Cytomegalovirus, Aging, and HIV: A Perfect Storm

The success of highly active antiretroviral therapy in preventing progression of HIV-infected individuals to AIDS has greatly reduced the burden of opportunistic infections. Individuals with HIV infection are living longer, but as a group are at greater risk to develop age-related disorders, such as certain cancers, cardiovascular disease, type II diabetes, and cognitive impairment, at earlier ages than non-HIV-infected persons. This premature susceptibility to age-related morbidities reflects a syndrome referred to as accelerated aging, wherein deleterious features associated with aging emerge decades earlier in the setting of chronic HIV infection. A prominent immunological feature of accelerated aging in HIV infection is inflation of cytomegalovirus-specific memory T-cell responses to levels associated with an immune risk phenotype. In the absence of HIV infection, immune risk phenotypes develop in cytomegalovirus-infected octogenarians and signify some degree of immune senescence and an elevated risk for all-cause mortality. Chronic inflammation is a probable factor in health risks conveyed by the immune risk phenotype and in putative relationships between cytomegalovirus infection and the same set of age-related disorders arising in chronic HIV infection. Most HIV-infected individuals are cytomegalovirus-seropositive, both HIV and cytomegalovirus are associated with inflammation-related morbidities, and HIV infection accelerates the development of cytomegalovirus-dependent immunological abnormalities. Therefore, closer investigation of the relationship between cytomegalovirus and age-related morbidities emerging in chronic HIV infection appears warranted. This review summarizes evidence that cytomegalovirus could be an important cofactor in the development of age-related morbidities in HIV infection and discusses research to address underlying mechanisms.     

The aging of the HIV epidemic

Since the advent of highly active antiretroviral therapy, life expectancies for persons with HIV infection are similar to those for unifected people. A growing proportion of HIV-infected individuals are now over the age of 50. We are also seeing an increase in the incidence of HIV infection in older adults. To meet the challenges of the ongoing HIV epidemic, prevention efforts should include a focus on older adults. Also, HIV care providers must address the many comorbidities that are common in the aging population. Additional research will clarify how the processes of aging and HIV infection overlap and interact. This review addresses many of these important considerations.     

HIV,Aging, and Viral Coinfections: Taking the Long View

Viral suppression of human immunodeficiency virus (HIV) with combination antiviral therapy (cART) has led to increasing longevity but has not enabled a complete return to health among aging HIV-infected individuals (HIV+). Viral coinfections are prevalent in the HIV+ host and are implicated in cancer, liver disease, and accelerated aging. We must move beyond a simplistic notion of HIV becoming a “chronic controllable illness” and develop an understanding of how viral suppression alters the natural history of HIV infection, especially at the intersection of HIV with other common viral coinfections in the context of an altered, aging immune system.     

Aging and HIV Infection: A Comparison Between Older HIV-Infected Persons and the General Population

Abstract

Background: As HIV-infected persons age, the relative contribution of HIV infection, combination antiretroviral therapy (cART), and the normal aging process to the frequent comorbidities is unknown.Methods: We prospectively evaluated comorbidities, cardiovascular risk, cognitive function, and anthropomorphic and laboratory parameters of HIV-infected persons aged 50 years and over in two US urban clinics. Results were compared to controls from the National Health and Nutrition Examination Survey (NHANES) matched 1:1 by age, race, gender, smoking status, and body mass index (BMI).Results: We enrolled 122 HIV-infected persons; median age 55 years, 83% male, 57% Caucasian, 39% current smokers, mean BMI 26 kg/m², and 92% on cART. Compared to controls, HIV-infected persons had a higher prevalence of hypertension (54% vs 38%), hypertriglyceridemia (51% vs 33%), low bone mineral density (BMD) (39% vs 0%), and lipodystrophy and greater receipt of antihypertensive and lipid-lowering medications (all Ps < .05). Groups were similar in prevalence of coronary heart disease, diabetes mellitus, chronic viral hepatitis, non-AIDS-defining malignancies and Framingham Risk and cognitive function scores.Conclusions: Older HIV-infected persons have a higher prevalence of hypertension, hypertriglyceridemia, low BMD, and lipodystrophy than matched controls, suggesting that HIV and treatment-related factors exceed “normal” aging in the development of those problems.     

Inflammation Strikes Again: Frailty and HIV

Purpose of Review

As a consequence of antiretroviral therapy, the proportion of older HIV-infected adults is increasing, with a concomitant shift in burden of illness to age-related syndromes and disease. Frailty is an age-related syndrome of increased vulnerability to stress, predictive of major adverse clinical outcomes among HIV-infected and uninfected persons alike. Understanding frailty pathogenesis is critical to developing interventions to improve health outcomes in HIV. Here, we review the current evidence for the relationship between inflammation and frailty in HIV, and the potential for novel, inflammation-targeted interventions.

Recent Findings

Dysregulated inflammation has been consistently associated with frailty in elderly HIV-uninfected persons. Dysregulated inflammation is also central to HIV pathophysiology and several recent studies have demonstrated the important association of inflammation with frailty in HIV. Some evidence suggests that anti-inflammatory therapies may be effective in ameliorating the adverse impact of frailty among aging HIV-infected adults, though further investigation is necessary.

Summary

Inflammation has been implicated in frailty in HIV infection, and improved understanding of the role that inflammation plays in frailty pathogenesis is key to the development of effective therapies to slow or prevent frailty in the vulnerable HIV-infected population.

     

Autoantibodies against peripheral blood cells appear early in HIV infection and their prevalence increases with disease progression.

The presence of platelet- and neutrophil-bound immunoglobulin (PBIg and NBIg) in thrombocytopenic or neutropenic HIV-infected individuals has led to the concept that in HIV infection thrombocytopenia and neutropenia are mediated by autoimmunity. However, PBIg and NBIg were also demonstrated in non-cytopenic HIV-infected individuals. We determined the prevalence of autoantibodies against neutrophils and platelets by immunofluorescence in randomly chosen persons in different stages of asymptomatic and symptomatic HIV infection. Platelet and neutrophil autoantibodies already appeared in the asymptomatic stage and their prevalence further increased in the symptomatic stages. No correlation was found between the presence of either platelet or neutrophil antibodies and the occurrence of circulating immune complexes in the blood or the serum immunoglobulin level. There was no significant difference in neutrophil counts in HIV-infected persons with or without neutrophil autoantibodies. In addition, no significant difference in neutrophil count was found between HIV-infected and non-HIV-infected persons. HIV-infected individuals with platelet autoantibodies tended to have a lower platelet count than HIV-infected individuals without these antibodies. However, the platelet count in HIV-infected individuals without platelet antibodies was significantly lower than in the non-HIV infected persons. Thus, autoantibodies against platelets and neutrophils occur early in HIV infection and their prevalence is correlated with disease progression. Their presence is associated with cytopenia only in a limited number of persons. Non-immune mechanisms also mediate thrombocytopenia in HIV infection.     

Quantitation of antigen-specific immune responses in human immunodeficiency virus (HIV)-infected individuals by limiting dilution analysis

The lymphocyte proliferative response to recall antigens is lost following HIV infection. We sought to devise a means by which the functional immune status of persons in the early stages of HIV infection could be monitored quantitatively. The response to tetanus toxoid was examined in 45 HIV-infected individuals and 11 controls using conventional lymphocyte proliferative assays concurrently with limiting dilution analysis utilizing the secretion of interleukin-2 as the measure of a response. Our data show that the limiting dilution analysis detects tetanus toxoid-reactive T cells in 80% of those tested, as compared to only 44% by proliferation. However, the frequency of tetanus-reactive T cells in HIV-infected individuals (median frequency = 1/59,156) is decrease five-fold as compared to seronegative controls (median frequency = 1/11,599). Longitudinal studies demonstrated a time-dependent decrease in the frequency of tetanus-specific T cell responses in the HIV-infected individuals. Thus, the limiting dilution analysis is a quantitative approach for detecting antigen-specific T cells in HIV-infected individuals, and may be used to monitor changes in T cell function in HIV infection.     

HIV partner notification outcomes for HIV-infected patients by duration of infection, San Francisco, 2004 to 2006

BACKGROUND: The San Francisco Department of Public Health conducts HIV third-party partner notification in the following populations based on standard Centers for Disease Control and Prevention (CDC) guidelines: (1) persons with acute and nonacute incident HIV infection tested at the municipal sexually transmitted disease (STD) clinic and the county hospital and (2) all county residents with early syphilis and long-standing HIV infection. METHODS: We reviewed routinely collected demographic and partner notification outcome data among acute and nonacute cases between 2004 and 2006 and among long-standing cases between July 2005 and December 2006. Outcomes were examined among the 3 case types. RESULTS: Most acute (n = 30), nonacute (n = 398), and long-standing cases (n = 335) occurred in gay/bisexual men (89%), and most case-patients were interviewed (80%). In acute and nonacute cases, 13% of partners tested for HIV were newly identified as HIV-infected. The number of patients interviewed per new HIV infection identified was 25 for acute cases, 21 for nonacute cases, and 39 for long-standing cases; however, half of recent new HIV infections were identified among partners of long-standing patients. Few patients or partners refused partner notification services. CONCLUSIONS: Partner notification was acceptable and successfully identified new HIV infections. Other jurisdictions should consider implementing or expanding partner notification for HIV infection. More evaluation is needed of the effectiveness of partner notification among HIV-infected persons with other STDs.     

Coronary heart disease risk, dyslipidemia, and management in HIV-infected persons

Dyslipidemia and coronary heart disease (CHD) are of increasing concern in persons with human immunodeficiency virus (HIV) infection who are living longer because of the benefits of highly active antiretroviral therapy (HAART). All classes of drugs used in HAART have been associated with atherogenic changes in lipid profiles. The management of HIV-infected persons with dyslipidemia and/or CHD currently emphasizes the importance of monitoring and optimizing lipid levels through lifestyle changes, switching antiretrovirals (ARVs), and lipid-lowering treatments utilizing guidelines developed for persons without HIV infection. In HIV-infected persons, the use of lipid-lowering drugs may result in pharmacokinetic interactions with ARVs, complicating the management of patients. Recent advances in our understanding of the differential effects of specific ARVs on lipids is beginning to alter the clinical approach to management. In the absence of randomized clinical trials, clinicians should aggressively treat atherogenic dyslipidemia by primarily utilizing or switching to ARVs with the lowest potential to induce CHD or, when this is not possible or is ineffective, secondarily by the addition of lipid-lowering therapy. The current optimal management of HIV infection requires careful selection of ARVs with consideration given to the potential development of CHD and an understanding of how to manage dyslipidemia.     

HIV/AIDS surveillance in Japan, 1984-2000

The HIV/AIDS surveillance system in Japan, which began collecting data on the number of AIDS patients in 1984 and the number of HIV-infected persons in 1987, has played an important role in monitoring the trend and magnitude of Japan's HIV/AIDS epidemic and its distribution across various population subgroups. However, the system lacks any personal identifiers, making it impossible to eliminate duplication or to track cases for disease progression. It also does not permit the identification of the residence of HIV-infected persons because the residence of only the reporting physician is documented under the New Infectious Diseases Control Law, effective since April 1, 1999. The number of people with HIV/AIDS in Japan continues to grow. Among youth, sexually transmitted diseases, induced abortion, and sexual activities have shown a marked increase since the mid-1990s. Behavioral risk of infection for both injection drug users (IDUs) and men who have sex with men (MSM) remains alarmingly high. Accurate monitoring of infection rates is critical to the planning and evaluation of treatment, care and prevention programs. Japan should restructure its HIV/AIDS surveillance system to more accurately monitor the HIV/AIDS epidemic and related risk behaviors.     

Coronary Heart Disease Risk,Dyslipidemia, and Management in HIV-Infected Persons

Abstract

Dyslipidemia and coronary heart disease (CHD) are of increasing concern in persons with human immunodeficiency virus (HIV) infection who are living longer because of the benefits of highly active antiretroviral therapy (HAART). All classes of drugs used in HAART have been associated with atherogenic changes in lipid profiles. The management of HIV-infected persons with dyslipidemia and/or CHD currently emphasizes the importance of monitoring and optimizing lipid levels through lifestyle changes, switching antiretrovirals (ARVs), and lipid-lowering treatments utilizing guidelines developed for persons without HIV infection. In HIV-infected persons, the use of lipid-lowering drugs may result in pharmacokinetic interactions with ARVs, complicating the management of patients. Recent advances in our understanding of the differential effects of specific ARVs on lipids is beginning to alter the clinical approach to management. In the absence of randomized clinical trials, clinicians should aggressively treat atherogenic dyslipidemia by primarily utilizing or switching to ARVs with the lowest potential to induce CHD or, when this is not possible or is ineffective, secondarily by the addition of lipid-lowering therapy. The current optimal management of HIV infection requires careful selection of ARVs with consideration given to the potential development of CHD and an understanding of how to manage dyslipidemia.     

Diagnosis of diffuse CD8+ lymphocytosis syndrome in HIV-infected patients

The diffuse infiltrative lymphocytosis syndrome (DILS) in HIV-infected persons is characterized by a persistent circulating CD8+ lymphocytosis. Certain HIV-infected persons appear to respond to their infection by developing an oligoclonal expansion of CD8+ lymphocytes. These cells infiltrate multiple organs, but the salivary glands and the lung constitute the major sites involved in this process. This infiltrative process resembles in many aspects a Sj?gren-like syndrome, owing to the visceral lymphocytic infiltration. Unilateral parotid gland enlargement in a patient with HIV infection should prompt clinicians to suspect DILS. In addition, clinicians should be aware that the pulmonary process associated with DILS may mimic clinically and radiographically the pneumonic process caused by Pneumocystis carinii. Other manifestations of DILS to consider include a severe form of peripheral neuropathy; lymphocytic infiltration of the liver, evident as hepatitis; myositis; and lymphocytic interstitial nephritis.     

Support among persons infected with HIV for routine health department contact for HIV partner notification

Public health partner notification (PN) services are provided inconsistently to persons diagnosed with HIV/AIDS in the United States, and some community groups representing persons with HIV/AIDS have opposed widespread application of PN. We surveyed persons with HIV recently reported to our health department and a random sample of HIV-infected persons attending an HIV/AIDS clinic. A total of 95 persons, of whom 76 (80%) were men who have sex with men, completed an anonymous self-administered questionnaire. Eighty-four percent of participants believed the health department should routinely offer everyone diagnosed with HIV help in notifying their partners; 79% indicated they would be somewhat or very likely to provide information to a doctor, case worker, or health department employee for purposes of PN; and 20% indicated they wanted help in notifying a recent sex partner. Seventy-eight percent of participants believed the health department should contact all HIV-infected persons after diagnosis to help them access medical care and social services, and 68% wanted the health department to contact them about the availability of medical or social services. In contrast to common public perceptions, these results suggest that most persons with HIV support health departments routinely contacting people after HIV diagnosis and that many want assistance with PN.     

HIV and aging: state of knowledge and areas of critical need for research. A report to the NIH Office of AIDS Research by the HIV and Aging Working Group

HIV risk behaviors, susceptibility to HIV acquisition, progression of disease after infection, and response to antiretroviral therapy all vary by age. In those living with HIV, current effective treatment has increased the median life expectancy to >70 years of age. Biologic, medical, individual, social, and societal issues change as one ages with HIV infection, but there has been only a small amount of research in this field. Therefore, the Office of AIDS Research of the National Institutes of Health commissioned a working group to develop an outline of the current state of knowledge and areas of critical need for research in HIV and Aging; the working groups' findings and recommendations are summarized in this report. Key overarching themes identified by the group included the following: multimorbidity, polypharmacy, and the need to emphasize maintenance of function; the complexity of assessing HIV versus treatment effects versus aging versus concurrent disease; the inter-related mechanisms of immune senescence, inflammation, and hypercoagulability; the utility of multivariable indices for predicting outcomes; a need to emphasize human studies to account for complexity; and a required focus on issues of community support, caregivers, and systems infrastructure. Critical resources are needed to enact this research agenda and include expanded review panel expertise in aging, functional measures, and multimorbidity, and facilitated use and continued funding to allow long-term follow-up of cohorts aging with HIV.     

Brief strengths-based case management promotes entry into HIV medical care: results of the antiretroviral treatment access study-II

OBJECTIVE: The Antiretroviral Treatment Access Study-II (ARTAS-II) evaluated a brief case management intervention delivered in health departments and community-based organizations (CBOs) to link recently diagnosed HIV-infected persons to medical care rapidly. METHODS: Recently diagnosed HIV-infected persons were recruited from 10 study sites across the United States during 2005 to 2006. The intervention consisted of up to 5 sessions with an ARTAS linkage case manager over a 90-day period. The outcome measure was whether or not the participant had seen an HIV medical care provider at least once within 6 months of enrollment. Multivariate logistic regression was used to identify significant predictors of receiving HIV medical care. RESULTS: Seventy-nine percent (497 of 626) of participants visited an HIV clinician at least once within the first 6 months. Participants who were older than 25 years of age, Hispanic, and stably housed; had not recently used noninjection drugs; had attended 2 or more sessions with the case manager; and were recruited at a study site that had HIV medical care colocated on its premises were all significantly more likely to have received HIV care. CONCLUSIONS: The ARTAS linkage case management intervention provides a model that health departments and CBOs can use to ensure that recently diagnosed HIV-infected persons attend an initial HIV care encounter.     

Sexually transmitted infection services as a component of HIV care: findings of a demonstration project among HIV-infected women in Thailand

OBJECTIVES: As Thailand scales up its antiretroviral treatment program, the role of sexually transmitted infection (STI) services to prevent HIV transmission has not been addressed. We provided STI services for HIV-infected women as a component of HIV care and assessed STI prevalence and risk behaviors. METHODS: HIV-infected women attending an infectious disease clinic and an STI clinic in Bangkok were screened for the presence of genital ulcers by visual inspection, for gonorrhea and chlamydial infection by polymerase chain reaction, for trichomoniasis by wet mount, and for syphilis by serology. Women were asked about sexual risk behavior and use of antiretroviral treatment. Risk-reduction counseling, condoms, and STI treatment were provided. RESULTS: Two-hundred ten HIV-infected women at an infectious disease clinic (n = 150) and an STI clinic (n = 60) received STI services from July 2003 through February 2004. The prevalence for any STI was 8.0% at the infectious disease clinic and 30.0% at the STI clinic (P < 0.01). Of the 116 (55.2%) sexually active women, 42 (36.2%) reported sex without a condom during the last 3 months. Women receiving antiretroviral treatment reported condom use during last sex more often compared with those not receiving antiretroviral treatment (82.2% vs. 58.8%; P = 0.03). CONCLUSION: STIs and sexual risk behavior were common among these HIV-infected women, and STI services for HIV-infected persons have been expanded to more clinics in Thailand. Further analysis of HIV transmission risk is necessary for developing a national strategy for prevention of HIV transmission among HIV-infected persons.     

Pathogenesis of HIV and the Lung

Antiretroviral therapy has improved longevity for HIV-infected persons, but long-term HIV infection is now complicated by increased rates of chronic medical conditions including pulmonary disorders. Chronic obstructive pulmonary disease, lung cancer, asthma, and pulmonary hypertension are becoming common comorbidities of HIV infection, and these diseases may develop as a result of HIV-related risk factors, such as antiretroviral drug toxicities, colonization by infectious organisms, HIV viremia, immune activation, or immune dysfunction. It also appears that the ability to control HIV infection does not completely eliminate the risk for infectious complications, such as bacterial pneumonia and tuberculosis. The effect of HIV infection on lung-specific immune responses is being elucidated to help develop better prevention and treatment strategies in HIV-infected persons.     

Cancer Screening in Patients Infected with HIV

Non–AIDS-defining cancers are a rising health concern among HIV-infected patients. Cancer screening is now an important component of health maintenance in HIV clinical practice. The decision to screen an HIV-infected patient for cancer should include an assessment of individualized risk for the particular cancer, life expectancy, and the harms and benefits associated with the screening test and its potential outcome. HIV-infected patients are at enhanced risk of several cancers compared to the general population; anal cancer, hepatocellular carcinoma, Hodgkin’s lymphoma, and lung cancer all have good evidence demonstrating an enhanced risk in HIV-infected persons. A number of cancer screening interventions have shown benefit for specific cancers in the general population, but data on the application of these tests to HIV-infected persons are limited. Here we review the epidemiology and background literature relating to cancer screening interventions in HIV-infected persons. We then use these data to inform a conceptual model for evaluating HIV-infected patients for cancer screening.     

Estimated HIV incidence among high-risk heterosexuals in New York City, 2007

We sought to describe virologic and clinical retention outcomes among a group of HIV-infected adolescents and young adults (AYA) newly established in an adult HIV clinic compared with matched HIV-infected adults. AYA demonstrated lower rates of HIV-1 virologic suppression and higher rates of HIV-1 viral rebound and loss to follow-up compared with adults. African American AYA had the lowest rates of virologic suppression and the highest rates of viral rebound. Adult providers should consider HIV-infected AYA, particularly African American HIV-infected AYA, to potentially be at high risk for poor clinical outcomes in adult care.     

Small alveolar macrophages are infected preferentially by HIV and exhibit impaired phagocytic function

HIV-1-infected persons are at higher risk of lower respiratory tract infections than HIV-1-uninfected individuals. This suggests strongly that HIV-infected persons have specific impairment of pulmonary immune responses, but current understanding of how HIV alters pulmonary immunity is incomplete. Alveolar macrophages (AMs), comprising small and large macrophages, are major effectors of innate immunity in the lung. We postulated that HIV-1 impairs pulmonary innate immunity through impairment of AM physiological functions. AMs were obtained by bronchoalveolar lavage from healthy, asymptomatic, antiretroviral therapy-naive HIV-1-infected and HIV-1-uninfected adults. We used novel assays to detect in vivo HIV-infected AMs and to assess AM functions based on the HIV infection status of individual cells. We show that HIV has differential effects on key AM physiological functions, whereby small AMs are infected preferentially by the virus, resulting in selective impairment of phagocytic function. In contrast, HIV has a more generalized effect on AM proteolysis, which does not require direct viral infection. These findings provide new insights into how HIV alters pulmonary innate immunity and the phenotype of AMs that harbors the virus. They underscore the need to clear this HIV reservoir to improve pulmonary immunity and reduce the high incidence of lower respiratory tract infections in HIV-1-infected individuals.