Disease In HIV-infected Patients Research Articles

Coronary heart disease in HIV-infected patients

Increased risk of coronary heart disease has emerged as a long-term concern among HIV-infected patients receiving antiretroviral therapy. HIV-infected patients may have modifiable risk factors for heart disease that are associated with HIV itself, antiretroviral therapy, or factors unrelated to HIV. Dyslipidemia, insulin resistance, and diabetes mellitus are often multifactorial in origin. Patients with lipodystrophy frequently have a constellation of metabolic changes that may predispose them to accelerated atherosclerosis. There is also concern about contributions of chronic inflammation and prothrombotic tendencies in the pathogenesis of coronary heart disease in the HIV-infected population. Several epidemiological studies support an increased relative risk of myocardial infarction in HIV-infected patients on highly active antiretroviral therapy. Although absolute risk appears low in the short term, patients may accrue significant risk over time. Clinicians are advised to assess coronary heart disease risk in HIV-infected patients and to intervene to reduce the impact of modifiable risk factors.

HIV-associated immune complex glomerulonephritis with “lupus-like” features: A clinicopathologic study of 14 cases

While the most common glomerular lesion associated with human immunodeficiency virus (HIV) infection is collapsing focal segmental glomerulosclerosis (FSGS) [HIV-associated nephropathy (HIVAN)], immune complex-mediated forms of glomerulonephritis have been increasingly reported. One form of glomerulonephritis that has been described in the HIV-infected population is immune complex glomerulonephritis with "lupus-like" features, characterized by histologic, immunohistologic, and ultrastructural features resembling lupus nephritis, but occurring in patients without evidence of systemic lupus erythematosus (SLE). Data regarding clinical outcomes in patients with this form of glomerulonephritis are very limited. We reviewed pathology reports for all native renal biopsy specimens from HIV-positive patients processed at our center from January 1999 through December 2003. Of 77 total specimens, 14 met the following criteria for lupus-like glomerulonephritis: (1) immunofluorescence microscopy showed granular glomerular staining for IgG, IgA, IgM, C3 and C1q, with > or=1+ (0 to 4+ scale) staining for C1q; and (2) the patient's serum was negative for antinuclear antibodies (ANA), or weakly positive (titer < or =1:80) for ANA and negative for antidouble-stranded DNA. Clinically, ten of the 14 patients with lupus-like glomerulonephritis presented with nephrotic syndrome, all had microscopic hematuria, and nine had serum creatinine >3.0 mg/dL. All but one were African American. Histologically, seven biopsies showed diffuse proliferative glomerulonephritis, six focal proliferative glomerulonephritis, and one membranous nephropathy. All but two biopsies showed moderate or severe chronic change, and three showed concurrent HIVAN. Ten of the 14 patients developed end-stage renal disease (ESRD) within 1 year of the biopsy. Nine of these ten patients presented with proteinuria >5.0 g/24 hours and nephrotic syndrome, while three of four patients who did not develop ESRD had proteinuria < or =3.0 g/24 hours. Lupus-like glomerulonephritis, defined by immunohistologic features and absence of serologic evidence of SLE, is not an uncommon form of glomerular disease in HIV-infected patients undergoing a renal biopsy. Renal outcomes in these patients were poor, although this may be due largely to most patients presenting with advanced disease.

AIDS/HIV Infection and Cerebrovascular Disease

The occurrence of cerebrovascular disease in patients with human immunodeficiency virus (HIV) infection has been reported mainly in advanced stages of the disease and was generally associated with nonbacterial thrombotic endocarditis, opportunistic infections, or tumors, although in recent series a large number of cryptogenic strokes were found, probably related to HIV vasculopathy. Recently a population-based study reported a strong association between acquired immunodeficiency syndrome (AIDS) and both ischemic stroke and intracerebral hemorrhage, with an incidence of 0.2% per year. However, with the advent of highly active retroviral therapy (HAART)-causing immune restoration in HAART-treated patients and avoiding early death and leading to a lengthening of the disease free-survival, an older population was created, which is at higher risk for stroke. Furthermore, recent evidence suggests that accelerated atherosclerosis may be a potential risk for stroke in these patients as it accompanies dyslipidemia and insulin resistance that were found to be more frequent among patients in the HAART regimen. The relationship of HIV infection and stroke is undergoing remarkable changes and epidemiological studies should be performed on aging HIV populations to state the impact of this new information on the incidence of cerebrovascular disease in HIV-infected patients and to identify factors that are associated with its occurrence.

Protease inhibitor exposure and increased risk of cardiovascular disease in HIV‐infected patients

To study the relationship between exposure to protease inhibitor (PI) therapy and increased risk of cardiovascular events in HIV-infected patients. We estimated the risk of cardiovascular disease (CVD) events with PI exposure in a cohort of HIV-infected patients using a time-dependent Cox proportional hazards model adjusting for the major CVD risk factors. Only the first CVD event for each subject was counted. Of a total of 7542 patients, 77% were exposed to PIs. CVD event rates were 9.8/1000 and 6.5/1000 person-years of follow-up (PYFU) in the PI-exposed and nonexposed groups, respectively (P=0.0008). PI exposure >/=60 days was associated with an increased risk of CVD event [adjusted hazards ratio (HR(adj)) 1.71; 95% confidence interval (CI) 1.08-2.74; P=0.03]. Results from a subgroup of patients aged between 35 and 65 years were similar (HR(adj) 1.90; 95% CI 1.13-3.20; P=0.02). Other significant risk factors included smoking status, age, hypertension, diabetes mellitus and pre-existing CVD. Patients exposed to PI therapy had an increased risk of CVD events. Clinicians should evaluate the risk of CVD when making treatment decisions for HIV-infected patients.

Cerebral Mycobacterium avium abscesses: Late immune reconstitution syndrome in an HIV‐1‐infected patient receiving highly active antiretroviral therapy

A patient who developed an atypical manifestation of Mycobacterium avium complex (MAC) infection almost two years after starting effective highly active antiretroviral therapy is described. The recurrence, manifested as brain abscesses in the central nervous system, was an uncommon form of MAC disease usually reported postmortem. An increased CD4 cell count, localized and suppurative infection, and the absence of systemic evidence of infection were consistent with a late immune reconstitution syndrome. The present case report adds to the understanding of MAC disease in HIV-infected patients.

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

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

Immune reconstitution syndrome. A new disease in HIV-infected patients effectively treated with antiretroviral drugs

Immune reconstitution syndrome. A new disease in HIV-infected patients effectively treated with antiretroviral drugs

Is inflammatory joint disease in HIV-infected patients a form of spondyloarthropathy?

In Congo–Brazzaville, the seroprevalence of HIV infection is in the range 7–8%, and AIDS is the leading cause of aseptic arthritis (60% of cases). Patients, material and methods. – The ESSG and Amor’s criteria for spondyloarthropathy were evaluated in 83 patients with HIV infection admitted for aseptic arthritis to the rheumatology department of the Brazzaville teaching hospital, over an 8–year period. Results. – All 83 patients were CDC stage IV; 66 (80%) had polyarthritis and 17 (20%) oligoarthritis. A single patient met ESSG and Amor’s criteria, with six points; one patient had five points and 15 had three points. The joint involvement was asymmetrical and nonerosive. Nonsteroidal antiinflammatory therapy ensured resolution of the manifestations within 4–8 weeks. The most common sites of involvement were the knees (84%), ankles (59%), and great toes (23%) at the lower limbs and the wrists (41%), elbows (29%), and metacarpophalangeal and interphalangeal joints (25%) at the upper limbs. Conclusion. – Inflammatory arthritis in HIV patients does not meet ESSG or Amor’s criteria for spondyloarthropathy.

Enfermedad cardiovascular sintomática en pacientes infectados por el virus de la inmunodeficiencia humana que reciben tratamiento antirretroviral de gran actividad

Our goal was to assess the main characteristics of cardiovascular disease in HIV-infected patients on highly active antiretroviral therapy (HAART). Retrospective analysis of the clinico-epidemiological characteristics of 16 HIV-infected patients treated with HAART who had suffered a cardiovascular event from a 1,459 patients' cohort. Clinical presentation of cardiovascular disease was an acute coronary syndrome in 12 cases, ischemic stroke in 2 and peripheral vascular disease in 2. Patients included in the study had a mean of 3.2 cardiovascular risk factors, smoking and low HDL levels being the more prevalent risk factors. Eight (50%, 95% CI, 25-75%) patients fulfilled the criteria of metabolic syndrome. The mean CD4 count was 548 x 10(6)/l. HIV-infected patients on HAART ha-ve a high cardiovascular risk. A strict management of modifiable risk factors must be warranted in these patients.

Cardiovascular effects of antiretroviral therapy and noninvasive assessments of cardiovascular disease in HIV infection.

The heart is frequently affected in patients with the acquired immune deficiency syndrome (AIDS). Although the introduction of potent antiretroviral therapy (ART) has produced a sharp decline in mortality and morbidity in HIV-infected patients, the use of ART is associated with the development of peripheral insulin resistance, dyslipidemia, and lipodystrophy. These abnormalities are also associated with coronary artery disease, and numerous reports of myo-cardial infarction in young HIV-infected patients have raised concerns of pre-mature coronary disease in this population. A comprehensive review of the epidemiology of coronary artery disease is given. In recent years, several non-invasive methods to detect early development of atherosclerosis have been evaluated. Two noninvasive techniques using ultrasound have emerged as valid methods to detect early development of atherosclerosis: intima-media thickness and endothelial dysfunction assessed by the measurement of flow-mediated brachial artery dilatation. Multicenter, randomized trials using either technique may provide more information about whether HIV infection alone, long-term HAART use, or both may increase the risks of or accelerate coronary disease in HIV-infected patients.

Prevalence of proteinuria and the development of chronic kidney disease in HIV-infected patients.

HIV-related renal diseases are increasingly prevalent and are associated with proteinuria and rapid progression to end-stage renal failure. Early treatment with highly active antiretroviral therapy (HAART) and ACE inhibition may prevent the development of chronic kidney disease (CKD), but studies evaluating the epidemiology of proteinuria and early CKD in HIV-infected patients are lacking. All consecutive patients at Wishard Memorial Hospital (Indiana University) whose initial HIV documentation occurred from 1990 to 1998, were retrospectively studied using a computerized medical record system. Clinical data were abstracted from time of first HIV documentation through 12/31/2000. The proportions of patients who developed CKD (doubling of serum creatinine from an initial level < or = 1.5 mg/dl) and who had proteinuria (> or = 1+ protein on the first urine dipstick after HIV documentation) were calculated. Case mix and laboratory variables at the time of HIV documentation were compared between those who did and did not develop CKD and between those who had and did not have initial proteinuria. Of 487 subjects with initially normal renal function, 10 (2% (95% CI, 1-4%)) developed CKD. In univariable analysis, black race, a diagnosis of diabetes or hypertension and proteinuria were all significantly associated with the development of CKD; 89 (29% (95% CI, 24-35%)) of 289 evaluable subjects had > or = 1+ proteinuria on urine analysis. Multivariable regression revealed only older age (OR 1.08 per year increase; 95% CI, 1.03-1.14) to be associated with proteinuria. A small, but potentially clinically meaningful proportion of HIV-infected patients develop CKD, and there appears to be a high prevalence of proteinuria on the first urine analysis obtained after HIV documentation.

Les patients infectés par le virus de l'immunodéficience humaine sous traitement antirétroviral ont-ils un risque cardiovasculaire accru ?

There is a growing concern about an increased risk for cardiovascular disease in HIV infected patients receiving antiretroviral therapy (ART). This risk could be related to metabolic abnormalities associated with long-term use of antiretroviral drugs. In fact, well recognized cardiovascular risk factors such as hypertension, dyslipidaemia, diabetes mellitus and central fat deposition are increasingly seen in HIV patients on ART. These factors can also be associated with non reversible risk factors, such as male sex, age greater than 40 years and family history of premature coronary artery disease. In addition, cigarette smoking and sedentary lifestyle may predispose these patients to significant cardiovascular disease. A direct atherogenic effect of HIV infection itself or antiretroviral drugs is unlikely. Epidemiological studies have suggested an increased risk for coronary artery disease in HIV infected persons; nevertheless, only long term follow-up could confirm this statement. Despite these uncertainties, it seems reasonable to identify and manage cardiovascular risk factors in HIV infected patients.

Introduction

This supplement summarizes presentations made at the Spring Symposium sponsored by Boehringer Ingelheim International entitled Optimising HIV Treatment - Building on Experience. It took place at the Alcora Hotel, Seville, Spain, on 15 March 2002. The aim of the symposium was to provide an overview of the field of HIV/AIDS with a particular emphasis on the non-nucleoside reverse transcriptase inhibitor, nevirapine. The mechanism of action, resistance profile and pharmacokinetics of nevirapine were reviewed by Drs Wainberg and Back. Three presentations, by Drs Murphy, Mayers and Dieterich, focused on the safety profile of nevirapine, especially recently obtained hepatic safety data about the drug. Drs Lange and Harris discussed a number of clinical studies that have demonstrated the safety and efficacy of nevirapine in two very different patient populations: antiretroviral naïve and treatment experienced patients. Dr Rockstroh addressed the complex issues involved in managing hepatitis B and C infections in HIV co-infected patients. Single dose nevirapine has been shown to be effective in preventing mother-to-child transmission of HIV-1. Dr Sullivan presented these data and outlined the issues that need to be resolved in order to ensure that HIV-infected mothers can have healthy children, in both the developed and developing world, as well as the chance of improving their own health. Concerns have been growing about the potential risk of cardiovascular disease in HIV-infected patients taking antiretroviral drugs. Dr Carr put these into perspective by summarizing the current status of this area. Dr Clotet then described the effect of nevirapine on a number of lipid parameters, including high density lipoprotein (HDL) cholesterol and triglycerides, in both antiretroviral naïve and protease-inhibitor-experienced patients. The effects of antiretroviral therapy on mitochondrial function are another growing area of concern, reviewed by Dr Montaner. He also described a novel experimental assay that is currently under evaluation to further characterize and possibly monitor mitochondrial toxicity. The last two presentations focused on future treatment options for patients with HIV/AIDS. Dr Yeni presented preclinical and early clinical data on tipranavir, a novel non-peptidic protease inhibitor, and Dr Vella discussed future treatment perspectives in the field. The symposium was very stimulating and we trust that you find this supplement a useful and educational record of the event. Editors and Co-chairs of the Symposium: David Cooper (Australia) Joep Lange (The Netherlands) Julio Montaner (Canada)

New sexually transmitted diseases in HIV-infected patients: markers for ongoing HIV transmission behavior.

The objective of this study was to describe the rate of new sexually transmitted diseases (STDs) among HIV-infected patients and to define the behavioral and clinical characteristics of HIV-infected patients who return with a new STD in follow-up. The study design was a record-based clinical cohort study focusing on patients testing HIV-seropositive in the STD clinics of Baltimore, Maryland from 1993 to 1998. The authors identified those HIV-infected patients later diagnosed with an STD in follow-up and compared their demographic, behavioral, and clinical characteristics with those who were not diagnosed with an STD in follow-up. Of 796 men and 354 women with HIV infection, 13.9% of men and 11.9% of women were diagnosed with an STD after their initial HIV diagnosis. HIV-infected men returned with a new STD at a rate of 7 cases per 100 person-years; HIV-infected women returned at a rate of 5.6 cases per 100 person-years. In men, multiple sex partners and sex worker contact were associated with a subsequent STD diagnosis (OR = 1.67, p =.037; OR = 1.82, p =.015, respectively). In women, age younger than 30 years was associated with the diagnosis of an STD after the diagnosis of HIV infection (OR = 2.94, p =.0009). Patients diagnosed with HIV in an STD clinic setting commonly return with new STDs in follow-up, suggesting continued exposure of HIV to others. More intensive screening and counseling interventions focused on STD prevention in those with HIV infection is a necessary HIV prevention strategy.

Efficacy of clofazimine–modified cyclodextrin against Mycobacterium avium complex in human macrophages

Clofazimine, a water insoluble substituted iminophenazine derivative with anti-mycobacterial and anti-inflammatory activity, is recommended by the WHO for the treatment of leprosy. It is also active against disseminated Mycobacterium avium complex (MAC) disease in HIV-infected patients. Recently, we achieved a 4000-fold increase of clofazimine water solubility using a novel modified clofazimine–cyclodextrin complex synthesized and patented by our group [Wasserlösliche, Iminiophenazinderivate enthaltende pharmazeutische Zusammensetzungen, deren Herstellung und Verwendung, German Patent, DE19814814C2]. In this paper we examine the activity of this complex against MAC in human macrophages, and evaluate its cytotoxicity. MAC-infected macrophages were treated for 24 h with free or complexed clofazimine. The in vitro minimum inhibitory concentrations of both free and complexed clofazimine were 0.1 μg/ml. Free and complexed clofazimine inhibited the growth of MAC inside macrophages to a similar extent, while modified cyclodextrin alone had no observable effects on MAC or macrophages. Complexed clofazimine was not toxic to cells at concentrations effective against MAC. The TD 50 of the modified cyclodextrin in THP-1 cell line was 297 μg/ml.

Coronary artery disease in HIV infected patients.

To assess the incidence, clinical features, treatment, and follow-up of coronary events in HIV-infected patients over a period of 5 years. A cohort of 840 patients. A coronary event occurred in 17 patients (5.9/1000 persons-years). Sixteen of them were exposed to highly active antiretroviral therapy (HAART). Patients with coronary events differed in age (48.3 vs. 43 years), CD4 T-cell count (284 vs. 486/mm(3)), total cholesterol (6.2 vs. 5.3 mmol/l), HDL cholesterol (0.72 vs. 1.16 mmol/l), and LDL cholesterol (4.95 vs. 3.391.61 mmol/l). No difference was observed regarding duration of HAART, weight, glucose level, or smoking status between the two groups. Acute coronary syndrome was the first manifestation in 14 patients. Coronary angiography showed 2.56 stenosis per patient, with a single vessel involvement in one-half. Percutaneous angioplasty was performed in all cases, with stenting in 11. After a mean follow-up of 36 months, 14 patients remain alive. Restenosis ( n=4) occurred in 3 patients (PTCA 3; stenting 4). All 14 patients are free of heart failure symptoms. Their mean left ventricular ejection fraction is 61%. A higher coronary-event rate is observed among HIV-infected patients, associated with drug-induced metabolic disturbances and a high prevalence of tobacco smoking. However, treatment and prognosis of acute myocardial infarction has no specificity.

Coronary heart disease in HIV-infected patients in the highly active antiretroviral treatment era.

To assess the incidence and the clinical features of coronary heart disease in HIV-infected patients. To assess atherosclerosis risk factors in this population. A review of our experience consisting of 16 patients with acute myocardial infarction (AMI) was the basis of our retrospective analysis of two cohorts in France. Incidence was compared with the national database on the incidence of AMI in the general population. Incidence appears to be between 5 and 5.5 per 1000 person-years among HIV-infected patients. This accounts for at least a threefold increase in incidence (1.52 per 1000 person-years reported in the Monica database registry in France). Age of onset of AMI in HIV-infected patients (younger than 50 years in most cases) is a point of major concern and is an indirect way to confirm the increased incidence. AMI was typically of sudden onset without prior history of angina pectoris. Treatment and prognosis of AMI in this population has no specificity. Patients with coronary heart disease present several risk factors such as tobacco smoking, hypertension, diabetes mellitus and low high-density lipoprotein level. The links between AMI and protease inhibitor exposure is still a matter of debate, and longer duration of follow-up is needed in order to reach any conclusion. Coronary heart disease is of a higher than expected incidence in HIV-infected patients. The limitation of risk factors (mainly tobacco smoking) is a new challenge. An adaptation of the Framingham score is necessary to state the individual risk. Prospective, controlled studies are necessary to assess new strategies such as the role of statins and switching therapeutic regimens.

Opportunistic infections in patients with AIDS admitted to an university hospital of the Southeast of Brazil.

Opportunistic diseases in HIV-infected patients have changed since the introduction of highly active anti-retroviral therapy (HAART). This study aims at evaluating the frequency of associated diseases in patients with AIDS admitted to an university hospital of Brazil, before and after HAART. The medical records of 342 HIV-infected patients were reviewed and divided into two groups: group 1 comprised 247 patients before HAART and, group 2, 95 patients after HAART. The male-to-female rate dropped from 5:1 to 2:1for HIV infection. There was an increase in the prevalence of tuberculosis and toxoplasmosis, with a decrease in Kaposi's sarcoma, histoplasmosis and cryptococcosis. A reduction of in-hospital mortality (42.0% vs. 16.9%; p = 0.00002) has also occurred. An agreement between the main clinical diagnoses and autopsy findings was observed in 10 out of 20 cases (50%). Two patients with disseminated schistosomiasis and 2 with paracoccidioidomycosis are reported. Overall, except for cerebral toxoplasmosis, it has been noticed a smaller proportion of opportunistic conditions related to severe immunosuppression in the post HAART group. There was also a significant reduction in the in-hospital mortality, possibly reflecting improvement in the treatment of the HIV infection.

CMV pp65 antigen testing is of limited utility in the diagnosis of concomitant CMV disease in HIV-infected patients in the HAART era

There are limited data on the utility of the CMV pp65 antigen (Ag) test for the diagnosis of concomitant CMV end-organ disease (EOD) in HIV+ patients in the highly active antiretroviral therapy era. We sought to assess the predictive value of a single pp65 test for the diagnosis of concomitant CMV EOD in HIV-infected patients. A review of all pp65 Ag tests conducted at a large county teaching hospital from January 1998 through July 1999 was conducted. A diagnosis of CMV EOD required histopathologic evidence (except for retinitis). Concomitant disease was defined as CMV EOD within 30 days of Ag test. Results were reported as number of Ag positive cells/300000 cells counted. Two-hundred and thirty patient charts (308 antigen tests) were reviewed. The median follow-up time was 334 days. Thirty-two patients had a prior diagnosis of CMV EOD. The most common reasons for testing were fever (45), pneumonia (10), and monitoring for recurrent retinitis (8). Ag tests were positive (range 1-1042 cells) in 51 patients. Twelve patients were diagnosed with concomitant CMV EOD. A diagnosis other than CMV was made in a significant majority of patients (154). The mean initial pp65 level was significantly higher in patients with concomitant CMV EOD versus those without concomitant CMV: 314 cells versus 13 cells, P<0.0001. The overall sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 67, 81, 16 and 98%, respectively. Using a 50-cell cutoff and including only patients with CMV symptoms and CD4<100, improved test accuracy: sensitivity, specificity, PPV, and NPV of 60, 91, 60, and 91%. The CD4 cell count but not the HIV viral load was predictive of CMV EOD. The CMV pp65 Ag test is useful in excluding concomitant CMV disease, but has limited utility in the diagnosis of acute CMV disease. The highest test utility will be in patients with a high likelihood of CMV disease based on symptoms, and CD4 cell count.

Thiazolidinediones could improve endothelial dysfunction and risk of premature coronary heart disease in HIV-infected patients.

The use of Human Immunodeficiency Virus (HIV) protease inhibitors as part of the Highly Active Antiretroviral Therapy (HAART) is associated with atherogenic dyslipoproteinemia, insulin resistance, hypertension and endothelial dysfunction, all of which contribute to premature coronary heart disease. These abnormalities appear to be associated with an increase in cardiovascular events in HIV-infected patients. Beneficial metabolic effects of anti-diabetic agents used in HIV-infected patients have been reported. The thiazolidinediones (TZDs), a new group of antidiabetic drugs, may modulate the proliferative and inflammatory cascades involved in atherosclerosis. Thus, an increasing totality of evidence suggests that TZDs may represent a unique and powerful research tool to find a common denominator underlying the pathophysiology and treatment of the metabolic cardiovascular risk factors associated with HIV infection.