Management of cytomegalovirus infection in pregnancy: is it time for valacyclovir?

BACKGROUND: Congenital cytomegalovirus (CMV) infection is the leading infectious cause of neurological impairment for which, currently, there are no approved antenatal treatment options. OBJECTIVES: The aim of this article was to summarize the available evidence on the use of valacyclovir during pregnancy to prevent and treat congenital CMV infection and disease. SOURCES: Two databases (PubMed and ClinicalTrial.gov) were reviewed. CONTENT: Six relevant documents were identified, namely one observational study, three clinical trials, two case reports. Most relevant findings were those from two clinical trials. A phase 2/3 placebo-controlled study showed a decrease of 71% (5 of 45 vs 14 of 47) in rate of CMV vertical transmission in women treated with 8 g/day valacyclovir following primary CMV infection in pregnancy. A phase 2, single-arm clinical trial, showed that 8 g/day valacyclovir administered to mothers of symptomatic infected foetuses increased the portion of asymptomatic neonates to 82% (34 of 41), compared with 43% (20 of 47) in untreated pregnancies from a historical cohort. IMPLICATIONS: Studies in favour of using valacyclovir during pregnancy for prevention and treatment of congenital CMV infection are emerging but are still few. Randomized clinical trials on large cohorts of patients investigating the efficacy on prevention and treatment of congenital CMV are required. Unfortunately, this will be probably not be feasible at least in the short period. In the meantime, data on the 'off label' use of valacyclovir for CMV in pregnancy could be collected within a multicentre observational study.

Risk of congenital toxoplasmosis in women with low or indeterminate anti-Toxoplasma IgG avidity index in the first trimester of pregnancy: an observational retrospective study.

OBJECTIVES: Congenital toxoplasmosis (CT) affects one to ten fetuses per 10 000 live newborns in western countries. Without knowing pre-conception serostatus, it is hard to date the infection when anti-Toxoplasma IgG and IgM antibodies are positive at first screening. Although a high IgG avidity index (AI) in the first trimester excludes CT, the same cannot be said of intermediate and low AI. The aim of this study was to estimate the risk of CT when intermediate or low AI is detected in the first trimester of pregnancy. METHODS: Our observational retrospective study enrolled women with positive anti-Toxoplasma IgG and IgM, and low/intermediate AI in the first trimester of gestation seen at two reference centres in northern Italy between 2006 and 2015. All women received spiramycin. When requested by women, a sample of fluid obtained through amniocentesis was tested with a commercial real-time PCR. CT was defined by positive PCR result confirmed on aborted materials or by newborn follow up. RESULTS: Overall, 778 first-trimester pregnant women were included; AI was low in 532/778 (68%) and intermediate in 246/778 (32%). Amniocenteses were performed in 528/778 (67.9%), with no fetal loss. In all, 19/778 (2.4%) miscarriages and 15/778 (1.9%) pregnancy terminations were recorded; 9/778 (1.6%) were lost to follow up. In two women, PCR on amniotic fluid was positive, but CT was confirmed in only 1/747 cases (0.13%, 95% CI 0.02%-0.75%). CONCLUSION: In our study, the risk of CT was much lower than anticipated. These data must be considered when counselling these women.

Cardiovascular involvement in psoriatic arthritis.

Psoriasis is a chronic, genetically determined and immunomediated inflammatory skin disease that affects 2-3% of the Caucasian population. A considerable proportion of these patients develop a form of inflammatory arthritis known as psoriatic arthritis (PsA), although the prevalence of this has not been well defined. Patients with PsA have a higher mortality rate than the general population and the risk of mortality is related to disease severity at the time of presentation. Endothelial dysfunction and early atherosclerosis have been found in patients with PsA without any cardiovascular disease (CVD) risk factors, and experts believe that CVD is one of the leading causes of death, as it is in patients with rheumatoid arthritis (RA). Various disease-related mechanisms may be involved in the development of premature vascular damage in both cases, including an increased synthesis of proinflammatory mediators (such as cytokines, chemokines and adhesion molecules), autoantibodies against endothelial cell components, perturbations in T-cell subsets, genetic polymorphisms, hyperhomocysteinemia, oxidative stress, abnormal vascular repair, and iatrogenic factors. In a recent study of 22 patients with PsA without any signs of CVD, we found that the plasma concentration of asymmetric dimethylarginine (ADMA) levels were significantly high and coronary flow reserve (CFR) was significantly reduced. Moreover, there was a significant correlation between CFR and plasma ADMA levels in the PsA group. The significant correlation between the reduced CRF and increased ADMA levels suggests that, like patients with early RA, PsA patients suffer from endothelial dysfunction and impaired coronary microcirculation. Active PsA is a risk factor for CVD, and so PsA patients should be screened for subclinical forms of the disease and its risk factors, and an early treatment approach should be adopted.

Knowledge, attitudes and practice (KAP) regarding newborn feeding modalities in HIV-infected and HIV-uninfected pregnant women in sub-Saharan Africa: a multicentre study.

Exclusive formula feeding, exclusive breastfeeding (EBF) with early weaning or the administration of antiretroviral therapy to lactating mothers and/or to breastfed newborns may lower postnatal HIV transmission. The aim of this study was to assess mothers' knowledge, attitudes and practice (KAP) on lactation in various real-life settings in sub-Saharan Africa. A questionnaire survey investigating KAP with regard to breastfeeding in pregnant women of unknown status (Questionnaire A, 16 items) or HIV-infected women (Questionnaire B, 37 items) was administered. Associations between newborn feeding KAP and demographic, socioeconomic, cultural and obstetric variables were investigated. From January 2007 to January 2008, 2112 pregnant women answered Questionnaire A in Burkina Faso, Cameroon, Chad, Tanzania, Uganda and Zambia. Most women (53.0%) declared EBF as the preferred feeding modality. The practice of strictly defined EBF in previous pregnancies was only 11.4%, which was inversely correlated with education and parity. Questionnaire B was answered by 225 HIV-infected pregnant women in Burkina Faso, Tanzania and Uganda. Knowledge about the lactation-associated risk was associated with previous dead children. Significant variability was observed among collaborating sites. The introduction of fluids other than maternal milk within 6 months of age is common practice in sub-Saharan Africa, requiring intensive health education efforts if strictly defined EBF is to be adopted to decrease HIV postnatal transmission. Significant variation in newborn feeding determinants was observed.

Effects of treatment strategy on endothelial function.

A large body of evidence indicates that endothelial dysfunction is a characteristic of patients with arterial hypertension. As functional abnormalities lead to impaired endothelium-dependent vasodilation, this early step of atherogenesis is potentially reversible. In addition to reducing blood pressure, the major families of anti-hypertensive drugs have a number of pleiotropic effects that could improve endothelial function. In particular, the renin-angiotensin system plays an important role in the pathogenesis of both arterial hypertension and endothelial dysfunction, and so drugs capable of limiting the dangerous effects of this hormonal axis, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers and renin inhibitors, could help prevent/delay/reverse the atherosclerotic process. New third-generation ß-blockers and 5-phosphodiesterase inhibitors may affect endothelial function. Furthermore, the HMGCoA-reductase inhibitors currently used to reduce cholesterol levels have major pleiotropic anti-inflammatory and anti-hypertensive effects. The preservation or recovery of endothelial function in hypertensive patients is crucial to inhibit the development of atherosclerosis and the onset of cardiovascular events. This review focuses on the ancillary effects of hypertensive drugs and HMGCoA-reductase inhibitors that go beyond lowering blood pressure and cholesterol levels.

From endothelial dysfunction to atherosclerosis.

It has recently emerged that endothelial dysfunction is an early step in the development of atherosclerosis and is mainly characterised by a reduction in the bioavailability of nitric oxide. All of the traditional cardiovascular (CV) risk factors (dyslipidemia, arterial hypertension, hyperglycemia and diabetes) are associated with endothelial dysfunction, and oxidised low-density lipoproteins, the renin-angiotensin axis and insulin resistance play important roles in the pathogenesis of impaired endothelial function. The increased expression of adhesion molecules and pro-inflammatory cytokines leads to abnormal endothelium-dependent vasodilation which could be investigated using vasoreactivity tests such as flow-mediated dilation in the brachial artery. Recently, new evidences showed that the immune system plays an important role in the pathogenesis of endothelial dysfunction and atherosclerosis with a particular regard towards autoimmunity. The high prevalence of the atherosclerotic process in systemic autoimmune diseases supports the hypothesis of the immune pathogenesis. Evaluating coronary microvascular dysfunction by means of transthoracic echocardiography with non-invasive coronary flow reserve assessment is particularly interesting as it could detect preclinical impairment of coronary microvascular function. The discovery that the mechanisms responsible for endothelial damage have a genetic basis could improve the approach to CV diseases. This review summarises the most important aspects of the pathogenesis and development of endothelial dysfunction, with particular attention to the role of traditional CV risk factors, the usefulness of vasoreactivity tests, and the future perspectives opened by genetic studies.

Effects of long-term disease-modifying antirheumatic drugs on endothelial function in patients with early rheumatoid arthritis.

Rheumatoid arthritis (RA) is associated with enhanced atherosclerosis and impaired endothelial function early after the onset of the disease and cardiovascular (CV) disease represents one of the leading causes of morbidity and mortality. It is well known that disease modifying antirheumatic drugs (DMARDs) are able to improve the course of the disease and the quality of life of these patients, but little is known about the effects of DMARDs on CV risk and endothelial dysfunction. Our goal was to examine the effects of long-term therapy with DMARDs on endothelial function and disease activity in early RA (ERA). Twenty-five ERA patients (mean age 52 ± 14.6 years, disease duration 6.24 ± 4.10 months) without evidence of CV involvement were evaluated for disease activity score (DAS-28), 2D-echo derived coronary flow reserve (CFR), common carotid intima-media thickness (IMT) and plasma asymmetric dimethylarginine (ADMA) levels at baseline and after 18 months of treatment with DMARDs (10 patients with methotrexate and 10 with adalimumab). DMARDs significantly reduced DAS-28 (6.0 ± 0.8 vs. 2.0 ± 0.7; P < 0.0001) and improved CFR (2.4 ± 0.2 vs. 2.7 ± 0.5; P < 0.01). Common carotid IMT and plasma ADMA levels did not show significant changes. The present study shows that DMARDs, beyond the well known antiphlogistic effects, are able to improve coronary microcirculation without a direct effect on IMT and ADMA, clinical markers of atherosclerosis. Treatment strategies in ERA patients with high inflammatory activity must be monitored to identify beneficial effects on preclinical markers of vascular function.

Maternal HIV Status and Infant Feeding Practices among Ugandan Women

To describe the infant feeding practices in the general population in Uganda; and to assess the impact of maternal HIV status on these practices; a questionnaire was administered to women attending the follow-up clinics for child vaccination. Among the mothers who were still breastfeeding at the time of interview (N=838); 61.4of the HIV-infected women had planned to breastfeed for a maximum of 6 months; compared with 12.1of the HIV-uninfected women (p0.001). Among the women who were not breastfeeding at the time of interview (Nof the HIV-infected women had stopped breastfeeding within 3 months; compared with 23.5of the HIV-uninfected women (p0.001). Only 2.1of HIV-infected women seen up to 14 weeks postnatally practised mixed feeding; compared with 23.6of HIV-uninfected women (p0.001). After 6 months; however; 30of the HIV-infected women and 55of the HIV-uninfected mothers were using mixed feeding; with no significant differences. Programmes for the prevention of motherto- child transmission of HIV should re-enforce counselling activities to address the issue of early weaning by HIV-infected women; and to support safe breastfeeding up to 6 months

[Cardiac involvement in rheumatoid arthritis]. / Il coinvolgimento cardiaco nell'artrite reumatoide.

Rheumatoid arthritis (RA) is a systemic disease of unknown etiology characterized by a chronic inflammatory process mainly leading to destruction of synovial membrane of small and major diarthrodial joints. The prevalence of RA within the general adult population is about 1% and female subjects in fertile age result mostly involved. It's an invalidating disease, associated with changes in life quality and a reduced life expectancy. Moreover, we can observe an increased mortality rate in this population early after the onset of the disease. The mortality excess can be partially due to infective, gastrointestinal, renal or pulmonary complications and malignancy (mainly lung cancer and non-Hodgkin lymphoma). Among extra-articular complications, cardiovascular (CV) involvement represents one of the leading causes of morbidity and mortality. Every cardiac structure can be affected by different pathogenic pathways: heart valves, conduction system, myocardium, endocardium, pericardium and coronary arteries. Consequently, different clinical manifestations can be detected, including: pericarditis, myocarditis, myocardial fibrosis, arrhythmias, alterations of conduction system, coronaropathies and ischemic cardiopathy, valvular disease, pulmonary hypertension and heart failure. Considering that early cardiac involvement negatively affects the prognosis, it is mandatory to identify high CV risk RA patients to better define long-term management of this population.

Congenital syphilis in Italy.

The cases are described of two infants who developed clinical and laboratory signs of congenital syphilis in Northern Italy, a region where the disease had not been documented for several years. The report urges greater vigilance and screening for syphilis among pregnant women and newborns, and contributes to the evidence that the incidence of syphilis is rising among women in Italy.

Predictors of long-term immunological outcome in rebounding patients on protease inhibitor-based HAART after initial successful virologic suppression: implications for timing to switch.

OBJECTIVE: To assess predictive factors of long-term immune restoration in patients who started protease inhibitor (PI)-based HAART and experienced virological rebound after initial complete success. METHOD: A retrospective longitudinal analysis of all HIV-infected patients who started their first PI-based HAART and reached viral load below 500 copies/mL was carried out in a large academic center in Italy. Patients were classified either as complete virologic responder (CR) or rebounders (REB) when confirmed plasma viremia was detected thereafter. Immunological outcome was the area under the curve (AUC) of the absolute CD4+ cell count change since the 8th month after treatment initiation (CD4+ T-cell AUC). Association between baseline characteristics, virological outcome, and CD4+ T-cell AUC was assessed by univariate and multivariate analysis. RESULTS: There were 374 patients who were included in the study. Mean follow-up was 30.2 months. There were 226/374 patients (60.4%) who remained CR while 148/374 (39.6%) presented at least one rebound (REB). Among REB patients, complete viral suppression was regained in 15/42 (35.7%) and 50/106 (47.1%) patients who underwent therapy changes or not, respectively. When multiple linear regression was carried out, previous nucleoside reverse transcriptase inhibitor (NRTI) experience and baseline CD4+ cell count below 350 cells/muL did not impair long-term immune restoration. The occurrence of rebound, its duration (> 18 months), and its magnitude (peak of viral load > 10,000 copies/mL) were independent negative prognostic factors. CONCLUSION: The occurrence of viral rebound is independently associated with significantly impaired long-term immunological restoration. The magnitude of viral rebound (< 10,000 copies/mL) and its duration (< 18 months) may be useful to identify those rebounding patients who may still profit from maintaining the current failing therapy if a more aggressive approach may be expected to be deleterious for tolerability reasons or lack of options.

Characterization of viro-immunological responses in a closely followed cohort of heavily pretreated patients: evidence from the GenPheRex Study.

OBJECTIVES: To assess prevalence and predictive factors of viro-immunological discordant trends in a cohort of heavily pretreated patients. METHODS: Factors associated with viro-immunological discordant trends either as categorical or continuous measures have been studied in 159 heavily pretreated HIV-positive patients from a multicentre prospective study of real- vs. virtual-phenotype. Univariate and multivariate logistic regressions were used to assess risk factors for categorical discordant responses, ceasing follow-up at week 32 since enough patients had been on the original drug combination for a sufficient amount of time to evaluate their immune response. Complementary linear regression analysis was performed over the entire 48 weeks' follow-up considering CD4 and plasma viral load (pVL) as continuous measures. RESULTS: Among 58 virological responder patients (> or =1 log10 HIV-1 RNA copies/mL decrease) and 101 virologically non-responders, immunological discordances (increase in CD4 count of< or > or =100 cells/microL) were observed in 58.6% and 38.6%, respectively. Baseline CD4 count was associated with discordant responses in both groups. Multivariable linear regression over the entire 48 weeks' follow-up demonstrated significant correlation between absolute decrease in pVL and increase in CD4 count (HR 28.06, 95%CI 35.32-20.79; P<0.001), also the use of protease inhibitors (PIs) in the salvage regimen (HR 36.57, 95%CI 15.45-57.68; P<0.001) and >8 months on treatment (HR 41.64, 95%CI 19.27-64.01; P<0.001) correlated with highly significant immune recovery. CONCLUSIONS: These data confirm that therapy, possibly including PIs, should be continued in heavily pretreated patients and that hard-to-reach pVL undetectability is not essential to obtain immunologic recovery; however, this is strongly increased by the degree of pVL reduction that should be achieved.

Implementation of an Italian multicentric care network for early HIV infection diagnosis: 1999-2001 report.

BACKGROUND: Diagnosis of a new HIV infection during the primary phase (PHI) is sometimes misleading in a primary care setting. Since 1999 the Italian network for the study of acute HIV infection (ISAI) has been operative. At the time of PHI diagnosis the case is reported to the coordinating centre and enrolled in the National Register which records all epidemiological, demographic and clinical information. PATIENTS AND METHODS: From 1999 to September 2001, 51 symptomatic or asymptomatic patients with diagnosis of primary HIV infection were signalled to the coordinating centre. At screening, assessments were: interview to collect demographic and epidemiological data, clinical history (regarding PHI signs and symptoms) and, if available, relevant index case information; physical examination; routine hematology and chemistry; lymphocyte count; plasma HIV-RNA. In a subset of patients PBMC HIV-DNA, HIV-RNA, resistance genotyping and HIV subtype characterization were assessed. RESULTS: 74.5% of patients were males and all but four were Italian. Hetero and homosexual contacts were the prevalent route of HIV transmission. Forty-five patients (89%) were symptomatic and the most frequent signs and symptoms were: fever, lymphadenopathy, malaise and pharyngodinia. Baseline reverse-transcriptase (RT) and protease (PR) genotyping analysis was available for 29 patients. Only one of 29 patients harbored a virus with a resistance-associated mutation in the RT region (215Y); NNRTI mutations were identified in 3 of 29 patients. In the remaining 20 (69%) patients no mutations were found in the RT region. Sequence data from PR region were successfully obtained in 21 patients. Only one of these had a high-level resistance mutation (46L); in an additional 10 cases 1 or more secondary mutations were identified. The remaining 10 patients harbored a PR region wild type virus. One patient presenting two secondary mutations in the PR region, even if highly adherent and tolerant to drug regimen, showed a slow viral load decrease. CONCLUSIONS: Our cohort confirms the uptrend of new infections through unsafe sexual contacts involving both homosexual and heterosexual couples. Genotype sequencing for antiretroviral resistant viral variants describes a low prevalence of RT resistance-associated mutations, as well as primary mutations in the PR region. On the contrary, a higher prevalence of PR gene polymorphisms and mutations is not known with any certainty to confer resistance to NRTI and NNRTI. The identification of antiretroviral drug resistant HIV strains is strategic for clinical and therapeutical intervention, even though from a public health point of view cost-efficacy must be considered.

Low nitric oxide values associated with low levels of zinc and high levels of cardiac necrosis markers detected in the plasma of rabbits treated with L-NAME.

Nitric oxide plays a key role as a vasodilating agent and its deficiency is associated with ischemic heart diseases. The aim of this study was to induce biochemical alterations associated with ischemic heart lesions by blocking nitric oxide synthase. L-NAME, a nitric oxide synthase inhibitor, was administered to rabbits and its effects on blood pressure, plasma levels of nitric oxide, zinc and cardiac necrosis markers, heart histology, and electrocardiographic profile were examined. L-NAME administration reduced the nitric oxide levels and consequently increased the diastolic blood pressure. It also caused small areas of myocardial coagulative necrosis, whose dispersed nature made it undetectable by electrocardiograph, and decreased the plasma levels of zinc, which is involved in the enzymatic activities that remove the peroxides damaging the myocardium. This model is proposed for the development of drugs affecting nitric oxide levels with the aim of controlling coronary ischemia.

Tolerability of twice-weekly rifabutin-isoniazid combinations versus daily isoniazid for latent tuberculosis in HIV-infected subjects: a pilot study.

The tolerability of and adherence to intermittent short-term rifabutin-isoniazid preventive treatment was assessed in subjects dually infected with Mycobacterium tuberculosis and the human immunodeficiency virus (HIV). In a randomised, open-label, phase II pilot study, 44 subjects received either rifabutin 300 mg and isoniazid 750 mg twice weekly for 3 months (group A, n = 16) or the same regimen with rifabutin at 600 mg (group B, n = 14), or isoniazid 300 mg/day for 6 months (group C, n = 14). Three, two and four subjects in groups A, B, and C, respectively, did not complete their treatment (one case of flu-like syndrome in group B; one methadone withdrawal syndrome in group A; and patient decision in two cases in group A and four in group C). Overall, adverse events were reported by four, nine, and seven subjects in groups A, B and C, respectively. Intermittent combined rifabutin + isoniazid for 3 months had lower default rates than daily standard isoniazid for 6 months. The regimen with rifabutin at 300 mg dose compared favourably to standard isoniazid, and warrants larger efficacy studies to assess its role for the prevention of latent tuberculosis in HIV-infected subjects.

Effects of carbamazepine treatment on pain threshold values and brain serotonin levels in rats.

The administration of carbamazepine to rats caused a significant increase in pain threshold values. Furthermore, treatment with carbamazepine lowered the concentration of tryptophan bound to plasma proteins and elevated the brain serotonin values. The high brain serotonin levels, observed in carbamazepine-treated rats, are probably attributable to an increased availability of brain tryptophan, since this amino acid has been substantially removed from the plasma protein compartment by carbamazepine treatment, which exhibits a high binding capacity to plasma proteins. The analgesic effects caused by carbamazepine administration have been attributed to increased levels of brain serotonin which is involved in the control of pain transmission.

Comparison of pharmacokinetics and dynamics of two dosage regimens of foscarnet in AIDS patients with Cytomegalovirus retinitis.

OBJECTIVE: To compare the pharmacokinetics of foscarnet administered as an infusion twice daily (BID) or thrice daily (TID), and to compare the effects on the electrolyte balance, cardiac and renal functions over a 3-week induction treatment of Cytomegalovirus (CMV) retinitis. METHODS: Pharmacokinetics/dynamics of foscarnet were investigated on treatment days 1, 14 and 21. Twelve AIDS patients with CMV retinitis completed the investigation period. Concentrations of foscarnet and electrolytes were assayed by high-performance liquid chromatography (HPLC) and by an ion-selective analyser, respectively. RESULTS: The pharmacokinetics of the two regimens were essentially similar. Foscarnet plasma and creatinine clearances were 2.0 and 1.6 ml.min-1.kg-1, respectively, in the BID group at steady state (day 21). In the TID group the corresponding values were 1.8 and 1.7 ml.min-1.kg-1, respectively. In both regimens the elimination half-life of foscarnet was 2-3 h. Ionized calcium concentrations were transiently decreased and strongly inversely correlated to foscarnet plasma concentrations in both regimens with no significant differences between groups. A trend towards prolongation of the QTc interval was seen when data from both treatments were analysed together. CONCLUSION: Our data suggest comparable pharmacokinetics of foscarnet after intermittent administration BID or TID during a 3-week induction period.