Impact of growth hormone (GH) deficiency and GH replacement upon thymus function in adult patients.
Morrhaye, Gabriel ; ; Legros, Jean-Jacques et al
in PLoS ONE (2009), 4(5), 5668
BACKGROUND: Despite age-related adipose involution, T cell generation in the thymus (thymopoiesis) is maintained beyond puberty in adults. In rodents, growth hormone (GH), insulin-like growth factor-1 ... [more ▼]
BACKGROUND: Despite age-related adipose involution, T cell generation in the thymus (thymopoiesis) is maintained beyond puberty in adults. In rodents, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and GH secretagogues reverse age-related changes in thymus cytoarchitecture and increase thymopoiesis. GH administration also enhances thymic mass and function in HIV-infected patients. Until now, thymic function has not been investigated in adult GH deficiency (AGHD). The objective of this clinical study was to evaluate thymic function in AGHD, as well as the repercussion upon thymopoiesis of GH treatment for restoration of GH/IGF-1 physiological levels. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-two patients with documented AGHD were enrolled in this study. The following parameters were measured: plasma IGF-1 concentrations, signal-joint T-cell receptor excision circle (sjTREC) frequency, and sj/beta TREC ratio. Analyses were performed at three time points: firstly on GH treatment at maintenance dose, secondly one month after GH withdrawal, and thirdly one month after GH resumption. After 1-month interruption of GH treatment, both plasma IGF-1 concentrations and sjTREC frequency were decreased (p<0.001). Decreases in IGF-1 and sjTREC levels were correlated (r = 0.61, p<0.01). There was also a decrease in intrathymic T cell proliferation as indicated by the reduced sj/beta TREC ratio (p<0.01). One month after reintroduction of GH treatment, IGF-1 concentration and sjTREC frequency regained a level equivalent to the one before GH withdrawal. The sj/beta TREC ratio also increased with GH resumption, but did not return to the level measured before GH withdrawal. CONCLUSIONS: In patients with AGHD under GH treatment, GH withdrawal decreases thymic T cell output, as well as intrathymic T cell proliferation. These parameters of thymus function are completely or partially restored one month after GH resumption. These data indicate that the functional integrity of the somatotrope GH/IGF-1 axis is important for the maintenance of a normal thymus function in human adults. TRIAL REGISTRATION: ClinicalTrials.gov NTC00601419. [less ▲]Detailed reference viewed: 190 (30 ULg)
Autoimmune angioneurotic edema in a patient with Helicobacter pylori infection.
; ; Giot, Jean-Baptiste et al
in Helicobacter (2009), 14(1), 9-11
Association of acquired autoimmune angioneurotic edema with other diseases is increasing. However, the precise mechanism by which antibodies to C1-esterase inhibitor (C1-INH) are produced, is not ... [more ▼]
Association of acquired autoimmune angioneurotic edema with other diseases is increasing. However, the precise mechanism by which antibodies to C1-esterase inhibitor (C1-INH) are produced, is not elucidated. We describe a patient with IgA antibodies against C1-INH without other autoimmune markers. Our patient had gastritis and Helicobacter pylori infection, proven by biopsy. This case suggests that H. pylori infection can act as triggering factor for acquired autoimmune angioneurotic edema. [less ▲]Detailed reference viewed: 58 (2 ULg)
Activation and coagulation biomarkers are independent predictors of the development of opportunistic disease in patients with HIV infection.
; ; et al
in Journal of Infectious Diseases (2009), 200(6), 973-83
BACKGROUND: Activation and coagulation biomarkers were measured within the Strategies for Management of Antiretroviral Therapy (SMART) trial. Their associations with opportunistic disease (OD) in human ... [more ▼]
BACKGROUND: Activation and coagulation biomarkers were measured within the Strategies for Management of Antiretroviral Therapy (SMART) trial. Their associations with opportunistic disease (OD) in human immunodeficiency virus (HIV)-positive patients were examined. METHODS: Inflammatory (high-sensitivity C-reactive protein [hsCRP], interleukin-6 [IL-6], amyloid-A, and amyloid-P) and coagulation (D-dimer and prothrombin-fragment 1+2) markers were determined. Conditional logistic regression analyses were used to assess associations between these biomarkers and risk of OD. RESULTS: The 91 patients who developed an OD were matched to 182 control subjects. Patients with an hsCRP level > or =5 microg/mL at baseline had a 3.5 higher odds of OD (95% confidence interval [CI], 1.5-8.1) than did those with an hsCRP level <1 microg/mL (P=.003, by test for trend) and patients with an IL-6 level > or =3 pg/mL at baseline had a 2.4 higher odds of OD (95% CI, 1.0-5.4) than did those with an IL-6 level <1.5 pg/mL (P=.02, by test for trend). No other baseline biomarkers predicted development of an OD. Latest follow-up hsCRP level for those with an hsCRP level > or =5 microg/mL (compared with a level <1 microg/mL; odds ratio [OR], 7.6; 95% CI, 2.0-28.5; [P=.002, by test for trend), latest amyloid-A level for those with an amyloid-A level > or =6 mg/L (compared with a level <2 mg/L; OR, 3.8; 95% CI, 1.1-13.4; P=.03, by test for trend), and latest IL-6 level for those with an IL-6 level > or =3 pg/mL (compared with a level <1.5 pg/mL; OR 2.4; 95% CI, 0.7-8.8; P=.04, by test for trend) were also associated with development of an OD. CONCLUSIONS: Higher IL-6 and hsCRP levels independently predicted development of OD. These biomarkers could provide additional prognostic information for predicting the risk of OD. [less ▲]Detailed reference viewed: 16 (2 ULg)
Bases immunologiques a la comprehension du concept d'anticorps monoclonal.
Moutschen, Michel ; Scheen, André
in Revue Médicale de Liège (2009), 64(5-6), 237-43
Antibodies (Ab) are molecules with dual functions: on the one hand, they bind to antigens (Ag) through their variable regions (Fab, "Fragment antigen binding"), located at one of their extremities; on the ... [more ▼]
Antibodies (Ab) are molecules with dual functions: on the one hand, they bind to antigens (Ag) through their variable regions (Fab, "Fragment antigen binding"), located at one of their extremities; on the other hand, they recruit cells of the immune system, via the other extremity, the constant region or Fc region, which results in a selective destruction of cells that have the corresponding Ag. The capacity of recognition of Ag by Ab is unique. Ag generally have several different epitopes that all are binding sites for Ab. Ab may be classified according to their ability to recognize one single epitope or several epitopes. They are called monoclonal Ab (mAb) or polyclonal Ab, respectively. MAbs recognize the same epitope because they are issued from one single line of plasmocytes, originating from one single cell. It is the reason why they are so selective. MAbs exert complex, but unique mechanisms of action: they inhibit or activate signal transduction, and they specifically drive the immune system against target cells, such as tumoral cells. After their extensive use in fundamental and in applied research as wells as diagnostic tools, mAbs are now largely exploited in therapeutics. [less ▲]Detailed reference viewed: 144 (4 ULg)
Infection humaine par le virus B du singe en Afrique
; Moutschen, Michel ; Thiry, Etienne et al
in Santé : Cahiers d'Etude et de Recherches Francophones (2008), 18(1), 3-8
Simian herpes B virus or Cercopithecine herpesvirus 1 (CeHV-1) is enzootic (80% to 100%) in Asian monkeys of the genus Macaca but is also present in other monkey species. This virus, discovered in 1933 ... [more ▼]
Simian herpes B virus or Cercopithecine herpesvirus 1 (CeHV-1) is enzootic (80% to 100%) in Asian monkeys of the genus Macaca but is also present in other monkey species. This virus, discovered in 1933, is closely related to human herpesvirus 1 and human herpesvirus 2, responsible respectively for labial and genital herpes. CeHV-1 infection is generally asymptomatic or mild in monkeys but in humans it may lead to fulminant encephalomyelitis that has an 80% lethality rate without treatment. Infections in humans are usually attributed to animal bites or scratches or to percutaneous or mucosal inoculation with infected materials from asymptomatic monkeys. Although the incidence of human infection with CeHV-1 is low, until the availability of antiviral therapy its death rate made this virus a serious zoonotic threat. Even now, good knowledge of its clinical signs and risk factors is essential for only they allow early and swift antiviral therapy (acyclovir, valacyclovir, or famciclovir) and prevent severe disease or fatal outcome. This article describes the virus, the resulting disease in human and a suspected clinical case involving a woman bit by a vervet monkey (Cercopithecus aethiops) in Garamba National Park in the Democratic Republic of the Congo. [less ▲]Detailed reference viewed: 86 (10 ULg)
Chronic hepatitis C infection in a patient with bone marrow hypoplasia.
; ; de Leval, Laurence et al
in World Journal of Gastroenterology (2008), 14(26), 4238-40
Chronic hepatitis C virus (HCV) infection is associated with multifarious extra-hepatic manifestations; the most described and discussed being mixed cryoglobulinemia which is strongly related to B-cell ... [more ▼]
Chronic hepatitis C virus (HCV) infection is associated with multifarious extra-hepatic manifestations; the most described and discussed being mixed cryoglobulinemia which is strongly related to B-cell lymphoproliferative disorders (LPDs). We present a case of chronic HCV infection and mixed cryoglobulinemia, with minimal liver involvement. The case is a 53-year-old patient who was diagnosed as having bone marrow hypoplasia at the age of three. She received several blood transfusions to normalize her haemoglobin. At the age of 31, she was diagnosed with rheumatoid arthritis on account of her diffuse joint pain and inflammation, elevated rheumatoid factor (RF) and Raynaud's phenomenon. Twenty years later, monoclonal gammopathy of IgG Lambda (one year later, changed to IgM Kappa) was detected during a routine examination. A bone marrow biopsy showed hypoplasia, Kappa positive B-lymphocytes and low-grade malignant lymphoma cells. PCR of the bone marrow aspirate was not contributory. No treatment was initiated owing to her poor bone marrow function and she is under regular follow-up. [less ▲]Detailed reference viewed: 57 (7 ULg)
Syphilis en 2008: controverses et attitudes pratiques.
Frippiat, Frédéric ; GIOT, Jean-Baptiste ; et al
in Revue Médicale Suisse (2008), 4(168), 1823-7
Rising incidence rate of syphilis is observed in economically advanced countries, particularly among homosexual men and subpopulation with low socioeconomic status. The various clinical presentations are ... [more ▼]
Rising incidence rate of syphilis is observed in economically advanced countries, particularly among homosexual men and subpopulation with low socioeconomic status. The various clinical presentations are divided into early and late stages, including neurosyphilis. The latter can occur during any stage of the disease, leading to the question "when to perform lumbar puncture", particularly in HIV positive patients. Penicillin continues to be the first-line therapy for all stages of syphilis. An alternative treatment should be considered as an exemption, after advice from a specialist. All patients require prolonged clinical and serological follow-up after treatment to rule out relapse or re-infection. The diagnosis of syphilis is an opportunity to search and treat other sexually transmitted diseases in patients and their sexual partner(s). [less ▲]Detailed reference viewed: 100 (10 ULg)
Viral resuppression and detection of drug resistance following interruption of a suppressive non-nucleoside reverse transcriptase inhibitor-based regimen.
; ; et al
in AIDS (2008), 22(17), 2279-89
BACKGROUND: Interruption of a non-nucleoside reverse transcriptase inhibitor (NNRTI)-regimen is often necessary, but must be performed with caution because NNRTIs have a low genetic barrier to resistance ... [more ▼]
BACKGROUND: Interruption of a non-nucleoside reverse transcriptase inhibitor (NNRTI)-regimen is often necessary, but must be performed with caution because NNRTIs have a low genetic barrier to resistance. Limited data exist to guide clinical practice on the best interruption strategy to use. METHODS: Patients in the drug-conservation arm of the Strategies for Management of Antiretroviral Therapy (SMART) trial who interrupted a fully suppressive NNRTI-regimen were evaluated. From 2003, SMART recommended interruption of an NNRTI by a staggered interruption, in which the NNRTI was stopped before the NRTIs, or by replacing the NNRTI with another drug before interruption. Simultaneous interruption of all antiretrovirals was discouraged. Resuppression rates 4-8 months after reinitiating NNRTI-therapy were assessed, as was the detection of drug-resistance mutations within 2 months of the treatment interruption in a subset (N = 141). RESULTS: Overall, 601/688 (87.4%) patients who restarted an NNRTI achieved viral resuppression. The adjusted odds ratio (95% confidence interval) for achieving resuppression was 1.94 (1.02-3.69) for patients with a staggered interruption and 3.64 (1.37-9.64) for those with a switched interruption compared with patients with a simultaneous interruption. At least one NNRTI-mutation was detected in the virus of 16.4% patients with simultaneous interruption, 12.5% patients with staggered interruption and 4.2% patients with switched interruption. Fewer patients with detectable mutations (i.e. 69.2%) achieved HIV-RNA of 400 copies/ml or less compared with those in whom no mutations were detected (i.e. 86.7%; P = 0.05). CONCLUSION: In patients who interrupt a suppressive NNRTI-regimen, the choice of interruption strategy may influence resuppression rates when restarting a similar regimen. NNRTI drug-resistance mutations were observed in a relatively high proportion of patients. These data provide additional support for a staggered or switched interruption strategy for NNRTI drugs. [less ▲]Detailed reference viewed: 23 (1 ULg)
In vivo administration of a PKA type I inhibitor (Rp-8-Br-cAMPS) restores T-cell responses in retrovirus-infected mice
Nayjib, Btissam ; Zeddou, Mustapha ; Drion, Pierre et al
in Open Immunol journal (2008), 1
Murine AIDS (MAIDS) is caused by infection with the murine leukemia retrovirus RadLV-Rs and is characterized by T-cell anergy and severe immunodeficiency with increased susceptibilty to several ... [more ▼]
Murine AIDS (MAIDS) is caused by infection with the murine leukemia retrovirus RadLV-Rs and is characterized by T-cell anergy and severe immunodeficiency with increased susceptibilty to several experimental opportunistic infections as observed in HIV infection. T cell anergy is associated with an increase of intracellular cAMP level, triggering a multistep pathway involving activation of PKA type I and resulting in inhibition of proximal TCR signaling. We have reviously demonstrated that blocking PKA type I using the selective inhibitor Rp-8-Br-cAMPS, restores T-cell function in vitro in MAIDS as well as in HIV infection. In the present report, we investigated the effect of parenteral administration of Rp-8-Br-cAMPS in mice with MAIDS. We show that the compound is not toxic and partially restores the ex vivo proliferative responses to anti-CD3 mAb, but that it has no effect on the lymphadenopathy and splenomegaly characterizing the MAIDS syndrome. [less ▲]Detailed reference viewed: 102 (13 ULg)
Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection.
; ; et al
in New England Journal of Medicine [=NEJM] (2008), 359(14), 1442-55
BACKGROUND: We conducted subanalyses of the combined results of the Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and MOTIVATE 2 studies to ... [more ▼]
BACKGROUND: We conducted subanalyses of the combined results of the Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and MOTIVATE 2 studies to better characterize the efficacy and safety of maraviroc in key subgroups of patients. METHODS: We analyzed pooled data from week 48 from the two studies according to sex, race or ethnic group, clade, CC chemokine receptor 5 (CCR5) delta32 genotype, viral load at the time of screening, the use or nonuse of enfuvirtide in optimized background therapy (OBT), the baseline CD4 cell count, the number of active antiretroviral drugs coadministered, the first use of selected background agents, and tropism at baseline. Changes in viral tropism and the CD4 count at treatment failure were evaluated. Data on aminotransferase levels in patients coinfected with hepatitis B virus (HBV) or hepatitis C virus (HCV) were also analyzed. RESULTS: A treatment benefit of maraviroc plus OBT over placebo plus OBT was shown in all subgroups, including patients with a low CD4 cell count at baseline, those with a high viral load at screening, and those who had not received active agents in OBT. Analyses of the virologic response according to the first use of selected background drugs showed the additional benefit of adding a potent new drug to maraviroc at the initiation of maraviroc therapy. More patients in whom maraviroc failed had a virus binding to the CXC chemokine receptor 4 (CXCR4) at failure, but there was no evidence of a decrease in the CD4 cell count at failure in such patients as compared with those in whom placebo failed. Subanalyses involving patients coinfected with HBV or HCV revealed no evidence of excess hepatotoxic effects as compared with baseline. CONCLUSIONS: Subanalyses of pooled data from week 48 indicate that maraviroc provides a valuable treatment option for a wide spectrum of patients with R5 HIV-1 infection who have been treated previously. (ClinicalTrials.gov numbers, NCT00098306 and NCT00098722.) [less ▲]Detailed reference viewed: 76 (2 ULg)
Risk for opportunistic disease and death after reinitiating continuous antiretroviral therapy in patients with HIV previously receiving episodic therapy: a randomized trial.
; ; et al
in Annals of Internal Medicine (2008), 149(5), 289-99
BACKGROUND: Episodic use of antiretroviral therapy guided by CD4+ cell counts is inferior to continuous antiretroviral therapy. OBJECTIVE: To determine whether reinitiating continuous antiretroviral ... [more ▼]
BACKGROUND: Episodic use of antiretroviral therapy guided by CD4+ cell counts is inferior to continuous antiretroviral therapy. OBJECTIVE: To determine whether reinitiating continuous antiretroviral therapy in patients who received episodic treatment reduces excess risk for opportunistic disease or death. DESIGN: Randomized, controlled trial. SETTING: Sites in 33 countries. PATIENTS: 5472 HIV-infected individuals with CD4(+) cell counts greater than 0.350 x 10(9) cells/L enrolled from January 2002 to January 2006. INTERVENTION: Episodic or continuous antiretroviral therapy initially, followed by continuous therapy in participants previously assigned to episodic treatment. MEASUREMENTS: Opportunistic disease or death was the primary outcome. RESULTS: Eighteen months after the recommendation to reinitiate continuous therapy, mean CD4+ cell counts were 0.152 x 10(9) cells/L (95% CI, 0.136 to 0.167 x 10(9) cells/L) less in participants previously assigned to episodic treatment (P < 0.001). The proportion of follow-up time spent with CD4+ cell counts of 0.500 x 10(9) cells/L or more and HIV RNA levels of 400 copies/mL or less was 29% for participants initially assigned to episodic therapy and 66% for those assigned to continuous therapy. Participants who reinitiated continuous therapy experienced rapid suppression of HIV RNA levels (89.7% with HIV RNA levels < or =400 copies/mL after 6 months), but CD4+ cell counts after 6 months remained 0.140 x 10(9) cells/L below baseline. The hazard ratio (episodic versus continuous treatment) for opportunistic disease or death decreased after the recommendation to reinitiate continuous therapy (from 2.5 [CI, 1.8 to 3.5] to 1.4 [CI, 1.0 to 2.0]; P = 0.033 for difference). The residual excess risk was attributable to failure to reinitiate therapy by some participants and slow recovery of CD4+ cell counts for those who reinitiated therapy. LIMITATION: Follow-up was too short to assess the full effect of switching from episodic to continuous antiretroviral therapy. CONCLUSION: Reinitiating continuous antiretroviral therapy in patients previously assigned to episodic treatment reduced excess risk for opportunistic disease or death, but excess risk remained. Episodic antiretroviral therapy, as used in the SMART study, should be avoided. [less ▲]Detailed reference viewed: 26 (1 ULg)
Maraviroc for previously treated patients with R5 HIV-1 infection.
; ; et al
in New England Journal of Medicine [=NEJM] (2008), 359(14), 1429-41
BACKGROUND: CC chemokine receptor 5 antagonists are a new class of antiretroviral agents. METHODS: We conducted two double-blind, placebo-controlled, phase 3 studies--Maraviroc versus Optimized Therapy in ... [more ▼]
BACKGROUND: CC chemokine receptor 5 antagonists are a new class of antiretroviral agents. METHODS: We conducted two double-blind, placebo-controlled, phase 3 studies--Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and MOTIVATE 2--with patients who had R5 human immunodeficiency virus type 1 (HIV-1) only. They had been treated with or had resistance to three antiretroviral-drug classes and had HIV-1 RNA levels of more than 5000 copies per milliliter. The patients were randomly assigned to one of three antiretroviral regimens consisting of maraviroc once daily, maraviroc twice daily, or placebo, each of which included optimized background therapy (OBT) based on treatment history and drug-resistance testing. Safety and efficacy were assessed after 48 weeks. RESULTS: A total of 1049 patients received the randomly assigned study drug; the mean baseline HIV-1 RNA level was 72,400 copies per milliliter, and the median CD4 cell count was 169 per cubic millimeter. At 48 weeks, in both studies, the mean change in HIV-1 RNA from baseline was greater with maraviroc than with placebo: -1.66 and -1.82 log(10) copies per milliliter with the once-daily and twice-daily regimens, respectively, versus -0.80 with placebo in MOTIVATE 1, and -1.72 and -1.87 log(10) copies per milliliter, respectively, versus -0.76 with placebo in MOTIVATE 2. More patients receiving maraviroc once or twice daily had HIV-1 RNA levels of less than 50 copies per milliliter (42% and 47%, respectively, vs. 16% in the placebo group in MOTIVATE 1; 45% in both maraviroc groups vs. 18% in MOTIVATE 2; P<0.001 for both comparisons in each study). The change from baseline in CD4 counts was also greater with maraviroc once or twice daily than with placebo (increases of 113 and 122 per cubic millimeter, respectively, vs. 54 in MOTIVATE 1; increases of 122 and 128 per cubic millimeter, respectively, vs. 69 in MOTIVATE 2; P<0.001 for both comparisons in each study). Frequencies of adverse events were similar among the groups. CONCLUSIONS: Maraviroc, as compared with placebo, resulted in significantly greater suppression of HIV-1 and greater increases in CD4 cell counts at 48 weeks in previously treated patients with R5 HIV-1 who were receiving OBT. (ClinicalTrials.gov numbers, NCT00098306 and NCT00098722.) [less ▲]Detailed reference viewed: 45 (2 ULg)
Cervix carcinoma is associated with an up-regulation and nuclear localization of the dual-specificity protein phosphatase VHR.
Henkens, Rachel ; Delvenne, Philippe ; et al
in BMC Cancer (2008), 8
BACKGROUND: The 21-kDa Vaccinia virus VH1-related (VHR) dual-specific protein phosphatase (encoded by the DUSP3 gene) plays a critical role in cell cycle progression and is itself regulated during the ... [more ▼]
BACKGROUND: The 21-kDa Vaccinia virus VH1-related (VHR) dual-specific protein phosphatase (encoded by the DUSP3 gene) plays a critical role in cell cycle progression and is itself regulated during the cell cycle. We have previously demonstrated using RNA interference that cells lacking VHR arrest in the G1 and G2 phases of the cell cycle and show signs of beginning of cell senescence. METHODS: In this report, we evaluated successfully the expression levels of VHR protein in 62 hysterectomy or conization specimens showing the various (pre) neoplastic cervical epithelial lesions and 35 additional cases of hysterectomy performed for non-cervical pathologies, from patients under 50 years of age. We used a tissue microarray and IHC technique to evaluate the expression of the VHR phosphatase. Immunofluorescence staining under confocal microscopy, Western blotting and RT-PCR methods were used to investigate the localization and expression levels of VHR. RESULTS: We report that VHR is upregulated in (pre) neoplastic lesions (squamous intraepithelial lesions; SILs) of the uterine cervix mainly in high grade SIL (H-SIL) compared to normal exocervix. In the invasive cancer, VHR is also highly expressed with nuclear localization in the majority of cells compared to normal tissue where VHR is always in the cytoplasm. We also report that this phosphatase is highly expressed in several cervix cancer cell lines such as HeLa, SiHa, CaSki, C33 and HT3 compared to primary keratinocytes. The immunofluorescence technique under confocal microscopy shows that VHR has a cytoplasmic localization in primary keratinocytes, while it localizes in both cytoplasm and nucleus of the cancer cell lines investigated. We report that the up-regulation of this phosphatase is mainly due to its post-translational stabilization in the cancer cell lines compared to primary keratinocytes rather than increases in the transcription of DUSP3 locus. CONCLUSION: These results together suggest that VHR can be considered as a new marker for cancer progression in cervix carcinoma and potential new target for anticancer therapy. [less ▲]Detailed reference viewed: 89 (16 ULg)
Raltegravir with optimized background therapy for resistant HIV-1 infection.
; ; et al
in New England Journal of Medicine [=NEJM] (2008), 359(4), 339-54
BACKGROUND: Raltegravir (MK-0518) is an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase active against HIV-1 susceptible or resistant to older antiretroviral drugs. METHODS: We ... [more ▼]
BACKGROUND: Raltegravir (MK-0518) is an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase active against HIV-1 susceptible or resistant to older antiretroviral drugs. METHODS: We conducted two identical trials in different geographic regions to evaluate the safety and efficacy of raltegravir, as compared with placebo, in combination with optimized background therapy, in patients infected with HIV-1 that has triple-class drug resistance in whom antiretroviral therapy had failed. Patients were randomly assigned to raltegravir or placebo in a 2:1 ratio. RESULTS: In the combined studies, 699 of 703 randomized patients (462 and 237 in the raltegravir and placebo groups, respectively) received the study drug. Seventeen of the 699 patients (2.4%) discontinued the study before week 16. Discontinuation was related to the study treatment in 13 of these 17 patients: 7 of the 462 raltegravir recipients (1.5%) and 6 of the 237 placebo recipients (2.5%). The results of the two studies were consistent. At week 16, counting noncompletion as treatment failure, 355 of 458 raltegravir recipients (77.5%) had HIV-1 RNA levels below 400 copies per milliliter, as compared with 99 of 236 placebo recipients (41.9%, P<0.001). Suppression of HIV-1 RNA to a level below 50 copies per milliliter was achieved at week 16 in 61.8% of the raltegravir recipients, as compared with 34.7% of placebo recipients, and at week 48 in 62.1% as compared with 32.9% (P<0.001 for both comparisons). Without adjustment for the length of follow-up, cancers were detected in 3.5% of raltegravir recipients and in 1.7% of placebo recipients. The overall frequencies of drug-related adverse events were similar in the raltegravir and placebo groups. CONCLUSIONS: In HIV-infected patients with limited treatment options, raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.) [less ▲]Detailed reference viewed: 59 (15 ULg)
Report of a case of Streptococcus agalactiae mycotic aneurysm and review of the literature.
; Giot, Jean-Baptiste ; de Leval, Laurence et al
in International Journal of Surgical Pathology (2008), 16(3), 314-9
A unique case of mycotic aneurysm of the abdominal aorta caused by Streptococcus agalactiae in an afebrile patient presenting with abdominal pain is described. Although this bacterium is associated with a ... [more ▼]
A unique case of mycotic aneurysm of the abdominal aorta caused by Streptococcus agalactiae in an afebrile patient presenting with abdominal pain is described. Although this bacterium is associated with a variety of infections in human beings, aortitis is uncommon. Chronic alcoholism and diabetes mellitus are the 2 major predisposing conditions for group B Streptococci infection and both were present in this case. The abdominal pain and elevated inflammatory markers in the absence of fever were elusive in presentation; however, the diagnosis of mycotic aneurysm was established by abdominal computed tomography scan. The patient was treated successfully by resection of the diseased aorta and aortic allograft replacement. Culture of the excised tissue grew Streptococcus agalactiae sensitive to penicillin G and (other commonly tested antibiotics) fluoroquinolones. A prolonged course of moxifloxacin (for 6 months) was administered due to the persistence of elevated inflammatory markers and was remarkably well tolerated. Sixteen months after stopping the antibiotics, the patient is doing well, and the control imaging studies are satisfactory. [less ▲]Detailed reference viewed: 104 (12 ULg)
Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study.
; ; et al
in Journal of Infectious Diseases (2008), 197(8), 1133-44
BACKGROUND: The SMART study randomized 5,472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts >350 cells/microL to intermittent antiretroviral therapy (ART; the drug conservation ... [more ▼]
BACKGROUND: The SMART study randomized 5,472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts >350 cells/microL to intermittent antiretroviral therapy (ART; the drug conservation [DC] group) versus continuous ART (the viral suppression [VS] group). In the DC group, participants started ART when the CD4+ cell count was <250 cells/microL. Clinical outcomes in participants not receiving ART at entry inform the early use of ART. METHODS: Patients who were either ART naive (n=249) or who had not been receiving ART for >or= 6 months (n=228) were analyzed. The following clinical outcomes were assessed: (i) opportunistic disease (OD) or death from any cause (OD/death); (ii) OD (fatal or nonfatal); (iii) serious non-AIDS events (cardiovascular, renal, and hepatic disease plus non-AIDS-defining cancers) and non-OD deaths; and (iv) the composite of outcomes (ii) and (iii). RESULTS: A total of 477 participants (228 in the DC group and 249 in the VS group) were followed (mean, 18 months). For outcome (iv), 21 and 6 events occurred in the DC (7 in ART-naive participants and 14 in those who had not received ART for >or= 6 months) and VS (2 in ART-naive participants and 4 in those who had not received ART for 6 months) groups, respectively. Hazard ratios for DC vs. VS by outcome category were as follows: outcome (i), 3.47 (95% confidence interval [CI], 1.26-9.56; p=.02); outcome (ii), 3.26 (95% CI, 1.04-10.25; p=.04); outcome (iii), 7.02 (95% CI, 1.57-31.38; p=.01); and outcome (iv), 4.19 (95% CI, 1.69-10.39; p=.002 ). CONCLUSIONS: Initiation of ART at CD4+ cell counts >350 cells/microL compared with <250 cells/microL may reduce both OD and serious non-AIDS events. These findings require validation in a large, randomized clinical trial. [less ▲]Detailed reference viewed: 200 (1 ULg)
Inferior clinical outcome of the CD4+ cell count-guided antiretroviral treatment interruption strategy in the SMART study: role of CD4+ Cell counts and HIV RNA levels during follow-up.
; ; et al
in Journal of Infectious Diseases (2008), 197(8), 1145-55
BACKGROUND AND METHODS: The SMART study compared 2 strategies for using antiretroviral therapy-drug conservation (DC) and viral suppression (VS)-in 5,472 human immunodeficiency virus (HIV)-infected ... [more ▼]
BACKGROUND AND METHODS: The SMART study compared 2 strategies for using antiretroviral therapy-drug conservation (DC) and viral suppression (VS)-in 5,472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts >350 cells/microL. Rates and predictors of opportunistic disease or death (OD/death) and the relative risk (RR) in DC versus VS groups according to the latest CD4+ cell count and HIV RNA level are reported. RESULTS: During a mean of 16 months of follow-up, DC patients spent more time with a latest CD4+ cell count <350 cells/microL (for DC vs. VS, 31% vs. 8%) and with a latest HIV RNA level >400 copies/mL (71% vs. 28%) and had a higher rate of OD/death (3.4 vs. 1.3/100 person-years) than VS patients. For periods of follow- up with a CD4+ cell count <350 cells/microL, rates of OD/death were increased but similar in the 2 groups (5.7 vs. 4.6/100 person-years), whereas the rates were higher in DC versus VS patients (2.3 vs. 1.0/100 person-years; RR, 2.3 [95% confidence interval, 1.5-3.4]) for periods with the latest CD4+ cell count >or= 350 cells/microL-an increase explained by the higher HIV RNA levels in the DC group. CONCLUSIONS: The higher risk of OD/death in DC patients was associated with (1) spending more follow-up time with relative immunodeficiency and (2) living longer with uncontrolled HIV replication even at higher CD4+ cell counts. Ongoing HIV replication at a given CD4+ cell count places patients at an excess risk of OD/death. [less ▲]Detailed reference viewed: 97 (1 ULg)
Prevalence and epidemiology of HIV type 1 drug resistance among newly diagnosed therapy-naive patients in Belgium from 2003 to 2006.
; ; et al
in AIDS Research and Human Retroviruses (2008), 24(3), 355-62
This study is the first prospective study to assess the prevalence, epidemiology, and risk factors of HIV-1 drug resistance in newly diagnosed HIV-infected patients in Belgium. In January 2003 it was ... [more ▼]
This study is the first prospective study to assess the prevalence, epidemiology, and risk factors of HIV-1 drug resistance in newly diagnosed HIV-infected patients in Belgium. In January 2003 it was initiated as part of the pan-European SPREAD program, and continued thereafter for four inclusion rounds until December 2006. Epidemiological, clinical, and behavioral data were collected using a standardized questionnaire and genotypic resistance testing was done on a sample taken within 6 months of diagnosis. Two hundred and eighty-five patients were included. The overall prevalence of transmitted HIV-1 drug resistance in Belgium was 9.5% (27/285, 95% CI: 6.6-13.4). Being infected in Belgium, which largely coincided with harboring a subtype B virus, was found to be significantly associated with transmission of drug resistance. The relatively high rate of baseline resistance might jeopardize the success of first line treatment as more than 1 out of 10 (30/285, 10.5%) viruses did not score as fully susceptible to one of the recommended first-line regimens, i.e., zidovudine, lamivudine, and efavirenz. Our results support the implementation of genotypic resistance testing as a standard of care in all treatment-naive patients in Belgium. [less ▲]Detailed reference viewed: 57 (4 ULg)
Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection.
; ; et al
in New England Journal of Medicine [=NEJM] (2008), 359(4), 355-65
BACKGROUND: We evaluated the efficacy of raltegravir and the development of viral resistance in two identical trials involving patients who were infected with human immunodeficiency virus type 1 (HIV-1 ... [more ▼]
BACKGROUND: We evaluated the efficacy of raltegravir and the development of viral resistance in two identical trials involving patients who were infected with human immunodeficiency virus type 1 (HIV-1) with triple-class drug resistance and in whom antiretroviral therapy had failed. METHODS: We conducted subgroup analyses of the data from week 48 in both studies according to baseline prognostic factors. Genotyping of the integrase gene was performed in raltegravir recipients who had virologic failure. RESULTS: Virologic responses to raltegravir were consistently superior to responses to placebo, regardless of the baseline values of HIV-1 RNA level; CD4 cell count; genotypic or phenotypic sensitivity score; use or nonuse of darunavir, enfuvirtide, or both in optimized background therapy; or demographic characteristics. Among patients in the two studies combined who were using both enfuvirtide and darunavir for the first time, HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 89% of raltegravir recipients and 68% of placebo recipients. HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 69% and 80% of the raltegravir recipients and in 47% and 57% of the placebo recipients using either darunavir or enfuvirtide for the first time, respectively. At 48 weeks, 105 of the 462 raltegravir recipients (23%) had virologic failure. Genotyping was performed in 94 raltegravir recipients with virologic failure. Integrase mutations known to be associated with phenotypic resistance to raltegravir arose during treatment in 64 patients (68%). Forty-eight of these 64 patients (75%) had two or more resistance-associated mutations. CONCLUSIONS: When combined with an optimized background regimen in both studies, a consistently favorable treatment effect of raltegravir over placebo was shown in clinically relevant subgroups of patients, including those with baseline characteristics that typically predict a poor response to antiretroviral therapy: a high HIV-1 RNA level, low CD4 cell count, and low genotypic or phenotypic sensitivity score. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.) [less ▲]Detailed reference viewed: 40 (2 ULg)