Multidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cells.
; Vossius, Sofie ; Rahmouni, Souad et al
in Journal of Medicinal Chemistry (2009), 52(21), 6716-23
Loss of VHR phosphatase causes cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells. We recently reported that VHR is ... [more ▼]
Loss of VHR phosphatase causes cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells. We recently reported that VHR is upregulated in several cervix cancer cell lines as well as in carcinomas of the uterine cervix. Here we report the development of multidentate small-molecule inhibitors of VHR that inhibit its enzymatic activity at nanomolar concentrations and exhibit antiproliferative effects on cervix cancer cells. Chemical library screening was used to identify hit compounds, which were further prioritized in profiling and kinetic experiments. SAR analysis was applied in the search for analogs with improved potency and selectivity, resulting in the discovery of novel inhibitors that are able to interact with both the phosphate-binding pocket and several distinct hydrophobic regions within VHR’s active site. This multidentate binding mode was confirmed by X-ray crystallography. The inhibitors decreased the proliferation of cervix cancer cells, while growth of primary normal keratinocytes was not affected. These compounds may be a starting point to develop drugs for the treatment of cervical cancer. [less ▲]Detailed reference viewed: 77 (24 ULg)
Synergistic activation of HIV-1 expression by deacetylase inhibitors and prostratin: implications for treatment of latent infection
; ; et al
in PLoS ONE (2009), 4(6), 6093
The persistence of transcriptionally silent but replication-competent HIV-1 reservoirs in Highly Active Anti-Retroviral Therapy (HAART)-treated infected individuals, represents a major hurdle to virus ... [more ▼]
The persistence of transcriptionally silent but replication-competent HIV-1 reservoirs in Highly Active Anti-Retroviral Therapy (HAART)-treated infected individuals, represents a major hurdle to virus eradication. Activation of HIV-1 gene expression in these cells together with an efficient HAART has been proposed as an adjuvant therapy aimed at decreasing the pool of latent viral reservoirs. Using the latently-infected U1 monocytic cell line and latently-infected J-Lat T-cell clones, we here demonstrated a strong synergistic activation of HIV-1 production by clinically used histone deacetylase inhibitors (HDACIs) combined with prostratin, a non-tumor-promoting nuclear factor (NF)- kappaB inducer. In J-Lat cells, we showed that this synergism was due, at least partially, to the synergistic recruitment of unresponsive cells into the expressing cell population. A combination of prostratin+HDACI synergistically activated the 5' Long Terminal Repeat (5'LTR) from HIV-1 Major group subtypes representing the most prevalent viral genetic forms, as shown by transient transfection reporter assays. Mechanistically, HDACIs increased prostratin-induced DNA-binding activity of nuclear NF-kappaB and degradation of cytoplasmic NF-kappaB inhibitor, IkappaBalpha . Moreover, the combined treatment prostratin+HDACI caused a more pronounced nucleosomal remodeling in the U1 viral promoter region than the treatments with the compounds alone. This more pronounced remodeling correlated with a synergistic reactivation of HIV-1 transcription following the combined treatment prostratin+HDACI, as demonstrated by measuring recruitment of RNA polymerase II to the 5'LTR and both initiated and elongated transcripts. The physiological relevance of the prostratin+HDACI synergism was shown in CD8(+)-depleted peripheral blood mononuclear cells from HAART-treated patients with undetectable viral load. Moreover, this combined treatment reactivated viral replication in resting CD4(+) T cells isolated from similar patients. Our results suggest that combinations of different kinds of proviral activators may have important implications for reducing the size of latent HIV-1 reservoirs in HAART-treated patients. [less ▲]Detailed reference viewed: 84 (12 ULg)
Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled 48 week analysis of two randomized, controlled trials.
; ; et al
in AIDS (2009), 23(17), 2289-300
OBJECTIVE: To evaluate the efficacy, safety and virologic resistance profile of etravirine (TMC125), a next-generation nonnucleoside reverse transcriptase inhibitor, over 48 weeks in treatment-experienced ... [more ▼]
OBJECTIVE: To evaluate the efficacy, safety and virologic resistance profile of etravirine (TMC125), a next-generation nonnucleoside reverse transcriptase inhibitor, over 48 weeks in treatment-experienced adults infected with HIV-1 strains resistant to a nonnucleoside reverse transcriptase inhibitor and other antiretrovirals. DESIGN: DUET-1 (NCT00254046) and DUET-2 (NCT00255099) are two identically designed, randomized, double-blind phase III trials. METHODS: Patients received twice-daily etravirine 200 mg or placebo, each plus a background regimen of darunavir/ritonavir, investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors and optional enfuvirtide. Eligible patients had documented nonnucleoside reverse transcriptase inhibitor resistance, at least three primary protease inhibitor mutations at screening and were on a stable but virologically failing regimen for at least 8 weeks, with plasma viral load more than 5000 copies/ml. Pooled 48-week data from the two trials are presented. RESULTS: Patients (1203) were randomized and treated (n = 599, etravirine; n = 604, placebo). Significantly more patients in the etravirine than in the placebo group achieved viral load less than 50 copies/ml at week 48 (61 vs. 40%, respectively; P < 0.0001). Significantly fewer patients in the etravirine group experienced at least one confirmed or probable AIDS-defining illness/death (6 vs. 10%; P = 0.0408). Safety and tolerability in the etravirine group was comparable to the placebo group. Rash was the only adverse event to occur at a significantly higher incidence in the etravirine group (19 vs. 11%, respectively, P < 0.0001), occurring primarily in the second week of treatment. CONCLUSION: At 48 weeks, treatment-experienced patients receiving etravirine plus background regimen had statistically superior and durable virologic responses (viral load less than 50 copies/ml) than those receiving placebo plus background regimen, with comparable tolerability and no new safety signals reported since week 24. [less ▲]Detailed reference viewed: 29 (2 ULg)
Interruption of antiretroviral therapy is associated with increased plasma cystatin C.
; ; et al
in AIDS (2009), 23(1), 71-82
BACKGROUND: Cystatin C has been proposed as an alternative marker of renal function. We sought to determine whether participants randomized to episodic use of antiretroviral therapy guided by CD4 cell ... [more ▼]
BACKGROUND: Cystatin C has been proposed as an alternative marker of renal function. We sought to determine whether participants randomized to episodic use of antiretroviral therapy guided by CD4 cell count (drug conservation) had altered cystatin C levels compared with those randomized to continuous antiretroviral therapy (viral suppression) in the Strategies for Management of Antiretroviral Therapy trial, and to identify factors associated with increased cystatin C. METHODS: Cystatin C was measured in plasma collected at randomization, 1, 2, 4, 8 and 12 months after randomization in a random sample of 249 and 250 participants in the drug conservation and viral suppression groups, respectively. Logistic regression was used to model the odds of at least 0.15 mg/dl increase in cystatin C (1 SD) in the first month after randomization, adjusting for demographic and clinical characteristics. RESULTS: At randomization, mean (SD) cystatin C level was 0.99 (0.26 mg/dl) and 1.01 (0.28 mg/dl) in the drug conservation and viral suppression arms, respectively (P = 0.29). In the first month after randomization, 21.8 and 10.6% had at least 0.15 mg/dl increase in cystatin C in the drug conservation and viral suppression arms, respectively (P = 0.0008). The difference in cystatin C between the treatment arms was maintained through 1 year after randomization. After adjustment, participants in the viral suppression arm had significantly reduced odds of at least 0.15 mg/dl increase in cystatin C in the first month (odds ratio 0.42; 95% confidence interval 0.23-0.74, P = 0.0023). CONCLUSION: These results demonstrate that interruption of antiretroviral therapy is associated with an increase in cystatin C, which may reflect worsened renal function. [less ▲]Detailed reference viewed: 24 (3 ULg)
Selective defect of anti-pneumococcal IgG in a patient with persistent polyclonal B cell lymphocytosis.
Hafraoui, Kaoutar ; Moutschen, Michel ; et al
in European Journal of Internal Medicine (2009), 20(3), 62-5
BACKGROUND: Persistent polyclonal B cell lymphocytosis (PPBL) is a rare condition characterized by increased IgM and large excess of B cells with an IgD(+) CD27(+) phenotype. In normal individuals, these ... [more ▼]
BACKGROUND: Persistent polyclonal B cell lymphocytosis (PPBL) is a rare condition characterized by increased IgM and large excess of B cells with an IgD(+) CD27(+) phenotype. In normal individuals, these cells play a central role in the defense against pneumococcal infection. So far, few studies have characterized humoral immune responses in PPBL patients. We therefore measured IgG directed against S. pneumoniae antigens in a 51 yr-old woman with PPBL before and after vaccination with a pneumococcal 23-valent polysaccharide vaccine. METHODS: Antibodies against pneumococcal antigens were measured first with an overall immunoassay using microplates coated with the 23-valent pneumococcal vaccine. A serotype-specific test was also performed according to the WHO consensus protocol. RESULTS: Despite a large number of IgD(+) CD27(+) cells, our patient had low baseline titers of IgG directed against pneumococcal antigens and did not significantly respond to a 23-valent polysaccharide vaccine against S. pneumoniae. On the contrary, she had good titers of IgG directed against tetanus toxoid. CONCLUSION: IgM(+) IgD(+) CD27(+) cells which accumulate in this patient with typical PPBL patient failed to perform IgG isotype switch after a polysaccharide vaccine. The potential mechanisms and relationships with the main features of PPBL are discussed. Further studies on a larger number of similar patients are needed. [less ▲]Detailed reference viewed: 40 (10 ULg)
Triom une: la tritherapie du pauvre ?
; ; Vaira, Dolorès et al
in Revue Médicale de Liège (2009), 64(1), 32-6
Despite a relative global stabilization of its incidence, HIV infection remains a major threat for public health, principally in Africa where it concerns more than 22 million people and constitutes the ... [more ▼]
Despite a relative global stabilization of its incidence, HIV infection remains a major threat for public health, principally in Africa where it concerns more than 22 million people and constitutes the first cause of death on the continent. To face the emergency of the HIV/AIDS epidemics on the African continent, the primary goal is to make available to all patients free and efficient antiretroviral medications. Such a goal cannot be dissociated from large scale prevention campaigns. In 2000, Triomune, one of the first fixed dose combinations of three antiretrovirals (stavudine, lamivudine & nevirapine) was launched by the Indian drug company Cipla, specialized in the production of low cost medications. Its convenient pill burden (one pill twice a day) and its very low cost (around 30 US $ per month) make Triomune an appealing solution for the treatment of HIV/AIDS in Africa. Unfortunately, Triomune presents several drawbacks (low genetic barrier, frequent side effects) and one of its constituents is not used in Europe anymore. Other first line treatments are urgently needed. [less ▲]Detailed reference viewed: 56 (6 ULg)
Gentamicin in infective endocarditis: how to use it?
Frippiat, Frédéric ; ; Moutschen, Michel
in Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America (2009), 49(2), 320-1321Detailed reference viewed: 28 (1 ULg)
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: 192 (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: 68 (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: 161 (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: 93 (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: 59 (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: 101 (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: 25 (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: 116 (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: 79 (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: 46 (2 ULg)