Contribution of metabolic and anthropometric abnormalities to cardiovascular disease risk factors.

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.

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

With successful antiretroviral therapy, patients infected with the human immunodeficiency virus (HIV) are living longer; however, recent reports suggest increased rates of coronary heart disease (CHD) among HIV-infected patients,1 and cardiovascular disease has become an important cause of morbidity and mortality in this population.2 Increased CHD rates in the HIV population may relate to traditional risk factors, including advancing age, higher smoking rates, dyslipidemia, insulin resistance, and impaired glucose tolerance. Cardiovascular disease may also be due to nontraditional factors, including changes in body composition with loss of subcutaneous fat and/or accumulation of visceral fat in some patients, inflammation, and direct effects of the virus on the vasculature, as well as to direct effects of specific antiretroviral drugs. Important questions remain as to the pathogenesis, detection, and treatment of cardiovascular disease and related risk factors in HIV-infected patients. These questions concern, among other things, the design of adequate trials to determine CHD incidence and the utility of existing CHD guidelines for screening, prevention, treatment, and risk stratification. To ascertain the state of the science with respect to these and related questions, a multidisciplinary conference with interested HIV specialists, cardiologists, endocrinologists, primary care physicians, National Institutes of Health representatives, and patient advocates was convened June 28–30, 2007, in Chicago, Ill, and chaired by Drs Steven Grinspoon and Robert Eckel. The discussions focused on 6 areas of interest, each with its own working group, including the following: (1) the contribution of metabolic and anthropometric abnormalities to cardiovascular disease risk factors (chaired by Drs Carl Grunfeld and Donald Kotler); (2) the epidemiological evidence for cardiovascular disease and its relationship to highly active antiretroviral therapy (HAART; chaired by Drs Judy Currier and Jens Lundgren); (3) the effects of HIV infection and antiretroviral therapy on the heart and vasculature (chaired by Drs Michael Dube …

Roles and Mechanisms of Human Immunodeficiency Virus Protease Inhibitor Ritonavir and Other Anti-Human Immunodeficiency Virus Drugs in Endothelial Dysfunction of Porcine Pulmonary Arteries and Human Pulmonary Artery Endothelial Cells

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

Human Immunodeficiency Virus: The Initial Physician-Patient Encounter

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

The antiviral drug acyclovir is a guanosine nucleoside analog that potently inhibits herpes simplex virus (HSV) replication. Acyclovir treatment in patients coinfected with HSV and human immunodeficiency virus (HIV) has been observed to alter disease course and decrease HIV viral load, a finding that has been attributed to indirect effects of HSV suppression on HIV replication. Based on this hypothesis, several clinical studies have recently investigated the use of acyclovir for treatment of patients coinfected with HSV and HIV or for prophylaxis against HIV transmission. In this report, we use a single round HIV infectivity assay to show that acyclovir directly inhibits HIV infection with an IC50 of approximately 5 microm. The target of acyclovir in HIV-infected cells is validated as HIV reverse transcriptase (RT) by the emergence of the RT variant V75I under the selective pressure of acyclovir. The V75I mutation is part of the multidrug resistance pathway that enhances viral resistance to many of the best RT inhibitors approved for the treatment of HIV. Biochemical analyses demonstrate that acyclovir triphosphate is a chain terminator substrate for HIV RT and can compete with dGTP for incorporation into DNA. Although acyclovir may prove a useful lead for development of new HIV treatments, the selection of resistant mutants raises a cautionary note to the use of acyclovir monotherapy in patients coinfected with HSV and HIV.

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

CONFERENCE ON RETROVIRUSES AND OPPORTUNISTIC INFECTIONS OVERVIEW The 14th Conference on Retroviruses and Opportunistic Infections was held in Los Angeles, Calif, on February 25 to 28, overlapping with the Academy Awards weekend. Fifty-seven percent of abstract submissions were accepted (totaling 921) and, along with webcasts and pedcasts, are accessible through the conference Web site www.retroconference.org/2007). The following is a review of highlights of the meeting attended by over 3800 leading researchers and clinicians from around the world; the material presented is referenced by author and abstract number. VIROLOGY Although it has been well established that simian immunodeficiency virus-Pan troglodytes troglodytes (SIVcpzPtt)-in west central African chimpanzees was the source of human cross-species spread of human immunodeficiency virus (HIV) (HIV-1 group M [pandemic], HIV-1 group N [nonpandemic in Cameroon], and HIV-1 group O [west central Africa]), recently, SIVgor in gorillas has been linked to a new HIV-1 group O-like virus also in Cameroon (M. Peeters, abstract 4). In addition, the simian foamy virus found in 75% to 100% of nonhuman adult primates with high concentrations in saliva has caused infection in 1% to 4% of humans occupationally exposed in zoos and primate centers in North America and humans engaged in hunting activities (A. Gessain et al, abstract 5). Emerging classification schemata include primate T-lymphotrophic virus 1 that encompasses simian T-lymphotrophic virus 1 and human T-lymphotrophic virus 1 (severe lymphoproliferative diseases in 1% to 2% of infected people) and primate T-lymphotrophic virus 2 that contains simian T-lymphotrophic virus 2 and human T-lymphotrophic virus 2 (W. Switzer, abstract 6). The association of HIV-2 with long-term nonprogressors or so-called elite controllers is in part explained by preserved HIV-specific T-helper responses characterized by interleukin 2 production and proliferation and strong responses toward a highly conserved region of the HIV-2 gag protein (S. Rowland-Jones, abstract 7). There seems to be a more rapid disease progression with HIV subtypes D and A/D and circulating recombinant forms versus clade A (J. Baeten et al, abstract 68; and N. Kiwanuka et al, abstract 307). The cause of this difference is unclear, but receptor tropism may be a contributing factor; there is a higher prevalence of CXCR4 HIV-1 coreceptors (CXCR) 4 in subtype D versus A and a lower prevalence in subtype C (D. Kuritzkes, abstract 108). EPIDEMIOLOGY Dr Kevin De Cock of the World Health Organization in the opening workshop for new investigators and trainees discussed changing patterns of US and Global HIV epidemiology. He used the World Bank life expectancy data to emphasize the extreme heterogeneity of the epidemic, stating that prevalence is greater than incidence, prevalence can increase rapidly but decrease slowly, prevalence increases most rapidly with high incidence (eg, in Eastern Europe), and that prevalence decreases most rapidly with high mortality (eg, acquired immune deficiency syndrome [AIDS] deaths now exceed new infections in Kenya). The European epidemic is being driven by regional trends in economics, drug trafficking patterns, migration, sexual behavior (including sex tourism), public health care practices, sexually transmitted disease (STD) rates, and availability of antiretrovirals (A. Johnson, abstract 54). Disturbingly, after almost a decade of approximately 40,000 new infections annually in the United States, there was more than 10% increase in 2005 (the last year for which numbers are available). In addition, death rates in the United States are 2 times higher than those in Western Europe and 10 times higher than those in the United Kingdom (H. Jaffe, abstract 63). Rates of HIV infection are 8 times higher among African Americans versus whites. Abstract 55 used modeling to assess the incidence and future prevalence of HIV among men who have sex with men (MSM) in the United States; with an estimated incidence of 1.9% and assuming an 8% prevalence in MSM aged 20 years with no mortality due to HIV, more than 50% of all MSM in the United States could be HIV infected by the age of 60 years. Among African American MSM with an incidence of 4%, almost 80% are projected to be HIV positive by age of 60 years. The latest statistics, tables, and slides can be found at the following Web sites: www.worldbank.org, www.who.int, and www.cdc.gov (recently redesigned to improve usability and performance including a new search engine). GENOMICS One workshop focused on the emerging field of genomics and host-HIV interactions. A practical application is the association of HLA B 5701 with the abacavir hypersensitivity reaction (HSR) that occurs in more than 5% of patients. This acute (within the first 6 weeks with a median onset of 9 days) systemic (fever, rash, and gastrointestinal and/or respiratory symptoms) adverse reaction is most common in whites (African Americans and men having half the risk). All patients with HSR have HLA B 5701 (plus or minus other haplotypes) that can be ordered commercially for between $100 and $200. Only 4% of patients with HLA B 5701 will not experience HSR. Some argued that obtaining this as a screening test was similar to ordering a G6PD level. ECONOMICS Globally, only 24% of eligible HIV-infected patients now receive antiretroviral therapy (ART; 1.65 of 6.8 million as per the World Health Organization as of June 2006). In resource-limited countries, primarily Africa and Asia, there are few regimens available (the most common being the fixed combination of stavudine, lamivudine, and nevirapine [NVP] given BID) leading to fewer opportunities to switch therapies secondary to either intolerance or lack of efficacy (M. Egger, abstract 62). However, several studies have shown that virological and immunologic responses are similar to those in industrialized countries. Tragically, most patients in resource-limited areas start ART late or very late, and mortality rate is higher, especially with low CD4 lymphocyte counts. The 4-year mortality is 15% in sub-Saharan Africa compared with 5% in North America and Europe. Tuberculosis remains the most common fatal opportunistic infection worldwide. DIAGNOSTICS A review of new HIV infections in South Carolina from 2001 to 2005 showed missed opportunities for HIV testing (K. Weis et al, abstract 957). Among 4221 new infections, 73% had 1 or more health care visits before their first HIV-positive test, mostly in emergency departments. Only 20% had diagnoses that would possibly prompt an HIV test, but 42% developed AIDS within 1 year of being diagnosed. The study emphasized the importance of routine HIV screening in all health care settings, especially emergency departments, as has been recommended by the Centers for Disease Control and Prevention (CDC) (MMWR 2006;55:RR-14). A CDC study suggested that annual testing of MSM would reduce the proportion of undiagnosed HIV-positive MSM from 48% to 14% (P. Denning, abstract 956). In a New York City hospital, the use of rapid oral HIV testing found that 7% of patients tested HIV positive on a general medicine ward, 2% in the ambulatory care center, and 3% in the ED (R. Smerd et al, abstract 958). Ninety-nine percent of patients with negative rapid oral tests in the San Francisco City STD Clinic agreed to HIV RNA testing, leading to 1.1% being positive (J. Klausner et al, abstract 953). CLINICAL TRIALS: EFFICACY/DURABILITY OF RESPONSE Several trials looked at established agents in novel ways. ACTG A5073 (D. Mildvan et al, abstract 138) assessed once-daily versus twice-daily lopinavir/ritonavir (LPVr; softgel capsule Kaletra) plus a once-daily 2 nucleoside/nucleotide backbone in treatment-naive patients. Overall, there was no difference with regard to the probability of a sustained virological response (SVR). However, twice-daily LPVr had a statistical advantage for those with high baseline HIV RNA (≥100,000 copies/mL). In a study named GESIDA (J. Berenguer et al, abstract 504), the understudied once-daily combination of didanosine, lamivudine, and efavirenz (EFV) (given with food in this study) provided similar antiviral efficacy to that of Combivir plus EFV at 24 weeks. Abstract 503 (D. Rey et al for the DAUFIN study) reported that, in ART treatment-naive patients, the once-daily regimen of lamivudine, tenofovir (TDF), and NVP was associated with an unexpectedly high rate of early nonresponse with a high incidence of K65R and M184V mutations. Abstracts 513 (F. Pulido et al) and 514 (R. Campo et al) dealt with simplification to LPVr monotherapy; in each study, suboptimal adherence was a major risk factor for losing virological suppression. There are 2 formulations of a ritonavir tablet that have met bioequivalence criteria (Y. Cai et al, abstract 52LB); we hope to have one of these tablets available in the near future without the refrigeration requirement of the standard capsule. RESISTANCE Session 115 (W. Wheeler et al, abstract 648; S. Sirivichayakul et al, abstract 649; S. Eshleman et al, abstract 650; A. Low et al, abstract 651; N. Zetola et al, abstract 652; M. Para et al, abstract 653; L. Drumright et al, abstract 654; G. Somi et al, abstract 655; C. de Mendoza et al, abstract 656; and K. Nambiar et al, abstract 657) was devoted to transmitted drug resistance (TDR). The prevalence of TDR is now 11% to 15% of newly infected patients and 7% to 11% of newly diagnosed patients. In 1 cohort of 793 patients, 45% failed to reach undetectability over 6 years. Nonnucleoside reverse transcriptase inhibitor (NNRTI) TDR is associated with a higher set point compared with nucleoside reverse transcriptase inhibitor (NRTI) or protease inhibitor (PI) TDR. Unlike acquired resistant viruses, transmitted drug-resistant viruses must "back mutate" to get to wild type, and the mean time to first detection of a wild-type/drug-resistant mixture is 2 years. Transmitted drug-resistant viruses have replication capacities similar to wild-type viruses. Abstract 639 evaluated to what extent conventional genotyping underestimates the presence of transmitted resistance. Using real-time polymerase chain reaction assays for 6 common mutations (M41L, K70R, Y181C, M184V, and L90M), they found that patients with these polymerase chain reaction-detected mutations were 11 times more likely to experience treatment failure compared with those who had no resistance with conventional methods. These data further support the need for baseline resistance testing before initiation of antiretroviral therapy. A Swiss study (V. von Wyl et al, abstract 667) compared the development of resistance with first-line boosted PI and NNRTI-based regimens. They concluded that, while boosted PI-containing regimens have similar potency as NNRTI-based regimens, boosted PI regimens lead to less resistance in cases of virological failure.TABLE 1NEW AGENTS This year, 3 major classes of antiretrovirals headlined the discussion about new agents, and each drug now has a generic name (one with a trade name): A few of the major presentations on drugs from each class that are nearest to being available for clinical use are reviewed below. Rilpivirine Abstract 144LB (A. Pozniak et al)-Formerly TMC278, rilpivirine is a new NNRTI that was tested at 3 different doses against EFV in ART-naive patients (with either Truvada or Combivir as the backbone). The antiviral activity was comparable at all 3 doses, and there were lower rates of central nervous system toxicity and rash in the rilpivirine arm compared with the EFV arm. It remains to be seen whether rilpivirine might challenge or even replace EFV in treatment-naive patients. Efavirenz was approved 9 years ago and has never been beaten in any clinical trial. Maraviroc Abstracts 104aLB and 104bLB (M. Nelson et al and J. Lalezari et al)-Twenty-four-week data from 2 large phase 2b/3 ongoing randomized controlled trials evaluating the CCR5 inhibitor maraviroc were presented as late breakers. These studies were entitled "Efficacy and Safety of Maraviroc plus Optimized Background Therapy In Viremic, ART-Experienced Patients Infected With CCR5-Tropic HIV-1" or "MOTIVATE" 1 and 2. Triple class-experienced patients were screened with the Monogram Biosciences tropism assay (Trofile) to determine the presence or absence of the CCR5 or CXCR4 entry coreceptor. The roughly 50% with no detectable X4 (CXCR4 utilizing) virus were randomized 1:2:2 to receive an optimized background regimen alone or an optimized background regimen with maraviroc 150 mg, given either once or twice daily. The results were similar in both MOTIVATE 1 and 2, with virological and immunologic responses being superior in both arms receiving maraviroc compared with controls; in addition, there was no difference in safety between the maraviroc and control arms. Although not evident in these studies, long-term data are needed to examine the emergence of malignancies (such as occurred in the vicriviroc studies) and the concern about driving a switch from CCR5 to the potentially more pathogenic X4 virus. Raltegravir Abstracts 105aLB and 105bLB (D. Cooper et al and R. Steigbigel et al)-Formerly MK-0518, raltegravir is an integrase strand transfer inhibitor. Two studies named BENCHMRK 1 and 2 were presented ("Blocking Integrase in Treatment Experienced Patients With a Novel Compound Against HIV:MeRcK"). The studies were similarly designed ongoing phase 3 randomized, double-blind, placebo-controlled trials; BENCHMRK 1 was carried out in Europe, Asia/Pacific, and Peru, whereas BENCHMRK 2 was done in North and South America. Both studies randomized patients with triple class-resistant HIV viruses in a ratio of 2:1 to optimized background plus either raltegravir 400 mg twice daily or placebo. Results were similar in both studies. Combining the data, at 16 weeks, the results showed that 61% to 62% of the raltegravir patients and 33% to 36% of the placebo patients were suppressed to less than 50 copies/mL; when raltegravir was used with either enfuvirtide or darunavir, 90% of patients were suppressed. Response was increased with lower baseline RNA, higher baseline CD4, and additional active agents in the regimen. There were no differences in adverse effects across the arms. Raltegravir failure was generally associated with 1 of 2 genetic pathways (N155H or Q148K/R/H). METABOLIC AND CARDIOVASCULAR EFFECTS ACTG 5142 is a randomized, open-label, prospective trial comparing an NRTI-sparing arm (EFV plus LPVr), an NNRTI-sparing arm (LPVr), and a PI-sparing arm (EFV) in treatment-naive patients; it is the first head-to-head comparison of EFV and LPVr. Earlier reported efficacy results favored EFV, but LPVr had a resistance and immune reconstitution advantage. At his meeting, Haubrich and colleagues reported on the comparative metabolic effects from the study (abstract 38). The NRTI-sparing regimen (EFV + LPVr) increased lipids significantly more than the EFV or LPV + 2 NRTI regimens. Triglyceride increases were also greater in LPVr compared with EFV + NRTI regimens, but cholesterol changes were not significantly different. Compared with EFV, LPVr had less lipoatrophy (defined as >20% reduction in extremity fat) when given with NRTI. The frequency of lipoatrophy was lowest in the NRTI-sparing and TDF-containing regimens; it was most frequent in the stavudine- and zidovudine (AZT)-containing regimens. Study 613 (D. Cameron et al, abstract 44LB) explored body composition changes with LPVr monotherapy (deintensification after 3 consecutive HIV RNA <50 copies/mL by week 24 on initial LPVr plus Combivir) versus EFV plus Combivir. The LPVr monotherapy arm was significantly associated with less lipoatrophy, greater limb fat gain, and increased triglyceride levels than the EFV arm; these findings are consistent with the observations above in ACTG 5142. McGarth and colleagues conducted body composition assessments (metabolic and lipid parameters, lipodystrophy case scores, and imaging studies) in treatment-naive patients receiving atazanavir (ATV) with or without ritonavir (RTV) in combination with stavudine XR (a once-daily formulation that was Food and Drug Administration-approved but never marketed) and lamivudine (abstract 804). There were no clinically significant differences in body composition between the ATV and ATV/RTV regimens at 48 weeks based on computed tomography and dual-energy x-ray absorptiometry imaging and a validated questionnaire; thus, the addition of RTV to ATV does not seem to be associated with clinically significant changes in body composition at 48 weeks. Both regimens increased visceral, subcutaneous, and total adipose tissue, and neither regimen caused increases in lipoatrophy or lipodystrophy. The SMART Study was a planned 8-year study in more than 5000 treatment-experienced patients. Patients were randomized to have CD4-guided drug conservation (DC arm with ART with CD4 and ART when CD4 to or antiretroviral therapy at in the study was in when the data and safety found a significantly increased risk of disease progression or in the arm compared with the arm. Abstract (A. et al) reported on the of disease in the SMART A significant risk of was in compared with patients; increases in HIV RNA and decreases in CD4 associated with of therapy were not associated with an increased risk of Results from this study that ART not be of risk of The group data on HIV and disease and They estimated rates and of disease and over 3 active antiretroviral therapy early and late rates were higher among HIV-positive compared with (D. et al, abstract The rate of among HIV-positive patients was the early compared with the late clinical can be in patients adherence to antiretroviral therapy. Using of adherence and statistical investigators that the of antiretroviral regimens per and total daily with adherence and virological In addition, the use of was similarly with (A. et al, abstract and M. et al, abstract to at risk for drug CDC (J. et al, abstract used a to patients with antiretroviral regimens to Drug were reported by of patients. suggested that patients with drug MSM or drug use HIV high and adherence were more likely to drug several the adherence among patients in as to these increases in these et al, abstract A. et al, abstract and J. et al, abstract the drug different metabolic pathways than those to be by researchers were to a of at when with use of this combination was higher doses of have been associated with increased rates of adverse effects (D. et al, abstract may in the treatment of HIV infection and associated 2 receptor may decrease of which for and even when with may ATV by and from an regimen of ATV with each 20 mg twice daily with mg 24 by and 20 mg given 2 after ATV in ATV similar to that without the ATV was when was 2 after the ATV regimen (S. et al, abstract treatment of HIV and is by drug especially when is Two HIV treatment were all but out by 2 studies reported at this was suboptimal even when given in doses as high as 400 mg twice a with was not et al, abstract A patients on regimens were randomized to antiretroviral regimens 400 mg or mg of NVP daily. 400 was whereas NVP mg daily was associated with a high rate of NVP is ongoing (A. et al, abstract Two of investigators reported experience concentrations to the of in the treatment of C used a to was shown to be a of early virological response and for a group of patients infected with 1 or 4 but was not significant for was seen more in patients with C of greater than (abstract high performance with detection of both and showed with of efficacy and toxicity (S. et al, abstract of the drug in this and for further similar AND of the antiretroviral with toxicity have been for several years. is similar to when tested in high doses as an presentations (R. et al, abstract et al, abstract C. et al, abstract and M. et al, abstract reported to effects of In cohort studies more than patients, both antiretroviral and all with more than 2 years of and 3 American and 1 Swiss of investigators several use over time seems to be associated with a but risk of in use of RTV may increase this an lack of association with changes in of clinical further HIV AND from the United Kingdom of acute C virus infection sexually transmitted among was presented (M. et al, abstract and sexually transmitted diseases were common among these newly This to the body of that infection is now an emerging STD in this risk group that lead to The of acute infection are very it leading to disease that, in the presence of HIV One of the for this of disease among HIV-infected patients might be the increase in factor production (F. et al, abstract to the proportion of and this was significantly higher in of these not changes in the production of factor when was also Treatment of in the between and has been In a of the use of abacavir and was found to be associated with early virological as a decrease in the RNA of at 2 compared with baseline levels (F. et al, abstract It can be that both are they may within the group of researchers reported that the use of lamivudine along with either stavudine or as NRTI backbone was associated with to treatment (J. et al, abstract studies are needed to these given that could be in these other be when combination treatment is In a study patients with and to of use was associated with greater decreases in levels at week 4 (M. et al, abstract However, the doses of were well in this and this was of the safety of these doses in patients. was and not on in this of with infection an especially The group leading the in HIV-infected patients reported the results of plus treatment in 16 patients with active replication after (J. et al, abstract Only 4 patients and 6 as a of due to the of additional treatment are needed to against this that has a very negative on the of patients receiving a for in a researchers from that one of the Food and Drug Administration-approved drugs for the treatment of could resistance mutations in the HIV (M. et al, abstract They reported that the HIV in 3 exposed to in the absence of antiretroviral therapy and that the M184V was in the HIV of one of The also that in further suggested that showed These findings were with by the this drug has been the that it has no activity against data are needed to this this is recommended for the treatment of in HIV-infected who not antiretroviral therapy by The behavior of HIV (the of be and have not as had been also need including and could reduce a risk of HIV infection through sex by to the data from the 2 of studies conducted in and In 2 presentations (R. et al, abstract and M. et al, abstract from was shown to reduce HIV incidence and There was no of and were comparable in HIV-positive and A of studies (H. et al, abstract and M. et al, abstract presented suggested that the of in might the risk of HIV In who were by HIV-positive from to age of 6 had increased rates of that in or death compared with who were for than 6 study found high rates of and among in after a to The was to only not as an in it was and for the and the be an It is does not significant of and is active against and to and per It well in 1 and 2 studies. a phase 3 study in Africa and (the et al, abstract was in of an increased risk of HIV The search for the

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