Maria C. Rodriguez-Barradas

Immune reconstitution inflammatory syndrome. Emergence of a unique syndrome during highly active antiretroviral therapy

The discovery of effective therapy for human immunodeficiency virus (HIV) infection has improved the outlook for patients with the acquired immunodeficiency syndrome (AIDS) (75, 88, 115, 121, 134). Since the introduction of highly active antiretroviral therapy (HAART), there has been a decrease in the incidence of opportunistic infections among HIVinfected patients along with a corresponding reduction in the mortality rate (7, 30, 45, 102, 117). The basis for these improvements appears to be a result of partial recovery of the host’s immune system. Suppression of viral replication by antiretroviral therapy allows for the reappearance of immune effector cells, that in turn, provide vital protection against opportunistic pathogens (15, 32, 92, 95, 132). However beneficial HAART has been, experience during the past several years has disclosed the emergence, in a small proportion of cases, of a unique set of complications. Soon after treatment is begun, some patients experience clinical deterioration due to restoration of their capacity to mount an inflammatory immune response against both infectious and noninfectious antigens. This phenomenon which carries such labels as the immune reconstitution syndrome (IRS) and immune restoration disease (IRD), has been described for a wide variety of infectious pathogens (26, 36, 46). The manifestations of this syndrome are diverse and depend on the particular infectious agent involved. Given that an increased inflammatory response underlies its presentation, we propose the name immune reconstitution inflammatory syndrome (IRIS). Autoimmune diseases that occur following institution of HAART may also be considered as part of the same process. For the purpose of this review, IRIS is defined as a paradoxical deterioration in clinical status attributable to the recovery of the immune system during HAART. Recognition of this entity is crucial, for successful treatment relies on alleviation of the patient’s symptoms without compromising antiretroviral or antimicrobial therapy. In this article, we review the present understanding of the basic science underlying IRIS, with illustrative examples from our case series, and review the existing clinical literature.

Hepatitis C Virus Infection-Related Morbidity and Mortality among Patients with Human Immunodeficiency Virus Infection

Hepatitis C virus (HCV) has emerged as a major pathogen among patients with human immunodeficiency virus (HIV). Morbidity and mortality were compared among 263 patients with HIV alone, 166 patients with HIV and HCV, and 60 patients with HCV alone (mean duration of follow-up, 2 years and 10 months). No differences in HIV loads and CD4 cells counts were observed between the HIV and HIV/HCV groups. Alanine aminotransferase levels were higher (52 U/L versus 35 U/L; P<.05) and albumin levels were lower (3.5 g/dL versus 3.8 g/dL; P <.02) among coinfected patients than they were among patients with HIV alone. Liver decompensation developed in 10% of patients with HIV/HCV coinfection. In contrast, no liver-related deaths or decompensation occurred in patients without coinfection (P<.05). Of the patients with HIV alone, 7% died, compared with 11% of the coinfected patients (P<.02); 47% of the deaths in the latter group were due to liver-related causes. In summary, HCV infection causes increased morbidity and mortality in patients with HIV infection.

Molecular Epidemiology of Bartonella Infections in Patients with Bacillary Angiomatosis–Peliosis

BACKGROUND Bacillary angiomatosis and bacillary peliosis are vascular proliferative manifestations of infection with species of the genus bartonella that occur predominantly in patients infected with the human immunodeficiency virus. Two species, B. henselae and B. quintana, have been associated with bacillary angiomatosis, but culture and speciation are difficult, and there has been little systematic evaluation of the species-specific disease characteristics. We studied 49 patients seen over eight years who were infected with bartonella species identified by molecular techniques and who had clinical lesions consistent with bacillary angiomatosis-peliosis. METHODS In this case-control study, a standardized questionnaire about exposures was administered to patients with bacillary angiomatosis-peliosis and to 96 matched controls. The infecting bartonella species were determined by molecular techniques. RESULTS Of the 49 patients with bacillary angiomatosis-peliosis, 26 (53 percent) were infected with B. henselae and 23 (47 percent) with B. quintana. Subcutaneous and lytic bone lesions were strongly associated with B. quintana, whereas peliosis hepatis was associated exclusively with B. henselae. Patients with B. henselae infection were identified throughout the study period and were epidemiologically linked to cat and flea exposure (P< or =0.004), whereas those with B. quintana were clustered and were characterized by low income (P=0.003), homelessness (P = 0.004), and exposure to lice (P= 0.03). Prior treatment with macrolide antibiotics appeared to be protective against infection with either species. CONCLUSIONS B. henselae and B. quintana, the organisms that cause bacillary angiomatosis-peliosis, are associated with different epidemiologic risk factors and with predilections for involvement of different organs.

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.

The Impact of Cigarette Smoking on Mortality, Quality of Life, and Comorbid Illness Among HIV‐Positive Veterans

AbstractBACKGROUND: The impact of smoking on outcomes among those with HIV infection has not been determined in the era of highly active antiretroviral therapy (HAART). STUDY OBJECTIVE: Determine the impact of smoking on morbidity and mortality in HIV-positive patients post-HAART. DESIGN: Prospective observational study. PARTICIPANTS: Eight hundred and sixty-seven HIV-positive veterans enrolled in the Veterans Aging Cohort 3 Site Study. MEASUREMENTS: Clinical data were collected through patient questionnaire, International Classification of Diseases—9th edition codes, and standardized chart extraction, and laboratory and mortality data through the national VA database. Quality of life was assessed with the physical component summary (PCS) of the Short-Form 12. RESULTS: Current smokers had increased respiratory symptoms, chronic obstructive pulmonary disease (COPD), and bacterial pneumonia. In analyses adjusted for age, race/ethnicity, CD4 cell count, HIV RNA level, hemoglobin, illegal drug and alcohol use, quality of life was substantially decreased (β=−3.3, 95% confidence interval [CI] −5.3 to −1.4) and mortality was significantly increased (hazard ratio 1.99, 95% CI 1.03 to 3.86) in current smokers compared with never smokers. CONCLUSIONS: HIV-positive patients who currently smoke have increased mortality and decreased quality of life, as well as increased respiratory symptoms, COPD, and bacterial pneumonia. These findings suggest that smoking cessation should be emphasized for HIV-infected patients.

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.

HIV infection and the risk of diabetes mellitus.

Background:The influence of HIV infection on the risk of diabetes is unclear. We determined the association and predictors of prevalent diabetes mellitus in HIV infected and uninfected veterans. Methods:We determined baseline prevalence and risk factors for diabetes between HIV infected and uninfected veterans in the Veterans Aging Cohort Study. Logistic regression was used to determine the odds of diabetes in HIV infected and uninfected persons. Results:We studied 3227 HIV-infected and 3240 HIV-uninfected individuals. HIV-infected individuals were younger, more likely to be black males, have HCV coinfection and a lower BMI. HIV-infected individuals had a lower prevalence of diabetes at baseline (14.9 vs. 21.4%, P < 0.0001). After adjustment for known risk factors, HIV-infected individuals had a lower risk of diabetes (odds ratio = 0.84, 95% confidence interval = 0.72–0.97). Increasing age, male sex, minority race, and BMI were associated with an increased risk. The odds ratio for diabetes associated with increasing age, minority race and BMI were greater among HIV-infected veterans. HCV coinfection and nucleoside and nonnucleoside reverse transcriptase inhibitor therapy were associated with a higher risk of diabetes in HIV-infected veterans. Conclusion:Although HIV infection itself is not associated with increased risk of diabetes, increasing age; HCV coinfection and BMI have a more profound effect upon the risk of diabetes among HIV-infected persons. Further, long-term ARV treatment also increases risk. Future studies will need to determine whether incidence of diabetes mellitus differs by HIV status.

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.

Incidence of Non-AIDS-Defining Malignancies in HIV-Infected Versus Noninfected Patients in the HAART Era: impact of Immunosuppression

Background:The incidence of non-AIDS-defining malignancies (non-ADMs) is reported as unchanged or increasing in the highly active antiretroviral therapy era. Whether incidence of non-ADM is significantly higher in HIV-infected than in HIV-uninfected patients remains unclear. Methods:Incidence rates of malignancies were calculated in a cohort of veterans in care for HIV-infected and age, race, and gender-matched uninfected patients from 1997 to 2004. For HIV-infected patients, CD4 counts closest to first observation date were compared between those with and without cancer. Results:Thirty three thousand four hundred twenty HIV-infected and 66,840 HIV-uninfected patients were followed for a median of 5.1 and 6.4 years. The incidence rate ratio of HIV infected to HIV uninfected was 1.6 (1260 vs. 841 per 100,000 person-years; 95% confidence interval: 1.5 to 1.7). Incidence rate ratio for individual cancers was highest for anal cancer (14.9; confidence interval: 10.1 to 22.1). Among HIV-infected patients, median CD4 counts were lower for those with non-ADM (249 vs. 270, P = 0.02), anal cancer (156 vs. 270; P < 0.001), and Hodgkin lymphoma (217 vs. 269; P = 0.03). Prostate cancer was associated with a higher CD4 count (311 vs. 266; P < 0.001). Conclusions:In the highly active antiretroviral therapy era, the incidence of non-ADMs is higher among HIV-infected than HIV-uninfected patients, adjusting for age, race, and gender. Some non-ADMs do not seem to be associated with significantly lower CD4 counts.