Humanized mice as a useful model to study HIV-1 induced immune activation, its mechanisms and potential therapeutic approaches
; ; VAIRA, Dolorès et al
in Retrovirology (2011, October 03), 8
Recent understanding of HIV-1 pathogenesis mechanism has changed our views about possible mechanisms of CD4T-cell depletion during infection. Apart from HIV-1-mediated killing a more comprehensive ... [more ▼]
Recent understanding of HIV-1 pathogenesis mechanism has changed our views about possible mechanisms of CD4T-cell depletion during infection. Apart from HIV-1-mediated killing a more comprehensive explanation has appeared that includes T cell exhaustion and chronic immune activation as a central feature in HIV-1 pathogenesis. While highly active antiretroviral therapy (HAART) markedly reduces viral load, T cell activation levels and soluble markers of inflammation remain abnormally high. Markers of chronic activation, such as CD38, PD-1 or HLA-DR on T cells, appear to be better predictors for clinical progression during HIV infection than HIV RNA levels and CD4Tcell counts alone. Therefore, a better understanding of HIV-índuced immune activation and the design of new immunomodulatory approches in combination with HAART are needed. We have generated an efficient model of human stem cells (HSCs) engraftment in NOD/LtsZ-scidlL-2Rnull (NSG) mice that supports chronic HIV infection with high plasma viral loads. HIV-1 infection in these humanized mice is characterized by widespread immune activation with increased expression of PD-1, HLA-DR, CD38, CD69, CD25 and other immune activation markers. These humanized mice provide an effective in vivo system for the assessing novel approaches for their potential in suppressing chronic immune activation during HIV-1 infection, in absence of interference of antiretroviral therapy. In this study, we evaluated in vivo the benefits of two novel approaches aimed at reducing HIV-induced immune activation. Minocycline is an antibiotic of the tetracycline family with anti-inflammatory and immunomodulatory properties affecting CD4 T cells activation by a mechanism involving the inhibition of the NF-AT1 transcription factor activity. We hypothesized that this antibiotic could suppress the HIV-1-induced chronic immune activation and thus, limit the HIV pathogenesis when combined to HAART. Therefore, we treated HIV-1 (JRCSF) infected-humanized NSG mice with minocycline (100mg/kg/day) for 60 days. We next evaluated the expression, by flow cytometry, of several T cells activation markers together with CD4+T cells counts. Our data suggest that minocycline is effective in suppressing HIV-1 induced immune activation in peripheral blood and lymphoid organs (spleen, lymph nodes and bone marrow). Levels of cellular immune activation markers such as PD-1, HLA-DR, CD38, CD69, CD25, CD28 and CTLA-4 were significantly lower in minocycline treated group. These immunological benefits of minocycline were correlated with higher CD4+T cell counts in the treated group. The immune activation which is associated with retroviral infection is also associated with increased levels of intracytoplasmic cyclic AMP which could act as a positive feedback loop in the infection since several reports have suggested that cAMP and downstream signaling pathways play an important role in the permissivity of susceptible cells to HIV infection and replication. We have used a peptide which prevents the binding of the catalytic subunit of PKA type I to its anchoring protein and therefore blocks most effects of cyclic AMP within lymphocytes and monocytes (RIAD peptide). Mice were treated with 3.5 mg/kg of RIAD peptide weekly. Treatment of humanized mice with RIAD peptide limited viral replication after high dose of HIV intraperitoneal challenge and reduced the intracytoplasmic levels of cyclic AMP. Further experiments are needed to better appreciate the therapeutic potential of these novel therapies in the suppression of HIV-induced chronic immune activation. [less ▲]Detailed reference viewed: 22 (1 ULg)
Mucosal junctions: open doors to HPV and HIV infections?
Herfs, Michael ; Hubert, Pascale ; Moutschen, Michel et al
in Trends in microbiology (2011), 19(3), 114-120
Throughout adult life, new developmental commitment of adult stem cells causes reversible epithelial replacements in various mucosal surfaces, including the uterine cervix and the anal canal. Located at ... [more ▼]
Throughout adult life, new developmental commitment of adult stem cells causes reversible epithelial replacements in various mucosal surfaces, including the uterine cervix and the anal canal. Located at the squamocolumnar junctions, these metaplastic conversions are associated with chronic inflammation and deregulated expression of soluble and cell-membrane factors important for antiviral immune response. In this paper, we propose that these histological and immunological features increase the susceptibility of these metaplastic microenvironments to human papillomavirus and human immunodeficiency virus infections. Identification of the anatomical sites and cell populations within the anogenital tract, which is the site primary infected by these viruses, is crucial for the understanding of the pathogenesis of viral disease and development of antiviral strategies. [less ▲]Detailed reference viewed: 37 (10 ULg)
A pauci-symptomatic case of documented Hantavirus (Puumala) infection in a patient under anti-TNF treatment.
; Bourhaba, Maryam ; FRIPPIAT, Frédéric et al
in Journal of Clinical Virology (2011), 50(3), 247-8
We describe the case of an 18-yr-old male under anti-TNF treatment for Crohn's disease for more than 8 months. He developed fever and biological inflammatory syndrome without absolutely no accompanying ... [more ▼]
We describe the case of an 18-yr-old male under anti-TNF treatment for Crohn's disease for more than 8 months. He developed fever and biological inflammatory syndrome without absolutely no accompanying sign or symptom or paraclinical abnormality despite extensive work-up performed in the context of his immunocompromised state. Symptoms disappeared after 10 days and a diagnosis of Puumala infection was made retrospectively on a serological basis. The case illustrates that anti-TNF treatment does not worsen the course of Puumala infection and could even be associated with a milder clinical picture. [less ▲]Detailed reference viewed: 63 (13 ULg)
Mice with Disrupted Type I Protein Kinase A Anchoring in T Cells Resist Retrovirus-Induced Immunodeficiency
; ; et al
in Journal of Immunology (2011), 186(9), 5119-30
Type I protein kinase A (PKA) is targeted to the TCR-proximal signaling machinery by the A-kinase anchoring protein ezrin and negatively regulates T cell immune function through activation of the C ... [more ▼]
Type I protein kinase A (PKA) is targeted to the TCR-proximal signaling machinery by the A-kinase anchoring protein ezrin and negatively regulates T cell immune function through activation of the C-terminal Src kinase. RI anchoring disruptor (RIAD) is a high-affinity competitor peptide that specifically displaces type I PKA from A-kinase anchoring proteins. In this study, we disrupted type I PKA anchoring in peripheral T cells by expressing a soluble ezrin fragment with RIAD inserted in place of the endogenous A-kinase binding domain under the lck distal promoter in mice. Peripheral T cells from mice expressing the RIAD fusion protein (RIAD-transgenic mice) displayed augmented basal and TCR-activated signaling, enhanced T cell responsiveness assessed as IL-2 secretion, and reduced sensitivity to PGE2- and cAMP-mediated inhibition of T cell function. Hyperactivation of the cAMP–type I PKA pathway is involved in the T cell dysfunction of HIV infection, as well as murine AIDS, a disease model induced by infection of C57BL/6 mice with LP-BM5, a mixture of attenuated murine leukemia viruses. LP-BM5–infected RIADtransgenic mice resist progression of murine AIDS and have improved viral control. This underscores the cAMP–type I PKA pathway in T cells as a putative target for therapeutic intervention in immunodeficiency diseases. [less ▲]Detailed reference viewed: 44 (6 ULg)
Syphilis treatment in the human immunodeficiency virus-infected patient: follow the guidelines.
FRIPPIAT, Frédéric ; Moutschen, Michel
in Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America (2011), 53(8), 845Detailed reference viewed: 43 (3 ULg)
Comparison of phenotypic and genotypic tropism determination in triple-class-experienced HIV patients eligible for maraviroc treatment.
; ; et al
in Journal of Antimicrobial Chemotherapy (2011), 66(2), 265-72
BACKGROUND: Determination of HIV-1 tropism is a pre-requisite to the use of CCR5 antagonists. This study evaluated the potential of population genotypic tropism tests (GTTs) in clinical practice, and the ... [more ▼]
BACKGROUND: Determination of HIV-1 tropism is a pre-requisite to the use of CCR5 antagonists. This study evaluated the potential of population genotypic tropism tests (GTTs) in clinical practice, and the correlation with phenotypic tropism tests (PTTs) in patients accessing routine HIV care. METHODS: Forty-nine consecutive plasma samples for which an original Trofile(TM) assay was performed were obtained from triple-class-experienced patients in need of a therapy change. Viral tropism was defined as the consensus of three or more tropism calls obtained from the combination of two independent population PTT assays (Trofile Biosciences, San Francisco, CA, USA, and Virco, Beerse, Belgium), population GTTs and GTTs based on ultra-deep sequencing. If no consensus was reached, a clonal PTT was performed in order to finalize the tropism call. This two-step approach allowed the definition of a reference tropism call. RESULTS: According to the reference tropism result, 35/49 samples were CCR5 tropic (R5) (patients eligible for maraviroc treatment) and 14/49 were assigned as non-R5 tropic. The non-R5 samples [patients not eligible for maraviroc treatment according to the FDA/European Medicines Agency (EMEA) label] group included both the CXCR4 (X4) samples and the dual and mixed CCR5/CXCR4 (R5/X4) samples. Compared with Trofile(TM) population PTTs, population GTTs showed a higher sensitivity (97%) and a higher negative predictive value (91%), but almost equal specificity and an equal positive predictive value. CONCLUSIONS: In line with recent reports from clinical trial data, our data support the use of population genotypic tropism testing as a tool for tropism determination before the start of maraviroc. [less ▲]Detailed reference viewed: 51 (6 ULg)
Des interactions complexes entre les origines du VIH et sa pandemie, les activites coloniales en Afrique et la medecine coloniale Belge au Congo
DOUPAGNE, Gaëlle ; ; Moutschen, Michel
in Revue Médicale de Liège (2011), 66(9), 478-84
In this review article on the origin of HIV, we start from a historical fact which involved physicians from Liege working in Belgian Congo: the vaccination against polio of hundreds of thousands of ... [more ▼]
In this review article on the origin of HIV, we start from a historical fact which involved physicians from Liege working in Belgian Congo: the vaccination against polio of hundreds of thousands of Congolese between 1957 and 1960. We explain the genesis of an alternative hypothesis postulating that this campaign was at the origin of HIV pandemy. We show that the hypothesis is unfounded in view of genetic and epidemiological evidence on the one hand and after thorough examination of the activity reports of the Laboratoire Medical de Stanleyville on the other. In the second part of the article, we analyse the importance of other factors which might have contributed to the emergence of the pandemy. Some of these are clearly iatrogenic such as the prophylactic injections of pentamidine against trypanosomiasis, others are of demographic and sociological nature. All of them have a direct link with colonisation. [less ▲]Detailed reference viewed: 139 (14 ULg)
Vaccinations in patients with immune-mediated inflammatory diseases.
; Moutschen, Michel ; et al
in Rheumatology (2010), 49(10), 1815-27
Patients with immune-mediated inflammatory diseases (IMID) such as RA, IBD or psoriasis, are at increased risk of infection, partially because of the disease itself, but mostly because of treatment with ... [more ▼]
Patients with immune-mediated inflammatory diseases (IMID) such as RA, IBD or psoriasis, are at increased risk of infection, partially because of the disease itself, but mostly because of treatment with immunomodulatory or immunosuppressive drugs. In spite of their elevated risk for vaccine-preventable disease, vaccination coverage in IMID patients is surprisingly low. This review summarizes current literature data on vaccine safety and efficacy in IMID patients treated with immunosuppressive or immunomodulatory drugs and formulates best-practice recommendations on vaccination in this population. Especially in the current era of biological therapies, including TNF-blocking agents, special consideration should be given to vaccination strategies in IMID patients. Clinical evidence indicates that immunization of IMID patients does not increase clinical or laboratory parameters of disease activity. Live vaccines are contraindicated in immunocompromized individuals, but non-live vaccines can safely be given. Although the reduced quality of the immune response in patients under immunotherapy may have a negative impact on vaccination efficacy in this population, adequate humoral response to vaccination in IMID patients has been demonstrated for hepatitis B, influenza and pneumococcal vaccination. Vaccination status is best checked and updated before the start of immunomodulatory therapy: live vaccines are not contraindicated at that time and inactivated vaccines elicit an optimal immune response in immunocompetent individuals. [less ▲]Detailed reference viewed: 45 (8 ULg)
Thymic self-antigens for the design of a negative/tolerogenic self-vaccination against type 1 diabetes.
Geenen, Vincent ; Mottet, Marie ; Dardenne, Olivier et al
in Current Opinion in Pharmacology (2010), 10
Before being able to react against infectious non-self antigens, the immune system has to be educated in the recognition and tolerance of neuroendocrine proteins and this critical process takes place only ... [more ▼]
Before being able to react against infectious non-self antigens, the immune system has to be educated in the recognition and tolerance of neuroendocrine proteins and this critical process takes place only in the thymus. The development of the autoimmune diabetogenic response results from a thymus dysfunction in programming central self-tolerance to pancreatic insulin-secreting islet β cells, leading to the breakdown of immune homeostasis with an enrichment of islet β-cell reactive effector T cells and a deficiency of β-cell specific natural regulatory T cells (nTregs) in the peripheral T-lymphocyte repertoire. Insulin-like growth factor 2 (IGF-2) is the dominant member of the insulin family expressed during fetal life by the thymic epithelium under the control of the autoimmune regulator (AIRE) gene/protein. The very low degree of insulin gene transcription in normal murine and human thymus explains why the insulin protein is poorly tolerogenic as evidenced in many studies, including the failure of all clinical trials that have attempted immune tolerance to islet β cells via various methods of insulin administration. Based on the close homology and cross-tolerance between insulin, the primary T1D autoantigen, and IGF-2, the dominant self-antigen of the insulin family, a novel type of vaccination, so-called “negative/tolerogenic self-vaccination”, is currently being developed for prevention and cure of T1D. If this approach were found to be effective for reprogramming immunological tolerance in T1D, it could pave the way for the design of other self-vaccines against autoimmune endocrine diseases, as well as other organ-specific autoimmune diseases. [less ▲]Detailed reference viewed: 54 (17 ULg)
Fibromyalgie et affections voisines : analyse du comportement électromyographique au cours d’un effort musculaire isométrique
Maquet, Didier ; Croisier, Jean-Louis ; Dupont, Catherine et al
in Revue du Rhumatisme (2010), 77Detailed reference viewed: 146 (20 ULg)
Long-term efficacy and safety of Raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 phase iii trials.
; ; et al
in Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America (2010), 50(4), 605-12
BENCHMRK-1 and -2 are ongoing double-blind phase III studies of raltegravir in patients experiencing failure of antiretroviral therapy with triple-class drug-resistant human immunodeficiency virus ... [more ▼]
BENCHMRK-1 and -2 are ongoing double-blind phase III studies of raltegravir in patients experiencing failure of antiretroviral therapy with triple-class drug-resistant human immunodeficiency virus infection. At week 96 (combined data), raltegravir (400 mg twice daily) plus optimized background therapy was generally well tolerated, with superior and durable antiretroviral and immunological efficacy, compared with optimized background therapy alone. [less ▲]Detailed reference viewed: 24 (2 ULg)
Fibromyalgia and related conditions: Electromyogram profile during isometric muscle contraction
Maquet, Didier ; Croisier, Jean-Louis ; Dupont, Catherine et al
in Joint Bone Spine (2010), 77
Objectives: To evaluate electromyogram (EMG) profiles in patients with three related conditions: fibromyalgia, chronic fatigue syndrome, and depression. Methods: We studied 44 healthy volunteers, 22 ... [more ▼]
Objectives: To evaluate electromyogram (EMG) profiles in patients with three related conditions: fibromyalgia, chronic fatigue syndrome, and depression. Methods: We studied 44 healthy volunteers, 22 patients with fibromyalgia, 11 patients with chronic fatigue syndrome, and 10 patients admitted for depression. The trapezius electromyogram was recorded during maximally sustained, bilateral, 90◦ abduction of the shoulders. EMG signal frequency and amplitude were measured throughout the test. Results: In the fibromyalgia group, isometric contraction duration was significantly shorter than in the other two patient groups (P < 0.001) and the EMG frequency and amplitude pattern indicated premature discontinuation of the muscle contraction. Findings in the chronic fatigue patients were similar to those in the healthy controls. The patients with depression had a distinctive EMG profile characterized by excessive initial motor-unit recruitment with a shift in the frequency spectrum. Conclusions: Fibromyalgia was associated with a specific EMG pattern indicating premature discontinuation of the muscle contraction. Therefore, maximal voluntary muscle contraction tests may be of limited value for assessing function in fibromyalgia patients. Chronic fatigue syndrome patients had similar EMG findings to those in the healthy controls. The EMG alterations in the patients with depression were consistent with manifestations of psychomotor retardation. [less ▲]Detailed reference viewed: 77 (17 ULg)
Epidemiology, assessment, and management of excess abdominal fat in persons with HIV infection.
; Moutschen, Michel ; et al
in AIDS Reviews (2010), 12(1), 3-14
Metabolic and morphologic abnormalities in persons with HIV remain common contributors to stigma and morbidity. Increased abdominal circumference and visceral adiposity were first recognized in the late ... [more ▼]
Metabolic and morphologic abnormalities in persons with HIV remain common contributors to stigma and morbidity. Increased abdominal circumference and visceral adiposity were first recognized in the late 1990s, soon after the advent of effective combination antiretroviral therapy. Visceral adiposity is commonly associated with metabolic abnormalities including low HDL-cholesterol, raised triglycerides, insulin resistance, and hypertension, a constellation of risk factors for cardiovascular disease and diabetes mellitus known as "the metabolic syndrome". Medline and conference abstracts were searched to identify clinical research on factors associated with visceral adiposity and randomized studies of management approaches. Data were critically reviewed by physicians familiar with the field. A range of host and lifestyle factors as well as antiretroviral drug choice were associated with increased visceral adiposity. Management approaches included treatment switching and metformin, both of which have shown benefit for insulin-resistant individuals with isolated fat accumulation. Testosterone supplements may also have benefits in a subset of individuals. Supra-physiological doses of recombinant human growth hormone and the growth hormone releasing hormone analog tesamorelin both significantly and selectively reduce visceral fat over 12-24 weeks; however, the benefits are only maintained if doping is continued. In summary, the prevention and management of visceral adiposity remains a substantial challenge in clinical practice. [less ▲]Detailed reference viewed: 25 (2 ULg)
HIV-1 V3 envelope deep sequencing for clinical plasma specimens failing in phenotypic tropism assays.
; ; et al
in AIDS Research and Therapy (2010), 7
ABSTRACT : BACKGROUND : HIV-1 infected patients for whom standard gp160 phenotypic tropism testing failed are currently excluded from co-receptor antagonist treatment. To provide patients with maximal ... [more ▼]
ABSTRACT : BACKGROUND : HIV-1 infected patients for whom standard gp160 phenotypic tropism testing failed are currently excluded from co-receptor antagonist treatment. To provide patients with maximal treatment options, massively parallel sequencing of the envelope V3 domain, in combination with tropism prediction tools, was evaluated as an alternative tropism determination strategy. Plasma samples from twelve HIV-1 infected individuals with failing phenotyping results were available. The samples were submitted to massive parallel sequencing and to confirmatory recombinant phenotyping using a fraction of the gp120 domain. RESULTS : A cut-off for sequence reads interpretation of 5 to10 times the sequencing error rate (0.2%) was implemented. On average, each sample contained 7 different V3 haplotypes. V3 haplotypes were submitted to tropism prediction algorithms, and 4/14 samples returned with presence of a dual/mixed (D/M) tropic virus, respectively at 3%, 10%, 11%, and 95% of the viral quasispecies. V3 tropism prediction was confirmed by gp120 phenotyping, except for two out of 4 D/M predicted viruses (with 3 and 95%) which were phenotypically R5-tropic. In the first case, the result was discordant due to the limit of detection for the phenotyping technology, while in the latter case the prediction algorithms were not computing the viral tropism correctly. CONCLUSIONS : Although only demonstrated on a limited set of samples, the potential of the combined use of "deep sequencing + prediction algorithms" in cases where routine gp160 phenotype testing cannot be employed was illustrated. While good concordance was observed between gp120 phenotyping and prediction of R5-tropic virus, the results suggest that accurate prediction of X4-tropic virus would require further algorithm development. [less ▲]Detailed reference viewed: 60 (13 ULg)
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: 83 (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: 23 (3 ULg)