Federica Tordato

Infections after T‐replete haploidentical transplantation and high‐dose cyclophosphamide as graft‐versus‐host disease prophylaxis

Recently, a platform of T‐cell replete haploidentical hematopoietic stem cell transplantation (haplo‐HSCT) using post‐transplant cyclophosphamide (Cy) has shown high reproducibility and acceptable safety profile.

Evaluation of glomerular filtration rate in HIV-1-infected patients before and after combined antiretroviral therapy exposure*

The prevalence and factors associated with an increased risk of renal dysfunction in HIV‐infected patients receiving or not receiving antiretroviral therapy (ART) have been poorly evaluated in observational settings.

Steatohepatitis in HIV-infected subjects: pathogenesis, clinical impact and implications in clinical management.

Antiretroviral medications have significantly improved the prognosis of subjects infected by human immunodeficiency virus (HIV). However, long-term complications of these drugs are increasingly recognized as significant causes of morbidity and mortality. Non-alcoholic fatty liver disease (NAFLD), which can evolve into non-alcoholic steato-hepatitis (NASH), cirrhosis and ultimately hepatic failure is one of the more often observed complications in the current clinical practice and the correlation with liver enzyme elevations is controversial. Multiple factors have been considered as possibly correlated to this event in the HIV-infected population, including metabolic abnormalities (such as hyperlipidaemia, hyperglycaemia and being overweight), chronic inflammation, concurrent infection with hepatitis C and B viruses, and treatment with certain nucleoside reverse transcriptase inhibitors (NRTI). HIV-associated syndromes such as lactic acidosis and lypodystrophy are frequently associated with fatty liver disease and a mitochondrial injury has been considered as its possible pathogenetic factor. In particular, treatment containing stavudine and didanosine have proven to be the most commonly implicated in the occurrence of mitochondrial abnormalities. Epidemiologic data to better define the role of predictive factors and drugs associated with the development of NAFLD are still lacking. Furthermore, it remains unclear the better therapeutic management for this condition, even if the current best therapeutic option for NAFLD is the treatment of the underlying disease. Other studies are mandatory to better elucidate the pathogenesis of NAFLD and the optimal therapeutic strategy for the underlying conditions.

Monitoring of human cytomegalovirus (HCMV)-specific CD4+ T cell frequency by cytokine flow cytometry as a possible indicator for discontinuation of HCMV secondary prophylaxis in HAART-treated AIDS patients

OBJECTIVE Absolute CD4+ T cell count and human cytomegalovirus (HCMV)-specific CD4+ T cell frequency (as determined by cytokine flow cytometry, CFC) were compared for their ability to predict HCMV disease and safe discontinuation of HCMV secondary prophylaxis. STUDY DESIGN Three groups of AIDS patients with previous nadir CD4+ T cell count <100/microl were studied. Group A included 48 HAART-treated patients with no HCMV disease. Group B included 11 HAART-treated patients with previous HCMV disease who discontinued HCMV prophylaxis. Group C included 23 HAART-treated (n = 16) or -naive (n = 7) patients with previous HCMV disease either continuing or starting HCMV prophylaxis. Patients underwent follow-up for detection of HCMV viremia or disease (groups A and B) and for discontinuation of HCMV secondary prophylaxis on the basis of either HCMV-specific or absolute CD4+ T cell count (group C). RESULTS During follow-up, while some patients showed a stable HCMV-specific CD4+ T cell response, others had a fluctuating response (unstable responders) or showed no response at all. In detail, 13/48 group A patients were either HCMV non-responders or unstable responders and 2 of them developed HCMV viremia; 3/11 group B patients were unstable responders, none developing either HCMV viremia or disease; finally, 9 group C patients discontinued HCMV prophylaxis based on absolute CD4+ T cell count > 150 cells/microl, but in 2 of them lacking HCMV-specific response HCMV retinitis relapsed. None of the seven group C patients discontinuing HCMV prophylaxis on the basis of CFC showed HCMV disease relapse. CONCLUSIONS CFC may support absolute CD4+ T cell count for both guiding HCMV prophylaxis discontinuation and better monitoring HCMV infection in AIDS patients with no previous HCMV disease or having discontinued HCMV prophylaxis.

Insulin resistance affects early virologic response in HIV-infected subjects treated for hepatitis C infection.

To the Editor: The use of highly active antiretroviral therapy (HAART) has been associated with an increased frequency of insulin resistance (IR) and of its clinical correlates, such as glucose intolerance and type-2 diabetes. A direct role of protease inhibitors (PIs) has been proposed; however, traditional risk factors for IR other than HIV infection and HAART use may also predict glucose intolerance or type-2 diabetes in HIVinfected population. In the general population, a correlation between hepatitis C virus (HCV) infection and IR has been demonstrated; the possible mechanisms at the basis of this finding seem to be increased tumor necrosis factor (TNF) production, together with the enhancement of suppressor cytokines (SOC-3), both blocking PI3K and Akt phosphorylation. In HIVnegative patients with chronic HCV receiving pegylated interferon plus ribavirin, IR, as measured by the hemostatic model of assessment (HOMA) index, has been related to the 6-month virologic response. In addition, subjects with a sustained virologic response had lower HOMA values compared with others. Whether IR represents a marker of difficult-to-cure subjects or whether it acts through a pathogenic mechanism by blocking the antiviral activity of interferon is unknown. HCV infection is often a comorbidity in HIV-infected subjects, especially if they are intravenous drug abusers. It has often been associated with IR and hyperglycemia in HIVinfected patients receiving HAART. At the moment, few data are available on the role of IR in influencing the virologic response to anti-HCV treatment in the HIV-infected population. The aim of this study is to evaluate the correlation between IR and early virologic response (EVR) in HIV/HCVcoinfected subjects receiving pegylated interferon plus ribavirin. We included in this study 29 consecutive HIV-infected subjects followed at our clinic who started an antiHCV treatment with pegylated interferon a-2a plus ribavirin (at a dosage of 1000 to 1200 mg according to body weight) in January 2006. The following variables were collected at baseline (time of starting anti-HCV treatment): gender, age, race, body mass index (BMI), platelet count, aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum glucose, insulin, total cholesterol, triglycerides, CD4 cell count, HIV RNA level, HCV RNA level, HCV genotype, and use of HAART (defined as use of

Tenofovir Plus Didanosine as Nrti Backbone in HIV-Infected Subjects

2 nucleoside reverse transcriptase inhibitors with any PI or nonnucleoside reverse transcriptase inhibitors). Serum insulin levels were measured by electrochemiluminescence immunoassay using an autoanalyser (Elecsys 1010/2010; Elecsys Modular Analytics E170; Roche, Basel, Switzerland). HIV-RNA load was assessed using the reverse transcriptase (RT) polymerase chain reaction (PCR), with a detection limit <60 copies/mL (Arthus Qiagen, Heiden, Germany). Qualitative PCR analysis for HCV was performed by nested PCR (Amplicor Roche, Basel, Switzerland; detection limit <15 IU/L). HCV genotyping was performed using a line-probe assay (INNOLiPA HCV II; Immunogenetics, Belgium). IR was calculated through the HOMA equation: fasting insulin (mIU/L) 3 fasting glucose (mmol/L)/22.5. IR was defined as a HOMAvalue >3.8, according to other studies on white populations with low risk for diabetes. EVR was defined as HCV RNA level <15 IU/mL after 3 months of anti-HCV treatment; additionally, we evaluated the rapid virologic response (RVR), defined as HCV RNA level <15 IU/L after 1 month of anti-HCV treatment. Differences between variables were calculated using the x and Student t tests when appropriate. Table 1 shows the demographics and clinical characteristics of the subjects included in our study according to the HOMA values at baseline. All the patients were white. Ten subjects (34.5%) had a HOMA index >3.8, and 19 (65.5%) had values #3.8. No statistically significant differences were observed in the 2 groups according to the variables considered. After 3 months of anti-HCV treatment, median AST and ALT levels decreased in both groups. In subjects with IR at baseline, median AST and ALT levels decreased from 109 (interquartile range [IQR]: 60 to 141) IU/ L to 54 (IQR: 42 to 65) IU/L (P < 0.01) and from 105 (IQR: 76 to 124) IU/L to 53 (IQR: 45 to 88) IU/L (P < 0.01), whereas in subjects without IR, AST and ALT levels decreased from 108 (IQR: 61 to 147) IU/L to 37 (IQR: 30 to 50) IU/L (P < 0.01) and from 101 (IQR: 68 to 109) IU/L to 33 (IQR: 27 to 48) IU/L (P < 0.01), respectively. RVR was achieved in 8 (42.1%) of 19 subjects without IR and in 0 of 10 with IR at baseline (P < 0.001); EVR was observed in 16 (84.2%) of 19 subjects without IR and in 0 of 10 with IR (P < 0.001). The 3 subjects who did not achieve EVR had genotype 1a, 3a, and 4c/4d, respectively. HCV infection and HAART are conditions associated with a higher probability of developing IR. Such a condition is a known predictor of reduced sustained virologic response to anti-HCV treatment in HCV-infected subjects. Conversely, the achievement of RVR and EVR is a strong predictor of recovery from HCV infection; therefore, subjects who do not achieve this endpoint may be discontinued from anti-HCV treatment because of a low probability of sustained virologic response. In the present study, including only HIV/HCV-coinfected subjects, we found that subjects without IR at baseline are more likely to reach RVR and EVR than the others. Also, in subjects with genotype 3, which is known to respond better to anti-HCV treatments, the presence of IR does not allow for the achievement of RVR or EVR. These results, obtained on a limited number of subjects, suggest that IR should always be evaluated before starting anti-HCV treatment. Therefore, the correction of IR, and the consequent recovery of insulin sensitivity, could improve RVR and EVR in the HIV/ HCV-coinfected population treated with pegylated interferon and ribavirin, and

A reduced dose of fluconazole as primary antifungal prophylaxis is not associated with increased risk of invasive fungal infections after allogeneic stem cell transplantation from a HLA identical sibling

Nucleoside reverse transcriptase inhibitors (NRTI) are essential components of highly active antiretroviral treatment (HAART). Although several combinations can be used as NRTI backbones, not all are associated with good virological and/or immunological results. In particular, some NRTI combinations should be avoided due to antagonism (zidovudine plus stavudine) or to high rate of toxicity (didanosine plus stavudine). Tenofovir (TDF) and didanosine (ddI) are among the more often prescribed NRTI for their convenient posology (one pill each per day), relatively high genetic barrier for resistance, quite acceptable safety profile and remarkable antiviral potency when such drugs have been used as single drug or in combinations with other NRTIs. However, antiretroviral regimens containing TDF and ddI have been associated with a high rate of virological failure in HIV-infected naïve patients due to possible drug-interactions. The virological efficacy of this backbone in HIV-infected, HAART pre-treated subjects, is still controversial. Aim of this review is to assess the possible role that antiretroviral regimens containing TDF and ddI can have in the treatment of HIV-positive subjects, focusing on their plasmatic and/or intracellular interactions to optimize the antiretroviral efficacy and minimize the toxicities of this combination.

Efficacy of intraventricular amikacin treatment in pan-resistant Pseudomonas aeruginosa postsurgical meningitis

Invasive fungal infections (IFI) represent a common side effect of allogeneic hematopoietic stem cell transplant (allo‐SCT), resulting in increased non relapse mortality (NRM) and reduced overall survival (OS) rates. Seventy‐five days of Fluconazole 400 mg/d represents the standard primary antifungal prophylaxis (PAP) after allo‐SCT, especially for low‐risk transplants. However, the ideal dosage of fluconazole has never been tested.

Virological success of lopinavir/ritonavir salvage regimen is affected by an increasing number of lopinavir/ritonavir-related mutations

Background We describe a case of pan-resistant Pseudomonas aeruginosa postsurgical meningitis associated with the presence of an external ventricular device. We changed therapy twice; finally, by using amikacin and a continuous infusion of cefepime, we obtained clinical improvement. Case presentation A female patient, who underwent surgery for a cavernous angioma, presented with meningitis. Cerebrospinal fluid culture revealed a multidrug-resistant Pseudomonas aeruginosa, initially sensitive only to colistin. We successfully used intrathecal amikacin and intravenous cefepime continuous infusion plus intravenous amikacin after two previous ineffective therapeutic approaches. Conclusion The evaluation of the antibiotic concentration and the bactericidal activity in cerebrospinal fluid may contribute to the choice of the drug in cases of multidrug-resistant meningitis.