By E. Cobryn. University of Maine.
Ann Intern Med 2009; 150: 604- 612 Lucas buy dapoxetine 90 mg on line, GM generic 60mg dapoxetine visa, Metha SH purchase 30mg dapoxetine amex, Atta MG, et al. End stage renal disease and chronic kidney disease in a cohort of african- american hiv-infected and at risk- seronegative participants followed between 1988 and 2004. Acute renal failure and Fanconi syndrome in an AIDS patient on tenofovir treat- ment-case report and review of literature; J Infect 2005; 51: E61-65. Chronic renal failure among HIV-1-infected patients. Renal safety of tenofovir disoproxil fumarate in HIV -1 treatment-experienced patients with adverse events related to prior NRTI use. Assessment of safety and efficacy of abacavir/lamivudine and tenofovir/emtricitabine in treatment- naive HIV-1 infected subjects. The safety of TDF for the treatment of HIV infection in adults: the first 4 years. Cystatin C level as a marker of kidney function in human immunode- ficiency virus infection: the FRAM study. Use of glomerular filtration rate estimating equations for drug dosing in HIV-positive patients. Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Comparison of Glomerular Filtration Rate Estimates vs. HIV Medicine 2009, 10: 219- 228 Sax P, DeJesus E, Mills A, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-for- mulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double- blind, phase 3 trial, analysis of results after 48 weeks. Lancet 2012;379:2439-2448 Scherzer R, Estrella M, Li Y, et al. Association of tenofovir exposure with kidney disease risk in HIV infection. AIDS 2012, 26:867-75 Schooley RT, Ruane P, Myers RA, et al. Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study. Pathophysiologie und Pathodiagnostik HIV assoziierter Nierenerkrankungen, Nephro Script 2011;14: 21-24. Predictors of proteinuria and renal failure among women with HIV infection. Renal diseases associated with HIV infection: epidemiology, clinical course, and management. HIV-related renal disease and the utility of empiric therapy: not everyone needs to be biopsied. HIV-1-associated nephropathy and response to highly-active antiretroviral therapy. Lancet 1998, 352:783-784 Wever K, van Agtmael MA, Carr A. Incomplete reversibility of tenofovir-related renal toxicity in HIV-infected men. Nephropathy and establishment of a renal reservoir of HIV type 1 during primary infection. Minor changes in calculated creatinine clearance and anion-gap are associ- ated with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy. Kidney disease in patients with HIV Infection and AIDS. Acute renal failure in hospitalized patients with HIV: risk factors and impact on in-hospital mortality. Microalbuminuria is associated with all-cause and AIDS mortality in women with HIV infection. HIV and Cardiac Diseases ACHIM BARMEYER, MARKUS UNNEW EHR With growing age and duration of the disease, the prevalence of cardiovascular dis- eases is increasing in HIV+ patients. The increase of cardiovascular morbidity results from an elevated cardiovascular risk profile as well as being a direct consequence of HIV infection itself. Knowledge of the diagnosis and therapy of HIV-associated cardiovascular disease is becoming more and more important (Neumann 2002a, Dakin 2006).
In short order order dapoxetine 60mg amex, it th Abl1 transcripts to 1/1000 that of untreated levels ( 3 log became apparent that signiﬁcant fractions of patients could achieve reduction) deﬁned a new threshold below which events on study deep and lasting response with continued TKI therapy proven 90 mg dapoxetine, particularly 9 discount dapoxetine 60mg without a prescription,10 3 (loss of response and progression) were notably lower. During the further development advent of deﬁning this threshold, increasing numbers of patients of imatinib and subsequent generations of Bcr-Abl1 kinase inhibi- achieving high-quality remissions on TKI therapy for CML, and tors for Philadelphia chromosome–positive (Ph ) leukemia and still hematologic and CyR becoming more the norm than the exception, ongoing today, optimization of dose to maximize response, desire to increasing focus was turned onto the depth and implications of minimize both early and late toxicity, and focus on increasingly molecular response in CML. In the last several years, the quest for ﬁnality of treatment has In the last 10 years since MMR was deemed and proven to be a continued and an additional goal of “treatment-free remission” meaningful molecular threshold for CML patients on TKI therapy, (TFR) has been deﬁned as the next frontier. The functional capacity Initially in the evolution of Bcr-Abl1 kinase inhibitor therapy, of quantitative PCR as it is used broadly (good-quality academic response thresholds in CML were those historically deﬁned in and commercial laboratories) is limited to measurement down to previous eras of nonspeciﬁc cytoreductive therapy, conventional response levels of 4-5 logs below standardized untreated levels; cytotoxic chemotherapy and IFN-based therapy. The use of 2-step nested PCR11 can allow for normal or a nonelevated state and clinical ﬁndings (splenomegaly) better qualitative assessment, and newer technologies such as digital resolved. Cytogenetic response (CyR) was the mainstay of correla- PCR12 could offer reliable quantitation of smaller amounts of 234 American Society of Hematology residual transcripts. In the current era of large numbers of patients The 3-month question (or perhaps the 3- to 6-month with response beyond MMR and signiﬁcant research into the question) potential for treatment cessation and TFR, the response threshold of Certainly, with the majority of patients on imatinib achieving complete molecular remission (CMR) was born13,14 and continues to threshold CyRs within the ﬁrst year of TKI therapy, logic dictated ﬁnd its place. CMR deﬁnes a response threshold at which no closer scrutiny to speed the identiﬁcation of the minority of patients detectable transcripts are noted with a sensitivity of 4. As mentioned above, IRIS trial data International Scale (IS) baseline. In an effort to redirect away from analyzed molecular response and highlighted the beneﬁt of “early the potential misunderstanding of determining a response “com- molecular response. First demonstrated during trials of IFN and CyR and the ability to interchange was evolving. Although ultimately degree to which it would drive change in therapy. Multiple reports CCyR was itself associated with improved outcome after IFN-based conﬁrmed the 10% threshold and emphasized the prognostic value of 5-7 this response by 3 months of therapy; additional analyses21-23 noted the therapy, it is perhaps the fact that pre-TKI therapies were unlikely to engender CCyR that led to the focus on MCyR and its prognostic merit of combined 3- and 6-month assessment to more precisely deﬁne signiﬁcance as TKI therapy emerged and began clinical trials. As the role of a patient’s initial transcript levels was reexamined, strategies to be more exacting and to perhaps considered “in transit” to CCyR. CCyR has been deemed “personalize” guidelines have emerged to account for variability at and stands ﬁrmly as a response milestone affording critical protec- 23,24 diagnosis and examine the fold-reduction and “halving time” of tion against transforming disease. During the IRIS trial, early disease burden early in treatment to increase the predictive value and landmark analyses of imatinib-treated patients conﬁrmed a shorter minimize premature therapy change. The potential shift forthcoming in survival free of progression to accelerated or blastic phase CML for 3 view of early response and from what point it should be measured is patients not achieving a CCyR both at 12 and 18 months of therapy. Widely accepted progression offered by CCyR and that risk of competing events rose methods and further data validating individualized measure response for those achieving CCyR later in treatment. Further reanalysis of this landmark dataset, progression-free and overall survival. What is missing at ( 1% by 12 months) were noted to be associated with superior this time are crucial data to prove the value of intervention at 3 or 6 event-free survival and the lowest rates of progression to advanced months; that is, bringing response back on track and which strategy phase disease. This reanalysis highlighted the controversy regarding to do so. Planned and ongoing trials have incorporated this pivotal the timing and added value of MMR, noting that those with 0. Loss of CyR was noted to be more likely (26% vs 3%) for those without the added margin of MMR at 18 months. Arrows represent individual patient initial Bcr-Abl1 transcript level reduction. EMR early molecular response; CHR complete hematologic response; PCyR partial cytogenetic response; CCyR complete cytogenetic response; MMR major molecular response; MR molecular response (3,4,4. Anderson group of a large number of functional cure only a glimmer of hope, patients early in the TKI era imatinib and second-generation TKI-treated chronic phase CML aimed for PCR negative, and in Canada even formed a “Zero Club” patients critically examined the impact of ‘undetectable’ molecular for those patients having an undetectable transcript level at least response (beyond MR4. As longer-term imatinib patients and survival, this was not sustained when adjusting for lead-time bias increasing numbers of patients treated with nilotinib and dasatinib (greater time required to achieve undetectable status) by landmark gained such depths of remission, the signiﬁcance of CCyR and analysis; in addition, the notion of ‘sustained MR4. A second analysis by the remission morphed into response milestones. The current reality of Bordeaux/Lyon group examined the impact of CMR (MR4. So if not of eradication, what of controversial; the long-term follow-up of increasingly vast numbers deep molecular remission and its beneﬁts?
Mixed treatment comparison meta analysis: A meta-analytic technique that simultaneously compares multiple treatments (typical 3 or more) using both direct and indirect evidence dapoxetine 30mg visa. The multiple treatments form a network of treatment comparisons purchase dapoxetine 60mg amex. Also called multiple treatment comparisons generic 90mg dapoxetine with mastercard, network analysis, or umbrella reviews. Monotherapy: the use of a single drug to treat a particular disorder or disease. Multivariate analysis: Measuring the impact of more than one variable at a time while analyzing a set of data. N-of-1 trial: A randomized trial in an individual to determine the optimum treatment for that individual. Noninferiority trial: A trial designed to determine whether the effect of a new treatment is not worse than a standard treatment by more than a prespecified amount. Nonrandomized study: Any study estimating the effectiveness (harm or benefit) of an intervention that does not use randomization to allocate patients to comparison groups. There are many types of nonrandomized studies, including cohort studies, case-control studies, and before- after studies. Null hypothesis: The statistical hypothesis that one variable (for example, treatment to which a participant was allocated) has no association with another variable or set of variables. Number needed to harm: The number of people who would need to be treated over a specific period of time before one bad outcome of the treatment will occur. The number needed to harm (NNH) for a treatment can be known only if clinical trials of the treatment have been performed. Number needed to treat: An estimate of how many persons need to receive a treatment before one person would experience a beneficial outcome. Observational study: A type of nonrandomized study in which the investigators do not seek to intervene, instead simply observing the course of events. Odds ratio: The ratio of the odds of an event in one group to the odds of an event in another group. Off-label use: When a drug or device is prescribed outside its specific FDA-approved indication, to treat a condition or disease for which it is not specifically licensed. Outcome: The result of care and treatment and/ or rehabilitation. In other words, the change in health, functional ability, symptoms or situation of a person, which can be used to measure the effectiveness of care/treatment/rehabilitation. Researchers should decide what outcomes to measure before a study begins; outcomes are then assessed at the end of the study. Outcome measure: Is the way in which an outcome is evaluated---the device (scale) used for measuring. One-tailed test (one-sided test): A hypothesis test in which the values that reject the null hypothesis are located entirely in one tail of the probability distribution. For example, testing whether one treatment is better than another (rather than testing whether one treatment is either better or worse than another). Open-label trial: A clinical trial in which the investigator and participant are aware which intervention is being used for which participant (that is, not blinded). Random allocation may or may not be used in open-label trials. Per protocol: The subset of participants from a randomized controlled trial who complied with the protocol sufficiently to ensure that their data would be likely to exhibit the effect of treatment. Per protocol analyses are sometimes misidentified in published trials as intention-to- treat analyses. Pharmacokinetics: the characteristic interactions of a drug and the body in terms of its absorption, distribution, metabolism, and excretion. Placebo: An inactive substance commonly called a "sugar pill. It does not contain anything that could harm a person.
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