Alba Bigoloni

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.

Switching to unboosted atazanavir improves glucose tolerance in highly pretreated HIV-1 infected subjects

OBJECTIVE To evaluate the 24-week effects on glucose tolerance of switching from a protease inhibitor (PI)-based to an unboosted atazanavir-including regimen in highly pretreated HIV-1 infected subjects with metabolic alterations. DESIGN Prospective, open-label, single-center, 24-week pilot study. METHODS Twenty-one subjects underwent an oral glucose tolerance test (OGTT) at baseline (BL) and after 24 weeks of unboosted atazanavir. Insulin sensitivity and beta-cell responsiveness were evaluated on the basis of static and dynamic data; fasting glucose, insulin, C-peptide, triglycerides (TG), total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-c), low-density lipoprotein-cholesterol (LDL-c), TC/HDL-c ratio, CD4+ cell count and HIV-1 RNA were measured. RESULTS After 24 weeks of unboosted atazanavir, the 120-min glucose level was significantly lower than the one measured at BL (P=0.021); there were no statistically significant differences in the insulin concentration profile. The SI(oral), an OGTT-based index of insulin sensitivity, was significantly higher at week 24 (P=0.017); the indices of first- and second-phase beta-cell responsiveness did not significantly change. There was no significant difference between BL and 24-week fasting glucose, insulin or C-peptide levels, and consequently no change in fasting homeostasis model assessment indices of insulin sensitivity and beta-cell function. There were significant improvements in TG (P=0.009), TC (P=0.0001), LDL-c (P=0.019) and TC/HDL-c ratio (P=0.001), and a similar trend in HDL-c levels (P=0.069). No significant changes in the immunological and virological parameters were detected. CONCLUSIONS Our results show that switching from a PI-based to an unboosted atazanavir-including regimen leads to a significant improvement in glucose tolerance in highly pretreated HIV-1 infected subjects with metabolic alterations.

Ten-year survival among HIV-1-infected subjects with AIDS or non-AIDS-defining malignancies.

Few data are available regarding the 10‐year survival among subjects with HIV and cancer. The aim of this study was to evaluate the 10‐year survival of HIV‐infected subjects with AIDS‐defining malignancies (ADM) or non‐AIDS‐defining malignancies (NADM). This was a single center, retrospective, observational study of subjects with HIV infection and a subsequent cancer diagnosis; the data were collected from January 1991 to April 2010. Malignancies were divided into ADM or NADM on the basis of the Centre of Diseases Control‐1993 classification. Survival curves were estimated using Kaplan–Meyer method and compared by the log‐rank test. Six hundred and fifteen (9.5%) of the 6,495 subjects recorded in the San Raffaele Infectious Diseases Database developed a malignancy: 431 (70%) an ADM and 184 (30%) a NADM. In the case of ADM, survival was more favorable when cancer was diagnosed during post‐highly active antiretroviral therapy (HAART) era (10‐year survival: 43.2% ± 4.4%) than when diagnosed during the pre‐HAART era (10‐year survival: 16.4% ± 2.7%; log‐rank test: p < 0.001). The same was true in the case of NADM (10‐year survival: 44.7% ± 5.5% vs. 33.3 ± 9.6%; log‐rank test: p = 0.03). An evaluation of survival probability by cancer type showed higher survival rates during the post‐HAART era in the case of non‐Hodgkin lymphoma (10‐year survival: 42.1% ± 5.3% vs. 11.4% ± 3.3%; log‐rank test: p = <0.001), Kaposis sarcoma (10‐year survival: 44.0% ± 8.4% vs. 23.5% ± 3.9%; log‐rank test: p < 0.001) and Hodgkins disease (10‐year survival: 49.5% ± 14.5% vs. 40.0% ± 12.7%; log‐rank test: p = 0.005). Despite the better cancer prognosis during the post‐HAART era, the 10‐year survival of HIV‐infected subjects with an ADM or NADM is poor.

Electrocardiographic changes in HIV-infected, drug-experienced patients being treated with atazanavir

The QRS interval of 56 out of 75 (74.7%) HIV-infected, drug-experienced patients (66.7% men) increased during treatment with boosted or unboosted atazanavir by a median 5 ms (interquartile range 0–9; P < 0.0001); the PR and the QTc intervals did not change significantly. New asymptomatic bundle branch blocks were observed in four patients; one subject with a baseline first-degree atrioventricular block developed symptomatic bradyarrhythmia while receiving atenolol. The electrocardiographic monitoring of patients treated with atazanavir seems advisable.

Use of statins and risk of AIDS-defining and non-AIDS-defining malignancies among HIV-1 infected patients on antiretroviral therapy

Objective:Previous studies have shown that statins use is associated with a lower mortality risk or occurrence of non-Hodgkins lymphoma or non-AIDS-defining malignancies (NADMs) in HIV-positive patients. We evaluated the effect of statin therapy on the occurrence of all AIDS-defining malignancy (ADM) and NADM among HIV-positive patients. Design:A chart study on HIV-1 infected patients attending the Infectious Diseases Department of the San Raffaele Scientific Institute, Italy. Methods:Incident malignancies diagnosed since antiretroviral treatment (ART) initiation until October 2012 among treated patients not taking statins at ART initiation. Statin therapy had to precede cancer diagnosis, if it occurred. Malignancies that occurred before ART or statin initiation were excluded. Follow-up was calculated since ART initiation until the first cancer diagnosis or loss to follow-up or death or last available visit, whichever occurred first. Results are described as median (interquartile range, IQR). Results:Five thousand, three hundred and fifty-seven HIV-1 treated patients were included. During 52 663 person-years, 740 (14%) patients had a history of statin use; 375 malignancies occurred: 12 (1.6%) malignancies (0 ADM; 12 NADM, crude incidence rate, 1.3/1000 person-years) among statin users and 363 (7.9%) malignancies (194 ADM; 169 NADM, crude incidence rate, 8.4/1000 person-years) among non-statin users. By multivariate Fine-Gray regression, statin use was associated with a lower risk of cancer [adjusted hazard ratio (95% confidence interval) for ever use: 0.45 (0.17–0.71)]. Conclusion:Among HIV-1 treated patients, statin use was associated with a lower risk of cancer; the benefit was mainly related to AIDS-defining malignancies. Confirmatory studies are needed to consider the residual confounding likely present in this study.

Long-term glucose tolerance in highly experienced HIV-infected patients receiving nucleoside analogue-sparing regimens.

Thirty-nine HIV-1-infected patients treated for 156 weeks with a new nucleoside analogue-sparing regimen [raltegravir, etravirine and maraviroc (REM) or raltegravir, etravirine and darunavir/ritonavir (RED)] showed a uniform increase in fasting glucose levels and a uniform decrease in insulin secretory capacity. Diabetes mellitus occurred in one RED-treated and four REM-treated patients. A worsening glucose tolerance was observed in highly treatment-experienced HIV-infected patients receiving effective antiretroviral therapy after virological failure.

Immune recovery and T cell subset analysis during effective treatment with maraviroc

OBJECTIVES Patients treated with maraviroc frequently show high CD4+ T cell increases. The aim of this study was to detail the characteristics of maraviroc-induced immune recovery. PATIENTS AND METHODS We studied T cell subsets from frozen peripheral blood mononuclear cells of patients treated with raltegravir, etravirine and either maraviroc (REM, n = 24) or darunavir/ritonavir (RED, n = 17). RESULTS The two groups showed a similar decrease in activated CD4+ and CD8+ T cells. A greater loss of naive CD4+ T cells and a reduction in cells expressing CXCR4 were observed in REM patients, while RED patients showed a greater loss of cells expressing CCR5. CONCLUSIONS Our findings do not support a role for reduction in activated T cell subsets to explain the greater maraviroc-induced immune recovery. Reduction in CXCR4+CD4+ and higher expression of CCR5+CD4+ T cells might represent a potential protection from non-R5 tropic viral strain overgrowth.

Excellent short-term CD4 recovery with a PI- and NRTI-sparing regimen in triple-class failure HIV-infected patients: raltegravir, maraviroc, etravirine

Methods We decided to simultaneously screen triple class failing patients (pts) followed at San Raffaele Hospital in three Expanded Access Programs: raltegravir (MK0518-023), maraviroc (A4001050), etravirine (TMC125-C214). Salvage therapy was prescribed according to: viral tropism, screening genotype and previous resistance tests. Data were collected at baseline (BL) and at 4, 12, 24, 36 and 48 weeks. Generalized linear regression model was applied. Results are reported as median (Q1–Q3).

Viro-immunological dynamics in HIV-1-infected subjects receiving once-a-week emtricitabine to delay treatment change after failure: a pilot randomised trial.

BACKGROUND In HIV-1-infected patients harbouring the M184V mutation (M184V), lamivudine monotherapy leads to a smaller decrease in CD4 percentages (CD4%) than treatment interruption, possibly due to the reduced fitness of the mutated virus. OBJECTIVE We assessed whether a minimal dose of a cytidine analogue that is theoretically sufficient to maintain M184V (one emtricitabine tablet once-weekly) may be as effective. STUDY DESIGN In a proof-of-concept, randomised clinical trial, HIV-1-infected patients with CD4 cells >400/mm(3), failing on lamivudine- or emtricitabine-containing combination antiretroviral therapy (cART), received emtricitabine once-a-week (A), or emtricitabine once-a-day (B), or lamivudine once-a-day (C). The primary endpoint was the proportion of subjects without a 12-week loss in CD4%. The patients resumed cART after 24 weeks or in the case of CD4 cells <350/mm(3). RESULTS The 38 enrolled patients had similar baseline characteristics across groups. The primary endpoint was reached by 5/13 patients (38.5%) in arm A, 3/13 (23.1%) in arm B, and 3/12 (25%) in arm C (P=0.644), and respectively 4/13 (30.8%), 4/13 (30.8%) and 5/12 (41.7%) had to resume cART within 24 weeks (P=0.805). The immunological changes over 24 weeks were similar in the three groups, but there was a higher median viral rebound in once-weekly treatment recipients (A) than in once-daily (B+C): 0.97 versus 0.52log(10)copies/ml (P=0.033). M184V was maintained in all the participants. CONCLUSIONS Once-weekly emtricitabine led to a higher viral rebound than once-daily monotherapy, but similar immunological changes, thus suggesting a role of M184V in slowing the decrease in CD4% in treatment failing subjects.

Viral rebound after switch to maraviroc/raltegravir dual therapy in highly experienced and virologically suppressed patients with HIV-1 infection

+ 800 mg of ribavirin daily + telaprevir (750 mg/ 8 h) she achieved undetectable HCV-RNA at weeks 4 and 12. Treatment was complicated by severe anaemia, requiring pegy-lated interferon and ribavirin dose reduction and blood transfusion. HCV-RNA remained ,15 IU/L, and she continued on pegylated interferon + ribavirin treatment. HIV-RNA remained undetectable at treatment weeks 4, 8 and 12. Darunavir and telaprevir PK data are shown in Table 1. There were decreases in all darunavir PK parameters when administered with telaprevir for both patients, except for unbound trough concentration in Patient 2. These decreases, ranging from 58% to 97%, were even higher than those previously described in healthy volunteers. 2,3 However, darunavir/ritonavir doses were different in both cases (800/100 mg once daily in our patients and 600/ 100 mg twice daily in healthy volunteers). 2 We also observed decreases in unbound darunavir concentrations in both patients (except for the aforementioned increase in unbound C trough in Patient 2), although the free fraction decreased less than total drug (ranging from 46% to 93%). There are scarce data on daru-navir PK in HIV/HCV-coinfected patients: in a Spanish cohort, dar-unavir once-daily concentrations (total and unbound) were higher than those observed in our two patients, even before telaprevir co-administration. 5 We could not evaluate the impact of darunavir on telaprevir concentrations, as antiretroviral therapy was maintained. However, telaprevir concentrations in our patients were much higher than previously reported in healthy volunteers or HCV-monoinfected patients. 2,3,6 These high telaprevir concentrations in our coinfected patients with advanced fibrosis could partially explain the marked reduction in darunavir levels, although an association between telaprevir exposure and extent of drug interaction with antiretrovirals has not been previously described. Despite the impact of telaprevir co-administration on daruna-vir concentrations (total darunavir C trough was below wild-type virus IC 50 in one patient), HIV-RNA remained undetectable during the 12 weeks of telaprevir therapy. Prolonged HIV suppression prior to starting anti-HCV therapy, preserved antiviral potency of the darunavir-based regimen and interferon anti-HIV effect 7 could have played a role in keeping HIV-RNA undetectable. Having only two patients, we must take into account all the potential confounding factors and the inter-and intra-individual variability , which hamper generalization of our results. However, our results are concordant between both patients. Besides, as PK parameters can be modified with hepatic impairment, it is very important to have data on interaction between telaprevir and darunavir/ ritonavir in …