Efficacy and safety of a switch to rilpivirine-based regimens in treatment-experienced HIV-1-infected patients: a cohort study.

BACKGROUND: Rilpivirine (RPV) is a second-generation once-daily non-nucleoside reverse transcriptase inhibitor (NNRTI) which has shown non-inferior antiviral activity to efavirenz in treatment-naive patients. Data in treatment-experienced patients are more limited. We wished to assess the efficacy and safety of a switch to RPV-based regimens in well-suppressed treatment-experienced patients. METHODS: Between September 2012 and June 2013, all antiretroviral therapy (ART)-experienced HIV-1-infected patients with a plasma HIV RNA level <50 copies/ml, and switching to an RPV-based regimen, were analysed in this retrospective observational monocentric cohort study. The primary end point was the proportion of patients with virological success defined as a plasma HIV RNA level <50 copies/ml at 12 months using the FDA snapshot algorithm. RESULTS: A total of 281 participants were studied and 97% received a combination of RPV/tenofovir disoproxil fumarate/emtricitabine. At month 12, the rate of virological success was 59% and increased to 72% using available data beyond month 12. Sixteen (6%) patients experienced virological failure, which was associated with the presence of the M184V/I resistance mutation in prior genotypes (P=0.02) and the use of a non-NNRTI as third agent before the switch (P=0.03). RPV-based regimens were overall well tolerated and only 23 (8%) patients discontinued ART because of adverse events, mostly neuropsychiatric adverse events. Switching to RPV was associated with significant but modest improvement of the lipid profile. CONCLUSIONS: In patients fully suppressed on ART, a switch to an RPV-based regimen should only be considered in the absence of prior virological failure or resistance mutations to nucleoside reverse transcriptase inhibitors and NNRTIs to avoid virological failures.

Molecular characterization of the 17D-204 yellow fever vaccine.

INTRODUCTION: The worldwide use of yellow fever (YF) live attenuated vaccines came recently under close scrutiny as rare but serious adverse events have been reported. The population identified at major risk for these safety issues were extreme ages and immunocompromised subjects. Study NCT01426243 conducted by the French National Agency for AIDS research is an ongoing interventional study to evaluate the safety of the vaccine and the specific immune responses in HIV-infected patients following 17D-204 vaccination. As a preliminary study, we characterized the molecular diversity from E gene of the single 17D-204 vaccine batch used in this clinical study. MATERIALS AND METHODS: Eight vials of lyophilized 17D-204 vaccine (Stamaril, Sanofi-Pasteur, Lyon, France) of the E5499 batch were reconstituted for viral quantification, cloning and sequencing of C/prM/E region. RESULTS: The average rate of virions per vial was 8.68 ± 0.07 log10 genome equivalents with a low coefficient of variation (0.81%). 246 sequences of the C/prM/E region (29-33 per vials) were generated and analyzed for the eight vials, 25 (10%) being defective and excluded from analyses. 95% of sequences had at least one nucleotide mutation. The mutations were observed on 662 variant sites distributed through all over the 1995 nucleotides sequence and were mainly non-synonymous (66%). Genome variability between vaccine vials was highly homogeneous with a nucleotide distance ranging from 0.29% to 0.41%. Average p-distances observed for each vial were also homogeneous, ranging from 0.15% to 0.31%. CONCLUSION: This study showed a homogenous YF virus RNA quantity in vaccine vials within a single lot and a low clonal diversity inter and intra vaccine vials. These results are consistent with a recent study showing that the main mechanism of attenuation resulted in the loss of diversity in the YF virus quasi-species.

Efficacy and safety of rilpivirine-based regimens in treatment-experienced HIV-1 infected patients: a prospective cohort study.

INTRODUCTION: Rilpivirine (RPV) is a new once-daily, non-nucleoside, reverse transcriptase inhibitor (NNRTI). In treatment-naïve patients, RPV has shown non-inferior antiviral activity to efavirenz but data in treatment-experienced patients are more limited. We assessed the efficacy and safety of RPV in treatment-experienced patients switching to a RPV-based regimen. METHODS: Between September 2012 and June 2013, all antiretroviral therapy (ART) experienced HIV-1 infected patients with a plasma HIV-RNA level <50 cp/mL, and switching to a RPV-based regimen, were enrolled in this prospective monocentric cohort study. Clinical and laboratory data were collected every 3 months to assess safety and efficacy. The primary endpoint was the proportion of patients with virologic success (HIV-RNA load <50 cp/mL) at 12 months using the FDA snapshot algorithm. RESULTS: A total of 281 patients (76% male, median age: 47 years, 56% MSM) were enrolled in this study. Median lymphocyte CD4 count at baseline was 640/mm(3). Patients have received ART for a median of 7 years and viral replication was fully suppressed for a median of 3 years. Before the switch, 39% patients were treated with NNRTI, 52% with protease inhibitor and 7% with integrase inhibitor-based regimens. Reasons for switch were simplification (176 cases), adverse events (AEs) (93 cases) and others (12 cases). At month 12 (database frozen on June 2014) in the snapshot analysis, 56% of patients met virologic success, 5% experienced virologic failure (n=14) and 39% had no data in the window period. In the LOCF analysis (using data from the previous available visit before month 12), 89% patients were suppressed, 5% had virologic failure and 6% had no data. Genotypic resistance analysis was performed in 7/14 patients at the time of virologic failure (3 of whom had previous NRTI/NNRTI resistance-associated mutations (RAMs)), and new NNRTI and NRTI RAMs emerged in 4 patients. RPV-based regimen was generally well tolerated and only 6% of patients discontinued treatment for AEs. Grade 2-4 treatment-related AEs occurred in 39 patients: 6 had rashes, 13 neuropsychiatric symptoms, 10 GI symptoms, 10 biological abnormalities. At month 12, significant changes from baseline were seen for total and LDL cholesterol (-0.5 and -0.28 mmol/L, respectively, p<0.05 for both), and plasma creatinine (+5.8 µmol/L, p<10-4). CONCLUSIONS: In patients fully suppressed on ART, switching to a RPV-based regimen in clinical practice was well tolerated and associated with few virologic failures.

Risk of Kaposi sarcoma during the first months on combination antiretroviral therapy.

OBJECTIVE: To determine whether incident AIDS-defining Kaposi sarcoma or Pneumocystis jiroveci pneumonia (PJP) is associated with combination antiretroviral therapy (cART) initiation. DESIGN: Compare risk for Kaposi sarcoma and PJP by time on cART and CD4 reconstitution. METHODS: : In the FHDH-ANRS CO4 cohort (N = 66 369), Kaposi sarcoma (N = 1811) and PJP (N = 1718) incidence rates were computed by demographic and HIV strata. Crude and adjusted relative risk (RR) with 95% confidence intervals (CIs) following cART initiation were calculated by Poisson regression with untreated patients during 1996-2009 as reference. CD4 cell counts were compared by Wilcoxon rank sum tests. RESULTS: The risk of Kaposi sarcoma was very high during months 1-3 on cART (N = 160, RRCrude 3.94, 95% CI 3.26-4.76), which was incompletely attenuated by adjustment for demographics and contemporaneous CD4 cell count (RRAdj 1.25, 95% CI 1.02-1.53). Corresponding PJP risk was minimally elevated (N = 84, RRCrude 1.80, 95% CI 1.42-2.30) and markedly reduced with adjustment on the same variables and PJP prophylaxis (RRAdj 0.52, CI 0.41-0.67). HIV load had no added effect. Median CD4 cell count at cART initiation was much lower in patients with incident Kaposi sarcoma (82 cells/µl) or PJP (61 cells/µl) within 3 months than in those who did not develop these conditions (>250 cells/µl). Notably, median CD4 cell count change was +44 cells/µl per month with incident Kaposi sarcoma within 3 months of cART initiation versus 0 cells/µl per month with incident PJP (P = 0.0003). CONCLUSION: Failure of CD4 cell count reconstitution during months 1-3 on cART fully accounted for incident PJP. In contrast, there were 1.6 additional Kaposi sarcoma cases per 1000 person-years during months 1-3 on cART, suggesting that immune reconstitution may contribute to the risk for AIDS-defining Kaposi sarcoma.