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Cerebrospinal fluid viral replication and burden of resistance in three HIV-1-infected people taking Ibalizumab with multiple drug class-wide resistance

2020; Lippincott Williams & Wilkins; Volume: 34; Issue: 14 Linguagem: Inglês

10.1097/qad.0000000000002687

1473-5571

Camilla Muccini, Vincenzo Spagnuolo, Diana Canetti, Alba Bigoloni, Massimo Cernuschi, Michela Franzin, Michela Sampaolo, Antonella Castagna,

HIV/AIDS drug development and treatment

Ibalizumab (IBA) is the first mAb approved by the Food and Drug Administration for the treatment of HIV-1 infection; it hampers HIV entry into cells by interfering CD4+ receptor binding [1–3]. IBA has demonstrated to be effective in the setting of multidrug resistant HIV-1 infection in combination with an optimized background therapy [4]. No data are available on viral replication in cerebrospinal fluid (CSF) during a regimen including IBA. Here, we evaluated viral load and resistance profile in CSF in three people living with HIV (PLWH) with multidrug resistance who were being treated with IBA, aiming to better investigate the role of IBA both in plasma and CSF. Three male adults with no fully active drugs from all the antiretroviral classes received an intravenous IBA loading dose of 2000 mg succeeded by 800 mg doses every 2 weeks, starting from March 2019. All the participants underwent computed tomography scan and lumbar puncture and paired CSF and blood samples were collected at a single time point. HIV-1 RNA was quantified by PCR (Cobas HIV-1 Test on 6800 Systems; Roche Diagnostics, Risch-Rotkreuz, Switzerland) and coreceptor tropism was inferred with the geno2pheno algorithm. Genotypic resistance tests were performed on HIV-1 RNA as previously described [5] and results were interpreted according to the Stanford HIVdb Program. Case 1 is a 23-year-old male with a vertical transmission of HIV-1 infection, who started antiretroviral therapy (ART) in 1997. Before initiating IBA, HIV-1 RNA was 21 966 copies/ml and CD4+ 278 cells/μl (13.6%); from week 2, HIV-1 RNA remained steadily below 200 copies/ml [6]. Lumbar puncture was performed at week 46: CSF analysis showed glucose 53 mg/dl (plasma glucose 72 mg/dl), protein 35 mg/dl and three white blood cells (WBC)/μl. CSF viral load was undetectable and plasma viral load was 59 copies/ml; therefore, samples were not amplifiable for genotypic testing. CD4+ were stable, counting for 432 cells/μl (14.4%). Cumulative ART exposure, ART regimen before starting IBA and optimized background therapy in association with IBA are reported in Table 1 .Table 1: Resistance mutations in plasma RNA and peripheral blood mononuclear cell DNA before starting Ibalizumab and current resistance mutations in plasma/cerebrospinal fluid RNA.Table 1 (Continued): Resistance mutations in plasma RNA and peripheral blood mononuclear cell DNA before starting Ibalizumab and current resistance mutations in plasma/cerebrospinal fluid RNA.Case 2 is a 61-year-old heterosexual man, known for HIV-1 infection since 1986 and treated with ART starting from 1990. IBA was initiated when HIV-1 RNA was 275 000 copies/ml and CD4+ 9 cells/μl (0.9%). At week 43, he underwent lumbar puncture: glucose was 56 mg/dl (plasma glucose 74 mg/dl), protein 27 mg/dl and WBC 3/μl. CSF viral load was 108 copies/ml and plasma viral load was 249 copies/ml; however, genotypic tests were not amplified for low-level viremia. CD4+ cell count recovered to 23 cells/μl (1.5%). Case 3 is a 55-year-old heterosexual man with HIV-1 infection since 1992; ART was introduced in 1995. Prior to start IBA, HIV-1 RNA was 62 600 copies/ml and CD4+ 5 cells/μl (0.7%). CSF was collected at week 30: glucose was reported 72 mg/dl (plasma glucose 147 mg/dl) protein 31 mg/dl, WBC 13/μl and CSF viral load 63 copies/ml. Plasma viral load was 3690 copies/ml, revealing a progressive reduction of viremia, and CD4+ 8 cells/μl (1.2%). Resistance mutations in plasma RNA and peripheral blood mononuclear cell DNA before starting IBA, current resistance mutations to antiretroviral drugs and coreceptor tropism were tested both in plasma and in CSF, as illustrated in Table 1 . Resistance mutations profile was comparable in plasma and in CSF. Previous studies have never assessed virological response in the central nervous system (CNS) during a regimen containing IBA; in fact, it is well known that large molecules like mAbs cannot pass the blood–brain barrier [7]. However, an intracranial impact of nivolumab and ipilimubab on brain metastases has been reported recently [8], leading to revise CNS effects of mAbs. All the three patients presented low-level viremia in CSF; despite the number of patients evaluated being limited, our results are encouraging in a difficult-to-treat setting of PLWH. Different degrees of antiretroviral drugs penetration across blood–brain barrier may select specific resistance profiles [9]. In our analysis, no substantial discrepancy emerged after comparing drug resistance mutations in two distinct compartments. In conclusion, low levels of viral replication were described in CSF and no discordance both with respect to viremia and the pattern of resistance was observed between plasma and CSF in all three PLWH with multidrug resistance who were being treated with IBA. Acknowledgements Conflicts of interest There are no conflicts of interest.