| 1. |
- Yilmaz, Aylin, 1974
(författare)
-
Antiretroviral treatment of HIV-1 in the central nervous system
- 2007
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- HIV-1 invades the central nervous system (CNS) early in the infectious course. It establishes a chronic progressive infection, and triggers an intrathecal immune response. If left untreated, a majority of patients will develop neurological complications, caused by opportunistic pathogens or HIV-1 itself. The most devastating manifestation of HIV-1 in the CNS is AIDS dementia complex (ADC), a subcortical dementia, occuring in about 20% of untreated patients. The incidence of neurological complications has decreased dramatically since the introduction of antiretroviral drugs. In order for these drugs to act in the CNS, they must penetrate the blood-brain barrier (BBB) into the cerebrospional fluid (CSF). It is, therefore, important to determine which agents have this capacity, and what impact they have on HIV-1 CNS infection. We analysed CSF concentrations of three protease inhibitors (PIs): lopinavir co-formulated with a low dose of ritonavir, and saquinavir in combination with nelfinavir. Lopinavir was detectable in 15/15 samples. The concentrations achieved were probably high enough for antiviral activity in the CSF, generally exceeding severalfold the concentration needed to inhibit viral replication by 50% (IC50). The concentrations of saquinavir were very low, and only detectable in 7/15 CSF samples. Nelfinavir was detectable in 9/15 CSF samples, with concentrations in the range of the IC50. Antiretroviral treatment (ART) containing lopinavir/ritonavir or saquinavir/nelfinavir significantly reduced plasma and CSF viral loads, as well as intrathecal cell-mediated immunoactivation, measured as decreasing levels of CSF neopterin and ?2-microglobulin. HIV-1 has the capacity of establishing viral latency in resting memory CD4+ T-cells, making the virus impossible to eradicate with ART alone. Even in patients on effective ART, a low-level viral replication in plasma can be detected. This probably originates from latently infected cells. To determine whether there is a similar low-level viral replication in CSF, we used an HIV-1 RNA quantification assay with a detection limit of 2 copies/mL in 13 neurologically asymptomatic individuals on effective ART. All patients had CSF viral loads < 2 copies/mL. In plasma, 5/13 patients had levels ranging from 2.3 to 8.2 copies/mL. This makes it unlikely that the CSF in neurologically asymptomatic individuals acts as a viral reservoir in which HIV-1 can replicate independently from the periphery. CSF neopterin levels remain abnormal in many patients, despite a long period on successful ART. We retrospectively evaluated what influence various levels of CSF HIV-1 RNA, different antiretroviral regimens, and different levels of plasma viral load have on CSF neopterin levels in patients on effective ART. We found that patients with the lowest CSF viral loads (< 2.5 copies/mL) also had the lowest CSF neopterin concentrations. Subjects treated with PI- or non-nucleoside analogue-based regimens had CSF neopterin in the same range. Plasma HIV-1 RNA levels did not affect CSF neopterin levels. These findings indicate that the low-grade persistent intrathecal immunoactivation observed in treated patients is mainly driven by residual viral replication within the CNS. The more the antiretroviral regimen suppresses viral replication in the CNS, the less the intrathecal immunoactivation.
|
|
| 2. |
- Yilmaz, Aylin, 1974, et al.
(författare)
-
Cerebrospinal fluid HIV-1 RNA, intrathecal immunoactivation, and drug concentrations after treatment with a combination of saquinavir, nelfinavir, and two nucleoside analogues: the M61022 study.
- 2006
-
Ingår i: BMC infectious diseases. - : Springer Science and Business Media LLC. - 1471-2334. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The way various antiretroviral drugs and drug combinations affect HIV-1 infection in the central nervous system is still largely unknown. The aim of this study was to determine the cerebrospinal fluid (CSF) steady-state concentrations of saquinavir and nelfinavir in relation to plasma concentrations, and to study their effect in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) on CSF viral loads, intrathecal immunoactivation, and blood-brain barrier integrity. METHODS: Paired CSF and plasma samples from 8 antiretroviral-naïve HIV-1 infected patients starting combination therapy with saquinavir, nelfinavir, and two nucleoside analogues were collected prior to treatment, and again after approximately 12 and 48 weeks of antiretroviral therapy. Additional plasma samples were taken at weeks 2, 4, 8, 24, and 36. The concentrations of protease inhibitors were analysed, as were levels of HIV-1 RNA, CD4+ T-cell count, beta2-microglobulin, neopterin, albumin ratio, IgG index, and monocytic cell count. RESULTS: None of the patients in the study presented with HIV-1 RNA < 50 copies/mL in CSF or plasma prior to treatment, compared to 5/7 at the end of the study. Signs of cell-mediated intrathecal immunoactivation, measured by neopterin and beta2-microglobulin, decreased significantly in both CSF and serum, although only 1/7 reached normal CSF neopterin levels after 48 weeks of treatment. There was no significant reduction of albumin ratio, IgG index or CSF monocytic cell count. Saquinavir median (range) concentrations were < 2.5 (< 2.5-96.0) nM unbound in plasma, and < 2.5 (< 2.5-9.0) nM total in CSF. Nelfinavir median (range) concentrations were 10.0 (< 2.0-31.0) nM unbound in plasma, and < 2.0 (< 2.0-23.0) nM total in CSF. Saquinavir and nelfinavir were detectable in 7/15 and 9/15 CSF samples, respectively. CONCLUSION: Saquinavir and nelfinavir, in combination with two NRTIs, decrease the CSF viral load and, to a lesser extent, intrathecal immunoactivation. We found reasonably high CSF concentrations of nelfinavir, but suboptimal concentrations of saquinavir.
|
|
| 3. |
- Yilmaz, Aylin, 1974, et al.
(författare)
-
Cerebrospinal fluid maraviroc concentrations in HIV-1 infected patients
- 2009
-
Ingår i: AIDS. - 0269-9370. ; 23:18, s. 2537-2540
-
Tidskriftsartikel (refereegranskat)abstract
- In order to assess the penetration of maraviroc to the central nervous system, we measured maraviroc concentrations in cerebrospinal fluid (CSF) and plasma. Concentrations were determined by liquid chromatography tandem mass spectrometry (lower limit of quantitation 1.25 ng/ml) in seven paired CSF and plasma samples. The median plasma maraviroc concentration was 94.9 ng/ml (range 21.4-478.0) and the median CSF concentration was 3.63 ng/ml (range 1.83-12.2). CSF samples exceeded the median EC90 for maraviroc (0.57 ng/ml) by at least three-fold. The CSF levels of maraviroc found in this study likely contribute to viral suppression in the CSF.
|
|
| 4. |
- Yilmaz, Aylin, 1974, et al.
(författare)
-
Cerebrospinal fluid viral loads reach less than 2 copies/ml in HIV-1-infected patients with effective antiretroviral therapy.
- 2006
-
Ingår i: Antiviral therapy. - 1359-6535. ; 11:7, s. 833-7
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A low-grade persisting viraemia despite long-term treatment with highly active antiretroviral therapy (HAART) has previously been demonstrated in HIV-1-infected patients. Whether ongoing viral replication also could be detected in cerebrospinal fluid (CSF) in those circumstances has not been studied before. METHODS: Paired CSF and blood samples from 13 neurologically asymptomatic HIV-1-infected patients on stable HAART were analysed regarding HIV-1 RNA, by using a PCR assay with a detection limit of 2 copies/ml. RESULTS: All 13 patients had HIV-1 RNA < 2 copies/ml in CSF, compared with 8/13 in plasma. CONCLUSION: We could not demonstrate any persistent viral replication in the CSF of neurologically asymptomatic HIV-1-infected patients on effective HAART, rendering it unlikely that CSF acts as a viral reservoir in this category of patients.
|
|
| 5. |
- Yilmaz, Aylin, 1974, et al.
(författare)
-
Darunavir concentrations in cerebrospinal fluid and blood in HIV-1-infected individuals
- 2009
-
Ingår i: AIDS Research and Human Retroviruses. - 0889-2229. ; 25:4, s. 457-61
-
Tidskriftsartikel (refereegranskat)abstract
- Darunavir is the most recently licensed protease inhibitor currently used in treatment-experienced HIV-infected individuals. Our objective was to determine darunavir concentrations in cerebrospinal fluid (CSF) and plasma in subjects receiving antiretroviral treatment regimens containing ritonavir-boosted darunavir. Darunavir concentrations were determined by liquid chromatography tandem mass spectrometry in 14 paired CSF and plasma samples from eight HIV-1-infected individuals. The lower limit of quantification was 5.0 ng=ml. All of the 14 CSF samples had detectable darunavir concentrations with a median darunavir concentration of 34.2 ng=ml (range 15.9–212.0 ng=ml). The median (range) plasma darunavir concentration was 3930 (1800–12900) ng=ml. All CSF samples had detectable darunavir concentrations. Most of them exceeded or were in the same range as levels needed to inhibit replication of wild type virus, making it probable that darunavir, at least to some extent, contributes to the suppression of HIV replication in the central nervous system.
|
|
| 6. |
- Yilmaz, Aylin, 1974, et al.
(författare)
-
Persistent intrathecal immune activation in HIV-1-infected individuals on antiretroviral therapy
- 2008
-
Ingår i: Journal of Acquired Immune Deficiency Syndromes. - 1525-4135. ; 47:2, s. 168-73
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Neopterin is a well-established marker of macrophage activation. The cerebrospinal fluid (CSF) neopterin levels are elevated in most HIV-1-infected individuals and decrease significantly after initiation of antiretroviral therapy (ART). Unexpectedly, CSF concentrations often remain mildly abnormal even in patients treated for a long time with suppressive ART. The aims of this study were to analyze if persistently elevated CSF neopterin levels were associated with the type of antiretroviral regimen or with low-level CSF HIV-1 concentrations and to evaluate if plasma HIV-1 RNA levels correlated to lingering CSF neopterin concentrations in patients with effective ART. METHODS: One hundred fifty-seven chronically HIV-1-infected patients with stable ART for > or =6 months and no neurologic symptoms were included, and 193 HIV-1-infected patients without ART served as controls. Neopterin was analyzed with a radioimmunoassay or an enzyme-linked immunosorbent assay. HIV-1 RNA quantification was performed with the Roche Amplicor assay (version 1.5; Hoffman-La Roche, Basel, Switzerland). Two quantitative HIV-1 RNA assays with sensitivities < or =2.5 copies/mL were used in 40 samples. RESULTS: As anticipated, HIV-1 RNA and CSF neopterin levels were markedly lower in patients on ART compared with untreated controls. No significant difference in CSF neopterin concentrations was found between those treated with protease inhibitor- and nonnucleoside reverse transcriptase inhibitor-based regimens in combination with 2 nucleoside analogues. Subjects with CSF HIV-1 RNA loads <2.5 copies/mL had the lowest CSF neopterin levels. Plasma viral load had no impact on intrathecal immune activation in cases with CSF viral loads <50 copies/mL. CONCLUSION: The persistent intrathecal cell-mediated immune response was associated with CSF viral load but not with treatment regimen in individuals on ART.
|
|
| 7. |
- Yilmaz, Aylin, 1974, et al.
(författare)
-
Raltegravir cerebrospinal fluid concentrations in HIV-1 infection
- 2009
-
Ingår i: PLoS One. - : Public Library of Science (PLoS). - 1932-6203. ; 4:9
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction Raltegravir is an HIV-1 integrase inhibitor currently used in treatment-experienced HIV-1-infected patients resistant to other drug classes. In order to assess its central nervous system penetration, we measured raltegravir concentrations in cerebrospinal fluid (CSF) and plasma in subjects receiving antiretroviral treatment regimens containing this drug. Methods Raltegravir concentrations were determined by liquid chromatography tandem mass spectrometry in 25 paired CSF and plasma samples from 16 HIV-1-infected individuals. The lower limit of quantitation was 2.0 ng/ml for CSF and 10 ng/ml for plasma. Results Twenty-four of the 25 CSF samples had detectable raltegravir concentrations with a median raltegravir concentration of 18.4 ng/ml (range, <2.0–126.0). The median plasma raltegravir concentration was 448 ng/ml (range, 37–5180). CSF raltegravir concentrations correlated with CSF:plasma albumin ratios and CSF albumin concentrations. Conclusions Approximately 50% of the CSF specimens exceeded the IC95 levels reported to inhibit HIV-1 strains without resistance to integrase inhibitors. In addition to contributing to control of systemic HIV-1 infection, raltegravir achieves local inhibitory concentrations in CSF in most, but not all, patients. Blood-brain and blood-CSF barriers likely restrict drug entry, while enhanced permeability of these barriers enhances drug entry.
|
|
