PURPOSE: 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. METHOD: 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. CONCLUSION: 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.
PURPOSE: 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. METHOD: We performed a cross-sectional analysis of sanctuary samples from 41 HIV-infectedpatients 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. CONCLUSION: 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: Cécile L Tremblay; Jean-Guy Baril; David Fletcher; Donald Kilby; Paul Macpherson; Stephen D Shafran; Mark W Tyndall Journal: Can J Infect Dis Med Microbiol Date: 2010-08 Impact factor: 2.471
Authors: M C Strain; S Letendre; S K Pillai; T Russell; C C Ignacio; H F Günthard; B Good; D M Smith; S M Wolinsky; M Furtado; J Marquie-Beck; J Durelle; I Grant; D D Richman; T Marcotte; J A McCutchan; R J Ellis; J K Wong Journal: J Virol Date: 2005-02 Impact factor: 5.103
Authors: Antonio Valentin; Matthew Morrow; Richard H Poirier; Karen Aleman; Richard Little; Robert Yarchoan; George N Pavlakis Journal: AIDS Res Hum Retroviruses Date: 2010-01 Impact factor: 2.205