Multivariable analysis found that there was an increased risk of death or rehospitalization for ACS in those patients taking both clopidogrel and a proton pump inhibitor; adjusted odds ratio 1 quality bentyl 10mg. The analysis controlled for multiple variables order 10 mg bentyl with amex, included demographic characteristics 10 mg bentyl visa, comorbidities buy 10 mg bentyl with amex, previous cardiac history, and other medications. In patients who had period with and without a proton pump inhibitor, but continued clopidogrel use, the risk of the primary outcome was also increased during the proton pump inhibitor periods; adjusted odds ratio 1. In addition to the primary outcome, secondary outcomes were evaluated. The risk of rehospitalization for ACS was increased (adjusted odds ratio 1. The authors also conducted a nested case-control analysis with these data in an attempt to confirm their findings, resulting in an adjusted odds ratio of 1. Multiple sensitivity analyses were conducted, with no meaningful change to the results. This study was conducted using data from the Veteran’s Affairs hospitals, and no patients were taking esomeprazole. Too few patients were taking pantoprazole or lansoprazole to be able to conduct individual analyses, but omeprazole and rabeprazole resulted in increased adjusted odds ratios for the primary outcome (adjusted odds ratios: 1. Analysis by dose of proton pump inhibitor indicated did not indicate a dose-response relationship. A population-based nested case-control study examined data from all patients in Ontario, Canada who were prescribed clopidogrel after hospital discharge following a myocardial 277 infarction between April 2002 and December 2007. Among this group, cases were identified as patients who were rehospitalized for myocardial infarction within 90 days of discharge (N=734), while controls were those who were not. Controls were identified in a 3:1 ratio to cases and matched on age, percutaneous coronary intervention, and a validated risk score (N=2057). Proton pump inhibitor exposure was defined as current (within 30 days of rehospitalization), previous (31 to 90 days) or remote (91 to 180 days). The logistic regression analysis controlled for demographic variables, socioeconomic status, Charlson comorbidity index, length of stay during initial admission for myocardial infarction, and 9 comorbid conditions (for example diabetes). A similar adjusted odds ratio was found in this study as the cohort study; 1. Previous or remote use was not associated with an increased risk of recurrent myocardial infarction. All-cause mortality was again not affected statistically significantly (adjusted odds ratio 0. Analysis of recurrent myocardial infarction within 1 year of initial discharge also indicated an increased risk with current proton pump inhibitor use; odds ratio 1. Because pantoprazole does not inhibit the P450 2C19 enzyme system responsible for activation of clopidogrel, it has been suggested that it may not result in a clinically-relevant drug interaction. An analysis of pantoprazole alone (N=cases 46, controls 125) found no statistically significant increase in risk (adjusted odds ratio 1. Analysis of all other proton pump inhibitors (which inhibit the P450 2C19 enzyme system to varying degrees) together resulted in increased risk; adjusted odds ratio 1. Analysis stratified further by individual proton pump inhibitor was not undertaken; insufficient data may have prevented such analysis. Proton pump inhibitors Page 67 of 121 Final Report Update 5 Drug Effectiveness Review Project Because these are post-hoc sub-group analyses of small groups, further research is needed to confirm these findings. Pregnancy A multicenter, prospective cohort study enrolled 410 pregnant women who had sought counseling after exposure to omeprazole (N=295), lansoprazole (N=62), or pantoprazole (N=53) 278 between 1992 and 2001. Details of exposure were collected during pregnancy before pregnancy outcome was known, and follow-up was performed in the neonatal period. A control group of 868 women who had been counseled during pregnancy about exposures known to be nonteratogenic served as a control group. There were some differences between control and treatment groups at baseline (for example, number of children was larger in then treatment than the control group), and confounders were not controlled for in the analysis. There was a higher rate of elective termination of pregnancy in the omeprazole and lansoprazole groups than the control group. Two of these terminations in the omeprazole group, 1 in the lansoprazole group, 0 in the pantoprazole group, and 5 in the control group were because of prenatal diagnosis of anomalies. There was no difference in the rate of major anomaly between each of the 3 groups and the control group; the relative risk was 0. Median birth weight was lower by 60 grams in the omeprazole group than the control group, but no difference was seen between groups for median gestational age at delivery or rates of preterm birth, miscarriage, ectopic pregnancy, or stillbirth. Applicability Applicability of most trials to community practice was difficult to determine. These studies generally excluded patients who had serious medical conditions. In addition, although most treatment and control groups received standard doses of anti-ulcer drug, there were instances where doses were higher or lower than typical. In trials comparing maintenance treatment or different strategies for longer-term treatment of gastroesophageal reflux disease, patients were enrolled on the basis of a successful response to acute treatment. This preselection may have resulted in a group of patients who were adherent to treatment, who were able to tolerate any side effects, and whose disease was less severe in comparison with patients who were not enrolled. Another concern is that of studies that stated their funding source, most were funded by the pharmaceutical industry, and industry employees often served as co-authors. SUMMARY Table 17 summarizes the evidence for this report. Summary table Key Question Strength of evidence Conclusion Key Question 1. Gastroesophageal reflux disease, short-term efficacy Erosive gastroesophageal Good In 16 head-to-head trials, the only difference between reflux disease: Symptoms proton pump inhibitors on the outcome of complete Proton pump inhibitors Page 68 of 121 Final Report Update 5 Drug Effectiveness Review Project Key Question Strength of evidence Conclusion symptom relief at 4 weeks was in the comparison of esomeprazole 40 mg with omeprazole 20 mg; the pooled risk difference in 3 trials was 8% (95% CI 3 to 13), with a number needed to treat of 13. Time to relief of heartburn was similar for all proton pump inhibitors in head-to-head trials, but the methods used to measure and report this outcome varied in the 14 studies. Erosive gastroesophageal Good Good evidence shows no difference between reflux disease: Esophagitis omeprazole, lansoprazole, pantoprazole, and healing rabeprazole for healing of esophagitis. Thirteen head- to-head trials found these 4 proton pump inhibitors to be equally effective in healing at 4 and 8 weeks. Pooled analysis of 4- and 8-week healing rates from 4 trials of esomeprazole 40 mg compared to omeprazole 20 mg indicate esomeprazole to be superior; risk difference 7% (95% CI 1 to 12) and a number needed to treat of 14 and 5% (95% CI 1 to 9), number needed to treat = 20, respectively. Three trials compared esomeprazole 40 mg with lansoprazole 30 mg. The pooled difference in healing rate was significantly greater with esomeprazole at 4 and 8 weeks, risk differences 5% (95% CI 2 to 7) and 3% (95% CI 1 to 5), respectively. Four trials compared esomeprazole 40 mg and pantoprazole 40 mg. Pooled difference in healing rate was significantly greater with esomeprazole at 4 weeks, but not at 8 weeks, risk differences 5% (95% CI 2 to 8) and 1% (95% CI –3 to 5).
Phase 1 single dose studies to optimize the pharmacoki- netics of DG17 discount bentyl 10 mg with amex, a novel HIV-protease inhibitor pro-drug proven bentyl 10mg, using sodium bicarbonate and ritonavir quality bentyl 10 mg. TMC310911 buy cheap bentyl 10mg on line, a novel hiv type 1 protease inhibitor, shows in vitro an improved resistance profile and higher genetic barrier to resistance compared with current protease inhibitors. Gulnik S, Afonina E, Eissenstat M, Parkin N, Japour A, Erickson J. SPI-256, a highly potent HIV protease inhibitor with broad activity against MDR strains. Antiviral activity and resistance profile of AG-001859, a novel HIV-1 pro- tease inhibitor with potent activity against protease inhibitor-resistant strains of HIV. Antiviral Therapy 2004; 9:S17 Hoetelmans RM, Dierynck I, Smyej I, et al. Safety and pharmacokinetics of the HIV-1 protease inhibitor TMC310911 coadministered with ritonavir in healthy participants: results from 2 phase 1 studies. Structure-activity relationships of novel HIV-1 protease inhibitors containing the 3-amino-2-chlorobenzoyl-allophenylnorstatine structure. Antiviral activity, pharmacokinetics, and safety of the HIV-1 pro- tease inhibitor TMC310911, coadministered with ritonavir, in treatment-naive HIV-1-infected patients. PL-100, a next generation protease inhibitor against drug-resistant HIV. New integrase inhibitors The integration of viral DNA, enabled by the HIV enzyme integrase into the host DNA, is a major step in the replication cycle of HIV. In 2007, raltegravir, the first integrase strand transfer inhibitor (INSTI) for treatment of HIV infection, was licensed, followed by the two INSTIs elvitegravir and dolutegravir (see Chapter 2). LEDGINs (or ALLINIs) are a new class of integrase inhibitors. As allosteric inhibitors these compounds bind to the LEDGF/p75 binding pocket in integrase, thereby block- ing the interaction with LEDGF/p75 and interfering not directly with the catalytic 6. ART 2017/2018: The horizon and beyond 127 activity of integrase. LEDGINs not only reduce the replication capacity of HIV par- ticles produced in their presence. They also modulate impair the formation of regular cores during the maturation step, resulting in a decreased infectivity of the viral par- ticles in the target cells. LEDGINs thus profile as unique antivirals with combined early (integration) and late (assembly) effects on the HIV replication cycle (Desimmie 2013, van Bel 2014). There is no doubt that LEDGINs are still early in development. A literature review, however, revealed that almost all major pharmaceutical compa- nies active in the treatment of HIV/AIDS have taken a significant interest in this class. As a result, several of these inhibitors may soon enter clinical trials (Demeule- meester 2014). BI 224436 acts through a mechanism that is distinct from that of INSTIs. Based on a promising biological and pharmacokinetic profile, BI 224436 was advanced into phase 1 clinical trials (Fenwick 2014). Cabotegravir (GSK-774) is probably more than a backup for dolutegravir. It is now mainly tested as a long acting drug (see above). GS-9224 is an analog of GS-9160, a previously reported investigational INSTI. GS- 9224 was designed in an effort to optimize the pharmacokinetic profile of GS-9160 while retaining its antiviral potency (Jones 2014). MK-2048 is a second-generation integrase inhibitor by MSD with presumably limited cross-resistance to raltegravir (Bar-Magen 2011, Van Weesenbeeck 2011). Out of sight, out of mind: integrase inhibitors no longer being studied: • BMS-707035, probably no advantage over raltegravir • GSK-364735, liver toxicity in monkeys, stopped in Phase I in 2007 • L-870810 (Merck), liver toxicity in dogs • S-1360 (Shionogi/GSK), stopped in 2005 due to toxicity References Bar-Magen T, Sloan RD, Donahue DA, et al. Identification of novel mutations responsible for resistance to MK- 2048, a second-generation HIV-integrase inhibitor. LEDGINs, non-catalytic site inhibitors of HIV-1 integrase: a patent review (2006 – 2014). Viral Particles Produced in Presence of LEDGIN Are Impaired for Infectivity. Preclinical profile of BI 224436, a novel HIV-1 non-catalytic-site integrase inhibitor. Preclinical and Clinical Profile of HIV-1 Integrase Strand-transfer Inhibitor GS-9224 Compared to its Parent Compound GS-9160. The Allosteric HIV-1 Integrase Inhibitor BI-D Affects Virion Maturation but Does Not Influence Packaging of a Functional RNA Genome. PLoS One 2014, 9:e103552 Van Wesenbeeck L, Rondelez E, Feyaerts M, et al. Cross-resistance profile determination of two second-genera- tion HIV-1 integrase inhibitors using a panel of recombinant viruses derived from raltegravir-treated clinical iso- lates. New entry inhibitors As mentioned above, each of the three steps of HIV entry can theoretically be inhib- ited. Step 1 is inhibited by attachment-inhibitors, step 2 by co-receptor antagonists and step 3 by fusion inhibitors. All three drug classes are currently called entry inhibitors. Two entry inhibitors have already been licensed, namely the fusion inhibitor T-20 and and the co-receptor antagonist maraviroc (see Chapter 2). Even if the antiviral effects of the drugs are not overwhelming, the concept is intriguing and entry inhibitors could open up new possibilities for the treatment of HIV infec- 128 ART tion in the coming years. On the other hand, a lot of the data below does not go beyond basic science at this stage and many of the drugs discussed may eventually disappear. New attachment inhibitors Attachment of the viral glycoprotein gp120 to the CD4 receptor is the first step in the entry of HIV into the target cell. In theory, this step can be inhibited by at least two different mechanisms, namely blocking either gp120 or CD4. Both modes of action are currently under investigation. Consequently, attachment inhibitors are very heterogeneous and it is not possible to speak of a single drug class. Since the beginning of the nineties, there have been a number of investigations into soluble CD4 molecules that prevent the attachment of HIV to the CD4 cell (Daar 1990, Schooley 1990). But, after disappointing results (probably due to the very short half-life of soluble CD4), this approach was abandoned for a time. With the growing knowledge of the mechanism of HIV entry, as well as following the success of T-20, the development of attachment inhibitors has been reinvigorated.
The large OI trials generic bentyl 10mg line, planned only a few months before best bentyl 10mg, faltered due to a lack of patients order bentyl 10mg overnight delivery. Hospices discount 10mg bentyl mastercard, which had been receiving substantial donations, shut down or changed their focus. The first patients began to leave the hospices and went back to work; ambulatory nursing services shut down. However, in early 1997, some patients began to complain of an increasingly fat stomach, but was this not a good sign after years of wasting and supplementary nutrition? The lower viremia was thought to use up far less energy. It was assumed that, because patients were less depressed and generally healthier, they would eat more. At most, it was slightly disturbing that the patients retained thin faces. However, more and more patients also began to complain about the high pill burden. In June 1997, the FDA published the first warning about the development of diabetes mellitus associated with the use of PIs. In February 1998, CROI in Chicago finally brought home the realization among clinicians that PIs were perhaps not as selective as had long been believed. One poster after another, indeed whole walls of pictures, showed fat abdomens, buffalo humps, thin legs and faces. Lipodystrophy has become an ubiquitous term in HIV medicine today. However, our understanding of the reasons and mechanisms behind this phenomenon remains incomplete. Fortunately, lipodystrophy prevalence has decreased, with the introduction of new antiretroviral drug classes. In 1997, it was estimated that viral suppression with a maximum duration of three years was nec- essary; it was predicted that all infected cells would die in this time. Since then, the duration has constantly been adjusted upwards. Estimates evolved upwards to around 60 to 70 years (Silicano 2003). These numbers show one thing: HIV will not be cured with standard ART. More recent studies have come to the sobering conclusion that HIV remains detectable in latent infected cells, even after long-term suppression. And Timothy Brown, the only person up to now who has been cured from HIV infec- tion (by an allogenous stem cell transplantation that transferred a rare genetic vari- ation to his immune system) remains a singular case. In fact, today’s reality seemed impossible ten years ago: HIV infection is a chronic disease which, although incurable, is manageable lifelong with therapy, even in patients with resistant virus. CCR5 antagonists as well as integrase inhibitors have opened up new possibilities of treatment. It has become increasingly possible to lower viral loads to below detection in most patients. The pioneer drugs maraviroc and raltegravir have been shown to be extremely well-tolerated. These new drug classes will bring about fundamental changes to current ART. The dogma of always using two nucleoside analogs as the backbone of every therapy may start to change. Many of the currently widespread drugs will disappear over the next few years. The end of HIVID, Agenerase, Fortovase or Viracept is just the beginning. Veteran agents like AZT, d4T, ddI, nelfinavir or indinavir are not recommended by guidelines anymore although they served us in HIV management in the nineties. Will we be needing saquinavir, fosampranavir or even efavirenz and lopinavir as much as we do today five years from now? A normal life expectancy seems realistic today with treatment. This will pose a tremendous challenge for patients, physicians and for the pharmaceutical industry and payors. The comfortable situation at present does not mean one can relax. There is uncertainty about whether our drugs can stand the test of time over decades. Effects on the heart, kidney, bones and other organs in an aging HIV population are difficult to foresee. If the cure is delayed, over the decades one will need a wider breadth and range of available drugs. It will not be easy for new drugs to be approved, as vicriviroc has shown. How do you show the advantages of a new drug over other successful ther- apies today? Approval for new drugs is becoming more strict and the market is tight- ening. Already one can observe the pharmaceutical industry’s caution. The days may be over when an HIV drug got from the laboratory to the market within five years. Compared to the previous decade, the HIV ARV pipeline is now drying up. At the same time, the simple question of “when to start” with ART has remained unanswered for a long time. Instead of David Ho’s recommendation from the nineties “hit hard, hit early”, we often heared “hit HIV hard, but only when necessary” (Harrington 2000) during the last decade. With the START study results appearing at the horizon, there is no doubt that this will change again. What roles do the following play: viral load, CD4 T cell changes, CD4 percentages, age, gender, host elements and viral tropism? These strategically important questions will hopefully find some answers through detailed analysis of the START study that are underway now. HIV clinicians are well-advised to keep an open mind to new approaches. Those who do not make an effort to constantly expand their knowledge at conferences will not 6.
Prevalence is calculated by dividing the number of people who have the disease or condition by the total number of people in the group discount bentyl 10 mg fast delivery. Newer antiplatelet agents 69 of 98 Final Update 2 Report Drug Effectiveness Review Project Probability: The likelihood (or chance) that an event will occur effective bentyl 10 mg. In a clinical research study generic 10 mg bentyl with visa, it is the number of times a condition or event occurs in a study group divided by the number of people being studied bentyl 10mg for sale. Publication bias: A bias caused by only a subset of the relevant data being available. The publication of research can depend on the nature and direction of the study results. Studies in which an intervention is not found to be effective are sometimes not published. Because of this, systematic reviews that fail to include unpublished studies may overestimate the true effect of an intervention. In addition, a published report might present a biased set of results (for example, only outcomes or subgroups for which a statistically significant difference was found). P value: The probability (ranging from zero to one) that the results observed in a study could have occurred by chance if the null hypothesis was true. Q-statistic: A measure of statistical heterogeneity of the estimates of effect from studies. It is calculated as the weighted sum of the squared difference of each estimate from the mean estimate. Random-effects model: A statistical model in which both within-study sampling error (variance) and between-studies variation are included in the assessment of the uncertainty (confidence interval) of the results of a meta-analysis. When there is heterogeneity among the results of the included studies beyond chance, random-effects models will give wider confidence intervals than fixed-effect models. Randomization: The process by which study participants are allocated to treatment groups in a trial. Adequate (that is, unbiased) methods of randomization include computer generated schedules and random-numbers tables. Randomized controlled trial: A trial in which two or more interventions are compared through random allocation of participants. Regression analysis: A statistical modeling technique used to estimate or predict the influence of one or more independent variables on a dependent variable, for example, the effect of age, sex, or confounding disease on the effectiveness of an intervention. Relative risk: The ratio of risks in two groups; same as a risk ratio. Retrospective study: A study in which the outcomes have occurred prior to study entry. Risk: A way of expressing the chance that something will happen. It is a measure of the association between exposure to something and what happens (the outcome). Risk is the same as probability, but it usually is used to describe the probability of an adverse event. It is the rate of events (such as breast cancer) in the total population of people who could have the event (such as women of a certain age). Risk difference: The difference in size of risk between two groups. In intervention studies, it is the ratio of the risk in the intervention group to the risk in the control group. A risk ratio of 1 indicates no difference between comparison groups. For undesirable outcomes, a risk ratio that is <1 indicates that the intervention was effective in reducing the risk of that outcome. Newer antiplatelet agents 70 of 98 Final Update 2 Report Drug Effectiveness Review Project Run-in period: Run in period: A period before randomization when participants are monitored but receive no treatment (or they sometimes all receive one of the study treatments, possibly in a blind fashion). The data from this stage of a trial are only occasionally of value but can serve a valuable role in screening out ineligible or non-compliant participants, in ensuring that participants are in a stable condition, and in providing baseline observations. A run-in period is sometimes called a washout period if treatments that participants were using before entering the trial are discontinued. This term (or the term ‘‘safe’’) should not be used when evidence on harms is simply absent or is insufficient. Sample size: The number of people included in a study. In research reports, sample size is usually expressed as "n. Larger sample sizes also increase the chance that rare events (such as adverse effects of drugs) will be detected. Sensitivity analysis: An analysis used to determine how sensitive the results of a study or systematic review are to changes in how it was done. Sensitivity analyses are used to assess how robust the results are to uncertain decisions or assumptions about the data and the methods that were used. Side effect: Any unintended effect of an intervention. Side effects are most commonly associated with pharmaceutical products, in which case they are related to the pharmacological properties of the drug at doses normally used for therapeutic purposes in humans. Standard deviation (SD): A measure of the spread or dispersion of a set of observations, calculated as the average difference from the mean value in the sample. Standard error (SE): A measure of the variation in the sample statistic over all possible samples of the same size. The standard error decreases as the sample size increases. Standard treatment: The treatment or procedure that is most commonly used to treat a disease or condition. In clinical trials, new or experimental treatments sometimes are compared to standard treatments to measure whether the new treatment is better. Statistically significant: A result that is unlikely to have happened by chance. Study: A research process in which information is recorded for a group of people. The data are used to answer questions about a health care problem. Study population: The group of people participating in a clinical research study. The study population often includes people with a particular problem or disease. It may also include people who have no known diseases. Subgroup analysis: An analysis in which an intervention is evaluated in a defined subset of the participants in a trial, such as all females or adults older than 65 years. Superiority trial: A trial designed to test whether one intervention is superior to another.