Evaluation of virological response and resistance profile in HIV-1 infected patients starting a first-line integrase inhibitor-based regimen in clinical settings

Background: Virological response and resistance profile were evaluated in drug-naïve patients starting their first-line integrase inhibitors (INIs)-based regimen in a clinical setting. Study design: Virological success (VS) and virological rebound (VR) after therapy start were assessed by survival analyses. Drug-resistance was evaluated at baseline and at virological failure. Results: Among 798 patients analysed, 38.6 %, 27.1 % and 34.3 % received raltegravir, elvitegravir and dolutegravir, respectively. Baseline resistance to NRTIs, NNRTIs, PIs and INIs was: 3.9 %, 13.9 %, 1.6 % and 0.5 %, respectively. Overall, by 12 months of treatment, the probability of VS was 95 %, while the probability of VR by 36 months after VS was 13.1 %. No significant differences in the virological response were found according to the INI used. The higher pre-therapy viremia strata was (<100,000 vs. 100,000-500,000 vs. > 500,000 copies/mL), lower was the probability of VS (96.0 % vs. 95.2 % vs. 91.1 %, respectively, P < 0.001), and higher the probability of VR (10.2 % vs. 15.8 % vs. 16.6 %, respectively, P = 0.010). CD4 cell count <200 cell/mm3 was associated with the lowest probability of VS (91.5 %, P < 0.001) and the highest probability of VR (20.7 %, P = 0.008) compared to higher CD4 levels. Multivariable Cox-regression confirmed the negative role of high pre-therapy viremia and low CD4 cell count on VS, but not on VR. Forty-three (5.3 %) patients experienced VF (raltegravir: 30; elvitegravir: 9; dolutegravir: 4). Patients failing dolutegravir did not harbor any resistance mutation either in integrase or reverse transcriptase. Conclusions: Our findings confirm that patients receiving an INI-based first-line regimen achieve and maintain very high rates of VS in clinical practice

Oloprosencefalia: problemi medici ed etici in 5 casi

in Contributi di specialisti e allievi di Neuropsichiatria Infantile dell'Ateneo Patavino all'esordio del 2000. Istituto Cortivo Editore, Padova, maggio 2000, 89 - 93

Impact of circulating resistance-associated mutations on HIV pre-exposure prophylaxis (PrEP) efficacy: Modeling from antiretroviral resistance cohort analysis (ARCA) national database

Background PrEP with FTC/TDF has shown great efficacy in preventing new HIV infections but issues remain (low adherence, high costs, toxicity and resistance development). No data are available about the impact of circulating Resistance-Associated Mutations (RAMs) on its efficacy. Objectives describe the prevalence of FTC and/or TDF-related RAMs in Italian HIV-infected population and their potential impact on PrEP efficacy. Study design ARCA is a national database that collects data about RAMs and epidemiological correlates from sites throughout Italy; it was queried about the prevalence of these RAMs in the last decade. PrEP efficacy was adjusted for a dynamic score based on RAMs prevalence. Absolute and relative risk increases (ARI and RRI) and number needed to harm (NNH) were calculated after this score. Results the query retrieved 3579 HAART-naïve and 5781 experienced subjects. Resistance to TDF is low and more common among naïve MSM in the area of Milan (where it topped to 14.3%), without other significant differences. If good adherence is not attained, RRI for receptive anal sex increases by 16% (in naïve) and 93.4% (in experienced MSM). NNH is largely above 10000 except for having receptive anal sex with a HAART-experienced MSM on a failing treatment (970). Conclusions according to this model, PrEP may be introduced in Italy without general concerns, but efficacy may be partly reduced in young MSM having sex in Rome and Milan

Potential role of raltegravir-based therapy to induce rapid viral decay in highly viraemic HIV-infected neonates

We report safety and tolerability of raltegravir (RAL) as a forth HIV agent in two highly viraemic newborns. Raltegravir (6 mg/kg) was given orally twice daily. The other antiretrovirals were assumed according to standard dose for newborns. The first baby was born at week 36. An antiretroviral therapy consisting of zidovudine, lamivudine, and lopinavir/ritonavir was started 96 hour after delivery. Raltegravir was added at hour 120, being plasma HIV-1 RNA above 10\uc3\u97106 copies/ml. HIV RNA declined to 5\uc2\ub7000 copies/ml at day 30. The second baby was born at week 40. He was started on zidovudine, lamivudine, and nevirapine at day 0, while RAL was added at day 3. Plasma HIV-1 RNA declined from 6\uc2\ub76\uc3\u97106 at birth to 52 copies/ml at day 28. RAL tolerability was good in both patients, one with gamma-glutamyltransferase increase, which normalized after RAL discontinuation. Raltegravir-based four drug regimen may be effective and well tolerated in highly viraemic HIV neonates up to 4 weeks

Impact of pre-existent drug resistance on virological efficacy of single-tablet regimens in people living with HIV

Despite the wide use of single-tablet regimens (STRs), few real-life data are available regarding the impact of pre-existent drug resistance on virological failure (VF). We aimed to fill this gap by analysing a large cohort of individuals selected from the ARCA database. The impact on VF of pre-existent resistance-associated mutations (RAMs) and cumulative genotypic susceptibility score (cGSS) before STR start was evaluated through survival analysis. Potential emergence of resistance at VF was also evaluated. Overall, 3916 individuals were included, comprising 678 treatment-naïve (G1), 2309 treatment-experienced aviraemic (G2) and 929 viraemic (G3), of whom 65.2% were treated with a STR based on efavirenz (35.2%) or rilpivirine (30.0%). At 2 years after starting a STR, the overall probability of VF was 5.9% in G1, 8.7% in G2 and 20.8% in G3. No impact of pre-existent resistance on VF was found in G1. The probability of VF was higher in patients with cGSS < 3 (reduced susceptibility to at least one drug) than in those with cGSS = 3 (full susceptibility to STR drugs) both in G2 and G3. A higher probability of VF was also found in the presence of pre-existent M184V (alone or in combination with pre-existent thymidine analogue mutations). Among patients who failed STR, a significant emergence of RAMs was found only in those exposed to EFV/FTC/TDF in G3 (specifically K103N and M184V). Our results confirm a high efficacy of STRs in clinical settings. Pre-existent resistance appears to influence virological efficacy of STRs in treatment-experienced individuals (both aviraemic and viraemic). © 2022 Elsevier Ltd and International Society of Antimicrobial Chemotherap

Treatment with the Fusion Inhibitor Enfuvirtide Influences the Appearance of Mutations in the Human Immunodeficiency Virus Type 1 Regulatory Protein Rev▿

The gp41-encoding sequence of the env gene contains in two separate regions the Rev-responsive elements (RRE) and the alternative open reading frame of the second exon of the regulatory protein Rev. The binding of Rev to the RRE allows the transport of unspliced/singly spliced viral mRNAs out of the nucleus, an essential step in the life cycle of human immunodeficiency virus type 1 (HIV-1). In this study, we have investigated whether the fusion-inhibitor enfuvirtide (ENF) can induce mutations in Rev and if these mutations correlate with the classical ENF resistance gp41 mutations and with viremia and CD4 cell count. Specific Rev mutations were positively associated with ENF treatment and significantly correlated with classical ENF resistance gp41 mutations. In particular, a cluster was observed for the Rev mutations E57A (E57Arev) and N86Srev with the ENF resistance gp41 mutations Q40H (Q40Hgp41) and L45Mgp41. In addition, the presence at week 48 of the E57Arev correlates with a significant viremia increase from baseline to week 48 and with a CD4 cell count loss from baseline to week 48. By modeling the RRE structure, we found that the Q40gp41 and L45gp41 codons form complementary base pairs in a region of the RRE involved in Rev binding. The conformation of this Rev-binding site is disrupted when Q40Hgp41 and L45Mgp41 occur alone while it is restored when both mutations are present. In conclusion, our study shows that ENF pressure may also affect both Rev and RRE structures and can provide an excellent example of compensatory evolution. This highlights the multiple roles of ENF (and perhaps other entry inhibitors) in modulating the correct interplay between the different HIV-1 genes and proteins during the HIV-1 life cycle