Francesca Cossarini

Cross-resistance Profile of the Novel Integrase Inhibitor Dolutegravir (S/GSK1349572) Using Clonal Viral Variants Selected in Patients Failing Raltegravir

Novel integrase inhibitors are in advanced clinical development, and cross-resistance data are needed to consider the possibility to plan a sequential usage within this class of antiretroviral drugs. Ex vivo phenotypic assays were conducted on 11 wild-type and 27 fully replicating recombinant viruses obtained from 11 patients failing previous raltegravir-containing regimens. Dolutegravir maintained its activity in vitro on viruses with mutations in position 143 and 155. However, viruses with mutation Q148R associated with secondary mutations and the combination Q148H+G140S were instead associated with a reduced level of susceptibility to dolutegravir in vitro.

Residual viraemia does not influence 1 year virological rebound in HIV-infected patients with HIV RNA persistently below 50 copies/mL

OBJECTIVES It is currently debated whether patients with residual viraemia are at higher risk of virological failure than those attaining <1 HIV RNA copy/mL. We therefore investigated the effect of residual viraemia on virological rebound. METHODS We used a prospective, non-interventional, single-centre, study. This analysis was based on HIV-infected patients with two consecutive HIV RNA viral loads (VLs) of <50 copies/mL as tested by Versant bDNA, followed by two HIV RNA VLs of <50 copies/mL as tested using the Versant kinetic PCR molecular system (kPCR; limit of quantification = 1 copy/mL). Virological rebound was defined as two consecutive HIV RNA values of >50 copies/mL after baseline, and the time to virological rebound was calculated using the Kaplan-Meier method. RESULTS There were 739 eligible patients; 446 (60.4%) had HIV RNA <1 copy/mL (group A) and 293 (39.6%) had residual viraemia (1-49 HIV RNA copies/mL; group B). After a follow-up (median 48.9 weeks), virological rebound occurred in four patients in group A (0.9%) and six patients in group B (2%); the time to virological rebound was similar in the two groups (log-rank test P = 0.231). CD4+ cell recovery (slope) was significantly less in the patients with residual viraemia; +14.3 (-7.7, 43.9) cells/mm(3) per year versus +21.2 (-2.5, 53.2) cells/mm(3) per year; P = 0.036. CONCLUSIONS Residual viraemia assessed by kPCR was not associated with virological rebound during 1 year of follow-up. However, the patients attaining <1 HIV RNA copy/mL showed a small but statistically significant improvement in CD4+ cell recovery.

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.

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.

Mortality of HIV-infected patients with or without cancer: comparison with the general population in Italy.

BACKGROUND HAART has reduced mortality in HIV-infected patients; however, the risk of non-AIDS-related events has increased, including cancer. We compared mortality in HIV-infected patients with or without cancer with the general population in Italy. METHODS Eligible patients were recorded in the San Raffaele Infectious Diseases Department database. The ratio of observed deaths to expected all-cause deaths (standardized mortality ratio [SMR]) was standardized for age and gender, and stratified by cancer occurrence or year of HIV infection (≤1998 or >1998). Expected all-cause deaths were obtained from the Istituto Superiore di Sanità (Rome, Italy; 2002 data). RESULTS Among 6,495 HIV-infected patients, contributing 75,171 person-years, the SMR was 6.0 (95% CI 5.7, 6.4); SMRs decreased as age increased. Mortality rates were significantly higher than the general population for patients with or without cancer (SMR=15.1 [95% CI 13.6, 16.7] and 4.8 [95% CI 4.5, 5.1], respectively). For patients with or without cancer, SMRs were higher in those aged <45 years than older patients. SMRs for patients with cancer were almost stable in those infected with HIV ≤1998 (15.3; 95% CI 13.7, 17.0) or >1998 (13.5; 95% CI 9.2, 19.1). Among patients with cancer diagnosed with HIV >1998, age-adjusted SMRs ranged from 216.0 (95% CI 43.4, 631.3) to 6.8 (95% CI 4.7, 9.7) in patients <30 years or ≥70 years, respectively. CONCLUSIONS Mortality in HIV-infected patients remains higher than the general population in Italy, with marked differences according to age, and cancer contributing to an increased excess of mortality.

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.

Survival of HIV-1 infected multidrug-resistant patients recycling enfuvirtide after a previous failure.

Introduction:A substantial proportion of HIV-1 infected multidrug-resistant patients previously exposed to enfuvirtide (ENF) have recently recycled the drug as part of their optimized backbone therapy when starting a new antiretroviral regimen including investigational drugs, but no data are available concerning the impact of this strategy on clinical outcome. We evaluated long-term survival in multidrug-resistant patients recycling ENF after a previous failure. Methods:A retrospective analysis of clinical outcomes in 32 multidrug-resistant patients receiving fewer than 3 active drugs who reintroduced ENF with those who did not. Results:Patients characteristics were not different in the 2 groups at the start of ENF treatment. During follow-up, 6 of the 15 patients (40%) who did not recycle ENF died, as did 3 of the 17 (17.7%) who recycled ENF. Survival probability was higher among patients who recycled ENF (P = 0.0006), also when the analysis was subdivided by CD4 cells gain (P = 0.003) or viral load decrease (P = 0.0003) at the end of the first cycle or the use of investigational drugs during follow-up (P = 0.003). Conclusions:We found significantly longer survival in patients who reintroduced an ENF-containing regimen after a previous failure on the drug. We therefore suggest considering ENF recycling in patients starting a new regimen with fewer than 3 active drugs.

Raltegravir in treatment naïve patients

Raltegravir is the first integrase inhibitor approved for the treatment of HIV infection based on the superior efficacy it showed compared to optimized backbone therapy alone in patients harboring multidrug resistant viruses. Studies on naïve patients showed comparable efficacy of raltegravir and efavirenz and just recently the US Food and Drug Administration (FDA) approved raltegravir for the use in naïve patients based on the favorable results of the international double-blind phase III STARTMRK trial. Additional interesting findings were the faster, and not yet explained, decay of HIV-1 RNA and the higher CD4+ cells increase in the raltegravir group as compared to the efavirenz group.Raltegravir is generally well tolerated and adverse events were generally similar in raltegravir and comparator arms throughout all studies. When compared to efavirenz, patients on raltegravir showed less incidence of central nervous system-related adverse events. In studies on experienced patients higher incidence of cancers was found in the raltegravir arm: a relationship with the drug was, however not confirmed in a recent review considering all raltegravir studies. Raltegravir also showed a safe lipid profile expecially in naïve patients, finding that renders the drug attractive for patients with other cardiovascular risk factors.All this characteristics in association with its specific mechanism of action, make raltegravir an interesting drug for naïve patients and a large use in this type of patients is predictable. Only time and experience, however, will tell us whether raltegravir will maintain its promises in the long run.