Showing papers by "Anders Sönnerborg published in 2007"

Early immune activation in gut-associated and peripheral lymphoid tissue during acute HIV infection.

Abstract: Objective To study innate and adaptive immune responses in gut-associated lymphoid tissue (GALT) as well as peripheral lymphoid tissue (pLT) obtained from individuals with acute HIV-1 infection syndrome. Design The expression of chemokines [regulated upon activation: normal T cell expressed/secreted (RANTES), macrophage-inflammatory protein (MIP) 1alpha/beta], cytokines (IL-1beta, TNF-alpha, IL-12, IL-4, IL-10, IL-2, IFN-gamma) and cytotoxic effector molecules (granzyme A, perforin) and cell marker (CD8) were analysed at the single cell level in GALT and pLT of patients experiencing acute HIV-1 infection (day -3 to 48 days from onset of acute symptoms). Results Substantial pro-inflammatory immune responses (TNF-alpha, IL-1beta, IL-12) and expansion in the CD8 T-cell population were noted in both compartments compared with uninfected controls. This was associated with an early increased expression of beta-chemokines (RANTES, MIP-1alpha/beta) and granzyme, but not with an increase in the expression of perforin. The upregulation of IL-2, IL-12 and IL-4 was noted in both pLT and GALT, whereas IL-10 expression was mainly increased in GALT. Conclusion Taken together, these findings demonstrate that there was a broad and early immune activation in GALT and pLT during acute HIV-1 infection. The relative lack of perforin expression in both GALT and pLT, however, questions the functional efficacy of the observed immune activation in generating cytotoxic T cells that were able to eliminate HIV-infected cells.

Early virologic rebound in a pilot trial of ritonavir-boosted atazanavir as maintenance monotherapy.

Abstract: Objective: To investigate the feasibility of ritonavir-boosted atazanavir monotherapy in HIV-1-infected patients with stable antiretroviral therapy (ART). Design: Single-armed single-center pilot trial. Methods: Adult HIV-1-infected patients, without protease inhibitor (PI) experience, were eligible if they had maintained a viral load <20 copies/mL for a minimum of 12 months on conventional ART. The trial regimen was atazanavir/ritonavir at a dose of 300/100 mg once daily. The atazanavir dose could be adjusted if plasma concentrations showed a low exposure. The study was intended to recruit 30 patients to be followed over 72 weeks. If 5 cases of virologic failure occurred during this period, the study was to be terminated. Results: The study was terminated according to protocol when 15 of the planned 30 patients had been recruited, because 5 cases of virologic failure had occurred. In patients failing therapy, viral rebound was seen at weeks 12 through 16. Plasma atazanavir concentrations were not associated with the outcome. The median serum bilirubin concentration was significantly lower in the patients failing therapy, however. No PI resistance was found in samples from patients failing therapy. Conclusions: Ritonavir-boosted atazanavir as maintenance monotherapy in HIV-1 infection might not be as potent as conventional ART. Serum bilirubin should be further studied as a biomarker of adequate atazanavir exposure.

Authorsʼ Response to “Early Virologic Rebound in a Pilot Trial of Ritonavir-Boosted Atazanavir as Maintenance Monotherapy”

Abstract: OBJECTIVE To investigate the feasibility of ritonavir-boosted atazanavir monotherapy in HIV-1-infected patients with stable antiretroviral therapy (ART). DESIGN Single-armed single-center pilot trial. METHODS Adult HIV-1-infected patients, without protease inhibitor (PI) experience, were eligible if they had maintained a viral load <20 copies/mL for a minimum of 12 months on conventional ART. The trial regimen was atazanavir/ritonavir at a dose of 300/100 mg once daily. The atazanavir dose could be adjusted if plasma concentrations showed a low exposure. The study was intended to recruit 30 patients to be followed over 72 weeks. If 5 cases of virologic failure occurred during this period, the study was to be terminated. RESULTS The study was terminated according to protocol when 15 of the planned 30 patients had been recruited, because 5 cases of virologic failure had occurred. In patients failing therapy, viral rebound was seen at weeks 12 through 16. Plasma atazanavir concentrations were not associated with the outcome. The median serum bilirubin concentration was significantly lower in the patients failing therapy, however. No PI resistance was found in samples from patients failing therapy. CONCLUSIONS Ritonavir-boosted atazanavir as maintenance monotherapy in HIV-1 infection might not be as potent as conventional ART. Serum bilirubin should be further studied as a biomarker of adequate atazanavir exposure.

Elevated plasma levels of high mobility group box protein 1 in patients with HIV-1 infection.

Abstract: High mobility group box protein 1 (HMGB1) is a potent proinflammatory mediator. It has a dichotomic effect on HIV-1 replication in vitro but its role in vivo is unknown. Here we report the novel finding that plasma HMGB1 levels are elevated in HIV-1-infected patients, with the highest concentrations in patients with clinical complications. HMGB1 is likely to contribute to immunoactivation in HIV-1 infection in vivo.

Antiretroviral treatment of HIV infection: Swedish recommendations 2007.

Abstract: On 3 previous occasions, in 2002, 2003 and 2005, the Swedish Medical Products Agency (Lakemedelsverket) and the Swedish Reference Group for Antiviral Therapy (RAV) have jointly published recommendations for the treatment of HIV infection. An expert group, under the guidance of RAV, has now revised the text again. Since the publication of the previous treatment recommendations, 1 new drug for the treatment of HIV has been approvedthe protease inhibitor (PI) darunavir (Prezista † ). Furthermore, 3 new drugs have become available: the integrase inhibitor raltegravir (MK-0518), the CCR5-inhibitor maraviroc (Celsentri † ), both of which have novel mechanisms of action, and the non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine (TMC-125). The new guidelines differ from the previous ones in several respects. The most important of these are that abacavir is now preferred to tenofovir and zidovudine, as a first line drug in treatment-nao¨ve patients, and that initiation of antiretroviral treatment is now recommended before the CD4 cell count falls below 250/ml, rather than 200/ml. Furthermore, recommendations on the treatment of HIV infection in children have been added to the document. As in the case of the previous publication, recommendations are evidence-graded in accordance with the Oxford Centre for Evidence Based Medicine, 2001 (see http://www.cebm.net/levels_of_evidence.asp#levels).

Presence of M184I/V in minor HIV-1 populations of patients with lamivudine and/or didanosine treatment failure.

Abstract: Objectives The aim of the study was to investigate the presence of M184I/V in minor HIV-1 populations of patients who failed lamivudine (3TC) and/or didanosine (ddI) treatment. Materials and methods Fourteen 3TC-experienced patients who, after switching therapy to a ddI regimen, had a new failure without M184I/V in the major viral population were included in the study. Ninety plasma samples were analysed by direct sequencing and selective real-time polymerase chain reaction (SPCR), which detects GTG/GTA and ATA mutants down to 1 and 0.2% of the population, respectively. Results In five samples, SPCR detected resistant virus when direct sequencing detected wild-type M184. In patients with mixed viral populations at sequencing, the median proportion of mutants detected by SPCR was 30%. SPCRGTG reactivity dominated, while SPCRATA reactivity only was uncommon. M184I/V disappeared in patients in whom 3TC was stopped but ddI continued. Ten patients with ddI failure had no M184I/V. Conclusions Minor HIV-1 strains may harbour M184I/V in patients failing ddI therapy, despite direct sequencing showing wild-type virus. Although M184I/V may reduce the genetic barrier of ddI for mutations such as K65R and L74V, the lack of re-emergence of M184I/V in the minor quasispecies of most patients who failed ddI suggests that M184I/V was not a preferred route to ddI resistance in our patient population.

5th European HIV Drug Resistance Workshop

Abstract: The European HIV Drug Resistance Workshop is the most important meeting in Europe for preclinical researchers, clinically orientated researchers and clinicians, creating a meeting point for translational activities within the important field of HIV drug resistance. The meeting in Cascais, Portugal, was the fifth meeting and a development of the presentations towards enhanced scientific quality and clinical relevance was easily identified. Areas of specific interest included, for example, epidemiology of HIV resistance, resistance to new drugs, viral tropism assays and clinical relevance of drug resistance.