Stefania Cicalini

Pathogenesis of HIV‐Related Pulmonary Hypertension

Abstract: Human immunodeficiency virus (HIV)‐related pulmonary hypertension (HRPR) is a cardiovascular complication of HIV infection that has been recognized in the last years with increasing frequency. The etiology of HRPH is unknown. All the attempts to isolate HIV on pulmonary vessels in HRPH patients failed, and an indirect role for HIV in this disease has been hypothesized. Current theories on the pathogenesis focus on abnormalities of endothelial and smooth muscle cells of pulmonary vasculature. Endothelial and smooth muscle cell injury could be due to a high production or to a reduced clearance of cytokines in these patients. In fact, in several studies high levels of ET‐1, IL‐1α, IL‐6 and PDGF in primary pulmonary hypertension (PPH) and in HRPH have been found. HIV gp 120 could induce the production of these cytokines by a stimulation of monocytes/macrophages. A high α1‐adrenoreceptors stimulation of pulmonary vessels could be also implicated in the pathogenesis of HRPH. Chronic hypoxia is observed with increased frequency in HIV patients, and this could induce a chronic stimulation of α1‐receptors of pulmonary vasculature with typical pathological changes. However, only a small percentage of HIV− patients develop HRPH. This observation suggests the existence of an idiosyncratic susceptibility to the development of vascular disease. This susceptibility could have a genetic basis, and might be determined by particular major histocompatibility complex alleles.

Pulmonary hypertension and human immunodeficiency virus infection: epidemiology, pathogenesis, and clinical approach

In recent years, the pathogenic role of human immunodeficiency virus (HIV) and the clinical manifestations of HIV-associated pulmonary arterial hypertension (HIV-PAH), which currently represents one of the most severe complications of HIV infection, have received more attention HIV-PAH occurs at all stages of the disease, and does not seem to be related to the degree of immune deficiency. Many of the symptoms in HIV-PAH result from right ventricular dysfunction: the first clinical manifestation is effort intolerance and exertional dyspnoea that will progress to the point of breathlessness at rest. Echocardiography is an extremely useful tool for the diagnosis of HIV-PAH, and Doppler echocardiography can be used to estimate systolic pulmonary artery pressure. Assessment of haemodynamic measures by catheterization remains, however, the best test for evaluating the response to therapy. Cardiac catheterization is mandatory to definitively diagnose the disease and exclude any underlying cardiac shunt as the aetiology. Recently, effective therapies for pulmonary arterial hypertension (PAH) have been available, including prostanoids, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors, allowing amelioration of symptoms and a better prognosis. However, HIV-PAH remains a progressive disease for which treatment is often unsatisfactory and there is no cure. As new efficient antiretroviral treatment is introduced, clinicians should expect to encounter an increasing number of cases of PAH in HIV-infected patients in the future.

Smoking and HIV: time for a change?

Cigarette smoking is one of the most important causes of morbidity and mortality in the general population, and is a well-recognized risk factor for a variety of serious clinical conditions, including cardiovascular diseases, pulmonary diseases and cancers.Smoking-related morbidity and mortality are of particular concern in patients with HIV infection, as the prevalence of current cigarette smoking is higher among HIV-positive patients than among the general population.In a study by De et al., it has been evidenced that smoking is a risk factor for bacterial pneumonia in HIV-positive patients and smoking cessation reduces this risk.HIV-positive patients who smoke have significantly increased mortality compared to those who have never smoked, indicating that smoking confers different mortality risk in HIV-positive as compared to HIV-negative patients, and lifestyle-related factors may pose a greater hazard to long-term survival of HIV-positive patients than those related to the HIV infection per se.The high prevalence of smoking among HIV population, the many health risks that can result from this behavior, and the proven efficacy of cessation interventions in HIV-positive patients should encourage HIV care providers to make smoking cessation a high priority.

Treatment and outcome of pulmonary arterial hypertension in HIV-infected patients: a review of the literature.

Pulmonary arterial hypertension (PAH) is a life-threatening complication of HIV infection. The prevalence of HIV-associated PAH (HIV-PAH) seems not to be changed over time, regardless of the introduction of highly active antiretroviral therapy (HAART). HIV-PAH treatment is similar to that for all PAH conditions and includes lifestyle modifications, general treatments, and disease-specific treatments. We reviewed the cases of HIV-PAH reported in the Literature in order to evaluate the role of HAART and specific PAH therapy in the prognosis and outcome of HIV-PAH. The research was performed through the PubMed database, by using the following key words: human immunodeficiency virus, AIDS, pulmonary hypertension, antiretroviral, and treatment. The outcome was reported as survival at the end of the observation period of each study. We found 509 patients with HIV-PAH described in the literature to date. At the end of follow-up period, survival rates were 55% and 22% among patients treated or not with antiretroviral therapy (ART), respectively (p = 0.02). Moreover, survival rates at the end of follow-up were 76% and 32% among patients treated or not with specific therapy for PAH (PAH-ST), respectively (p<0.0000001). Survival rates were 69% and 38% among patients treated or not with ART and PAH-ST, respectively (p = 0.02). Specific therapy for PAH should be strongly recommended in patients with HIV-PAH. The role of the HAART in influencing the outcome of HIV-PAH is controversial, even if some evidences seem to indicate a beneficial effect in the clinical course of the disease.

Sildenafil plasma concentrations in two HIV patients with pulmonary hypertension treated with ritonavir-boosted protease inhibitors

Sildenafil is increasingly used for the therapy of pulmonary arterial hypertension (PAH) in HIV infected patients. However, concerns exist about pharmacokinetic interactions between sildenafil and protease inhibitors (PI); in particular, ritonavir has been shown to increase sildenafil AUC and Cmax by several folds. The aim of our study was to determine the plasma levels of sildenafil and PI in two HIV patients with PAH treated with antiretroviral therapy including ritonavir-boosted PI. Our patients both experienced sildenafil Cmax above 500 ng/mL; however, they did not report any significant adverse reactions to sildenafil during the follow-up period. Therapeutic drug monitoring of sildenafil should be taken in consideration during treatment in order to avoid overdosage.

HIV infection and pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare but severe disease that results from chronic obstruction of small pulmonary arteries, leading to right ventricular failure and, ultimately, death. One established risk factor for the development of PAH is HIV infection. In comparison with the incidence of idiopathic PAH in the general population (1–2 per million), HIV-infected patients have a 2500-fold increased risk of developing PAH. The presence of PAH is an independent risk factor for mortality in patients with HIV infection, and in most cases death is causally related to PAH rather than to other complications of HIV infection. This article will focus on HIV-PAH with special considerations to epidemiology, pathogenesis, clinical presentation, diagnostic approach and available treatments.

Pulmonary arterial hypertension and HIV infection.

In their recent article on the role of HIV and human herpes virus-8 (HHV-8) infection in pulmonary arterial hypertension (PAH), Hsue et al. [1] found a high prevalence of elevated pulmonary artery systolic pressure (PASP) in HIV-infected persons as compared with HIVnegative controls, suggesting a causal role of HIV in PAH, whereas no association between HHV-8 infection and elevated PASP in HIV-infected individuals was found.

QTc interval prolongation in HIV-infected patients: a case–control study by 24-hour Holter ECG recording

BackgroundAim of the study was to assess QTc interval by a 24-hour ECG recording in a group of HIV-infected individuals with a basal prolonged QTc. The risk factors associated with QTc prolongation and the indices of cardiovascular autonomic control were also evaluated.MethodsA case–control study was performed using as cases 32 HIV-infected patients with prolonged (>440 msec) QTc interval as assessed by Holter ECG, and as controls 64 HIV-infected subjects with normal QTc interval. Autonomic function was evaluated by heart rate variability analysis during 24-hour recording.ResultsDuration of HIV disease was significantly longer among cases than among controls (p=0.04). Waist/hip ratio was also higher among cases than among controls (p=0.05). Frequency domain analysis showed the absence of physiologic decrease of low frequency (LF) in the night period in both cases and controls. The LF night in cases showed a statistically significant reduction when compared with controls (p=0.007).ConclusionsIn our study group, QTc interval prolongation was associated with a longer duration of HIV infection and with a greater waist/hip ratio. HIV patients with QTc interval prolongation and with a longer duration of HIV infection were more likely to have an impairment of parasympathetic and sympathetic cardiac component.

Neurocysticercosis: an unusual presentation of a rare disease

Sirs: Cysticercosis is a systemic infestation by the larval form of the tape-worm Taenia solium and is the most common parasitic disease affecting the central nervous system in the world [9]. Humans acquire intestinal T. solium infection by eating undercooked pork containing cysticerci: the larva attaches to the gut wall and grows into the intestinal tape-worm. Cysticercosis can result from ingestion of T. solium eggs from human faeces, from contamined food or from faecal-oral autoinfection in patients who harbour adult parasites in their intestinal tract [8]; the egg shell is digested in the stomach, liberating oncospheres that cross the intestinal wall, enter the circulation and are carried to many parts of the body of the host (brain, muscle, eye, subcutaneous tissue). The incidence of cysticercosis is highly variable and is related principally to sociocultural and economic factors; neurocysticercosis is commonly observed in Latin America and developing countries of Asia and Africa where the disease has always been endemic [4]. The frequent world travel today and the increasing immigration of persons from endemic areas spread cysticercosis widely, and clinicians are more often called upon to diagnose and treat patients with conditions that are not familiar in developed countries. We report the case of a patient who had an unusual clinical manifestation of neurocysticercosis. A 40-year-old Peruvian woman was hospitalized because of 24-h history of agitation, acute confusional state and deteriorating consciousness. The woman had been living in Italy for 2 years, and she did not have a history of fever, seizures, diabetes, asthma, arterial hypertension, drug or alcohol abuse or any other known disease. She had suffered no head injury. At admission to our hospital she was in coma (Glasgow Coma Scale 9). Her temperature was 36.8°C, blood pressure 120/80 mmHg, pulse regular at 70 bpm. No neurological deficits or meningeal signs were present. Routine laboratory tests were normal. Magnetic resonance imaging (MRI) of the brain showed multiple parenchymatous and intraventricular cysts at various stages of development, measuring 5–35 mm in diameter, most of which were located in the left frontal lobe (Fig. 1). The fluid inside the cysts had a MRI signal similar to that of cerebrospinal fluid (CSF), and some cysts were surrounded by a ring enhancement. Inside some cysts could be visualized on T1-weighted images a high-intensity signal. Multiple nodular calcified lesions were also present. Plain radiography of the skull also revealed multiple calcified cysts of the skeletal muscle. The electroencephalography performed at the time of presentation was normal. CSF examination revealed 10 cells/mm3, 43 mg/dl protein, 69 mg/dl sugar (with a serum glucose of 112 mg/dl). No microorganisms were seen on Gram’s stain, and culture for bacteria, fungi and mycobacteria was negative. Serological tests for anticysticercus antibodies by enzymelinked immunosorbent assay and Immunoblot tests were positive both in the CSF and in the serum. Microscopic search for eggs in stool specimens was negative. The patient received intravenous 100 ml 20 % mannitol every 4 h and intravenous dexamethasone 8 mg per day. She showed improvement in consciousness within 36 h. Anthelminthic therapy with albendazole was started orally at a dose of 400 mg twice daily. The patient also received antiepileptic drugs during treatment. Brain MRI after 1 month of albendazole therapy showed no significant changes in number or size of parasitic lesions. Albendazole treatment was continued at the same dose, and the patient was further evaluated. At 3-month follow-up examination the patient was in a good clinical condition with no evidence of neurological abnormalities or clinical manifestation of adverse reactions to the therapy; brain MRI showed a reduction in the size of the cysts. Cysticercosis is the major cause of late-onset epilepsy in most developing countries [1, 5–7]. Nevertheless, there are no pathognomonic features or typical syndrome of neurocysticercosis because the disease is quite comLETTER TO THE EDITORS

Cardiovascular risk and dyslipidemia among persons living with HIV: A review

BackgroundAim of this review is to focus the attention on people living with HIV infection at risk of developing a cardiovascular event. What is or what would be the most suitable antiretroviral therapy? Which statin or fibrate to reduce the risk? How to influence behavior and lifestyles?DiscussionPrevention of cardiovascular disease (CVD) risk remains the first and essential step in a medical intervention on these patients. The lifestyle modification, including smoking cessation, increased physical activity, weight reduction, and the education on healthy dietary practices are the main instruments.Statins are the cornerstone for the treatment of hypercholesterolemia. They have been shown to slow the progression or promote regression of coronary plaque, and could also exert an anti-inflammatory and immunomodulatory effect. However the current guidelines for the use of these drugs in general population are dissimilar, with important differences between American and European ones. The debate between American and European guidelines is still open and, also considering the independent risk factor represented by HIV, specific guidelines are warranted.Ezetimibe reduces the intestinal absorption of cholesterol. It is effective alone or in combination with rosuvastatin. It does not modify plasmatic concentrations of antiretrovirals. A number of experimental new classes of drugs for the treatment of hypercholesterolemia are being studied.Fibrates represent the first choice for treatment of hypertriglyceridemia, however, the renal toxicity of fibrates and statins should be considered.Omega 3 fatty acids have a good safety profile, but their efficacy is limited. Another concern is the high dose needed. Other drugs are acipimox and tesamorelin.Current antiretroviral therapies are less toxic and more effective than regimens used in the early years. Lipodistrophy and dyslipidemia are the main causes of long-term toxicities. Not all antiretrovirals have similar toxicities. Protease Inhibitors may cause dyslipidemia and lipodystrophy, while integrase inhibitors have a minimal impact on lipids profile, and no evidence of lipodystrophy. There is still much to be written with the introduction of new drugs in clinical practice.ConclusionsCardiovascular risk among HIV infected patients, interventions on behavior and lifestyles, use of drugs to reduce the risk, and switch in antiretroviral therapy, remain nowadays major issues in the management of HIV-infected patients.