Antonella Cingolani

Usefulness of monitoring HIV drug resistance and adherence in individuals failing highly active antiretroviral therapy: a randomized study (ARGENTA).

Objective To establish the influence of genotypic resistance-guided treatment decisions and patient-reported adherence on the virological and immunological responses in patients failing a potent antiretroviral regimen in a randomized, controlled trial in a tertiary care infectious diseases department. Patients A total of 174 patients with virological failure were randomly assigned to receive standard of care (SOC) or additional genotypic resistance information (G). Adherence was measured by a self-administered questionnaire. Main outcomes measures Primary endpoints were the proportion with HIV-RNA < 500 copies/ml at 3 and 6 months by intention-to-treat analysis. Secondary endpoints were changes from baseline HIV-RNA levels and CD4 cell counts. Results At entry, 25% had failed three or more highly active antiretroviral therapy (HAART) regimens and 41% three drug classes; there were more resistance mutations in G. In 127 evaluable questionnaires, 43% reported last missed dose during the previous week. At 3 months, 11 of 89 patients (12%) in SOC and 23 of 85 (27%) in G had HIV-RNA < 500 copies/ml (OR 2.63, 95% CI 1.12–6.26); the relative proportions were 17 and 21% at 6 months. CD4 cell changes did not differ between arms. Six month CD4 cell changes were +62 in adherent and −13 cells/μl in non-adherent patients (P < 0.01). Being assigned to G, good adherence, previous history of virological success, fewer experienced HAART regimens and lower baseline viral load were independently predictive of 3 month virological success. Conclusion The virological benefit of genotype-guided treatment decisions in heavily pre-exposed patients was short term. Patients adherence and residual treatment options influenced outcomes.

Better response to chemotherapy and prolonged survival in AIDS-related lymphomas responding to highly active antiretroviral therapy

Objectives To evaluate the impact of response to highly active antiretroviral therapy (HAART) on the natural history of AIDS non-Hodgkins lymphoma (NHL) and to analyse the feasibility, efficacy and toxicity of HAART in combination with chemotherapy. Design Prospective observational study in two AIDS clinical centres in Italy. Methods All consecutive HIV-infected patients with NHL were included (n = 44; 48% high-risk group) and prospectively followed for 27 months. HAART was administered concomitantly with chemotherapy. The association between response to HAART and clinical presentation, response to chemotherapy and toxicity was analysed by univariate and multivariate models. Survival analysis was performed by Kaplan–Meier estimates and the Cox proportional hazards regression model. Results A complete response (CR) to chemotherapy was achieved in 71% of HAART responders and 30% of non-responders. Virological response to HAART was the only variable associated with tumour response on multivariate analysis. A higher relative dose intensity (RDI) of chemotherapy was administered in patients with virological response compared with those without. The probability of 1 year survival was higher in patients with virological or immunological response. At Cox regression analysis, immunological response, a higher RDI and a CR to chemotherapy were all associated with a reduced risk of death. Conclusion In HIV-infected patients with NHL, response to HAART was strongly associated with a better response to chemotherapy and prolonged survival. Concurrent treatments were well tolerated, and HAART-responder patients could receive a higher RDI of chemotherapy. In patients with AIDS lymphomas, combining HAART with chemotherapy could be a feasible and effective approach.

Patient-reported nonadherence to HAART is related to protease inhibitor levels.

Objective: To compare self‐reported nonadherence with antiretroviral therapy (ART) with predose plasma levels of protease inhibitor (PI). Design: A cross‐sectional study of consecutive patients from a university‐based HIV clinic in Rome, Italy, was conducted. One hundred and forty HIV‐infected patients were prescribed regimens containing ritonavir or indinavir. A patient questionnaire assessing knowledge of treatment regimen, adherence behavior, reasons for taking and missing therapy, factors influencing adherence, and health behaviors was administered. A predose PI plasma level was measured concurrently. Results: By patient report, 12% missed at least one dose “yesterday,” and 24% missed doses in the last 3 days; 14% had a predose plasma concentration below the assay limit of quantitation (2 ritonavir and 18 indinavir samples). Confusion, poor psychological well‐being, long office wait, running out of drugs between visits, having relatives to remind the patient to take medication, children, and alteration of sense of taste were related to unquantifiable predose levels of PI. In multivariable analysis, reported nonadherence (odds ratio [OR], 15.8; 95% confidence interval [CI], 4.0‐63.3) and confusion (OR, 9.9; 95% CI, 1.4‐69.6) were related to unquantifiable predose levels of PI. Conclusion: Self‐report of missing a dose of antiretroviral medication “yesterday” was related to an unmeasurable plasma PI level.

Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: Data from the Italian Registry Investigative Neuro AIDS (IRINA)

Human immunodeficiency virus (HIV)-associated progressive multifocal leukoencephalopathy (PML) remains a relevant clinical problem even in the era of highly active antiretroviral therapy (HAART). Aims of the study were to analyze clinical and treatment-related features and the survival probability of PML patients observed within the Italian Registry Investigative Neuro AIDS (IRINA) during a 29-month period of HAART. Intravenous drug use, the presence of focal signs, and the involvement of white matter at neuroradiology increased the risk of having PML. A reduced probability of PML was observed when meningeal signs were reported. Patients starting HAART at PML diagnosis and previously naïve for antiretrovirals showed significantly higher 1-year probability of survival (.58), compared to those continuing HAART (.24), or never receiving HAART (.00). Higher CD4 cell count were associated with a higher survival probability (.45). At multivariate analysis, a younger age, higher CD4, starting HAART at PML diagnosis, the absence of previous acquired immunodeficiency syndrome (AIDS)-defining events, and the absence of a severe neurologic impairment were all associated with a reduced hazard of death. The use of cidofovir showed a trend towards a reduced risk of death.

Value of Combined Approach With Thallium-201 Single-Photon Emission Computed Tomography and Epstein-Barr Virus DNA Polymerase Chain Reaction in CSF for the Diagnosis of AIDS-Related Primary CNS Lymphoma

PURPOSE To determine the diagnostic capability of thallium-201 (201Tl) single-photon emission computed tomography (SPECT) combined with Epstein-Barr virus DNA (EBV-DNA) in CSF for the diagnosis of AIDS-related primary CNS lymphoma (PCNSL). PATIENTS AND METHODS All human immunodeficiency virus (HIV)-infected patients with focal brain lesions observed between June 1996 and March 1998 underwent lumbar puncture and 201Tl SPECT. Each CSF sample was tested with polymerase chain reaction (PCR) for EBV-DNA. RESULTS Thirty-one patients were included, 13 with PCNSL and 18 with nontumor disorders. In 11 PCNSL patients, EBV-DNA was positive. Thallium-201 uptake ranged from 1.90 to 4.07 in PCNSL cases (mean, 2.77; 95% confidence interval [CI], 2.35 to 3.19) and from 0.91 to 3.38 in nontumor patients (mean, 1.62; 95% CI, 1.30 to 1.94) (P<.0002). Using a lesion/background ratio of 1.95 as cutoff, a negative SPECT was found in one PCNSL case and 16 nonneoplastic cases. A cryptococcoma and a tuberculoma showed highly increased 201Tl uptake. Epstein-Barr virus DNA was never detected in nonneoplastic patients. For PCNSL diagnosis, hyperactive lesions showed 92% sensitivity and 94% negative predictive value (NPV), whereas positive EBV-DNA had 100% specificity and 100% positive predictive value. The presence of increased uptake and/or positive EBV-DNA had 100% sensitivity and 100% NPV. CONCLUSION Combined SPECT and EBV-DNA showed a very high diagnostic accuracy for AIDS-related PCNSL. Because PCNSL likelihood is extremely high in patients with hyperactive lesions and positive EBV-DNA, brain biopsy could be avoided, and patients could promptly undergo radiotherapy or multimodal therapy. On the contrary, in patients showing hypoactive lesions with negative EBV-DNA, empiric anti-Toxoplasma therapy is indicated. In patients with discordant SPECT/PCR results, brain biopsy seems to be advisable.

Cross-Resistance among Nonnucleoside Reverse Transcriptase Inhibitors Limits Recycling Efavirenz after Nevirapine Failure

Heterogeneity in genotype mutations associated with resistance of HIV to nonnucleoside reverse transcriptase inhibitors (NNRTIs) should allow identification of patients failing nevirapine (NVP) who might benefit from efavirenz (EFV)-containing salvage regimens. To establish the feasibility of recycling EFV after failure of NVP-containing regimens genotypic data on 103 NVP-failed patients were analyzed to evaluate the prevalence of EFV resistance-conferring mutations. A clinically significant resistance to EFV was found in 50 of 103 (58%) of NVP-failed subjects. Furthermore, the 3-month virological response to salvage regimens containing EFV was assessed in patients previously treated with NVP and carrying single mutations conferring resistance to this drug. A proportion of HIV RNA less than 500 copies/ml at 3 months was obtained only in 2 of 12 (17%) of EFV-treated subjects compared with 35 of 67 (52%) of those without NNRTI mutations (OR, 0.18; 95% CI, 0.03-0.79). The median HIV-1 RNA decrease after 3 months was -0.63 log(10) among patients carrying single NNRTI-associated mutations compared with -1.32 log(10) among those without any NNRTI mutations. No virological response was observed in six patients harboring a single Y181C/I mutation. On the basis of the present data, sequential use of NNRTIs should be avoided in the management of treatment failure.

AIDS–related focal brain lesions in the era of highly active antiretroviral therapy

Objective: To compare the years since the introduction of highly active antiretroviral therapy (HAART) with the pre-HAART era for trends in the proportions of HIV-related focal brain lesion–causing disorders. Methods: A prospective, single-center study of all consecutive HIV-infected patients with a neurologic presentation and focal brain lesions observed between January 1991 and December 1998 was undertaken. Results: The major diagnoses in the 281 patients were toxoplasmic encephalitis (36.4%), primary CNS lymphoma (26.7%), progressive multifocal leukoencephalopathy (18.2%), and focal HIV encephalopathy (5.0%). During the HAART period, patients were less likely to be male, contracted HIV more often through heterosexual exposure, had fewer previous AIDS-defining events, received anti-Toxoplasma prophylaxis less frequently, had a CD4+ lymphocyte count 2.5 times higher, and had diagnosis based more often on PCR assays from CSF, reducing the need for brain biopsy and enhancing the likelihood of in vivo diagnosis. Using all patients hospitalized per year as reference population, the risk of focal brain lesions strongly increased during the pre-HAART period and declined significantly during the HAART years. In the HAART period a relevant decline of primary CNS lymphoma was found (OR for 1998, 0.25; p for trend = 0.03) and the effect of progressive calendar year was confirmed on multivariable analysis (OR, 0.52; 95% CI, 0.28 to 0.97). The frequency of toxoplasmic encephalitis decreased during the pre-HAART era and was stable afterwards. For progressive multifocal leukoencephalopathy, a slight increase was seen over time. Focal white matter lesions without enhancement or mass effect increased between 1991 and 1998. Conclusions: During the HAART era, AIDS-related primary CNS lymphoma showed a strong decline, toxoplasmic encephalitis remained stable, and progressive multifocal leukoencephalopathy showed a slight increase. Focal white matter lesions without mass effect or contrast enhancement became the most frequently seen focal brain lesion. For differential diagnosis, PCR-based assays from CSF led to a shift from brain biopsy toward a minimally invasive approach with an augmented likelihood of in vivo diagnosis.

Cidofovir in addition to antiretroviral treatment is not effective for AIDS-associated progressive multifocal leukoencephalopathy: a multicohort analysis

Objective:To establish the effectiveness of cidofovir for AIDS-related progressive multifocal leukoencephalopathy (PML) in patients concomitantly receiving combination antiretroviral therapy. Design:Analysis of raw data pooled from one prospective and five cohort studies. Setting:Tertiary care centers for the treatment of HIV-associated complications. Patients:Three hundred seventy HIV-infected PML patients diagnosed from 1996 treated with combination antiretroviral therapy with or without cidofovir. All studies had already published their results but for four of them, additional patients and follow-up data are included in this report. Follow-up was started from the date of first abnormal neuroimaging; those treated with cidofovir were entered at risk at the date of cidofovir initiation.Main study outcomes were time to PML-related death and odds of 12-month moderately severe to severe disability (Rankin score ≥4). Results:Sixty-four percent of the PML cases were confirmed by histopathology or JC virus DNA detection in cerebrospinal fluid; 185 (50%) received cidofovir (median five cycles). During 463 person-years of follow-up, 167 PML-related deaths occurred (36.6 per 100 person-years of follow-up). Estimated 1 year survival was 0.56 (95% confidence interval, 0.50–0.61). In multivariate models stratified by cohort and adjusted for type of diagnosis and relevant prognostic confounders, cidofovir treatment was not associated with survival (hazard ratio for death 0.93, 0.66–1.32). Results were similar using time to death from any cause as the outcome. Furthermore, 12-month moderately severe to severe disability was not associated with the use of cidofovir. Conclusion:In combination antiretroviral therapy-treated PML patients, cidofovir use did not influence PML-related mortality or residual disability. New treatments for AIDS-related PML are urgently needed.

Plasma levels of interleukin-6 and interleukin-10 in preterm neonates evaluated for sepsis

Abstract In a prospective study, plasma interleukin-6 (IL-6) and interleukin-10 (IL-10) levels were measured by enzyme-linked immunosorbent assay in 45 premature neonates (25–34 weeks gestational age) with signs and symptoms of suspected sepsis at 0, 12 and 24 h; C-reactive protein (CRP) was measured at 0–24 h after enrolment. Six subjects were excluded due to insufficient blood sampling. The remaining 39 neonates were assigned to one of three groups: 25 newborns with sepsis (blood culture positive), seven with pneumonia (positive results on broncho-alveolar lavage fluid culture and characteristic chest radiography) and seven with necrotising enterocolitis (NEC) (characteristic intestinal and radiological signs according to the criteria of Bell et al.). A group of 20 healthy preterm neonates represented control subjects. On admission, higher levels of IL-6, IL-10 and CRP were observed in neonates with sepsis: IL-6 (median 1500 pg/ml, range 487–10000 pg/ml), IL-10 (median 113 pg/ml, range 70–196 pg/ml), CRP (median 22 mg/l, range 4–80 mg/l); pneumonia: IL-6 (median 1500 pg/ml, range 747–8000 pg/ml, IL-10 (median 84 pg/ml, range 76–92 pg/ml), CRP (median 10 mg/l, range 8–33 mg/l) and NEC: IL-6 (median 6650 pg/ml, range 1595–7950 pg/ml), IL-10 (median 80 pg/ml, range 61–147 pg/ml), CRP (median 3 mg/l, range 2.8–8 mg/l) as compared to controls (IL-6 median 208 pg/ml, range 198–349 pg/ml; IL-10 median 36 pg/ml, range 19–50 pg/ml; CRP median <2 mg/l) (P < 0.05). In neonates with sepsis, IL-6 levels were significantly correlated with IL-10 levels (r=0.65; P=0.04) at the time of the second sample. The highest IL-6 levels were observed at onset, while IL-10 was predominant 12 h later. On admission, IL-10 and CRP levels were significantly higher in non-survivors (IL-10 median 507 pg/ml, range 422–753 pg/ml; CRP median 123 mg/l, range 20–219 mg/l) than in survivors (IL-10 median 76 pg/ml, range 61–143 pg/ml; CRP median 8 mg/l range 3–46 mg/l), while IL-10 levels were significantly higher (P < 0.05) also 12 h after admission (non-survivors: IL-10 median 600 pg/ml, range 538–800 pg/ml; survivors: IL-10 median 74 pg/ml, range 53–161 pg/ml). IL-6 and IL-10 levels were significantly correlated with CRP levels on admission (r=0.45; P=0.05). Conclusion Preterm neonates with sepsis, pneumonia or necrotising enterocolitis showed increased interleukin-6, interleukin-10 and C-reactive protein levels. High interleukin-10 concentration was associated with mortality and could be an early indicator of prognosis.

Prevalence, associated factors, and prognostic determinants of AIDS-related toxoplasmic encephalitis in the era of advanced highly active antiretroviral therapy

BACKGROUND Characteristics, associated factors, and survival probability of toxoplasmic encephalitis (TE) in the era of advanced highly active antiretroviral therapy (HAART) have not been fully clarified. METHODS Data for 205 individuals with acquired immunodeficiency syndrome (AIDS)-related TE were derived from the Italian Registry Investigative NeuroAIDS database, and the cases were studied longitudinally to evaluate prevalence, clinical characteristics, and survival. Moreover, the relationship between the occurrence of TE and exposure to antiretroviral therapy and to TE prophylaxis was evaluated. RESULTS With an overall prevalence of 26%, TE represented the most frequent neurological disorder in the cohort. Female sex, severe immunodeficiency, and absence of primary TE prophylaxis significantly increased the risk of TE, and previous exposure to antiretroviral therapy reduced the probability of disease occurrence. Thirty-six percent of patients who had received antiretroviral therapy developed TE, although in most of these cases, the patient experienced failure of antiretroviral therapy. Of note, 66% of patients who had experienced antiretroviral therapy did not receive prophylaxis for TE at TE diagnosis. The 1-year probability of that infection with human immunodeficiency virus (HIV) would progress or that death would occur after TE was 40% and 23%, respectively. Cognitive symptoms, low CD4(+) cell count, not receiving HAART after TE, and initiating HAART >2 months after TE diagnosis were all significantly associated with an increased probability of progression of HIV infection. Not receiving HAART after diagnosis negatively affected survival. CONCLUSIONS TE remains a highly prevalent disorder of the central nervous system, even in the late HAART era, particularly among severely immunosuppressed patients and in absence of prophylaxis. Considering that persons with TE have a high probability of early death, prophylaxis should be maintained in immunosuppressed patients who experience failure of antiretroviral therapy, and HAART should be initiated as soon as possible after TE diagnosis.