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Quantification of Persistent Viremia in Cerebrospinal Fluid and Plasma: Initial Experience in a Raltegravir Intensification Study
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Viktor Dahl*1, S Spudich2, E Lee2, E Ho2, R Price2, and S Palmer1
1Swedish Inst for Infectious Disease Control and Karolinska Inst, Solna and 2Univ of California, San Francisco and San Francisco Gen Hosp, US
Background: Current therapy suppresses but does not eradicate HIV-1 and ultra-sensitive assays detect low-level viremia in patients on suppressive therapy. These virions are, to some extent, produced by infected memory T-cells. One additional site of virion production could be the central nervous system (CNS) where barriers to drug penetration attenuate antiviral effects. To evaluate virion production in the CNS, we used the single copy assay (SCA: limit 0.3 copies/mL in 7 mL) to analyze the levels of HIV RNA in cerebrospinal fluid (CSF) in treated patients.
Methods: HIV-infected patients on antiretroviral therapy for >2 years with plasma suppression below 50 copies/mL for >1 year were enrolled in a randomized, open-label study of a 12-week course of raltegravir intensification. Patients not randomized to receive raltegravir in the first study course could volunteer to cross over to receive raltegravir for the following 12 weeks. Paired plasma and CSF samples were collected at screening and/or baseline, and at 4, 12, 16, and 24 weeks. SCA was used to measure plasma and CSF HIV RNA from 5 patients: 2 receiving raltegravir for 12 weeks, 2 receiving no raltegravir at first and then crossing over to the intensification course, and one receiving no raltegravir. SCA was performed in triplicate for each sample and the average of 3 results was recorded. Background regimens contained 3 to 5 drugs and CSF penetration effectiveness scores ranged from 1 to 3.5.
Results: Screening and baseline CSF HIV RNA in all 5 patients was below the assay limit (<0.3 copies/mL), while persistent viremia was detected in the plasma of all 5 patients (median 1.7, range 0.3 to 9.5 copies/mL). In the 4 patients who received raltegravir for the first 12 weeks or who crossed over to receive raltegravir in the subsequent 12 weeks, CSF HIV RNA was below the assay limit in all but 1 of 11 samples collected after baseline. For the same 4 patients, 9 of 11 plasma samples had detectable virus (median 2.2, range 0.6 to 4.4). In the patient who chose not to receive raltegravir intensification, the HIV RNA was below the assay limit in all samples after baseline.
Conclusions: This initial study demonstrates the feasibility of using SCA to measure low concentrations of HIV RNA in CSF. In this preliminary study, CSF HIV RNA levels are controlled during suppressive therapy, while low-level viremia persists in plasma, suggesting that persistent viremia arises from sources other than the CNS compartment.
Raltegravir Intensification Does Not Reduce Persistent HIV-1 Viremia in Treatment-experienced Patients
Ann Wiegand1, F Cossarini1, C Poethke1, M Kearney1, J Spindler2, A O?Shea2, C Rehm2, J Coffin1, J Mellors3, and F Maldarelli1
1NCI-Frederick, MD, US; 2NIAID, NIH, Bethesda, MD, US; and 3Univ of Pittsburgh, PA, US
Background: ART-experienced patients with drug resistance can have HIV-1 RNA suppressed to <50 copies using newer combinations of antiretrovirals, but low-level viremia often persists. Determining whether this persistent viremia is due to ongoing cycles of HIV-1 replication is important because partially suppressive regimens facilitate the emergence of drug resistance. To investigate the contribution of ongoing replication to persistent viremia in treatment-experienced patients, we conducted a study of short term drug intensification with the integrase inhibitor, raltegravir.
Methods: We enrolled participants with a prior history of virologic failure and genotypic resistance who were subsequently suppressed to <75 copies/mL on a new regimen that did not contain raltegravir. Participants had baseline viral RNA levels determined during a 21-day period prior to drug intensification, then weekly during a 30-day intensification period with raltegravir 400 mg twice daily. Additional sampling was performed during the 6 weeks following intensification.
Results: Eight participants had undergone an average of 4 suboptimal regimens prior to successful therapy, and were suppressed on combinations with an average GSS score of 2.1 (range 1.5 to 3) for a mean of 6.1 years prior to enrollment; 6 have completed intensification thus far. Median viremia prior to raltegravir was 0.31 log10 HIV-1 copies/mL. No significant change in viral RNA levels was detected during intensification (median viral RNA 0.12 log10 copies/mL, P = 0.88) or following intensification (median 0.08 log10 copies/mL, P =0.41). Mean CD4 cell numbers were not significantly different after 30 days of intensification. Raltegravir was well tolerated with no adverse effects.
Conclusions: Raltegravir intensification of treatment-experienced patients on a suppressive regimen did not lower the level of persistent viremia. Low level viremia in treatment-experienced patients is not the product of ongoing cycles of HIV-1 replication in short-lived cells, even in patients with a prior history
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