Improvements In Surrogate Markers Research Articles

An extended analysis of cardiovascular benefits of indoor air filtration intervention among elderly: a randomized crossover trial (Beijing indoor air purifier study, BIAPSY)

ObjectiveEvidence on potential cardiovascular benefits of personal-level intervention among the elderly exposed to high levels of particulate matter (PM) remains limited. We aimed to assess improvements in surrogate markers of cardiovascular injury in vulnerable populations at risks by using indoor air filtration units. MethodsWe conducted a randomized crossover trial for 2 separate 2-week air filtration interventions in 20 households of patients with stable chronic obstructive pulmonary disease and their partners in the winter of 2013, with concurrent measurements of indoor PM. The changes in biomarkers indicative of cardiac injury, atherosclerosis progression and systemic inflammation following intervention were evaluated using linear mixed-effect models. ResultsIn the analysis, average levels of indoor PM with aerodynamic diameters < 2.5 µm (PM2.5) decreased significantly by 59.2% (from 59.6 to 24.3 µg/m3, P < 0.001) during the active air filtration. The reduction was accompanied by improvements in levels of high-sensitivity cardiac troponin I by −84.6% (95% confidence interval [CI]: −90.7 to −78.6), growth differentiation factor-15 by −48.1% (95% CI: −31.2 to −25.6), osteoprotegerin by −65.4% (95% CI: −56.5 to −18.7), interleukin-4 by −46.6% (95% CI: −62.3 to −31.0) and myeloperoxidase by −60.3% (95% CI: −83.7 to −3.0), respectively. ConclusionIndoor air filtration intervention may provide potential cardiovascular benefits in vulnerable populations at risks.

Lipid effects of glucagon-like peptide 1 receptor analogs.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are becoming more prominent as a therapeutic choice in diabetes management and their use is being expanded to other indications, such as obesity. Dyslipidemia and cardiovascular disease are common co-morbidities in these populations and understanding the impact of this class of medications on the lipid profile may be an important consideration. Several GLP-1RAs trials demonstrate them to be safe and potentially beneficial for cardiovascular outcomes; improvements in surrogate markers of atherosclerosis have also been observed. Lipid data collected as secondary outcomes from large clinical trials as well as some smaller dedicated trials show that GLP-1RAs can modestly lower low-density lipoprotein (LDL) and total cholesterol (C), and most show modest fasting triglyceride (TG) lowering. Effects on high-density lipoprotein-C have been less consistent. Some have also demonstrated substantial blunting of the postprandial rise in serum TGs. Favorable effects on lipoprotein metabolism, with reduced levels of small dense LDL particles and decreased atherogenic potential of oxidized LDL, have also been seen. Mechanisms underlying these observations have been investigated. This review summarizes the data available on the lipid effects of GLP-1RAs, and explores the current understanding of the mechanisms underlying these observed effects.

Treatment of hyperglycemia not associated with NAFLD improvement in children with type 2 diabetes mellitus.

Background and objectivesNonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) have become public health problems in the pediatric population. However, the relationship between these two conditions is not well understood. The primary objective of this study was to assess whether treatment of hyperglycemia in obese, treatment-naive children with type 2 diabetes (T2DM) was associated with an improvement of surrogate markers of NAFLD.Materials and methodsThis retrospective, longitudinal study included 151 obese children with a diagnosis of T2DM (Age: 14 ± 1 years, 72% female children, BMI: 98.6th percentile, and A1c: 10.3 ± 0.2%). Clinical/demographic information was collected before patients started any diabetes treatment and 1 and 3 years after starting metformin and/or insulin therapy.ResultsForty-eight patients (32%) had abnormal ALT/AST (i.e., >40 U/L), suggestive of NAFLD. After 1 year of therapy, there were no significant differences in plasma ALT among patients started on insulin, metformin, or combination: 5±4 vs. −10 ± 3 vs. −2±2 IU/L, respectively, P = .07. Of note, changes in plasma ALT were small, despite a significant reduction of A1c in patients prescribed insulin (alone or with metformin): -2.8 ± 1.0%, P = .01, and −2.7 ± 0.3%, P < .001, respectively. In line with this, no significant correlations were found between changes in A1c and plasma aminotransferases. In contrast, changes in plasma AST/ALT were more strongly associated with BMI changes (r = 0.32, P < .001, and r = 0.19, P = .04, respectively). Similar results were observed after 3 years of follow-up.ConclusionsNonalcoholic fatty liver disease is highly prevalent in obese children with T2DM. Treatment of hyperglycemia with metformin and/or insulin did not result in any significant improvement in surrogate markers of NAFLD (i.e., plasma aminotransferases). While changes in ALT and/or AST may not perfectly reflect histological changes in NAFLD, our findings suggest that the treatment of hyperglycemia per se may not be associated with NAFLD improvement.

Effectiveness of a Novel Nutraceutical Compound Containing Red Yeast Rice, Polymethoxyflavones and Antioxidants in the Modulation of Cholesterol Levels in Subjects With Hypercholesterolemia and Low-Moderate Cardiovascular Risk: The NIRVANA Study.

Background: Red yeast rice supplements are broadly accepted as treatment for dyslipidaemia in subjects without high cardiovascular (CV) risk. Their effect on lipid profile is well known, but few data are available on their effect on endothelial function.Objectives: To study the effect of a novel nutraceutical compound (NC) containing low monacolin K dose, polymethoxyflavones and antioxidants on lipid profile, endothelial function and oxidative stress.Methods: Fifty-two subjects with low-moderate CV risk and dyslipidaemia (according to European guidelines) were enrolled and treated for 8 weeks with the NC. Blood samples were collected at baseline and at the end of treatment to assess changes in lipid profile, endothelial function and oxidative stress. The primary endpoint was the reduction of low density lipoprotein (LDL) cholesterol. Endothelial function was assessed through measurement of rate of apoptosis and nitric oxide (NO) production in human umbilical vein endothelial cells (HUVECs) treated with subject’s serum. High-sensitivity C-reactive protein, 4-hydroxynonenal (HNE) and oxidized LDL (oxLDL) were markers of oxidative stress.Results: Fifty subjects completed the study. The treatment caused a significant decrease in LDL (−15.6%, p < 0.001), oxLDL (−21.5%, p < 0.001), total cholesterol (TC), triglycerides, and ApoB. Apoptosis rate of HUVECs significantly decreased (−15.9%, p < 0.001). No changes were noted for NO levels and 4-HNE protein adducts. The reduction of the apoptosis rate was correlated to the reduction of oxLDL.Conclusion: An 8-week treatment based on a novel NC containing low manocolin K dose, polymethoxyflavones and antioxidants improved lipid profile in subjects with dyslipidaemia and low-moderate CV risk. Secondarily, we observed an improvement in surrogate markers of endothelial function that may result from the reduction of oxLDL (Registered at www.clinicaltrials.gov, NCT03216811).

Cardiovascular actions of mineralocorticoid receptor antagonists in patients with chronic kidney disease: A systematic review and meta-analysis of randomized trials.

The safety and actions of mineralocorticoid receptor antagonists on surrogate markers of cardiovascular disease as well as major patient level cardiovascular end-points in patients with chronic kidney disease are unclear. MEDLINE, EMBASE, Trip Database, Cochrane Central Register of Controlled Trials, Cochrane Renal Group specialized register, Current Controlled Trials and clinicaltrials.gov were searched for relevant trials. Twenty-nine trials (1581 patients) were included. Overall, mineralocorticoid receptor antagonists lowered both systolic and diastolic blood pressure (-5.24, 95% confidence interval (CI) -8.65, -1.82 mmHg; p=0.003 and -1.96, 95% CI -3.22, -0.69 mmHg; p=0.002 respectively). There were insufficient data to perform a meta-analysis of other cardiovascular effects. However, a systematic review of the studies included suggested a consistent improvement in surrogate markers of cardiovascular disease. Overall, the use of mineralocorticoid receptor antagonists was associated with an increased serum potassium (0.23, 95% CI 0.13, 0.33 mmol/l; p<0.0001) and higher risk ratio (1.76, 95% CI 1.20, 2.57; p=0.001) of hyperkalemia. Data on long-term cardiovascular outcomes and mortality were not available in any of the trials. The long-term effects of mineralocorticoid receptor antagonists on cardiovascular events, mortality and safety need to be established.

Implementation of a surgical handover tool in a busy tertiary referral centre: a complete audit cycle.

The implementation of the European work-time directive has created increased transitions of care during weekends as doctors adhere to a shift-work structure. This raises concerns over continuity of care and patient safety. To address this, doctors must develop a time efficient yet safe system of handover of patients to the team on-call. Intuitively weekend care provides the ideal setting to develop a handover tool. To develop and implement a process of surgical handover and to improve weekend discharge rate on a surgical service. Data was collected at three time-points over a 6 months period (October 2013-March 2014) encompassing development, implementation, re-evaluation and modification of the handover process. The outcomes measured were: number of inpatients, number of weekend discharges, length of stay (LOS) of inpatients recorded for the four weekends within the month, and total emergency response team (ERT) calls each month. Mean number of included patients each month was 294 (σ = 14). Following the introduction of weekend handover there was a 40 % increase in weekend discharges which was consistent for subsequent time-points (p < 0.05). Following the second intervention there was a statistically significant reduction in mean LOS from 13 to 5.4 days (p < 0.05) and the total number of ERT calls for the month reduced from 12 to 4 (p < 0.05). The standardisation of weekend handover using a combination of an electronic tool supplemented with verbal handover is feasible. It resulted in a significant improvement in surrogate markers of patient care quality.

Comparative effectiveness of angiotensin-receptor blockers for preventing macrovascular disease in patients with diabetes: a population-based cohort study

Telmisartan, unlike other angiotensin-receptor blockers, is a partial agonist of peroxisome proliferator-activated receptor-γ, a property that has been associated with improvements in surrogate markers of cardiovascular health in small trials involving patients with diabetes. However, whether this property translates into a reduced risk of cardiovascular events and death in these patients is unknown. We sought to explore the risk of myocardial infarction, stroke and heart failure in patients with diabetes who were taking telmisartan relative to the risk of these events occurring in patients taking other angiotensin-receptor blockers. We conducted a population-based, retrospective cohort study of Ontario residents with diabetes aged 66 years and older who started treatment with candesartan, irbesartan, losartan, telmisartan or valsartan between Apr. 1, 2001, and Mar. 31, 2011. Our primary outcome was a composite of admission to hospital for acute myocardial infarction, stroke or heart failure. We examined each outcome individually in secondary analyses, in addition to all-cause mortality. We identified 54,186 patients with diabetes who started taking an angiotensin-receptor blocker during the study period. After multivariable adjustment, patients who took either telmisartan (adjusted hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.74-0.97) or valsartan (adjusted HR 0.86, 95% CI 0.77-0.95) had a lower risk of the composite outcome compared with patients who took irbesartan. In contrast, no significant difference in risk was seen between other angiotensin-receptor blockers and irbesartan. In secondary analyses, we found a reduced risk of admission to hospital for heart failure with telmisartan compared with irbesartan (adjusted HR 0.79, 95% CI 0.66-0.96), but no significant differences in risk were seen between angiotensin-receptor blockers in our other secondary analyses. Compared with other angiotensin-receptor blockers, telmisartan and valsartan were both associated with a lower risk of admission to hospital for acute myocardial infarction, stroke or heart failure among older adults with diabetes and hypertension. Telmisartan and valsartan may therefore be the preferred angiotensin-receptor blockers for use in these patients.

Dual renin-angiotensin system inhibition for prevention of renal and cardiovascular events: do the latest trials challenge existing evidence?

Circulatory and tissue renin-angiotensin systems (RAS) play a central role in cardiovascular (CV) and renal pathophysiology, making RAS inhibition a logical therapeutic approach in the prevention of CV and renal disease in patients with hypertension. The cardio- and renoprotective effects observed with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) monotherapy, together with the availability of a direct renin inhibitor (DRI), led to the investigation of the potential benefits of dual RAS inhibition. In small studies, ARB and ACE inhibitor combinations were shown to be beneficial in patients with CV or renal disease, with improvement in surrogate markers. However, in larger outcome trials, involving combinations of ACE inhibitors, ARBs or DRIs, dual RAS inhibition did not show reduction in mortality in patients with diabetes, heart failure, coronary heart disease or after myocardial infarction, and was in fact, associated with increased harm. A recent meta-analysis of all major trials conducted over the past 22 years involving dual RAS inhibition has clearly shown that the risk-benefit ratio argues against the use of dual RAS inhibition. Hence, the recent evidence clearly advocates against the use of dual RAS inhibition, and single RAS inhibition appears to be the most suitable approach to controlling blood pressure and improving patient outcomes.

Clinical Application of Preconditioning and Postconditioning to Achieve Neuroprotection

Ischemic conditioning is a form of endogenous protection induced by transient, subcritical ischemia in a tissue. Organs with high sensitivity to ischemia, such as the heart, the brain, and spinal cord, represent the most critical and potentially promising targets for potential therapeutic applications of ischemic conditioning. Numerous preclinical investigations have systematically studied the molecular pathways and potential benefits of both pre- and postconditioning with promising results. The purpose of this review is to summarize the present knowledge on cerebral pre- and postconditioning, with an emphasis in the clinical application of these forms of neuroprotection. A systematic MEDLINE search for the terms preconditioning and postconditioning was performed. Publications related to the nervous system and to human applications were selected and analyzed. Pre- and postconditioning appear to provide similar levels of neuroprotection. The preconditioning window of benefit can be subdivided into early and late effects, depending on whether the effect appears immediately after the sublethal stress or with a delay of days. In general, early effects have been associated posttranslational modification of critical proteins (membrane receptors, mitochondrial respiratory chain) while late effects are the result of gene up- or downregulation. Transient ischemic attacks appear to represent a form of clinically relevant preconditioning by inducing ischemic tolerance in the brain and reducing the severity of subsequent strokes. Remote forms of ischemic pre- and postconditioning have been more commonly used in clinical studies, as the remote application reduces the risk of injuring the target tissue for which protection is pursued. Limb transient ischemia is the preferred method of induction of remote conditioning with evidence supporting its safety. Clinical studies in a variety of populations at risk of central nervous damage including carotid disease, cervical myelopathy, and subarachnoid hemorrhage have shown improvement in surrogate markers of injury. Promising preclinical and early clinical studies noting improvement in surrogate markers of central nervous injury after the use of remote pre- and postconditioning treatments demand follow-up systematic investigations to address effectiveness. Challenges in the application of these techniques to pressing clinical cerebrovascular disease ought to be overcome through careful, well-designed, translational investigations.

101 Systematic review of controlled trials in the treatment of mitochondrial disorders

BackgroundMitochondrial respiratory chain disorders are the most prevalent group of inherited neurometabolic diseases. Treatment is supportive, although some treatments report disease-modifying efficacy in isolated cases and small trials. This review...

FDA Increases Focus on Postmarketing Studies

Under pressure from Capitol Hill, the U.S. Food and Drug Administration is pushing drug companies to channel more resources into completing confirmatory trials for cancer drugs approved under the accelerated approval program. The fi rst results of the campaign have raised anew a question that has dogged the program since its inception in 1992: Do improvements in surrogate markers in small or short clinical trials, which are the basis for accelerated approvals, translate into a survival benefi t or improved quality of life for patients? In June, Pfi zer voluntarily withdrew gemtuzumab ozogamicin (Mylotarg) from the market after a U.S. cooperative group study submitted to the FDA showed that the drug worsened outcomes for acute myeloid leukemia patients. Wyeth, which Pfi zer later acquired, had been granted accelerated approval for the drug in 2000. Pfi zer will continue producing the drug for acute myeloid leukemia patients already on the regimen but agreed to discontinue marketing it to new patients. Then, in mid-July, the FDA’s Oncology

Future Directions in Management of Anemia in Heart Failure

Anemia in patients with heart failure (HF) may be caused by several factors, including hemodilution, iron or erythropoietin deficiency, and chronic kidney disease. Published pilot studies of erythropoiesis-stimulating agents (ESAs) and intravenous iron therapy in anemic heart failure patients demonstrate improvement in surrogate markers of functional capacity and quality of life, and reasonable safety profile during short-term use. However, the long-term safety of ESA in treatment of anemia in patients with HF remains a concern due to documented harmful side effects of ESA in anemic patients with advanced chronic kidney disease and cancer. Ongoing prospective clinical outcomes studies of ESA and intravenous iron therapies will provide important data that may pave the way for new avenues in the treatment of anemia in the future.

Pharmacodynamic optimization of β-lactams in the patient care setting

In order to eradicate an infecting organism, it is necessary to achieve or maintain concentrations of an antibiotic in vivo that exceed the minimum inhibitory concentration (MIC) for the organism. Duration of exposure, or time above MIC, was recognized as being important for β-lactam antibiotics more than 60 years ago. Continuous infusion regimens are associated with higher clinical response rates, improvement in surrogate markers of outcome, and lower cost of therapy compared with intermittent infusion regimens, because the MIC can be exceeded for an entire dosing interval. However, for carbapenem antibiotics, it appears that the MIC must only be exceeded for 40% of the dosing interval for bactericidal activity in vivo. Therefore, a promising strategy to optimize carbapenem use is to administer the same dose at the same frequency of administration but to extend the infusion time. Extended infusion regimens take full advantage of a drug's exposure potential within the context of in vivo potency without altering the dose or dosing schedule and with no increase in toxicity or cost. Administering higher doses by extended infusion allows one to manage organisms with high MICs. Optimizing the pharmacokinetics/pharmacodynamics of an antibiotic allows one to 'make good drugs better'.

Illness of immune reconstitution: Recognition and management

Some individuals who initiate highly active antiretroviral therapy (HAART) develop new or worsening opportunistic infections or malignancies despite improvements in surrogate markers of HIV-1 infection. These events of paradoxical clinical worsening, also known as immune reconstitution syndromes (IRS), are increased in individuals with prior opportunistic infections or low CD4+ T-cell nadirs. They are thought to result from reconstitution of the immune system's ability to recognize pathogens or tumor antigens that were previously present, but clinically asymptomatic. There is no consensus regarding the diagnostic criteria or pathogenesis of IRS. Knowledge of their presentation and treatment is largely based on case reports. With the introduction of HAART into resource-limited settings, it is likely that significantly more and distinct forms of IRS will be observed. Prospective studies of the incidence and treatment of IRS in multiple settings are critical to better understand their pathogenesis and optimal management.

A review of leukofiltration therapy for decreasing the morbidity associated with cardiopulmonary bypass and acute inflammatory bowel disease.

Complications of cardiopulmonary bypass (CPB) and acute inflammatory bowel disease (IBD) are associated with increased morbidity and cost. During reperfusion post-CPB, activated neutrophils adhere to microvascular endothelial cells mediated by cell adhesion molecules (CAMs) and cytokines/chemokines with subsequent myocardial damage caused by activated neutrophil-derived oxidants and enzymes. Leukofiltration was shown to reduce myocardial reperfusion injury and improve gas exchange as suggested by improvements in surrogate markers of inflammation and clinical end points. In acute IBD, characterized by rectal bleeding and protracted hospital stays, circulating neutrophils emigrate to the inflamed colon and adhere to microvascular endothelial cells by CAMs. Multiple treatments with leukofiltration in IBD were shown to induce long-term remission of acute IBD. Hence, leukofiltration may reduce reperfusion injury and rectal bleeding in CPB and IBD, respectively, and therefore decrease the morbidity and cost associated with these diseases.

Zidovudine: a review of its use in the management of vertically-acquired pediatric HIV infection.

Zidovudine is a thymidine analog that, after intracellular phosphorylation to zidovudine triphosphate metabolite, inhibits HIV-specific reverse transcriptase and terminates proviral DNA. Zidovudine administered to mildly symptomatic women with HIV infection in the antepartum (100mg orally 5 times/day), intrapartum (2 mg/kg intravenously over 1 hour then 1 mg/kg/h) and then to the neonate for 6 weeks (2 mg/kg), significantly reduced the rate of vertical HIV transmission by about two thirds, in the absence of breast-feeding (The Pediatric AIDS Clinical Trials Group 076 trial, standard protocol). Shorter zidovudine regimens, reduced the risk of transmission of HIV by 50% in a non-breast-feeding population and by about 37% in breast-feeding populations. Zidovudine (standard protocol) in combination with lamivudine was superior to zidovudine alone. A short oral zidovudine regimen was not as effective as a two-dose oral nevirapine regime, although the combination of short-course zidovudine plus lamivudine was as effective. Suppression of viral replication in neonates, infants and children has been achieved with zidovudine when used in triple-therapy regimens that include other antiviral drugs. Results from a trial of treatment-naive children indicate that the antiviral efficacy of combinations of zidovudine and lamivudine or abacavir, given with the protease inhibitor nelfinavir, is superior to treatment with this combination minus nelfinavir. When zidovudine was used in other highly active antiretroviral therapy regimens significant improvements in surrogate markers were consistently seen. Changing to ritonavir-containing regimens was superior to changing to treatment with two new nucleoside reverse transcriptase inhibitors. Short- and long-term (up to 5.6 years) outcomes from clinical trials showed that prenatal and neonatal exposure to zidovudine was generally well tolerated with the exception of mild anemia that resolved spontaneously after treatment cessation. Zidovudine was generally well tolerated as monotherapy in clinical trials of pediatric patients with HIV infection, and adverse events were similar to those reported in adults, with anemia and neutropenia being the most common. Zidovudine, as monotherapy or in combination with other antiretroviral agents, remains a first-choice therapy for the prophylaxis of mother-to-child HIV transmission as shown by substantial reductions in transmission rates. Where feasible, the optimal strategy to prevent vertical transmission is to combine drug therapy with Cesarean section delivery and no breast-feeding. In addition, zidovudine in combination with another nucleoside analogue and a protease inhibitor is a first- or second-choice therapy for the treatment of pediatric HIV infection as significant and sustained reductions in viral load have been shown in both plasma and cerebrospinal fluid.

Delavirdine: a review of its use in HIV infection.

Delavirdine, a bisheteroarylpiperazine derivative, is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that allosterically binds to HIV-1 reverse transcriptase, inhibiting both the RNA- and DNA-directed DNA polymerase functions of the enzyme. Delavirdine in combination with nucleoside reverse transcriptase inhibitors (NRTIs) produced sustained reductions in plasma viral loads and improvements in immunological responses in large randomised, double-blind, placebo-controlled studies of 48 to 54 weeks' duration. In patients with advanced HIV infection, triple therapy with delavirdine, zidovudine and lamivudine, didanosine or zalcitabine for 1 year significantly prolonged the time to virological failure compared with dual therapy (delavirdine plus zidovudine or 2 NRTIs; p < 0.0001). After 50 weeks' treatment, plasma HIV RNA levels were below the limit of detection (LOD; <50 copies/ml) for 40% of patients receiving triple therapy but for only 6% of those receiving dual NRTI therapy. Preliminary results suggest that delavirdine also has beneficial effects on surrogate markers as a component of protease inhibitor-containing triple or quadruple regimens. At 16 to 48 weeks, the minimum mean reduction in plasma viral load from baseline was 2.5 log10 copies/ml and mean CD4+ counts increased by 100 to 313 cells/microl. The proportion of patients with plasma HIV RNAlevels below the LOD (usually 200 to 500 copies/ml) ranged from 48 to 100% after > or = 16 weeks. Delavirdine was also effective as a component of saquinavir soft gel capsule-containing salvage regimens. Since delavirdine shares a common metabolic pathway (cytochrome P450 3A pathway) with other NNRTIs, HIV protease inhibitors and several drugs used to treat opportunistic infections in patients infected with HIV, the drug is associated with a number of pharmacokinetic interactions. Some of these drug interactions are clinically significant, necessitating dosage adjustments or avoidance of co-administration. Delavirdine is not recommended for use with lovastatin, simvastatin, rifabutin, rifampicin, sildenafil, ergot derivatives, quinidine, midazolam, carbamazepine, phenobarbital or phenytoin. Importantly, the drug favourably increases the plasma concentration of several protease inhibitors. Delavirdine is generally well tolerated. Skin rash is the most frequently reported adverse effect, occurring in 18 to 50% of patients receiving delavirdine-containing combination therapy in clinical trials. Although a high proportion of patients developed a rash, it was typically mild to moderate in intensity, did not result in discontinuation or adjustment of treatment in most patients and resolved quickly. The occurrence of Stevens-Johnson syndrome was rare (1 case in 1,000 patients). A retrospective analysis of pooled clinical trial data indicated that there was no significant difference in the incidence of liver toxicity, liver failure or noninfectious hepatitis between delavirdine-containing and non-delavirdine-containing antiretroviral treatment groups. In addition, the incidence of lipodystrophy, metabolic lipid disorders, hyperglycaemia and hypertriglyceridaemia was not significantly different between these 2 treatment groups. In combination with NRTIs. delavirdine produces sustained improvements in surrogate markers of HIV disease and prolongs the time to virological failure in adult patients with HIV infection. Preliminary data of delavirdine as a component of protease inhibitor-containing triple or quadruple highly active antiretroviral therapy regimens indicate that patients achieve marked improvements in virological and immunological markers. The drug is generally well tolerated, with a transient skin rash, typically of mild to moderate intensity, being the most common adverse effect. Delavirdine is an effective component of recommended antiretroviral treatment strategies for adult patients with HIV infection and, in combination with 2 NRTIs as a first-line therapy, the drug has the advantage of sparing protease inhibitors for subsequent use. Since delavirdine favourably increases plasma concentrations of several protease inhibitors, the drug may also be beneficial as a component of salvage therapy in combination with protease inhibitors.

Saquinavir soft-gel capsule: an updated review of its use in the management of HIV infection.

Saquinavir is a potent and highly selective HIV protease inhibitor. Initially formulated as a hard-gel capsule (HGC), saquinavir was the first protease inhibitor available commercially for the treatment of patients with HIV infection. The limited oral bioavailability of saquinavir HGC has been improved significantly with the introduction of a soft-gel capsule (SGC) formulation. Saquinavir SGC displays greater than dose-proportional pharmacokinetics and mean area under the plasma concentration-time curve (AUC) values are 8- to 10-fold higher with saquinavir SGC 1200 mg 3 times daily than with the HGC formulation 600 mg 3 times daily, the recommended dosages of the 2 formulations. In combination with other protease inhibitors (particularly "low dose" ritonavir), the oral bioavailability of saquinavir (as either the HGC or SGC formulation) is markedly increased, allowing for reduced dosing frequency and/or dosage. The efficacy and tolerability of once- or twice-daily saquinavir SGC/"low dose" ritonavir combinations are currently being evaluated in patients with HIV infection. Data (up to 48 weeks) from noncomparative and comparative clinical trials evaluating saquinavir SGC-containing combination regimens in adult patients with HIV infection, support and strengthen the clinical efficacy profile of the drug that was demonstrated in initial trials. In antiretroviral therapy-naive and -experienced patients, saquinavir SGC combined with > or =2 nucleoside reverse transcriptase inhibitors (NRTIs), or nelfinavir, or nelfinavir plus 2 NRTIs or nonnucleoside reverse transcriptase inhibitors (NNRTIs), markedly improved immunological and virological surrogate markers (increased mean CD4+ cell counts and decreased mean plasma HIV RNA levels) of HIV infection. Saquinavir SGC demonstrated a trend to greater antiviral efficacy (measured by improvements in surrogate markers) than the HGC formulation (not statistically significant); a significantly greater proportion of patients treated with saquinavir SGC had plasma HIV RNA levels <400 copies/ml than patients receiving the HGC formulation. In the first direct comparison of 2 protease inhibitors, saquinavir SGC plus 2 NRTIs demonstrated similar antiviral efficacy to indinavir plus 2 NRTIs in patients with HIV infection (almost all of whom were antiretroviral therapy-naive); at 24 weeks, a significantly greater increase in CD4+ cell count from baseline was obtained in the saquinavir SGC group compared with the indinavir group, although this difference was not apparent at week 32. Triple therapy with saquinavir SGC plus 2 NRTIs was as effective as nelfinavir-containing triple therapy, or quadruple therapy (saquinavir SGC plus 2 NRTIs plus nelfinavir) in markedly suppressing HIV RNA levels in antiretroviral therapy-experienced or -naive patients. Saquinavir SGC is generally well tolerated. Gastrointestinal disturbances (generally nausea, diarrhoea, abdominal pain, vomiting and dyspepsia of moderate or greater intensity) are the most common adverse events associated with saquinavir SGC-containing therapy. In comparative trials, saquinavir SGC-containing therapy was as well tolerated as indinavir- and nelfinavir-containing therapy; although there were no statistical differences between treatment groups, the incidence of diarrhoea was lower in patients receiving saquinavir SGC compared with nelfinavir, saquinavir SGC plus nelfinavir (all combined with 2 NRTIs) or saquinavir SGC plus nelfinavir without additional therapy. Compared with the HGC formulation, saquinavir SGC appears to be associated with a higher overall incidence of adverse events. Clinical trial data have shown that as part of triple or quadruple combination therapy, saquinavir SGC is an effective and generally well tolerated protease inhibitor in antiretroviral therapy-naive or -experienced patients with HIV infection. (ABSTRACT TRUNCATED)

Human Immunodeficiency Virus Protease Inhibitors

Summary Continued surveillance of the acquired immunodeficiency syndrome (AIDS) pandemic has shown that it has now spread to most areas of the world. Recent estimates suggest that more than six million people have already died from human immunodeficiency virus (HIV)-related diseases, and that more than 25 million are currently infected with the virus. The first drugs to be approved for the treatment of AIDS, the nucleoside analogue reverse transcriptase inhibitors, are of limited value in extending life; moreover, many of them have serious, and often dose-limiting, side-effects. The effectiveness of some of these drugs has also been compromised by the fairly rapid emergence of resistant strains of virus. The discovery of an essential virally-encoded protease in the mid-1980s provided the basis for a new class of rationally-designed antiretroviral agents, the protease inhibitors. Three protease inhibitors have already been licensed (saquinavir [Invirase ® , Hoffmann-La Roche, 1995], ritonavir [Norvir™ , Abbott Laboratories, 1996] and indinavir [Crixivan ® , Merck & Co., 1996]), with many more in varying stages of development. Three of the most advanced compounds in clinical development are believed to be nelfinavir (Viracept ™ ) from Agouron (Phase III), VX-478 which is being developed jointly by Vertex and Glaxo Wellcome (Phase II), and KNI-272 from Nippon Mining Co. Ltd. (Phase II). Although treatment with all of these inhibitors as monotherapy has led to improvements in surrogate markers of disease, there is increasing evidence that combination therapy is more effective than any agent used alone, both in reducing viral load and in delaying the emergence of resistant strains of virus, and it is likely that all of the protease inhibitors will find their major application in such combination therapies. As more information about resistance and cross-resistance becomes available, it seems likely that these issues will also be of great importance in choosing drug regimens.

Lamivudine. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in the management of HIV infection.

Lamivudine is a dideoxynucleoside analogue which undergoes intracellular phosphorylation to the putative active metabolite, lamivudine triphosphate. Lamivudine triphosphate prevents HIV replication by competitively inhibiting viral reverse transcriptase. Lamivudine has a unique resistance profile and has the ability to delay resistance to zidovudine and restore zidovudine sensitivity in zidovudine-experienced patients. Combination antiretroviral drug therapy is now generally considered preferable to monotherapy as first-line treatment for patients with HIV infection. In double-blind trials in antiretroviral drug-experienced or -naive adults, improvements in surrogate markers of disease progression were significantly greater in patients receiving lamivudine plus zidovudine combination therapy than in patients who received either drug as monotherapy. Preliminary results of CAESAR, a large multicentre trial in patients with moderately advanced HIV infection receiving zidovudine-based treatment regimens, show a 54% reduction in the rate of disease progression or death with the addition of lamivudine, compared with the addition of placebo. Initial virological data from studies of combination regimens including lamivudine and protease inhibitors are also promising, although the longer term efficacy of these regimens remains to be established. Improvements in surrogate disease markers were also seen in children and adolescents with symptomatic HIV infection who received lamivudine monotherapy. Studies of lamivudine-containing combination therapy in children and adolescents are in progress, but few data have yet been published. Lamivudine is generally well tolerated as monotherapy or in combination with other antiretroviral agents in HIV-infected adults with CD4+ counts > or = 100 cells/microliter. Gastrointestinal disturbances were reported as the most common adverse events during lamivudine monotherapy or combination therapy. Lamivudine appears to be less well tolerated in patients with advanced disease (CD4+ cell counts < 100 cells/microliter), but more data are required to clarify its tolerability in such patients. Pancreatitis has been reported in children with advanced disease during treatment with the drug, but was not directly attributable to lamivudine therapy. Thus, lamivudine, administered in combination with zidovudine, is now established as an effective agent for the treatment of antiretroviral drug-experienced or -naive individuals with asymptomatic or symptomatic HIV disease. Moreover, encouraging preliminary data suggest that lamivudine is poised to become an important component of other regimens, in combination with drugs such as the protease inhibitors.