Disorders In HIV-infected Patients Research Articles

Symptomatic bone disorders in HIV‐infected patients: incidence in the Aquitaine cohort (1999–2002)

Since the inception of highly active antiretroviral therapy (HAART), mortality among HIV-infected patients has decreased, but this has been accompanied by the appearance of several complications. To estimate the incidence of symptomatic bone disorders in HIV-infected patients of the Aquitaine cohort (from south-west France) for the period 1999-2002, and to describe cases. We retrospectively studied the records of 2700 patients of the Aquitaine cohort, which was derived from a hospital-based surveillance system of HIV infection in France. All cases of symptomatic bone disorders diagnosed from 1 January 1999 to 30 June 2002 were reviewed. Fourteen cases of bone disorders were diagnosed, eight cases of aseptic osteonecrosis and six cases of severe osteoporosis, representing incidences of 0.3/1000 patient-years [95% confidence interval (CI): 0.14-0.62] and 0.22/1000 patient-years (95% CI: 0.09-0.52), respectively. All patients with aseptic osteonecrosis were male, while all but one with osteoporosis were female. The ages of patients ranged from 36 to 54 years for osteonecrosis and from 39 to 50 for severe osteoporosis. At the time of clinical diagnosis, all patients were treated with nucleoside reverse transcriptase inhibitors (duration of treatment ranging from 19 to 123 months for osteonecrosis and from 46 to 132 months for severe osteoporosis). Ten patients were treated with nonnucleoside reverse transcriptase inhibitors [duration of treatment ranging from 6 to 31 months for osteonecrosis (n=6) and from 4 to 29 months for severe osteoporosis (n=4)]. Thirteen patients were treated with protease inhibitors [duration of treatment ranging from 12 to 62 months for osteonecrosis (n=8) and from 3 to 44 months for severe osteoporosis (n=5)]. All osteonecrosis and five osteoporosis patients had at least one known risk factor or comorbidity associated with the bone disorder occurrence. In our study, the aetiology of clinical bone disorders seemed to be multifactorial, as almost all the patients had at least one possible risk factor in addition to HAART exposure.

Evaluation and management of metabolic and coagulative disorders in HIV-infected patients receiving highly active antiretroviral therapy.

A number of metabolic disorders, including hypercholesterolemia, hypertriglyceridemia, insulin resistance, elevated fasting glucose and diabetes mellitus, were reported in a high proportion of HIV-infected patients receiving highly active antiretroviral therapy (HAART). Less frequently, coagulative disorders were described in patients receiving HAART. Since all these metabolic disorders may predispose to coronary heart disease, an early evaluation and treatment is advisable. Existing guidelines for uninfected patients may be applied, taking into account, however, the potential for drug interactions and accumulated toxicity. It may be helpful to stratify all patients in three risk groups to plan regular diagnostic screening. Treatment of dyslipidemia and diabetes mellitus should include a first-line approach with non-pharmacological interventions. Statins and fibrates are proposed for HIV-infected patients with HAART-related hyperlipidemia, but concern has been raised on their potential for interaction with antiretrovirals and hepatic and muscle toxicity. Metformin and thiazolidenediones (or glitazones), hypoglycemic agents that increase insulin sensitivity, are presently under evaluation in diabetic and glucose-intolerant HIV-infected patients treated with HAART. Glitazones also have a potential for ameliorating the lipodystrophic syndrome. The routine evaluation of coagulative parameters is probably not advisable until a benefit of widespread screening is assessed in prospective studies. A heightened awareness of the possiblity of coagulative disorders, together with controlled trials and basic research, is needed.

Cardiovascular manifestations of HIV infection.

Studies 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.1 The 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 is recognized as an important cause of dilated cardiomyopathy, with an estimated annual incidence of 15.9 in 1000 before the introduction of HAART3 (Table 1). The importance of cardiac dysfunction is demonstrated by its effect on survival in acquired immunodeficiency syndrome (AIDS). Median survival to AIDS-related death is 101 days in patients with left ventricular dysfunction and 472 days in patients with a normal heart as shown by echocardiography at a similar infection …

Stimulation of peroxisome proliferator-activated receptors alpha and gamma blocks HIV-1 replication and TNFalpha production in acutely infected primary blood cells, chronically infected U1 cells, and alveolar macrophages from HIV-infected subjects.

Metabolic disorders in HIV-infected patients, especially those receiving highly active antiretroviral therapy (HAART) regimens containing protease inhibitors, are associated with insulin resistance. These metabolic disorders include fat redistribution, diabetes, and hypertriglyceridemia. Thiazolidinediones (TZDs) are used to treat patients with diabetes secondary to insulin resistance, and TZDs are being studied in HAART-related metabolic disorders. We studied the effects of TZDs (peroxisome proliferator-activated receptor-gamma [PPARgamma] agonists) and a PPARalpha agonist on HIV replication and TNFalpha production in peripheral blood mononuclear cells (PBMCs) acutely infected with HIV-1, in a chronically infected monoblastoid cell line (U1) and in alveolar macrophages (AMs) from HIV-infected subjects and uninfected controls. Rosiglitazone, ciglitazone, troglitazone, and PgJ (PPARgamma agonists) as well as fenofibrate (PPARalpha agonist) inhibited HIV replication in both PBMCs and U1 cells. These agents also inhibited TNFalpha production, but the magnitude of TNFalpha inhibition was not directly correlated with the quantitative decreases in HIV replication. In AMs, ciglitazone, rosiglitazone, and troglitazone reduced TNFalpha production. We hypothesize that alterations in mitogen-activated protein kinase signaling pathways have contemporaneous and interrelated effects on HIV replication, cytokine production, and lipid metabolism. Modulation of these pathways using PPAR agonists may improve the metabolic alterations during HAART in conjunction with desirable decreases in HIV replication and TNFalpha production.

Antiretroviral therapy-associated hyperlipidaemia in HIV disease.

Widespread utilization of highly active antiretroviral therapy (HAART) for HIV-infection, primarily protease inhibitors in combination with nucleoside analogue reverse transcriptase inhibitors, has recently led to a sustained reduction in the morbidity and mortality of this disease. However, administration of HAART is frequently associated with the development of lipid disorders. The severity and prevalence of dyslipidaemia vary, depending on the type of HAART, nutritional status, HIV disease stage, and concomitant presence of lipodystrophy and insulin resistance (two additional adverse effects of HAART). The mechanism that is responsible for HAART-associated dyslipidaemia remains incompletely understood. Recent data indicate that this effect may be, at least in part, accounted for by protease inhibitor-mediated inhibition of the proteasome activity and accumulation of the active portion of sterol regulatory element-binding protein-1c in liver cells and adipocytes. Whether lipid disorders in HIV-infected patients receiving HAART translate into an increased cardiovascular risk, and the indications for lipid-lowering interventions in this population, remain to be established.

In vitro metabolism of trazodone by CYP3A: inhibition by ketoconazole and human immunodeficiency viral protease inhibitors

Background: Pharmacologic treatment of emotional disorders in HIV-infected patients can be more easily optimized by understanding of potential interactions of psychotropic drugs with medications used to treat HIV infection and its sequelae. Methods: Biotransformation of the antidepressant trazodone to its principal metabolite, meta-chlorophenylpiperazine (mCPP), was studied in vitro using human liver microsomes and heterologously expressed individual human cytochromes. Interactions of trazodone with the azole antifungal agent, ketoconazole, and with human immunodeficiency virus protease inhibitors (HIVPIs) were studied in the same system. Results: Formation of mCPP from trazodone in liver microsomes had a mean (± SE) K m value of 163 (± 21) μmol/L. Ketoconazole, a relatively specific CYP3A inhibitor, impaired mCPP formation consistent with a competitive mechanism, having an inhibition constant (K i) of 0.12 (± 0.01) μmol/L. Among heterologously expressed human cytochromes, only CYP3A4 mediated formation of mCPP from trazodone; the K m was 180 μmol/L, consistent with the value in microsomes. The HIVPI ritonavir was a potent inhibitor of mCPP formation in liver microsomes (K i = 0.14 ± 0.04 μmol/L). The HIVPI indinavir was also a strong inhibitor, whereas saquinavir and nelfinavir were weaker inhibitors. Conclusions: CYP3A-mediated clearance of trazodone is inhibited by ketoconazole, ritonavir and indinavir, and indicates the likelihood of pharmacokinetic interactions in vivo.

Diarrhea and enteric emerging viruses in HIV-infected patients.

To evaluate the prevalence of enteric viruses and their possible association with diarrhea, 244 stool samples were collected from HIV-infected and uninfected patients with or without diarrhea (subgroups I-a, Ib, II-a, and II-b, respectively). Subjects were screened by polyacrylamide gel electrophoresis, latex agglutination, and enzyme immunoassays for rotaviruses, adenoviruses, picobirnaviruses, and astroviruses. Enteric viruses were found significantly more often in specimens from HIV patients (20%) than in specimens from uninfected HIV patients (0%) (p < 0.05). Picobirnavirus was detected in 14.63% of 82 HIV-infected patients with diarrhea, but it was detected neither in those without diarrhea (0%) (p < 0.05) nor in the groups of uninfected HIV subjects (0%) (p < 0.05). Nor could astrovirus (subgroups I-a [4.00%] versus subgroup I-b [5.26%],p > 0.05) or enteric adenovirus (subgroup I-a [1.22%] versus subgroup I-b [0%], p > 0.05) be linked to the diarrhea disorder in HIV-infected patients. Rotaviruses were not detected in any of the clinical subgroups studied. Enteric viruses were detected in 15 of 93 (16.13%) of the HIV-infected patients with CD4+ T cell count <200/microl and 3 of 19 (15.79%) of those HIV-infected individuals with a CD4+ T cell count 200-499/microl, showing no significant difference (p > 0.05). According to our data, unusual enteric viruses such as picobirnavirus, astrovirus, and enteric adenovirus occur in HIV-infected population in Córdoba, Argentina. However, only picobirnaviruses could be significantly associated with diarrhea in these patients.

Mood disorders in HIV infection.

Summary Major depression and mania have increased prevalence in HIV-infected patients, particularb in clinical settings and at later stages of disease. Varied rates of major depression have been reported but dzzerences in definition, methods of study, and population may partly explain these dafferences. We describe the clinical characteristics, assessment and treatment of mood disorders in HIV-infected patients, with emphasis on aspects specific to the setting of HIV infection. Diagnosis and treatment are complicated by medical complexity, stigma and psychosocial stress. Treatment is associated with clinical improvement. Mood disorders are associated with impulsivity, substance abuse, hopelessness, and demoralization, all of which may increase risk for HIV infection. Also, HIV-associated subcortical damage may be a risk factor for mood disorders, which are increased in late stage HIV infection. We discuss the data supporting the thesis that both of these factors may be at work in producing the high rates of mood disorders seen, and speculate that aggressive treatment of mood disorders may improve outcome and risk behaviors in HIV-infected patients.

Viral lesions of the mouth in HIV-infected patients.

Viral lesions of the mouth in patients with HIV infection are common and these diseases any be a marker for HIV and disease progression. We review the spectrum of oral viral manifestations and discuss treatment modalities. The most common Epstein-Barr virus (EBV)-induced disorder in HIV-infected patients is oral hairy leukoplakia. EBV-related oral B-cell and T-cell lymphoma in AIDS patients has been described repeatedly. Herpes virus type 1 and rarely type 2 may lead to painful and resistant oral ulcers, and systemic treatment with acyclovir, valaciclovir or famciclovir is indicated. In acyclovir-resistant cases foscarnet is the treatment of choice. In recent years it has been documented that Kaposi's sarcoma, which often affects oral mucosa, is probably induced by herpesvirus type 8. Cytomegalovirus was found in 53% of cases with herpesviridae-induced mucosal ulcers as the only ulcerogenic viral agent in AIDS patients. In severe cytomegalovirus infection treatment with ganciclovir is helpful. Viral warts induced by different HPV may occur in the mouth. Several physical treatment modalities are possible in the oral mucosa. In AIDS patients mollusca contagiosa may occur as large and atypical lesions in the face and lips and rarely in the oral cavity. Cryotherapy is a bloodless treatment in such patients.

Anomalies de l'hémostase et infection par le virus de l'immunodéficience humaine

Because hemostasis disorder in HIV infected patients are frequent and have clinical effects, they have aroused the interest of internal medicine. Such anomalies are not yet clearly defined and include various parameters. Thrombocytopenia which is the most widespread and the best documented manifestation, whether of peripheral origin by immunological platelet destruction or of central origin by a shortage in platelet production, responds well to medical treatment, especially to zidovudine. The circulating anti-coagulants frequently observed in HIV infected patients, whether anti-phospholipid antibodies or anti-cardiolipines are mostly asymptomatic. Other coagulation disorders (affection of the inhibitory system or fibrinolysis) are rarely observed and generally have no clinical incidence. Apart from thrombocytopenias and thrombotic thrombocytopenic purpura the incidence of clinical signs (thrombotic or hemorrhagic accidents) in HIV infected patients is not higher than in an HIV-free population and respond to the same treatment.

The Effect of Simian Immunodeficiency Virus Infectionin Vitroandin Vivoon the Cytokine Production of Isolated Microglia and Peripheral Macrophages from Rhesus Monkey

Microglia are the major target for human immunodeficiency virus (HIV) infection within the central nervous system. Because only a few cells are productively infected, it has been suggested that an aberrant cytokine production by this cell population may be an indirect mechanism leading to the development of neurological disorders in HIV-infected patients. Therefore we decided to study the secretion pattern of several interleukins (IL) by microglial cells and peripheral blood macrophages isolated from uninfected and simian immunodeficiency virus (SIV)-infected Rhesus monkeys. We found that uninfected, unstimulated primate microglia produce more IL-6 and less TNFα than peripheral blood macrophages, but generate comparable levels of IL-1β and IL-8. After infection with SIVin vitro,synthesis of all cytokines tested is increased compared to uninfected cultures and to peripheral blood macrophages. Microglia isolated from infected animals produce more IL-8 and TNFα than the uninfected cultures and display a strongly increased capacity to secrete TNFα upon stimulation with lipopolysaccharide. In addition, production of IL-6 byin vivo-infected microglia increases with time in culture to very high levels despite the fact that only a few cells contained replicating virus. These findings clearly show that the cytokine production of microglia is impaired after SIV infection bothin vitroandin vivoand that a low level of viral replication is sufficient for these alterations to occur. In conclusion, the results of this study further support a possible role of cytokines in the pathogenesis of neuro-AIDS.

Mood disorders in HIV infection

Major depression and mania have increased prevalence in HIV-infected patients, particularly in clinical settings and at later stages of disease. Varied rates of major depression have been reported but differences in definition, methods of study, and population may partly explain these differences. We describe the clinical characteristics, assessment and treatment of mood disorders in HIV-infected patients, with emphasis on aspects specific to the setting of HIV infection. Diagnosis and treatment are complicated by medical complexity, stigma and psychosocial stress. Treatment is associated with clinical improvement. Mood disorders are associated with impulsivity, substance abuse, hopelessness, and demoralization, all of which may increase risk for HIV infection. Also, HIV-associated subcortical damage may be a risk factor for mood disorders, which are increased in late stage HIV infection. We discuss the data supporting the thesis that both of these factors may be at work in producing the high rates of moo...

Myopathy and HIV infection.

Skeletal muscle involvement may occur at all stages of HIV infection. The most simple classification of muscular disorders in HIV-infected patients is 1) HIV-associated myopathies, 2) zidovudine myopathy, 3) HIV wasting syndrome, and 4) opportunistic infections and tumoral infiltrations of muscle. Immunohistology for major histocompatibility complex class I antigen and histochemical reaction for cytochrome c oxidase are helpful in correctly classifying a myopathy as HIV polymyositis or zidovudine myopathy. Studies of cytokine expression in HIV-infected patients and of supplementation with compounds such as carnitine or micronutrients such as selenium might yield new insights into the pathogenesis and treatment of the various AIDS-associated muscular disorders.

Psychiatric Disorders in HIV-Infected Patients

Summary HIV infection is associated with considerable psychiatric, as well as medical, morbidity. Epidemiological studies indicate that patients who are infected with HIV are at an increased risk of having a psychiatric disorder compared with uninfected individuals. Knowledge of infection with HIV is associated with considerable psychological stress. Moreover, HIV infection produces direct and indirect brain injury leading to the development of psychiatric conditions. Conversely, the vulnerabilities and behaviours necessary for contracting HIV are associated with some psychiatric disorders, so that increasingly large numbers of patients with these disorders are becoming infected with the virus. Patients with psychiatric disorders are at higher risk than others in the general population of continuing high-risk HIV-related behaviour, and are less responsive to education. The psychiatric disorders that are most common among individuals who have HIV infection are substance abuse, mood, anxiety and cognitive disorders. Psychiatric disorders are an aspect of HIV infection that responds to appropriate treatment. Such treatment is based on careful evaluation and differential diagnosis of psychiatric symptoms. A variety of psychotherapeutic agents are available to the clinician to treat these disorders. These are best administered after the establishment of good doctor-patient rapport, and in tandem with ongoing education and supportive psychotherapy.

Screening for psychiatric morbidity in a medical outpatient clinic for HIV infection: the need for a psychiatric presence.

To ascertain the prevalence and type of psychiatric morbidity present in HIV infected patients presenting for the first time to a specialty HIV medical clinic. Also, to develop a way of screening for psychiatric cases in this setting using established self-report questionnaires. Fifty patients who presented consecutively for medical care at the Johns Hopkins Hospital General HIV Clinic participated in this study. These patients were first screened using the General Health Questionnaire and the Beck Depression Inventory and subsequently underwent a comprehensive neuropsychiatric evaluation. Fifty-four percent were found to suffer from a psychiatric disorder with an additional 22 percent from an active substance use disorder. These rates are one-and-one-half to two times higher than those reported from other medical clinics. The GHQ and BDI used together as screens could identify psychiatric "cases" with a sensitivity of 81 percent and a specificity of 61 percent, an efficacy similar to that found in other clinics. Given the high prevalence of psychiatric disorders in HIV infected patients presenting for medical care, screening, evaluating, and treating for these disorders is crucial and should be pursued systematically. This is best done through the presence of a psychiatric team within HIV medical clinics rather than in affiliation with such clinics.

Benign Intracranial Hypertension Associated with HIV Infection

We report the case of a 24-year-old woman with HIV-seropositivity, who developed a clinical picture of pseudotumor cerebri, an association not previously described. The patient improved with the use of acetazolamide. We suggest the possible existence of this disorder in HIV-infected patients with persistent headaches, visual deficits and/or extraocular muscle palsies.

HIV-Related Encephalitis Presenting as Convulsant Disease

Because of the growing incidence of neurological disorders in HIV-infected patients, an early detection of the disease seems to be of paramount importance, especially in asymptomatic subjects. By using electroencephalography coupled with computerized spectral analysis and "mapping" (EEG-CSA), paroxysmal sharp activity was detected in 26 patients belonging to different stages of HIV infection. Seven of them (27%) were also symptomatic, (table; see text) showing signs of convulsant disease. The presence of focal or generalized paroxysmal activity, often associated with seizures, might suggest an early localization of HIV in cortical structures.

Dissociated nystagmus as a common sign of ocular motor disorders in HIV-infected patients.

In order to determine if ocular motor disturbances due to brainstem and cerebellar dysfunction provide a frequent and early marker for HIV infection of the brain, neurological examination was performed in 133 HIV-infected persons who were consecutively admitted to our hospital. In 22 patients (17%) we found no other reason for cerebellar or pontomesencephalic signs than HIV encephalopathy. Ocular motor disorders accounted for the most frequent signs of cerebellar and pontomesencephalic dysfunction. Ocular motor disorders mainly consisted of dissociated nystagmus (n = 12), gaze-evoked nystagmus (n = 10) and impaired smooth pursuit (n = 6). Cerebellar ataxic gait and dysmetria were present in 3 patients. Since dissociated nystagmus was the primary ocular motor disorder, we assume that the medial longitudinal fasciculus may be a predilected circumscribed area for HIV infection of the brain. We suppose that cerebellar and pontomesencephalic disorders may be an early marker for HIV encephalopathy because they were the only neurological signs found in 12 patients.