Alessandro Soria

Raltegravir, maraviroc, etravirine: an effective protease inhibitor and nucleoside reverse transcriptase inhibitor-sparing regimen for salvage therapy in HIV-infected patients with triple-class experience.

We prospectively evaluated 28 triple-class experienced HIV-1-infected patients harbouring R5 virus, who received maraviroc, raltegravir and etravirine. By on-treatment analysis, 26 (92%) had less than 50 copies HIV-RNA/ml at week 48. The median (interquartile range) 48-week increase in CD4+ cell counts was 267 (136–355) cells/μl. Three serious adverse events occurred: one recurrence of mycobacterial spondylodiscitis, one anal cancer, one Hodgkin lymphoma. Although long-term safety needs further study, this protease inhibitor and nucleoside analogue-sparing regimen showed sustained efficacy.

CD4+ T cell depletion, immune activation and increased production of regulatory T cells in the thymus of HIV-infected individuals.

Mechanisms by which HIV affects the thymus are multiple and only partially known, and the role of thymic dysfunction in HIV/AIDS immunopathogenesis remains poorly understood. To evaluate the effects of HIV infection on intra-thymic precursors of T cells in HIV-infected adults, we conducted a detailed immunophenotypic study of thymic tissue isolated from 7 HIV-infected and 10 HIV-negative adults who were to undergo heart surgery. We found that thymuses of HIV-infected individuals were characterized by a relative depletion of CD4+ single positive T cells and a corresponding enrichment of CD8+ single positive T cells. In addition, thymocytes derived from HIV-infected subjects showed increased levels of activated and proliferating cells. Our analysis also revealed a decreased expression of interleukin-7 receptor in early thymocytes from HIV-infected individuals, along with an increase in this same expression in mature double- and single-positive cells. Frequency of regulatory T cells (CD25+FoxP3+) was significantly increased in HIV-infected thymuses, particularly in priorly-committed CD4 single positive cells. Our data suggest that HIV infection is associated with a complex set of changes in the immunophenotype of thymocytes, including a reduction of intrathymic CD4+ T cell precursors, increased expression of activation markers, changes in the expression pattern of IL-7R and enrichment of T regulatory cells generation.

Neurocognitive Impairment in HIV-Infected Naïve Patients with Advanced Disease: The Role of Virus and Intrathecal Immune Activation

Objective. To investigate intrathecal immune activation parameters and HIV-RNA in HIV-associated neurocognitive disorders (HAND) of advanced naïve HIV-infected patients and to evaluate their dynamics before and after initiation of antiretroviral therapy (ART). Methods. Cross-sectional and longitudinal analysis of HIV RNA, proinflammatory cytokines (IL-6, IL-10, INF-γ, TNF-α, TGF-β1, and TGF-β2) and chemokines (MIP-1α, MIP-1β, and MCP-1) in plasma and cerebrospinal fluid (CSF) of HIV-infected patients with CD4 <200/μL. Results. HAND was diagnosed at baseline in 6/12 patients. Baseline CSF HIV-RNA was comparable in patients with or without HAND, whereas CSF concentration of IL-6 and MIP-1β, proinflammatory cytokines, was increased in HAND patients. CSF evaluation at 12 weeks was available in 10/12 cases. ART greatly reduced HIV-RNA in all patients. Nevertheless, IL-6 and MIP-1β remained elevated after 12 weeks of therapy in HAND patients, in whom CSF HIV RNA decay was slower than the plasmatic one as well. Conclusion. Immune activation, as indicated by inflammatory cytokines, but not higher levels of HIV-RNA is observed in advanced naïve HIV-infected patients with HAND. In HAND patients, ART introduction resulted in a less rapid clearance of CSF viremia compared to plasma and no modifications of intratechal immune activation.

Antiretroviral treatment strategies and immune reconstitution in Treatment-Naive HIV-Infected patients with advanced disease

Treatment-naive advanced HIV-infected patients have a lower life expectancy than those treated early with highly active antiretroviral therapy (HAART). Early treatment allows greater immunological recovery, a reduction of AIDS progression, a reduced risk of related illnesses, and lower mortality compared with HAART initiation in advanced disease. Given the numbers with advanced disease worldwide and the high cost of care, strategies encouraging early detection may be life saving and cost effective. Factors associated with increased clinical progression include higher baseline HIV viral load and older age, emphasizing the need for early viral load suppression. HAART initiation faces many challenges; interactions between antiretroviral agents and drugs used to treat life-threatening opportunistic infections may cause subtherapeutic antiretroviral exposure and the development of resistance or supratherapeutic levels resulting in adverse effects. Immune reconstitution inflammatory syndrome can be another cause of suboptimal outcomes. The management of patients with advanced HIV infection should include rapid short-term immune reconstitution to limit the risk of disease progression plus aggressive antiviral treatment to achieve rapid virological suppression. Clear evidence on the optimal regimen and agents to use to target advanced HIV disease is lacking. Therefore, antiretroviral treatment for these patients has to be carefully tailored to the individual according to many variables.

Maraviroc as intensification strategy in HIV-1 positive patients with deficient immunological response: an Italian randomized clinical trial.

Background Immunological non-responders (INRs) lacked CD4 increase despite HIV-viremia suppression on HAART and had an increased risk of disease progression. We assessed immune reconstitution profile upon intensification with maraviroc in INRs. Methods We designed a multi-centric, randomized, parallel, open label, phase 4 superiority trial. We enrolled 97 patients on HAART with CD4+<200/µL and/or CD4+ recovery ≤25% and HIV-RNA<50 cp/mL. Patients were randomized 1:1 to HAART+maraviroc or continued HAART. CD4+ and CD8+ CD45+RA/RO, Ki67 expression and plasma IL-7 were quantified at W0, W12 and W48. Results By W48 both groups displayed a CD4 increase without a significant inter-group difference. A statistically significant change in CD8 favored patients in arm HAART+maraviroc versus HAART at W12 (p=.009) and W48 (p=.025). The CD4>200/µL and CD4>200/µL + CD4 gain ≥25% end-points were not satisfied at W12 (p=.24 and p=.619) nor at W48 (p=.076 and p=.236). Patients continuing HAART displayed no major changes in parameters of T-cell homeostasis and activation. Maraviroc-receiving patients experienced a significant rise in circulating IL-7 by W48 (p=.01), and a trend in temporary reduction in activated HLA-DR+CD38+CD4+ by W12 (p=.06) that was not maintained at W48. Conclusions Maraviroc intensification in INRs did not have a significant advantage in reconstituting CD4 T-cell pool, but did substantially expand CD8. It resulted in a low rate of treatment discontinuations. Trial Registration ClinicalTrials.gov NCT00884858 http://clinicaltrials.gov/show/NCT00884858

Imported ciprofloxacin-resistant Neisseria meningitidis.

To the Editor: Emergence and spread of antimicrobial drug resistance in community-acquired infections is a global threat. Resistance of Neisseria meningitidis raises concern because of severity of disease caused by this organism and the need for immediate treatment of infected patients. We report an imported case of meningococcal disease caused by fluoroquinolone-resistant N. meningitidis. The patient, a previously healthy, unvaccinated 43-year-old man who had traveled internationally, was hospitalized because of high fever, neck stiffness, and a diffuse petechial rash. Signs and symptoms were observed 24 hours after he had returned to Italy from a 10-day business trip during February–March 2009, to New Delhi and Chennai in India and a stopover of a few hours in Frankfurt, Germany. Microscopic examination of cerebrospinal fluid showed gram-negative diplococci and culture documented N. meningitidis serogroup A. The strain was characterized as serotype 4,21 subtype P1.9 by using monoclonal antibodies. Multilocus sequence typing performed at the National Reference Laboratory for Invasive Meningococcal Diseases in Rome characterized the strain as sequence type (ST)-4789 and belonging to clonal complex ST-5/subgroup III. Antimicrobial drug susceptibility was determined by using an agar dilution test, and MICs were determined by using an agar disk-diffusion test (Etest; AB Biodisk, Solna, Sweden) and standard techniques. The strain was resistant to ciprofloxacin, levofloxacin, and trimethoprim/sulfamethoxazole and susceptible to penicillin, ampicillin, ceftriaxone, chloramphenicol, rifampin, and azithromycin. MICs for ciprofloxacin, levofloxacin, penicillin, ampicillin, and ceftriaxone were 0.25, 0.25, 0.03, 0.12, and <0.016 mg/L, respectively (Figure). The patient recovered after treatment with ceftriaxone. Figure Antimicrobial drug–susceptibility test, showing resistance to levofloxacin (LEV, lower strip), ciprofloxacin (CIP, upper strip), and nalidixic acid (NA, disk) for the strain of Neisseria meningitidis isolated from the patient. Before results of antimicrobial drug–susceptibility testing were available, 15 adult contacts of the patient received ciprofloxacin as chemoprophylaxis according to public health recommendations in Italy. After positive test results, all contacts were offered repeat chemoprophylaxis with rifampin; 13 of them accepted. A diagnosis of meningitis and results of antibiograms were sent to the patient’s place of employment in India and to the airport manager in Frankfurt. However, we were not able to assess what chemoprophylaxis was given to the patient’s fellow employees and air travel contacts. No secondary cases have been detected so far in Italy. Sporadic cases of infection with N. meningitidis (mainly serogroup B) with reduced susceptibility to ciprofloxacin have been reported in Europe, North and South America, and Australia since 2000 (1–4). Ciprofloxacin-resistant N. meningitidis of serogroup A caused an outbreak of meningococcal meningitis in Delhi, India, in 2005 and a recurrence in 2006 (5). Although the patient reported in our study had no known contact in India with patients who had meningococcal disease, multilocus sequencing typing analysis showed that the isolate had the same sequence type as isolates from the epidemic in India (5,6). We report isolation of an imported, ciprofloxacin-resistant strain of N. meningitidis isolated from a patient with meningococcal disease. During the past 2 years, 182 strains of N. meningitidis have been sent to the Istituto Superiore di Sanita; all were susceptible to ciprofloxacin and MICs ranged from 0.002 mg/L to 0.006 mg/L (National Reference Laboratory for Invasive Meningococcal Diseases, pers. comm.) Serogroup A N. meningitidis accounted for only 1 of these strains; serogroups B and C are the most common groups in Italy. In contrast, group A meningococci are the major cause of meningitis outbreaks worldwide, especially in Africa and Asia. To date, spread of ciprofloxacin resistance in serogroup A appears to be limited to India because a recent report of antimicrobial drug susceptibility of N. meningitidis in the meningitis belt of Africa during 2000–2006 showed no evidence of ciprofloxacin resistance (7). Temporal correlation and epidemiologic features strongly suggest that transmission of N. meningitidis to our patient occurred during his journey to India. Meningococcal disease is rarely imported because onset of symptoms is often rapid and severe. Nonetheless, the enormous increase in global trade and travel and shortening of international travel time may increase the risk for spread of infectious diseases and drug-resistant organisms. In addition, carriage of N. meningitidis in the nasopharynx of otherwise healthy persons can occur. Emergence of fluoroquinolone resistance in some countries raises concerns about current chemoprophylaxis recommendations for meningococcal disease. Ciprofloxacin is widely used for postexposure prophylaxis of close contacts of infected persons because it is simple to use (single oral dose) and lacks toxicity. However, patients and their contacts should be questioned about possible recent travel. When transmission of N. meningitidis is suspected in regions where fluoroquinolone resistance has been found (New Delhi, India, and North Dakota and western Minnesota in the United States), alternative chemoprophylaxis such as rifampin or ceftriaxone should be used. Emergence of autochthonous ciprofloxacin-resistant N. meningitidis is possible in countries where fluoroquinolones are widely used. In vitro drug susceptibility testing is not routinely and uniformly used in all settings because treatment or chemoprophylaxis are usually started before antibiogram results are available. Our case demonstrates that drug susceptibility testing should be encouraged and routinely performed for all isolates. Local and worldwide surveillance for antimicrobial drug–resistant N. meningitidis is crucial for determining antimicrobial drug resistance trends and future recommendations for chemoprophylaxis and treatment.

KIR-HLA genotypes in HIV-infected patients lacking immunological recovery despite effective antiretroviral therapy

Background In HIV-infected individuals, mechanisms underlying unsatisfactory immune recovery during effective combination antiretroviral therapy (cART) have yet to be fully understood. We investigated whether polymorphism of genes encoding immune-regulating molecules, such as killer immunoglobulin-like receptors (KIR) and their ligands class I human leukocyte antigen (HLA), could influence immunological response to cART. Methods KIR and HLA frequencies were analyzed in 154 HIV-infected and cART-treated patients with undetectable viral load divided into two groups: ‘immunological non responders’ (INR, N = 50, CD4+ T-cell count <200/mm3) and full responders (FR, N = 104, CD4+ T-cell count >350/mm3). Molecular KIR were typed using polymerase chain reaction-based genotyping. Comparisons were adjusted for baseline patient characteristics. Results The frequency of KIR2DL3 allele was significantly higher in FR than in INR (83.7% vs. 62%, P = 0.005). The functional compound genotype HLA-C1+/KIR2DL3+, even at multivariable analysis, when adjusted for nadir CD4+ T-cell count, was associated with reduced risk of INR status: odds ratio (95% Confidence Intervals) 0.34 (0.13−0.88), P = 0.03. Conclusions Reduced presence of the inhibitory KIR2DL3 genotype detected in INR might provoke an imbalance in NK function, possibly leading to increased immune activation, impaired killing of latently infected cells, and higher proviral burden. These factors would hinder full immune recovery during therapy.

96 Week Follow-Up of HIV-Infected Patients in Rescue with Raltegravir Plus Optimized Backbone Regimens: A Multicentre Italian Experience

Background Long term efficacy of raltegravir (RAL)-including regimens in highly pre-treated HIV-1-infected patients has been demonstrated in registration trials. However, few studies have assessed durability in routine clinical settings. Methods Antiretroviral treatment-experienced patients initiating a RAL-containing salvage regimen were enrolled. Routine clinical and laboratory follow-up was performed at baseline, week 4, 12, and every 12 weeks thereafter. Data were censored at week 96. Results Out of 320 patients enrolled, 292 (91.25%) subjects maintained their initial regimen for 96 weeks; 28 discontinued prematurely for various reasons: death (11), viral failure (8), adverse events (5), loss to follow-up (3), consent withdrawal (1). Eight among these 28 subjects maintained RAL but changed the accompanying drugs. The mean CD4+ T-cell increase at week 96 was 227/mm3; 273 out of 300 patients (91%), who were still receiving RAL at week 96, achieved viral suppression (HIV-1 RNA <50 copies/mL). When analyzing the immuno-virologic outcome according to the number of drugs used in the regimen, 2 (n = 45), 3 (n = 111), 4 (n = 124), or >4 (n = 40), CD4+ T-cell gain was similar across strata: +270, +214, +216, and +240 cells/mm3, respectively, as was the proportion of subjects with undetectable viral load. Laboratory abnormalities (elevation of liver enzymes, total cholesterol and triglycerides) were rare, ranging from 0.9 to 3.1%. The mean 96-week total cholesterol increase was 23.6 mg/dL. Conclusions In a routine clinical setting, a RAL-based regimen allowed most patients in salvage therapy to achieve optimal viral suppression for at least 96 weeks, with relevant immunologic gain and very few adverse events.

Maraviroc intensification for HIV-1-positive immunological non-responders (INRs) despite virological suppression during HAART

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

Unexpected dramatic increase in CD4+ cell count in a patient with AIDS after enfuvirtide treatment despite persistent viremia and resistance mutations.

An unexpected dramatic immune recovery was observed in a patient with full‐blown AIDS receiving enfuvirtide‐based antiretroviral therapy after multiple treatment failures. A complex interplay of viral and host factors, including the control of X4 viruses and proviral burden, may favor immune restoration with HIV neutralizing activity, despite persistent viremia. J. Med. Virol. 80:937–941, 2008.