HIV disease: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

Patients with human immunodeficiency virus (HIV) infection have sustained alterations in metabolism (lipids and insulin/glucose homeostasis) and body composition (fat distribution) that are proatherogenic (the Figure). HIV infection itself and/or its therapies may contribute to these alterations (the Table); although most effects are reversible, there are some possibly irreversible consequences of treatment. With the relative restoration to health seen in the era of highly active antiretroviral therapy (HAART), many traditional risk factors and promoters of dyslipidemia and diabetes also are present; they interact with HIV-specific inducers to worsen dyslipidemia and to increase the prevalence of insulin resistance and diabetes. Figure. Overview of the effects of HIV and its therapies on CVD risk. The contribution of traditional risk factors must be kept in mind, and they may occur with increased prevalence in people with HIV infection (eg, smoking). HIV, likely through the inflammatory response, and antiretroviral therapies independently affect many of the mediators of CVD risk. The effects on lipids are a prominent but complex example; HIV infection lowers LDL levels, but antiretroviral therapy raises LDL back up to normal levels. The bidirectional arrows indicate associations, but there is not yet adequate proof of causality. The dotted arrow between body composition and CVD indicates that body fat is known to affect the mediators such as dyslipidemia and insulin resistance but may also have a direct effect. FFA indicates free fatty acids; ARV, antiretroviral. View this table: Table. Effects of HIV Treatment These disturbances in lipid and glucose metabolism and renal disease may contribute, at least in part, to the excess cardiovascular disease (CVD) morbidity and mortality observed in HIV-infected individuals (the Figure). However, the relative contribution to excess CVD risk of traditional CVD risk factors, especially smoking, compared with these infection- and treatment-specific complications requires clarification. More prospective data with multivariable modeling are needed. …

Gastrointestinal Disease in Simian Immunodeficiency Virus-Infected Rhesus Macaques Is Characterized by Proinflammatory Dysregulation of the Interleukin-6-Janus Kinase/Signal Transducer and Activator of Transcription3 Pathway

With the development of effective therapies against human immunodeficiency virus (HIV), hepatitis C virus (HCV) infection has become a major cause of morbidity and mortality among patients with both infections (coinfection). In addition to the high prevalence of chronic HCV, particularly among HIV-infected injection drug users, the rate of incident HIV infections is increasing among HIV-infected men who have sex with men, leading to recommendations for education and screening for HCV in this population. Liver disease is the second leading and, in some cases, a preventable cause of death among coinfected patients. Those at risk for liver disease progression are usually treated with a combination of interferon (IFN) and ribavirin (RBV), which is not highly effective; it has low rates of sustained virologic response (SVR), especially for coinfected patients with HCV genotype 1 and those of African descent. Direct-acting antivirals might overcome factors such as immunodeficiency that can reduce the efficacy of IFN. However, for now it remains challenging to treat coinfected patients due to interactions among drugs, additive drug toxicities, and the continued need for combination therapies that include pegylated IFN. Recently developed HCV protease inhibitors such as telaprevir and boceprevir, given in combination with pegylated IFN and RBV, could increase the rate of SVR with manageable toxicity and drug interactions. We review the latest developments and obstacles to treating coinfected patients.

Idiopathic AIDS Enteropathy and Treatment of Gastrointestinal Opportunistic Pathogens

S tudies published over the past 3 years have tracked the incidence and course of human immunodeficiency virus (HIV) infection in relation to cardiac illness in both children and adults. 1 These studies show that subclinical echocardiographic abnormalities independently predict adverse outcomes and identify high-risk groups to target for early intervention and therapy.The Joint United Nations Program on HIV/AIDS estimates that 36.1 million people were living with HIV infection at the end of the year 2000. 2 If 8% to 10% of patients develop symptomatic heart failure over a 2-to 5-year period, 3 then 3 million cases of HIV-related heart failure will present during that period. 1 Cardiovascular manifestations of HIV have been altered by the introduction of highly active antiretroviral therapy (HAART) regimens.On one hand, HAART has significantly modified the course of HIV disease, lengthened survival, and improved the quality of life of HIV-infected patients.On the other hand, the early data have raised concerns that HAART is associated with an increase in both peripheral and coronary arterial diseases. 1The HAART-associated changes are relevant only to the minority of HIV-infected individuals worldwide who have access to HAART.Thus, studies conducted before HAART became available remain globally applicable.In this review article, the principal HIV-associated cardiovascular manifestations will be discussed, with an emphasis on new knowledge about prevalence, pathogenesis, and treatment.

The Uncertain Significance of Anti–Glomerular Basement Membrane Antibody Among HIV-Infected Persons With Kidney Disease

Hepatitis viruses and human immunodeficiency virus co-infection: pathogenisis and treatment

OVERVIEW OF MALIGNANCY IN PATIENTS WITH AIDS: Despite the advent of highly active antiretroviral therapy, the incidence of human immunodeficiency virus (HIV)-associated malignancies has not decreased. The United States Centers for Disease Control (CDC) has determined that Kaposi's sarcoma, non-Hodgkin's lymphoma (including primary central nervous system lymphoma), and cervical carcinoma define the acquired immune deficiency syndrome (AIDS). Some literature reports include Hodgkin's disease, anal carcinoma, lung cancer, and non-melanomatous skin cancers as ones commonly found in people infected with HIV. The oncologist is further challenged treating a patient with malignancy whose malignancy is complicated by a concurrent compromised marrow function. This article will review the clinical presentation and current treatment for the HIV-associated malignancies and selected other tumors in the HIV-infected patient. Furthermore, HIV-associated myelosuppression is a common problem in antiviral-undertreated or antiviral-resistant patients.

Repeated exposure to HIV does not necessarily result in infection and HIV infection does not inevitably lead to the development of the AIDS. Multiple immunological and genetic features can confer resistance to HIV acquisition and progression at different steps in viral infection; a full understanding of these mechanisms could result in the development of novel therapeutic and vaccine approaches for HIV infection. In this review, we focus on the genetic mechanisms associated with resistance to HIV infection and to the progression to AIDS.

TABLEMore than 90% of new infections with the human immunodeficiency virus (HIV) occur in the developing world, where the global pandemic is still expanding in traditionally underserved populations and has an overwhelming impact on community-wide patterns of morbidity and mortality. Under such circumstances, the most important areas of HIV management concern the strategies for prevention of mother-to-child transmission and models to improve access to resources and care. The issue of research as direct development aid for many countries is contrasted with ethical questions concerning therapeutic research on populations who are unlikely to benefit from such research. The situation concerning HIV in industrialized countries is sharply different. In these countries, the research emphasis has shifted toward lessening the number of missed opportunities for prevention and to optimizing the outcome of a chronic condition in a reducing number of new patients. Similar epidemiologic differences to those listed between the developed and the developing world also exist within societies of all countries. The research issue of improving access to and compliance with care and management advice applies equally to socially disadvantaged children in the developed world. The gut is the most common portal of entry for vertically acquired postnatal HIV infection. Physiologic alterations affect gut mucosal function and the nutritional state even before the onset of frequent opportunistic infections. In the developing world, this evolving condition may be aggravated by gut damage from both undernutrition and from repeated infections due to environmental contamination, insufficient safe water and inadequate hygiene. Because gut epithelial cells do not express the CD4 receptor, HIV gains entry to the lamina propria by means of additional receptors and coreceptors. Coreceptor expression may be inducible and appears to affect susceptibility to infection. The mechanisms of mucosal infection and susceptibility remain areas of intense research. The pathogenesis of HIV enteropathy involves mucosal immune factors, lamina propria infection and inflammatory mediators. Immunomediated gut disease is associated with indicators of mucosal inflammation and damage. Malnutrition, wasting and poor growth are considered to be of multifactorial origin in HIV-infected children. Contributors include anorexia secondary to physical, pharmacological and psychosocial factors, emesis, diarrhea and alterations in metabolic rate and energy use, predominantly via increased proinflammatory cytokines. The introduction and widespread use of highly active antiretroviral therapy (HAART) has raised new concerns regarding its long-term use and side effects, as well as the differences in its availability, affordability and access. In many centers, the management of HIV/AIDS has now changed from that of treating opportunistic infections to that of managing a chronic condition. Long-term metabolic toxicities include lipodystrophy and mitochondrial damage in many different organ systems. The presence of these complications requires that interruption of antiretroviral therapy be weighed against virologic progression and the risk of development of drug resistance. Adherence to treatment schedules and compliance with medications has a number of determinants but is considered to be critical to long-term virologic success. Immune system reconstitution with a successful response to HAART is paradoxically accompanied by heightened inflammatory reactions in some instances. The scale and extent of the HIV pandemic are nothing short of overwhelming. The most effective response will require the development of new paradigms in global health care that are built on unprecedented international communication and cooperation. RESEARCH The unprecedented magnitude of the HIV/AIDS epidemic has resulted in huge research efforts and large funding opportunities at international, national, and local levels. International alliances include the United Nations Programme on AIDS (UNAIDS) as well as governmental and nongovernmental organizations and charitable foundations. Cooperative research opportunities are available on many different levels between universities, research organizations and institutes and sites in the developing world. The ethical controversies sparked by the maternal-fetal transmission trials in developing countries during the 1990s provided an impetus for revision of the Helsinki Declaration. However, it remains unresolved how to deal with absolutist ethical guidelines, which are applicable to donor countries but which may potentially prevent appropriate research into essential drugs and vaccines from taking place in developing countries, where such research might actually be welcomed as a form of direct development aid. Health Ministries should support local independent, authoritative and credible ethics committees in their own countries in their ability to decide what research is appropriate. Research Goals Improved Understanding of the Determinants of Mother-to-Child Transmission of HIV Infection A huge gap has developed between the epidemiologic patterns of childhood HIV disease applicable to the developed and the developing world. In many countries without access to the means and infrastructure to mount effective preventive and management strategies, the epidemic persists at an escalating level, and the majority of pediatric hospital admissions and deaths are now due to HIV-related complications (1). The economic and social impact of this epidemic has national and international consequences. Family and community systems are breaking down around children infected or affected by HIV through loss of caretakers and through physical, social and economic deprivation. Epidemiologic differences also apply within the societies of all countries. Social, economic and educational stratification influences the risk of infection, access to, and compliance with therapy. Even in the developed world, socially disadvantaged children have a higher risk of infection and show lesser rates of compliance with care and management advice. The most serious impediment to the introduction of cost-effective strategies for the prevention of mother-to-child transmission is a lack of the capacity and infrastructure required to provide counseling, testing, and management follow-up of all eligible women in many countries of the developing world. Prerequisites to the prevention of mother-to-child transmission are an efficient system of identification of infected women during the antenatal period by informed counseling and voluntary testing, resolution of all the issues of access, availability of therapy options and compliance and support at both the community and the healthcare system levels. In all environments, locally operative epidemiologic factors that may confer additional risk of, or indeed protection against, transmission or disease progression need to be researched in greater detail and must be documented to develop rational community-specific strategies for management and prevention. Plans to Achieve Research Goal In the developed world, the concern must be to improve identification, access and compliance in reducing numbers of patients. Multicenter studies help to maximize information gained from the study of individual patients. Research networking through scientific meetings and electronic communication must be strengthened to enable sharing of experiences, information, and even biologic materials. An instrument to follow infected children should be developed in an open, Internet-based forum and made widely available. Caregivers involved with HIV-infected children worldwide should be encouraged to enter their patients' data into the instrument every 3 to 4 months. A paid consultant should review and present the findings at 2 years and at the next international conference. In the developing world, much research effort must be trained on reducing the transmission rates to young women and their babies. Environmental factors such as intestinal parasites may influence the risk of vertical transmission by their effects on the nutritional state, gut mucosal integrity or coreceptor expression (2). Such studies should be initiated. Multicenter and multicountry cooperation supports service delivery in developing countries and maximizes research opportunities. Research is still needed to fully elucidate the role of breast milk in mother-to-child transmission in the context of societal traditions and norms, so that the impact of feeding advice and policy on community-wide patterns of infant feeding can be appreciated. In resource-limited countries with high infant mortality rates, excess deaths are usually due to gastrointestinal and respiratory infections and malnutrition. If the availability, safety and nutritional adequacy of replacement feeding cannot be guaranteed, a lowered HIV transmission rate could be cancelled out by increased morbidity and mortality from enteral infection and malnutrition in non-breast-fed infants. Improved Understanding and Management of Intestinal and Hepatic Side-Effects of Highly Active Antiretroviral Therapy The introduction of HAART has improved the outlook for children infected by HIV. Pediatric patients potentially face many decades of living with HIV/AIDS and its therapies. In view of the special requirements for childhood growth and maturation, the long-term effects and side effects of drug treatment pose particular challenges related to growth itself, metabolic toxicities, hypersensitivity reactions, compliance and virologic outcome. Poor growth is found in about 50% of HIV-infected children and is associated with the HIV RNA load, insufficient nutrient intake, and inconsistent relationships with gut abnormalities, malabsorption or neuroendocrine abnormalities. Suppression of HIV replication with HAART has a favourable effect on growth (3). Hyperlipidemia and body fat redistribution occur in 22% to 75% of adult patients exposed to HAART. This appears to be related to mitochondrial dysfunction, a direct drug effect and altered cytokine profiles. Nucleoside reverse transcriptase inhibitors cause mitochondrial dysfunction, and proteinase inhibitor drugs additionally inhibit specific enzymes in the metabolism of fat. Lipodystrophy is common and increases with duration of proteinase inhibitor use (4). At present, the long-term risks of lipodystrophy and hypercholesterolemia are unknown, as is optimal management of these conditions. Metabolic toxicities due to HAART are common and principally mediated via damage to mitochondria (5). These include presentations with anemia, myopathy, pancreatitis, neuropathy, hepatic steatosis and lactic acidosis. In addition, altered glucose metabolism and insulin resistance are seen, as are osteoporosis and osteonecrosis. The long-term effects of life-long therapy with HAART are not fully known at this stage. Apart from coping with numerous side effects, a critical element of therapy is adherence to complicated treatment schedules. Frequent regimen changes are related to virologic failure or toxicity (6). Adherence with HAART is associated with lower viral loads, and virologic failure may be related to issues of compliance. Viral suppression with HAART is followed by reconstitution of CD4 counts due to a falling viral load. Paradoxically, this may be associated with heightened inflammatory responses due to persistent immune system dysregulation, leading to atypical presentations of several coinfections (7). Research efforts are directed at possibilities of stimulating immune reconstitution in patients on HAART and counteracting injurious cytokine effects (8). Plans to Achieve Research Goal Large multicenter trials are needed to track HAART-treated children and to document the evolution of metabolic and other consequences. An Internet-based HAART utilization instrument should be established in which investigators prescribing these medications would track their efficacy and side effects. Supplemental funding should be provided so that investigators conducting therapeutic trials on HAART side effects would be encouraged to share results with other investigators, adding data to this website. Cooperative trials will be needed to delineate the best management for the complications and side effects of HAART. Improved Understanding of the Epidemiology, Pathogenesis, Pathophysiology and Management of HIV Enteropathy The gut is a common portal of entry for vertically acquired HIV infection. After crossing the gastrointestinal epithelium, HIV infects macrophages and lymphocytes in the lamina propria. Viral replication occurs in the mucosa throughout the natural history of HIV infection. In HIV infection, there is dysregulation of gut immunity (9). The immune disorder leads to both humoral and cell-mediated immune defects. Mucosal inflammation occurs with increased lamina propria mononuclear cells and increased numbers of intraepithelial lymphocytes in areas of enterocyte damage. A decrease in the CD4 cells of the lamina propria appears to be an early event. As this decline in CD4 cells continues, the histologic examination shows villous atrophy and crypt hyperplasia. This is more common in cases in which the lamina propria cells express p24 antigen. The disordered immune system itself contributes to mucosal injury, termed “HIV enteropathy” (10). Activation of T cells results in the release of various cytokines, particularly tumor necrosis factor α (TNF-α) and interferon-γ. These cytokines affect enterocyte differentiation and function. Ultrastructural studies reveal irregular, joined bases, shortened and broadened microvilli, mitochondrial swelling, formation of lysosomal and vesicular bodies and dilated endoplasmic reticulum, as well as tubuloreticular inclusions in the endothelial cells (11). Further studies are needed to elucidate the precise pathogenesis of intestinal injury and possible methods of management. Initially, the ongoing immune response to HIV infection results in disease; later, this is due to opportunistic infection. Adult studies suggest that the earliest stage is characterized by delayed hypersensitivity phenomena. In the intermediate stage, there is generalized activation of all classes of cytokines. In the late stage of HIV infection, there is predominant activation of the proinflammatory cytokines TNF-α and interleukin-1β. These immune reactions are likely directed at HIV, but some features are similar to graft-versus-host disease and may include autoimmune processes. Some studies did not support the role of inflammatory mediators and CD4 T-cell activation in the pathogenesis of HIV enteropathy (12). Thus, the relative role and importance of direct HIV-mediated effects or cytokine-mediated mucosal changes has yet to be clearly elucidated. The mucosal inflammation is accompanied by disproportionately severe functional disturbance. As a result, the patients develop diarrhea, malnutrition, growth retardation and immune dysfunction. The pathogenesis of the wasting syndrome in patients with HIV infection is most likely to be multifactorial. Possible contributing factors are insufficient intake due to anorexia, vomiting, psychosocial factors, malabsorption, increased energy requirements and increased circulating cytokines such as TNF-α, interleukin-1 or interleukin-6. Derangements in lipid cycling and metabolism compromise the growth of HIV-infected children in between opportunistic infections. Because depression of immune function secondary to malnutrition is potentially reversible, nutritional rehabilitation in HIV-infected children may have a positive effect on immune function, lower serum cytokine levels, decrease opportunistic infection and diminish HIV replication (13). The role of proactive nutritional management, including gastrostomy feeding, needs to be defined in relation to its potential beneficial effect on immune status and outcome. Altered gut motility can be caused by several mechanisms, including potassium and magnesium depletion, as well as by altered release of gastrointestinal hormones and autonomic dysfunction. In adult patients, jejunal autonomic nerve degeneration has been shown to occur quite early in the disease. In the late stage of HIV infection, gastrointestinal disease is most commonly due to opportunistic and nosocomial infection. The same spectrum of enteric pathogens is seen as in HIV-uninfected children, but certain pathogens are more often associated with chronic diarrhea. Continued exclusive breast-feeding of infected infants supplies protective factors and avoids exposure to potentially contaminated food and water, but at the same time permits continued exposure to infectious virus. The role of breast-feeding in nutritional management of HIV-infected children still needs to be defined. Plans to Achieve Research Goal Prior to assigning a diagnosis of HIV enteropathy, standardized investigations should be used and specific infections ruled out. The results of these investigations as well as other serial data should be entered into an Internet database, developed and supported with appropriate funding. A salaried consultant should be responsible for reviewing these data and preparing reports to define the natural course of HIV enteropathy in 2 years and again at the next international meeting. Multicenter cooperative studies should be done to further define the evolution and management of enteropathy separate from infectious gut disease. Studies are needed in the developing world to identify the relative importance of the continuing exposure to HIV in breast milk in the rate of progression of disease and nutritional deterioration. Agreements to exchange biologic materials and research expertise, such as with specific cytokines or receptor studies, or molecular hybridization studies, will enable greater scientific advances to be made. Photomicrographs of autopsy and biopsy materials should also be transmitted via the Internet to create a morphologic evolution of HIV enteropathy. INTERVENTIONS The interventions with the largest impact include those that concern policies on prevention and care and engender public involvement. Intervention Goals Improved Access to Care and Implementation of Strategies to Prevent Infections Because antiretroviral drugs are not a cure, access to HIV care needs to be intimately linked to prevention efforts. Treatment will in fact provide new opportunities for prevention, because it will create a larger demand and infrastructure for HIV testing, providing new entry points to the healthcare system for those who are infected, including critical opportunities to support them, their sexual partners and families to prevent ongoing transmission. Children and families with diverse clinical and social needs should be able to access care in an integrated fashion for voluntary counseling and testing, for health and social services, and for community-based support and home care (14,15). Major challenges for healthcare systems include building and sustaining human resources, ensuring quality and consistency of services and making better use of existing infrastructure. Plans to Achieve Intervention Goal There must be structured linkages of primary, secondary and tertiary care in different disciplines and at different facilities. Regional subspecialty programs with special expertise in treating and monitoring children with HIV infection can be linked to primary care and community service programs. The regional subspecialty program should have multidisciplinary expertise and a strong knowledge of and commitment to community linkages. In addition to public education campaigns, free, voluntary, confidential counselling and testing services must be made available in public health facilities and antenatal services to pregnant women and their partners. HIV-positive women should then be offered counselling, management and follow-up support in line with the best available package applicable to that particular country or community. Mothers who have taken prophylaxis and delivered uninfected infants in areas with high prevalence should be recruited to encourage pregnant women from their to in the programs. women can be the of replacement feeding in developing countries, a of or must be However, the of infant feeding advice to HIV-infected must be particularly to individual context and the of the breast-feeding breast-feeding is this should be fully supported and Improved and of related to and monitoring of antiretroviral drugs out of of most children in developing countries. Even in the context of healthcare systems in the developed world, there are challenges in improving access to antiretroviral drugs The healthcare a role in providing treatment and and other effective resources and providing Plans to Achieve Intervention Goal should be encouraged to a public health to the of antiretroviral drug use in resource-limited access to for living with HIV/AIDS must be an established of all access can be improved not by on the rational and use of antiretroviral drugs but also by improved affordability and of drug and by appropriate and healthcare The medications must be made available. The of regarding side effects and should be by an on an The should be further in drug including of increased from an increased role for international regarding and the of charitable to provide additional funding. Strategies should be developed to and through the of these strategies include of at which could of a system to track the of and of a of for clinical should be by Internet-based so that in this as well as effects of can be The Health should be with in public monitoring of the of on and Management of HIV Enteropathy In the developing world, the evolving gut condition of HIV enteropathy is on and aggravated by a high prevalence of and nutritional gut Under such circumstances, a cost-effective is needed for the and management of HIV-infected children with chronic or persistent diarrhea or nutritional deterioration. Plans to Achieve Intervention Goal A must to cost-effective treatment of children with gut disease and to prevent nutritional as as The nutritional management of patients with enteropathy food and to and to maximize and The energy is increased to of available and methods of should be used where possible to and Goals Improved and to on of Mother-to-Child Transmission Because prevention of infection in the is the it is on all healthcare involved in the counselling of HIV-infected women at antenatal to be informed about all of mother-to-child transmission during the period and through The is to the viral during the of and during to exposure to a during and and to provide therapy as prophylaxis for the who might have been infected during Plans to Achieve Goal In countries, the of all in including the education and healthcare must be in public This should be by a public commitment to management and must be to and affected patients that will the community-wide and of Improved on Management challenges will require the healthcare to its and to new with the with and infected and affected with HIV, and with the models of with the community are particularly important to with Ministries of Health and to improve the quality and of health Plans to Achieve Goal An international of should be established to support the development and of programs that provide information and education for healthcare programs offered to in developing countries should be with national to to improve treatment for children living with HIV include of health and other Research on improved treatment needs to include Internet-based sharing of information about so that can be to programs. In this for home and will be made available for healthcare in and are important of and require the addition of and to educational The of patients who have to and to therapy may have a impact on community by public role but must be done with of individual and societal and Antiretroviral treatment programs should be developed and should a and a number of for use, that who cannot or who the and would be for care by Treatment programs should be on the best scientific to the use of treatment that compromise the outcome of treatment in individual and create the potential for the of virus. Improved and in Care of Children and wasting are the most chronic and to HIV-infected children. A poor nutritional state and wasting are associated with a and an improved nutritional state and growth may from effective viral suppression with HAART. successful nutritional rehabilitation may improve function. including and have an important role in and in the outcome of HIV-infected children. are but may have effects. Plans to Achieve Goal should include a greater emphasis on nutritional care. This should be at programs and service should be to provide specific and these should be on the nutritional is most effective in the early of disease and should be provided in with management of other associated but nutritional interventions should be the to growth The is to the and then to maximize energy by the addition of fat or breast-feeding is the this should be offered as the exclusive as often as possible and the own and state of health as as HIV-infected children with diarrhea require in to nutritional of and There are many opportunities for and and education in childhood HIV disease. The commitment of funding for this from and is The that now the healthcare is to a role in the available resources to have a impact on the largest number of infected

HAART and the HCV-infected liver: friend or foe?

Treating Children With HIV in Chicago

Since the first announcement of acquired immune deficiency syndrome (AIDS) in 1981, around 33 million people worldwide are now infected with human immunodeficiency virus (HIV) [1]. This pandemic is associated with 6 million new annual HIV infections, resulting in 1.8 million deaths each year due to AIDS. During these past 30 years, an immense amount of knowledge regarding the pathology of HIV/AIDS has accrued. These valiant efforts have provided greater understanding about HIV/AIDS and its associated diseases and have undoubtedly improved the clinical management of afflicted persons. Despite this noteworthy effort, however, a tangible cure still seems remote as HIV infected individuals continue to succumb to many AIDS-defining and non-AIDS-defining conditions. In this special issue on AIDS-related pathology, we have assembled diverse papers that showcase this fascinating disease and underscore some of the many unanswered questions. We are fortunate to have some truly superb papers with accompanying striking images. They teach us that the observation of subtle defects can immediately lead to diagnoses with enormous implications for the patient. Such conditions are often seldom observed outside of HIV. Occam's razor, the principle named after the 14th century philosopher William of Occam, does not apply in this setting. This generalization states that if there are a number of explanations for observed phenomena, the simplest explanation is preferred—called also scientific parsimony. Rare manifestations of common diseases and common presentations of rare conditions may be seen together; only HIV and its subsequent immunosuppression link these phenomena. Fortunately, with the advent of HAART in established market economies, the spectrum has changed with a notable shift from infection to cancer and “standard” diseases that non-HIV-infected people are routinely affected by, but often their manifestations have subtle differences. A variety of diseases may be encountered related directly and/or indirectly to HIV infection. This is well illustrated in the paper reporting the spectrum of pathological manifestations of AIDS in a series of 236 autopsied cases in Mumbai, India. This article points out that the vast majority of underlying pathologies discovered by necropsy were either preventable or treatable conditions. The paper dealing with HIV-associated gastrointestinal (GI) disease diagnosed with endoscopic biopsy nicely portrays the variety of inflammatory, infectious and neoplastic diseases that may be seen in the upper and lower GI tract. Given the increased frequency of coinfections and broad diversity of diseases likely to be seen, it is not surprising that pathology specimens procured from HIV-infected are diagnostically challenging for anatomic pathologists. This is demonstrated in the beautifully illustrated article about multiple pathologies seen in skin biopsies from patients with HIV/AIDS, as well as the comprehensive review of HIV-related cytopathology. Owing to the progressive reduction of the host immune system, HIV infected individuals are susceptible to many opportunistic infections. As the paper that stems from South Africa on primary oral tuberculosis shows, these often serve as an indicator for HIV infection. The article on Penicillium marneffei makes the point that in endemic areas like Hong Kong, disseminated penicilliosis is now included in the list of AIDS-indicator conditions. Human polyomavirus frequently reactivates in individuals infected with HIV, which typically manifests with sinister pathological consequences. This issue is addressed in the paper about novel human polyomavirus-associated cerebral disorders seen primarily in the era of highly active antiretroviral therapy (HAART). As HIV+ patients are increasingly qualifying for transplants, the complications of concomitant infection and management in this setting are manifold. The case report of zygomycosis associated with HIV infection and liver transplantation deals with just this conundrum. The oncogenic viruses associated with HIV infection have incited much interest in the field over the years. Kaposi's sarcoma-associated herpesvirus/Human herpesvirus-8 (KSHV/HHV-8) was first found in 1994 by isolating DNA fragments of this virus from a Kaposi sarcoma (KS) tumor in an AIDS patient [2]. KSHV was subsequently found to cause several other diseases, such as primary effusion lymphoma and multicentric Castelman′s disease (MCD). The case report describing HHV-8 infection associated with KS, MCD, and plasmablastic microlymphoma in a single lymph node of a Kenyan man with AIDS commendably reviews the pathology of this oncogenic process. The number of reported cases of Epstein-Barr virus-(EBV) related smooth muscle tumor arising in patients with AIDS has been increasing since the mid 1990s. The epidemiology, clinical manifestations, pathologic features, prognosis, and management of this fascinating entity are methodically reviewed in this special edition. HIV-infected patients are at increased risk of developing cancer. Despite the advent of HAART, malignancy in this population is a leading cause of morbidity and mortality. Like KS, AIDS-related non-Hodgkin lymphoma (AIDS-NHL) is one of the most common AIDS-defining malignancies. One of the articles in this edition is a five-year retrospective case series in which the authors review their institutions experience with numerous lymphoproliferative lesions in the setting of HIV infection. The pathological heterogeneity of AIDS-NHL reflects the heterogeneity of their associated molecular lesions [3]. Even though new molecular evidence continues to emerge regarding AIDS-NHL, several biological features about these AIDS-NHL remain perplexing. This is exemplified in the case report of a 47-year-old HIV+ man with a diffuse large B-cell lymphoma observed to undergo an immunophenotypic switch from a germinal center to nongerminal center origin. These authors offer several plausible explanations to explain this phenomenon. The incidence and spectrum of non-AIDS-defining cancers (NADCs) continues to grow [4, 5]. As HIV-infected individuals live longer due to HAART, their risk of dying from one of these cancers is increased. The role of HIV-induced immunosuppression in the development of these NADCs appears to be less important than coinfection with certain viruses such as human papilloma virus (HPV). This edition offers an interesting review of the various carcinomas arising in the head and neck region in HIV+ patients, several of which are related to oncogenic viruses. While several NADCs are on the rise, it remains unclear why others such as breast cancers are decreased in this population [6]. The case report of an invasive ductal carcinoma of the breast surrounded by an intense lymphocytic response in the setting of HIV provides some insight into this interesting association, demonstrating the unique interplay between breast cancer and the HIV+ host's immune response. It is of great interest that the two hormonally driven tumors, breast and prostate cancers, may have a decreased incidence in the setting of HIV. Of course, many of the studies about HIV-associated breast and prostate cancer are small, and this may be a statistical aberration. Apart from the direct and indirect effects related to HIV infection, treatment of HIV+ patients too has untoward side effects. For example, HAART may be associated with lipodystrophy, gynecoamastia, insulin resistance, hyperlipidemia and increased cardiovascular risk. Glitazones, a novel class of insulin-sensitizing antidiabetic agents, have been investigated in the management of HAART-associated lipid disorders. The effect of rosiglitazone, an agonist of peroxisome proliferator-activated receptor (PPARƴ), on skeletal muscle gene expression with regard to insulin sensitivity in individuals with HIV-insulin resistance is presented in this special AIDS-related edition of the journal. Additional basic science articles provide unique perspectives on osteoimmunopathology in HIV/AIDS and nanotherapeutics using a HIV-1 poly A and transactivator of the HIV-1 LTR-(TAR-) specific siRNA. The challenges for diagnosis and management of sick people with HIV remains, despite the remarkable success of HAART. We should keep in mind that fewer than one million HIV-infected individuals are currently receiving antiretroviral therapy. Present anti-retroviral therapy costs between $10,000 and $20,000 per year, which provides excellent value for money in developed countries with a cost of about $10,000 per life-year saved; the lives saved are essentially the young and potentially economic productive section of the population. This compares very favorably with many other drugs for chronic therapies in current use. The limitations of anti-retroviral treatment strategies at a physical (suppression of viremia) and political (widespread availability) level have underscored the need to develop more effective strategies to control the spread and pathogenesis of HIV and the diseases related to it that we describe herein. In recent years, the demand for new antiviral strategies has increased markedly. There are many contributing factors to this increased demand, including the ever-increasing prevalence of chronic viral infections and other pathogens individuals are coinfected with, many of which are described in these papers. While this great collection of papers certainly bears testimony to how much we have learned about HIV/AIDS to date, these papers also serve to remind us of how much we still do not understand. Liron Pantanowitz Antonino Carbone Justin Stebbing

Campylobacter is a very rare cause of bloodstream infection, although it has been found relatively frequently in patients infected with human immunodeficiency virus (HIV). The impact of highly active antiretroviral therapy (HAART) and new forms of immunosuppression on the incidence of Campylobacter bacteremia has not been sufficiently assessed. In this study we analyzed the incidence and microbiologic and clinical characteristics of Campylobacter bacteremia over 23 years.We reviewed the clinical records of all patients who had Campylobacter bacteremia from 1985 to 2007. Available strains were reidentified using universal polymerase chain reaction (PCR).During the study period, there were 71 episodes of Campylobacter bacteremia in 63 patients (0.24% of all bloodstream infections), and the incidence remained stable (mean, 0.06/1000 admissions per year and 0.47/100,000 inhabitants per year). Median age was 52 years (interquartile range, 31.25-72.5 yr), and 82% of patients were male. The underlying conditions included liver disease (21/64, 32.8%), HIV infection (15/64, 23.4%), malignancy (7/64, 10.9%), solid organ transplantation (2/64, 3%), hypogammaglobulinemia (10/64, 15.6%), and other (18/64, 31.2%). Twelve patients shared more than 1 underlying condition. Campylobacter bacteremia was community acquired in 81% of the episodes. The origin of the bloodstream infection was abdominal (43.5%), primary (26%), or extraintestinal (31%: respiratory 15%, cellulitis 4.8%, urinary 8%, other 3%). C jejuni was recovered in 66% of cases, C fetus in 19%, and C coli in 12%.Universal PCR was performed on 14 available strains. Molecular and conventional identification matched in 8 isolates. In contrast, molecular methods classified as C fetus (n = 2) and C jejuni (n = 1) 3 strains formerly identified only to genus level as Campylobacter species. In another 3 isolates, molecular identification was not consistent with the phenotypic identification (C fetus identified as C jejuni).Complications appeared in 23.9% of patients. Quinolone resistance was observed in 50% of the isolates. Only 37.8% of patients received appropriate empirical therapy. Mortality was 16.4%, although it was higher in HIV-infected patients than uninfected patients (33% vs. 10%; p = 0.04), in cases of hospital-acquired Campylobacter bacteremia compared with community-acquired cases (38.5% vs. 9.4%; p = 0.02), and in the presence of complications compared with patients without complications (100% vs. 0%; p < 0.001). The incidence of recurrence was 5% (3 patients with humoral immunodeficiency). There was a higher proportion of HIV-infected patients among patients with Campylobacter bacteremia in the pre-HAART era (1985-1996) than in the HAART era (1997-2007)-27.5% (11/40) vs. 14.3% (4/28)-although the difference was not statistically significant. Debilitating diseases such as chronic obstructive pulmonary disease emerged as predisposing conditions in the HAART era (0% before HAART era vs. 14.3% in HAART era; p = 0.032).Campylobacter bacteremia is no longer a significant disease of HIV-positive patients on HAART, but often affects other immunocompromised patients as well. Campylobacter bacteremia has an extraintestinal origin in as many as 31% of cases, and humoral immunodeficiency must be sought in patients with recurrent episodes. Quinolones should not be considered for empirical therapy.

Approximately 30 years ago, in June 1981, it was reported from theCenter forDiseaseControl andPrevention (CDC) that five, otherwise healthy, homosexual men in California had presented with pneumonia caused by Pneumocystis jiroveci pneumonia, a rare disease seen exclusively in individualswith a severely suppressed immune system. Several reports confirmed the initial observation and lent support to the possibility that a new sexually transmitted, infectious agent was circulating within the gay community in the United States. The clinical condition was named acquired immunodeficiency syndrome (AIDS). Two years later, a research team at the Institut Pasteur under the guidance of Francoise Barre-Sinoussi and Luc Montagnier isolated human immunodeficiency virus (HIV), the causative agent of AIDS, from a lymph node biopsy of a French patient. The isolation and characterization of HIV paved the way for the design of diagnosticmethods to identify the virus in blood andbloodproducts and towards the development of novel antiretroviral treatment (ART) to control HIV replication in infected patients. For their discoveries, Barre-Sinoussi and Montagnier were awarded the Nobel Prize in Physiology and Medicine in 2008.