S. Di Giambenedetto

Efavirenz associated with cognitive disorders in otherwise asymptomatic HIV-infected patients

Background: Despite the availability of potent antiretroviral regimens (combination antiretroviral therapy [cART]), HIV-associated neurocognitive disorders (HAND) are increasingly recognized. Our aim was to investigate the prevalence and treatment-related correlates of HAND, exploring the potential neurotoxicity of antiretrovirals on cognitive functions. Methods: We performed a cross-sectional single cohort study by consecutively enrolling asymptomatic HIV+ subjects during routine outpatient visits. Each patient was submitted to a comprehensive neuropsychological battery and was considered cognitively impaired on the basis of results obtained in matched healthy HIV-negative subjects. CNS penetration effectiveness (CPE) rank was calculated for cART regimens according to 2010 CHARTER criteria. Factors associated with cognitive impairment were investigated by linear or logistic regression analysis. Results: A total of 146 patients were enrolled. Of these, 129 (88.4%) were on cART and 59.6% of them were on current regimen from ≥1 year. Sixty-nine patients (47%) were classified as cognitively impaired (35.6% asymptomatic and 11.6% mild neurocognitive impairment). In the multivariate analysis, efavirenz use (odds ratio [OR] = 4.00; p = 0.008) and non-Italian nationality (OR = 3.46; p = 0.035) were associated with increased risk of cognitive impairment, whereas higher education was associated with a lower risk (OR = 0.85; p = 0.002). Furthermore, efavirenz use and age ≥65 years independently predicted worse performance on the double barrage and the Stroop test (time). No association between CPE rank and cognitive impairment was observed. Conclusions: A high prevalence of HAND was observed in apparently asymptomatic HIV+ individuals. HAND was associated with efavirenz use, suggesting the potential neurotoxicity of this drug. Routine neuropsychological examinations could help clinicians make correct diagnoses and manage mild, but clinically relevant, forms of HAND.

A novel methodology for large-scale phylogeny partition

Phylogenetic analysis is used to identify transmission chains, but no software is available for the automated partition of large phylogenies. Prosperiet al. apply a new search algorithm to identify transmission clusters within the phylogeny of HIV-1gene sequences linking molecular and epidemiological data. Supplementary information The online version of this article (doi:10.1038/ncomms1325) contains supplementary material, which is available to authorized users.

Cardiovascular risk factors and carotid intima‐media thickness are associated with lower cognitive performance in HIV‐infected patients

The aim of the study was to investigate the relationship between metabolic comorbidities, cardiovascular risk factors or common carotid intima‐media thickness (cIMT) and cognitive performance in HIV‐infected patients.

Prevalence of transmitted HIV-1 drug resistance in HIV-1 infected patients in Italy: evolution over 12 years and predictors

OBJECTIVES Transmitted HIV-1 drug resistance (TDR) can reduce the efficacy of first-line antiretroviral therapy. PATIENTS AND METHODS A retrospective analysis was performed to assess the prevalence and correlates of TDR in Italy over time. TDR was defined as the presence of at least one of the mutations present in the surveillance drug resistance mutation (SDRM) list. RESULTS Among 1690 antiretroviral therapy-naive patients, the most frequent HIV subtypes were B (78.8%), CRF02_AG (5.6%) and C (3.6%). Overall, TDR was 15%. TDR was 17.3% in subtype B and 7.0% in non-B carriers (P < 0.001). TDR showed a slight, although not significant, decline (from 16.3% in 1996-2001 to 13.4% in 2006-07, P = 0.15); TDR declined for nucleoside reverse transcriptase inhibitors (from 13.1% to 8.2%, P = 0.003) but remained stable for protease inhibitors (from 3.7% to 2.5%, P = 0.12) and non-nucleoside reverse transcriptase inhibitors (from 3.7% to 5.8%). TDR to any drug was stable in B subtype and showed a decline trend in non-B. In multivariable analysis, F1 subtype or any non-B subtype, compared with B subtype, and higher HIV RNA were independent predictors of reduced odds of TDR. CONCLUSIONS Prevalence of TDR to nucleoside reverse transcriptase inhibitors seems to have declined in Italy over time. Increased prevalence of non-B subtypes partially justifies this phenomenon.

Cardiovascular risk score change in HIV‐1‐infected patients switched to an atazanavir‐based combination antiretroviral regimen

We aimed to establish whether the limited impact of atazanavir on the plasma lipid profile could translate into a reduction in the predicted cardiovascular risk in antiretroviral (ARV)‐experienced patients switching to an atazanavir‐containing regimen.

Fatal inflammatory AIDS-associated PML with high CD4 counts on HAART: A new clinical entity?

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the human CNS caused by polyomavirus JC.1 Its characteristic pathologic features include lytic infection of oligodendrocytes, with typical nuclear inclusions, formation of large bizarre astrocytes, and demyelination. PML is common in immunosuppressed individuals and is the third most frequent neurologic complication in HIV-infected patients in the era of highly active antiretroviral therapy (HAART).2 Except for HAART, no therapy has been demonstrated to be effective against PML; the efficacy of cidofovir, a nucleotide analogue that inhibits the replication of simian polyomavirus in vitro, is controversial. Selected reports demonstrate that in patients with AIDS, PML can occur early after the introduction of HAART during the phase of recovery of the immune system. These cases are sometimes associated with inflammatory reaction as shown by the presence of perivascular lymphomonocytic infiltrates or contrast enhancement on neuroimaging studies and show variable clinical outcomes.3–6⇓⇓⇓ In this …

Efficacy and safety of treatment simplification to atazanavir/ritonavir + lamivudine in HIV-infected patients with virological suppression: 144 week follow-up of the AtLaS pilot study

OBJECTIVES AtLaS was a single-arm pilot study that demonstrated promising efficacy and safety of treatment simplification to a dual regimen with atazanavir/ritonavir + lamivudine in virologically suppressed HIV-positive patients. Here, we report data from the 144 week follow-up. METHODS At baseline, patients treated with a three-drug atazanavir/ritonavir-based regimen were switched to 300/100 mg of atazanavir/ritonavir plus 300 mg of lamivudine once daily. Major clinical events, laboratory parameters, neurocognitive performance, bone composition and body fat distribution were monitored. Treatment failure was defined as a discontinuation/switch of the regimen or virological failure (HIV-RNA >50 copies/mL in two consecutive determinations or a single level above 1000 copies/mL). RESULTS After 144 weeks, 9/40 (22.5%) treatment failures occurred, including two virological failures (Weeks 48 and 53, without resistance). A significant increase in the CD4 count was observed at Week 96 (+124 cells/mm(3); P = 0.002) and Week 144 (+94 cells/mm(3); P = 0.008). After 144 weeks, a significant increase in total cholesterol (+25 mg/dL; P = 0.001), HDL cholesterol (+6 mg/dL; P = 0.024) and LDL cholesterol (+12 mg/dL; P = 0.008) was observed, without any change in triglyceride levels, total cholesterol/HDL ratio or LDL/HDL ratio. A significant increase in the estimated glomerular filtration rate (+25 mL/min/1.73 m(2); P < 0.001) and lumbar spine T-score and Z-score (+0.2, P = 0.011; and +0.35, P = 0.001, respectively) and a decrease in trunk fat (-1.898 g; P = 0.005) were also observed. Neurocognitive function did not decline over time. Concerning safety, 10 moderate to severe adverse events were recorded in eight patients; overall seven cases of renal colic (possibly treatment related) were observed, leading to a discontinuation of treatment in two patients. CONCLUSIONS Data from the 144 week follow-up suggested good long-term efficacy of the simplification strategy that was investigated, with rare virological failure and a potential for improvement of the CD4 count, renal function and bone mineral density. This strategy warrants further investigation in a randomized trial.

Evolution of transmitted HIV-1 drug resistance in HIV-1-infected patients in Italy from 2000 to 2010

Prevalence and predictors of transmitted drug resistance (TDR), defined as the presence of at least one WHO surveillance drug resistance mutation (SDRM), were investigated in antiretroviral-naïve HIV-1-infected patients, with a genotypic resistance test (GRT) performed ≤6 months before starting cART between 2000 and 2010. 3163 HIV-1 sequences were selected (69% subtype B). Overall, the prevalence of TDR was 12% (13.2% subtype B, 9% non-B). TDR significantly declined overall and for the single drug classes. Older age independently predicted increased odds of TDR, whereas a more recent GRT, a higher HIV-RNA and C vs. B subtype predicted lower odds of TDR.

Mid-dosing interval concentration of atazanavir and virological outcome in patients treated for HIV-1 infection

We investigated the clinical significance of monitoring the mid‐dosing interval atazanavir (ATV) concentration (measured 12 ± 2 h after intake; C12 h) in patients taking this drug once daily in the evening.

Genotypic Resistance Profile and Clinical Progression of Treatment-Experienced HIV Type 1-Infected Patients with Virological Failure

We explored the relationship between HIV-1 drug resistance in treatment-experienced patients and disease progression in a cohort of patients undergoing resistance testing to guide treatment decisions. A total of 601 treatment-failing individuals tested for genotypic HIV-1 drug resistance between 1998 and 2004 were selected. At genotypic testing, median HIV-1 RNA levels and CD4 counts were 3.8 log copies/ml and 293 cells/mul, respectively; 84% had resistance mutations to nucleoside reverse transcriptase inhibitors (NRTIs), 42% had resistance mutations to non-NRTIs, 51% had major resistance mutations to protease inhibitors (PI), 12% had no major resistance mutations to any drug class, 22% had mutations to one class, 42% had mutations to two classes, and 23% had mutations to three classes. During a follow-up of 714.7 patients/year, 80 patients showed an AIDS-defining event or died. In multivariable models adjusting for prior AIDS, baseline CD4 counts, HIV-1 RNA, and calendar year, viral resistance variables associated with increased hazards of clinical progression were the presence of reverse transcriptase substitution T215F (p = 0.002) and the presence of three or more protease substitutions among L33F/I/V, V82A/F/L/T, I84V, and L90M (p = 0.003). Resistance to three drug classes remained independently predictive of clinical progression only when calendar year was not used as an adjustment factor. Prevention and treatment of multiple drug class resistance are clinical priorities for HIV-infected patients. In recent years, improved treatment options may have helped in reducing part of the resistance-associated clinical progression.