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• W1985510965 abstract "Before highly active antiretroviral therapy (HAART) era, central nervous system (CNS) HIV infection was frequent and presented as HIV-associated dementia complex. Incidence of symptomatic CNS HIV infection was reduced subsequent to the large use of HAART, partially due to the fact that most patients achieve undetectable HIV-RNA in cerebrospinal fluid (CSF) and/or in the CNS [1–3]. The neurological antiviral efficacy of the antiretroviral combination depends on the penetration of each drug into the CNS/CSF [4]. Nevertheless, minor cognitive impairments are now widely described in HIV-infected patients receiving HAART [5], but the relationship between CSF drug penetration score and neuropsychological performance remains uncertain [3]. Among the antiretroviral drugs, ritonavir-boosted lopinavir (LPV/r) is recognized with a good penetration index in CSF [4,6]. We report the case of a patient presenting unexpected HIV-associated neurological symptoms with HIV virological escape in CSF after 5 years of suppressive HAART, including 18 months of LPV/r monotherapy. A 39-year old South American woman presented with known HIV-1 infection since January 2002. At this time, CD4 cell count was high (740 cells/μl), but HAART with zidovudine, lamivudine, and LPV/r was systematically introduced in February 2002 for pregnancy. This regimen was maintained unchanged after delivery with continuous viral suppression, except transitory drug interruption for 3 months in 2004, with plasma viral load detected at 1660 copies/ml. HIV-1 was then identified as group M-CRF12_BF and plasma genotype revealed resistance mutations 103S, 106I, 190A on the reverse transcriptase gene, and 10I, 20R, 35D, 36I, 41K, 54V, 82A on the protease gene. Despite a slight decreased susceptibility to LPV, the same regimen was resumed until 2006 with continuous suppressive viral load and high CD4 cell count (950 cells/μl). In January 2006, nucleoside analogs were switched to tenofovir-DF + emtricitabine to improve hematological and metabolic tolerance of the combination, and viral load remained undetectable. In January 2008, frightened by the renal and bone toxicity risk of tenofovir, the patient decided to stop nucleoside analogs and LPV/r monotherapy (400 mg b.i.d.) was continued. Plasma viral load was maintained always undetectable until last control in June 2009: viral load less than 20 copies/ml (Taqman-Amplicor, version 2.0; Roche, Branchburg, New Jersey, USA) and CD4 cell count 992 cells/μl (30%). Plasma LPV-trough concentration (Ctrough), quantified with a validated liquid chromatography–mass spectrometry method, was 10 730 ng/ml. On 26 August 2009, the patient was admitted in emergency unit for mild fever (38°C), asthenia, headaches, dizziness, altered visual field, and moderate neck stiffness. Usual plasma biological and hematological values were normal and unchanged. CSF examination revealed a mild pleiocytosis (240 cells/ml, 80% lymphocytes), elevated albumin 0.94 g/l, normal glucose, and negative bacterial examinations. CD4 cell count was 855 cells/μl and plasma viral load was detected at 364 copies/ml and CSF viral load at 2270 copies/ml. No other viral infection was detected in CSF (negative PCR for cytomegalovirus, Epstein–Barr virus, herpes simplex virus, enterovirus, varicella-zoster virus, JC virus). A cerebral MRI scan revealed punctiform T2-hypersignal white matter lesions without specificity. Plasma/CSF 2009 HIV genotypes were identical to the 2004 plasma genotypic test, except the absence of the 54V mutation. LPV concentration was low in CSF (9 ng/ml) and plasma LPV Ctrough was moderately reduced at 4580 ng/ml. The patient acknowledged having taken a self-medication with orlistat 60 mg twice daily for 3 months in an effort to reduce body weight, which has possibly reduced the intestinal absorption of drugs, especially LPV. The diagnosis of lymphocytic meningitis and mild encephalitis related to HIV1 was assessed and antiretroviral therapy was modified for abacavir, r/darunavir, and raltegravir b.i.d. in order to optimize drug penetration in CNS [4,7,8]. Clinical and neurological symptoms rapidly improved and plasma viral load reached less than 20 copies/ml after 2 weeks of this combination. In this case, we observed a symptomatic HIV-related meningo-encephalitis in a patient with previously plasma HIV-replication suppression during 5 years, including 18 months of LPV/r monotherapy. As previously described [3,5], viral load was higher in CSF than in plasma, arguing for independent HIV replication in CNS. Despite a continuous antiretroviral pressure selection by LPV/r, a distinct HIV variant (without the 54V mutation) emerged in CSF, leading to the subsequent plasmatic low-level viral escape. These two findings, higher viral load and different genotype in CSF, provide arguments for independent viral replication and HIV compartmentalization in CSF. Treatment with LPV/r is usually recognized with good CNS penetration index and efficacy [4,6,9]. Different factors may have explained CSF compartmentalized HIV replication in this case. Protease inhibitor monotherapy has been proven efficacious in switch trials [10–13], but HIV encephalitis under LPV/r or r/darunavir monotherapy have been recently reported [13,14]; a low CD4 cell count nadir, reported as risk factor for CNS HIV replication [14], was not observed in our case. An absence of combined antiretroviral drugs could weaken the efficacy of protease inhibitor, especially in CNS where concentrations are lower than in plasma [4]. In our case, lopinavir concentration in CSF was low and may have even been reduced by possible partial malabsorption due to oristat. Moreover, the presence of minor protease gene mutations leading to possible HIV-reduced susceptibility to lopinavir may have worsened the effects of low LPV concentration. This observation emphasizes the higher risk of virological escape under protease inhibitor monotherapy, especially in the CNS compartment, when the effective drug concentration is reduced by concomitant events such as drug interaction, reduced observance, or partial resistance." @default.
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• W1985510965 date "2010-05-15" @default.
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• W1985510965 title "Cerebrospinal fluid HIV-1 virological escape with lymphocytic meningitis under lopinavir/ritonavir monotherapy" @default.
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