title: Differences in the detection of three HIV-1 protease inhibitors in non-blood compartments: clinical correlations.
abstract: OBJECTIVE
  To study the presence of three HIV-1 protease inhibitors (PIs) in the cerebrospinal fluid (CSF), semen, and lymph nodes and to assess the correlations with residual viral replication in these compartments.
  
  
  METHODS
  We performed a cross-sectional analysis of sanctuary samples from 41 HIV-infected patients on stable highly active antiretroviral therapy (HAART) regimens containing indinavir, nelfinavir, or lopinavir combined with ritonavir (lopinavir/r) and a longitudinal analysis of PI levels and HIV-1 RNA in plasma and CSF of 6 additional patients on nelfinavir or lopinavir/r monotherapy (3 cases each). Plasma, CSF, semen, and a lymph node (LN) biopsy were taken on the same day. Samples were assayed for PI concentrations, HIV-1 RNA levels, and, when detectable, sequencing of the reverse transcriptase and protease genes on seminal viral RNA.
  
  
  RESULTS
  In the cross-sectional analysis, the CSF/plasma ratio was 0.14 for indinavir. Nelfinavir and lopinavir/r were consistently undetectable in CSF. The semen/plasma ratio was 1.9 for indinavir, 0.07 for nelfinavir, and 0.07 for lopinavir. The LN/plasma ratio was 2.07 for indinavir, 0.58 for nelfinavir, 0.21 for lopinavir, and 0.64 for ritonavir. Plasma HIV-1 RNA was <50 copies/mL in 28 patients and was detectable in 13 patients. HIV-1 RNA was <50 copies/mL in CSF samples when plasma RNA was undetectable. Three semen samples taken from patients with viremia <50 copies/mL showed detectable HIV-1 RNA with resistance mutations. HIV-1 RNA was detectable in all LNs, with no differences in patients on indinavir compared with those on nelfinavir or lopinavir/r. In the longitudinal analysis, HIV-1 RNA decreased in the plasma of the 6 patients on nelfinavir or lopinavir/r monotherapy, although CSF HIV-1 RNA decreased only in patients on lopinavir/r.
  
  
  CONCLUSIONS
  Major differences exist between PIs in terms of detection in non-blood compartments. An undetectable PI level in CSF does not rule out drug activity in the brain for lopinavir/r, although this is not the case for nelfinavir. Poor penetration of PIs in semen in some patients can lead to double nucleoside therapy in this compartment. The persistence of HIV-1 RNA in LNs does not seem to be related to PI levels in this tissue.
authors.affiliation: Department of Infectious Diseases, General Hospital, Toulon, France. avps@club-internet.fr
authors.forename: Alain
authors.initials: A
authors.lastname: Lafeuillade
authors.forename: Caroline
authors.initials: C
authors.lastname: Solas
authors.forename: Philippe
authors.initials: P
authors.lastname: Halfon
authors.forename: Stéphane
authors.initials: S
authors.lastname: Chadapaud
authors.forename: Gilles
authors.initials: G
authors.lastname: Hittinger
authors.forename: Bruno
authors.initials: B
authors.lastname: Lacarelle
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D002851:Chromatography, High Pressure Liquid; D003430:Cross-Sectional Studies; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D008137:Longitudinal Studies; D061466:Lopinavir; D008198:Lymph Nodes / Q000601:surgery / Q000821:virology; D008297:Male; D009154:Mutation; D019888:Nelfinavir / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D011744:Pyrimidinones / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D012367:RNA, Viral / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D019438:Ritonavir / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D012661:Semen / Q000821:virology
chemical_list: D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D012367:RNA, Viral; D061466:Lopinavir; D019469:Indinavir; D019888:Nelfinavir; D019438:Ritonavir