Impact of transmitted drug resistance in naïve-patients starting 2 NRTI plus a boosted protease-inhibitor (PI) or integrase-inhibitor (INSTI).

Background The role of transmitted drug resistance (TDR) in predicting outcomes of initial antiretroviral therapy including PI or INSTI has not been fully explored. Methods From the ARCA database we selected adult naïve HIV-1 infected patients starting first-line 3-drugs therapy including INSTI or PI, from 1/2008 to 6/2016, with baseline resistance genotype and at least 1 HIV-1 RNA during follow up. TDR was defined as the detection of at least one mutation among those included in the WHO-recommended SDRM list (Bennett 2009). The primary endopoints were: virological failure (VF, defined as an HIV-RNA, VL, > 200 copies/ml after week 24) and treatment failure (TF, defined as VF or treatment change for any reason). Survival analysis was used to investigate predictors of TF and VF. Results 1147 pts were analyzed: 1031 (89.9%) treated with PI and 116 (10.1%) with INSTI. Baseline characteristics are shown in table. In the PI-group baseline VL was higher while CD4+ cells count was lower than in INSTI. Overall TDR were 4.7% for NRTI, 4.4% NNRTI, 1.5% PI without significant differences between groups. During a median observation time of 57 wks (IQR 26-107) TF occurred in 771 treatments in PI-group, with an estimated probability at 48 wks of 36% (CI 34.5-37.5) and in 46 in INSTI-group with an estimated probability at 48 wks of 31% (26.2-35.8); during a median observation time of 55 wks (26-107) VF occurred in 161 treatments in PI-group, with an estimated probability at 48 wks of 12% (10.8-13.1) and in 11 in INSTI-group with an estimated probability at 48 wks of 12% (8.5-15.5). After adjusting for gender, nationality, TDF/FTC use and viral subtype, independent predictor of VF was AZT/3TC use (vs other backbones HR 3.8, CI 95% 2.2-6.3, p<0.001); adjusting for nationality and viral subtype, independent predictors of TF were geographic area (Southern vs Northern Italy, HR 0.8, 0.6-0.9, p=0.04), baseline VL (+ 1 log10 HR 1.1, 1.0-1.2, p=0.03) and AZT/3TC (versus other backbones HR 2.1, 1.5-2.8, p=<0.001). Third drug class was not associated with VF or TF. In the INSTI-group, but not in the PI-group, the presence of any NRTI TDR was predictor of VF (HR 7.1, 1.8-28.2, p=0.005) after adjusting for nadir CD4 cells count and TF (HR 2.7, 1.1-7.0, p=0.03). Among patients in the INSTI-group with VF, 3 presented NRTI TDR (2 M41L and 1 M184V). In the PI-group, adjusting for gender, nationality, geographic area, viral subtype, TDF/FTC use, baseline and nadir CD4 cells count, independent predictor of VF was AZT/3TC use (HR 3.4, 1.8-6.2, p<0.001); adjusting for nationality and viral subtype, independent predictor of TF was AZT/3TC use (vs other backbones HR 2.3, 1.7-3.1, p<0.001). Conclusions PI and INSTI based first-line regimens show high efficacy in the real practice; despite the low incidence of TDR, our data support the need of pre-treatment genotyping to optimize therapy in patients starting INSTI-therapy. Further studies are required to confirm our suggestions

Decline of Prevalence of Resistance Associated Substitutions to NS3 and NS5A inhibitors at DAA-failure in Hepatitis C Virus in Italy over the years 2015 to 2018

Background: A minority of patients fail to eliminate HCV and resistance-associated substitutions (RASs) are commonly detected at failure of interferon-free DAA regimens. Material and methods: Within the Italian network VIRONET-C, the prevalence of NS3/NS5A/NS5B RASs was retrospectively evaluated in patients who failed an EASL recommended DAA-regimen in 2015-2018. NS3, NS5A and NS5B Sanger sequencing was performed using homemade protocols. The geno2pheno system was used to infer HCV-genotype/subtype and predict drug resistance. The changes in the prevalence of RASs over time were evaluated using the chi-square test for trend, predictors of RASs at failure were analysed by logistic regression. Results: We included 386 real-life HCV pts failed to recommended DAA regimens: 92% (271/294) Italians, 75% (286/384) males, median age was 56 years (IQR 52-61); 106 (28%) were treatment-experienced: 91 (86%) with IFN-based treatments, 26 (25%) with DAA-based regimens. Metavir fibrosis stage was F4 in 76% (245/322), 65% (240/369) had clinical cirrhosis. Patients with HIV and HBV coinfection were 10% (33/317) and 8% (6/72), respectively. HCV genotype (G) was G1b in 122 pts (32%), G3a 103 (27%), G1a 97 (25%), G4d 30 (8%), G2c 19 (5%), G3h 5 (1.3%), G4a 4 (1%) and 1 (0.3%) each for G3g, G4n/o/v. DAA regimens were: LDV/SOF in 115 (30%), DCV/SOF in 103 (27%), 3D in 83 (21%), EBR/GRZ in 32 (8%), VEL/SOF in 29 (7%), GLE/PIB in 18 (5%) and 2D in 6 (2%); ribavirin was administered in 123 (32%). Antiviral treatment was completed by 352 pts (91%), while 34 (9%) discontinued prematurely. The NS5A fasta-sequence was available for all pts, NS5B for 361 (94%), NS3 for 365 (95%). The prevalence of any RASs was 87%, namely 78/135 (58%) in NS3, 303/359 (85%) in NS5A, 114/286 (40%) in NS5B (Tab 1). The prevalence of any RASs significantly declined from 2015 to 2018 (100%, 13/13 vs 81%, 101/125, p=0.01): NS5A RASs from 100%, 13/13 to 76%, 76/100 (p&lt;0.001), NS3 RASs from 88%, 7/8 to 44%, 28/63 (p=0.02), while NS5B RASs remained stable. Independent predictors of any RASs included liver cirrhosis/advanced fibrosis (AOR 3.72, CI 95% 1.51-9.17, p=0.004) and genotype (G2 vs G1a AOR 0.01, CI 95% 0.0-0.3, p&lt;0.001; G3 vs G1a AOR 0.22, CI 95% 0.05-0.98, p&lt;0.047; G4 vs G1a AOR 0.13, CI 95% 0.03-0.63, p&lt;0.011), with a modest effect scored for past treatment (AOR 3.45, CI 95% 1.00-11.92, p=0.05), after adjusting for DAA regimen and year of genotype. Notably, full activity was predicted for GLE/PIB in 75.9% of cases and for at least two components of VEL/SOF/VOX in 59% of cases and no case with full-resistance to either regimen was found (Tab 2). Conclusions: Despite decreasing prevalence over the years, RASs remain a common signature at virological failure of DAA treatment, particularly in patients with the highest grade of liver fibrosis. Their distribution may vary according to genotype, so the identification of RASs after failure could play a crucial role in optimizing retreatment strategies

Long-Term Serological Response to 13-Valent Pneumococcal Conjugate Vaccine Versus 23-Valent Polysaccharide Vaccine in HIV-Infected Adults

Introduction: Long-term comparative immunologic response to 13-valent pneumococcal conjugate vaccine (PCV13) versus 23-valent polysaccharide vaccine (PPV23) among HIV-infected adults has not yet been investigated. Methods: In this prospective pilot study, we quantified in HIV-positive adults serotype-specific IgG concentrations of the 12 pneumococcal serotypes shared by both vaccines 5&nbsp;years after vaccination with two doses of PCV13 8 weeks apart (group 1) or one dose of PPV23 (group 2) and compared them with those assessed prior to vaccination (BL) and after 1&nbsp;year (T1). Comparison of immunogenicity was based on geometric mean concentration (GMC), proportion of individuals with ≥ twofold increase from BL in specific antibody concentration against ≥ 2 serotypes and percentage of individuals with serotype-specific IgG ≥ 0.35&nbsp;μg/ml, ≥ 1&nbsp;μg/ml and ≥ individual serotype-specific correlates of protection. Results: We included 91 subjects (median CD4+ 650 cells/µl, &gt; 90% with HIV-RNA &lt; 50 copies/ml); patients in groups 1 (n = 42) and 2 (n = 49) were homogeneous for the main characteristics. GMCs were significantly higher in the PCV13 group than in the PPV23 group for serotype 19F (p = 0.003). Both vaccines revealed higher significant GMCs to most serotypes compared with BL, i.e., eight in group 1 vs. seven in group 2. With respect to T1, GMCs decreased significantly in the PCV13 group for eight vs. ten serotypes in the PPV23 group. More participants in the PCV13 group had ≥ 2 increase from BL in antibody levels to ≥ 2 serotypes compared with the PPV23 group (78.6% vs. 59.2%, p = 0.042). Overall, the percentage of subjects with serotype-specific IgG ≥ 0.35&nbsp;μg/ml, ≥ 1&nbsp;μg/ml and ≥ individual serotype-specific correlates of protection was similar between groups. Conclusion: In this study with HIV-positive adults with a favorable viro-immunologic profile, both vaccines were shown to achieve a long-term durable serologic response. We found minor differences in immunogenicity between the two vaccines, which favored PCV13 over PPV23 5 years after immunization. Trial Registration: ClinicalTrials.gov identifier, NCT02123433