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The HIV progenome and virus have so far been detected in the seminal plasma buy sotalol 40 mg with visa blood pressure chart by age canada, the concomitant cells order sotalol 40mg online pulse pressure close together, and occasionally in immobile sper- matozoa order 40mg sotalol overnight delivery blood pressure drops after exercise. Several studies have indicated that viable, motile spermatozoa are not likely to be a target for HIV infection (Pena 2003, Gilling-Smith 2003). Motile spermatozoa can be isolated by standardized preparation techniques. After separation of the spermatozoa from plasma fractions and NSC (non-spermatozoa cells), the spermatozoa are washed twice with culture medium and re-suspended in fresh culture medium. Incubation for 20–60 minutes allows motile sperm to “swim up” to the supernatant. To be more certain that it is not contaminated with viral particles, an aliquot of the sample should be tested for HIV nucleic acid using highly sensitive detection methods (Weigel 2001, Gilling-Smith 2003, Pasquier 2006). Depending on the method, the limit of detection is 10 copies/ml. After having studied the effectiveness of several methods of sperm processing, Anderson (2005) concluded that the combination of gradient density centrifugation and swim-up allows a 10,000-fold decrease of HIV-1 concentration in sperm. Since HIV could theoretically remain undetected, sperm washing is currently regarded as a very effective risk reduc- tion, although not risk-free. Most of the European centers that offer assisted reproduction to HIV-discordant couples are part of the CREATHE network, which aims to optimize treatment and safety of the methods as well as to compile an extensive database. Compiled data from several centers hint on the safety and reliability of sperm washing (Bujan 2007). Pre-Exposure Prophylaxis (PrEP) Even before the FDA approval of Truvada as the first antiretroviral agent for the prevention of HIV transmission through sexual intercourse, PrEP before periovula- tory unprotected intercourse was an option for serodiscordant couples in some coun- tries. Couples abstain from condom use only during the woman’s fertile days. HIV and Wanting to be a Parent 551 Preconditions are an effectively suppressed viral load, the exclusion of sexually trans- mitted diseases, and unimpaired fertility status of both partners. Data from Switzerland and Germany shows high acceptance in couples. No case of HIV trans- mission has been reported in 53 couples, the pregnancy rate was 75% (Vernazza 2011). A growing number of studies shows the feasibility of this approach, especially in resource-limited settings (Adenji 2013, Whetham 2013). The fertility of HIV-neg- ative men does not seem to be impaired by taking PrEP (Were 2014). Up to now, there is no evidence that PrEP further reduces the already negligible risk of infection when the viral load of the HIV+ partner is effectively suppressed. Nevertheless, some couples prefer this option because it increases their feeling of safety. Female HIV infection For many HIV+ women having a child now is an important part of planning for the future (Fiore 2008, Loutfy 2009). In France 32% of the HIV+ women of reproductive age want to become mothers (Heard 2007). Treatment and care during pregnancy should be carried out according to the pre- vailing national or international guidelines (Fakoya 2008, DAIG 2011, Loutfy 2012). In some European countries reproductive options for women with unimpaired fer- tility include natural conception on the basis of the EKAF Statement as well as self- insemination, while self-insemination is still seen as the safest procedure. Couples who decide for natural conception should undergo screening to exclude STDs. The transmission risk might be further reduced when the intercourse without condoms is limited to the time of ovulation. Women should be advised on the impor- tance of adherence and regular checks of the viral load (Fakoya 2008). If a woman is not taking ART, the viral load is not successfully suppressed, or concerns about the remaining risk are strong, self-insemination may be the method of choice. In some cases, ovarian stimulation may be advisable. This, however, requires highly qualified supervision to avoid multiple gestations. A simple inexpensive way of determining whether the cycles are ovulatory, helpful in women who have regular cycles, is a basal temperature chart beginning about three months before the first self-insemination. At the time of ovulation, couples can either have protected intercourse with a sper- micide-free condom and introduce the ejaculate into the vaginal cavity afterwards, or the ejaculate can be vaginally injected using a syringe or applied with a diaphragm or portio cap. Thus the conception remains within the private sphere of the couple. After 6–12 months of unsuccessful self-insemination, the couple should have further fertility investigations with a view to assisted conception. Should the couple experience problems with self-insemination, intrauterine insemination (IUI) can be considered. HIV-specific and infective diagnostics are recommended. If no pregnancy has occurred over a period of 6–12 months (or earlier, if the couple so wishes) fertility diagnostics should be carried out (Table 1). If there are indicators of reduced fertil- ity in one or both partners, fertility diagnostics might be carried out at an earlier stage in the counselling process. Fertility disorders In some cases, women will only be able to conceive by intercourse without condom or self insemination. Dependent on the fertility status of both partners, IVF and ICSI can be considered as methods of choice. Fertility disorders in HIV+ women seem to have a higher prevalence than in an age- matched negative population (Ohl 2005, Gingelmaier 2010) and might lead to a 552 Women and Children lower success rate of assisted reproduction (Coll 2006) although data show some conflicting results. Reasons might be infection of the upper genital tract (Sobel 2000), surgery due to cervical intraepithelial neoplasia (Gilles 2005) or a depletion of mito- chondrial DNA in the oocytes (Garrabou 2006, Lopez 2008). Data reported from a program in Strasbourg indicated infertility problems in most HIV+ women. IVF and ICSI were far more effective than IUI (Ohl 2005). In the Barcelona program, Coll (2006) observed a decreased pregnancy rate after IVF com- pared to age-matched HIV-negative controls and HIV+ women who received donated oocytes. Results indicated a decreased ovarian response to hyperstimulation.

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Both sets of data support haplotypes H3 and H4 had a higher risk of developing FVIII the importance of the activation state of the innate immune system inhibitors than patients with the haplotypes H1 or H2 cheap 40mg sotalol mastercard hypertension symptoms high blood pressure. However buy discount sotalol 40mg on-line arrhythmia beta blocker, for the outcome of the immune response to FVIII generic sotalol 40 mg amex blood pressure kits at walgreens. Furthermore, the investigators did not take into developing FVIII inhibitors. In an independent study, Pavlova et account potential differences in polymorphisms of the HLA com- al26 confirmed the importance of these polymorphisms, which were plex or in immunoregulatory genes between patients with H1/H2 shown to be associated with an increased expression of the and patients with H3/H4. Therefore, it is still not clear whether such respective genes. IL10 is known to be a growth and differentiation mismatches do indeed contribute to the risk of patients developing factor for activated human B cells and to induce activated B cells to FVIII inhibitors. Indeed, Schwarz et al39 could not confirm this secrete large amounts of antibodies. TNF- is a well-characterized association when they analyzed their data from 49 patients of proinflammatory cytokine with multiple functions in inflammatory African ancestry. Astermark et al35 also identified a protective association between a polymorphism in the promoter region of the cytotoxic In conclusion, genetic polymorphisms that result in a modulation of T-lymphocyte associated protein-4 (CTLA-4) gene and the risk of the activation state of the innate or adaptive immune system or in patients developing FVIII inhibitors. CTLA-4 is a regulatory changes of the frequencies of specific B or T cells can substantially 376 American Society of Hematology alter the risk of patients with hemophilia developing antibodies different cohorts of hemophilia A patients. Oracki SA, Walker JA, Hibbs ML, Corcoran LM, Tarlinton DM. Plasma single nucleotide polymorphisms from 1081 genes for the associa- cell development and survival. Nat Rev study group included 833 patients from 3 independent hemophilia A Immunol. Marginal zone B cells: virtues of innate-like cohorts. The investigators identified 53 single nucleotide polymor- antibody-producing lymphocytes. Germinal center selection and the develop- of the genetic polymorphisms that might modulate antibody re- 40 ment of memory B and plasma cells. Loss of high-responder inhibitors in patients with severe hemophilia A and human immunodeficiency virus Summary and conclusion type 1 infection: A report from the multi-center hemophilia cohort Neutralizing antibodies against FVIII or FIX are generated as a study. Prevention and treatment of cells of the innate and the adaptive immune system located in factor VIII inhibitors in murine hemophilia A. Selection of the T-cell repertoire: receptor-controlled phisms in immunoregulatory genes, and FVIII/FIX mutations were checkpoints in T-cell development. However, the immunoregulatory pathways that give rise peptides bound to class II MHC molecules. Dangerous liaisons: how the immune system deals with factor VIII. Conflict-of-interest disclosure: The author is employed by Baxter 22. HLA class II molecules influence Correspondence susceptibility versus protection in inflammatory diseases by determining Birgit M. Reipert, Baxter Innovation GmbH, Industriestrasse 72, the cytokine profile. A-1220 Vienna, Austria; Phone: 43-1-20100-2471285; Fax: 43-1- 24. HLA class II profile: a weak 20100-5049; e-mail: birgit_reipert@baxter. Oldenburg J, Picard JK, Schwaab R, Brackmann HH, Tuddenham EG, 1. HLA genotype of patients with severe haemophilia A due to inhibitor development in severe hemophilia A. Factor VIII inhibitors in mild and moderate-severity haemo- 26. Factor VIII gene (F8) tumor necrosis factor-alpha and cytotoxic T-lymphocyte antigen-4 mutation and risk of inhibitor development in nonsevere hemophilia A. Inhibitor development in haemophilia B: an orphan ously applied human FVIII in humanized hemophilic E17 HLA- disease in need of attention. Factor IX: molecular structure, epitopes, and mutations 28. HLA-DR-presented peptide repertoires derived from human 7. Genetic risk factors for inhibitors to factors monocyte-derived dendritic cells pulsed with blood coagulation factor VIII and IX. Basic aspects of inhibitors to factors VIII and IX and the 29. Observations regarding the influence of non-genetic risk factors. How tolerogenic dendritic cells inhibitor development in severe hemophilia A. In: Lee C, Berntorp E, oxygenase-1 in factor VIII-deficient mice reduces the immune response Hoots KW, eds. Oxford: Blackwell; 2005:235- to therapeutic factor VIII. Improve- antibodies to therapeutic factor VIII in severe hemophilia A is associ- ments in factor VIII inhibitor detection: from Bethesda to Nijmegen. Astermark J, Oldenburg J, Pavlova A, Berntorp E, Lefvert AK; MIBS antibody responses against factor VIII in healthy individuals and in Study Group. Polymorphisms in the IL10 but not in the IL1beta and IL4 Hematology 2014 377 genes are associated with inhibitor development in patients with possible role for pharmacogenetics in FVIII inhibitor development? Inhibitors of factor VIII in gene and the risk of inhibitor development in patients with hemophilia black patients with hemophilia. Astermark J, Wang X, Oldenburg J, Berntorp E, Lefvert AK; MIBS 39.

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In the trial that compared candesartan to perindopril cheap sotalol 40 mg line blood pressure stroke level, reduction in albumin excretion rates –44% and 57 –47% discount 40mg sotalol free shipping blood pressure medication effects on sperm, respectively order sotalol 40 mg online heart attack during sex. In the trial that compared candesartan to lisinopril, reductions were only 72 displayed in graphical form. Rate of overall withdrawals was 17% in the candesartan group and 72 4% in the lisinopril group (P value not reported). There were no significant differences between candesartan and either lisinopril or perindopril. Compared with lisinopril (4%), the proportion of participants who withdrew due to adverse events was somewhat greater for candesartan (12%), but the difference was not 72 statistically significant. There were no significant differences between candesartan and perindopril in proportions of participants with any adverse event (10% compared with 6%), cough (0% compared with 4%), or gastrointestinal-related adverse events (2% in both groups), 57 and no participant withdrew from either group due to adverse events. Neither trial reported results of the comparison of candesartan to lisinopril or perindopril based on any subgroup characteristics. Valsartan Valsartan compared with benazepril, lisinopril, and ramipril 65, 80 We included 2 trials of valsartan compared with lisinopril and 1 trial each of valsartan 79 59 compared with benazepril 10 mg or ramipril 5 mg to 10 mg. The “Blood Pressure Reduction and Tolerability of Valsartan in Comparison with Lisinopril” (PREVAIL) trial was rated good quality and compared 4 months of treatment with either valsartan 160 mg or lisinopril 20 mg, both in combination with low-dose hydrochlorothiazide, in 1213 adults with mild to severe 65 hypertension. In the fair quality VALERIA trial, 133 adults with hypertension and microalbuminuria were randomized to 30 weeks of treatment with either lisinopril 40 mg, 80 valsartan 320 mg, or a combination of valsartan/lisinopril 320/20 mg. In VALERIA, 73% of participants also had type 2 diabetes. In a fair-quality, 3-month trial of 90 adults with stages 1 or 2 hypertension (European Society of Cardiology), participants were randomized to valsartan 80 79 mg or benazepril 10 mg. Dosages of valsartan and benazepril were doubled after the first 2 weeks if the blood pressure remained at or above 140/90 mm Hg, and hydrochlorothiazide 12. Valsartan was compared with ramipril in 369 adults with mild hypertension and symptomatic atrial fibrillation 59 in a fair-quality trial with a follow-up duration of 12 months. Participants were randomized to receive valsartan 160 mg or ramipril 5 mg, and then were titrated after 4 weeks to 240 mg and 7. The only significant difference between valsartan and an ACE-I comparator came from the trial of adults with mild hypertension and symptomatic atrial fibrillation, in which the rate of atrial fibrillation recurrence was significantly lower for valsartan 59 (16%; P<0. In the 80 lisinopril group of the VALERIA trial, 1 of 47 participants died (2%). There were no significant differences in reduction of albumin/creatinine ratio between valsartan and either DRIs, AIIRAs, and ACE-Is Page 41 of 144 Final Report Drug Effectiveness Review Project 79 80 benazepril (–35% in both groups) or lisinopril (-51% compared with -41%). In the VALERIA trial, microalbuminuria had normalized by the end of the trial for a greater proportion of 80 participants in the valsartan group (31% compared with 17%; P value not reported). There were no significant differences between valsartan and any ACE-I comparator in overall withdrawals in any trial. Overall withdrawal rates were highest in the longest-term trial that 59 compared valsartan to ramipril over 12 months of follow-up (19% compared with 25%). Significant differences between valsartan and an ACE-I comparator were only 65, 80 found in the largest of the 4 trials, the PREVAIL trial (N=1213). In PREVAIL, compared with lisinopril, incidence of withdrawal due to adverse events (1% compared with 4%; P=0. In the smaller trials, with sample sizes 59, 79, 80 ranging from 55 to 146 participants, incidence of withdrawal due to adverse events and 80 cough were numerically greater, but the differences were not statistically significant. No trial of valsartan compared with an ACE-I in adults with hypertension reported results of subgroup analyses based on demographics, comorbidities, or concomitant medication use. Eprosartan Eprosartan compared with enalapril We included 3 fair-quality trials (reported in 7 publications) of eprosartan compared with 53, 55, 58, 61, 64, 67, 70 enalapril in adults with hypertension. Duration of follow-up ranged from 6 67 53, 55, 58, 61, 64 67 weeks to 6 months. Sample sizes ranged from 136 participants to 529 53, 55, 58, 61, 64 participants. Two trials involved the comparison of eprosartan 300 mg to enalapril 20 53, 55, 58, 61, 64, 67 mg. In the third trial, the starting dose was 600 mg for eprosartan and 5 mg for 70 enalapril. Eprosartan could be titrated only once, to 800 mg, and enalapril could be titrated first to 10 mg and then to 20 mg, each at 3-week intervals to reach a target systolic blood pressure 53, 55, 58, 61, 64, 67 goal of below 140 mm Hg. Mean age ranged from 56 years to 57 years in 2 trials. The third trial exclusively enrolled participants aged over 65 years and had a mean age of 73 70 years. Although not powered to be evaluated as a primary outcome, differences in mortality between eprosartan and enalapril were not statistically 53, 55, 58, 61, 64, 70 significant across 2 trials. In the trial of all elderly participants, there was 1 death 70 in each group (0. In the second trial, there was 1 death in the eprosartan group (0. The death of that participant came 1 month after having an acute myocardial infarction. Changes in quality of life were measured using the Psychological General Wellbeing Index in 2 trials and no significant differences between eprosartan and 53, 55, 58, 61, 64, 67 enalapril were found. Across the 3 trials, incidence of overall withdrawal ranged from 13% to 15% for eprosartan and 12% to 22% for enalapril, but differences were not statistically significant. Results of the comparison between eprosartan and enalapril in incidence of 53, 55, 58, 61, 64, 70 overall adverse events were inconsistent across 2 trials. After 3 months, in the trial of exclusively elderly participants, more patients in the enalapril group (51%) experienced at 70 least 1 adverse event than those in the eprosartan group (36%; P value not reported). After 6 months in the largest trial of 529 adults with a mean age of 56 years, incidence of adverse events were generally higher than in the shorter-term trial, and the difference between eprosartan (76%) 53, 55, 58, 61, 64 and enalapril (81%) was not statistically significant. Incidence of withdrawals due to DRIs, AIIRAs, and ACE-Is Page 42 of 144 Final Report Drug Effectiveness Review Project adverse events was generally low, ranging from 2% to 5% in the eprosartan groups and 9% in the 53, 55, 58, 61, 64, 67 enalapril groups in 2 trials and the differences between drugs were not significant. Incidence of serious adverse events was only reported in 1 trial and the difference between 53, 55, 58, 61, 64 eprosartan (1%) and enalapril (3%) was not significant. Cough-related adverse events were reported in all 3 trials and incidence was consistently lower for eprosartan compared with enalapril (Table 5). Few participants withdrew due to cough, 55, 58, however, and the difference between eprosartan and enalapril was not significant in 2 trials. Comparison of eprosartan and enalapril on cough-related adverse events Incidence for Sample size eprosartan compared Author Year Duration Event with enalapril, P value Gained a definite or possible 2% vs.

Is there a difference in the ability Good for most For patients who require low-density lipoprotein cholesterol of a statin or fixed-dose combination comparisons reductions of up to 35% to meet their goal buy 40mg sotalol otc blood pressure top number high, any of the statins product containing a statin and (see text) are effective order sotalol 40mg on-line blood pressure question. In patients requiring a low-density lipoprotein another lipid-lowering drug to cholesterol reduction of 35% to 50% to meet the National achieve National Cholesterol Cholesterol Education Program goal buy generic sotalol 40mg on-line blood pressure newborn, atorvastatin 20 mg or Education Panel goals? Atorvastatin 80 mg daily and rosuvastatin 20 mg or more can reduce low-density lipoprotein cholesterol by 50% or more. Based on fair-quality studies, atorvastatin 80 mg daily resulted in 5 to 6 additional percentage points of low-density lipoprotein reduction than simvastatin 80 mg (53% to 54% vs. In head-to-head studies rosuvastatin 40 mg had greater reduction in low-density lipoprotein cholesterol than atorvastatin 80 mg with similar frequency of adverse events. In patients requiring a low-density lipoprotein cholesterol reduction of greater than 50%, the higher doses of ezetimibe-simvastatin at 10/40 mg and 10/80 mg are more likely to meet the National Cholesterol Education Program Adult Treatment Panel III goal than an equivalent high potency statin. How do statins and fixed-dose Fair-to-good When statins are provided in doses that are approximately combination products containing a equipotent for lowering LDL-C, a similar percent increase in statin and another lipid-lowering high-density lipoprotein cholesterol can be achieved. There drug compare in their ability to raise is conflicting evidence about simvastatin vs. Some studies found greater increases in high-density lipoprotein cholesterol with rosuvastatin compared with atorvastatin, while other studies found no difference. How do statins and fixed-dose NA There are no controlled trials comparing equivalent doses of combination products containing a 2 or more statins to reduce the risk of coronary events, statin and another lipid-lowering stroke, or death. Which statins have been shown to Good Patients who have never had CHD: pravastatin (high-risk reduce all-cause mortality? Patients with CHD: simvastatin, atorvastatin Which statins have been shown to Fair-to-good Patients who have never had CHD: atorvastatin (high-risk reduce CHD events? Which statins have been shown to Good Atorvastatin, pravastatin, simvastatin, rosuvastatin (patients reduce strokes? Atorva 10 mg reduced cardiovascular events in a primary prevention trial of patients with diabetes (CARDS), and simvastatin 40 mg reduced cardiovascular events in patients with diabetes (Heart Protection Study). In a subgroup analysis of the LIPS trial, there was a reduction in coronary events (cardiac death, nonfatal MI, CABG, or repeat PCI) with fluvastatin 80 mg in patients with diabetes who had undergone successful PCI. Studies that included people with diabetes had rates of adverse effects similar to other studies. Are there differences in Good (elderly, The benefits of statins have been documented in women effectiveness of statins and fixed- women)-to- and the elderly. There are almost no data about African dose combination products Fair to Poor Americans, Hispanics, or other ethnic groups. In short-term containing a statin and another lipid- (African head-to-head trials, reductions in LDL-C and frequency of lowering drug in different Americans, adverse events with rosuvastatin 10 to 20 mg and demographic groups or in patients Hispanics, and atorvastatin 10 to 20 mg in Hispanic, South Asian, and with comorbid conditions (e. Are there differences in safety of Poor There are no data from clinical trials comparing the safety of statins in different demographic different statins in women, the elderly, or African Americans. A pharmacokinetic study of rosuvastatin conducted in the United States demonstrated an approximate 2-fold elevation in median exposure in Asian subjects (having either Filipino, Chinese, Japanese, Korean, Vietnamese, or Asian-Indian origin) compared with a Caucasian control group. Are there differences in the harms Good for Although creatine kinase elevations are common, the risk of of statins or fixed-dose combination statins symptomatic myopathy is low. All of the available statins products containing a statin and monotherapy (simvastatin, lovastatin, atorvastatin, fluvastatin, pravastatin, another lipid-lowering drug when rosuvastatin), when administered alone, have been used in the general population of Fair to poor for associated with infrequent myotoxic adverse effects ranging children or adults? There is no evidence that elevated transaminases Statins Page 80 of 128 Final Report Update 5 Drug Effectiveness Review Project Strength of Key question evidence Conclusion associated with statin use increase the risk of clinically significant liver failure. In a trial of 2 doses of atorvastatin, the incidence of persistent elevations in liver aminotransferase levels 2 per 1000 in patients taking atorvastatin 10 mg daily, vs. There is insufficient evidence to determine which statin or statins are safer with regard to muscle toxicity or elevated liver enzymes. Among high potency statins, at doses below 80 mg, rates of adverse events and withdrawals due to adverse events were similar in patients taking atorvastatin or simvastatin. Atorvastatin 80 mg had a higher rate of some adverse effects (gastrointestinal disturbances and transaminase elevation) than simvastatin 80 mg daily in a trial in which the low-density lipoprotein lowering of atorvastatin was greater than that of simvastatin. Adverse event rates in patients using rosuvastatin 40 mg were similar to rates in patients using atorvastatin 80 mg in short-term trials. We identified very little evidence of harms in the trials of the fixed dose combination product trials. The majority of trials were not longer than 12 weeks in duration. Are there differences in the harms of statins or fixed-dose combination products containing a statin and another lipid-lowering drug when used in special populations or with other medications (drug-drug interactions)? In addressing this question, we will focus on the following populations: Special populations: Patients with Good Studies that included people with diabetes had rates of diabetes adverse effects similar to other studies. Drug interactions Fair The combination of any statin with fibrates, and to a lesser extent niacin, can result in a higher risk for myopathy or rhabdomyolysis. How do statins and fixed-dose Fair-to-poor In one head-to-head trial conducted in adults and children combination products containing a with homozygous familial hypercholesterolemia, atorvastatin statin and another lipid-lowering 80 mg and rosuvastatin 80 mg were similarly efficacious for drug compare in their ability to reducing low-density lipoprotein cholesterol (18% for reduce low-density lipoprotein atorvastatin, 19% for rosuvastatin). In placebo-controlled trials of atorvastatin, lovastatin, pravastatin, and simvastatin, statins reduced low-density lipoprotein cholesterol in children with familial hypercholesterolemia by 32% (95% CI, 37 to 26). In one trial, the fixed dose combination product simvastatin/ezetimibe reduced low-density lipoprotein more Statins Page 81 of 128 Final Report Update 5 Drug Effectiveness Review Project Strength of Key question evidence Conclusion than simvastatin alone (54% vs. There were no trials of fluvastatin or the fixed dose combination products lovastatin/niacin extended-release or simvastatin/niacin extended-release in children. How do statins and fixed-dose Fair-to-poor In one head-to-head trial of atorvastatin 80 mg vs. In placebo-controlled trials of atorvastatin, lovastatin, pravastatin, and simvastatin, statins increased high-density lipoprotein cholesterol in children with familial hypercholesterolemia by 3% (95% CI, 0. One trial of the fixed dose combination product simvastatin/ezetimibe compared with simvastatin alone showed no change in high-density lipoprotein levels. There were no trials of fluvastatin or the fixed dose combination products lovastatin/niacin extended-release or simvastatin/niacin extended-release in children. How do statins and fixed-dose Poor No evidence in children. Are there differences in Poor No evidence in children with diabetes or obesity. Are there differences in the harms Fair-to-poor Multiple studies reported no significant elevations in creatine of statins or fixed-dose combination kinase and AST/ALT. If AST/ALT elevations occurred, they products containing a statin and were either lower than 3 times the upper limit of normal, or another lipid-lowering drug when resolved with discontinuation of medication.