Immune activation in patients infected with HIV type 1 and maintaining suppression of viral replication by highly active antiretroviral therapy

Immune activation associated with HIV infection declines after highly active antiretroviral therapy (HAART), but may persist or recur in some patients. It is not clear whether this reflects a resurgence of HIV replication or another cause of immune activation, such as inflammatory reactions to opportunistic pathogens (immune restoration disease [IRD]). Here, we studied plasma and cellular immune activation markers in adult HIV-1 patients who had received HAART for >12 months and maintained plasma HIV RNA levels of <400 copies/ml for >6 months. Plasma interleukin 1 receptor antagonist and tumor necrosis factor receptor I levels were similar in patients and HIV-negative control subjects, but the highest levels occurred mainly in patients with a history of IRD. In contrast, expression of HLA-DR and CD38 on monocytes and of HLA-DR on CD8(+) T cells was higher in patients than in control subjects. Thus, cellular markers of immune activation are abnormal in some patients with a good virological response to HAART, and abnormalities of plasma immune activation markers correlate with a history of IRD.     

Up-regulation of TLR2 and TLR4 in dendritic cells in response to HIV type 1 and coinfection with opportunistic pathogens

The ability to trigger an innate immune response against opportunistic pathogens associated with HIV-1 infection is an important aspect of AIDS pathogenesis. Toll-like receptors (TLRs) play a critical role in innate immunity against pathogens, but in HIV-1 patients coinfected with opportunistic infections, the regulation of TLR expression has not been studied. In this context, we have evaluated the expression of TLR2 and TLR4 in monocytes, plasmacytoid dendritic cells, and myeloid dendritic cells of HIV-1 patients with or without opportunistic infections. Forty-nine HIV-1-infected individuals were classified according to viral load, highly active antiretroviral therapy (HAART), and the presence or absence of opportunistic infections, and 21 healthy subjects served as controls. Increased expression of TLR2 and TLR4 was observed in myeloid dendritic cells of HIV-1 patients coinfected with opportunistic infections (without HAART), while TLR4 increased in plasmacytoid dendritic cells, compared to both HIV-1 without opportunistic infections and healthy subjects. Moreover, TLR2 expression was higher in patients with opportunistic infections without HAART and up-regulation of TLR expression in HIV-1 patients coinfected with opportunistic infections was more pronounced in dendritic cells derived from individuals coinfected with Mycobacterium tuberculosis. The results indicate that TLR expression in innate immune cells is up-regulated in patients with a high HIV-1 load and coinfected with opportunistic pathogens. We suggest that modulation of TLRs expression represents a mechanism that promotes HIV-1 replication and AIDS pathogenesis in patients coinfected with opportunistic pathogens.     

Immune restoration disease after antiretroviral therapy

Suppression of HIV replication by highly active antiretroviral therapy (HAART) often restores protective pathogen-specific immune responses, but in some patients the restored immune response is immunopathological and causes disease [immune restoration disease (IRD)]. Infections by mycobacteria, cryptococci, herpesviruses, hepatitis B and C virus, and JC virus are the most common pathogens associated with infectious IRD. Sarcoid IRD and autoimmune IRD occur less commonly. Infectious IRD presenting during the first 3 months of therapy appears to reflect an immune response against an active (often quiescent) infection by opportunistic pathogens whereas late IRD may result from an immune response against the antigens of non-viable pathogens. Data on the immunopathogenesis of IRD is limited but it suggests that immunopathogenic mechanisms are determined by the pathogen. For example, mycobacterial IRD is associated with delayed-type hypersensitivity responses to mycobacterial antigens whereas there is evidence of a CD8 T-cell response in herpesvirus IRD. Furthermore, the association of different cytokine gene polymorphisms with mycobacterial or herpesvirus IRD provides evidence of different pathogenic mechanisms as well as indicating a genetic susceptibility to IRD. Differentiation of IRD from an opportunistic infection is important because IRD indicates a successful, albeit undesirable, effect of HAART. It is also important to differentiate IRD from drug toxicity to avoid unnecessary cessation of HAART. The management of IRD often requires the use of anti-microbial and/or anti-inflammatory therapy. Investigation of strategies to prevent IRD is a priority, particularly in developing countries, and requires the development of risk assessment methods and diagnostic criteria.     

Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy

Background To determine if infectious disease events in HIV-infected patients treated with highly active antiretroviral therapy (HAART) are a consequence of the restoration of pathogen-specific immune responses, a single-centre retrospective study of all HIV-infected patients commencing HAART prior to 1 July 1997 was undertaken to determine the incidence, characteristics and time of onset of disease episodes in HAART responders (decrease in plasma HIV RNA of > 1 log₁₀ copies/mL).
Methods Baseline and post-therapy changes in CD4 T-cell counts and HIV RNA were compared in patients with and without disease and delayed-type hypersensitivity responses to mycobacterial antigens were measured in selected patients.
Results Thirty-three of 132 HAART responders (25%) exhibited one or more disease episodes after HAART, related to a pre-existent or subclinical infection by an opportunistic pathogen. Disease episodes were most often related to infections by mycobacteria or herpesviruses but hepatitis C virus (HCV), molluscum contagiosum virus and human papilloma virus were also implicated. They were most common in patients with a baseline CD4 T-cell count of < 50/uL and occurred most often during the first 2 months of therapy and when CD4 T-cell counts were increasing. Mycobacteria- and HCV-related diseases were associated with restoration of pathogen-specific immune responses.
Conclusions We conclude that improved immune function in immunodeficient patients treated with HAART may restore pathogen-specific immune responses and cause inflammation in tissues infected by those pathogens.     

Pulmonary infections in the HIV-infected patient in the era of highly active antiretroviral therapy: An update

The highly active antiretroviral therapy (HAART) era began in 1996 when the combination of multiple antiretroviral agents was found to improve outcomes in HIV-infected patients. HAART has made a tremendous impact on the progression of HIV and on the morbidity and mortality associated with its opportunistic infections. HIV-positive patients who respond to HAART have a decreased incidence of opportunistic infections. Studies have documented close to a 50% decline in the incidence of pneumocystis pneumonia and bacterial pneumonia with the use of antiretroviral therapy. Primary and secondary prophylaxis for pneumocystis pneumonia can be discontinued in patients who show a sustained response to antiretroviral therapy. Unique to the HAART era, immune reconstitution syndrome is characterized by a paradoxical deterioration of a preexisting infection that is temporally related to the recovery of the immune system. Recently, more and more patients are being admitted for non-AIDS related illnesses in the HAART era.     

Opportunistic Diseases in HIV-Infected Patients in Gabon following the Administration of Highly Active Antiretroviral Therapy: A Retrospective Study

Opportunistic diseases cause substantial morbidity and mortality to human immunodeficiency virus (HIV)-infected patients. Highly active antiretroviral therapy (HAART) leading to immune reconstitution is the most effective treatment of preventing opportunistic diseases. This retrospective study established an epidemiologic profile of opportunistic diseases 10 years after the introduction of HAART. The HIV antiretroviral therapy-naive patients matching inclusion criteria were included. The primary outcome was the prevalence of opportunistic diseases. From January 1, 2002 to September 30, 2010, 654 opportunistic diseases were identified in 458 patients. Pulmonary tuberculosis, herpes zoster, cerebral toxoplasmosis, oral candidiasis, and severe pneumonia accounted for 22.05%, 15.94%, 14.19%, 14.19%, and 9.39%, respectively. Cryptococcal meningitis and pneumocystosis accounted for 0.44% and 0.21%, respectively. The prevalence of opportunistic diseases in Gabon remains high. New guidelines emphasize the importance of initiating antiretroviral therapy early to reconstitute the immune system, and reduce disease risk, and treat the primary opportunistic infection of pulmonary tuberculosis.     

Etiology and Pharmacologic Management of Noninfectious Diarrhea in HIV-Infected Individuals in the Highly Active Antiretroviral Therapy Era

Diarrhea remains a common problem for patients with human immunodeficiency virus (HIV) infection despite highly active antiretroviral therapies (HAART) and can negatively affect patient quality of life and lead to discontinuation or switching of HAART regimens. In the era of HAART, diarrhea from opportunistic infections is uncommon, and HIV-associated diarrhea often has noninfectious causes, including HAART-related adverse events and HIV enteropathy. Diarrhea associated with HAART is typically caused by protease inhibitors (eg, ritonavir), which may damage the intestinal epithelial barrier (leaky-flux diarrhea) and/or alter chloride ion secretion (secretory diarrhea). HIV enteropathy may result from direct effects of HIV on gastrointestinal tract cells and on the gastrointestinal immune system and gut-associated lymphoid tissue, which may be active sites of HIV infection and ongoing inflammation and mucosal damage. New therapies targeting the pathogenic mechanisms of noninfectious diarrheas are needed.     

Immune restoration disease: a consequence of dysregulated immune responses after HAART

Immune Restoration Diseases (IRD) are a collection of atypical 'opportunistic infections' and inflammatory diseases seen in human immunodeficiency virus (HIV) patients after HIV viraemia is suppressed by highly active antiretroviral therapy (HAART). IRD probably reflect dysregulated immune responses against pre-existing infections by opportunistic pathogens, with different immunopathological mechanisms for different pathogens. For example, mycobacterial IRD are associated with delayed type hypersensitivity (DTH) responses to mycobacterial antigens, whereas patients who experience cytomegalovirus (CMV) IRD have elevated plasma levels of soluble CD30, a marker of a T2 cytokine environment expressed by activated CD8 T-cells. As IRD are often compartmentalised to organs, monitoring serological markers such as pathogen-specific IgG antibody, may be informative, as demonstrated for CMV and hepatitis C virus (HCV)-associated IRD. Genetic studies have provided evidence of distinct immunopathological mechanisms and inherited susceptibility to IRD associated with mycobacterial and herpesviridae infections. The expansion of HAART in the developing world where many HIV patients have low CD4+ T-cell counts and high rates of concomitant infections will place a large number of patients at-risk of developing IRD. It is therefore important to understand the immunopathology so that prevention, diagnosis and treatment can be improved.     

Das entzündliche Immunrekonstitutionssyndrom

Overwhelming immune reaction resulting in granulomatous inflammation after infection with opportunistic pathogens has been termed immune reconstitution inflammatory syndrome (IRIS). IRIS has mainly been described in patients with human immunodeficiency virus (HIV). However, IRIS is not restricted to HIV-patients and may occur in other infections and immunodeficiencies. In our clinic, we experienced a Whipple's disease patient with IRIS. IRIS occurs mainly after initiation of the highly active anti-retroviral therapy (HAART). Soon after HAART initiation, a marked inflammatory reaction can occur, triggered by restoration of pathogen-specific immunity. IRIS may be targeted by various infective antigens, dead or dying infective antigens, host antigens, tumor antigens and other antigens, giving rise to a heterogenous range of clinical manifestations. Treatment should be optimized for the associated condition and initiated immediately. Glucocorticoids should be used in patients who are severely affected by IRIS.     

Infectious lung complications in patients with HIV/AIDS

PURPOSE OF REVIEW: The aim of this article is to review recent observations in the area of infectious lung complications in individuals with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). Since the immunodeficiency was first characterized, it has been associated with enhanced susceptibility to opportunistic infection, and life-threatening infections of the lung in particular. In the past few years there have been a large number of reports documenting the changes to this disease profile in the age of highly active antiretroviral therapy (HAART). Furthermore, there have been considerable advances in our understanding of the immunology and vaccinology of many of the pathogens implicated in pulmonary infections in this context, including Mycobacterium tuberculosis, Streptococcus pneumoniae and Pneumocystis pneumonia. RECENT FINDINGS: In considering the time-course and spectrum of HIV-associated respiratory infections, the field must now be divided into studies undertaken in parts of the world where HAART is accessible and those where it is not. Despite the enormous impact of HAART, it has brought with it a new set of concerns, including the effects of immune restoration disease (IRD), and the complex interplay between HAART and tuberculosis therapy. SUMMARY: The overriding conclusion from recent experience is that HAART, in those parts of the world where it is readily available, has changed the clinical picture of infections associated with HIV, and needs to be available to patients across the developing world as well. Furthermore there have been important developments in vaccination programs against pathogens involved in HIV-associated pneumonia.     

Coccidioidomycosis among persons with human immunodeficiency virus infection in the era of highly active antiretroviral therapy (HAART).

Coccidioidomycosis remains an important opportunistic infection among individuals infected with human immunodeficiency virus (HIV) who live in the coccidioidal endemic area. There are several manifestations of coccidioidomycosis during HIV infection, but pulmonary disease, either diffuse or focal, is the most common. The most important factor associated with the risk for developing clinically active coccidioidomycosis is a CD4 peripheral blood lymphocyte count of less than 250/microL. The advent of highly active antiretroviral therapy (HAART) for the treatment of HIV infection has changed our approach to the management of opportunistic infections, including coccidioidomycosis. Few data are available regarding the incidence of coccidioidomycosis since the initiation of HAART, but these suggest a decline. It is currently recommended that antifungal therapy for coccidioidomycosis during HIV infection be continued indefinitely, even among those with asymptomatic disease. Future studies should indicate whether this is necessary if immune function has been reconstituted through appropriate therapy for the HIV infection.     

Opportunistic infections...is it safe to stop prophylaxis?

An opportunistic infection (OI) rarely affects people with healthy immune systems, but can be life-threatening to people whose immune systems are weakened by HIV. Prophylaxis is the use of drugs to prevent the occurrence or recurrence of a disease, such as an OI. Since the use of highly active antiretroviral therapy (HAART), OI incidence and progression, hospitalization, and AIDS-related deaths have declined. This treatment may be even more effective than specific OI prophylaxis regimens. The value of HAART in treating HIV and acting as a preventative regimen against OIs are discussed. Antiretroviral use may allow people with HIV to discontinue their OI prophylaxis. Discontinuing prophylaxis has many benefits, including a reduction in the large numbers of medications HIV-infected people must take. A summary of common OIs, symptoms, and treatment is provided.     

艾滋病抗病毒治疗后机会感染的变化和分布状况

目的探讨艾滋病(AIDS)抗病毒治疗后机会感染疾病谱的变化及分布状况。方法采用回顾性分析的方法,对2006年9月-2008年12月期间,在郑州市第六人民医院接受门诊及住院治疗的128例HIV/AIDS病人,抗病毒治疗前后机会感染发生情况进行总结分析。结果 (1)128例HIV/AIDS病人中,高效抗反转录病毒疗法(HAART)治疗3-12月期间共发生100例次机会感染,主要为呼吸系统(46.09%)和消化系统(11.72%)感染,其中前4位机会感染是细菌性肺炎(29.69%)、肺结核(9.38%)、口腔念珠菌感染(7.81%)、带状疱疹(3.91%);与HAART治疗前相比,治疗后机会感染中细菌性肺炎、肺结核占绝大多数(86.46%),存在一定比例的口腔念珠菌感染和带状疱疹,AIDS晚期常见的机会感染如肺孢子菌肺炎、感染性腹泻及消耗综合征、中枢神经系统病变发病明显减少。(2)128例HIV/AIDS病人HAART治疗前机会感染发病率为80.47%,治疗后3-6月时下降至28.13%,治疗6-12月时为25.89%,3组相比差异有统计学意义(P<0.05)。HAART治疗后同时合并多种机会感染的病例减少。结论 HAART治疗后的机会感染发病率明显下降,机会感染疾病谱较治疗前有所不同,同时合并多种机会感染的几率减少。     

Immune restoration inflammatory syndromes: The dark side of successful antiretroviral treatment

The prevalence of cellular immunodeficiency has increased due to rising use of immunosuppressive therapies and the pandemic spread of HIV infection. More recently, the introduction of highly active antiretroviral therapy (HAART) in HIV has led to significant immune reconstitution, even in patients with previously long-lasting secondary immunodeficiency. HAART reduces morbidity and mortality in HIV infection and also changes the clinical course of prevalent subclinical opportunistic infections or autoimmune diseases. Atypical inflammatory disorders develop after initiation of HAART and have been summarized as “immune reconstitution syndrome,” “immune restoration disease,” and “immune restoration inflammatory syndrome.” However, diagnostic criteria and standards of therapy are yet to be defined. The awareness for these diseases is of increasing importance from a clinical point of view. This review summarizes the variety of immunoreconstitution disorders and describes possible diagnostic pitfalls. We also propose possible therapeutic options.     

Elevated mucosal addressin cell adhesion molecule-1 expression in acquired immunodeficiency syndrome is maintained during antiretroviral therapy by intestinal pathogens and coincides with increased duodenal CD4 T cell densities

Reduced intestinal CD4 T cell numbers and gastrointestinal disease are common features of acquired immunodeficiency syndrome (AIDS). Duodenal lymphocyte densities and mucosal addressin cell adhesion molecule (MAdCAM)-1 expression were analyzed in patients with AIDS after highly active antiretroviral therapy (HAART). Compared with human immunodeficiency virus (HIV)-seronegative individuals, HAART-naive patients with AIDS displayed reduced duodenal CD4 T cell densities. After HAART, AIDS patients with opportunistic intestinal pathogens displayed greater increases in duodenal lamina propria (LP) CD4 T cell densities than patients without such infections. Duodenal MAdCAM-1 expression was elevated in all HAART-naive patients with AIDS but remained elevated only in the intestinal pathogen group after HAART. The data suggest that, in HIV-1 infection, lymphocyte migration to the intestine may be promoted by increased MAdCAM-1 expression. After HAART, opportunistic intestinal pathogens maintain elevated MAdCAM-1 expression, which results in prominent increases in LP CD4 T cell densities in the absence of HIV-mediated CD4 T cell destruction.     

Illness of immune reconstitution: Recognition and management

Some individuals who initiate highly active antiretroviral therapy (HAART) develop new or worsening opportunistic infections or malignancies despite improvements in surrogate markers of HIV-1 infection. These events of paradoxical clinical worsening, also known as immune reconstitution syndromes (IRS), are increased in individuals with prior opportunistic infections or low CD4+ T-cell nadirs. They are thought to result from reconstitution of the immune system’s ability to recognize pathogens or tumor antigens that were previously present, but clinically asymptomatic. There is no consensus regarding the diagnostic criteria or pathogenesis of IRS. Knowledge of their presentation and treatment is largely based on case reports. With the introduction of HAART into resource-limited settings, it is likely that significantly more and distinct forms of IRS will be observed. Prospective studies of the incidence and treatment of IRS in multiple settings are critical to better understand their pathogenesis and optimal management.     

Vacuolar myelopathy and vacuolar cerebellar leukoencephalopathy: a late complication of AIDS after highly active antiretroviral therapy-induced immune reconstitution

Controversy exists as to whether vacuolar myelopathy (VM) responds to highly active antiretroviral therapy (HAART) in a salutary fashion similar to other primary human immunodeficiency virus (HIV)-related neurologic complications such as acquired immune deficiency syndrome (AIDS) dementia complex and progressive multifocal leukoencephalopathy. Herein, we describe the case of a patient with AIDS, non-Hodgkin's lymphoma, and cytomegalovirus colitis, who began HAART and cytotoxic chemotherapy. After 6 months of therapy, restaging studies showed no residual lymphoma or active opportunistic infection. For 2 years he was maintained on HAART, during which time his HIV viral load remained nondetectable and his CD4+ count improved from 20 to 300 cells per microliter. Shortly after developing the acute onset of cerebellar ataxia, he aspirated, developed adult respiratory distress syndrome, and died. At autopsy the spinal cord demonstrated a characteristic vacuolated appearance that extended into the cerebellum. No relation between HIV and the development of VM was discerned by in situ hybridization studies. Experience with this one patient suggests that HAART may not alter the natural history of VM. Whether this case represents yet another variant of the recently described inflammatory immune response syndrome whereby progression of previously quiescent disorders evolve to symptomatic disease after initiation of HAART is uncertain.     

Soft tissue abscess and lymphadenitis due to Mycobacterium avium complex as an expression of immune reconstitution inflammatory syndrome after a second scheme of highly active antiretroviral therapy

Immune reconstitution inflammatory syndrome (IRIS) is an atypical and unexpected reaction related to highly active antiretroviral therapy (HAART) in human immunodeficiency virus (HIV) infected patients. IRIS includes an atypical response to an opportunistic pathogen (generally Mycobacterium tuberculosis, Mycobacterium avium complex, cytomegalovirus and herpes varicella-zoster), in patients responding to HAART with a reduction of plasma viral load and evidence of immune restoration based on increase of CD4+ T-cell count. We reported a case of a patient with AIDS which, after a first failure of HAART, developed a subcutaneous abscess and supraclavicular lymphadenitis as an expression of IRIS due to Mycobacterium avium complex after starting a second scheme of HAART.     

The impact of highly active antiretroviral therapy on prevalence and incidence of cervical human papillomavirus infections in HIV-positive adolescents

Background  

The implementation of highly active antiretroviral therapy (HAART) among HIV-positive patients results in immune reconstitution, slower progression of HIV disease, and a decrease in the occurrence of opportunistic infections. However, the impact of HAART on cervical human papillomavirus (HPV) infection, clearance, and persistence in high-risk adolescents remains controversial.