Hepatitis: Spain

Arribas López JR. · Consulta de Medicina Interna II, Unidad VIH, Hospital La Paz, Madrid, España. · Enferm Infecc Microbiol Clin. · Pubmed #19133218 links to  free full text

Abstract: Maraviroc is the first inhibitor of CCR5 co-receptors to be marketed as an antiretroviral. The pre-clinical studies and phase III trials have shown that it has a very favourable safety profile. No characteristic adverse effect of maraviroc has been identified. Unlike with aplaviroc, where its clinical development was stopped due to serious hepatoxicity, no increase in liver toxicity has been demonstrated in patients treated with maraviroc even if they are co-infected by hepatotropic virus. Nor was there any evidence of an increase in the incidence of neoplasms or serious infections in patients treated with maraviroc. In a study on naive patients, maraviroc produced nonsignificant changes in total cholesterol, LDL, HDL and triglycerides. Although CCR5 co-receptors play a role in the immune response of the body, it has not been shown whether individuals homozygote for its deletion (delta-32 mutation) have an increased risk of serious infections, with the possible exception of encephalitis due to the West Nile virus. However, long-term follow up is required on patients treated with to be able to rule out any increased susceptibility to infections or neoplasms.

Morillo Verdugo R, Madrazo Berenguer A, Gil Navarro MV, Suárez García E. · Unidad de Gestión Clínica de Farmacia, Hospital Universitario de Valme, Sevilla, España. · Farm Hosp. · Pubmed #19128731 links to  free full text

Abstract: OBJECTIVE: To define the role of those drugs available for hepatitis B treatment and analyse current treatment guides prepared by the leading scientific societies in the field. METHODS: Bibliographic searches were carried out in the databases PubMed and EMBASE, using the search word <<hepatitis B>>, limited by <<drug therapy>> plus <<clinical trial>>, <<meta-analysis>> or <<guidelines>>, within the period 1991-2007. RESULTS: Six drugs are currently available: interferon alpha (conventional or pegylated), lamivudine, adefovir, entecavir and telbivudine. In normal practice, pegylated interferon has almost completely displaced the conventional variety. HBeAg+ patients with high ALT levels, low HBV DNA counts and genotypes A and B show the best response to interferon. Lamivudine achieves faster and more potent viral suppression than adefovir; its principal drawback is the resistance that some patients develop. Its role will probably decrease as entecavir and telbivudine become more widespread, as they are associated with less resistance. Adefovir is useful in decompensated patients and/or those resistant to lamivudine. Because of the response rates it obtains, entecavir could be the drug of choice for HBeAG+ patients, particularly those with higher viral loads. For HBeAg- cases, any drug can be used as a first-choice drug. The main difference between the treatment guides lies in the way they define the illness and the serum markers that indicate active replication: viral loads and HBeAG positivity. CONCLUSIONS: All of the drugs are capable of accomplishing short-term biochemical, viral and histological objectives. There is no unanimous opinion on which patients should be treated with which drugs, during what length of time, and what objectives are to be reached.

Soriano V, Peters MG, Zeuzem S. · Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain. · Clin Infect Dis. · Pubmed #19123867 No free full text.

Abstract: Chronic hepatitis C virus (HCV) infection remains a global health threat with approximately 175 million carriers worldwide. Currently, treatment consists of pegylated interferon alpha plus ribavirin for 12-72 weeks, depending on HCV genotype, baseline viral load, and initial virological response to therapy. Serious adverse effects and limited sustained virological responses with this therapy warrant the need for novel HCV therapies. Specifically targeted antiviral therapies designed to inhibit the HCV serine protease and the RNA-dependent RNA polymerase have recently entered clinical development. Herein, the main characteristics of these new antiviral agents and the most important challenges arising with their use--namely, toxicities and rapid selection of resistance--are discussed.

Barreiro P, Martín-Carbonero L, García-Samaniego J. · Servicio de Enfermedades Infecciosas, Hospital Carlos III, Madrid, España. · Enferm Infecc Microbiol Clin. · Pubmed #19100234 links to  free full text

Abstract: Chronic hepatitis B virus infection affects approximately 10% of HIV-infected patients. There are an estimated 4 million patients with HIV/HBV coinfection. HIV infection has a deleterious effect on the natural history of chronic hepatitis B and increases the risk of progression to cirrhosis and terminal liver disease. Since the widespread use of highly active antiviral therapy (HAART), liver disease has emerged as one of the main causes of morbidity and mortality in HIV-positive patients. Therefore, all patients with HIV/HBV coinfection should be evaluated for treatment of hepatitis B, independently of the CD4 lymphocyte count. Six drugs are currently authorized for the treatment of chronic hepatitis B: standard interferon-alpha (2a and 2b), pegylated interferon alpha-2a, lamivudine, adefovir, entecavir and telbivudine. Other drugs with activity against HBV, such as tenofovir and emtricitabine, are used for the treatment of HIV infection. In patients not requiring HAART, treatment of hepatitis B should preferably consist of drugs without activity against HIV, such as pegylated interferon or adefovir. In contrast, in patients requiring HAART, a combination of drugs with activity against both viruses should be used, such as lamivudine, emtricitabine and tenofovir, with the aim of achieving maximal viral suppression and avoiding the development of resistance. Patients with HIV/HBV coinfection require periodic clinical and virological monitoring. Patients with cirrhosis should undergo ultrasonography and alphafetoprotein determination every 6 months for the early detection of hepatocellular carcinoma.

Jara P, Bruguera M. · Servicio de Hepatología y Trasplante Hepático, Hospital Infantil Universitario La Paz, Madrid, España. · Enferm Infecc Microbiol Clin. · Pubmed #19100233 links to  free full text

Abstract: In pregnant women and children, the hepatitis B virus can cause acute or chronic hepatitis or liver cirrhosis. Perinatally-acquired infection causes persistent infection in 90% of cases and can be avoided through administration of the hepatitis B vaccine and specific immunoglobulin in the first day of life. Prevention of mother-to-child transmission requires screening for hepatitis B surface antigen (HBsAg) in pregnant women to identify which newborns should be immunized. In some countries this strategy is substituted by universal vaccination of neonates. In infected children, inactivation of viral replication with conversion of HBeAG-positive to anti-HBe-positive status usually occurs. If this seroconversion does not take place and necroinflammatory activity persists in the liver, the use of antiviral agents such as interferon or nucleoside and nucleotide analogs is warranted.

Rodríguez M, González-Diéguez ML. · Servicio de Digestivo, Hospital Universitario Central de Asturias, Oviedo, Asturias, España. · Enferm Infecc Microbiol Clin. · Pubmed #19100232 links to  free full text

Abstract: Chronic hepatitis B is still a major public health problem, aggravated by the growing phenomenon of immigration from areas with a high prevalence of infection with this virus. In the last few years, marked progress has been achieved in diagnostic methods, knowledge of the natural history of the disease and in therapeutic options, including liver transplantation, which has improved survival in these patients. These advances have been accompanied by an increase in the complexity of decision making. Six treatments have currently been approved for hepatitis B, including two interferon formulations--standard and pegylated--and four neucleos(t)ide analogs, lamivudine, adefovir, entecavir and telbivudine, as well as two further drugs that are used in patients coinfected with HIV, tenofovir and emtricitabine. However, none of the current treatments is able to eradicate the virus and consequently prolonged treatments are often required with the consequent risk of generating resistance. For this reason, as well as the heterogeneity of the natural history of the disease, there is a lack of consensus on the indications for treatment and the parameters in which treatment should be based, the most suitable drug or drug combination, and the criteria to be used to continue, modify or suspend treatment. Therefore, despite the enormous progress made, numerous questions remain that make the clinical management of these patients a major challenge.

Sheldon J, Sarmento E Castro R, Soriano V. · Servicio de Enfermedades Infecciosas, Hospital Carlos III, Madrid, España. · Enferm Infecc Microbiol Clin. · Pubmed #19100231 links to  free full text

Abstract: The development hepatitis B virus (HBV) polymerase inhibitors has revolutionised the treatment of chronic HBV infection. However, the emergence of resistance mutations can compromise their clinical efficacy and it is mandatory to know the mechanisms of these resistances, its clinical implications, strategies for prevention and how to deal with the rescue. Since HBV has a high degree of replication and a high error rate, during their life cycle it will produce a large number of punctual mutations in individuals with active replication. Due to the large size of the HBV genome, all the possible changes may occur daily and should be screened before starting any antiviral therapy. Therefore, in individuals infected with HBV there is a mixture of similar viruses that evolves over time (quasispecies), some of which are carriers of resistance mutations to antivirals, which explains why they can be selected quickly after exposure to drug. Of the five drugs approved in Europe for the treatment of hepatitis B, three of them (lamivudine, adefovir and entecavir) are likely to be affected directly by these mutations, as well as other active drugs, such as telbivudine, tenofovir and the emtricitabine. The characterization of the resistance mutations is helpful for the prevention and the optimization of antiviral therapies.

Calleja JL, Peñas B. · Hospital Universitario Puerta de Hierro, Madrid, España. · Enferm Infecc Microbiol Clin. · Pubmed #19100230 links to  free full text

Abstract: Chronic hepatitis B continues to be a serious problem worldwide. Because a high viral load is associated with greater progression to cirrhosis and hepatocarcinoma in these patients, new drugs that achieve rapid, potent and lasting suppression of viral replication must be sought. Entecavir is a new, highly potent antiviral agent; phase II and III studies have demonstrated this drug to be superior to placebo and lamivudine in patients with chronic hepatitis B virus in terms of histological improvement, efficacy in achieving suppression of viral replication and normalizing transaminase counts. The drug is well tolerated, since its adverse effects are usually mild or moderate and their incidence is similar to that found with placebo or lamivudine. Moreover, in treatment-naïve patients, no resistance has been observed after 3 years of therapy. However, in patients with prior resistance to lamivudine, the incidence of resistance is approximately 15% at 3 years. Further studies are required that compare this drug with other currently available therapeutic options, as well as longer term trials to evaluate its safety. It seems that entecavir will occupy a major place in the treatment of patients with chronic hepatitis B virus infection.

Buti M. · Servicio de Hepatología y Medicina Interna, Hospital General Universitario Vall d'Hebron, CIBER del Instituto de Salud Carlos II, Barcelona, España. · Enferm Infecc Microbiol Clin. · Pubmed #19100229 links to  free full text

Abstract: At least 4 nucleos(t)ide analogs have been approved for the treatment of chronic hepatitis B: lamivudine, adefovir dipivoxil, entecavir, and telbivudine. The introduction of these drugs has radically changed the treatment of this disease. The advantages of these drugs are their oral administration, excellent tolerability and efficacy in all types of chronic hepatitis B (compensated and decompensated disease). The limitations are the need for prolonged treatments, which hampers adherence and can cause selection of HBV strains resistant to distinct drugs. The resistance rate differs for each of the drugs. Nucleotide analogs such as adefovir and tenofovir are useful in patients resistant to nucleoside analogs such as lamivudine, entecavir and telbivudine and vice versa. In cases of resistance to one of these drugs, combined treatment is advised.

García Buey L, González Mateos F, Moreno Otero R. · Servicio de Aparato Digestivo, Unidad de Hepatología, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, España. · Enferm Infecc Microbiol Clin. · Pubmed #19100228 links to  free full text

Abstract: Hepatitis B virus (HBV) infection is a worldwide public health problem. There are an estimated 350 million persons with chronic HBV infection that could progress to cirrhosis and hepatocarcinoma with nearly one million deaths per year. In the last few years the therapeutic options in chronic hepatitis B have increased and currently six treatments are authorized: standard interferon (IFN)-alpha, pegylated interferon-alpha (PEG-IFNalpha), lamivudine, adefovir, entecavir, and telbivudine. For the last 25 years, conventional IFNalpha has been used as the treatment of chronic hepatitis B (CHB) and currently PEG-IFNalpha is indicated due to its greater effectiveness. Both drugs are first line options for HBeAg(+) and HBeAg(-) CHB. The advantages of IFNalpha and PEG-IFNalpha are that these drugs are administered for a limited time period, they achieve a higher sustained response rate and do not induce HBV mutants with antiviral resistance. These drugs achieve greater HBeAG and HBsAG clearance due to their antiviral and immunomodulatory activity. PEG-IFNalpha induces sustained biochemical and virological response in approximately one third of patients with HBeAg(+) CHB. The best response to IFNalpha and PEG-IFNalpha is obtained in patients with elevated transaminase levels, moderate viral load and HBV genotypes A and B. The disadvantages of IFNalpha and PEG-IFNalpha are their adverse effects and contraindications. These drugs cannot be administered in patients with decompensated cirrhosis. The combination of nucleos(t)ide analogs with PEG-IFNalpha could achieve much higher sustained response rates; however, which treatment constitutes the most suitable therapeutic strategy requires investigation.

Rodríguez-Frias F, Jardi R. · Servicio de Bioquímica, Unidad de Hepatología, Hospital Vall d'Hebron, Barcelona, España. · Enferm Infecc Microbiol Clin. · Pubmed #19100226 links to  free full text

Abstract: The hepatitis B virus (HBV) belongs to the hepadnavirus family. The genome of the virus, formed by a small DNA molecule with 3,200 base pairs, has 4 strongly overlapping protein coding regions: ORF preS/S, corresponding to the envelope proteins that constitute the HBV surface antigen (HBsAg); ORF preC/C, which encodes the viral capsid component (core antigen or HBcAg) and a non-structural protein that, after postranslation modification, is secreted and constitutes the "e" antigen (HBeAg); ORF P, which encodes the viral polymerase (polyprotein with DNA polymerase activity, reverse transcriptase and RNAase), and ORF X, which encodes a protein that acts as a multifunctional regulator for both the viral and cell cycles. HBV has a mutation rate of 1.4-3.2 x 105 substitutions/nucleotide/year. As a result of this variability, the virus circulates as a complex mixture of genetic variants, constituting a semi-species, that evolves throughout the infection depending on the evolutionary pressure of factors such as the immune response and antiviral treatments. Based on this variability, HBV has been classified into 8 genotypes (A-H) defined by a difference of more than 8% in the sequences of the complete viral genome. This variability is also responsible for HBV resistance to antiviral treatments with nucleotide and nucleoside analogs. Diagnosis of HBV infection includes determination of virological markers: viral antigens (HBsAg, HBeAg), specific antibodies (anti-HBc, anti-HBe, anti-HBs) and study of HBV-DNA for its detection and quantification and determination of genotypes and viral variants.

Robles M, Andrade RJ. · Servicio de Aparato Digestivo, Unidad de Hepatologia, Hospital Universitario Virgen de la Victoria, Malaga, Espana. · Rev Esp Quimioter. · Pubmed #19031123 links to  free full text

Abstract: Although antibiotics are the most commonly incriminated drugs in instances of hepatotoxicity in medical literature. However, it is mainly due to its wide prescription and the absolute risk of hepatotoxicity related to antibiotic use is thought to be low. Nevertheless, among the different penicillins, amoxicillin-clavulanate is the single leading drug involved in hepatotoxicity in cohorts of patients with drug-induced liver injury (DILI), representing between 12.8% to 14% of the cases. It is the most frequent cause of hospitalization for DILI. The incidence of amoxicillin-clavulanate induced hepatotoxicity has been estimated to be 9.91 per 100,000 users and its clinical presentation varies, the type of injury strongly influenced by age, with the hepatocelullar pattern predominating in younger patients and the cholestatic/mixed ones in older subjects. Among macrolides, erythromycin is a classical example of drug capable of inducing cholestatic injury. Recently, concern has arisen regarding telithromycin, a new generation macrolide, is hepatotoxic came from the identification of several cases of DILI related to this drug, with a typical signature, including abrupt commence of fever, abdominal pain, jaundice and ascites in some cases. Tetracyclines, especially in intravenous high doses, may be associated with dose-dependent microvesicular steatosis, and minocycline has been involved in an autoimmune like type I hepatitis. Quinolones, in spite of their extensive use in patients with cirrhosis and biliary infections, have been very rarely associated with hepatotoxicity.

Ramos-Casals M, Brito-Zerón P, Soto MJ, Cuadrado MJ, Khamashta MA. · Laboratory of Autoimmune Diseases Josep Font, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Department of Autoimmune Diseases, Hospital Clínic, Barcelona, Spain. · Best Pract Res Clin Rheumatol. · Pubmed #19028367 No free full text.

Abstract: Anti-TNF agents are increasingly being used for a rapidly expanding number of rheumatic and systemic autoimmune diseases. As a result of this use, and of the longer follow-up periods of treatment, there are a growing number of reports of the development of autoimmune processes related to anti-TNF agents. The clinical characteristics, outcomes, and patterns of association with the different anti-TNF agents used in all reports of autoimmune diseases developing after TNF-targeted therapy, were analyzed through a baseline Medline search of articles published between January 1990 and May 2008 (www.biogeas.org). A total of 379 cases of autoimmune diseases secondary to TNF-targeted therapies were identified. The anti-TNF agents were administered for rheumatoid arthritis in more than 80% of cases. The use of anti-TNF agents has been associated with an increasing number of cases of autoimmune diseases, principally cutaneous vasculitis, lupus-like syndrome, systemic lupus erythematosus and interstitial lung disease. Other autoimmune diseases associated with TNF-targeted therapies have been recently described, e.g. sarcoidosis, antiphospholipid syndrome-related features, and autoimmune hepatitis or uveitis. Large, prospective, postmarketing studies are required to evaluate the risk of developing autoimmune diseases in patients receiving TNF-targeted therapies.

Fernández-Ruiz M, Muñoz-Codoceo C, López-Medrano F, Faré-García R, Carbonell-Porras A, Garfia-Castillo C, Muñoz-Gómez R, Aguado-García JM. · Department of Internal Medicine, University Hospital 12 de Octubre, Madrid, Spain. · Intern Med. · Pubmed #19015608 links to  free full text

Abstract: Primary infection by cytomegalovirus (CMV) commonly occurs subclinically or manifested by a self-limited mononucleosis-like syndrome in immunocompetent subjects. Severe clinical pictures are uncommon. We present a case of acute myopericarditis and hepatitis in a previously healthy 32-year-old man with primary CMV infection, assessed by serology and positive pp65 antigenemia. He was successfully treated with a course of oral valganciclovir therapy, with an immediate clinical response and normalization of laboratory tests. The literature on simultaneous presentation of CMV pericarditis and hepatitis in immunocompetent hosts, as well as the role of oral valganciclovir in this clinical setting, is reviewed.

Ramos-Casals M, Cuadrado MJ, Alba P, Sanna G, Brito-Zerón P, Bertolaccini L, Babini A, Moreno A, D'Cruz D, Khamashta MA. · Laboratory of Autoimmune Diseases Josep Font, Department of Autoimmune Diseases, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Barcelona, Spain. · Medicine (Baltimore). · Pubmed #19011502 No free full text.

Abstract: Few studies have evaluated the impact of viral infections on the daily management of patients with systemic lupus erythematosus (SLE). We analyzed the etiology and clinical features of acute viral infections arising in patients with SLE and their influence on the diagnosis, prognosis, and treatment of SLE. Cases occurring within the last 5 years were selected from the databases of 3 large teaching hospitals. Acute viral infections were confirmed by the identification of specific antiviral IgM antibodies and subsequent seroconversion with detection of specific IgG antibodies. In autopsy studies, macroscopic findings suggestive of viral infection were confirmed by direct identification of the virus or viruses in tissue samples. We performed a MEDLINE search for additional cases reported between January 1985 and March 2008. We included 88 cases (23 from our clinics and 65 from the literature review) of acute viral infections in patients with SLE. Twenty-five patients were diagnosed with new-onset SLE (fulfillment of the 1997 SLE criteria) associated with infection by human parvovirus B19 (n = 15), cytomegalovirus (CMV; n = 6), Epstein-Barr virus (EBV; n = 3), and hepatitis A virus (n = 1). The remaining 63 cases of acute viral infections arose in patients already diagnosed with SLE: in 18 patients, symptoms related to infection mimicked a lupus flare, 36 patients, including 1 patient from the former group who presented with both conditions, presented organ-specific viral infections (mainly pneumonitis, colitis, retinitis, and hepatitis), and 10 patients presented a severe, multiorgan process similar to that described in catastrophic antiphospholipid syndrome-the final diagnosis was hemophagocytic syndrome in 5 cases and disseminated viral infection in 5. Twelve patients died due to infection caused by CMV (n = 5), herpes simplex virus (n = 4), EBV (n = 2), and varicella zoster virus (n = 1). Autopsies were performed in 9 patients and disclosed disseminated herpetic infection in 6 patients (caused by herpes simplex in 4 cases, varicella in 1, and CMV in 1) and hemophagocytic syndrome in 3. A higher frequency of renal failure (54% vs. 19%, p = 0.024), antiphospholipid syndrome (33% vs. 6%, p = 0.023), treatment with cyclophosphamide (82% vs. 37%, p = 0.008), and multisystemic involvement at presentation (58% vs. 8%, p < 0.001); and a lower frequency of antiviral therapy (18% vs. 76%, p < 0.001) were found in patients who died, compared with survivors. The most common viral infections in patients with SLE are parvovirus B19 (predominantly mimicking SLE presentation) and CMV (predominantly presenting in severely immunosuppressed patients). CMV infection may mimic a lupus flare or present with specific organ involvement such as gastrointestinal bleeding or pulmonary infiltrates. Other herpesviruses are common in immunosuppressed SLE patients and may produce a wide range of manifestations. Physicians should examine the pharynx, eyes, skin, and genitalia and should conduct serologic and molecular studies to improve early detection of viral infection in patients with SLE.

López-Labrador FX. · CSISP, Public Health Department, Generalitat Valenciana, University of Valencia, Apt. Of. 22085, E-46071 Valencia, Spain. · Recent Pat Antiinfect Drug Discov. · Pubmed #18991798 No free full text.

Abstract: Chronic hepatitis C virus infection is a global problem worldwide due to the lack of an effective therapy (the current standard of care treatment is effective in about 40-50% of the cases), and the difficulties in developing a protective vaccine. Chronic infection progresses to end-stage liver disease and liver failure in a considerable number of infected individuals. Once liver function is compromised, the only reliable therapeutic intervention is liver transplantation. Unfortunately, re-infection of the graft is unavoidable, and a new chronic hepatitis is early established in transplant recipients, that can result in graft loss. Thus, there is an urgent need for new, specifically targeted therapies for the treatment of HCV chronic infection. Among the viral proteins, the NS3/4A protease and the NS5b RNA-dependent RNA-polymerase, essential for the virus life cycle, have concentrated the efforts in the development of new antivirals, and some promising ones have already entered clinical trials. In particular, inhibitors of the HCV NS3/4A protease are the most advanced in clinical development. This review summarizes the available data for the most important HCV NS3/4A protease inhibitors in development, the most recent patents of these type of compounds, the envisioned options for future HCV therapies, and the eventual impact of HCV genetic variability on resistance to new NS3/4A protease inhibitors.

Ramos-Casals M, Muñoz S, Zerón PB. · Laboratory of Autoimmune Diseases "Josep Font," IDIBAPS, Department of Autoimmune Diseases, C/Villaroel 170, Hospital Clinic, Barcelona 08036, Spain. · Rheum Dis Clin North Am. · Pubmed #18984409 No free full text.

Abstract: Patients who have chronic hepatitis C virus infection present some extrahepatic manifestations that may mimic the clinical, immunologic, and histologic manifestations of primary Sjögren's syndrome (SS). Various demographic, clinical, and immunologic features may aid differentiation between the two processes. Chronic hepatitis C virus infection should be considered an exclusion criterion for the classification of primary SS, not because it mimics primary SS, but because the virus may be implicated in the development of SS in a specific subset of patients.

Morello J, Rodríguez-Novoa S, Jiménez-Nácher I, Soriano V. · Pharmacy Unit, Hospital Carlos III, Madrid, Spain. · J Antimicrob Chemother. · Pubmed #18931138 No free full text.

Abstract: Ribavirin in combination with pegylated interferon alpha is the current standard treatment for chronic hepatitis C. Adequate exposure to ribavirin seems crucial for achieving the best virological response. However, anaemia is a frequent, dose-dependent limiting side effect of ribavirin use. Therefore, therapeutic drug monitoring of ribavirin plasma concentrations could be a useful tool for individualizing ribavirin dosing. Herein, we review the relationship between ribavirin plasma concentrations and both virological response and toxicity, in order to define an optimal therapeutic range for ribavirin.

Berenguer M. · Hospital Universitario La Fe, Valencia, Spain. · Liver Transpl. · Pubmed #18825715 No free full text.

Abstract: 1. An extended criteria donor is a donor who has certain characteristics that have an impact on the short-term and long-term outcomes of the recipient. 2. Grafts with reduced quality from extended criteria donors may show an increased sensitivity toward additional damaging events such as ischemia/reperfusion injury, acute rejection episodes, or recurrent hepatitis C. 3. Extended criteria donor features potentially having an impact on outcome in hepatitis C virus recipients include donor age, allograft steatosis, prolonged warm and cold ischemia times, and donation after cardiac death. 4. In hepatitis C virus-positive recipients, there is strong evidence showing an association between the use of grafts from older donors (>40-50 years) and increased fibrosis progression and reduced graft and patient survival. 5. A potential strategy to minimize the severity of recurrence is to optimize donor selection. Donor age limitations and exclusion of moderately to severely steatotic livers, in addition to minimization of ischemic times, may reduce the likelihood of preservation injury as well as biliary complications, which, in turn, have been shown to have an impact on survival for hepatitis C virus-positive recipients. 6. Although a donor graft biopsy is not required if an extended criteria donor is used, it is highly recommended when hepatitis C virus-positive donors, donation after cardiac death, or multiple extended criteria donor factors are involved.

Herrera S, Bruguera M. · Servicio de Hepatología, Hospital Clínico y Departamento de Medicina, Universidad de Barcelona, Barcelona, España. · Gastroenterol Hepatol. · Pubmed #18783691 No free full text.

Abstract: In the last few years, a considerable number of reports have been published on hepatotoxicity associated with herbal products attributed with weight-reducing properties. Clinical expression of hepatotoxicity has ranged from symptoms of self-limiting hepatitis, indistinguishable from those caused by the hepatitis viruses, to forms of fulminant hepatitis causing death or requiring liver transplantation. These products, which are sold as dietary products or supplements, do not undergo the safety tests required of drugs before their release on to the market. To prevent the toxic effects of herbal products, the general public should be made aware of their harmful effects and since the benefits of these products have not been demonstrated avoid their use, while physicians should strongly discourage patients from taking these products. Authorization of the commercialization of all these natural products should be strictly regulated to minimize the harm they can cause.

Toledano R, Gil-Nagel A. · Department of Neurology, Epilepsy Program, Hospital Ruber Internacional, Madrid, Spain. · Semin Neurol. · Pubmed #18777478 No free full text.

Abstract: Adverse effects of antiepileptic drugs (AEDs) are considered by patients to be at least as important as repetitive seizures in terms of quality of life. AED toxicity is frequent and contributes to a high proportion of treatment failures. Despite its high prevalence and clinical relevance, screening for adverse reactions to AEDs is not systematically included in everyday clinical practice; therefore it is very likely that it remains underestimated. Because there is little difference among AEDs in terms of efficacy, drug selection is often based on the adverse effects profile. AED toxicity is classified according to different parameters, such as severity, time of occurrence, organ system involvement, and mechanisms of action. Although most toxic reactions to drugs can be predicted from cumulative experience, prevention is not always possible, since multiple mechanisms and individual susceptibility to each drug participate in the final outcome. However, adverse effects can be reduced and appropriate action can be taken in time by means of a high degree of suspicion, knowledge of risk factors, and close follow-up. This article highlights factors to consider for detecting and managing AED adverse effects.

Pachkoria K, Lucena MI, Molokhia M, Cueto R, Carballo AS, Carvajal A, Andrade RJ. · Clinical Pharmacology Service, University Hospital Virgen de la Victoria, School of Medicine, Málaga, Spain. · Curr Drug Saf. · Pubmed #18690955 No free full text.

Abstract: The diagnosis of drug-induced liver injury (DILI) is challenging and based on complex diagnostic criteria. DILI falls into two main categories i) intrinsic "dose-dependent" Type A reactions ii) "idiosyncratic" or Type B reactions (which are usually not predictable). Idiosyncratic reactions can be immunoallergic (hypersensitivity), or metabolic, although overlap between categories can occur. The aim of this review is to summarise the general view of underlying mechanisms in DILI and to highlight individual risk factors for developing hepatotoxicity. Polymorphisms of bioactivation/toxification pathways through CYP450 enzymes (Phase I), detoxification reactions (Phase II) and excretion/transport (Phase III) are explored together with immunological factors that might determine DILI. The importance of establishing a multidisciplinary and multi-centric network to promote the understanding and research in hepatotoxicity is underlined. Challenges such as genetic analyses for association studies and whole genome studies, pharmacogenetic testing and future approaches to study DILI are considered. Knowledge regarding these operational mechanisms could provide further insight for the prospective identification of susceptible patients at risk of developing drug-induced hepatotoxicity.

Briones C, Domingo E. · Molecular Evolution Laboratory, Center for Astrobiology (CSIC-INTA), Torrejón de Ardoz, Madrid, Spain. · AIDS Rev. · Pubmed #18615120 No free full text.

Abstract: The RNA viruses replicate as complex distributions of closely related genomes termed viral quasispecies. The behavior of the evolving quasispecies and its response to selective pressures such as antiviral treatment is influenced by the ensemble of mutants that compose the viral population. One such influence is the presence of minority subpopulations in the mutant spectra of viral quasispecies. Biologically relevant mutants have long been known to be present as minority components of replicating viral populations. However, experiments designed with specific mutants of the animal pathogen foot-and-mouth disease virus in cell culture explained the presence of a class of minority genomes termed memory genomes. They descend from those variants that were dominant at an earlier phase of quasispecies evolution, and arise as a consequence of quasispecies dynamics, when viral populations are subjected to discontinuous selective pressures. The presence of memory genomes has also been documented during intrahost evolution of HIV-1 in vivo. The analysis of sequential viral samples of different HIV-1-infected patients showed that two distinct types of memory can operate in retroviruses: a replicative memory analogous to that observed in foot-and-mouth disease virus, as well as a reservoir memory derived from the integrative phase of the retroviral lifecycle. Despite being hidden as minority components of the HIV-1 viral population (ranging from about 0.1 to 20% of the total number of genomes in the quasispecies analyzed), memory genomes can drive the evolution of the virus during HIV-1 infections under antiviral therapy. The limited availability of current experimental data on minority HIV-1 subpopulations in vivo implies that further studies are required in order to define the cutoffs of clinically relevant minority genomes. Nevertheless, it is already evident that such low-abundance genomes remain undetectable by traditional genotyping methods such as consensus sequencing or conventional hybridization techniques. Several experimental systems are currently available for the detection and characterization of minority components of the mutant spectra of viral quasispecies including HIV, hepatitis C virus and hepatitis B virus. Some of these biotechnological approaches could, in the near future, be taken over and exploited in the clinical setting as useful biosensors with which to improve the management of HIV-infected patients.

Soriano V, Puoti M, Peters M, Benhamou Y, Sulkowski M, Zoulim F, Mauss S, Rockstroh J. · Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain. · AIDS. · Pubmed #18614862 No free full text.

Abstract: Nearly 10% of the estimated 36 million people having HIV worldwide suffer from chronic hepatitis B virus (HBV) infection. The advent of new antiviral agents against HBV and the recent availability of improved molecular diagnostic tools have revolutioned the management of HIV/HBV coinfected patients. The present study represents an update of the current knowledge about HBV/HIV coinfection and an intent to provide practical advise about how to give the best care to HIV-infected persons with chronic hepatitis B.

Mallolas J, Laguno M. · Servicio de Enfermedades Infecciosas, Hospital Clínic, Barcelona, Spain. · Expert Rev Anti Infect Ther. · Pubmed #18588492 No free full text.

Abstract: Since 1995, after the generalization of highly active antiretroviral therapy (HAART), HCV coinfection in patients with HIV has become a clinical problem of first magnitude. In fact, currently, HCV coinfection is the primary cause of morbi-mortality of AIDS patients in many hospitals. As a consequence, a significant number of clinical trials have been carried out during the past 8-10 years on HCV/HIV-coinfected patients, and have been coincident that the use of pegylated interferon (PEG-IFN) plus ribavirin should be now the gold standard for treating these patients. Various prospective, randomized studies have reached the conclusion that PEG-IFN-alpha(2b) plus ribavirin achieves HCV cure rates in approximately 50% of all patients, together with important clinical consequences, since hepatic illness progression stops or even reverts. Although adverse events are extremely common with this combined treatment, it is also true that their handling by experts means that only 10-15% of patients must abandon treatment.