Joseph L. Goulet

The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals

Objective:To estimate the effect of combined antiretroviral therapy (cART) on mortality among HIV-infected individuals after appropriate adjustment for time-varying confounding by indication. Design:A collaboration of 12 prospective cohort studies from Europe and the United States (the HIV-CAUSAL Collaboration) that includes 62 760 HIV-infected, therapy-naive individuals followed for an average of 3.3 years. Inverse probability weighting of marginal structural models was used to adjust for measured confounding by indication. Results:Two thousand and thirty-nine individuals died during the follow-up. The mortality hazard ratio was 0.48 (95% confidence interval 0.41–0.57) for cART initiation versus no initiation. In analyses stratified by CD4 cell count at baseline, the corresponding hazard ratios were 0.29 (0.22–0.37) for less than 100 cells/μl, 0.33 (0.25–0.44) for 100 to less than 200 cells/μl, 0.38 (0.28–0.52) for 200 to less than 350 cells/μl, 0.55 (0.41–0.74) for 350 to less than 500 cells/μl, and 0.77 (0.58–1.01) for 500 cells/μl or more. The estimated hazard ratio varied with years since initiation of cART from 0.57 (0.49–0.67) for less than 1 year since initiation to 0.21 (0.14–0.31) for 5 years or more (P value for trend <0.001). Conclusion:We estimated that cART halved the average mortality rate in HIV-infected individuals. The mortality reduction was greater in those with worse prognosis at the start of follow-up.

Do Patterns of Comorbidity Vary by HIV Status, Age, and HIV Severity?

Patterns of comorbidity among persons with human immunodeficiency virus (HIV) are not well described. We compared comorbidity among veterans with and without HIV infection. The sample consisted of 33,420 HIV-infected veterans and 66,840 HIV-uninfected veterans. We identified and clustered 11 comorbid conditions using validated International Classification of Diseases, 9th Revision, Clinical Modification codes. We defined multimorbidity as the presence of conditions in all clusters. Models restricted to HIV-infected veterans were adjusted for CD4 cell count and viral load. Comorbidity was common (prevalence, 60%-63%), and prevalence varied by HIV status. Differences remained when the veterans were stratified by age. In multivariable analyses, older HIV-infected veterans were more likely to have substance use disorder and multimorbidity. Renal, vascular, and pulmonary diseases were associated with CD4 cell count <200 cells/mm(3); hypertension was associated with CD4 cell count >200 cells/mm(3). Comorbidity is the rule, and multimorbidity is common among veterans with HIV infection. Patterns of comorbidity differ substantially by HIV status, age, and HIV severity. Primary care guidelines require adaptation for persons with HIV infection.

HIV Infection and Risk for Incident Pulmonary Diseases in the Combination Antiretroviral Therapy Era

RATIONALE In aging HIV-infected populations comorbid diseases are important determinants of morbidity and mortality. Pulmonary diseases have not been systematically assessed in the combination antiretroviral therapy (ART) era. OBJECTIVES To determine the incidence of pulmonary diseases in HIV-infected persons compared with HIV-uninfected persons. METHODS We analyzed data from the Veterans Aging Cohort Study Virtual Cohort, consisting of 33,420 HIV-infected veterans and 66,840 age, sex, race and ethnicity, and site-matched HIV-uninfected veterans. Using Poisson regression, incidence rates and adjusted incidence rate ratios were calculated to determine the association of HIV with pulmonary disease. The Virtual Cohort was merged with the 1999 Veterans Large Health Survey to adjust for self-reported smoking in a nested sample (14%). MEASUREMENTS AND MAIN RESULTS Incident chronic obstructive pulmonary disease, lung cancer, pulmonary hypertension, and pulmonary fibrosis, as well as pulmonary infections, were significantly more likely among HIV-infected patients compared with uninfected patients in adjusted analyses, although rates of asthma did not differ by HIV status. Bacterial pneumonia and chronic obstructive pulmonary disease were the two most common incident pulmonary diseases, whereas opportunistic pneumonias were less common. Absolute rates of most pulmonary diseases increased with age, although the relative differences between those with and without HIV infection were greatest in younger persons. Chronic obstructive pulmonary disease and asthma, as well as pulmonary infections, were less likely in those with lower HIV RNA levels and use of ART at baseline. CONCLUSIONS Pulmonary diseases among HIV-infected patients receiving care within the Veterans Affairs Healthcare System in the combination ART era reflect a substantial burden of non-AIDS-defining and chronic conditions, many of which are associated with aging.

Increased Risk of Fragility Fractures among HIV Infected Compared to Uninfected Male Veterans

Background HIV infection has been associated with an increased risk of fragility fracture. We explored whether or not this increased risk persisted in HIV infected and uninfected men when controlling for traditional fragility fracture risk factors. Methodology/Principal Findings Cox regression models were used to assess the association of HIV infection with the risk for incident hip, vertebral, or upper arm fracture in male Veterans enrolled in the Veterans Aging Cohort Study Virtual Cohort (VACS-VC). We calculated adjusted hazard ratios comparing HIV status and controlling for demographics and other established risk factors. The sample consisted of 119,318 men, 33% of whom were HIV infected (34% aged 50 years or older at baseline, and 55% black or Hispanic). Median body mass index (BMI) was lower in HIV infected compared with uninfected men (25 vs. 28 kg/m2; p<0.0001). Unadjusted risk for fracture was higher among HIV infected compared with uninfected men [HR: 1.32 (95% CI: 1.20, 1.47)]. After adjusting for demographics, comorbid disease, smoking and alcohol abuse, HIV infection remained associated with an increased fracture risk [HR: 1.24 (95% CI: 1.11, 1.39)]. However, adjusting for BMI attenuated this association [HR: 1.10 (95% CI: 0.97, 1.25)]. The only HIV-specific factor associated with fragility fracture was current protease inhibitor use [HR: 1.41 (95% CI: 1.16, 1.70)]. Conclusions/Significance HIV infection is associated with fragility fracture risk. This risk is attenuated by BMI.

Veterans aging cohort study (VACS) : Overview and description

Background:The Veterans Aging Cohort Study (VACS) is a study of human immunodeficiency virus (HIV) infected and uninfected patients seen in infectious disease and general medical clinics. VACS includes the earlier 3 and 5 site studies (VACS 3 and VACS 5) as well as the ongoing 8 site study. Objectives:We sought to provide background and context for analyses based upon VACS data, including study design and rationale as well as its basic protocol and the baseline characteristics of the enrolled sample. Research Design:We undertook a prospectively consented multisite observational study of veterans in care with and without HIV infection. Measures:Data were derived from patient and provider self report, telephone interviews, blood and DNA samples, focus groups, and full access to the national VA “paperless” electronic medical record system. Results:More than 7200 veterans have been enrolled in at least one of the studies. The 8 site study (VACS) has enrolled 2979 HIV-infected and 3019 HIV-uninfected age–race–site matched comparators and has achieved stratified enrollment targets for race/ethnicity and age and 99% of its total target enrollment as of October 30, 2005. Participants in VACS are similar to other veterans receiving care within the VA. VACS participants are older and more predominantly black than those reported by the Centers for Disease Control. Conclusions:VACS has assembled a rich, in-depth, and representative sample of veterans in care with and without HIV infection to conduct longitudinal analyses of questions concerning the association between alcohol use and related comorbid and AIDS-defining conditions.

When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study.

BACKGROUND Most clinical guidelines recommend that AIDS-free, HIV-infected persons with CD4 cell counts below 0.350 × 10(9) cells/L initiate combined antiretroviral therapy (cART), but the optimal CD4 cell count at which cART should be initiated remains a matter of debate. OBJECTIVE To identify the optimal CD4 cell count at which cART should be initiated. DESIGN Prospective observational data from the HIV-CAUSAL Collaboration and dynamic marginal structural models were used to compare cART initiation strategies for CD4 thresholds between 0.200 and 0.500 × 10(9) cells/L. SETTING HIV clinics in Europe and the Veterans Health Administration system in the United States. PATIENTS 20, 971 HIV-infected, therapy-naive persons with baseline CD4 cell counts at or above 0.500 × 10(9) cells/L and no previous AIDS-defining illnesses, of whom 8392 had a CD4 cell count that decreased into the range of 0.200 to 0.499 × 10(9) cells/L and were included in the analysis. MEASUREMENTS Hazard ratios and survival proportions for all-cause mortality and a combined end point of AIDS-defining illness or death. RESULTS Compared with initiating cART at the CD4 cell count threshold of 0.500 × 10(9) cells/L, the mortality hazard ratio was 1.01 (95% CI, 0.84 to 1.22) for the 0.350 threshold and 1.20 (CI, 0.97 to 1.48) for the 0.200 threshold. The corresponding hazard ratios were 1.38 (CI, 1.23 to 1.56) and 1.90 (CI, 1.67 to 2.15), respectively, for the combined end point of AIDS-defining illness or death. LIMITATIONS CD4 cell count at cART initiation was not randomized. Residual confounding may exist. CONCLUSION Initiation of cART at a threshold CD4 count of 0.500 × 10(9) cells/L increases AIDS-free survival. However, mortality did not vary substantially with the use of CD4 thresholds between 0.300 and 0.500 × 10(9) cells/L.

HIV as an Independent Risk Factor for Incident Lung Cancer

Background:It is unclear whether the elevated rate of lung cancer among HIV-infected persons is due to biological effects of HIV, surveillance bias, or excess smoking. We compared the incidence of lung cancer between HIV-infected and demographically similar HIV-uninfected patients, accounting for smoking and stage of lung cancer at diagnosis. Design:Data from the Veterans Aging Cohort Study Virtual Cohort were linked to data from the Veterans Affairs Central Cancer Registry, resulting in an analytic cohort of 37 294 HIV-infected patients and 75 750 uninfected patients. Methods:We calculated incidence rates of pathologically confirmed lung cancer by dividing numbers of cases by numbers of person-years at risk. We used Poisson regression to determine incidence rate ratios (IRRs), adjusting for age, sex, race/ethnicity, smoking prevalence, previous bacterial pneumonia, and chronic obstructive pulmonary disease. Results:The incidence rate of lung cancer in HIV-infected patients was 204 cases per 100 000 person-years [95% confidence interval (CI) 167–249] and among uninfected patients was 119 cases per 100 000 person-years (95% CI 110–129). The IRR of lung cancer associated with HIV infection remained significant after multivariable adjustment (IRR 1.7; 95% CI 1.5–1.9). Lung cancer stage at presentation did not differ between HIV-infected and uninfected patients. Conclusion:In our cohort of demographically similar HIV-infected and uninfected patients, HIV infection was an independent risk factor for lung cancer after controlling for potential confounders including smoking. The similar stage distribution between the two groups indicated that surveillance bias was an unlikely explanation for this finding.

Relative prevalence of comorbidities and treatment contraindications in HIV-mono-infected and HIV/HCV-co-infected veterans.

Objectives:To determine the prevalence of hepatitis C virus (HCV) co-infection among HIV-infected veterans, assess the prevalence of comorbid conditions that may complicate or limit treatment options, and ascertain whether comorbid conditions were more common in co-infected veterans. Design and methods:We used the Veterans Administration electronic medical records system to identify all veterans receiving care for HIV during fiscal years 1997–2002. Demographic data and diagnostic codes for HIV, HCV, and comorbid conditions were extracted. The validity of using diagnostic codes was assessed by calculating the agreement between chart extraction and electronic data on a separate sample of veterans. Factor analysis was used to identify the structure underlying the intercorrelation between comorbid conditions. Logistic regression was used to compare the prevalence of comorbid conditions and factors between HIV/HCV-co-infected and HIV-mono-infected veterans, adjusting for age and race. Results:We identified 25 116 HIV-infected veterans in care, of whom 4489 (18%) were HCV co-infected. A validity assessment revealed moderate agreement between chart extraction and electronic data for each of the comorbid conditions assessed. HIV/HCV-co-infected veterans were significantly more likely to have each of the comorbid conditions, and to have significantly more comorbid conditions. Factor analysis revealed three dimensions of comorbidity: mental disorders, medical disorders, and alcohol-related complications. Veterans with co-infection were significantly more likely to have mental disorders and alcohol-related complications. Conclusions:HIV/HCV-co-infected veterans had a higher prevalence of comorbid conditions that may complicate and limit treatment options for HIV and for HCV co-infection. Strategies to improve treatment options for co-infected patients with comorbidities must be developed.

Prevalence of painful musculoskeletal conditions in female and male veterans in 7 years after return from deployment in Operation Enduring Freedom/Operation Iraqi Freedom

BackgroundWe sought to describe sex differences in the prevalence of painful musculoskeletal conditions in men and women Veterans after deployment in Operation Enduring Freedom (Afghanistan) and Operation Iraqi Freedom (Iraq) (OEF-OIF). MethodsThis is an observational study using Veterans Affairs (VA) administrative and clinical databases of OEF-OIF Veterans who had enrolled in and used VA care. The prevalence of back problems, musculoskeletal conditions, and joint disorders was determined at years 1 through 7 after deployment for female and male Veterans using ICD-9 code groupings for these conditions. ResultsFemale Veterans were younger (mean age 29 vs. 30, P<0.0001), more likely to be African American (26% vs. 13%, P<0.0001), and less likely to be married (34% vs. 47%, P<0.0001). For both female and male Veterans, the prevalence of painful musculoskeletal conditions increased each year after deployment. After adjustment for significant demographic differences, women were more likely than men to have back problems [year 1 odds ratio (OR) 1.06 (1.01, 1.11)], musculoskeletal problems [year 1 OR 1.32 (1.24, 1.40)], and joint problems [year 1 OR 1.36 (1.21, 1.53)] and the odds of having these conditions increased each year for women compared with men in years 1 to 7 after deployment. DiscussionTo provide quality care to female Veterans, the VA must understand the impact of deployment on womens health. Our findings provide an important picture of the increasing prevalence of musculoskeletal conditions in the female Veteran population and highlight the importance of the VA targeting treatment programs that focus on issues of particular importance to women with musculoskeletal pain.

Impact of cigarette smoking on mortality in HIV-positive and HIV-negative veterans.

It is unknown whether smoking confers similar mortality risk in HIV-positive as in HIV-negative patients. We compared overall mortality stratified by HIV and smoking of 1,034 HIV-positive block-matched to 739 HIV-negative veterans, enrolled 2001-2002 in the Veterans Aging Cohort 5 Site Study. Adjusted incidence rate ratios (IRR) for mortality were calculated using Poisson regression. Mortality was significantly increased in HIV-positive veterans according to both smoking status and pack-years in unadjusted and adjusted analyses (adjusted IRR 2.31, 95% confidence interval [CI] 1.53-3.49 for HIV-positive current smokers and IRR 1.32, 95% CI 0.67-2.61 for HIV-negative current smokers). Comorbid diseases were also significantly increased according to smoking status and pack-years. Current smoking is associated with poor outcomes; even lower levels of exposure appear to be detrimental in HIV-infected veterans. These findings support the need for improvements in smoking cessation and for studies of mechanisms and diseases underlying increased mortality in smokers with HIV.