bronchodilator use could impact lung function measurements. Respiratory infections are abstracted and standardized case definitions employed during systematic medical records review. As higher quality records were obtained from hospitalizations, it is possible that milder respiratory infections were not fully captured. However, our approach ensures that standardized clinical criteria are met and identifies the severe infections most likely to substantially impact FEV1.
In summary, through longitudinal observation of a large HIV-infected and HIV-uninfected cohort, we describe a strong association of advanced HIV disease, particularly among those with poor virological control, with accelerated lung function decline. The effect of uncontrolled HIV infection on FEV1 decline may exceed the effect of smoking on lung function decline observed in the general population, and is independent of prior respiratory infections and other risk factors. These findings provide longitudinal evidence supporting the observation that chronic lung disease is an emerging complication of HIV infection. In response, smoking cessation assumes greater priority in the care of persons living with HIV. All HIV-infected individuals with active tobacco use should receive aggressive counselling and assistance to help them abstain from tobacco use. Beyond smoking cessation, our data suggest that optimal ART with HIV virological control may diminish the accelerated lung function decline associated with HIV-infected smokers.
The authors wish to thank the ALIVE study participants and the clinic staff for their contributions to this work. M.D. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The funding agency (National Institutes of Health) had no role in the study design, data collection, analysis or writing of the manuscript. M.D. contributed to study design, analysis plan, interpretation and writing and editing of the article. C.M. contributed to study design, analysis plan, interpretation and editing of the article. J.A. contributed to the analysis plan, interpretation and was responsible for data analysis. M.K. contributed to study design, analysis plan, interpretation and editing of the article. A.K. contributed to data collection, interpretation of results and editing of the article. J.M. contributed to study design, analysis, interpretation and editing of the article. S.M. contributed to study design, interpretation and editing of the article. R.B. contributed to study design, interpretation and editing of the article. R.W. contributed to study design, analysis plan, interpretation and editing of the article. G.K. contributed to study design, analysis plan, interpretation and writing and editing of the article.
Funding for this study was provided by the National Institutes of Health.
Conflicts of interest
The authors declare that there are no conflicts of interest for any author as it pertains to this manuscript.
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