Impact of etravirine on hospitalization rate between 2005 and 2011 among heavily treated HIV-1-infected individuals on failing regimens.

BACKGROUND: Etravirine (ETR), a non-nucleoside reverse transcriptase inhibitor (NNRTI) available in France since 2006, is indicated for antiretroviral-experienced HIV-infected adults, in combination with a ritonavir-boosted protease inhibitor (PI). To assess its clinical impact in routine care, we compared hospitalization rates according to ETR + PI prescription or not, among heavily treated HIV-1 infected individuals on failing regimens between 2005 and 2011. METHODS: From the French Hospital Database on HIV (ANRS CO4), we selected heavily treated individuals (prior exposure to at least 2 nucleoside reverse transcriptase inhibitor (NRTI), 2PI and 1 NNRTI) with viral load (VL) > 50 copies/mL who started a new antiretroviral (ARV) regimen between 2005 and 2011. Using an intention-to-continue-treatment approach, hospitalization rates were calculated for the individuals who received ETR + PI, during the months after initiating ETR + PI (ETR + PI) or for the individuals who received ETR + PI, in the months before ETR + PI initiation and for the individuals who never received ETR + PI (no ETR + PI). hospitalization from an AIDS-defining cause and hospitalization from a non-AIDS defining cause rates were also calculated. Poisson regression models were used to compare the incidences between the two groups, with adjustment for potential confounders. RESULTS: Of 3884 patients who met the inclusion criteria, 838 (21.6%) received ETR + PI. During 13,986 person-years (P-Y) of follow-up, there were 2484 hospitalizations in 956 individuals. The hospitalization rates per 1000 P-Y were 169.0 among individuals exposed to ETR + PI and 179.3 among those not exposed to ETR + PI. After adjustment, the respective hospitalization rates were 148.8 and 186.7 per 1000 P-Y, with an estimated relative risk of 0.80 (95%CI: 0.71-0.90), AIDS hospitalization rates were 11.5 and 22.7 per 1000 P-Y, with an estimated relative risk of 0.51(95%CI: 0.39-0.66) and non-AIDS hospitalization rates were 139.5 and 152.2 per 1000 P-Y, with an estimated relative risk of 0.92 (95%CI: 0.80-1.05). CONCLUSIONS: Between 2005 and 2011, access to ETR + PI was associated with a 20% reduction in the hospitalization rate among heavily treated HIV-1-infected individuals. This reduction was mainly due to a reduction in the AIDS hospitalization rate.

Susceptibility to antiretroviral drugs of CRF01_AE, CRF02_AG, and subtype C viruses from untreated patients of Africa and Asia: comparative genotypic and phenotypic data.

Non-B HIV-1 viruses are predominant in developing countries where access to antiretroviral drugs (ARVs) is progressively being intensified. It is important to obtain more data on the susceptibility of these viruses to available ARVs. CRF01_AE, CRF02_AG, and subtype C strains of HIV-1 obtained from untreated patients from Vietnam, Cote d'Ivoire, and India were analyzed for their in vitro susceptibility to NRTIs, NNRTIs, PIs, and an entry inhibitor (T-20) using a recombinant viral assay (PHENOSCRIPT). The corresponding viruses, which had been previously sequenced in reverse transcriptase (RT), protease (prot), plus envelope (env) C2/V3 genes and had therefore been fully characterized, were further sequenced in env HR1 + HR2 regions. CRF01_AE isolates are sensitive to NRTIs and NNRTIs with the exception of one isolate that exhibits a decreased susceptibility to NNRTIs associated with a I135T substitution in RT. CRF02_AG and subtype C viruses are sensitive to NRTIs and NNRTIs but some CRF02_AG isolates tend to be resistant to abacavir, potentially related to associated substitutions of RT at positions 123 (D123N) plus 135 (I135V). Whereas all but one CRF01_AE isolates are fully susceptible to PIs, some CRF02_AG and, more frequently, some subtype C isolates are resistant to atazanavir. The role of substitutions in prot at positions of secondary resistance mutations 20, 36, 63, and 82 is raised with a potentially crucial role of the V82I substitution. Finally, all viruses tested, regardless of the CRF or subtype, are fully susceptible to T-20.

Long-term efficacy and safety of etravirine-containing regimens in a real-life cohort of treatment-experienced HIV-1-infected patients.

OBJECTIVES: Etravirine (ETR) was approved in France in September 2008 and is used in combination with a boosted protease inhibitor (bPI) and other anti-retrovirals (ART) in HIV-infected pre-treated patients. This study aimed to report in a real-life setting the efficacy and tolerability of ETR-based regimens and factors associated with virological response. METHODS: The study population included all treatment-experienced patients who initiated an ETR-based regimen between September 2008 and July 2013 from the French Dat'AIDS cohort. Analyses were performed in ART-experienced patients starting ETR after virological failure (VF) or as a maintenance therapy (MT), with or without bPI. RESULTS: A total of 2006 patients (VF, n = 1014 (51%); MT, n = 992 (49%)) were included. At M12, the proportion of patients with HIV RNA < 50 copies/ml was 71.7% (72.0% and 71.1% with or without bPI) in the VF group and 90.5% (85.0% and 92.3% with or without bPI) in the MT group, without significant differences regarding the use of bPI. ETR was discontinued in 8.8% of patients for adverse events in 23.9% of cases (21.5% in VF, 29.5% in MT), treatment failure in 15.2% (16.2% in VF, 7.4% in MT) or simplification in 5.4% (4.6% in VF, 7.4% in MT). In the VF group, factors associated with virological response were a longer duration of HIV infection (OR = 2.7; p < 0.001) and baseline HIV RNA < 5 log10 copies/mL (OR = 2.1; p = 0.002). CONCLUSION: This study shows that in ART-experienced patients ETR is well tolerated with a high efficacy when combined with other active drugs, even when the regimen does not include a bPI.

Comparison of metabolic abnormalities and clinical lipodystrophy 48 weeks after switching from HAART to Trizivir versus continued HAART: the Trizal study.

PURPOSE: To analyze the evolution of clinical lipodystrophy (LD) and metabolic abnormalities in patients continuing to receive HAART versus patients switched to Trizivir (zidovudine, lamivudine, abacavir) after 48 weeks. METHOD: Patients treated with HAART >6 months with plasma HIV-1 RNA viral load (VL) <400 copies/mL and <50 copies/mL at screening were randomly assigned to continue HAART (103 patients) or to receive Trizivir (106 patients). Clinical LD was evaluated using a standardized patient questionnaire only at baseline, weeks 4 and 8, and then every 8 weeks until Week 48. Laboratory evaluation was performed every 4 weeks. RESULTS: The proportion of patients exhibiting >or=1 LD symptom at baseline was 40% in the Trizivir arm and 50% in HAART arm (difference not significant). After 48 weeks, the prevalence was 28% and 42% respectively (p =.03), and the median number of LD symptoms per patient was 2 in the Trizivir arm and 4 in the continued HAART arm (p =.016). Median decreases in cholesterol levels over the 48-week study period were greater in the Trizivir arm than in the continued HAART arm (-0.80 vs. -0.44 mmol/L; p lt.001). Median triglyceride levels decreased in the Trizivir arm but increased in the continued HAART arm (-0.17 and +0.01 mmol/L; p =.006). Suppression of VL was maintained in most patients with no differences between the two arms. CONCLUSION: A switch from "standard" HAART to Trizivir was associated with an improvement in clinical LD and blood lipid abnormalities after 48 weeks.

Impact of etravirine use on hospitalization rates among highly pre-treated failing HIV-1 infected individuals between 2005 and 2011.

INTRODUCTION: Etravirine (ETR), a non-nucleoside reverse transcriptase inhibitor available in France since 2006, is indicated for the treatment of HIV-1 infection in combination with a ritonavir boosted protease inhibitor (PI) in antiretroviral treatment-experienced adult patients. To assess its impact in routine clinical care, our objective was to compare hospitalization rates in highly pre-treated failing HIV-1 infected individuals between 2005 and 2011 depending on whether or not they received ETR+PI. METHODS: From the French Hospital Database on HIV (ANRS CO4), we selected highly pre-treated individuals (prior exposure to at least 2NRTI, 2PI and 1 NNRTI) with a viral load (VL)>50 copies/mL initiating a new regimen between 2005 and 2011. Hospitalization rates were calculated for each calendar month and depending on whether patients never received ETR+PI at any time or during months before initiating ETR+PI (no ETR+PI) or during months after initiating ETR+PI (ETR+PI), using an intention to continue treatment approach. Poisson regression models were used to compare incidence between the two groups, after adjustment for potential confounders (age, transmission group, origin, AIDS, PCP prophylaxis, viral load, CD4, nb of previous ARV). RESULTS: Overall 3884 patients fulfilled inclusion criteria. Among them 838 (21.6%) received ETR+PI at least once. Among all enrolled patients, 35.8% had CD4 <200/mm(3), 17.5% had VL >100,000 copies/ml, 42.8% had had an AIDS event and 47.8% had received more than 10 different antiretroviral drugs. There were 2484 hospitalizations in 808 individuals over 13,986 patient-years. The hospitalization rates for 1000 P-Y were 169.0 for the ETR+PI group and 179.3 for the no ETR+PI group. After adjustment, the corresponding figures were 144.8 for 1000 P-Y and 192.7 for 1000 P-Y respectively, with a relative risk estimated as 0.75 (95% CI 0.67-0.84). CONCLUSIONS: Access to ETR+PI between 2005 and 2011 was associated with a 25% reduction in the hospitalization rate among highly pre-treated failing HIV-1 infected individuals.

Efficacy and tolerability of Etravirine in HIV-1 adult patients: Results of a large French prospective cohort.

BACKGROUND: IEtravirine (ETR) was approved in France in Sept 2008, to be used in combination with a ritonavir-boosted protease inhibitor (bPI) and others antiretrovirals (ARV) in HIV-infected pre-treated patients. OBJECTIVES: To describe in a real life setting efficacy and tolerability of ETR-including regimen and factors associated with virologic response. METHOD: In the French DatAIDS cohort including 18,647 patients, we selected patients who initiated an ETR-including regimen between September 2008 and July 2013. Demographic data and clinico-biological data were collected from the standardized electronic medical record Nadis(®). Analyses were done in patients starting ETR and sub-analyses were performed in pre-treated patients starting ETR for virologic failure (VF) or maintenance (MT) therapy, with or without bPI. RESULTS: 2083 patients (ARV-naïve n=77, VF n=1014, MT n=992) were included: median age 47 years, 73.3% male, median duration of HIV infection 15.7 years, CDC stage C 38.7%, HBV/HCV co-infection 25.7%. In pre-treated patients, 75.5% previously received NNRTIs (median duration on EFV and NVP of 480 and 396 days, respectively), 94.3% bPIs, 30.8% raltegravir (RAL) and 19.4% enfuvirtide. The most frequent ARVs associated with ETR were two NRTIs in 37.2% of the cases (21.9% in VF, 52.9% in MT), 1 bPI+RAL in 10.1% (13.5% in VF, 6.6% in MT), RAL in 6.2% (2% in VF, 10.5% in MT). Median duration on ETR was 3.7 and 2.2 years in the VF and MT group, respectively. In the VF group, HIV RNA was <50 c/ml in 71.7% (71.1% without bPI, 72% with bPI) of the patients at M12, 72.8% (71% without bPI, 73.3% with bPI) of the patients at M24. In the MT group, HIV RNA was<50 c/ml in 90.5% of the patients at M12 and 93.1% at M24. ETR was discontinued in 8.8% of the patients (12.8% in VF, 5.4% in MT) for adverse events in 23.9% of cases (21.5% in VF, 29.5% in MT), treatment failure in 15.2% (16.2% in VF, 7.4% in MT) or simplification in 5.4% (4.6% in VF, 7.4% in MT). In the VF group, factors associated with virologic failure in multivariate analysis were a longer duration of HIV infection (OR 2.6; 95% CI 1.7-4.0) and baseline HIV RNA >5 log10 c/ml (OR: 2.0; 95% CI 1.3-3.2) but not the association with a bPI. CONCLUSION: This large study shows that in ARV-pre-treated patients ETR is well tolerated with a high efficacy when combined with other active drugs, even when the regimen does not include a bPI.

Simian immunodeficiency virus resistance of macaques infused with interferon beta-engineered lymphocytes.

To test the in vivo anti-simian immunodeficiency virus (SIV) efficacy of interferon (IFN)-beta-engineered lymphocytes, peripheral blood lymphocytes harvested from two uninfected macaques were transduced with a retroviral vector carrying a constitutively expressed IFN-beta gene and reinfused, resulting in approximately 1 IFN-beta-transduced cell out of 1000 circulating cells. The gene-modified cells were well tolerated and could be detected for at least 74 days without causing any apparent side effects. These two animals together with three untreated control macaques were then infected with SIVmac251. The two IFN-beta-infused macaques are in good health, 478 days after infection, with a reduced plasma virus load and sustained numbers of CD4(+) and CD8(+) cells. Throughout the study, the proportion of IFN-beta-transduced cells has been maintained. Of the three control macaques, two were characterized by a high plasma virus load and a decrease in CD4(+) cells. One was moribund and was sacrificed 350 days after infection and the other now has fewer than 100 circulating CD4(+) cells/ml. Unexpectedly, the third control macaque, which, like the two IFN-beta-infused animals, had a low plasma virus load and a maintenance of CD4(+) and CD8(+) cell number, was characterized by a permanent level of serum IFN-beta, of unknown origin, already present before SIV infection. Although no definite conclusion can be made in view of the limited number of animals, these data indicate that further exploration is warranted of an IFN-beta-based anti-human immunodeficiency virus gene therapy.

Expression of chemokines and their receptors in human and simian astrocytes: evidence for a central role of TNF alpha and IFN gamma in CXCR4 and CCR5 modulation.

Chemokines are key mediators of the selective migration of leukocytes that occurs in neurodegenerative diseases and related inflammatory processes. Astrocytes, the most abundant cell type in the CNS, have an active role in brain inflammation. To ascertain the role of astrocytes during neuropathological processes, we have investigated in two models of primary cells (human fetal and simian adult astrocytes) the repertoire of chemokines and their receptors expressed in response to inflammatory stimuli. We demonstrated that, in the absence of any stimulation, human fetal and simian adult astrocytes express mRNA for receptors APJ, BOB/GPR15, Bonzo/CXCR6, CCR2, CCR3, CCR5, CCR8, ChemR23, CXCR3/GPR9, CXCR4, GPR1, and V28/CX3CR1. Moreover, TNFalpha and IL-1beta significantly increase BOB/GPR15, CCR2, and V28/CX3CR1 mRNA levels in both models. Furthermore, TNFalpha and IFNgamma act synergistically to induce expression of the major coreceptors for HIV infection, CXCR4 and CCR5, at both the mRNA and protein levels in human and simian astrocytes, whereas CCR3 expression was not affected by cytokine treatment. Finally, TNFalpha/IFNgamma was the most significant cytokine combination in leading to a pronounced upregulation in a comparable, time-dependent manner of the production of chemokines IP-10/CXCL10, RANTES/CCL5, MIG/CXCL9, MCP-1/CCL2, and IL-8/CXCL8. In summary, these data suggest that astrocytes serve as an important source of chemokines under the dependence of a complex cytokine regulation, and TNFalpha and IFNgamma are important modulators of chemokines and chemokine receptor expression in human as well as simian astrocytes. Finally, with the conditions we used, there was no difference between species or age of tissue.